Journal of Renal Endocrinology; 2021

Open Access

Case Series J Renal Endocrinol 2021;7:e01.

Journal of

Renal Endocrinology

http://www.jrenendo.com

Nickan

doi: 10.34172/jre.2021.01

Research Institute

Clinical profile of chronic kidney disease of unknown origin in patients of Yavatmal district, Maharashtra, India ID

ID

ID

Dhananjay Ookalkar1 , Ashwini Ookalkar1 , V.L. Gupta1 , Manish R Balwani2*

ID

Abstract We present a case series of patients with chronic kidney disease of unknown etiology (CKDu) coming from a well-defined geographic area, Yavatmal, district of Maharashtra, in central India. These patients presented with advanced renal failure, variable proteinuria, and bilateral hyperechoic kidneys, largely normotensive and belonged to poor economic class from agricultural communities. The study highlights the need for large epidemiological survey in Yavatmal region to detect patients with CKDu and investigate the possible etiology.

Keywords: Chronic kidney disease of unknown origin, Glomerular filtration rate, Proteinuria Citation: Ookalkar D, Ookalkar A, Gupta VL, Balwani MR. Clinical profile of chronic kidney disease of unknown origin in patients of Yavatmal district, Maharashtra, India. J Renal Endocrinol. 2021;7:e01. doi: 10.34172/jre.2021.01.

Copyright © 2021 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction Chronic kidney disease of unknown origin (CKDu) has been reported from many hotspots across the globe from central America, Egypt, Srilanka, and coastal India (1).

In the first report of Indian CKD Registry, CKDu is the cause of CKD in 18% of the population (2). The study of Global dimensions and perspectives of CKD by Jha et al have shown that the poorest populations are at the highest risk (3).

Patients and Methods It is a single center retrospective study carried out at Ashwini Kidney and Dialysis Centre Pvt Ltd, Nagpur, India where medical data of all patients diagnosed to have CKDu were retrospectively reviewed. All patients from Yavatmal district reporting between April 2018 till June 2019 were identified. Total 2365 patients were seen during this period. 357 patients were from yavatmal district. Out of these, 19 patients fulfilled all the criteria as per the definition of probable and confirmed CKDu as given by the WHO group in Srilanka (4). Estimated glomerular filtration rate (eGFR) was calculated using CKD EPI (Chronic Kidney Disease Epidemiology Collaboration equation) formula. The eGFR and serum creatinine were estimated at intervals minimum 12 weeks apart. The KDIGO guidelines 2012 was followed for the staging (5).

The inclusion criteria for probable CKDu were eGFR< 60 mL/min with at least two eGFR readings more than 12

weeks apart or proteinuria more than 150 mg/day or urine protein creatinine ratio of more than 0.15. Demographic, clinical, biochemical data were collected and analyzed.

The study was conducted according to the Helsinki Declaration and informed consent was obtained from all participants. The study was approved by Institutional Ethics Committee, DMIMS, Wardha, India.

Results Sociodemographic profile The mean age group was 55.42 ± 10.5 years with majority of the patients between the age group of 40 to 70 years (84.21%). There was a progressive increase in the number of patients for each decade beyond 30 years up to 70 years of age. CKDu was seen more in males as compared to females. Most of the affected patients belonged to Banjara community (73.69%) and remaining five patients (26.31%) were from other communities. The subjects were predominantly farm labourers (63.15%) and rest (36.84%) were engaged in non-farming activities. The subject population has well water as the source of drinking water (100%) (Table 1).

Clinical and biochemical profile At the time of presentation, mean serum creatinine was 3.8 ± 2.4 mg/dL and the mean eGFR was 23.85 ± 14.24 mL/ min/1.73 m2. As per KDIGO staging, 5 patients presented (26.31%) with stage 3, 7 patients (36.84%) with stage 4 and

Received: 15 May 2020, Accepted: 17 July 2020, ePublished: 21 August 2020 Department of Nephrology, Ashwini Kidney Care Center, Nagpur, Maharashtra, India. 2Department of Nephrology, Jawaharlal Nehru Medical College, Sawangi, Wardha, Maharashtra, India. *Corresponding Author: Manish R Balwani, Email: balwani.manish@yahoo.com, rddmimsu@gmail.com 1

Ookalkar D et al Table 1. Demographic, social variables of patients (n=19) Age

Range (37-73 y)

Mean + SD (55.42 y ± 10.5)

Sex distribution

Males, 15 (78.95 %)

Females, 4 (21.05%)

Community

Banjara, 14 (73.69%)

Non-Banjara, 5 (26.31%)

Occupation

Farm labourers, 12 (63.15%)

Others 7 (36.84%)

Source of water

Well water, 19 (100%)

7 patients (36.84%) with stage 5 CKD. There were 11 patients (57.89%) with less than 1 g/d proteinuria and 8 (42.10%) with proteinuria more than 1 g/d. Mean proteinuria was 0.93 ± 0.35 g/d.

14 patients were normotensive while 5 patients were hypertensive. Mean systolic and diastolic blood pressure was 116.53 ± 18.67 and 77.27 ± 12.48 mm Hg respectively.

Out of the 5 hypertensive patients, single drug therapy (80%) was sufficient to control blood pressure while one patient required two drugs. None of the patients included in study had hypertension for more than 5 years duration.

Mean hemoglobin was 11.04 ± 1.75 g/dL. Mean serum sodium was 135 ± 3.33 meq/L and the mean serum potassium was 4.6 ± 0.7 meq/L (Table 2).

Mean eGFR in first reading data set was 23.85 ± 14.24 (SD) mL/min/1.73 m2. Mean eGFR in second reading data set after a gap of three months was 21.62 ± 9.35 (SD) mL/min/1.73 m2. The 2003 Weissgerber Paired Data Scatterplot table shows difference in the two sets of readings, majority of which lie below the mean. Only four patients showed increase in eGFR but this was still below 60 mL/min/1.73 m2.

Histopathology One patient underwent a kidney biopsy. Histopathological features showed 7 glomeruli of which 5 were globally sclerosed and the remaining two were normal by light microscopy. Foci of tubular atrophy and interstitial fibrosis (40%) were seen. Widespread flattening and loss of brush border of proximal tubules was noted. The interstitium showed diffuse mononuclear cell inflammatory infiltrate with few eosinophils. The blood vessels were normal. The Table 2. Clinical and Biochemical characteristics of subject population in the Yavatmal region Parameters

Mean ± SD

Min

Max

Serum creatinine (mg/dL)

3.8 ± 2.4

1.3

8.0

eGFR (mL/min/1.73 m2)

23.85 ± 14.24

7

58

Systolic BP (mm Hg)

116.53 ± 18.67

102

146

Diastolic BP (mm Hg)

77.27 ± 12.48

65

101

Urine protein/creatinine ratio

0.93 ± 0.35

0.38

1.59

Haemoglobin (gm/dL)

11.04 ± 1.75

8.8

14.1

Serum sodium (mEq/L)

135 ± 3.33

130

139

Serum potassium (mEq/L)

4.6 ± 0.7

3.2

5.4

2

Journal of Renal Endocrinology, Volume 7, 2021

Implication for health policy/practice/research/ medical education The study highlights the need for large epidemiological survey in Central India region to detect patients with CKDu and investigate the possible underlying etiologies.

biopsy was negative for immunofluorescence deposits.

Kidney biopsy could not be performed in majority of the patients as kidney size was already small, or there were logistic issues.

Discussion The Yavatmal district lies in the southwestern part of the Wardha-Penganga-Wainganga plain. The District lies between 19o 26’ and 20o 42’ north latitudes and 77o 18’ and 79o 9’ east longitudes. The District has an area of 13,582 km2, and a population of 27,72,348 persons according to 2011 Census carried out by government of India. Most of the people of this district are engaged in agricultural activities. As per 2011 census, 24.59 % of the total workers are engaged as cultivators and 54.55% of the total workers are engaged as agricultural labourers in the district. Together it constitutes 79.14 % of the total workers of the district (6).

They are exposed to various agrochemicals and extreme heat during their work. In this case series of a single specialty tertiary centre, there is a predominance of males amongst the affected (78.94%). This may be due to the fact that agricultural labourers and farmers are predominantly males. They are exposed to extreme heat while working due to which they have excessive sweating and continuous work without necessary water intake may lead to repeated dehydration. Such frequent dehydration episodes may cause subtle kidney injury which may go undetected. In a similar finding, young males were predominantly affected in the study on endemic nephropathy around the world (7). Author suggests that such hard working population must be made aware of importance of frequent hydration while working in such climatic conditions.

The age group in our study is nearly similar to the findings of Uddanam study where mean age of the subjects was 43.2 ± 14.2 years (range: 18–98). However, in their study 44.3% were men and 55.7% were women (8).

Only five of the 19 patients had hypertension, and were on antihypertensive medications. All the patients had varying degrees of proteinuria, measured by the urine protein creatinine ratio but majority had proteinuria less than 1 gm per day. In a similar study in central America, there was little or no proteinuria (9). The lack of hypertension and proteinuria less than one gm per day in majority of our patients despite advanced CKD points possibly to tubulointerstitial pathology.

The article on global epidemic of CKDu (10) expresses concerns about the Tatapudi’s study (8) which does not

CKD of unknown origin

have prevalence data as there are no repeat measurements of serum creatinine. Also, the Tatapudi’s study does not address “long standing hypertension”. Our study has taken only the patients with repeat serum creatinine measurements at 3 months.

Hyponatremia was seen in six patients. Again euvolemic hyponatremia points towards the tubular pathology.

Renal biopsy may help in arriving at anatomical etiology for which biopsy needs to be performed in earlier stages of CKDu. The kidney biopsy finding in our patient is consistent with CKDu biopsy findings compared in the study on global dimension of CKDu (11).

This case series although small in number and being a single centre experience, highlights the need for large epidemiological study in Yavatmal and adjoining districts.

There is also need of CKDu registry in this area. This will help in identifying the geographic distribution of CKDu. Many suspected CKDu patients did not come for a follow up visit. Therefore many suspected CKDu patients could not be included as probable and CKDu patients in this study. This calls for better nephrology services in Yavatmal and adjoining areas.

Conclusion Our limited sample study shows that CKDu affects mainly agricultural communities consuming well water.

Although the total number of patients in this area must be many times more than the numbers reported here, only a registry and epidemiological study with protocol-based workup will help in bringing the true CKDu numbers to public notice.

Limitations of the study Small sample size results could not be generalized.

Authors’ contribution DO, AO & VG were the principal investigators of the study. DO, AO & VG were included in preparing the concept and design. DO and AO revised the manuscript and critically evaluated the intellectual contents. All authors participated in preparing the final draft of the manuscript, revised the manuscript and critically evaluated the intellectual contents. All authors have read and approved the content of the manuscript and confirmed the accuracy or integrity of any part of the work.

Competing interests The authors declare that they have no competing interests.

Ethical considerations Ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the authors.

Funding/Support None.

References 1. Martín-Cleary C, Ortiz A. CKD hotspots around the world: where, why and what the lessons are. A CKJ review series. Clin Kidney J. 2014;7:519-23 doi: 10.1093/ckj/sfu118.

2. Rajapurkar MM, John GT, Kirpalani AL, Abraham G, Agarwal SK, Almeida AF et al. What do we know about chronic kidney disease in India: first report of the Indian CKD registry. BMC Nephrol. 2012;13:10. doi: 10.1186/1471-2369-13-10.

3. Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, et al. Chronic kidney disease: global dimension and perspectives. Lancet. 2013;382:260-72. doi: 10.1016/S01406736(13)60687-X. 4. World Health Organization.Interna-tional Expert Consultation on Chronic Kidney Disease of UnknownEtiology. Colombo, Sri Lanka; 2016. https://apps.who.int/iris/handle/10665/255137.

Accessed 25 April 2020.

5. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.

Kidney Int Suppl. 2013;3:1–150 6. District Census Handbook (DCHB) 2011 GOI (2011). https:// censusindia.gov.in/2011census/dchb/DCHB.html. Retrieved 08 August 2019 7. Gifford FJ, Gifford RM, Eddleston M, Dhaun N. Endemic Nephropathy Around the World. Kidney Int Rep. 2017;2:282– 92. doi: 10.1016/j.ekir.2016.11.003.

8. Tatapudi RR, Rentala S, Gullipalli P, Komarraju AL, Singh AK, Tatapudi VS, et al. High prevalence of CKD of unknown etiology in Uddanam, India. Kidney Int Rep. 2018;4:380-9. doi: 10.1016/j.ekir.2018.10.006.

9. Almaguer M, Herrera R, Orantes CM. Chronic kidney disease of unknown etiology in agricultural communities. MEDICC Rev. 2014;16:9–15.

10. Pearce N, Caplin B, Gunawardena N, Kaur P, O’CallaghanGordo C, Ruwanpathirana T. CKD of Unknown Cause: A Global Epidemic?

Kidney Int Rep. 2018;4:367-9. doi: 10.1016/j.ekir.2018.11.019.

11. Weaver VM, Fadrowski JJ, Jaar BG. Global dimensions of chronic kidney disease of unknown etiology (CKDu): a modern era environmental and/or occupational nephropathy? BMC Nephrol. 2015;16:145. doi: 10.1186/s12882-015-0105-6.

Journal of Renal Endocrinology, Volume 7, 2021

3

Open Access

Case Report J Renal Endocrinol 2021;7:e02.

Journal of

Renal Endocrinology

http://www.jrenendo.com

Nickan

doi: 10.34172/jre.2021.02

Research Institute

Renal salt wasting syndrome in a patient with COVID-19; a case report and review of the literature ID

ID

ID

Bassam Al-Helal1 , Emad Abdallah1* , Altayyeb Yousef2, Reem Asad1 , Mahmoud Reda1 Abstract Introduction: Cerebral salt wasting or renal salt wasting (RSW) syndrome, may be more common than syndrome of inappropriate antidiuretic hormone secretion (SIADH) and may even occur in the absence of cerebral disease. We report a case of RSW in a Bangladeshi patient positive for COVID-19 without clinical cerebral disease.

Case Presentation: A 53 years-old Bangladeshi patient presented with history of chest pain and acute MI. On examination, the patient was conscious, alert, vitally stable, chest with fine bilateral basal crepitation and heart with additional S3 sound and abdomen was lax with no organomegaly. There was no lower limbs oedema. His serum creatinine; 68 umol/L, urea; 3.4 mmol/L, K; 4.7 mmol/L, sodium; 135 mmol/L, uric acid; 141 mmol/L and phosphate was 1.3 mmol./L. Echocardiography (ECG) revealed anterior lateral wall STEMI. PCI was done for LAD. ECG revealed ejection fraction (EF) 10-15 %. Nasopharyngeal swab for COVID-19 was positive. Serum sodium decreased from 135 to 108 with signs of hypovolemia. Work up for hyponatremia revealed serum osmolality of 237 mOsm/kg, urine NA; 109 mmol/L, urine osmolality; 295 mOsm/kg, urine uric acid; 685 umol/L, and urine phosphate; 6.5 mmol/L. Additionally serum T3, T4, TSH and serum basal cortisol were normal. The patient received normal saline infusion and fludrocortisone and serum sodium increased to 134 mmol/L. Our patient had all the important clinical and laboratory characteristics of RSW in the absence of cerebral disease which include hyponatremia associated with hypovolemia, high urinary sodium excretion, increased fraction excretion of phosphate and persistent hypouricemia with increased fractional excretion of urate after correction of hyponatremia and with normal renal, adrenal and thyroid functions. Furthermore, there was a prompt response to saline replacement and fludrocortisone and steady improvement in serum sodium with negativity and improvement of COVID-19. Our diagnosis was RSW in the absence of cerebral disease and to our knowledge; this is the first case of RSW in a patient with COVID-19 in the literature.

Conclusion: RSW should be considered in patients with COVID-19 with hyponatremia and absence of cerebral disease. We suggest changing cerebral salt wasting to the more appropriate term RSW. Keywords: COVID-19, Cerebral salt-wasting syndrome, Renal salt wasting syndrome, Syndrome of inappropriate antidiuretic hormone secretion, SARS-CoV-2 Citation: Al-Helal B, Abdallah E, Yousef A, Asad R, Reda M. Renal salt wasting syndrome in a patient with COVID-19; a case report and review of the literature. J Renal Endocrinol. 2021;7:e02. doi: 10.34172/jre.2021.02.

Copyright © 2021 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction Cerebral salt-wasting syndrome (CSW), or renal salt wasting (RSW) described by Peters et al in 1950 (1), and may be more common than syndrome of inappropriate antidiuretic hormone secretion (SIADH). CSW syndrome is defined by the development of extracellular volume depletion due to a renal sodium transport abnormality in patients with intracranial disease and normal adrenal and thyroid function (1,2). CSW may even occur in the absence of cerebral disease (3-5). As such, it may be more appropriately termed RSW syndrome.

COVID-19 – the disease caused by the coronavirus that’s led to the global pandemic – is known to damage the lungs.

But, as more people become infected, more understanding of the disease emerges. Researchers are finding that this coronavirus – officially called SARS-CoV-2-can also cause severe and lasting harm in other organs, including

the heart and kidneys (6-12). We report a case of RSW syndrome in a Bangladeshi patient positive for COVID-19 and to our knowledge; this is the first case report of RSW in a patient with COVID-19 in the literature.

Case Presentation A 53 years-old Bangladeshi patient presented to AlAdan hospital casualty, Kuwait on 28/4/2020, with a history of chest pain and acute myocardial infarction.

On examination, the patient was conscious, alert, body mass index was 30 kg/m2, blood pressure 113/57 mm Hg, pulse 84 b/m, temperature 37.3oC, chest with fine bilateral basal crepitation and heart with additional S3 sound and abdomen was lax with no organomegaly.

There was no lower limbs edema. His serum creatinine ;68 umol/L, urea; 3.4 mmol/L, K; 4.7 mmol/L, sodium; 130 mmol/L, uric acid; 141 mmol/L, ALT; 39 IU/L, AST;

Received: 7 May 2020, Accepted: 4 July 2020, ePublished: 28 August 2020 Al-Khezam Dialysis Center, Al-Adan Hospital, Kuwait. 2Al Dabous Cardiology Center, Al-Adan Hospital, Kuwait. *Corresponding Author: Prof. Emad Abdallah, Email: drabdallah96@gmail.com 1

Al-Helal B et al

30 IU/L and serum albumin of 36.1 g/L. Serum calcium; 2.4 mmol/L and phosphorus was 1.3 mmol/L. CBC revealed hemoglobin of 10.3 g/dL, WBCs 3.4 × 109/L with a normal differential and platelet count of 174 × 109/L. Lipid profiles revealed total cholesterol 6.34 mmol/L, LDL-cholesterol 3.84 mmol/L, HDL-cholesterol 1.12 mmol/L and triglycerides 2.17 mmol/L. Urine analysis revealed WBCs 6-10/hpf, RBCs 61-80/hpf, urine PH 7, no casts with good urine output 70-80 mL/h. ECG revealed anterior lateral wall STEMI. PCI was done (29/4/2020) for LAD with IABP for cardiogenic shock which was removed after 24 hours. Echocardiography revealed EF 10-15 %.

Nasopharyngeal swab for COVID-19 (11/5/2020) was positive. Serum sodium decreased from 135 (28/4/2020) to 108 (11/5/2020) with signs of hypovolaemia. Work up for hyponatremia revealed serum osmolality 237 mOsm/ kg, urine sodium; 109 mmol/L, urine K; 11.5 mmol/L, urine osmolality 295 mOsm/kg, urine CL 104 mmol/L, urine uric acid 685 umol/L, urine creatinine 1.9 mmol/L, urine urea 49 mmol/L and urine phosphate 6.5 mmol/L. Serum T3, T4, TSH and serum basal cortisol were normal.

Serum PCT; 0.27, CRP; 53, PH; 7.4, HCO3; 20.3 and PCO2 was 3.9. The patient was on lasix and spironolactone for one day and stopped when the patient developed hyponatremia and this stopping did not lead to correction of hyponatremia.

The patient received normal saline infusion 200 mL/h and serum sodium increased to 131 mmol/L and then dropped again to 124 mmol/L and fludrocortisone 0.2 mg tab twice daily (only two doses were given) was initiated with normal saline 60 mL/h and serum sodium increased to 128-129 mmol/L and normal saline stopped when serum sodium became 132 on May 22, 2020 and with follow up serum sodium was 134 on May 30, 2020 (Table 1). Serum electrolytes, BUN, creatinine, urate, and phosphate were determined concomitantly with urine osmolality, sodium, potassium, creatinine, urate, and phosphate at regular intervals during the study. Plasma renine, aldosterone, ADH not were assessed. Our patient had all the important clinical and laboratory characteristic of RSW in the absence of cerebral disease including hyponatremia associated with hypovolemia, high urinary sodium excretion, increased fraction excretion of phosphate (FE phosphate) and persistent hypouricemia with increased fractional excretion of urate (FE urate) after correction of hyponatremia and with normal renal, adrenal and thyroid functions. Furthermore, there was a prompt response to saline replacement and fludrocortisone and steady improvement in serum sodium with improvement and negativity of COVID-19 (Table 1). Our diagnosis was RSW in the absence of cerebral disease and to our knowledge, this is the first case report of RSW in a patient with COVID-19 in the literature.

Discussion Hyponatremia 2

is

the

most

common

electrolyte

Journal of Renal Endocrinology, Volume 7, 2021

Implication for health policy/practice/research/ medical education Renal salt wasting syndrome should be considered in patients with COVID -19 with hyponatremia and absence of cerebral disease.

abnormality that is undergoing dramatic changes in terms of its diagnostic approach and clinical outcomes (13).

In CSW or RSW, abnormalities in the proximal tubule result in excessive sodium losses, which lead to decreased effective circulating volume. This activates baroreceptors, which increase antidiuretic hormone (ADH) secretion.

This results in water conservation and a return to an equilibrated state. In contrast, SIADH primarily occurs due to an inappropriate euvolemic rise in ADH secretion (14).

In our case the abnormalities most probably in proximal tubule due to increased urinary sodium excretion with increased FEurate, urea and phosphate.

Differentiation of this disorder from the SIADH, a common cause of hyponatremia, can be difficult because both can present with hyponatremia and concentrated urine with natriuresis. However, distinguishing between the two disorders is important because treatment options differ. Attention to the volume status of the patient is important in making the distinction. Failure to distinguish CSW syndrome from SIADH in a patient with hyponatremia who has brain injury could lead to inappropriate therapy with fluid restriction. RSW should be considered a discrete clinical entity and may be more common than perceived (4). It should also be considered in patients without cerebral disease (3,15).

The relationship among serum urate, FEurate, and hyponatremia in CSW syndrome is unclear. FEurate may remain elevated even after correction of hyponatremia in patients with CSW syndrome. This is distinct from SIADH, in which FEurate returns to the reference range once the hyponatremia is corrected (4,15). The physiologic basis for this in CSW syndrome may be related to the receptormediated processing of sodium and urate in the proximal tubule, which may be defective in this syndrome. The physiologic basis for hypouricemia in SIADH remains unclear.

The abnormalities in proximal tubular transport may be secondary to a plasma natriuretic factor that reduces proximal and, possibly, distal sodium transport in renal salt-wasting syndrome. It may also inhibit the tubular transport of urate, phosphate, and urea in addition to sodium (16).

The cause of kidney involvement in COVID-19 is likely to be multifactorial, with cardiovascular comorbidity and predisposing factors (such as sepsis, hypovolemia, and nephrotoxins) as important contributors (6).

Cardiorenal syndrome, particularly right ventricular failure secondary to COVID-19 pneumonia, might lead

3.4

135

4.7

S. urea (mmol/L)

S, NA (mmol/L)

S. K (mmol/L)

-

-

-

-

-

-

Urine K (mmol/L)

Urine CL (mmol/L)

Urine creatinine (mmol/L)

Urine urea (mmol/L)

Urine Po4 (mmol/L)

FEurate (%)

40

60

CVP

Urine output (mL/h)

CRP

COVID-19

-

6

Fludrocortisone

-

-

Urine urate (umol/L)

Normal saline

-

Urine osmolality (mosmo/kg)

-

-

Urine NA (mmol/L)

+

-

S.PO4 (mmol/L)

Frusimide/spironolactone

-

S. uric acid (mmol/L)

FEphosphate (%)

89

S.CL (mmol/L)

S. osmolality (mosmo/kg)

68

28/4/020

Creatinine (umol/L)

Variables

-VE

53

70

4

-

+

-

-

-

-

-

-

-

-

-

-

-

-

-

-

4.7

108

1.7

58

11/5/020

+VE

67

70

2

-

+

-

-

-

-

-

-

-

-

-

-

88

-

141

89

237/240

4.5

110/113

3.5

60

15/5/020

Table 1. Time course of clinical and laboratory examination of our patient

68

70

4

-

+

-

60

70-80

5

+

+

-

-

-

-

0.3

-

74

-

-

-

-

446

160

-

-

94

254/253

4.3

124/128

3.6

58

19-20/5/020

14.6

49

1.93

104

11.6

685

295

109

-

-

85

258

3.8

131

3.3

58

18/5/020

-

70

4

-

-

-

-

-

0.3

74

-

-

-

-

446

146

1.1

-

-

-

4.3

129

3.2

67

21/5/020

64.85

100

6

-

-

-

-

-

4.1

-

-

132

27.04

-

452

141

-

-

-

-

4.4

133

2.8

61

23/5/020

81.2

100

3

-

-

-

-

-

6.5

200

4.26

66

20.7/42.7

-

346/505

78/59

-

157

94.1

281

4.5

132

3.7

61

24-25/5/020

80

5

-

-

-

-

14.58

-

-

3.3

38

27.6

1187

252

44

1.3

148

92

273

4.8

131

4.2

60

-

-

80 -VE

18.4

70 29.2

7

6

-

-

13.9 +

14.57

5.7

-

4

113

45.07

1543

463

102

-

9.2

143

4.1

-

42.3

1508

321

46

1.2

95 172

-

282

88

5.3

134

5.6

65

30/5/020

5

125

6.4

70

26/5/020 28/5/020

Renal salt wasting a COVID-19

Journal of Renal Endocrinology, Volume 7, 2021

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Al-Helal B et al

to kidney congestion and subsequent acute kidney injury (AKI). Similarly, left ventricular dysfunction might lead to low cardiac output, arterial under-filling, and kidney hypoperfusion.

Autopsy data (7), indicates that the endothelium is affected in the lung and in the kidney, where it is probably responsible for proteinuria. Furthermore, virus particles were reported to be present in renal endothelial cells, indicating viremia as a possible cause of endothelial damage in the kidney and a probable contributor to AKI (7).

Additionally, SARS-CoV-2 can directly infect the renal tubular epithelium and podocytes through an angiotensinconverting enzyme 2 (ACE2)-dependent pathway and cause mitochondrial dysfunction, acute tubular necrosis, the formation of protein reabsorption vacuoles, collapsing glomerulopathy, and protein leakage in Bowman’s capsule (8,9).

Another potential mechanism of AKI involves SARSCoV-2-related immune response dysregulation, as indicated by observed lymphopenia and cytokine release syndrome (cytokine storm) (10,11).

Other contributors to AKI might include rhabdomyolysis, macrophage activation syndrome, and the development of microemboli and microthrombi in the context of hypercoagulability and endotheliitis (7,12).

Maesaka et al (13) identified the various causes of hyponatremia by determining FEurate to propose an algorithm to approach hyponatremic conditions. In this algorithm, conditions with low FEurate <4% include extrarenal salt losses with normal kidney function, Addison’s disease, and edematous states such as heart failure, cirrhosis, and nephrosis. Normal FEurate of 4%-11% include psychogenic polydipsia and reset osmostat (RO), and increased FEurate >11% SIADH/hydrochlorothiazide and C/RSW. SIADH can be differentiated from C/RSW by correcting the hyponatremia by any possible means and observing normalization of FEurate in SIADH as compared to being persistently increased in C/RSW. This algorithm greatly simplifies the diagnosis of patients with Addison’s disease and RO. The report of C/RSW occurring in patients without cerebral disease has led to proposal to change CSW to RSW (13). Maesaka et al (13) utilized this algorithm and differences in physiologic response to isotonic saline infusions between SIADH and RSW to evaluate hyponatremic patients from the general medical wards of the hospital. Isotonic saline does not induce excretion of dilute urines or correct the hyponatremia in SIADH as compared to inducing excretion of dilute urines and correction of the hyponatremia in RSW. In the absence of cerebral disease and by exclusion of other reported causes that may be cause RSW as chemotherapy with cisplatin, myeloproliferative disorders, and post-operative fracture (13,16) and as our patient is

4

Journal of Renal Endocrinology, Volume 7, 2021

positive for COVID-19, hence we suggest that COVID-19 is the cause of RSW by affecting proximal kidney tubule transport through SARS-CoV-2 which can directly infect the renal tubular epithelium and podocytes through an angiotensin-converting enzyme 2 (ACE2)-dependent pathway (8.9) and other different mechanism involves SARS-CoV-2-related immune response dysregulation, as indicated by observed lymphopenia and cytokine release syndrome (cytokine storm) (10,11).

Conclusion In conclusion, RSW should be considered in patients with COVID -19 with hyponatremia and absence of cerebral disease. We suggest changing CSW to the more appropriate term RSW. Acknowledgments Many thanks to my colleagues in the Al Khezam dialysis center and Al Dabous cardiology center, Al-Adan hospital for following and collection of all data about the patient.

Authors’ contribution All authors contributed equally to prepare the manuscript.

Conflicts of interest The authors declared that they have no conflict of interest.

Ethical considerations Ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the authors.

Funding/Support None.

References 1. Peters JP, Welt LG, Sims EA, Orloff J, Needham J. A salt-wasting syndrome associated with cerebral disease. Trans Assoc Am Physicians. 1950;63:57-64.

2. Tenny S, Thorell W. Cerebral Salt Wasting Syndrome. Treasure Island (FL): StatPearls Publishing; 2020.

3. Bettinelli A, Longoni L, Tammaro F, Fare PB, Garzoni L, Bianchetti MG. Renal salt-wasting syndrome in children with intracranial disorders. Pediatr Nephrol. 2012;27:733-9.

4. Moritz ML. Syndrome of inappropriate antidiuresis and cerebral salt wasting syndrome: are they different and does it matter? Pediatr Nephrol. 2012;27(5):689-93.

5. Maesaka JK, Imbriano LJ, Ali NM, Ilamathi E. Is it cerebral or renal salt wasting? Kidney Int. 2009;76(9):934-8.

6. Ronco C , Bellomo R . Kellum JA . Acute kidney injury. Lancet.

2019;394:1949-64.

7. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395:1417-8. doi: 10.1016/S0140-6736(20)30937-5.

8. Su H, Yang M, Wan C, Yi LX, Tang F, Zhu HY, et al. Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China. Kidney Int. 2020;98(1):21927. doi: 10.1016/j.kint.2020.04.003.

9. Larsen CP, Bourne TD, Wilson JD, Saqqa O, Sharshir MA. Collapsing Glomerulopathy in a Patient With Coronavirus Disease 2019 (COVID-19) . Kidney Int Rep. 2020;5:935-9. doi:10.1016/j.ekir.2020.04.002.

10. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet.

Renal salt wasting a COVID-19 2020;395:1054-62. doi: 10.1016/S0140-6736(20)30566-3.

11. Ronco C, Reis T. Kidney involvement in COVID-19 and rationale for extracorporeal therapies. Nat Rev Nephrol.

2020;16:308-310. doi: 10.1038/s41581-020-0284-7.

12. Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, et al.

Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. N Engl J Med. 2020;382:e38. doi: 10.1056/ NEJMc2007575.

13. Maesaka JK, Imbriano LJ, Miyawaki N. High Prevalence of Renal Salt Wasting Without Cerebral Disease as Cause of Hyponatremia in General Medical Wards. Am J Med Sci. 2018;35615-22. doi: 10.1016/j.amjms.2018.03.020.14.

14. Rahman M, Friedman WA. Hyponatremia in neurosurgical patients: clinical guidelines development. Neurosurgery.

2009;65(5):925-35; discussion 935-6 15. Maesaka JK, Miyawaki N, Palaia T, Fishbane S, Durham JH. Renal salt wasting without cerebral disease: diagnostic value of urate determinations in hyponatremia. Kidney Int. 200;71(8):822-6.

16. Bitew S, Imbriano L, Miyawaki N, Fishbane S, Maesaka JK. More on renal salt wasting without cerebral disease: response to saline infusion. Clin J Am Soc Nephrol. 2009;4(2):309-15.

Journal of Renal Endocrinology, Volume 7, 2021

5

Open Access

Photoclinic J Renal Endocrinol 2021;7:e03.

Journal of

Renal Endocrinology

http://www.jrenendo.com

Nickan

doi: 10.34172/jre.2021.03

Research Institute

Reversible acute renal failure in a middle aged woman secondary to intravascular hemolysis caused by favism ID

Muhammed Mubarak1 , Firouzeh Moeinzadeh2, Hamid Nasri2*

Case Presentation A 58-year-old woman was referred with the complaints of nausea, vomiting and left flank pain since last night.

She had a history of renal colic during previous years and in this presentation, she received medication for relieving the pain. She was discharged from the clinic with analgesic drugs and intravenous (IV) line therapy with normal saline. Urine analysis revealed, +1 blood and 4-5 red blood cells (RBCs) in microscopic urine sediment. When she presented to us, she was anuric and had severe pain in the left flank. She had a history of favism after exposure to beans a few years ago. She had consumed some food containing beans 2 days ago. On admission, she had severe left flank pain and anuria of 12 hours duration. She had dyspnea and on physical examination had end-expiratory crackles in the base of both lungs. The relevant laboratory tests on the day of admission and several days thereafter are summarized in Table 1. Her peripheral blood film showed polychromasia, anisocytosis, poikilocytosis and blister cells.

The viral and autoimmune serology was negative. On abdominal ultrasonography, the size of the right kidney was 105 mm and that of the left, 128 mm. No stone or hydronephrosis was seen. Doppler ultrasonography of renal vessels (arterial and venous) was done and normal finding was reported.

The patient’s renal functions continued to deteriorate and hemodialysis was started for ameliorating her

ID

Implication for health policy/practice/research/medical education In this report we explained a case of pigment cast associated.

Keywords: Pigment cast associated nephropathy, Acute renal failure, Intravascular hemolysis, Favism

symptoms. Her symptoms progressed and daily dialysis was done. Meanwhile, at the end of first week of admission, percutaneous renal biopsy was also performed, which is shown in Figure 1.

After three dialysis sessions, the renal function tests showed improving trend with a serum creatinine of 2 mg/ dL on 12th day of admission, when she was discharged.

Given the past history of favism and the current clinical and laboratory features favoring this diagnosis, red cell enzymatic analysis for glucose 6 phosphate dehydrogenase (G6PD) levels was contemplated but not performed due to the acute presentation. However, she was advised to undergo the same after a suitable interval.

Questions 1. What do the laboratory investigations indicate?

2. What are the renal biopsy findings?

3. What is the diagnosis?

4. What is the course and prognosis of the condition?

Table 1. The results of the main laboratory investigations of the patient on the day of admission and for seven days thereafter On admission

Day 2

Day3

Day 4

Day 5

Day 6

Blood urea nitrogen (mg/dL)

26

44

66

101

123

129

97

Creatinine (mg/dL)

2.6

5.5

6

8.3

9.4

10.1

9.4

Creatine phosphokinase (U/L)

161

122

145

123

-

-

-

Lactate dehydrogenase (U/L)

3600

6760

5987

4271

3992

3060

2841

Total bilirubin (mg/dL)

1.2

1.1

0.7

0.5

0.5

0.7

0.5

Aspartate transaminase (IU/L)

212

382

209

65

33

29

17

Alanine aminotransaminase (IU/L)

127

286

239

173

114

94

52

Hemoglobin (g/dL)

10.5

9

8.4

7.9

8.5

7.5

8.7

235000

200000

137000

136000

156000

139000

192000

Platelet count (/mm3)

Received: 4 July 2020, Accepted: 17 August 2020, ePublished: 10 September 2020 Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan.

Department of Internal Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. *Corresponding Author: Prof. Hamid Nasri, hamidnasri@yahoo.com 1 2

Day 7

Mubarak M et al A

B

C

D

Figure 1. (A) Low-power view showing many normal looking glomeruli, acute tubular injury, and pigment casts in many tubular lumena. (Hematoxylin and Eosin, ×100). (B). Medium-power view showing one normal looking glomerulus, acute tubular injury, interstitial edema, and pigment casts in many tubular lumena. (Hematoxylin and Eosin, ×200). (C) High-power view showing one normal looking glomerulus, acute tubular injury, interstitial edema, and pigment casts in one tubular lumen. (Hematoxylin and Eosin, ×400). (D) Medium-power view showing one normal looking glomerulus, acute tubular injury, interstitial edema, and pigment casts staining intense red on Masson’s stain. (Masson’s trichrome, ×200).

5. What advise would you give to the patient regarding prevention of such episodes in future?

Answers 1. The laboratory indices show acute kidney injury, hepatocyte damage and hemolytic anemia. There is gradual increase in blood urea and serum creatinine till dialysis was started. Liver enzymes were also elevated during first few days of admission but normalized within one week. Hepatitis virus workup was negative. There was a drop in hemoglobin but it started to rise from one week of admission. No blood transfusion was given. Platelet count remained in normal range, albeit with a transient decline in between.

2. Renal biopsy contained both cortex and medulla with upto 16 glomeruli showing minor changes. The vessels were unremarkable. The main pathology was seen in the tubulointerstitial compartment. There is moderate to severe acute tubular injury associated with interstitial edema and mild, focal interstitial inflammation. In addition, many tubular lumena contain pigment casts. These casts are bright red in

colour and granular in appearance and they stain bright red with Masson’s trichrome stain (Figures 1 to 4).

3. Pigment cast associated nephropathy secondary to favism.

4. Favism denotes the disease caused by the ingestion of broad beans (Vicia faba) in persons with deficiency of G6PD enzyme in the red blood cells (1-4). Because G6PD deficiency is an X linked disorder, the main clinical manifestations are seen in hemizygous males.

However, in areas of high prevalence of the disorder, homozygous females can be affected as severely as males. In the heterozygous females, the disease is often milder or goes unnoticed. It can present in atypical forms also. Red cell enzyme studies during the hemolytic phase may yield normal enzyme levels.

The overall prognosis of the condition is excellent (1-4).

5. The patient should be counseled about the possible precipitating factors for hemolysis, such as drugs like sulfonamides and quinolones and fava beans and to avoid these in future (3).

Authors’ contribution All authors contributed equally to the conception and study designing, collection and interpretation of data, drafting of paper and its final approval.

Conflicts of interest The authors declared no competing interests.

Ethical considerations Ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the author.

Funding/Support None.

References 1. Nik-Akhtar B, Khakpour M, Rashed MA. Recovery from acute renal failure from favism by means of dialysis. Trans R Soc Trop Med Hyg. 1972;66:801-802.

2. Demetrio TC, Mauricio CC. Favism presenting as an acute renal failure: Report of one case. Rev Med Chil 2012;140(8):10431045. doi: 10.4067/S0034-98872012000800011.

3. Lim F, Vulliamy T, Abdalla SH. An Ashkenazi Jewish woman presenting with favism. J Clin Pathol 2005;58:317-319.

4. Laosombat V, Sattayasevana B, Chotsampancharoen T, Wongchanchailert M. Glucose-6-phosphate dehydrogenase variants associated with favism in Thai children. Int J Hematol 2006;83:139-43.

Citation: Mubarak M, Moeinzadeh F, Nasri H. Reversible acute renal failure in a middle aged woman secondary to intravascular hemolysis caused by favism. J Renal Endocrinol. 2021;7:e03. doi: 10.34172/jre.2021.03.

Copyright © 2021 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

2

Journal of Renal Endocrinology, Volume 7, 2021

Open Access Journal of

Renal Endocrinology

Original J Renal Endocrinol 2021;7:e04. http://www.jrenendo.com

Nickan

doi: 10.34172/jre.2021.04

Research Institute

Impact of gender, C-reactive protein and body mass index on erythropoietin resistance index in maintenance hemodialysis patients Asim Osman1, Nada Awad Alkareem2, Baha eldin Elawad3, Ogail Dawod4, Mohammed Elshiekh5* Abstract Introduction: Anemia is caused by a variety of mechanisms in chronic kidney disease (CKD), including erythropoietin (EPO) deficiency, resistance to erythropoiesis-stimulating agents (ESAs), impaired iron metabolism and its clinical management remains challenging.

Objectives: The aim of the current study was to evaluate the impact of CRP, BMI, gender and duration of hemodialysis.

Patients and Methods: A total of 94 maintenance HD patients participated in this study. Laboratory investigation included CBC, renal function test and qualitatively C-reactive protein was performed. Erythropoietin resistance index (ERI) was calculated as weekly EPO dose/ body weight in kg/hemoglobin level.

Results: Female gender had significantly higher ERI (11.36 ± 1.52) compared to male HD patients (10.68 ± 1.56) (P ˃ 0.05). Patients with low BMI had significant higher ERI (12.08 ± 1.09) compared to HD patients with overweight (10.62 ± 0.79) and obese (9.62 ± 1.68) (P ˃ 0.05). The highest ERI were found in the positive CPR group (P ˃ 0.05) compared to negative CRP group. There is no significant difference between duration of hemodialysis.

Conclusion: Our data exposed that female gender; low BMI and inflammation (positive CRP) contributed to EPO hyporesponsiveness. In addition, there is no significant difference between lengths on hemodialysis.

Keywords: Hemodialysis, Erythropoietin, Hyporesponsiveness, C-reactive protein, Anemia Citation: Osman A, Alkareem NA, Elawad B, Dawod O, Elshiekh M. Impact of gender, C-reactive protein and body mass index on erythropoietin resistance index in maintenance hemodialysis patients. J Renal Endocrinol. 2021;7:e04. doi: 10.34172/jre.2021.04.

Copyright © 2021 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction Erythropoietin resistance index (ERI) calculation has been used to find out the degree of responsiveness to erythropoietin (EPO). Previous studies documented that there are many factors have been shown to independently increase ERI include male sex, shorter period on dialysis, low body mass index (BMI), low serum albumin level, low iron saturation, higher parathyroid hormone (PTH) levels, and the use of angiotensin-converting enzyme inhibitors/ angiotensin receptor blockers (1-3).

The sensitivity of the ERI enables the prompt detection of primary variations (4). The most ordinarily cause of ERI change is inflammation and malnutrition, ignoring iron deficiency. ERI has been considered a good marker for predicting mortality in dialysis patients. The BMI is a factor in the modification of body response to EPO (3).

However, whether or not this factor is solely or partially responsible for ERI change involves to be investigated.

Hence, hypo-responsiveness to EPO has also been shown to be related to increased hospitalization and mortality.

The highest ERI tertile was related to higher all-cause mortality (hazard ratio 4.2) (5). Interestingly, this association between all-cause mortality and ERI is seen in HD patients but not in PD patients (6).

Inflammation is prevalent in HD patients. As an inflammatory marker, C-reactive protein (CRP) is an important sensitive acute phase reactant (7). Previous researches manifested that elevated level of serum CRP is a strong predictor of cardiovascular mortality both in healthy subjects and HD patients (8,9).

In addition to being a prognostic indicator, elevated level of CRP may also affect responsiveness to EPO therapy in HD patients. Previous studies in small samples have shown a strength correlation between elevated levels of inflammation and hypo-responsiveness to ESAs (10, 11), as measured by total ESA dose requirements.

Objectives Regarding the great inter-patient variability of administered EPO doses needed to maintain patients

Received: 11 June 2020, Accepted: 7 July 2020, ePublished: 16 September 2020 Department of Human Physiology, Faculty of Medicine, University of Gadarif, Gadarif, Sudan. 2Department of Physiology, Faculty of Medicine, Merowe University of Technology, Merowe, Sudan. 3Department of Physiology, Faculty of Medicine, University of Umm-Alqura, Holy Makkah, Kingdom of Saudi Arabia. 4Department of MLT, Faculty of Applied Medical Sciences, Jazan University, Jazan, Kingdom of Saudi Arabia. 5Department of Physiology, Faculty of Medicine and Health Sciences, University of Dongola, Dongola, Sudan. *Corresponding Author: Mohammed Elshiekh, Email: m.a.saeed@uofd.edu.sd, mishairmo@gmail.com 1

Osman et al

Implication for health policy/practice/research/ medical education ESAs are the main treatment used to manage anemia in HD patients. The response ESAs in patients with CKD is variable and can be modified in several circumstances. The ERI is considered to be a helpful parameter in assessing the body’s response to ESA. However, an association between higher ESA doses and mortality has been observed in many interventional studies. In recent years, there has been growing interest in defining the effective factors and optimal ESA doses that will help patients reach the hemoglobin target without increasing their mortality.

at particular hemoglobin levels (12,13), evaluating the influence of inflammation on hemoglobin response to ESA dose is important for guiding anemia management. So far few studies have had adequate sample size and collection of factors that may influence ESA dosing to evaluate the independent role of inflammation, BMI on ERI. Therefore, the aim of the current study was to evaluate the impact of CRP, BMI, gender and duration of hemodialysis that may contribute to reduce responsiveness to ESA in patients on regular hemodialysis.

Patients and Methods Study design This was a descriptive retrospective cross-sectional study, conducted among maintenance hemodialysis patients in North State, Sudan in the following dialysis centers Kariam, Merowe and Nori centers. 94 Sudanese hemodialysis patients, aged 25-60 years diagnosed as an ESRD were included randomly. The current study was approved by the ethics committee of Ministry of Health, Northern State, Sudan. Written informed consent from participants was obtained prior to study.

Demographic data, time of dialysis per week, length (duration) on dialysis, administration of EPO and dose of EPO (Unit/week) were recorded. Height and weight were measured and BMI was calculated as weight/height2 (kg/m2).

In all patients, the HD procedure was carried out by using dialyzers containing high flux membranes such as polysulfone, polyester-polymer alloy, or cellulose triacetate at a blood flow rate of 200–250 mL/min and a dialysate flow rate of 500 mL/min. The surface area of the dialyzer membrane was chosen according to patient body weight. The glucose concentration of the dialysate was 100 mg/dL. Heparin was administered at 2600–5000 U per 4-h HD session for anticoagulation. The volume of ultrafiltration was maintained on the basis of clinical dry weight during each session.

Blood tests Five milliliters of blood was drawn from patients during the first 15 minutes of hemodialysis For CBC blood 2

Journal of Renal Endocrinology, Volume 7, 2021

Samples were processed using EDAN CBC fully auto hematology analyzer machine. Total and differential white blood cells (WBC) counts and percentages were determined. The absolute counts for the neutrophils, eosinophils, basophils, lymphocytes, and monocytes were computed from the WBCs total counts and the differential counts (%) of each type of white blood cells. In addition, red blood cells (RBCs) count, hematocrit percentage (HCT %), hemoglobin content, and platelets counts were determined in each blood sample.

ERI was defined as the average weekly ESA dose divided by clinical dry weight and average blood hemoglobin (weekly ESA dose (units)/dry weight (kg)/hemoglobin (g/ dL)), as described previously (14).

For determination of Renal Function Tests, measurement of serum and urine creatinine was done using Newman and Price method using BioSystems reagent kits. Measurement of serum urea was done by colorimetric method using end-point determination Urease-Berthelot Reaction, using BioSystems reagent kits. Measurement of serum sodium, potassium, calcium and phosphate was done using the flame photometer. For estimation of serum, CRP blood samples were collected in plain container. CRP levels were detected (qualitatively) using latex agglutination method (Spinreact kit, Spain).

Ethical issues Before starting the study, the patients were informed about the aims, the expected benefits to them and/or others, the risks and inconveniences involved, and their right to refuse to participate or to withdraw from the study at any time without sanction. Their written consent was obtained. The study was carried out in accordance with the Declaration of Helsinki and its subsequent modifications, and was approved by the Ethics Committees of Ministry of Health, Northern State, Sudan (approval number #451).

This study was extracted from MS.c thesis of Nada Awad Alkareem at Merowe University of Technology.

Statistical analysis Data was analyzed by using SPSS software version 24 (SPSS Inc, IL, USA). Data were presented as mean ± standard deviation for quantitative variables and summarized as frequencies and percentages for categorical variables.

Student t test was used to compare between two groups.

Data were analyzed using one-way ANOVA followed by post hoc Tukey’s test. P value of less than 0.05 was considered significant.

Results A total 94 CKD patients maintenance on HD were included in this study. The demographics and clinical data of maintenance HD patients participated as subjects were shown in Table 1.

Our results demonstrated that female HD patients had significantly higher ERI (11.36 ± 1.52) compared to male

Erythropoietin resistance HD Table 1. Demographics and clinical data study participants Variables Gender

BMI

CRP

EPO use Duration of dialysis

Mean or (n) Percent Male

(57) 60.6%

Female

(37) 39.4%

Normal weight

(75) 79.8%

Over weight

(12) 12.8%

Obese

(7) 7.4%

Positive

(45) 47.9%

Negative

(49) 52.1%

Use

(88) 93.6%

Did not use

(6) 6.4%

<36 months

(55) 58.5%

>36 months

(39) 41.5%

SD

Height

162.67

16.31

Weight

59.93

15.60

Hb (g/dL)

9.94

2.14

RBCs (x106/uL)

4.0077

3.48

PCV (%)

33.93

9.34

MCV (um3)

91.18

6.52

MCH (pg)

29.37

9.62

MCHC (g/dL)

31.80

7.34

ERI

10.95

1.56

WBCs (x103/uL)

6.013

2.325

PLT (x103/uL)

223.37

72.67

8.05

2.81

Urea (mg/dL)

116.37

4.19

PO4 (mg/dL)

5.19

1.69

Ca2+ (mg/dL)

8.87

1.27

K (mmol/L)

5.24

1.02

Na+ (mmol/L)

134.26

6.26

Creatinine (mg/dL)

+

Data presented as (frequency) percent or mean ± S.D. BMI; body mass index.

CRP; C-reactive protein. EPO; erythropoietin. Hb; hemoglobin. RBCs; red blood cells. PCV; package cell volume. MCV; mean corpuscle volume. MCH; mean hemoglobin concentration. MCHC; mean corpuscle of hemoglobin concentration. ERI; erythropoietin resistance index. WBCs; white blood cells.

PLT; platelet.

HD patients (10.68 ± 1.56) (P ˃ 0.05; Figure 1A).

HD patients with normal weight had significant higher ERI (12.08 ± 1.09) compared to HD patients with overweight (10.62 ± 0.79) and obese (9.62 ± 1.68) (P ˃ 0.05). In addition, HD patients with overweight had significant higher ERI compared to obese HD patients (P ˃ 0.05) (Figure 1B).

In our results, we divided HD patients into two groups on the basis of qualitative CPR and found significant difference in ERI. The highest ERI were found in the positive CPR group (P ˃ 0.05; Figure 2A).

Patients with length on dialysis less than 36 months had lower ERI (10.87 ± 1.25) compared to patients with length on dialysis more than 36 months but there is no significant difference between two lengths (Figure 2B).

Figure 1. Impact of gender (A) and BMI (B) on ERI. Data represent as mean ± S.D. ERI: Erythropoietin resistance index; **P ˃ 0.05 vs Male group; **P ˃ 0.05 vs normal weight and overweight; @P ˃ 0.05 vs normal weight.

Figure 2. Impact of C-reactive protein (A) and duration of hemodialysis (B) on ERI. Data represent as mean ± S.D. **P ˃ 0.05 vs positive CRP group. ERI: erythropoietin resistance index; CRP: C-reactive protein.

Our data showed that there is no significant difference in hemoglobin levels (Figure 3A) and mean corpuscle hemoglobin concentration (Figure 3B) between positive and negative CRP groups. In addition, we demonstrated that there is no significant difference in hemoglobin levels between BMI categories (Figure 3C).

Discussion Anemia is caused by a variety of mechanisms in CKD, including erythropoietin deficiency, resistance to ESAs, impaired iron metabolism and its clinical management remains challenging. The aim of the current study was to evaluate the impact of CRP, BMI, gender and duration of Journal of Renal Endocrinology, Volume 7, 2021

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Osman et al

Figure 3. Impact of CRP on hemoglobin (A) levels and MCHC (B). Impact of BMI (C) on hemoglobin levels. Data represent as mean ± S.D. CRP; C-reactive protein; MCHC: mean corpuscle of hemoglobin concentration; BMI: body mass index.

hemodialysis. The finding of our current study the mean of ERI was 10.95 ± 1.56 U/kg/week EPO/Hb g/dL. In addition, our data showed that male sex had higher ERI than female; patients with normal weight category of BMI had significant higher ERI than other BMI categories and patients with positive CRP had significant elevated ERI than patients with negative CRP. In our current study, we found that patients with duration of hemodialysis more than 36 months had higher ERI than patients with duration of hemodialysis less than 36 months but there is not reach significant value.

EPO has been applied in the clinic for many decades and has greatly improved anemia, EPO hyporesponsiveness is still observed in some HD patients. Previous studies have documented a relation between EPO hyporesponsiveness and poor clinical outcomes, such as anemia, heart failure, and increased cardiovascular and all-cause mortality (15,16). The ERI is a sensitive evaluation index of EPO responsiveness and can predict composite events (CVD, infection, hospitalization, or death) (16) and all-cause mortality in HD patients (17,18). Our current study showed that ERI values were from 8.02 to 13.72 U/kg/ week EPO/Hb g/dL, and the mean ERI value was (10.95 ± 1.56) U/kg/week EPO/Hb g/dL. These data are consistent with data reported by other studies (3,19).

Recent studies have established considerable variability in ESA dose requirements among hemodialysis patients (12,20). Inflammatory conditions, already established as an important factor limiting the response to ESA treatment in hemodialysis patients, are the probable cause of the positive association that exists between ferritin and the ERI (21,22). Gunnell et al demonstrated that elevated level of CRP is associated with the highest EPO dose needs for any given hemoglobin concentration (23).

A study done by Locatelli and colleagues showed that a 4

Journal of Renal Endocrinology, Volume 7, 2021

strong association between CRP levels and both absolute EPO dose and the ERI, even after adjustment for many potential confounding factors (24). Our current study demonstrated that HD patients with positive CRP had elevated ERI than patients with negative CRP. In addition, we demonstrated that negative CRP patients had greater hemoglobin concentration and MCHC than positive CRP patients, but there was not reach significant value.

Since the proposed of EPO in the late 1980s, it has been possible for HD patients to achieve desirable Hemoglobin concentrations. As a result, the mean Hemoglobin level in HD patients has improved significantly over the past two decades (25). EPO achieving dosing can be challenging in HD patients due to variations in patient response. In our current study mean of ERI in normal weight patients was significantly higher than overweight and obese patients.

In addition, the mean of ERI in overweight patients was significantly higher than obese patients. The results of our study similar to previous study reported that the median ESA dose and ERI value were significantly higher in non-obese than obese patients (26). This rising in ERI in normal weight patients did not seem to result in worsens anemia control. We documented that there is no significant difference in hemoglobin levels among patients in the different BMI categories. A variety of factors have been described to impact the responsiveness to EPO in HD patients, including secondary hyperparathyroidism, iron deficiency, systemic inflammation, dialysis adequacy and malnutrition (1,15,27).

The higher ERI in some patients is a condition that has been studied. A study on low response to EPO established that female receive higher EPO doses to attain the hematocrit target. It also found a higher proportion of female receiving EPO doses, but no association between iron levels or high levels of PTHs and the use of EPO

Erythropoietin resistance HD

doses (28). Other publications have found that women require higher doses of EPO, or even that low response is associated with iron deficiency, poor nutritional state, high‑turnover bone disease, and tunneled‑catheter vascular access (3,29). Our current study demonstrated that the ERI was greater in female HD patients than male.

Our findings concur with other publications observing a relation between gender and EPO requirements. A study assessing the association of anemia and survival found that the masculine gender was one of the predictors of higher levels of Hemoglobin, with an inverse relationship between hemoglobin levels and EPO doses.

Physiologically, women have lower hemoglobin levels than men, which are attributed to the effect of androgens and estrogens on erythropoiesis. This occurs mainly because of the vasodilator effect that estrogens have on the kidney microvasculature, which causes higher oxygen liberation per red blood cells mass unit at a juxtaglomerular apparatus level (30). According to the World Health Organization, there are gender‑associated differences in the hemoglobin levels that are considered normal, as well as in the hemoglobin thresholds used to define anemia, which is also applicable to patients with CKD (31). Despite the differences between normal levels of hemoglobin and the anemia cut‑off, the current guidelines of anemia management in patients with CKD establish a hemoglobin target with no gender distinction. A study conducted on a population that was not undergoing dialysis or receiving EPO reported that there is a higher absolute hemoglobin level in men than in women in different stages of CKD. They proposed considering a relative gender‑specific hemoglobin level defined as the percentage of measured hemoglobin value in relation to the normal hemoglobin inferior limit for each gender and found that relative hemoglobin is higher in women than in men. They considered that this finding was worth taking into account in future recommendations and suggested the establishment of a lower hemoglobin target in women (32). Our findings regarding the fact that women required higher doses of EPO to achieve the hemoglobin target could be the result of considering women values of hemoglobin levels as similar to men and might not indicate a difference in responsiveness to EPO. Conclusion Our data exposed that female gender, low BMI and inflammation (positive CRP) contributed to EPO hyporesponsiveness. In addition, there is no significance different between lengths on hemodialysis Limitations of the study The limitations of our study include the fact that its crosssectional design means that it can only estimate the effect of the explored variables, but cannot investigate the direction of the link between the cause (gender, BMI and CRP) and EPO resistance. Secondly, as a single-center (State) cross-

sectional study, our data may not be representative of MHD patients in other states or other countries. Thirdly, given that we detected CRP qualitatively.

Acknowledgments The authors thank patients for their participation. We would like to thank staff and administration of dialysis centers Kariam, Merowe and Nori for their cooperation.

Authors’ contribution NAA and AO were the principal investigators of the study. ME, AO, BE and NAA were participated in preparing the concept and design of study. ME, BE and OD analyzed data and revised the final manuscript. All authors participated in preparing the final manuscript, revised the manuscript and critically evaluated the intellectual concepts. All authors have read and approved the content of the manuscript and confirmed the accuracy or integrity of any part of the work.

Conflicts of interest There are no conflicts of interest.

Ethical considerations Ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the authors.

Funding/Support This study was carried out without any financial support from any company.

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Bradbury BD, Critchlow CW, Weir MR, Stewart R, Krishnan M, Hakim RH. Impact of elevated C-reactive protein levels on erythropoiesis- stimulating agent (ESA) dose and responsiveness in hemodialysis patients. Nephrol Dial Transplant. 2009;24:919-25. doi: 10.1093/ndt/gfn543.

Higuchi T, Abe M, Yamazaki T, Mizuno M, Okawa E, Ando H, et al. Effects of levocarnitine on brachial-ankle pulse wave velocity in hemodialysis patients: a randomized controlled trial. Nutrients 2014;6:5992–6004. doi: 10.3390/nu6125992 Szczech LA, Barnhart HX, Inrig JK, Reddan DN, Sapp S, Califf RM, et al. Secondary analysis of the CHOIR trial epoetinalpha dose and achieved hemoglobin outcomes. Kidney Int. 2008;74(6):791–8. doi: 10.1038/ki.2008.295.

Kilpatrick RD, Critchlow CW, Fishbane S, Besarab A, StehmanBreen C, Krishnan M, et al. Greater epoetin alfa responsiveness is associated with improved survival in hemodialysis patients.

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Kuragano T, Kitamura K, Matsumura O, Matsuda A, Hara T, Kiyomoto H, et al. ESA Hyporesponsiveness Is Associated with Adverse Events in Maintenance Hemodialysis (MHD) Patients, But Not with Iron Storage. PLoS One. 2016;11:e0147328. doi: 10.1371/journal.pone.0147328 Okazaki M, Komatsu M, Kawaguchi H, Tsuchiya K, Nitta K. Erythropoietin resistance index and the all-cause mortality of chronic hemodialysis patients. Blood Purif. 2014;37:106–12. doi: 10.1159/000358215 Chang JH, Jung JY, Lee HH, Chung W, Joo KW, Kim S. Serum resistin as a novel marker of erythropoietin resistance in nondiabetic patients on hemodialysis. Tohoku J Exp Med. 2011;224:281-5. doi: 10.1620/tjem.224.281 Bradbury BD, Critchlow CW, Rothman KJ, Heagerty P, Keen M, Acquavella JF, et al. Exploring relative mortality and epoetin alfa among hemodialysis patients. Am J Kidney Dis 2008 Jan

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1; 51: 62–70. doi: 10.1053/j.ajkd.2007.09.015 21. Romão Jr JE, Haiashi AR, Elias RM, Luders C, Ferraboli R, Castro MCM, et al. Positive Acute-Phase Inflammatory Markers in Different Stages of Chronic Kidney Disease. Am J Nephrol 2006;26:59–66. doi: 10.1159/000091806 22. Abensur H. Iron deficiency in chronic kidney disease. Rev. Bras. Hematol. Hemoter. 2010 Jun; 32 (Suppl 2): 95-98. doi: 10.1590/S1516-84842010005000047 23. Gunnell J, Yeun JY, Depner TA, Kaysen GA. Acute-phase response predicts erythropoietin resistance in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis 1999;33: 63–72. doi: 10.1016/S0272-6386(99)70259-3 24. Locatelli F, Andrulli S, Memoli B, Maffei M, Vecchio LD, Aterini S, et al. Nutritional-inflammation status and resistance to erythropoietin therapy in haemodialysis patients. Nephrol Dial Transplant 2006;21:991-8. doi: 10.1093/ndt/gfk011.

25. Freburger JK, Ng LJ, Bradbury BD, Kshirsagar AV, Brookhart MA. Changing patterns of anemia management in US hemodialysis patients. Am J Med. 2012;125:906-914.e9, 2012. doi: 10.1016/j.amjmed.2012.03.011.

26. El-Kannishy GM, Megahed AF, Tawfik MM, El-Said G, Zakaria RT, Mohamed NA, et al. Obesity may be erythropoietin dose-saving in hemodialysis patients. Kidney Res Clin Pract.

2018;37(2):148-56. doi: 10.23876/j.krcp.2018.37.2.148.

27. Di Iorio BR, Stellato D, De Santo NG, Cirillo M. Campanian Dialysis Registry Research Group. Association of gender and age with erythropoietin resistance in hemodialysis patients: role of menstrual status. Blood Purif. 2004;22:423-7. doi: 10.1159/000080234.

28. Eschbach JW, Varma A, Stivelman JC. Is it time for a paradigm shift? Is erythropoietin deficiency still the main cause of renal anemia? Nephrol Dial Transplant 2002;17 Suppl 5:2‑7. doi: 10.1093/ndt/17.suppl_5.2.

29. Kalantar‑Zadeh K, Lee GH, Miller JE, Streja E, Jing J, Robertson JA, et al. Predictors of hyporesponsiveness to erythropoiesis‑stimulating agents in hemodialysis patients. Am J Kidney Dis 2009;53:823‑34. doi: 10.1053/j.ajkd.2008.12.040 30. Murphy WG. The sex difference in haemoglobin levels in adults – Mechanisms, causes, and consequences. Blood Rev. 2014;28:41‑7. doi: 10.1016/j.blre.2013.12.003 31. Benoist B, McLean E, Egli I, Cogswell M. Worldwide Prevalence of Anaemia 1993‑2005: WHO Global Database on Anaemia.

Geneva: World Health Organization; 2008.

32. Duncan JA, Levin A. Sex, haemoglobin and kidney disease: New perspectives. Eur J Clin Invest 2005;35Suppl 3:52‑7. doi: 10.1111/j.1365-2362.2005.01531.x.

Open Access

Original J Renal Endocrinol 2021;7:e05.

Journal of

Renal Endocrinology

http://www.jrenendo.com

Nickan

doi: 10.34172/jre.2021.05

Research Institute

Safety and efficacy of intranasal recombinant human interferon alfa 2b as prophylaxis for COVID-19 in patients on a hemodialysis program ID

ID

ID

Anselmo Abdo-Cuza1* , Roberto Castellanos-Gutiérrez1 , Janete Treto-Ramirez1, Sandra Arencibia-Larin1 , ID Thalía Gómez-Pariente1, Tania González-Fernández1, Julio C. Hernández-Perera1 , Katia Arocha-Stalella1, Niurka 1 1 1 ID Verdecia-Gorrita , Lisy Vento-Buigues , Yanet Cordero-Vasallo , Yusmel Rivero-Yi1, Odalys González-Dias2, ID ID Hugo Nodarse-Cuni2, Rafael Machado-Martínez1 , Miguel A. Blanco-González1 , Julio Valdivia-Arencibia1, ID 1 1 1 Daymiris Mendez-Felipe , Ernesto Delgado-Almora , Carlos Gutiérrez-Gutiérrez , Juliette Suárez-López3 , Jorge 1 1 1 L. Leiva-Torres , Alicia Rodríguez-Sotolongo , Nilda Bejerano-Gil Abstract Introduction: Patients diagnosed with end-stage chronic kidney disease on a hemodialysis program (HDP) represent a risk group for COVID-19. Scientific societies have developed guidelines for the prevention of contagion, but there is no prophylactic medicine in them.

Objectives: To describe the safety and efficacy of recombinant intranasal human Interferon alfa 2b as prophylaxis for COVID-19 in patients in an HDP. Patients and Methods: Intervention description through the monitoring of 15 patients in outpatient HDP. Prior to the administration of the drug, clinical, radiological evaluation and hematology and blood chemistry studies were performed. Daily contact was made with each study patient in person or by telephone, asking about the occurrence of adverse events or symptoms of disease.

Results: In 47% of the patients, there was leukopenia, lymphopenia in 67% and anemia and thrombocytopenia in 33% respectively, prior to the use of the drug. There was no clinical suspicion of COVID-19 in any of them. Adverse events occurred in 3 patients (20%), all were mild and non-severe. All patients were negative for SARS-CoV-2 real-time polymerase chain reaction (rtPCR) and antibody studies 45 days after the study started.

Conclusion: the use of intranasal recombinant human interferon alfa 2b as prophylaxis of COVID-19 in patients in a HDP at a dose of 1 MIU daily for ten days, as part of a prevention protocol, has an adequate safety profile. None of the patients in the series was infected with SARS-CoV-2 during the surveillance period.

Keywords: Interferon type I, Coronavirus infections, COVID-19, Hemodialysis units hospital, SARS-CoV-2, Renal insufficiency chronic, Prevention & control Citation: Abdo-Cuza A, Castellanos-Gutiérrez R, Treto-Ramirez J, Arencibia-Larin S, Gómez-Pariente T, González-Fernández T, HernándezPerera JC, Arocha-Stalella K, Verdecia-Gorrita N, Vento-Buigues L, Cordero-Vasallo Y, Rivero-Yi Y, González-Dias O, Nodarse-Cuni H, Machado-Martínez R, Blanco-González MA, Valdivia-Arencibia J, Mendez-Felipe D, Delgado-Almora E, Gutiérrez-Gutiérrez C, SuárezLópez J , Leiva-Torres JL, Rodríguez-Sotolongo A, Bejerano-Gil N. Safety and efficacy of intranasal recombinant human interferon alfa 2b as prophylaxis for COVID-19 in patients on a hemodialysis program. J Renal Endocrinol. 2021;7:e05. doi: 10.34172/jre.2021.05.

Copyright © 2021 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction The disease which is caused by the new SARS-CoV-2 coronavirus named COVID-19 has risk factors for infection and poor evolution, consist of old age and the presence of comorbidities such as high blood pressure, diabetes mellitus, ischemic heart disease and end-stage chronic kidney disease (1). The common factor among them is vascular damage, specifically the endothelium, which has been found to be a target for SARS-CoV-2 (2).

Patients diagnosed with end-stage chronic kidney disease on hemodialysis program (HDP) represent a particular risk group. A lot of COVID-19 risk factors exist commonly in these patient. Patients on HDP are considered as immunosuppressed patients because of alteration in lymphocyte population and uremic milieu (3). A proinflammatory state has been described in patients on HDP with a higher risk for cardiovascular diseases (4). The behavior of social isolation cannot be

Received: 8 August 2020, Accepted: 12 September 2020, ePublished: 29 September 2020 Centro de Investigaciones Médico Quirúrgicas, La Habana, Cuba. 2Centro de Ingeniería Genética y Biotecnología, La Habana, Cuba.

Hospital Hermanos Ameijeiras. La Habana, Cuba. *Corresponding Author: Anselmo A. Abdo-Cuza, MD, PhD, Email: aaabdo@infomed.sld.cu 1 3

Abdo-Cuza A et al

Implication for health policy/practice/research/ medical education The research is of current importance given the global situation that has caused the SARS-CoV-2 pandemic. The article shows the hygienic-epidemiological measures adopted in hemodialysis units in Cuba. In particular, the safety and efficacy of incorporating a drug for preventive purposes are described. Intranasal recombinant human interferon alfa 2b has antiviral properties and its generalization may be useful in the prophylaxis of COVID-19, in patients on hemodialysis programs, which constitute risk groups for infection.

fully complied with, since HDP patients must periodically attend in medical centers where they will share spaces with other patients and healthcare personnel.

Scientific societies and groups of specialties have elaborated action guides for the prevention of contagion, which generally include hygienic-epidemiological measures aimed at patients, health personnel and the hemodialysis room (5-7).

The revision of the prevention guidelines show to medicine for prophylaxis. There are reports of the use of interferon in the form of nasal drops as an preventive tool in viral respiratory diseases (influenza, rhinovirus, coronavirus) with evidence of antiviral and mitigating effects of the symptomatic period (8,9). However, there have been controversies regarding the dose that provides an antiviral effect with certainty in relation to the appearance of adverse events.

Interferons are glycoproteins known as cytokines, molecules that make up the protective defenses of the immune system for the eradication of pathogens.

Interferons get their name for their ability to “interfere” with viral replication and have other functions such as activating immune system cells (eg. natural killer

cells and macrophages) and increasing host defenses by regulating antigen presentation through of the major histocompatibility complex (10). Current research results have shown that SARS-CoV-2 can inhibit the physiological secretion of interferon by host cells and therefore creates a terrain of susceptibility to viral infection (11).

In the current situation motivated by COVID-19, the use of recombinant intranasal human interferon alfa 2b (rinhIFNα2b) as prophylaxis of COVID-19 in patients on HDP may be an interesting option to incorporate into the group of prevention measures established by scientific societies.

Objectives To describe the safety and efficacy of using rinh-IFNα2b as COVID-19 prophylaxis in patients in a HDP. Patients and Methods Study design The drug was applied to 15 patients in the HDP of the Centro de Investigaciones Médico Quirúrgicas.

In-hospital hemodialysis was performed three times a week on an outpatient basis. Table 1 shows the demographic characteristics, associated diseases, and time on dialysis.

Dosage and method of administration of the drug Presentation: Recombinant intranasal human interferon alfa 2b, 10 million international units (MIU) per milliliter (mL).

Dose: one drop (0.05 mL = 0.5 MIU) in each nostril, once a day, for 10 consecutive days Active ingredient: Recombinant human IFN alpha-2b, produced in Escherichia Coli at the Centro de Ingeniería Genética y Biotecnología , Havana, Cuba.

Other ingredients: for each mL Ethylenediaminetetraacetic acid, disodium salt dihydrate, polysorbate 80 (Tween 80), beta cyclodextrin,

Table 1. Demographic characteristics, time on dialysis and personal pathological history of the patients under study Patient

Gender

Age

HD time (y)

AHT

ACEI/ARA 2

1

Male

63

20

x

x

DM

IHD

HCV

x

x

COPD

Others

2

Male

50

12

x

x

x

3

Male

60

18

x

x

x

x

Post-transplant lymphoproliferative syndrome

4

Female

40

2

x

5

Male

74

3

x

6

Female

67

8

x

7

Male

62

3

x

x

8

Male

47

3

x

x

9

Female

73

2

x

10

Male

70

7

x

11

Female

54

8

x

Systemic lupus erythematosus

12

Male

75

1

x

Cerebrovascular disease

13

Male

69

1

14

Male

40

20

x

x

15

Male

37

13

x

x

x x

Multiple myeloma Breast cancer (liver and lung metastases) Psoriatic arthritis

x x

x

Gastric neoplasm

x

Prostate neoplasm

Systemic lupus erythematosus

HD: hemodialysis, AHT: arterial hypertension, ACEI: angiotensin converting enzyme inhibitor, ARA: angiotensin receptor antagonist, DM: diabetes mellitus, IHD: ischemic heart disease, HCV: hepatitis C virus, COPD: chronic obstructive pulmonary disease.

2

Journal of Renal Endocrinology, Volume 7, 2021

Recombinant human interferon alfa 2b

high viscosity carboxymethyl cellulose, thiomersal, sodium chloride, sodium dihydrogenphosphate dihydrate, disodium hydrogen phosphate, water for injection.

Information and prior evaluation Patients received detailed information about the study objectives, characteristics of the drug under evaluation, possible adverse events and behavior to follow, including the immediate report to the researchers.

Each patient under study was questioned to search for symptoms suggestive of disease, including those suspected of COVID-19. Physical examination, hematology, blood chemistry, chest radiology and thoracic ultrasound were conducted.

Security watch period Daily contact was made with each study patient in person or by telephone, in which patients were questioned regarding the occurrence of adverse events or symptoms of disease.

Adverse events (AE) were classified according to grade as: Mild: AE that is well tolerated, does not interfere with daily activities, does not require treatment and does not interrupt administration. Moderate: AE that interferes with daily activities, requires treatment, and does not necessarily require discontinuation of the causative medication. Severe: AE incapacitating work or usual activities, prolongs hospitalization of the patient because it directly threatens his life and requires the suspension of the causative drug and the administration of a specific treatment to counteract it.

AEs were classified according to severity as: 1. Not serious, 2. Causes death, 3. Threatens life, 4. Requires hospitalization, or prolongs it, 5. Causes significant disability/ disability, and 6. Causes birth defects After 48 hours after the end of the administration of the drug, hematology and blood chemistry studies were repeated.

Efficacy monitoring period Daily contact was made with each study patient in person or by telephone, in which the patients were questioned regarding the occurrence of symptoms suspected of

disease. On day 45 of the study, all patients underwent SARS-CoV-2 real-time polymerase chain reaction (rtPCR) for SARS-CoV-2 through pharyngeal exudate and blood collection for anti-SARS-CoV-2 LUNGENE® (IgM and IgG) and UMELISA® (IgG) rapid kits; Figure 1).

Other prevention actions The Centro de Investigaciones Médico Quirúrgicas and the Nephrology, Dialysis and Kidney Transplant Service adopted the preventive measures dictated by the Cuban state and the ministry of public health of the republic of Cuba (12). HDP patients and health personnel were questioned about suspected symptoms of COVID-19 and temperature measurement and hand washing with 0.1% sodium hypochlorite solution were performed at the hospital entrance. Facial protectors were added to the individual protection means of the HDP health personnel in addition to the protective glasses (Figure 1).

All patients wore surgical masks during hemodialysis and travel. At the end of the work session, in addition to conventional cleaning, general disinfection and surface cleaning with 0.5% sodium hypochlorite solution was performed.

Ethical issues The research conducted in accordance with the tenets of the Declaration of Helsinki. The Ethics Committee of Centro de Investigaciones Médico Quirúrgicas (Universidad de Ciencias Medicas de La Habana) approved this study. The institutional ethical committee at Centro de Investigaciones Médico Quirúrgicas accepted all study protocols (CEI-Cimeq 2020-011). Accordingly, written informed consent was taken from all participants before any intervention.

Statistical analysis Statistical evaluation was performed with the Statistical Package for the Social Sciences (SPSS® 20.0) for Microsoft Windows®. The mean as a summary measure of center for the quantitative variables and the standard deviation as a measure of dispersion were estimated, as well as the percentages for the quantitative variables. The comparison

Figure 1. A. Pharyngeal material sampling time for rtPCR SARS-Cov-2, B. Hemodialysis program patient with surgical mask and nurse with n95 respirator, face protector, hat, overcoat and gloves.

Journal of Renal Endocrinology, Volume 7, 2021

3

Abdo-Cuza A et al Table 2. Hemodialysis related data, nutritional status, and drugs of the patients under study Patient

Steroids

Statins

Pentoxifylline Nutritional status

Kt/V

Vascular access

>1.4

AVF

Obese

1 – 1.4

PC

Underweight

> 1.4

AVF

1 2

10 mg/d

3

Others Post-transplant lymphoproliferative syndrome

4

5 mg/d

>1.4

AVF

5

40 mg/d

>1.4

AVF

Multiple myeloma

>1.4

AVF

Breast cancer (liver and lung metastases)

>1.4

AVF

>1.4

AVF

Psoriatic arthritis

>1.4

PC

Gastric neoplasm

>1.4

AVF

Prostate neoplasm

>1.4

AVF

Systemic lupus erythematosus

>1.4

AVF

Cerebrovascular disease

13

>1.4

AVF

14

>1.4

AVF

15

>1.4

AVF

6

Malnourished

7 8

5 mg/d

x

9

x

10

x

11

x

Obese

10 mg/d

12

Underweight x

x

Systemic lupus erythematosus

AVF: arteriovenous fistula, PC: permanent catheter.

Table 3. Hematologic variables, coagulation, blood chemistry, markers of inflammation and endothelial dysfunction, prior to medication administration Hemoglobin (109/L)

Platelets (109/L)

D-Dimer (pg/ml)

Fibrinogen (mg/dl)

LDH (mg/dl)

Ferritin (ng/ml)

NLR

PLR

1.2

9.9

145

0.82

182

174

207.0

1.75

120.83

1.3

14.6

174

1.42

200

285

207.0

5.31

133.85

3.6

0.8

12.4

276

2.15

200

120

154.1

3.00

345.00

4

6.5

1.5

12.1

170

0.26

193

244

2000.0

2.87

113.33

5

7.2

4.6

12.6

194

0.70

192

219

709.7

0.43

42.17

6

5.8

0.8

8.1

215

0.67

179

262

471.5

5.50

268.75

7

4.4

0.9

10.2

230

0.49

326

255

728.7

3.33

255.56

8

10.6

1.5

12.1

125

1.11

196

246

2000.0

5.53

83.33

9

6.7

1.6

12.0

133

0.57

179

191

918.5

2.75

83.13

10

4.1

0.8

12.1

206

0.17

200

98

2000.0

3.38

257.50

11

3.1

0.7

12.8

57

0.35

192

250

1973.0

3.00

81.43

12

3.9

1.3

10.9

142

0.32

199

270

975.9

1.46

109.23

13

7.7

1.8

13.7

169

1.22

192

239

94.76

2.67

93.89

14

2.9

1.2

10.3

186

0.27

192

199

951.1

1.17

155.00

15

4.5

0.9

12.5

105

1.40

186

205

878.6

3.44

116.67

Patient

WBC (109/L)

1

3.7

2

8.7

3

Lymphocytes (109/L)

WBC: White blood cells, LDH: lactic dehydrogenase, NLR: neutrophil-lymphocyte ratio, PLR: platelet-lymphocyte ratio

of means was carried out by means of the Students’ t test.

Statistical significance was declared when P <0.05.

Results General characteristics of the study population The series consisted of 15 patients on a HDP, 11 (73%) male and 4 female (27%). The mean age was 58.7 years of age with age limits of 37-75 years. The mean time on hemodialysis was 8 years, with ranges between 1-20 years.

The main comorbidities were hypertension in 14 patients (93%), hepatitis C virus (HCV) infection in 6 patients (40%), neoplastic disease in 5 patients (33%), shown in Table 1.

Hemodialysis was performed with Fresenius® F6 HPS - F10 HPS low flux filters and a polysulfone membrane; except in patient 7, the FX Cordiax high flow filter was used. Table 2 shows the vascular accesses used, Kt/v and other data of interest. Patients received iron dextran intravenously, between 25-100 mg/wk.

4

Journal of Renal Endocrinology, Volume 7, 2021

Baseline status in relation to hematological variables, coagulation and inflammation markers In seven patients (47%) there was leukopenia, lymphopenia in 10 (67%), and anemia and thrombocytopenia in five (33%), respectively. Neutrophil-lymphocyte and plateletlymphocyte rates were found at risk values in three patients (20%) and in one patient (7%) respectively, see Table 3.

Elevated D-Dimer was found in nine patients (60%), see Table 3. There was not any abnormality in serum fibrinogen level, prothrombin time and partial thromboplastin time.

LDH was not elevated in any patient and in 11 (73%) patients there was an increase in ferritin, see Table 3.

Baseline physical exam In nine patients (60%) there was some auscultatory abnormality in the examination of the respiratory system.

The oxygen saturation by pulse oximetry was found between 93-100% and the radial pulse between 60-99

Recombinant human interferon alfa 2b

beats per minute.

No patient had symptoms and/or signs, nor radiological or ultrasound images suggestive of pneumonia in the course of COVID-19 such as those described in the scientific reports (13,14).

Incidence and characterization of adverse events Adverse events occurred in 3 patients (20%), all of mild severity and not serious, see Table 4.

Post-intervention status in relation to hematological variables and inflammation markers Table 5 presents the mean values of a group of laboratory variables at the pre-intervention and post-intervention times.

Viral studies SARS-CoV-2 rtPCR and COVID-19 antibody studies (IgM and IgG) were negative in all patients.

Discussion Patients diagnosed with chronic kidney disease in HDP are one of the risk groups for COVID-19.

In the present case series, the high prevalence of comorbidities in patients with chronic kidney disease is demonstrated, finding a higher proportion of hypertension and neoplastic diseases. The finding of lymphopenia is frequent in the study patients, similar to that reported by other authors as characteristics of patients in HDP (3).

Similarly, there are some patients with a baseline state characterized by elevation of some inflammation markers (eg. ferritin, LDH) and activation of coagulation [eg.

D-dimer] (4).

The baseline characteristics of the patients on HDP, including those that make up the present investigation, complicates the diagnostic suspicion of COVID-19, given that among the prognostic factors for SARS-CoV-2 infection are lymphopenia, elevation of D-Dimer and presence of inflammatory [eg. ferritin, LDH] (15,16).

On the other hand, although some authors have reported that the presentation symptoms of COVID-19 in HDP patients are similar to the patients without renal failure, other authors describe a higher frequency of atypical presentations [eg. digestive symptoms] (16,17).

In this group of patients, surveillance protocols require Table 4. Adverse events: type, grade and severity

an additional alert given the number of variables and confusing situations that can coexist. The possibility of prescribing pharmacological prophylaxis, in addition to hygienic-epidemiological prevention measures, may be useful.

Intranasal use of interferon as prophylaxis for viral respiratory infections has been demonstrated in in vitro and in vivo studies. In the authors’ opinion, the main controversy has been in the dose with antiviral effectiveness and minor adverse events.

The adverse events found in the present study were few, mild, not serious and didn’t necessitate drug discontinuation.

When comparing with other articles in the literature, we found that Douglas et al (18) described that the administration of a daily dose of rinh-IFNα2b of 10 MIU demonstrated antiviral effectiveness, but in a high percentage of participants, it was accompanied by adverse events (nasal irritation, mucosal ulceration, bleeding) that forced the clinical trial to be suspended.

Douglas et al (18), using doses of 2 MIU daily for 28 days, described modest anti-rhinovirus activity and 7.7% of adverse events in the interferon group vs. 0.9% in the placebo group. The main symptoms with this dose were nasal irritation, a dry nose and bleeding that reversed after Table 5. Comparison of pre- and post-intervention mean values (hematology, coagulation, blood chemistry and inflammation markers) Pre-intervention, mean (±SD)

Variable WBC (109/L)

Post-intervention, P mean (±SD)

5.6 (2.3)

5.7 (1.9)

0.395

Lymphocytes (10 /L)

1.4 (0.9)

1.2 (0.7)

0.115

Neutrophils (109/L)

3.6 (2.0)

3.8 (1.5)

0.345

11.7 (1.6)

11.5 (1.9)

0.454

168. 5 (54.0)

166. 1 (30.2)

0.896

9

Hemoglobin (10 /L) 9

Platelets (109/L) NLR

3.0 (1.5)

3.5 (1.9)

0.045

PLR

150.6 (88.0)

151.4 (47.9)

0.970

Fibrinogen (mg/dL)

200.5 (35.4)

291 (25.7)

0.001

LDH (mg/dL)

212.3 (52.4)

213.6 (62.5)

0.162

Ferritin (ng/mL)

1017.2 (728.9)

991 (623.7)

0.001

APL (UI/L)

386.8 (260.3)

214.6 (157.4)

0.023

GOT (U/L)

23.0 (8.6)

24.4 (11.1)

0.546

GPT (U/L)

26.2 (18.4)

31.8 (18.2)

0.004

GGT (U/L)

78.7 (73.6)

55.1 (53.1)

0.311

Total protein (g/L)

51.7 (5.2)

69.7 (6.5)

0.001

Albumin (g/L)

37.4 (6.4)

41.1 (3.1)

0.076

406.8 (83.2)

501.6 (89.5)

0.001

19.0 (6.0)

26.7 (7.8)

0.001

Patient

Adverse event

Grade

Severity

Uric acid (mmol/L)

7

Dry mouth

Mild

Not serious

Urea (mmol/L)

7

Headache

Mild

Not serious

Creatinine (mmol/L)

870.8 (260.5)

1062.9 (275.8)

0.001

7

Flu-like syndrome

Mild

Not serious

Glycemia (mmol/L)

5.0 (1.2)

4.9 (0.9)

0.791

8

Coryza

Mild

Not serious

11

Coryza

Mild

Not serious

11

Pharyngeal burning

Mild

Not serious

SD: standard deviation, WBC: White blood cells , NLR: neutrophil - lymphocyte ratio, PLR: platelets - lymphocyte ratio, LDH: lactic dehydrogenase, ALP: alkaline phosphatase, GOT: glutamic oxalacetic transaminase, GPT: glutamic pyruvic transaminase, GGT: gamma glutamyl transpeptidase.

Journal of Renal Endocrinology, Volume 7, 2021

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Abdo-Cuza A et al

one to two weeks of withdrawing the medication.

Turner et al (19) carried out a study in which they administered rinh-IFNα2b 2 MIU daily for 15 days and compared it with a placebo group. Eight days after the start of the study, all patients were inoculated with nasal solution with coronavirus 229E. In the placebo group 77% developed flu-like symptoms vs 21% in the interferon group, with the duration and severity of the symptoms being shorter in the last group. In relation to the appearance of adverse events (nasal bleeding) this was recorded in 34% in the interferon group vs. 19% in the placebo group.

Mucosal ulceration was not observed in any patient, and none of them required withdrawal of the drug.

In the reviewed literature, there is no evidence of adverse effects of the drug in relation to hematological, coagulation or blood chemistry alterations.

With respect to this research, the authors consider that the differences in some results in the laboratory variables monitored post-intervention (eg. creatinine, urea, uric acid) may be related to the time of sample collection with respect to the time of last hemodialysis session.

Basal taking was done 24 hours after the last session and post-intervention sample was done 48 hours after the last session.

In the current SARS-CoV-2 pandemic, researchers from the Taihe hospital in Hubei province used intranasal IFN alpha 1b for 28 days in healthcare personnel from areas exposed to the virus. They later compared their results with the situation found in the staff of other Hubei hospitals with new diagnoses of COVID-19. In the interferon group, no personnel was diagnosed with COVID-19, while in the other hospitals, 2,035 patients were diagnosed among the health personnel. There were no described adverse events [except for some cases with slight nasal irritation] (11).

None of the patients included in the present investigation were affected by SARS-CoV-2 infection during a period of more than 45 days under surveillance at times of regional viral circulation in the province with the highest national prevalence. The authors suggest new studies to confirm the effectiveness of the dose used in a similar study population.

Conclusion The use of intranasal recombinant human interferon alfa 2b as prophylaxis of COVID-19 in patients in a HDP at a dose of 1 MIU daily for ten days, together with a prevention protocol composed of hygienic-epidemiological measures, has an adequate profile of safety in relation to the appearance of few and slight adverse effects. None of the patients in the series was infected with SARS-CoV-2 during the surveillance period.

Limitations of the study The main limitations of the study consist of the sample size and being a monocentric study. Further studies are needed to confirm the results of the present investigation.

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Authors’ contribution AAC, RCG, JTR and JCHP were the principal investigators of the study. AAC, RCG, JTR and JCHP were included in preparing the concept and design. AAC, JTR and JSL revisited the manuscript and critically evaluated the intellectual contents. All authors participated in preparing the final draft of the manuscript, revised the manuscript and critically evaluated the intellectual contents. All authors have read and approved the content of the manuscript and confirmed the accuracy or integrity of any part of the work.

Conflicts of interest The authors declare that they have no competing interests.

Ethical considerations Ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the authors.

Funding/Support None.

References 1. Wei-jie Guan, Wen-hua Liang, Yi Zhao, Heng-rui Liang, Zisheng Chen, Yi-min Li, et al. Comorbidity and its impact on 1590 patients with Covid-19 in China: A Nationwide Analysis. Eur Respir J. 2020;55:2000547. doi: 10.1183/13993003.005472020 2. Sardu C, Gambardella J, Morelli MB, Wang X, Marfella R, Santulli G. Is COVID-19 an Endothelial Disease? Clinical and Basic Evidence. Preprints 2020; 2020040204. doi: 10.20944/ preprints202004.0204.v1 3. Lepe-Zúñiga JL, Morales-Molina P, García-Nandayapa GA. Caracterización y correlación clínica de la linfopenia en la enfermedad renal en estadio terminal. Rev Med Inst Mex Seg Soc. 2016;54(4):446-53.

4. Baragetti I, El Essawy B, Fiorina P. Targeting Immunity in EndStage Renal Disease. Am J Nephrol. 2017;45:310-319. doi: 10.1159/000458768 5. Arenas MD, Villar J, Gonzalez C, Cao H, Collado S, Crespo M, et al. Manejo de la epidemia por coronavirus SARS-CoV-2 (Covid 19) en unidades de hemodiálisis. Nefrología. 2020. doi:10.1016/j.nefro.2020.04.001 6. Basile C, Combe C, Pizzarelli F, Covic A, Davenport A, Kanbay M, et al. Recommendations for the prevention, mitigation and containment of the emerging SARS-CoV-2 (COVID-19) pandemic in haemodialysis centres. Nephrol Dial Transplant.

2020;35:737-741. doi: 10.1093/ndt/gfaa069.

7. Li J, Xu G. Lessons from the experience in Wuhan to reduce risk of COVID-19 infection in patients undergoing long-term hemodialysis. Clin J Am Soc Nephrol. 2020;15:717-9. doi: 10.2215/CJN.03420320.

8. Hayden FG, Albrecht JK, Kaiser DL, Gwaltney JM Jr. Prevention of natural colds by contact prophylaxis with intranasal alpha 2-interferon. N Engl J Med. 1986;314:71-5.

9. Turner RB, Felton A, Kosak K, Kelsey DK, Meschievitz CK. Prevention of experimental coronavirus colds with intranasal α-2b interferon. J Inf Dis 1986;154:443-7.

10. Parkin J, Cohen B. An overview of the immune system. Lancet.

2001;357:1777-89.

11. Meng Z, Wang T, Chen L, Chen X, Li L, Qin X, et al. An experimental trial of recombinant human interferon alpha nasal drops to prevent coronavirus disease 2019 in medical staff in an epidemic area. medRxiv 2020.04.11.20061473; doi: 10.1101/2020.04.11.20061473 12. Ministry of Public Health. Cuban Protocol against COVID 19.

Available in: https://instituciones.sld.cu/facultadfinlayalbarran/ protocolo-cuba-vs-covid-4-4-2020. Accessed: 20 may 2020.

Recombinant human interferon alfa 2b 13. Wong HYF, Lam HYS, Fong AH, Leung ST, Chin TW, Lo CSY, et al. Frequency and Distribution of Chest Radiographic Findings in COVID-19 Positive Patients. Radiology. 2020;296(2):E72-8. doi: 10.1148/radiol.2020201160.

14. Peng QY, Wang XT, Zhang LN, Chinese Critical Care Ultrasound Study Group (CCUSG). Findings of lung ultrasonography of novel corona virus pneumonia during the 2019-2020 epidemic. Intensive Care Med. 2020;46(5):849850. doi: 10.1007/s00134-020-05996-6.

15. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.

16. Wang R, Liao C, He H, Hu C, Wei Z, Hong Z, et al. COVID-19

in hemodialysis patients: a report of 5 cases. Am J Kidney Dis. 2020 Mar 31: S0272-6386(20)30612-0. doi: 10.1053/j. ajkd.2020.03.009.

17. Yuan H, Guo E, Gao Z, Hu F, Lu L. Coronavirus Disease 2019 in a Hemodialysis Patient. Blood Purif 2020. doi: 10.1159/000507877 18. Douglas RM, Albrecht JK, Miles HB, Moore BW, Read R, Worswick DA, Woodward AJ. Intranasal interferon-alpha 2 prophylaxis of natural respiratory virus infection. J Infect Dis. 1985;151:731-6.

19. Turner RB, Felton A, Kosak K, Kelsey DK, Meschievitz CK. Prevention of Experimental Coronavirus Colds with Intranasal α-2b Interferon . J Infect Dis. 1986;154(3): 443-7.

Journal of Renal Endocrinology, Volume 7, 2021

7

Open Access

Original J Renal Endocrinol 2021;7:e06.

Journal of

Renal Endocrinology

http://www.jrenendo.com

Nickan

doi: 10.34172/jre.2021.06

Research Institute

Effects of combined ethanol extract of Funtumia africana and Abutilon mauritianum leaves on prostate biomarkers and serum mineral levels in prostatic hyperplasia induced male rats ID

Robert Ikechukwu Uroko1* , Fatima Amin Adamude2, Simeon Ikechukwu Egba2, Chinedu Paulinus Nwuke2, Chidimma Lilian Asadu3, Peter Anyaorah1 Abstract Introduction: Benign prostatic hyperplasia (BPH) is a prostate disorder in ageing males that negatively affects the quality of life and requires multidimensional approaches to ameliorate its adverse health effects.

Objectives: This study evaluated the effects of combined ethanol extract of Funtumia africana and Abutilon mauritianum leaves on the prostate biomarkers, serum mineral levels and prostate histomorphology of BPH induced rats.

Materials and Methods: Thirty-six male Wistar albino rats randomly distributed into 5 groups containing 6 rats each was used for this study.

Group 1 served as the normal control rats without BPH induction while groups 2–5 were BPH induced rats that served as BPH control (untreated), finasteride control, and BPH induced treated with 200 and 600 mg/kg/d of the combined ethanol extract of F. africana and A. mauritianum leaves respectively. BPH was induced in the rats by subcutaneous injection of 5 mg/kg/d of testosterone propionate injection and treatment followed 1h after the induction for 28 consecutive days. All the biochemical analyses and prostate histological examinations were carried out using standard methods.

Results: BPH induction significantly elevated serum prostatic acid phosphatase activities and serum prostate-specific antigen (PSA) concentrations in the BPH control rats relative to the normal control. The BPH induction caused significant (P<0.05) reductions in the serum levels of calcium and selenium levels and significantly increased the serum inorganic phosphate concentration in the BPH control when compared with the normal control. Treatment with the combined extract significantly (P<0.05) increased the serum zinc, calcium, copper, iron and inorganic phosphate and significantly reduced serum selenium level when compared with the BPH control. The combined extract further significant (P<0.0) reduced the serum prostatic acid phosphatase activities and PSA level relative to the BPH control. The BPH control showed severe prostate histomorphological alterations consistent with BPH which were largely reduced to mild alterations in combined extract-treated BPH induced rats.

Conclusion: This study revealed that the combined ethanol extract of F. africana and A. mauritianum leaves positively regulate the serum mineral levels, serum prostatic acid phosphatase activities, PSA levels and improves prostate histomorphology BPH induced rats.

Keywords: Benign prostatic hyperplasia, Serum minerals, Prostate-specific antigens, Prostatic acid phosphatase activity, Funtumia africana, Abutilon. mauritianum Citation: Ikechukwu Uroko R, Amin Adamude F, Ikechukwu Egba S, Paulinus Nwuke C, Lilian Asadu C, Anyaorah P. Effects of combined ethanol extract of Funtumia africana and Abutilon mauritianum leaves on prostate biomarkers and serum mineral levels in prostatic hyperplasia induced male rats. J Renal Endocrinol. 2021;7:e06. doi: 10.34172/jre.2021.06.

Copyright © 2021 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction Benign prostatic hyperplasia (BPH) is a neoplastic disease common in ageing men that have significantly reduced their quality of life and increased the risk of kidney failure in older men (1,2). It is associated with a progressive proliferation of prostatic epithelial and stromal tissues due to increased dihydrotestosterone stimulation that leads to prostate enlargement and lower urinary tract symptoms (3). Significant increase in the prostatic

acid phosphatase (PAP) activities and prostate-specific antigen (PSA) concentrations have been reported in BPH patients and are usually considered reliable markers of BPH progression (4). There are increasing pieces of evidence that increasing concentration and response to dihydrotestosterone stimulation with ageing are the major factors responsible for increased prostate cell growth and hyperplasia in ageing men (5). Medicinal plant extracts and synthetic drugs that prevent the conversion

Received: 9 July 2020, Accepted: 14 September 2020, ePublished: 8 October 2020 Department of Biochemistry, College of Natural Sciences, Michael Okpara University of Agriculture, Umudike, Abia State, Nigeria.

Department of Biochemistry, Faculty of Medical Sciences, Federal University Lafia, Nasarawa State, Nigeria. 3Department of Biochemistry, Faculty of Biological Sciences, University of Nigeria, Nsukka, Enugu State, Nigeria. *Corresponding Author: Robert Ikechukwu Uroko, Email: ir.uroko@mouau.edu.ng 1 2

Ikechukwu Uroko R et al

Implication for health policy/practice/research/ medical education The investigation of the effects of combined ethanol extract of Funtumia africana and Abutilon mauritianum leaves on the prostate biomarkers, serum mineral levels and prostate histomorphology of benign prostatic hyperplasia (BPH) induced rats indicated that BPH negatively alters the serum mineral levels in addition to prostate biomarker and histology if not treated. The combined ethanol extract of F. africana and A. mauritianum leaves ameliorates adverse effects of BPH by maintaining normal serum mineral levels, reductions of serum prostatic acid phosphatase activities and prostate-specific antigen (PSA) levels and prevents prostate enlargement. The findings of this study suggest that regular monitoring and maintenance of normal serum mineral levels could prevent progression of BPH and improves the health status of a BPH patient. Further efforts are required to identify, isolate and characterise the phytochemical constituents of ethanol extract of Funtumia africana and Abutilon mauritianum leaves respectively and their combined ethanol extract as this could help to maximise their anti-BPH therapeutic potentials.

of testosterone to dihydrotestosterone by inhibiting the action of 5α-reductase enzyme activity like finasteride could significantly reduce BPH progression and severity (6).

Abutilon mauritianum (Jacq.) Medi°k a member of Malvaceae family is commonly called African mallow or, country mallow is highly potent medicinal plant with antiproliferative properties and has demonstrated effectiveness in the management of gonorrhoea, diarrhoea, asthma, dysentery, malaria, inflammation and various bacterial infections (7). Further studies have shown its leaves possess hepatoprotective, hypoglycemic, immunomodulatory, diuretic, laxative, antinociceptive, antimicrobial, antimalarial, antifertility, and wound healing properties (8). These pharmacological activities exhibited by A. mauritianum leaves are attributed to its rich phytochemical constituents such as alkaloids, saponins, tannins, glycoside, and flavonoids (9,10).

Funtumia africana (Benth.) Stapf commonly called “false rubber tree” is a member of the Apocynaceae family that has shown to be rich in many pharmacological activities.

F. African leaves possess wide medicinal properties including antidiarrhoea, hepatoprotectives, antioxidative stress, dysentery, kidneys disorders and as diuretics (11,12).

Objectives The enormous medicinal properties of A. mauritianum and F. africana leaves have prompted us to evaluate the effects of their combined ethanol extract on the prostate biomarkers, serum mineral levels and prostate histomorphology of BPH induced rats. This could enable the formulation of a potent herbal drug for the management of BPH and improving the health outcome of BPH patients.

Materials and Methods Leaves of F. africana and A. mauritianum were used to 2

Journal of Renal Endocrinology, Volume 7, 2021

form combined ethanol extract used in this study. The F. africana and A. mauritianum leaves were obtained from the Forestry Research Institute of Nigeria, Eastern Station, Ahia-Eke Ndume, Umuahia, Abia State. The fresh leaves were properly identified and authenticated as F. africana and A. mauritianum with voucher numbers 2694-5 (Preuss 1899) and Jones FHI 13749 respectively by Dr Ibe K. Ndukwe, a Taxonomist at the Department of Forestry, College of Natural Resources and Environmental Management, Michael Okpara University of Agriculture, Umudike, Abia State Nigeria.

Chemicals and reagents The chemicals and reagents used in this study were of analytical grades and were sourced from Sigma Aldrich, USA; AMEKO Inc., China, and other chemical stores located at Nsukka, Enugu State, Nigeria.

Experimental animals Thirty male Wistar albino rats weighing 120–170 g were obtained from the Animal House, Department of Zoology and Environmental Sciences, Faculty of Biological Sciences, University of Nigeria Nsukka, Nigeria. The rats were subjected to the environmental condition for acclimatization with free access to a standard laboratory diet (Vital feed) and drinking water ad libitum and under a 12 h light/dark cycle for 14 days before the experimental study.

Formulation of a combined extract The combined ethanol extract was obtained by the ethanol extraction F. africana and A. mauritianum leaves in the combining ratio of 1:1 (i.e. 250 mg of coarsely ground sample each, equivalent to 500 g of both plant samples).

The combined plant extract (500 g) was macerated in 1.5 L of cold absolute ethanol for 72 hours and filtered. It was then concentrated in a water bath at 65°C to allow the ethanol solvent evaporate completely and the percentage yield calculated.

Experimental design The rats were induced BPH was by subcutaneous injection of testosterone propionate in olive oil (5 mg/kg body weight) for 28 days consecutively. The rats were distributed randomly into five groups containing 6 rats each. Group 1 was the normal control rats that were not BPH induced, and group 2 was BPH control that was BPH induced untreated. Group 3 was the standard control that was BPH induced but treated with 5 mg/kg/d of finasteride for 28 days while group 4 and 5 were BPH induced rats treated with 200 and 600 mg/kg of combined ethanol extract of F. africana and A. mauritianum leaves respectively.

Treatments were given to the rats 1 h after testosterone administration every day for 28 days consecutively. After the last administration of testosterone propionate and treatments on the 28th day, the rats fasted overnight. Blood

Funtumia africana and prostate

samples were withdrawn from the rats, prostate tissues, were collected on the 29th day for the biochemical analyses and histological examinations. The rats used in this study were carefully and humanely handled according to the guidelines stipulated by the National Institute of Health’s guidelines for the care and use of animals for research (13).

Biochemical analyses The serum PSA levels were determined according to the immunoenzymometric method using the PSA ELISA Kit and procedure outlined by the manufacturer. The serum prostatic acid phosphatase activities were assayed with the method described by Uotila et al (14).

Determinations of serum mineral levels The serum zinc level was determined according to the method of Johnsen and Eliasson (15). Serum calcium and magnesium concentrations were determined using the colourimetric method as described by Lorentz, and methods of Faulkner respectively (16,17). Additionally, the serum iron, inorganic phosphate, selenium and copper were determined according to the methods of Henry (18) and Ochei & Kolhatkar (19).

Ethical issues This experimental protocol was performed in line with the regulations of the Research Ethics Committee of Iranian Ethical Guidelines for the use of animals in research.

Additionally, all animal experiments were performed in accordance with protocols approved by the United States National Research Council (NRC, 1985). This study was also approved and supported by the Ethics Committee of Michael Okpara University of Agriculture, Umudike (MOUAU/VPP/EC/18/003).

Statistical analysis The data obtained were statistically analysed using a oneway analysis of variance (ANOVA) with the aid of Statistical Products and Service Solutions (SPSS) version 22. Means were compared using Duncan’s multiple comparison post hoc test (LSD) and results were presented as mean ± standard deviation (n = 6). Statistical significance were established at 95 % confidence level (P < 0.05).

Results The serum zinc levels in the rats showed that the BPH induction caused no significant (P > 0.05) decreases in the BPH control, and standard control and increases in the BPH induced rats treated with 200 and 600 mg/ kg/d of combined ethanol extract of F. africana and A. mauritianum leaves respectively relative to the normal control. However, treatment with the combined ethanol extract of F. africana and A. mauritianum leaves caused significant (P < 0.05) elevation of the serum zinc levels in the BPH induced rats treated with 200 and 600 mg/ kg/d of combined ethanol extract of F. africana and A. mauritianum leaves when compared with the BPH control (Table 1).

There were significant (P < 0.05) increases in the serum inorganic phosphate (Pi) levels in the BPH control and BPH induced rats treated with 200 and 600 mg/kg/d of combined ethanol extract of F. africana and A. mauritianum leaves and significant (P < 0.05) in the standard control, respectively when compared with the normal control. The standard control treated with 5 mg/ kg/d of finasteride showed significant (P < 0.05) decrease in serum Pi level relative to the BPH control. The BPH induced rats treated with 200 mg/kg/d of combined ethanol extract of F. africana and A. mauritianum leaves showed significant (P < 0.05) increase in the serum Pi level relative to the BPH control. However, the BPH induced rats treated with 600 mg/kg/d of the combined ethanol extract of F. africana and A. mauritianum leaves showed no significant (P > 0.05) increase in the serum Pi level when compared with the BPH control. All the combined extract-treated BPH induced rats showed significant (P < 0.05) increases in the serum Pi level relative to the standard control treated with finasteride (Table 1).

The serum iron (Fe) level in the BPH induced rats showed that the serum Fe level was not significantly (P>0.05) reduced in the BPH control and elevated in the standard control when compared with normal control. the serum Fe level in the BPH induced rats treated with 200 and 600 mg/kg/d of combined ethanol extract of F. africana and A. mauritianum leaves, respectively showed significant (P<0.05) when compared with the normal control. Also, the standard control, and BPH induced rats

Table 1. Serum mineral level of the benign prostatic hyperplasia induced rats treated with combined ethanol extract of F. africana and A. mauritianum leaves (CFAAML) Groups

Zinc (mg/dL)

Ca (mg/dL)

Mg (mg/dL)

Cu (mg/dL)

Sn (mg/dL)

Fe (mg/dL)

Pi (mg/dL)

Normal control

181.29±8.17a

41.83±1.71b

11.33±0.60a

0.40±0.02a

9.44±0.32b

38.333±3.61ab

2.13±0.54a

BPH control

160.47±7.99a

33.97±2.07a

11.80±0.61a

0.44±0.02ab

1.61±0.37a

33.90±2.55a

17.39±0.72d

Standard control

176.15±8.75a

30.20±1.40a

12.17±0.47a

0.43±0.01ab

4.99±0.28a

41.13±1.56b

2.45±0.43a

TP + 200 mg/kg of CFAAML

198.96±11.32b

42.90±2.06b

11.03±0.85a

0.43±0.02ab

6.90±0.15a

50.27±3.02c

9.30±0.89c

TP + 600 mg/kg of CFAAML

200.81±7.59b

34.10±2.09a

13.00±0.57a

0.47±0.01b

6.95±0.30a

85.83±3.57d

6.80±0.50b

CFAAML, combined ethanol extract of F. africana and A. mauritianum leaves.

Values are presented as mean ± standard deviation (n = 6) and values with different superscripts are statistically significant at P < 0.05.

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Ikechukwu Uroko R et al

Prostatic acid phosphatase activities (U/mg)

treated 200 and 600 mg/kg/d of combined ethanol extract of F. africana and A. mauritianum leaves when compared with BPH control. However, the serum Fe levels in all the extract-treated BPH induced rats were significantly (P < 0.05) higher than the standard control treated with finasteride (Table 1).

In Table 1, it was observed that the BPH control, standard control treated with finasteride and BPH induced rats treated with 200 mg/kg/d of combined ethanol extract of F. africana and A. mauritianum leaves showed significant (P < 0.05) decreases in the serum calcium (Ca) level when compared with normal control. All the BPH induced rats treated with 200 and 600 mg/kg/d of combined ethanol extract of F. africana and A. mauritianum leaves showed significant (P < 0.05) increase in the serum Ca level relative to the BPH control, unlike the standard control that showed no significant (P > 0.05) decrease.

The serum magnesium (Mg) levels in the BPH induced rats treated with combined ethanol extract of F. africana and A. mauritianum leaves showed no significant (P > 0.05) increases in the BPH control and standard control when compared with the normal control. Similarly, the BPH induced rats treated with 600 mg/kg/d of combined ethanol extract of F. africana and A. mauritianum leaves when compared with the normal control. However, the BPH induced rats treated with 200 mg/kg/d of combined ethanol extract of F. africana and A. mauritianum leaves showed no significant (P > 0.05) decrease in the serum level relative to the normal control (Table 1).

The serum copper (Cu) levels in Table 1 show the BPH induced rats had no significant (P > 0.05) increases in the serum Cu levels in the BPH control, standard control and BPH induced rats treated with 200 mg/kg/d of combined ethanol extract of F. africana and A. mauritianum leaves when the normal control. The BPH induced rats treated with 600 mg/kg/d of combined ethanol extract of F. africana and A. mauritianum leaves showed significant (P < 0.05) in the serum Cu level relative to the normal control.

c

6.0 5.0 4.0

The serum selenium (Sn) level in the BPH induced rats showed that there were significant (P < 0.05) decreases in the serum Sn levels in the BPH control and standard control relative to the normal control. Also, the BPH induced rats treated with 200 and 600 mg/ kg/d of the combined ethanol extract of F. africana and A. mauritianum leaves when compared with the normal control. However, the standard control and BPH induced rats treated with graded doses of combined ethanol extract of F. africana and A. mauritianum leaves respectively showed no significant (P > 0.05) increases in the serum Sn levels when compared with the BPH control.

The serum acid phosphatase activities of the BPH induced rats in Figure 1 indicated significant (P < 0.05) increases in the acid phosphatase activities of the BPH control, and the BPH induced rats treated with the combined ethanol extract of F. africana and A. mauritianum leaves, respectively relative to the normal control. However, the standard control induced BPH and treated with 5 mg/kg/d of finasteride showed no significant (P > 0.05) increase in the acid phosphatase activity when compared with the normal control. The serum acid phosphatase activities in the standard control and all the extract-treated BPH induced rats showed significant (P < 0.05) reductions in the serum acid phosphatase activities relative to the BPH control.

The PSA concentrations in the BPH induced in Figure 2 showed that the PSA level of the BPH control, standard control, and BPH induced rats treated with 200 and 600 mg/kg/d of the combined ethanol extract of F. africana and A. mauritianum leaves respectively significantly (P < 0.05) increased relative to the normal control. It was also observed that there was significant (P < 0.05) decrease in the PSA level of the standard control and the BPH induced rats treated with 200 and 600 mg/kg/d of the combined ethanol extract when compared with the BPH control.

The section of prostate gland from the normal control rats showed the normal histomorphology of the rodent

ab a

b

b

3.0 2.0 1.0 0.0

Normal Control

BPH Control

Standard Control TP + 200 mg/kg/day TP + 600 mg/kg/day CFAAML CFAAML

Treatment Groups

Figure 1. Acid phosphatase activities of BPH induced rats treated with combined ethanol extract of F. africana and A. mauritianum leaves (CFAAML). Each bar represent mean ± standard deviation (n = 6). Bars with different superscripts are significantly different (P < 005). TP = testosterone propionate.

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Funtumia africana and prostate 6.0

c

Mean PSA level (ng/dL)

5.0 4.0 3.0

b

b

ab

Standard Control

TP + 200 mg/kg/day CFAAML

TP + 600 mg/kg/day CFAAML

a

2.0 1.0

0.0

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BPH Control

Treatment Groups Figure 2. Prostate-specific antigen concentrations of BPH induced rats treated with combined ethanol extract of F. africana and A. mauritianum leaves (CFAAML).

prostate gland (Figure 3A). The prostate section showed mostly normal prostatic acini (A) of varying sizes, lined by simple cuboidal to low columnar epithelial cells with basally located heterochromatic nuclei surrounded by thin fibromuscular stroma (S). The acini contained varying amounts of acidophilic intra-luminal secretions and a few epithelial infoldings (arrow) were observed.

The prostate gland from the BPH (BPH control) induced untreated showed histomorphological alterations consistent with benign prostate hyperplasia (Figure 3B).

There was an obvious increase in height of the mostly columnar epithelia with marked multiple infolding (black arrow) and sloughing (white arrow) of the acinar epithelium. Focal areas of intraepithelial stratification with preserved basement membrane and atypical cells with loss of polarity and euchromatic nuclei were frequently observed (red arrowhead). The fibromuscular stroma surrounding the prostatic acini were variably thickened (blue arrow).

Sections of the prostate gland from the standard control rats induced BPH and treated with finasteride indicated a heterogenous histomorphology with normal acini co-localizing with altered ones (Figure 3C). Multiple acini with epithelial infolding as well as multiple foci of intraepithelial stratification were observed. However, these alterations were most evident on the peripheral acini while the more central acini appeared normal. Normal acini containing acidophilic secretions (A); Intraepithelial stratification (arrow).

The prostate gland obtained from the benign prostatic induced rats treated with 200 mg/kg/d of combined ethanol extract of F. africana and A. mauritianum leaves (CFAAML) indicated an almost homogenous histomorphological alteration, consistent with benign prostatic hypoplasia (Figure 3D). It showed a few relatively normal central acini and obvious increase in the number and height of acinar epithelial cells, with numerous infolding of the epithelium (black arrow), intraepithelial stratifications (white arrow) and formation

cribriform growths in some of the acini (red arrow).

Variable thickening of the fibromuscular stroma (S) was also observed.

The sections of the prostate gland from benign prostatic induced rats treated with 600 mg/kg/d of CFAAML showed an almost homogenous histomorphological alteration, consistent with benign prostatic hypoplasia (Figure 3E).

There was an obvious increase in the number and height of acinar epithelial cells, with numerous infolding of the epithelium and intraepithelial stratifications (white arrow).

Discussion This study investigated the effects of CFAAML on the prostate biomarkers and serum mineral levels in prostatic hyperplasia (BPH) induced rats. BPH occurs in ageing males because of accelerated differentiation and proliferation of prostate epithelial and stromal tissues due to increased stimulatory effects of dihydrotestosterone generated from the metabolism of excess testosterone in the prostate gland while the small concentration of it can be found men with healthy prostate (20). In this study, testosterone propionate injection was used for the induction of BPH by the subcutaneous injection of 5 mg/ kg/d of it for 28 days.

The reductions in the serum zinc levels in the BPH control rats can be attributed to the effects of induction of BPH with testosterone propionate on serum zinc level and suggests that reductions in the serum zinc levels could increase the development and progression of BPH which could adversely impair the health outcome of BPH patients. The BPH induced rats treated with 200 and 600 mg/kg/d of the combine ethanol extract of F. africana and A. mauritianum leaves caused significant elevation of serum zinc levels which indicated that the combined extract effectively reversed the adverse effects of BPH on the serum zinc level. It showed that the combined ethanol extract could be rich in zinc content that replenished the inadequate zinc level in the BPH control and may prevent Journal of Renal Endocrinology, Volume 7, 2021

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B

D

E

C

Figure 3. (A) Histomorphology of prostate gland from the normal control rats that were not induced benign prostatic hyperplasia. (B) Histomorphology of prostate gland from the benign prostatic hyperplasia induced untreated rats (BPH control). (C) Histomorphology of prostate gland from the benign prostatic hyperplasia induced rats treated with 5 mg/kg/d of finasteride (standard drug). (D) Histomorphology of prostate s from benign prostatic hyperplasia induced rats treated with 200 mg/kg/d of CFAAML. (E) Histomorphology of prostate gland from the benign prostatic hyperplasia induced rats treated with 600 mg/kg/d of CFAAML.

zinc deficiency in BPH patients treated with the extract.

The significant reductions in the serum calcium level in the BPH induced rats indicated that the rats suffered impaired intestinal and kidney calcium reabsorption which could induce increased neuromuscular excitation in the patients with BPH. It has been reported that kidney failure, vitamin deficiency, low magnesium level and decreased thyroid functions are the major causes of low serum calcium level. The serum phosphorus level regulates the concentration of serum calcium. A reduction in the serum phosphate level will lead to an increase in the serum calcium level and vice versa (21). Low serum level can be manifest impaired blood coagulation, intestinal malabsorption, and defective bone mineralization and in extreme case may lead to convulsive seizures, and cardiovascular disorders (21,22). The increase in the serum calcium level in the BPH induced rats treated with the combined ethanol extract of F. africana and A. mauritianum leaves suggests that the extract contains a high level of calcium that replenished serum lost due to poor intestinal and kidney reabsorption of calcium. The extract could also have increased the ability of the proximal kidney tubule to reabsorb calcium and decreased its loss via urinary excretion and this could be responsible for the high serum calcium level in the BPH induced rats treated with a lower dose of the combined extract and prevents the rats from any possible adverse effects of calcium deficiency.

The serum magnesium level is primarily regulated by its rate of excretion in the urine by the kidneys and when there is a failure of the proximal tubule to reabsorb enough magnesium low serum level results (23). Low blood magnesium level could cause loss of appetite, nausea, vomiting, fatigue and weakness, and the condition progresses, the patient may experience tremor, depression, numbness, tingling, muscle contractions, cramps, and seizures (24). The no significant differences 6

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observed in the serum magnesium levels in the BPH induced rats treated with combined ethanol extract of F. africana and A. mauritianum leaves relative to the normal and positive controls, respectively showed that the combined extract and BPH have no adverse effects on the serum magnesium levels. The combined extract may not contain a sufficient amount of magnesium that could have significantly elevated the serum magnesium level in the BPH induced rats and thus has similar effects on serum magnesium level like finasteride. The normal serum magnesium level observed in the BPH induced rats would ensure that the functions of Mg which is to serve as a cofactor for some enzymes involved in carbohydrate breakdown and protein synthesis including regulation of blood pressure, transport of potassium and calcium across cell membrane and maintenance of glutathione structure are effectively carried out (25).

The elevated serum copper level in the BPH control and BPH induced rats treated with finasteride and combined ethanol extract of F. africana and A. mauritianum leaves respectively could be one the defence mechanisms adopted by the body to withstand the adverse effects of BPH in the rats. Copper together with zinc and glutathione containing antioxidant enzymes including superoxide dismutase and catalase play key catalytic roles in the conversion of reactive free radicals such as reactive oxygen species (ROS) and hydrogen peroxide (H2O2) into harmless products in the body (26,27). It has been reported that the increase in the estrogen level like estradiol implicated in the pathogenesis of BPH and also increases the serum and plasma copper level besides dietary intake of food rich in copper. The elevated serum copper level in the BPH induced treated with a high dose of the combined ethanol extract suggest that the extract contributed partly to the increased copper level in the rats.

Selenium is a trace element and a component of most antioxidant enzymes including glutathione peroxidase

Funtumia africana and prostate

that ameliorate oxidative stress via scavenging of free radicals such as reactive oxygen species and hydrogen peroxide thereby detoxifying them into harmless products and prevents lipid peroxidation and oxidative damage to critical biomolecules (28,29). The significantly reduced serum selenium level in the BPH control relative to the normal control suggests that lower serum selenium level promotes development and progression of BPH. The elevated serum selenium concentrations in the BPH induced rats treated with finasteride and combined ethanol extract of F. africana and A. mauritianum leaves, respectively relative to the BPH control are indicative that selenium plays a key therapeutic role in ameliorating the adverse effects of BPH. The selenium could have exerted its therapeutic effect by stimulating glutathione and antioxidant enzymes activities to reduce oxidative stress which is in agreement with findings of Mohamed et al, that increased antioxidant activities reduce progression and health burdens of BPH (30).

Iron (Fe) is a key element required in small quantity in the body for the synthesis of haemoglobin needed for transportation of oxygen in the body and diminished blood level could lead to anaemia while its excess blood level could trigger iron toxicity and induction of oxidative stress due to Fenton reactions (31). Moreover, poor nutrition, parasitic infections like malaria that destroy red blood cells, and inflammatory diseases such as BPH could lead to iron deficiency (32). The significantly reduced serum iron level in the BPH control relative to the normal control indicated that the BPH induced rats suffered a loss of iron which could have impaired haemoglobin synthesis and transport of oxygen in the body. The decrease in the serum iron level would have had additional adverse health effects on the BPH induced rats and thus suggests that BPH patients should receive iron supplementation to prevent iron deficiency and improve their quality of life. However, the significantly elevated serum iron levels in the BPH induced rats treated with finasteride and the combined ethanol extract, respectively showed that maintenance of normal serum iron level is critical to slowing the growth and proliferation of prostate epithelial and stromal cells involved in BPH progression. The combined ethanol extract could have prevented the loss of iron possibly from destruction red blood cells. The extract may be highly rich in iron content that replenished the lost iron as demonstrated by its dose-dependent effects on the BPH induced rats. Besides the therapeutic effects of the combined ethanol extract of F. africana and A. mauritianum leaves, its excessive consumption should be avoided to prevent iron overdose and its attendant adverse health effects(32-34).

The significantly elevated serum level of inorganic phosphate (Pi) in the BPH control could be attributed to the effect of the BPH on the kidney functions that decreased its ability to excrete sufficient amount of phosphate from the body. The kidney proximal tubule in

the BPH control could have reabsorbed a large amount of phosphate which reduced the serum calcium level the BPH induced rats in this study in line with findings of Slatopolsky (33). However, the significantly reduced serum phosphate levels in the BPH induced rats treated with the combined ethanol extract of F. africana and A. mauritianum leaves relative to the BPH control showed that the combined extract possesses lower regulatory effects on the serum phosphate level as it could protect the BPH induced rats from hyperphosphatemia. Finasteride had better effects in regulating the serum phosphate level as seen in the standard control than the combined extract as it could have maintained a normal level of circulating parathyroid hormones implicated in hyperphosphatemia in addition to the stimulation of the kidney to excrete enough phosphate from the body (30-34).

The significantly elevated serum prostatic acid phosphatase activities in the BPH control and BPH induced rats treated with combined ethanol extract of F. africana and A. mauritianum leaves indicated prostate hyperplasia that stimulated increased secretion of prostatic acid phosphatase into the blood and this agrees with the findings of Mohamed et al (30). The combined ethanol extract of F. africana and A. mauritianum leaves treated BPH induced rats showed dose-dependent reductions in the prostatic acid phosphatase activities relative to the BPH control and could be attributed to the therapeutic effects of the combined ethanol extract on BPH which prevented increased growth of prostate cells and secretion of prostatic acid phosphatase. The reductions in the prostatic acid phosphatase activities in the combined ethanol extract of F. africana and A. mauritianum leaves treated BPH induced rats is in agreement with the findings of Ejike and Ezeanyika; and Ezugwu et al, that reductions in prostate volume significantly reduces prostatic acid phosphatase secretion and activities and indicated recovery from BPH (4,34).

The PSA is generally considered a reliably selective marker of BPH and prostate cancer as the expression of PSA significantly increases under this conditions and besides PSA could increase under high prostate activity (35). It is also known as gamma-seminoprotein which is secreted by the prostate epithelial cells and its increases in the serum concentration and activities in BPH is due to the increased number of prostate epithelial cells that increases its secretions. The significantly elevated PSA level in the BPH control relative to the normal control indicated an increased number of prostate epithelial cells and prostate volume due to effects of testosterone propionate injection and resultant increased PSA secretions by the epithelial cells. The significant reductions in the PSA level of the BPH induced rats treated with the combined ethanol extract of F. africana and A. mauritianum leaves relative to the BPH control could be attributed to the anti-BPH activities of the combined extract that caused the reductions in the number of the prostate epithelial cells and decreased the Journal of Renal Endocrinology, Volume 7, 2021

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PSA secretions. The combined extract lowered the serum PSA level in a dose-dependent manner and suggested that a high dose of the combined ethanol extract of F. africana and A. mauritianum leaves possess therapeutic effects than a lower dose of it. This is in agreement with findings of Iweala and Ogidigbo that plant extract that reduces PSA level and improve prostate histomorphology of BPH induced rats possesses anti-BPH activity that prevents the development and progression of BPH (5).

The prostate histomorphology of the BPH control and BPH induced rats treated with the combined ethanol extract of F. africana and A. mauritianum leaves were consistent with the serum mineral levels, serum prostatic acid phosphatase activities and serum PSA level obtained in this study. The BPH induced rats treated with combined ethanol extract had significantly reduced number and height of acinar epithelial cells and improved prostate histomorphology relative to the BPH control which suggests therapeutic effects of the combined ethanol extract against BPH which is line with findings of Iweala and Ogidigbo (5).

Conclusion The findings of this study indicated that the combined ethanol extract of F. africana and A. mauritianum leaves restores normal serum prostatic acid phosphatase activities and serum PSA levels and improves prostate histomorphology of BPH induced rat. Thus, the combined ethanol extract of F. africana and A. mauritianum leaves possesses anti-BPH activity and further research should be conducted on it to identify its bioactive constituents and mechanism of action.

Authors’ contribution URI, AFA and ESI were the principal investigators of the study. URI, AFA, ESI, ACL and AP were included in preparing the concept and design. NCP, URI, AFA and ESI revised the manuscript and critically evaluated the intellectual contents. All authors have read and approved the content of the manuscript and confirmed the accuracy or integrity of any part of the work. .

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Conflicts of interest The authors declared no conflict of interests.

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Ethical considerations Ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the authors.

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Funding/Support There was no external funding or support for this study as all the resources used were provided by the authors.

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Ejike CE, Ezeanyika LU. Inhibition of the experimental induction of benign prostatic hyperplasia: a possible role for fluted pumpkin (Telfairia occidentalis Hook f.) seeds. Urol Int. 2011;87(2):218-24. doi: 10.1159/000327018.

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Open Access Journal of

Renal Endocrinology

Original J Renal Endocrinol 2021;7:e07. http://www.jrenendo.com

Nickan

doi: 10.34172/jre.2021.07

Research Institute

Impact of timing of initiation of dialysis on mortality of patients with acute kidney injury ID

ID

ID

Reginaldo Passoni dos Santos1,2* , Letícia Giroldo Vieira3 , Danielle Fernanda Miner de Oliveira3 , Raissa Fritz ID ID ID ID Schmitt3 , Vinicius Ferreira de Barros3 , Ariana Rodrigues da Silva Carvalho2,4 , Luis Alberto Batista Peres2,5 Abstract Introduction: In Brazil, primary studies on this issue are still limited and the ideal timing of initiation of dialysis in severe acute kidney injury (AKI) still generates disagreements among experts.

Objectives: To assess if the timing of initiation of dialysis is associated with the mortality of patients with AKI in intensive care unit (ICU).

Patients and Methods: We retrospectively analyzed medical records of patients that developed severe AKI in the ICU. Bivariate analysis was carried out to compare data between groups of patients who underwent early dialysis (ED - initiated up to two days after the AKI diagnosis) and late dialysis (LD – initiated more than two days after the AKI diagnosis), while multivariate logistic regression was applied to identify factors associated with mortality.

Results: Of the 76 patients included in the study, 27 (35.5%) were allocated in the ED group and 49 (64.5%) in the LD group. LD group had a higher frequency of sepsis [26 (53%) vs. 12 (44%); P = 0.472], while the ED group had a higher median number of dialysis sessions (6 vs. 3; P = 0.477) and higher total median time on dialysis (17.5 h vs. 13 h; P = 0.629). The overall mortality rate was 61.8% (n = 47) and of 76% (n = 22) in the ED group. The patients’ serum creatinine level at admission in the ICU was the only statistically significant risk factor for death [OR= 0.453 (95% CI= 0.257–0.801); P = 0.006].

Conclusion: The overall and in the ED group mortality rate was elevated, however, the timing of initiation of dialysis did not show statistically significant association with death. The serum creatinine at ICU admission seems to be an important mortality predictor.

Keywords: Acute kidney injury, Renal replacement therapy, Mortality, Dialysis, Risk factors, Intensive care unit Citation: Passoni dos Santos R, Giroldo Vieira L, Fernanda Miner de Oliveira D, Fritz Schmitt R, Ferreira de Barros V, Rodrigues da Silva Carvalho A, Alberto Batista Peres L. Impact of timing of initiation of dialysis on mortality of patients with acute kidney injury. J Renal Endocrinol. 2021;7:e07. doi: 10.34172/jre.2021.07.

Copyright © 2021 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction The dialysis therapy is one of the main management strategies for patients with acute kidney injury (AKI) in intensive care unit (ICU) (1-5). Studies suggest that early initiation of dialysis in these patients reduces adverse renal events and prevents metabolic complications (1,2).

On other hand, late initiation appears to be an option with some benefit when assessing the possibility of recovery of renal function after AKI without the need for complex, potentially dangerous, costly treatment with limited availability in developing countries (3,4).

Given the impact on patients’ prognosis and clinical outcomes, the decision on when to start dialysis in patients with severe AKI is crucial (1,5). In 2016, Gaudry et al (6), at France, and Zarbock et al (7), at Germany published data from two studies on the impact of timing of early dialysis (ED) initiation on the mortality of critical ill AKI patients. In this same sense, Brazilian researchers

conducting a systematic review, concluding that the early initiation of dialysis does not attribute greater survival to patients with severe AKI (8).

Objectives Notwithstanding, despite the valuable contributions added to the literature, in Brazil, primary studies on this issue are still limited and the ideal timing of initiation of dialysis in severe AKI still generates disagreements among experts. Like this, remains without an established consensus. Therefore, this study aimed to asses if the timing of initiation of dialysis is associated with the mortality of patients with AKI in ICU. Patients and Methods Study design The study protocol was previously approved by the research ethics committee of the Western State University

Received: 19 August 2020, Accepted: 20 September 2020, ePublished: 13 October 2020 Department of Nursing, Teaching Hospital, Western Paraná State University, Cascavel, PR, Brazil. 2Postgraduate Program in Biosciences and Health, Western Paraná State University, Cascavel, PR, Brazil. 3Undergraduate Course in Medicine, FAG University Center, Cascavel, PR, Brazil. 4Collegiate of Nursing, Western Paraná State University, Cascavel, PR, Brazil. 5Discipline of Nephrology, Undergraduate Course in Medicine, Western Paraná State University, Cascavel, PR, Brazil. *Corresponding Author: Reginaldo Passoni dos Santos, Email: regi-pas@hotmail.com 1

Passoni dos Santos R et al

Implication for health policy/practice/research/ medical education The timing of initiation of dialysis is one of the main dilemmas of clinical practice and, in this study, did not show statistically significant association with death. On the other hand, the serum creatinine level, presented by patients at the time of ICU admission, was shown to be a risk factor independently associated with death. However, more Brazilian studies need to be conducted and with a more appropriate methodological design, in order to verify the real impact of the moment of dialysis on the mortality of patients in our country.

Parana. The recommendations of STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) (9) guidelines were flowed.

Design, setting and participants We carried out a retrospective study, through the review of medical records of patients with severe AKI, hospitalized between January 2011 and December 2016, in the mixed ICU of a university hospital located in the Brazil’s Southern region. Our ICU consists of 14 beds to hospitalization of critically ill patients with clinical and surgical conditions.

For inclusion on study, were selected medical records of patients with 18 years or older, with a minimum stay in the unit of 48 hours and, who undergoing dialysis due to occurrence of severe AKI in the ICU, carried out by kidney disease improving global outcomes (KDIGO) criteria (10). The records were separated in two groups, according to the patients’ timing of initiation of dialysis.

Patients with initiation of dialysis within two days after AKI diagnosis were allocated in the ED group, while patients with initiation of dialysis more than two days after the AKI diagnosis were allocated in the late dialysis (LD) group.

Variables and outcome The data were retrieved in February 2018, using a semistructured form prepared by the authors. Information were collected regarding to socio-demographic (gender; age; race; comorbidities), admission data (previous unit; diagnosis clinical or surgical; elective or emergency admission; serum creatinine; urine output in the first 24 hours and mechanical ventilation at admission); acute physiology and chronic health evaluation II (APACHE II) (11) and sequential organ failure assessment (SOFA) (12) scores, as well as length of ICU stay also were retrieved.

In addition, we collected information about events that occurred in the ICU (days on mechanical ventilation; infection and sepsis occurrence; blood transfusions and need for surgical procedures) and data from dialysis (number of sessions; total time of dialysis in hours; intradialytic intercurrences and need of interruption).

Mortality rate was the outcome of interest and, the risk 2

Journal of Renal Endocrinology, Volume 7, 2021

factors for mortality were identified.

Ethical issues The research followed the tenets of the Declaration of Helsinki. The Ethics Committee of Western Paraná State University approved this study. The institutional ethical committee at Western Paraná State University approved all study protocols (Approval number#1.622.962).

Accordingly, written informed consent was taken from all participants before any intervention. This study was extracted from MSc thesis of Postgraduate Program in Biosciences and Health at this university (Thesis “Acute kidney injury in intensive care unit; a longitudinal study”).

Statistical analysis The data were tabulated in a Microsoft Excel® spreadsheet and analyzed using XLSTAT software, version 2018. After analyzing the assumptions normality (Shapiro-Wilk test) and homoscedasticity (F test), continuous variables were expressed by the mean and standard derivation or median and inter-quartile range, while categorical variables were presented by the gross (n) and relative (%) frequencies.

The crude mortality rate was calculated and according to timing of initiation of dialysis. We compared the data between ED and LD groups, as well as between survivors and non-survivors applying the chi-square and/or Fisher’s exact tests to the categorical variables and the student’s t test or Mann-Whitney U test to the continuous variables, as appropriate.

Variables that in the bivariate analysis had a P value <0.20 were included in the multivariate logistic regression model, to analyze the risk factors independently associated with death and the variables in the final multivariate model were selected using the stepwise method. To avoid selection bias, variables with an inflation factor of variance greater the five were excluded from the final model, which had its performance evaluated by the Hosmer–Lemeshow test and the area under the receiver operation characteristic curve. In all tests, P value <0.05 was considered statistically significant.

Results During the study period, 613 patients were diagnosed with AKI in the ICU, of whom 238 (38.8%) had severe AKI and, of these, the 76 (31.9%) undergoing dialysis were included in the present study. All patients (100%) undergoing intermittent hemodialysis and were allocated to the ED (n = 27; 35.5%) and LD (n = 49; 64.5%). The median age of the patients was 52 (43 – 62) years and the majority were male (n = 42; 55%) and Caucasian (n = 66; 87%).

Urine output in the first 24 hours of admission to the ICU was lower in the ED group (350 mL vs. 1600 mL; P ≤ 0.001), while the median of SOFA score was lower in the LD group (11 points vs. 13 points; P = 0.019). LD group needed more time on mechanical ventilation (15 days vs.

Mortality in AKI

13 days; P = 0.377), and a higher frequency of sepsis [26 (53%) vs. 12 (44%); P = 0.472]. Regarding the dialysis data, it was verified that the ED group had a higher median number of dialysis sessions (6 vs. 3; P = 0.477) and higher total median time on dialysis (17.5 h vs. 13 h; P = 0.629).

The need to interrupt the dialysis session was similar in both groups [24 (49%) to ED group vs. 13 (48%) to LD group; P = 0.996) (Table 1).

The overall mortality rate was 61.8% (n= 47) and of 76% (n= 22) in the ED group. In the bivariate analysis, survivors patients had higher serum creatinine levels (2.16 mg/dL vs. 1.68 mg/dL; P = 0.038), higher frequency of infection [24 (83%) vs. 25 (53%); P = 0.009], longer ICU stay (28 days vs. 17 days; P = 0.006) and, required more dialysis sessions (7 vs. 3; P = 0.034) (Table 2). By multivariate logistic regression, we verified that the patients’ serum creatinine level at admission in the ICU was the only statistically significant risk factor for death in

the studied sample (Table 3).

Discussion This retrospective and single-center study presented the general features of a sample of patients with severe AKI in the ICU and evaluated the impact of timing of initiation of dialysis on the mortality of patients. With regards to the clinical-epidemiological profile of the patients, there was some homogeneity between the ED and LD groups, with no statistically significant differences for most variables (Table 1). Still this, we found that patients in the LD group had lower serum creatinine levels at ICU admission and greater urine output in the first 24 hours. Considering that such variables make up the KDIGO (10) criteria, possibly, besides LD, characterized by initiation two days after AKI diagnosis, we believe, empirically, that the AKI diagnosis itself, in patients of LD group, also occurred later, compared to the patients in the ED group.

Table 1. Features of patients, according with the timing of initiation of dialysis All (n = 76)

ED (n= 27)

LD ( n= 49)

P

42 (55%)

15 (56%)

27 (55%)

0.970a

52 (43–62)

54 (40–63)

50 (43–60)

0.769b

Race (Caucasian)

66 (87%)

24 (89%)

42 (86%)

0.695a

Hypertension

28 (37%)

11 (41%)

17 (35%)

0.601a

Diabetes mellitus

18 (24%)

3 (11%)

15 (31%)

0.056a

Variables Gender (male) Age

Source unit

0.624c

Emergency room

51 (67%)

20 (74%)

31 (64%)

Surgical center

16 (21%)

4 (15%)

12 (24%)

Ward

9 (12%)

3 (11%)

6 (12%)

Admission diagnosis

0.374a

Clinical

37 (49%)

15 (56%)

22 (45%)

Surgical

39 (51%)

12 (44%)

27 (55%)

Admission type

0.434a

Elective

21 (28%)

6 (22%)

Urgency

55 (72%)

21 (78%)

34 (69%)

1.9 (1.1–2.5)

2.1 (1.4–3.2)

1.8 (1.1–2.3)

0.068b

Urine output at first 24 hours

1212 (326–2225)

350 (137–1190)

1600 (680–2400)

<0.001b

Mechanical ventilation need

68 (89%)

24 (89%)

44 (90%)

0.902a

Mechanical ventilation time (days)

14 (8–26)

13 (6–29,5)

15 (9–26)

0.397b

Infection

49 (64%)

14 (52%)

35 (71%)

0.088a

Sepsis

38 (50%)

12 (44%)

26 (53%)

0.472a

Blood transfusion

56 (74%)

17 (63%)

39 (80%)

0.115a

Surgery

50 (66%)

15 (56%)

35 (71%)

0.163a

Serum creatinine (mg/dL) at ICU admission

15 (31%)

Data from dialysis Number of sessions

4 (2–10)

6 (2–10)

3 (2–9)

0.487b

13.5 (6–29.3)

17.5 (6.5–30.5)

13 (6–28)

0.629b

3 (2–4)

2 (1–4)

3 (2–4)

0.945b

37 (49%)

13 (48%)

24 (49%)

0.996a

APACHE II

31 (26–34)

32 (29–35)

29 (25–33)

0.075b

SOFA

12 (10–14)

13 (10–15)

11 (9–13)

0.019b

Length ICU stay

21 (11–36)

18 (6.5–36)

25 (14–36)

0.193b

Total time (h) Intradialytic complications Need of interruption

ED: Early Dialysis; LD: Late dialysis; APACHE II: Acute Physiology and Chronic Health Evaluation II; SOFA: Sequential Organ Failure Assessment; ICU: Intensive Care Unit; Note: a Chi-square test; b Mann-Whitney test; c Fisher’s exact test.

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3

Passoni dos Santos R et al Table 2. Features of patients, according with the mortality Survivor (n= 29)

Non-survivor ( n= 47)

P

14 (48%)

28 (60%)

0.336a

48 (43–62)

54 (42–61)

0.653b

Race (Caucasian)

26 (90%)

40 (85%)

0.569a

Hypertension

12 (41%)

16 (34%)

0.520a

Diabetes mellitus

11 (38%)

7 (15%)

0.022a

20 (69%)

31 (66%)

Surgical center

6 (21%)

10 (21%)

Ward

3 (10%)

6 (13%)

Variables Gender (male) Age

Source unit

1.000c

Emergency room

Admission diagnosis

0.677a

Clinical

15 (52%)

22 (47%)

Surgical

14 (48%)

25 (53%)

6 (21%)

15 (32%)

Admission type

0.288a

Elective Urgency

23 (79%)

32 (68)

2.16 (1.45–3.39)

1.68 (0.99–2.29)

0.038b

Urine output at first 24 hours

1.275 (300–1.755)

1.150 (337–2.300)

0.646b

Mechanical ventilation need

26 (90%)

42 (89)

0.968a

17 (11–26)

13 (7–27)

0.248b

Infection

24 (83%)

25 (53%)

0.009a

Sepsis

13 (45%)

25 (53%)

0.479a

Blood transfusion

21 (72%)

35 (74%)

0.843a

Surgery

21 (72%)

29 (62%)

0.339a

Serum creatinine (mg/dL) at ICU admission

Mechanical ventilation time (days)

Data from dialysis Number of sessions

7 (2–11)

3 (1–7)

0.034b

Total time (hours)

21 (7–36)

12 (4–24)

0.100b

Intradialytic complications

8 (28%)

29 (62%)

0.339a

Need of interruption

11 (38%)

26 (55%)

0.141a

7 (23%)

22 (76%)

Timing of initiation of dialysis ED LD

0.103a 20 (43%)

27 (57%)

APACHE II

32 (27–36)

30 (25–33)

0.167b

SOFA

12 (10–14)

11 (10–13)

0.471b

Length ICU stay

28 (19–37)

17 (8–28)

0.006b

ED: Early Dialysis; LD: Late dialysis; APACHE II: Acute Physiology and Chronic Health Evaluation II; SOFA: Sequential Organ Failure Assessment; ICU: Intensive Care Unit; Note: a Chi-square test; b Mann-Whitney test; c Fisher’s exact test.

Regarding the overall mortality, we verified that it was 61.8%, showing itself to be higher than that observed in two large European studies (6,7) and similar to that identified in another Brazilian research (13). However, in this study, no statistically significant association was found between the timing of initiation of dialysis and death (Table 2).

The criteria established for grouping patients may be one of the factors that influenced this result. The existence of several criteria for the definition of “early” and “late” promotes great methodological heterogeneity among the studied that evaluate the impact of timing of initiation of dialysis on the different outcomes of interest, hindering the in-depth analytical comparison among publications (8).

In the multicenter randomized clinical trial (RCT) Artificial Kidney Initiation in Kidney Injury, Gaudry et al (6) defined as ED that occurred within six hours after diagnosis of stage three AKI by the KDIGO criteria, whereas the diagnosis of LD considered the urinary 4

Journal of Renal Endocrinology, Volume 7, 2021

volume, serum level of urea and potassium, pH or occurrence of pulmonary edema. The sample consisted of 619 patients, hospitalized in 31 ICUs in different countries.

The death rate of patients in the ED group was 48.5%, slightly lower than that presented by patients in the LD group, 49.7% (P = 0.79). It was also verified, that the rate of catheter-related bloodstream infection was significantly higher in patients in the ED group (10% versus 5%, P = 0.03). In the present study, the rate of general infections was 64% (n = 49), being higher in patients in the LD group compared to the ED group (52% versus 71%, P = 0.088).

In another RCT, called effect of early vs delayed initiation of renal Replacement therapy on mortality in critically ill patients with AKI, Zarbock et al (7) evaluated 231 patients from a single center, defining early and LD based on time, in hours, after the AKI diagnosis in stage two and three using the KDIGO criteria. Survival after 90 days was the primary outcome analyzed, and it was found that patients in the LD group had a higher death

Mortality in AKI Table 3. Mortality risk factors by multivariate logistic regression Variable

Unadjusted model

Adjusted model

OR

CI (95%)

P

OR

CI (95%)

P

Diabetes mellitus

0.286

0.095–0.859

0.026

0.496

0.125–1.963

0.318

Serum creatinine (mg/dL) at ICU admission

0.614

0.412–0.915

0.016

0.453

0.257–0.801

0.006

Infection

0.237

0.077–0.726

0.012

0.614

0.125–3.010

0.547

Number of sessions

0.949

0.889–1.014

0.124

-

-

-

Total time (hours)

0.987

0.969–1.005

0.152

-

-

-

Need of interruption

2.026

0.787–5.213

0.143

-

-

-

Late dialysis

0.413

0.154–1.201

0.107

-

-

-

Length ICU stay

0.971

0.947–0.996

0.023

0.972

0.937–1.008

0.128

Data from dialysis

OR: odds ratio; CI: confidence interval; ICU: intensive care unit.

rate (54.7% versus 39.3%, P = 0.03). In a second step, it was found that patients in the ED group had a higher rate of recovery of renal function after 90 days (53.6% versus 38.7%, P = 0.02).

In a retrospective analysis of data from patients with severe AKI in another Brazilian teaching hospital, Nascimento et al (13), defining the timing of initiation of dialysis according to the blood urea nitrogen (BUN), found that patients undergoing ED (BUN ≤75 mg/dL) had a lower mortality rate and a higher rate of recovery of renal function, when the timing of initiation of dialysis was determined by blood urea nitrogen levels. In the research, the multivariate analysis showed that patients in the LD group had almost four times greater chance of death than patients in the ED group (P = 0.02).

Unlike the cited findings, we verified that ED group presented high mortality rate compared to the LD group (Table 2). Promoting a systematic review and metaanalysis of individual data from 1879 patients with severe AKI, Gaudry et al (14) showed that the timing of initiation of dialysis does not negatively impact patient survival, and the onset can be delayed when there are no well-defined criteria for urgency in carrying out the therapy. Barbar et al (3) points out that besides not reducing the mortality of patients, ED is a treatment with potential hemorrhagic and others complication, as well as with high economic expenses which can be avoided.

Despite the recent evidence available, in clinical practice the discussion remains about the appropriate moment for starting dialysis and its effects on the mortality of patients with severe AKI in the ICU. However, other factors are involved and can also have a significant impact. In this study, the serum creatinine level, presented by patients at the time of ICU admission, was shown to be a risk factor independently associated with death (Table 3), and we verified that nonsurvivors had lower serum creatinine levels (Table 2). In another Brazilian study, this biomarker was also inversely proportional to mortality in critically ill patients with AKI (15).

Such an inverse association corroborates the possibility of late AKI diagnosis in the sample. In addition, patient

malnutrition and with fluid overload is other possible justifications (15). Thinking of minimizing the impact of fluid overload on the incidence of AKI and, consequently, delaying diagnosis and worse outcomes, Macedo et al (16) and more recently Thongprayoon et al (17) proposed specific mathematical formulas for calculating creatinine in these patients. Furthermore, the influence of severe AKI on macronutrient metabolism favors hyper-catabolism, contributing to the fact that serum creatinine levels remain low (18).

Finally, we point out the theme addressed as one of the strengths of our study, especially considering that the timing when dialysis starts is a major dilemma in daily clinical practice, and its study is essential to improve support for clinical decisions taken at bedside. In addition, our study contributes to the scientific literature, because, despite the importance of the topic, its research among Brazilian working groups is still restricted and, with this, the Brazilian medical literature is considerably limited.

Conclusion The overall and in the ED group mortality rate was elevated, however, the timing of initiation of dialysis did not show statistically significant association with death.

The serum creatinine at ICU admission seems to be an important mortality predictor. In despite this, more studies are needed to better understand the impact of the timing when dialysis starts on the different outcomes of patients.

Limitations of the study Despite of the importance of the theme and its main results, the findings of this study should not be extrapolated, given the limitations presented, among which the fact that the analyzes are based on a retrospective methodological design, with a small sample of patients admitted to a single center. Another limiting aspect refers to the criteria applied to define ED and LD. For these reasons, we encourage other primary studies to be conducted in Brazil, with more robust samples and methodological design with better levels of evidence. Thus, we will have Journal of Renal Endocrinology, Volume 7, 2021

5

Passoni dos Santos R et al

a better understanding of the real impact that the timing of initiation of dialysis has on the different outcomes evaluated in patients with AKI in Brazilian ICUs.

8.

Authors’ contribution RPS was the principal investigator of the study. LGV, DFMO, RFS and VFB were included in preparing the concept and design.

ARSC and LABP revised the manuscript and critically evaluated the intellectual contents. All authors have read and approved the content of the manuscript and confirmed the accuracy or integrity of any part of the work.

9.

Conflicts of interests The authors declare that they have no competing interests.

10.

Ethical considerations Ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the authors.

11.

Funding/Support The study received no financial support.

12.

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Cochrane Cochrane Database Syst Rev. 2018;12:CD010612. doi: 10.1002/14651858.CD010612.pub2.

2. Gaudry, S, Quenot JP, Hertig A, Barbar SD, Hajage D, Ricard JD, et al. Timing of renal replacement therapy for severe acute kidney injury in critically ill patients. Am J Respir Crit Care Med. 2019;199:1066-75. doi: 10.1164/rccm.201810-1906CP. 3. Barbar SD, Gaudry S, Dreyfuss D, Quenot JP. Renal replacement therapy: Time to give up on early initiation? Yes. Anaesth Crit Care Pain Med. 2018;37:501-3. doi: 10.1016/j. accpm.2018.11.008.

4. Meersch M, Zarbock A. Renal replacement therapy in critically ill patients: who, when, why, and how. Curr Opin Anaesthesiol.

2018;31:151-7. doi: 10.1097/ ACO.0000000000000564.

5. Romagnoli S, Clark WR, Ricci Z, Ronco C. Renal replacement therapy for AKI: When? How much? When to Stop?. Best Pract Res Clin Anaesthesiol. 2017;31:371-85. doi: 10.1016/j. bpa.2017.10.001.

6. Gaudry S, Hajage D, Schortgen F, Martin-Lefevre L, Pons B, Boulet E, et al. Initiation strategies for renal-replacement therapy in the intensive care unit. N Engl J Med 2016; 375:12233. doi: 10.1056/NEJMoa1603017.

7. Zarbock A, Kellum JA, Schmidt C, Aken HV, Wempe C, Pavenstädt H, et al. Effect of early vs delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury: The ELAIN randomized clinical trial.

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Von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP, STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008;61:344-9. doi: 10.1016/j. jclinepi.2007.11.008.

Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group (2012) KDIGO clinical practice guideline for acute kidney injury. Kidney Int. 2012;2:1-138.

Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818-29.

Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22:707-10. doi: 10.1007/BF01709751.

Nascimento GVR, Balbi AL, Ponce D, Abrão JMG. Early initiation of dialysis: mortality and renal function recovery in acute kidney injury patients. J Bras Nefrol. Oct-Dec 2012;34:337-42. doi: 10.5935/0101-2800.20120022.

Gaudry S, Hajage D, Benichou N, Chaibi K, Barbar S, Zarbock A, et al. Delayed versus early initiation of renal replacement therapy for severe acute kidney injury: a systematic review and individual patient data meta-analysis of randomised clinical trials. Lancet.

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Souza SP, Matos RS, Barros LL, Rocha PN. Inverse association between serum creatinine and mortality in acute kidney injury. J Bras Nefrol. 2014;36:469-75. doi: 10.5935/01012800.20140067.

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Thongprayoon C, Cheungpasitporn W, Srivali N, Ungprasert P, Kittanamongkolchai W, Kashani K. The impact of fluid balance on diagnosis, staging and prediction of mortality in critically ill patients with acute kidney injury. J Nephrol. 2016;29(2):2217. doi: 10.1007/s40620-015-0211-3.

Berbel MN, Pinto MPR, Ponce D, Balbi AL. Nutritional aspects in acute kidney injury. Rev Assoc Med Bras (1992). 2011;57:6006. doi: 10.1590/s0104-42302011000500022.

Open Access

Epidemiology and Prevention J Renal Endocrinol 2021;7:e08.

Journal of

Renal Endocrinology

http://www.jrenendo.com

Nickan

doi: 10.34172/jre.2021.08

Research Institute

Incidentally detected isolated Aspergillus fumigates infection of the renal allograft ID

ID

ID

Kajal N. Patel1* , Nitin A. Patel2 , Shruti P. Gandhi1 , Hargovind L. Trivedi3

ID

Abstract Fungal infection represents 5% of the infections of post renal transplant recipients. The frequency of invasive Aspergillus ranges from 0.5% to 2.2% with a mortality rate of 88%. In renal transplantation, Aspergillus infection usually affects primarily the lungs with occasional dissemination and the central nervous system. Involvement of a renal allograft in the isolated form is rare. A-35-year-old male post-renal transplant patient presented in our institute for routine follow up examination. Ultrasound and computed tomography (CT) were conducted in our radiology department, suggestive of abscess formation in mid pole of transplanted kidney. The patient did not have any clinical symptoms. His serum creatinine level was also within normal limit. Diagnosis of Aspergillus fumigates was made by aspiration of pus.

Treatment started according to culture and sensitivity report. Ultimately graft nephrectomy was performed to control infection. Aspergillus infection of a renal allograft remains a key issue for nephrologists and infection specialists. For diagnosis of fungal infection, a high index of suspicious is necessary. In the present case, the infected allograft nephrectomy and the elimination of immune-compromised state and the prompt administration of antifungal therapy, made recovery possible. However, early diagnosis remains difficult.

Keywords: Aspergillus fumigatus, Fungal infection, Kidney transplant, Aspergillosis Citation: Patel KN, Patel NA, Gandhi SP, Trivedi HL. Incidentally detected isolated Aspergillus fumigates infection of the renal allograft. J Renal Endocrinol. 2021;7:e08. doi: 10.34172/jre.2021.08.

Copyright © 2021 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction Infections are the second highest cause of mortality in kidney transplant (KT) recipients. The incidence of fungal infections depends on the type of organ transplantation, 5% to 17% in heart transplantation, 14% to 22% in simultaneous heart-lung transplant, 2% to 42% in liver transplantation, 2% to 14% of kidney transplantation (1). Species of the Aspergillus family account for the majority of these infections and Aspergillus fumigatus in particular, may be regarded as the most important air borne saprophytic fungus (2,3). Fungal infection has a tendency for invading blood vessels, both small and large, both arteries and veins, causes thrombosis and infarction.

Aspergillus infection incidence is 0.5% to 2.2% in post renal transplant recipients and mortality is nearly 88% (4,5). The majority of post-transplant recipients with Aspergillus infection have pulmonary (6), rhino-cerebral or disseminated infection. Infection of a single organ without a novert site of origin has been rarely reported. The renal lesions are characterized pathologically by multiple parenchymal micro abscesses, indicative of hematogenous spread to the organ. We report a case of incidentally

detected isolated Aspergillus fumigates infection of renal allograft without evidence of site of origin.

Study of a patient A-35-year-old non-diabetic male patient was come to our institute for routine follow up of post-renal transplantation after 4 months. The patient had basic end-stage renal disease due to solitary contracted ectopic kidney in right iliac fossa. The patient had history of living related renal transplant in left renal fossa with mother as a donor. Their maintenance immunosuppression regimen was prednisolone, tacrolimus and mycophenolate mofetil.

He was also taking fluconazole, Sulfamethoxazole, bacteriostatic antibiotic and valganciclovir for three months. The post operative course was uncomplicated.

His serum creatinine (sCr) level was stable 1.25 mg/dL at time of discharge.

During routine follow up examination after four months of post renal transplantation, basic investigation was done in our institute. The transplanted graft was non-tender on palpitation. Serum creatinine level was within normal limit. His ultrasonography and color Doppler study of

Received: 11 November 2020, Accepted: 20 December 2020, ePublished: 13 January 2021 Department of Radiology, Institute of Kidney Diseases and Research Centre (IKDRC)-Dr. H.L. Trivedi Institute of Transplantation Sciences (ITS), Ahmedabad, Gujarat, India. 2Department of Radiology, Surym –The World of Imaging centre, Shivranjani crossroads, Ahmedabad, Gujarat, India. 3Department of Nephrology and Transplantation Medicine, Institute of Kidney Diseases and Research Centre (IKDRC)-Dr. H.L. Trivedi Institute of Transplantation Sciences (ITS), Ahmedabad, Gujarat, India. *Corresponding Author: Kajal N. Patel, Email: drkajal@yahoo.co.in 1

Patel et al

Implication for health policy/practice/research/ medical education Incidence of fungal infections is only 5 % among the total infections of post-renal transplant recipients. In renal transplantation, Aspergillus infection usually affects primarily the lungs with occasional dissemination and the central nervous system. Involvement of a transplanted kidney in the isolated form is rare. The notable aspect of the case is lack of clinical symptoms.

graft vessels were done in our radio diagnosis department.

It displayed normal size transplanted kidney in left renal fossa with about 3.1 × 2.8 cm size hypoechoic lesion in mid pole without vascularity (Figure 1). There were no hydronephrosis and normal resistive index (RI) within graft. The patient did not have history of fever, pain, cough or dyspnea. Provisional diagnosis of non-liquefied abscess was kept. The plain chest film was normal. Blood, urine and sputum cultures yielded negative results. Due to non-liquefied smaller sized lesion, aspiration of lesion could not be possible at time of presentation. Therefore, the patient was treated with antibiotic of cefoperazone and sulbactam. Close follow up of lesion was conducted by ultrasonography and blood investigations. During this period patient also underwent plain CT scan and MRI study of abdomen, findings were consistent with USG (Figure 2). Ultimately aspiration of lesion of transplanted kidney became possible after 3 months of diagnosis of

Figure 1. Ultrasonography image of transplanted kidney shows well defined hypoechoic lesion in cortex of mid pole

Figure 2. Coronal image of plain CT scan of abdomen shows well defined hypodense subcapsular collection involving mid pole of transplanted kidney in left renal foosa.

2

Journal of Renal Endocrinology, Volume 7, 2021

renal allograft abscess. At that time lesion appeared quite enlarge measuring about 5.2 × 2.8 cm with sub-capsular extension at mid pole with elevated mean RI of about 0.81 and sCr of 2.37 mg/dL. Fluid cytology of aspirated pus suggested heavy growth of Aspergillus fumigates organism. Culture and sensitivity of pus showed very sensitive voriconazole and resistant amphotericin-B drug.

Thereby treatment with voriconazole 200 mg two times a day was started but the patient had same size abscess in renal allograft and his sCr level was increased day by day and ultrasonography also did not indicate resolving abscess. Finally, transperitoneal laparoscopic deroofing of subcapsular collection and subsequent allograft nephrectomy was conducted after two months of diagnosis of fungal abscess. Gross specimen of transplanted kidney shows few area of necrosis at cortex (Figure 3).

Microscopic findings also suggested Aspergillosis without ureteric extension or immune injury (Figure 4). After graft nephrectomy patient was improved. The patient was clinically stable on hemodialysis without infection within graft bed or any other site during three months follow up.

Discussion There has been a dramatic increase in the incidence of aspergillosis in the last two decades, yet the mortality has decreased from 92% (between 1990 and 1995) to 60% (between 1998 and 2001) (7). Aspergillus spores are ubiquitous and can be cultured from stored grains, most soil and vegetation, the organisms can be a laboratory

Figure 3. Gross specimen of transplanted kidney show few area of necrosis within cortex.

Figure 4. Histopathology showing tubular septate branching hyphae surrounded by polymorphonuclear cells, cell debris and lymphoplasmacytic cells (hematoxylin and eosin, ×400) consistent with Aspergillus.

A. fumigates infection of the renal allograft

contaminant, an allergic stimulant or a secondary colonizer if lung cavities (8).

Risk factors Fungal infections are more common between the first and sixth month after post-transplantation but they may appear earlier also (9). The use of immunosuppressive agents represents important predisposing factors for fungal infection, especially steroids. Other commonly related factors include diabetes mellitus, renal failure, hematological disease, broad spectrum antibiotics, indwelling catheters, increasing number of surgical procedures, infection with cytomegalovirus, exposure to infective fungi, chronic liver disease, prolong pre and post-transplant dialysis (10,11). As per past record of infections, the presence of Aspergillus species in the environment is the most important factor in nosocomial invasive Aspergillosis.

Diagnosis Diagnosis of Aspergillus infection has been based on evidence of fungal invasion in tissue biopsies. The aspergillosis is identified by their uniform, tubular and regularly septate hyphae with progressive and dichotomous branching. Renal transplant ultrasonography may be normal in earlier stage or show non-vascular hypo/iso-echoic lesion, which is a non-specific finding.

Imaging studies like contrast enhanced computed tomography(CECT) may help in the diagnosis of this fungal infection within transplanted kidney showing presence of perinephric collection suggesting intra-renal abscess and no or poor excretion of contrast.

Since Aspergillus species are respiratory pathogens, the most common form of infection is pneumonia, followed by sinusitis (12). Weiland et al, in a review of aspergillosis in renal transplant patients, describe three characteristic patterns 1) cavitary lung disease 2) diffuse pulmonary disease, and 3) central nervous disease always after a prior pulmonary infection (8). HRCT thorax scan could be useful for detecting a hypothetic pulmonary infiltrate in the present patient with normal X-ray. As another possibility, the fungus may have been seeded from sinuses.

However our patient neither had lung disease or sinusitis.

Although fungal endocarditis is uncommon in kidney transplant patients, it was also investigated. Nonetheless, 2-D echocardiography of our patient was normal. Because of the single kidney infection without evidence of a site of origin as in our case, we can speculate on transmission of the fungus together with the allograft. Donor-to-host transmission of infection is well documented in many case reports but they often do not differentiate donor-related transmission from iatrogenic contamination during preservation. In fact, the donor is a less likely source of contamination. Perfusate solution offers an excellent medium for microbial growth. In a recent review by

Gottesdiener et al (13), fungi accounted for 0.2%-2.5% of the isolates in cultures taken from perfusion solutions used for kidney preservation. Regarding the source of graft infection in our case, extensive investigation failed to reveal any origin of fungal infection.

After the introduction of voriconazole drug for treatment of fungal infection, it shows that mortality and morbidity is decreased in comparison with amphotericin B. The enhancement of the immune system with immunomodulatory agents like interferon-gammas an attractive alternative or adjuvant to established antifungal therapy (14). With any kind of antifungal treatment used, the cure rate depends on how early treatment is initiated.

In the present case, the nephrectomy of infected allograft and thus elimination of immunocompromised state and the prompt administration of antifungal therapy made recovery possible.

Conclusion Aspergillus infection of a renal allograft remains a key issue for nephrologists and infection specialists. The presence of an isolated aspergillus abscess within a renal allograft without evidence of systemic infection as in our case is very rare. The notable aspect of our case is lack of clinical symptoms. To improve prognosis, a high index of suspicious is necessary. Accurate information regarding colonization and the antifungal susceptibility of the isolated organisms is required to start suitable empirical treatment. However, early diagnosis remains difficult.

Authors’ contribution KNP and SPG were the principal investigators of the study. KNP and NAP had a major role in preparing the concept and design.

KNP, NAP and SPG participated in preparing the final draft of the manuscript and revised the manuscript. All authors have read and approved the content of manuscript and confirmed the accuracy and integrity of any part of the work.

Acknowledgments We are also thankful to our librarian Jyotsana Suthar for the literature search and submission.

Conflicts of interest The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Ethical considerations Ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the authors. The patient gave the consent to publish as a case report.

Funding/Support None.

References 1. Patel R, Paya CV. Infections in solid organ transplant recipients.

Clin Microbiol Rev. 1997; 10: 86-124. doi: 10.1128/ CMR.10.1.86 2. Denning DW, Invasive aspergillosis. Clin Infect Dis. 1998;26:

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781-803. doi: 10.1086/513943.

Latge JP. Aspergillosis fumigates and aspergillosis. Clin Microbiol Res. 1999;12:310-50. doi: 10.1128/CMR.12.2.310.

Ergin F, Arslan H, Azap A, Demirhan B, Karakayalı H, Haberal M. Invasive Aspergillosis in solid transplantation: report of eight cases and review of the literature. Traspl Int. 2003;16:280-6. doi: 10.1111/j.1432-2277.2003.tb00300.

Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis. 2001;32: 358-66. doi: 10.1086/318483.

Soutani AO, Chandrasakan PH. The clinical spectrum of pulmonary aspergillosis. Chest. 2002;121:1988-99. doi: 10.1378/chest.121.6.1988.

Singh N, Avery RK, Munoz P, Pruett TL, Alexander B, Jacobs R, et al. Trends in risk profiles for and mortality associated with invasive aspergillosis among liver trans‐ plant recipients. Clin Infect Dis. 2003;36:46‐52. doi: 10.1086/345441.

Weiland D, Ferguson RM, Peterson PK, Snover DC, Simmons RL, Najarian JS. Aspergillosis in 25 renal transplant patients. Epidemiology, clinical presentation, diagnosis, and management. Ann Surg. 1983;198:622‐9. doi: 10.1097/00000658-198311000-00011

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14.

Linden E, Restrepo D, Dikman S, Murphy B, Huprikae S. Aspergillosis infection limited to renal allograft: case report and review of literature. Transpl Infect Dis. 2006;8:177-81. doi: 10.1111/j.1399-3062.2006.00134.x.

Tharayil John G , Shankar V, Talaulikar G, Mathews MS, Abraham Abraham M, Punnakuzhathil Thomas P, et al.

Epidemiology of systemic mycoes among renal transplant recipients in India. Transplantation. 2003;75:1544-51. doi: 10.1097/01.tp.0000061610.34110.04.

Abbott KC, Hypolite I, Poropatich RK, Hshieh P, Cruess D, Hawkes CA. Hospitalizations for fungal infections after renal transplantation in the United States. Transpl Infect Dis. 2001: 3:203-11. doi: 10.1034/j.1399.

Bodey GP, Vartivarian S. Aspergillosis. Eur J Microbiol Infect Dis. 1989;8:413-37. doi: 10.1007/bf01964057.

Gottesdiener KM. Transplanted infections: donor-to-host transmission with the allograft. Ann Intern Med. 1989;110: 1001-16. doi: 10.7326/0003-4819-110-12-1001.

Estrada C, Desai AG, Chirch LM, Suh H, Seidman R, Darras F, et al. Invasive aspergillosis in a renal transplant recipient successfully treated with interferon-gamma. Case Rep Transplant. 2012;2012:493758. doi: 10.1155/2012/493758.

Open Access Journal of

Renal Endocrinology

Original J Renal Endocrinol 2021;7:e09. http://www.jrenendo.com

Nickan

doi: 10.34172/jre.2021.09

Research Institute

Cholecalciferol therapy; is it the gold standard for vitamin D deficiency and mineral disorders in hemodialysis?

Mouna Jerbi1*, Hiba Ghabi 2, Hanene Gaied2, Fathi Ben Hmida3, Raja Aoudia3, Rim Goucha1, Taieb Ben Abdallah3 Abstract Introduction: Vitamin D deficiency is frequently observed among dialysis patients. Previous studies suggested that 50 to 90% of end-stage renal disease patients are deficient in vitamin D. In Tunisia, studies regarding hypovitaminosis D in patients on dialysis are not numerous.

Actually, many data support the use of native vitamin D in hemodialysis (HD) patients. In Tunisia, using native vitamin D is not part of therapeutic habits of all dialysis centers.

Objectives: The aim of this study was to determine the prevalence of vitamin D deficiency in patients with chronic kidney disease stage 5 undergoing HD and to evaluate the effect of oral cholecalciferol supplementation, in intact parathormone (iPTH), serum calcium and serum phosphorus.

Patients and Methods: We conducted a pre-experimental study among HD patients. Monthly oral supplementation with Cholecalciferol, was instituted for six months.

Results: Forty-three participants were included. The mean 25-hydroxy vitamin D concentration was 17.89 ng/mL. Vitamin D deficiency was observed in 83.7% of our patients. We observed a significant increase in 25-hydroxy vitamin D and calcium levels and a significant decline in iPTH levels. No evidence of toxicity, nor severe hypercalcemia or hyperphosphatemia was noted.

Conclusion: The supplementation with cholecalciferol seems reasonable and well tolerated in HD patients if reasonable doses are used with regular monitoring.

Keywords: Vitamin D, Hemodialysis, Chronic kidney disease, Hemodialysis, Parathormone, End-stage renal disease Citation: Jerbi M, Ghabi H, Gaied H, Ben Hmida F, Aoudia R, Goucha R, Ben Abdallah T. Cholecalciferol therapy; is it the gold standard for vitamin D deficiency and mineral disorders in hemodialysis? J Renal Endocrinol. 2021;7:e09. doi: 10.34172/jre.2021.09.

Copyright © 2021 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction Vitamin D deficiency is frequently observed among hemodialysis (HD) patients. Previous studies suggest that 50% to 90% of end-stage renal disease (ESRD) patients are deficient in vitamin D (1). Significant evidence has been accumulated these recent years supporting the benefit of using vitamin D in HD patients. In fact, vitamin D deficiency has been associated with secondary hyperparathyroidism (SHPT) (2), since serum 25-hydroxyvitamin D (25(OH) D) levels should be maintained above 30 ng/mL in order to prevent parathyroid hormone (PTH) from increasing (3).

Its correction is relatively easy and well detected in a subject with normal renal function. Unfortunately in patients with chronic kidney disease (CKD), especially HD patients, the correction is not yet well codified due to the lack of prospective studies.

To be active, vitamin D must benefit from a double

hydroxylation; the first hydroxylation, is carried out by the liver and the second is carried out under the action of 1-alpha-hydroxylase, mainly at the level of the proximal convoluted tubule to form calcitriol (4).

CKD is associated with loss of renal 1 α hydroxylase activity. Classically, nephrologists use active vitamin D to compensate this deficit. Both the Kidney Disease Outcomes Quality Initiative (KDOQI) and Kidney Disease Improving Global Outcomes (KDIGO) experts recommend checking and supplementing low serum 25(OH)D levels in CKD and HD patients (5,6) why active vitamin D is usually administered.

Over the last fifteen years, many scientific advances have profoundly changed the understanding of the vitamin D physiology, the co-expression of vitamin D receptors with 1-α-hydroxylase, in many peripheral tissues, has come to light a new concept, while the active form of vitamin D, the 1.25 (OH) D3, can be synthesized in extrarenal sites and

Received: 11 September 2020, Accepted: 10 October 2020, ePublished: 20 November 2020 Department of Nephrology, Mongi Slim Hospital, Marsa, Laboratory of Kidney Pathology (LR00SP01) Charles Nicolle Hospital, Faculty of Medicine Tunis, University of Tunis El Manar, Tunis, Tunisia. 2La Rabta Hospital, Department of Nephrology, Faculty of Medicine Tunis, University of Tunis El Manar, Tunis, Tunisia. 3Department of Nephrology, Charles Nicolle Hospital, Laboratory of Kidney Pathology (LR00SP01) Charles Nicolle Hospital, Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia. *Corresponding Author: Mouna Jerbi, Email: mounaeleuch@outlook.fr 1

Jerbi M et al

Implication for health policy/practice/research/ medical education In a pre-experimental study on HD patients, we found vitamin D supplementation using cholecalciferol (800 000 UI during 6 months) was associated with significant increase in serum 25OH vitamin D and calcium and a significant decline in intact parathormone (iPTH) serum levels. No evident toxicity, nor severe hypercalcemia or increase in phosphorus level was noted.

generate local autocrine effects (7,8). Actually many data support the use of native vitamin D in HD patients (9).

There has been renewed interest in studying the effects of supplementation with native vitamin D (cholecalciferol) in CKD patients with low 25(OH) D levels (10,11).

Likewise, this interest has been shown by the studies that have demonstrated several potential non-skeletal benefits of vitamin D. These benefits include effect of vitamin D on immune system, cardiovascular disease, diabetes, and some cancers (12,13).

In Tunisia, studies regarding hypovitaminosis D in patients with CKD stage 5 on dialysis are not numerous and using native vitamin D is not part of therapeutic habits of all dialysis centers.

Objectives In the present study, we examined the prevalence of vitamin D deficiency in patients with CKD stage 5 undergoing HD and evaluated the effect of oral cholecalciferol supplementation, in intact parathyroid hormone (iPTH), serum calcium (Ca) and serum phosphorus in this population.

Materials and Methods This was a pre-experimental study conducted in HD department of Charles Nicolle hospital during six months.

All measurements were carried out at the biochemistry laboratory of the hospital.

We included patients of CKD stage 5 who were on maintenance HD for more than one year. They were adults (age >18 years). Patients were not included if they had a history of active vitamin D or calcimimetic treatment in the last year, parathyroidectomy, iPTH <300 pg/mL, hepatic failure or digestive malabsorption. Those with serum calcium greater than 2.55 mmol/L or serum phosphorus greater than 2 mmol/L were not included.

The calcium concentration during HD sessions was set at 1.5 mmol for all patients. Informed consent was required for all patients.

25(OH) vitamin D serum levels, intact PTH (iPTH), as well as serum calcium and phosphorus were analyzed in fasting samples before and 15 days after the end of treatment. Blood samples for 25(OH) vitamin D levels were obtained before dialysis. Serum 25(OH) vitamin D levels were measured using a commercially available 2

Journal of Renal Endocrinology, Volume 7, 2021

radioimmunoassay. Intact PTH was determined by an automated chemiluminescence immunoassay. Serum calcium and phosphorus were measured by standard laboratory methods.

In this study, we considered adequate vitamin D levels those above 30 ng/mL (US National Kidney Foundation DOQI guidelines), vitamin D insufficiency when levels were between 20 and 30 ng/mL, vitamin D moderate deficiency when levels were between 10 and 20 ng/mL and severe deficiency when levels were below 10 ng/mL. Monthly oral supplementation with cholecalciferol (200 000 UI), was then instituted for six months (M1, M2, M4 and M6) totaling 800 000 UI. For better compliance cholecalciferol was given in the morning on empty the day of non-HD. The response to treatment was evaluated as follows; • Partial response if 25 (OH) vitamin D level is <30 ng/ mL at M6.

• Adequate response if 25 (OH) vitamin D level is between 30 ng/mL and 60 ng/mL at M6.

• Excessive response if 25 (OH) vitamin D level is > 60 ng/mL at M6.

For all statistical analyses, P value ≤0.05 was considered to be significant. All statistical analyses were performed with Statistica software. We used a paired sample t test to compare means of quantitative variables before and after supplementation.

Results Forty-three Caucasian participants were included in the study. Mean age was 51.3 years. Of these, 18 were females and 25 were males. Median duration of dialysis was 6.5 years (range 1–19 years). Six (13.9%) patients had diabetic nephropathy.

We found that 83.7% of our patients had vitamin D insufficiency or deficiency (a serum 25-OH vitamin D level below 30 ng/mL) (n = 36). Before treatment, the mean 25 (OH)D was 17.89 ng/mL [6-57.3 ng/mL] (Table 1).

Changes in vitamin D, calcium, phosphorus and iPTH, after cholecalciferol supplementation The cholecalciferol supplementation allowed a significant increase of 25 (OH) vitamin D levels (from 17.89 ng/ mL to 51.8 ng/mL). The average plasma concentration of calcium has significantly increased between M0 and M6, 2.05 (M0) versus 2.15 mmol/L (M6). No episode of hypercalcemia was noted.

Basal iPTH concentration observed before vitamin D Table 1. Biomedical characteristics before treatment Vitamin D (ng/mL)

17.89 (6-57.3)

PTH (pg/mL)

956 ± 413.24

Phosphorus (mmol/L)

1.56 ± 0.27

Calcium (mmol/L)

2.05 ± 0.24

Cholecalciferol therapy in HD

supplementation was 956 pg/mL. After treatment, the mean concentration decreased significantly. Overall, iPTH concentration decreased from 956 pg/mL to 699 pg/ mL between M0 and M6.

The average serum phosphorus level progress was not significant: 1.56 mmol/L at M0, to 1.49 mmol/L at M6.

These values remain lower than the upper limit (1.78 mmol/L) according to the K/DOQI recommendations (Table 2).

The increase of serum 25 (OH) vitamin D level was conditioned by initial concentrations of 25 (OH) vitamin D (Table 3).

Discussion Our study confirms the high prevalence of the 25 (OH) vitamin D deficiency in HD patients, with a mean 25 (OH) vitamin D concentration of 17.89 ng/mL. Vitamin D deficiency was observed in 83.7% of our patients.

Referring to the concentrations recommended by the American Nephrology Society, only 16.3% of our patients reach desirable concentrations of 25 (OH) vitamin D >30 ng/mL (3).

At the dialysis stage, the deficit in vitamin D affects 53.5 to 89 % of HD (1). In Asian countries, studies have shown a high prevalence of vitamin D deficiency. The study of Hashemipour et al reported that 81.3% subjects had a decline in vitamin D reserves with a prevalence of vitamin D deficiency between 30% and 93% (14). Recently, a French team reported vitamin D insufficiency with serum 25(OH) vitamin D level <30 ng/mL in 72% of their HD patients (15). In Africa, data on dialysis are not numerous.

In Nigeria, a study reports a deficit in 1,25(OH)2D in 83.3% of patients (16). In Tunisia, a cumulative prevalence of vitamin D deficiency of 47.6% was reported in healthy population (17). In a study conducted in southern Tunisia involving 63 dialysis patients (HD, peritoneal dialysis), the average level of 25(OH) vitamin D was 10.5±9.13 ng/mL. Table 2. Changes in vitamin D, calcium, phosphorus and PTH, after cholecalciferol supplementation Pre-supplementation

Post-supplementation

P value

Vitamin D (ng/mL)

17.89

51.8

<0.001

Ca (mmol/L)

2.05

2.15

0.014

Phosphorus (mmol/L)

1.56

1.49

0.78

PTH (pg/mL)

956

699

<0.001

Serum 25OH vitamin D level <15 ng/mL was shown in 41.3% of patients and between 15 and 30 ng/mL in 50.8% of patients (18).

Vitamin D is a hormonal system involved in the regulation of hundreds of genes and metabolisms by the local or endocrine production of 1,25-OH 2 vitamin D with a primary effect on cellular differentiation and proliferation (19). Vitamin D deficiency has been associated with the risk of cancer (20) diabetes (13), autoimmune and cardiovascular diseases, osteoporosis, musculoskeletal function impairment, and neuropsychiatric disorders (12).

Therefore, it has an important role in the prevention of diabetes, different types of cancer, autoimmune diseases, and in the defense against tuberculosis (21).

In the general population, the optimal serum 25(OH) vitamin D level is not known, but it is thought to be above 30 ng/mL (22).

This deficiency is due to a restrictive diet in vitamin D, as well as low exposure to sunlight, which leads to a decrease in the cutaneous synthesis of vitamin D. In our study, all female population was veiled women with a low-sunlight exposure. In addition, chronic HD patients have decreased photoproduction of cholecalciferol, despite a normal epidermal content of the substrate, 7-dehydrocholesterol (23). A study suggests a decrease in hepatic 25-hydroxylase activity related to uremia too (24).

Vitamin D deficiency among dialysis patients has become an increasingly important problem for nephrologists in the last 10 years. In fact, end-stage renal disease is associated with a decrease in vitamin D activity by mechanism including the increase of plasma phosphate concentration, secretion of fibroblast growth factor-23 and decrease in 1 alpha hydroxylase activity. Currently is well established that a patient has to be substituted when 25OH vitamin D level is less than 30 ng/mL. The goals of vitamin D treatment in case of ESRD are to substitute the deficiency and to prevent or treat hyperparathyroidism.

Lowering excessive serum PTH levels have many beneficial effects by increasing myocardial contractility, decreasing myocardial fibrosis and vascular calcification, increasing immune function, insulin sensitivity, and erythropoiesis.

But the beneficial effects of vitamin D may also involve a direct action on hypertension, cardiac hypertrophy, tumorigenesis, immunologic function, atherosclerosis, and thrombosis (25). With the Kidney Disease: Improving Global Outcomes 2016 recommendation being recently released, it is hypothesized that nephrologists will

Table 3. Changes in the 25(OH) D after cholecalciferol treatment according to the baseline vitamin D level Partial response (Vit D <30 ng/mL)

Adequate response (Vit D between 30 and 60 ng/mL)

Excessive response (Vit D >60 ng/mL)

<10

54.5%

45.5%

0%

10-20

46.2%

46.2%

7.6%

20-30

0%

62.5%

37.5%

Baseline vitamin D level (ng/mL)

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Jerbi M et al

implement a strategy for 25(OH) vitamin D deficiency checking and supplementation more systematically (5).

However, the more appropriate vitamin D compounds for HD patients remain an unavoidable subject. The controversy about active vitamin D and native vitamin D heats up.

Past studies have recommended the use of native vitamin D in HD patients. As knowledge improves, this use then fell somewhat into disuse; especially for the benefit of active vitamin D. Actually, native vitamin D has regained an important place in our arsenal therapy. In a descriptive study conducted in 2011 in the Sahel of Tunisia involving 50 HD patients belonging to the same center, 38% of them were treated by active vitamin D versus 50% using native vitamin D (26).

In our study, vitamin D supplementation using cholecalciferol (800 000 UI during 6 months) was associated with significant increase in serum 25(OH) vitamin D and calcium and a significant decline in iPTH serum levels. No evident toxicity, nor severe hypercalcemia or increase in phosphorus level was noted.

Several studies have assessed the effect of native vitamin D on mineral parameters in HD patients. We will compare our results to the studies that used cholecalciferol in HD patients. We have deliberately omitted studies that have used other native vitamin D. Indeed, several scientific data suggest that these forms do not have the same bioavailability (23).

A significant improvement in 25 OH vitamin D level after cholecalciferol supplementations was reported by all previous studies. Jean et al observed a significant improvement of 25 (OH) vitamin D levels (from 13±5 ng/ mL to 42 ±11 ng/mL) in one cohort of 107 HD patients after 15 months of monthly doses of cholecalciferol. Serum PTH levels also decreased significantly (median 295-190 pg/mL, P < 0.001). No significant changes were observed in the values of serum calcium and phosphate (15).

Matias et al reported (11), a significant increase in 25OH vitamin D levels (from 22 ± 12 ng/mL to 42 ± 12 ng/mL) in one study of 158 HD patients receiving cholecalciferol treatment. Conversely, serum calcium, phosphorus, and iPTH were decreased (11). In 2013, Delanay et al (29) reported a decrease of PTH levels from 312 to 175 pg/ mL after cholecalciferol treatment for one year but it was a small patient number. In 2018, Tunisian authors compared the effect of cholecalciferol versus ergocalciferol on mineral discords in HD patients and reported a significant increase of vitamin D levels and a significant decrease of PTH levels with cholecalciferol. We specify that these patients have already received ergocalciferol for three months before cholecalciferol which could represent a bias of the study (30).

However, many studies reported that cholecalciferol treatment had an effect on only 25(OH) vitamin D levels and did not change either calcium, phosphorus or iPTH values (31-36).

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The question that arises now is why there is disparity from results especially regarding changes in iPTH levels after cholecalciferol treatment?

This disparity can be explained by several reasons.

First, in some previous studies reporting the effect of cholecalciferol supplementation, patients receiving therapy influencing calcium metabolism were not excluded. Some authors included patients having parathyroidectomy.

Thus the effect of 25(OH) vitamin D on parathyroid is less than expected. Secondly, this disparity can be explained by the variability of bioavailable 25(OH) vitamin D level between the Tunisian population and others. Bioavailable vitamin D is the free portion of 25(OH) vitamin D not bound to vitamin D binding protein (DBP). This is the only active fraction responsible for the biological effects of 25(OH) vitamin D (Table 4).

Prior studies demonstrated that bioavailable vitamin D but not 25(OH)D and 1,25(OH) vitamin D is significantly associated with iPTH and calcium level (37-39). The free 25(OH) vitamin D is influenced by vitamin D binding protein concentration and affinity and it varies in different clinical conditions. It may be affected by genetic, gender, hormones, ethnic and racial factors (33-39).

To assess the effect of cholecalciferol on PTH level; we noticed that previous studies included patients from different races. Our results suggest that Tunisian people may have lower DBP level and thus higher vitamin D bioavailability and greater PTH suppressing. This finding must be confirmed by genetic studies. It should be noted that the essential role of the kidney in producing the active form of vitamin D (1,25-hydroxy-vitamin D3 (1,25 (OH) D3) is an ancient concept. Dusso et al (39) confirmed that 1alpha hydroxylase secretion is stimulated by 25 (OH) vitamin D deficiency and can be produced by extra-renal sites. Additionally, 25(OH)vitamin D can be independent of calcitriol generation.

Indeed, many studies demonstrated that in vitro 25(OH) vitamin D can directly activate vitamin D receptor.

Otherwise, we noticed through this study that the response to cholecalciferol was better in vitamin D insufficiency group compared to vitamin D deficiency group. Therefore the more the deficit was accentuated the more difficult the correction is and we must supplement our patients earlier. In addition, 37.5% of our patients had excessive response with 25(OH) vitamin D levels >60 ng/mL but we did not notice any toxicity mainly hypercalcemia for hyperphosphatemia. In fact, supplementation with cholecalciferol seems reasonable and well tolerated in HD patients if reasonable doses are used with regular monitoring.

Conclusion In conclusion, our study is a Tunisian study regarding the prevalence of hypovitaminosis D in patients on HD and the effects of vitamin D supplementation on the serum level of 25(OH) vitamin D, iPTH, calcium and phosphorus. In

Cholecalciferol therapy in HD Table 4. Literature review Study

Jean et al

Tokmak et al

Matias et al.

No. of patient 107

Mean Age (y)

Initial value of 25(OH) Vit D

Initial value of PTH

Treatment

66.4±15

13±5 ng/mL

295 (190-450) pg/mL

Cholecalciferol 100000 UI/month

64

158

7±4 ng/mL

62.8±14.8

22±12 ng/mL

217±217 pg/mL

Cholecalciferol 20000 UI/week

15 months

25(OH) vit D after treatment 42±11 mg/mL Ca, phosphorus unchanged

9 month

25(OH) vit D after treatment 32±11 ng/mL Ca 2.28±0.17 to 2.37±0.19 mmol/PTH

1 year

25(OH) vit D after treatment 42±12 pg/mL Ca from 8.6±0.8 to 8.4±0.7 mg/dL Ph from 4.7±1.3 to 4.5±1.3 mg/dL PTH 233 to 200 pg/mL

233 pg/mL

Cholecalciferol 40000 UI/ month for 3 months to repeat if deficit persists

2 years

25(OH) vit D after treatment 22±6 ng/mL Ca from 2.28±0.14 to 2.16±0.17 mmol/L Ph and PTH unchanged

6 months

25(OH) vit D after treatment 40±10mg/ml Ph and PTH unchanged

6 months

25(OH) vit D after treatment 51.8. PTH from 956 to 699 pg/ mL Ca from 2.05 to 2.15 mmol/L

101

63.3±13.5

12±7 ng/mL

307.3±236.9 pg/mL

Bucharles et al

30

59±15

18.1±6.6 ng/mL

165±80 pg/mL

Cholecalciferol 50 000 UI/ week for 12 weeks 20 000 UI/week

51.3

17.89 (6-57.3) ng/mL

956 ±413.24

Cholecalciferol 200 000 UI (M1-M2-M4-M6)

43

Results

Cholecalciferol 50000 UI per week if 25(OH) vit D <15 pg/mL 10000 UI per week if 25(OH) vit D between 16 and 30 pg/mL 2700 UI 3 times a week if 25(OH) vit D >30 pg/mL

Jakopin et al

Our study

Study duration

Tunisia, studies regarding hypovitaminosis D in patients with CKD stage 5 on dialysis are not numerous and we do not have protocols of supplementation with native vitamin D. In fact, most centers are used to using only active vitamin D in HD patients.

The interpretation of the results of this study is limited by the relatively low number of patients and by the absence of a control group.

With the KDIGO recommendation being recently released, it is hypothesized that Tunisian nephrologists will implement a strategy for 25(OH) vitamin D deficiency checking and supplementation by native vitamin D more systematically.

This is a Tunisian study regarding the prevalence of hypovitaminosis D in patients on HD and the effects of vitamin D supplementation on the serum level of iPTH, calcium and phosphorus. However, vitamin D deficiency appears to be widely used in Tunisian HD people and we must have a national protocol. The supplementation with cholecalciferol seems reasonable and well tolerated in HD patients if reasonable doses are used with regular monitoring to prevent the development of toxicity, mainly hypercalcemia and hyperphosphatemia.

Many unanswered questions still exist; is there long-term toxicity associated with maintaining high serum 25(OH) vitamin D levels? Which is the best frequency of vitamin D administration; monthly weekly or daily? What is the

optimal serum 25(OH) vitamin D target level according to the severity of secondary hyperparathyroidism?

Other controlled studies are needed to answer these questions and must be based on hard criteria such as the risk of low bone remodeling, skeletal fractures and mortality.

Limitations of the study The most important was the relatively small number of patients.

Authors’ contribution All authors contributed equally to the manuscript.

Conflicts of interest The authors declare no conflicts of interest.

Ethical considerations Ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the authors. All patients gave written informed consent.

Funding/support There was no support/funding.

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Zellama D, Fradi M, Azzabi A, Belarbia A, Guedri Y, Mrabet S, et al. Évaluation des troubles du métabolisme minéral et osseux dans une population de patients hémodialysés, selon les recommandations des KDIGO et KDOQI. Néphrologie & Thérapeutique 2011;7:301-43.

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Open Access

Original J Renal Endocrinol 2021;7:e10.

Journal of

Renal Endocrinology

http://www.jrenendo.com

Nickan

doi: 10.34172/jre.2021.10

Research Institute

Comparison of two insulin injection methods on control of type 2 diabetes; is the new protocol effective or not?

ID

ID

Mohammad Ali Bayani1 , Hojjatollah Ghorbani2 , Roghayeh Akbari1*

ID

Abstract Introduction: Type 2 diabetes is a progressive disease with a significant risk for developing late complications.

Objectives: This study aimed to determine if the proportion of NPH to regular in day of discharge is similar to first day of admission or not.

In other words, we aimed to compare two insulin injection methods on the control of type 2 diabetes.

Patients and Methods: This cross-sectional study was performed on hospital records of type II diabetic patients admitted for insulin therapy with the conventional protocol from 2008-2013. Treatment was initiated with the following proportions; morning NPH: 44%, morning regular dosage: 22%, evening NPH dosage: 17% and evening regular dosage: 17%. Insulin doses of the discharge day in which optimal glycemic control has been achieved were recorded and based on their mean, a protocol was made. Finally, two groups were categorized.

Group 1 consisted of patients whose discharge insulin dose was in the range of the mean data of the study (±2 IU/mL) and patients whose discharge insulin dose was in accordance with the conventional protocol (±2 IU/mL) participated in group 2.

Results: At discharge day, the mean morning NPH dose was 34.2 ± 6.69, morning regular: 23.8 ± 6.36, evening NPH: 21.26±6.75 and evening regular: 20.74 ± 5.51. The discharge insulin ratios of the conventional protocol were similar to that of the admission ratios in only 17.7% of the patients. Only 34.5% of the patients could include in the new protocol and 50% of them did not fit any protocol.

Conclusion: It is suggested to inject one-third of the total daily insulin need as NPH in the morning and divide the remained two-thirds between morning regular, evening NPH and evening regular equally. This may decrease the length of hospital stay and decrease the time to reach the desired glycemic control.

Keywords: Type 2 diabetes; Regular insulin; Conventional protocol.

Citation: Bayani MA, Ghorbani H, Akbari R. Comparison of two insulin injection methods on control of type 2 diabetes; is the new protocol effective or not? J Renal Endocrinol. 2021;7:e10. doi: 10.34172/jre.2021.10.

Copyright © 2021 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction Diabetes mellitus is a chronic disease and a major global problem, with a global prevalence in adults in 2017 being 8.8% of the world population, with the anticipation of a further increase to 9.9% by 2045 which can cause serious complications (1). Treatment and management of type 2 diabetes is a major challenge (2). Prescribing patterns for diabetic patients show wide variability in different parts of the world (3). Diabetic patients whose blood glucose cannot be controlled with oral medications are treated with insulin. Intensive and conventional insulin therapy are the major insulin regimens used for glycemic control (4).

Insulin dose adjustment should be based on body weight (5). Conventional insulin therapy (1/3-2/3) is one of the most common protocols in which the total daily insulin need of the patient is calculated based on body weight (0.3-0.5 mg/kg). Two-thirds of insulin is injected in the morning, before breakfast (2/3 NPH [neutral protamine Hagedorn] and 1/3 regular) and the remaining portion of the total daily dose is administered in the evening before

dinner (½ NPH and ½ regular), approximately 65-70% of the total dose of insulin is NPH and 30-35% is regular (6).

Four daily glucose measurements are used to achieve the glycemic goals obtained by the proposed protocol; prebreakfast and 2 hours after the first bite of the food at each meal. NPH and the regular ratio are modified to reach glycemic glucose (if FBS is high, evening NPH increases and if 2-hour postprandial (2hpp) is high, mornings regular is increased) (7).

Given the lifelong diabetes course, treatment strategies should take a number of aspects into consideration including medication efficacy, patient satisfaction, and costs of the therapy (8). Health care professionals and policy-makers must assess the increasing burden of diabetes and design appropriate preventive and management strategies (9). For better glycemic control, the usual dose of morning and evening regular are modified.

Our experience with admitted patients in hospitals raised the question that: do patients need different doses of the conventional protocol to reach target blood glucose? So, in this study we aimed to know if we achieve glycemic goals

Received: 3 January 2021, Accepted: 25 February 2021, ePublished: 10 April 2021 Social Determinants of Health Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran. 2Students Research Committee, Babol University of Medical Sciences, Babol, Iran. *Corresponding Author: Roghayeh Akbari, Email: roghayeh.akbari@yahoo.com, r.akbari@mubabol.ac.ir 1

Bayani MA et al

Implication for health policy/practice/research/ medical education Diabetes mellitus is a chronic disease and a major global problem. Insulin dose adjustment should be based on body weight. Injecting one-third of the total daily insulin need as NPH in the morning and dividing the remained two-thirds between morning regular, evening NPH and regular equally may decrease the length of hospital stay and decrease the time to reach the desired glycemic control.

(discharge fasting blood sugar [FBS] <150 mg/dL and BS <200 mg/dL) with a new NPH to regular ratio or not.

Objectives In this study, we aimed to determine if the proportion of NPH to regular in day of discharge is similar to first day of admission or not. In other words, we aimed to compare two insulin injection methods on the control of type 2 diabetes so that if we need to increase regular dosage for better glycemic control, we adjust the regular insulin with a higher dose from the beginning.

Patients and Methods Study population and setting This cross-sectional study was performed on hospital records of type II diabetic patients admitted to Shahid Beheshti and Rohani hospitals of Babol for insulin therapy with the conventional protocol from 2008-2013. The daily need of the patients was calculated according to their weight and two-thirds was injected before breakfast and one-third before dinner. The following insulin protocol was considered: breakfast: 2/3 of NPH and 1/3 of regular; dinner: 1/2 of NPH and 1/2 of regular (6). The person who gathered the data and the analyzer were unaware of the study goals.

Patients with type II diabetes needing insulin therapy who were not pregnant and didn’t have renal failure or diabetic foot and their discharge FBS was <150 mg/dL and 2hpp was <200 mg/dL were included in this study.

Complications which prolonged the hospital stay duration (myocardial infarction or infection), or more than two insulin injections and those who received oral diabetes medications and renal failure were excluded from the study. Renal failure was defined as creatinine >1 mg/dL in patients older than 60 years and creatinine >1.2 mg/ dL in patients younger than 60 years. After evaluating the medical records of 600 diabetic patients for 5 years, finally, 220 patients were eligible to participate in the study.

In all patients, treatment was initiated with the following proportions: Morning NPH: 44%; morning regular: 22%; evening NPH: 17%; and evening regular: 17%. These proportions were in accordance with the conventional protocol’s recommendations.

All patients were treated with the conventional protocol 2

Journal of Renal Endocrinology, Volume 7, 2021

and the insulin dose of the last admission day in which optimal glycemic control has been achieved was recorded.

We didn’t aim to evaluate the total insulin dose but aimed to study the ratio of NPH insulin and regular insulin and also the ratio of breakfast and dinner insulin. Other variables included age, gender, and duration of diabetes and also hospital stay.

Morning and evening NPH insulin and morning and evening regular insulin doses were calculated separately as a total daily dose and their percentages were obtained.

In all 220 patients, optimal glycemic control has been achieved.

The average dose of all four insulin boluses was extracted and based on these means, a protocol was made.

Finally, two groups were categorized. Group 1 consisted of patients whose discharge insulin dose was in the range of the mean data of the study (±2 IU/mL) were called “in accordance with the mean” and patients whose discharge insulin dose was in accordance with the conventional protocol (±2 IU/mL) were placed in group 2. The number “±2” was determined based on clinical justification which believes that a 1-2 unit change in insulin dose doesn’t have a clinical impact on patients but ±6 unit change has many clinical impacts. Therefor, all insulin doses were calculated with ±2 and finally, both groups were compared.

If the patient had at least two insulins (of four) in accordance with the protocol, it was defined as “in accordance with the protocol”. Finally, the conventional protocol patients were compared with the new protocol (based on the mean) ones. Additionally, the patients were divided into two groups of early and late control (before and after 4 days).

Ethical issues The research followed the tenets of the Declaration of Helsinki. Accordingly, written informed consent was obtained from all participants before any intervention.

Ethical approval was obtained from the Ethics Committee of Babol University of Medical Sciences (#8930329) and patients’ information remained confidential. This study was extracted from MD thesis of Hojatollah Ghorbani at this university (Thesis #2028). ‫‏‬S‎ tatistical analysis Data analysis was performed using Statistical Package for the Social Sciences (SPSS) version 17.0 (SPSS Inc., Chicago, IL, USA) using t-test or ANOVA for continuous variables, and a chi-squared test for binary/categorical variables and proportions.

Results In this study, 220 patients were evaluated which 53 (24.1%) with the mean age of 54.91 ± 13.95 years were male and 167 (76.9%) ones with the mean age of 55.34 ± 11.77 years were female. One hundred and seven (48.6%) were admitted to Rohani hospital and 113 (51.4%) patients were admitted

Comparison of two insulin injection methods on the control of type 2 diabetes

to Shahid Beheshti hospital. The mean insulin doses were as follows: Morning NPH: 34.2% ± 6.69; morning regular: 23.8 ± 6.36; evening NPH: 21.26 ± 6.75; evening regular: 20.74 ± 5.51.

Eighteen (8.2%) patients had morning NPH between 42-46% while 65 ones (29.5%) had regular insulin between 20-24%. Fifty-two (23.6%) patients had evening NPH between 15-19% and evening regular 15-17% was observed in 51(23.2%) cases. Morning NPH between 3236% was seen in 57 ones (25.9%) and 64 ones (29.2%) had morning regular insulin dose between 21-25%. Evening NPH and regular insulin between 19-23% were observed in 56 (25.5%) and 72 cases (32.7%), respectively.

Table 1 shows the percentages of insulin separately.

Conformity has been defined if two of four insulins were in accordance with one protocol, the patient was assigned to participate in the non-conforming group.

Of 220 patients who started insulin therapy, only 39 patients (17.7%) had at least two insulin doses conforming to the conventional protocol and 76 ones (34.5%) had at least two insulin doses conforming to the mean protocol at discharge day (Table 2) and their difference was not statistically significant (P = 0.006).

The mean age of the patients in both groups was not statistically different (P = 0.08). Diabetes duration in conventional and the mean group were 11.44 ± 7.44 and 9.32±6.75 years, respectively (P = 0.051). The duration of hospitalization was between 2-13 days (5.25 ± 1.7 days) and 79 patients (36.1%) needed less than 4 days (early control group) while 140 patients (63.9%) needed more than 4 days to control their blood glucose (late control group).

Age and diabetes duration were not significantly different in these two groups (P = 0.89 and P = 0.94, respectively).

Also, they were not associated with both protocols.

costly disease due to its chronic nature, the severity of its complications, and the therapeutic approaches to control them (9). Consequently, patients need hospital inpatient care to initiate insulin therapy and finding a way to decrease its duration is economically important. In this study, we aimed to determine if the discharge NPH and regular doses in which optimal glycemic control can be achieved, are similar to those at the initiation of protocol or not. We found that the required dose of regular is higher than the conventional protocol’s prediction (44% versus 39%). In addition, the need to evening insulin increased in comparison with the conventional protocol (42% vs. 34%) which might be due to the difference in our diet and our physiological differences with the western community.

Previous studies showed that higher slow-acting insulincontaining regimens control the patients better (11-13).

The difference in insulin percentage between the two groups was a 10% reduction in morning NPH which was added to evening insulin. It may be due to the low-calorie breakfast and high-calorie dinner of the patients.

We found that the initiation of insulin therapy with the conventional method causes 17.7% control of the patients and 82% of the patients are controlled with different proportions of this protocol. These findings raised the question that can we define an insulin therapy protocol for type II diabetic patients based on the data mean? Based on the results, the insulin ratio of 34.5% of the patients who had glycemic control was within a range. This protocol can be used as a guideline for insulin therapy initiation and the physiological difference of the patients will change these ratios based on their blood glucose level. So, we made a new protocol. Maybe other studies confirm the impact of this protocol on faster glycemic control and reduce the hospitalization duration. It is recommended in conventional therapy to inject one-third of the patient’s insulin requirement in the morning as NPH and divide the remained two-third between morning regular and evening NPH and regular (6).

Our study showed that adherence to a certain protocol

Discussion Diabetes mellitus is emerging as a major health problem, with rising prevalence and complications (10). The economic burden of diabetes is enormous and it is a

Table 1. Frequency of the patients based on conventional protocol and the means Conventional

The mean

Kappa

P value

Morning NPH

18 (8.2%)

57 (26%)

0.14

0.009

Morning regular

65 (29.5%)

64 (29.2%)

0.01

0.58

Evening NPH

52 (23.6%)

56 (25.5%)

0.32

0.001

Evening regular

51 (23.2%)

72 (32.7%)

0.37

0.001

Protocol Insulin

Table 2. Comparison of total conform with two protocols Conventional protocol

Data mean Non-conforming

Conforming

Total

Non-conforming

111 (61.3%)

70 (38.4%)

181 (82.3%)

Conforming

33 (84.6%)

6 (15.4%)

39 (17.7%)

Total

144 (65.5%)

76 (34.5%)

220 (100%)

Journal of Renal Endocrinology, Volume 7, 2021

3

Bayani MA et al

and also hospitalization period are not related to age, gender and diabetes duration (P > 0.05). Comino et al reported that the association between male gender and the risk of hospitalization was enhanced in people with diabetes (14). In Schneider and colleagues’ study, diabetes duration was moderately associated with the risk of hospitalization, but this result was not significant (P = 0.102) (15).

We observed that the insulin ratio of the conventional protocol was unchanged in only 17.7% of the patients and these ratios were not found in 82.3% of them. Only 34.5% of the patients could include in the new protocol (about two-fold of the conventional protocol) and 50% of the patients’ ratio didn’t fit any protocol. It can be justified by the physiological difference of the patients (12,16). It confirms various protocols in different people and our study predicted the probability of these various protocols’ existence.

Not only a greater proportion of participants with diabetes admitted were younger than those without diabetes, but also the association between age and hospital admission was attenuated for participants with diabetes.

This suggests that diabetes may have an “aging effect” that leads to poorer health outcomes at an earlier age for diabetics compared to those without diabetes. Once adjusted for age and gender, the patterns of socioeconomic factors influencing the relative rate of hospitalization were broadly similar (14).

A frequent complication following glycemic control in diabetics is hypoglycemia which is defined as a blood glucose level <70 mg/dL (17). In the case of better hyperglycemic control, it is a predictable complication (18) and this protocol may increase the number of patients experiencing hypoglycemia. But using this protocol at beginning of treatment can reduce the time to achieve glycemic goals and hospitalization duration. It is suggested to evaluate this protocol for insulin therapy initiation at home (due to the difference of home regimen with the hospital).

In diabetic patients who were hospitalized for insulin therapy, insulin starts with a dose of two-third in the morning and one-third in the evening and increases based on patient’s glucose level. As shown in this study, this ratio is often disturbed when discharging and only 17% of the patients discharged with the initial insulin ratio.

Our study hypothesizes that if the pre-mix insulin dose, which usually starts with 70/30 pre-mix (2/3 in the morning and 1/3 in the evening), starts with 75/25 in the morning and 50/50 pre-mix at night, patients will probably have better glycemic control. RCT studies are required to prove this theory. The insulin proportion that we suggested in this study was 1/2 morning NPH, 1/3 other insulins with equal proportion and 1/3 evening NPH, and morning and evening regular because it is more consistent with the patient’s final insulin (43%).

4

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Conclusion The discharge insulin ratios of the conventional protocol were similar to that of the admission ratios in only 17.7% of the patients. It is suggested to inject one-third of the total daily insulin need of the patients as NPH in the morning and divide the remained two-third between morning regular, evening NPH and evening regular equally. This may decrease the length of hospital stay and decrease the time to reach the desired glycemia. We also found that 50% of the patients’ ratio didn’t fit any protocol that shows the physiological difference of the patients and can justify the existence of different protocols for patients.

Limitations of the study Limitations of this study must be stated. First, BMI and weight of the patients were not recorded and we were not able to calculate GFR. Second, the patients did not follow any diet. Although most of the patients ate hospital foods, some of them consumed other foods which might confound the study results. Another confounding factor may be the difference in patients’ physical activity during the hospitalization period. A sedentary lifestyle is a powerful but modifiable risk factor for diabetes; therefore, moderate exercise is of the utmost benefit in patients with diabetes (19).

Authors’ contribution MAB: concept, design, manuscript preparation and final revision; HG: performing experiments, data collection and writing proposal; RA: data collection, statistical analysis, provision of the first draft, manuscript editing.

Conflicts of interest The authors stated that they have no conflict of interest.

Ethical considerations Ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the authors. ‫‏‬‎Funding/Support ‎‫‏‬This manuscript was extracted from the internal medicine specialty thesis of Hojatollah Ghorbani (#2028) that was financially supported by the deputy of Research and Technology of Babol University of Medical Sciences (code #8930329).

References 1. Standl E, Khunti K, Birgitte Hansen T, Schnell O. The global epidemics of diabetes in the 21st century: Current situation and perspectives. Eur J Prev Cardiol 2019; 26: 7-14.

2. Sakamoto M, Inoue G, Tsuyusaki K, Usui K, Watanabe M, Irie J, et al. Comparison of oxidative stress markers in type 2 diabetes: Basal bolus therapy versus twice daily premixed insulin analogs. Intern Med. 2010;49:355-9.

3. Guidoni CM, Borges APdS, Freitas Od, Pereira LRL. Prescription patterns for diabetes mellitus and therapeutic implications: a population-based analysis. Arq Bras Endocrinol Metabol.

2012;56:120-7.

4. Ray KK, Seshasai SRK, Wijesuriya S, Sivakumaran R, Nethercott S, Preiss D, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised

Comparison of two insulin injection methods on the control of type 2 diabetes controlled trials. Lancet. 2009;373:1765-72. doi: 10.1016/ S0140-6736(09)60697-8.

5. Artigas CF, Stokes V, Tan GD, Theodorakis MJ. Insulin dose adjustments with add-on glucagon-like peptide-1 receptor (GLP1R) agonists in clinical practice. Expert Opin Pharmacother.

2015;16:1417-21. doi: 10.1517/14656566.2015.1052740.

6. Rodbard H, Blonde L, Braithwaite S, Brett E, Cobin R, Handelsman Y, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract. 2007;13 Suppl 1:1-68. doi: 10.4158/EP.13.S1.1 7. Schnell O, Hanefeld M, Monnier L. Self-monitoring of blood glucose: a prerequisite for diabetes management in outcome trials. J Diabetes Sci Technol. 2014;8:609-14. doi: 10.1177/1932296814528134.

8. García-Pérez LE, Alvarez M, Dilla T, Gil-Guillén V, OrozcoBeltrán D. Adherence to therapies in patients with type 2 diabetes. Diabetes Ther. 2013;4:175-94. doi: 10.1007/ s13300-013-0034-y.

9. Gyawali B, Ferrario A, van Teijlingen E, Kallestrup P. Challenges in diabetes mellitus type 2 management in Nepal: a literature review. Global Health Action. 2016;9:1-12. doi: 0.3402/gha. v9.31704.

10. Ma RCW. Epidemiology of diabetes and diabetic complications in China. Diabetologia. 2018;61:1249-60. doi: 10.1007/ s00125-018-4557-7.

11. Fritsche A, Larbig M, Owens D, Häring HU. Comparison between a basal‐bolus and a premixed insulin regimen in individuals with type 2 diabetes–results of the GINGER study.

Diabetes Obes Metab. 2010;12:115-23. doi: 10.1111/j.14631326.2009.01165.x.

12. Malone J, Bai S, Campaigne B, Reviriego J, Augendre‐Ferrante B. Twice‐daily pre‐mixed insulin rather than basal insulin

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therapy alone results in better overall glycaemic control in patients with Type 2 diabetes. Diabet Med. 2005;22:374-81. doi: 10.1111/j.1464-5491.2005.01511.x Qayyum R, Wilson LM, Bolen S, Maruthur N, Marinopoulos SS, Feldman L, et al. Comparative effectiveness, safety, and indications of insulin analogues in premixed formulations for adults with type 2 diabetes. Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. 2008.

Comino EJ, Harris MF, Islam MF, Tran DT, Jalaludin B, Jorm L, et al. Impact of diabetes on hospital admission and length of stay among a general population aged 45 year or more: a record linkage study. BMC Health Serv Res. 2015;15:12. doi: 10.1186/s12913-014-0666-2.

Schneider AL, Kalyani RR, Golden S, Stearns SC, Wruck L, Yeh HC, et al. Diabetes and Prediabetes and Risk of Hospitalization: The Atherosclerosis Risk in Communities (ARIC) Study. Diabetes Care. 2016;39:772-9. doi: 10.2337/ dc15-1335.

Roach P, Yue L, Arora V. Improved postprandial glycemic control during treatment with Humalog Mix25, a novel protamine-based insulin lispro formulation. Humalog Mix25 Study Group. Diabetes Care. 1999;22:1258-61.

American Diabetes Association. Standards of medical care in diabetes—2010. Diabetes Care. 2010;33:S11-61. doi: 10.2337/dc10-S011.

Saudek CD, Derr RL, Kalyani RR. Assessing glycemia in diabetes using self-monitoring blood glucose and hemoglobin A1c.

JAMA. 2006;295:1688-97. doi: 10.1001/jama.295.14.1688.

Nyenwe EA, Jerkins TW, Umpierrez GE, Kitabchi AE. Management of type 2 diabetes: evolving strategies for the treatment of patients with type 2 diabetes. Metabolism.

2011;60:1-23. doi: 10.1016/j.metabol.2010.09.010.

Journal of Renal Endocrinology, Volume 7, 2021

5

Open Access Original Journal of

Renal Endocrinology

J Renal Endocrinol 2021;7:e11. http://www.jrenendo.com

Nickan

doi: 10.34172/jre.2021.11

Research Institute

Examination of the relationship between health literacy and health perceptions in hemodialysis patients ID

Mukadder Mollaoğlu1 ID , Esra Başer1* , Ferhan Candan2

ID

Abstract Introduction: Patients’ high levels of health literacy and positive perception of health are effective in their compliance with the treatment.

Objectives: The aim of this study was to examine the relationship between health literacy and the perception of health of hemodialysis patients.

Patients and Methods: In the study, the sampling method was not performed, but it was performed with patients who received hemodialysis treatment and fulfilled the research criteria within the 3-month period. The descriptive study was conducted with a total of 110 patients in two dialysis centers Sivas province of Turkey.

Results: Data were collected using the patient information form, Health Literacy Index (HLI) and perception of health scale (PHS) to determine demographic characteristics. Around 56.4% of the patients had been receiving hemodialysis treatment for 0-4 years. The mean score of patients’ health literacy was 77.40±12.94, and they received the highest score from the appraisal of the subscales. Perception of health mean score was 47.56±4.10. When sociodemographic characteristics were examined, health literacy levels were found to be high in males between the ages of 36-45 years, those with a long duration of chronic kidney disease (CKD) and those with higher education level.

Conclusion: According to results patients’ health literacy and disease perception were found to be slightly above the middle level. We found a positive relationship between health literacy level and perception of health, and patients’ health literacy since the perception of health should be increased in order for the hemodialysis treatment process to be effective.

Keywords: Health literacy, Health perception, Hemodialysis patients Citation: Mollaoğlu M, Başer E, Candan F. Examination of the relationship between health literacy and health perceptions in hemodialysis patients. J Renal Endocrinol. 2021;7:e11. doi: 10.34172/jre.2021.11.

Copyright © 2021 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction Prevalence of chronic kidney disease (CKD) has increased in the world and in our country due to increased prevalence of diabetes, hypertension, obesity and aging (1,2). According to the current classification by The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI), CKD is divided into five stages (3). The 5th phase of CKD is defined as endstage renal failure (ESRD), and at this stage, dialysis, transplantation or only symptom control is required (4).

In Turkey, 75.84% of patients receiving renal replacement therapy also receive hemodialysis treatment (5).

The aim of CKD management is to reduce the progression of ESRD, reduce urinary complications and maintain kidney function (6). Due to the long-term treatment of CKD, the decrease in self-care ability of dialysis patients, loss of competence and the complexity of the life-style change, patients have difficulty in compliance

with the process and performing the specified strategies (7,8). The long-term treatment process requires patients’ decision making and participation in the process. Patients need to use and access health information in order to be able to effectively make health decisions and implement them. According to the WHO definition “Health literacy is based on general literacy and encompasses people’s knowledge, motivation and competences to access, understand, evaluate and apply information on health in order to make judgements and make decisions concerning healthcare, disease prevention and promotion of health to maintain and improve quality of life during their lifetime” (9).

Health literacy is an individual’s capacity to obtain, process, and understand basic health information and services required to make appropriate health decisions and act accordingly (10). Nutbeam, who has studies on health literacy, discusses health literacy in three levels

Received: 16 February 2021, Accepted: 14 March 2021, ePublished: 10 April 2021 Internal Medicine Nursing, Department of Nursing, Faculty of Health Science, Sivas Cumhuriyet University, Sivas, Turkey.

Internal Medicine, Department of Nephrology, Faculty of Medicine, Sivas Cumhuriyet University, Sivas, Turkey. *Corresponding Author: Esra Başer, Email: esra_baser568@hotmail.com 1 2

Mollaoğlu M et al

Implication for health policy/practice/research/ medical education In a study on hemodialysis patients, we found a positive relationship between health literacy level and perception of health.

as functional/basic, communicative and critical levels.

Health literacy enables an effective communication between health service providers and patients receiving health care, allowing both parties to understand each other correctly and fulfill their responsibilities (11). When the literature is examined, it is found that people who high level of health literacy apply to health services in a timely manner, follow the recommendations of health personnel more, improve their health and healthy behavior in a positive way and analyze their health status better (12-15).

When the literature is reviewed, it is seen that the health literacy in patients with CKD is low. In a study conducted in the United States, it was found that 23% of the patients who received hemodialysis treatment had insufficient health literacy (16). In a study conducted in Turkey, 52.7% of patients’ health literacy levels were found to be problematic or at an insufficient level (17). In a study examining the level of health literacy in elderly individuals with chronic disease, it was found that health literacy was between having little difficulty and having some difficulty according to the mean scores of the scale (18). Inadequate health literacy is associated with poor health outcomes, such as high blood pressure, insufficient dialysis and frequent referral to emergency services in patients with CKD (19,20).

Individual’s perceptions, beliefs and attitudes are effective in creating behaviors that affect the health of the individual (21). Perception of health is an indicator of how the individual evaluates his/her health with its biological, psychological and social aspects. The positive perception of the individual’s health status enables him/her to control his/her future health status and to develop behaviors that will positively affect his/her health (22). Patient’s positive perception of his/her health supports him/her in the treatment of chronic diseases such as CKD where patient’s self-management is influential. When there is a situation that threatens the individual’s health, the individual responds to it by improving his/her cognitive and emotional perceptions (23,24).

There is a direct relationship between health literacy and the perception of health. In studies conducted, it is seen that scores of health literacy scale decrease as the level of perception of health worsens (18,25-27). Positive health outcomes and health promotion efforts are directly related to health literacy (28).

In the light of the above data, it can be seen that the patient has a one-to-one participation in the course of the long-term treatment of CKD, and that he/she is required 2

Journal of Renal Endocrinology, Volume 7, 2021

to adapt to the lifestyle changes. Health literacy is greatly influential in the compliance of patients with CKD, and its importance in the field of health communication is increasing in terms of improving the health of individuals.

Objectives The aim of this study was to determine the levels of health literacy and perception of health of patients with CKD, which is one of the chronic diseases with increasing prevalence and to determine the relationship between health literacy and perception of health in hemodialysis patients, considering that the quality of nursing care to be given for the management of the disease would improve. Our hypothesis is that health literacy and health perception affect each other.

Patients and Methods Study design It was a descriptive study in order to examine the relationship between health literacy and the perception of health in hemodialysis patients. The research was carried out at two dialysis centers. In the study, the sampling method was not performed, but it was performed with patients who received hemodialysis treatment and fulfilled the research criteria within the 3-month period.

The descriptive study was conducted with a total of 110 patients in two dialysis centers Sivas province of Turkey.

One of the center is private and the other was university hospital dialysis center. The study was conducted by one researcher.

The exclusion criteria were as follows; those who had received hemodialysis treatment for less than one year, had difficulty in seeing, hearing and communicating, those under 18 years of age and those who wanted to leave the study were excluded from the study.

Data collection Research data were collected through the forms described below.

Patient information form It was prepared using the literature. The form consists of 11 questions to determine the sociodemographic characteristics of the patients.

Health literacy index The 47-item HLS-EU (Health Literacy Survey In Europe) developed by Sorensen (2013) and the 25-item Health Literacy Index (HLI), which was simplified afterwards

by Tochi, Bruzari and Sorenson, were used (9). The validity and reliability study of this scale was conducted by Çimen and Temel, who adapted it to Turkish (17).

The scale consists of 25 items and four sub-scales: access to Information contains five items (minimum: 5 points, maximum: 25 points), understanding Information seven items (min: 7 points, max: 35 points), appraisal eight items

Health literacy in HD

(min: 8 points, max: 40 points) and application five items (min: 5 points, max; 25 points). The minimum score to be received from the scale is 25 and the maximum score is 125. Scale items are answered by participants in the form of Likert as;5: I have no difficulty, 4; I have some difficulty, 3; I have little difficulty, 2; I have a lot of difficulties, 1; I am not able to do it/I have no skill/It is impossible Cronbach Alpha coefficient for the internal consistency of the original scale form’s subscales ranged from 0.90 to 0.94 (27). In the Turkish version, the Cronbach alpha value was found as 0.92, while the alpha value of sub-dimensions was 0.62 and 0.79. Low scores indicate that health literacy is insufficient, while high scores indicate that it is sufficient and very good (18).

Access to information evaluates information about how and where to obtain information about their disease.

Understanding information, evaluating and interpreting the data obtained. Appraisal the ability to distinguish the information provided with critical thinking from those that are useful and harmful to it. The application evaluates the ability to make lifestyle changes in line with the information obtained and to apply this information.

Perception of health scale It is developed by Diamond et al in 2007 (21). The scales measure previous health, current health, health appearance, resistance/sensitivity to illnesses, health concerns/anxiety, disease tendency, rejection of patient’s role and their attitudes towards attending the doctor. It was adapted to Turkish by Kadıoğlu and Yıldız (29). It is a 5-category Likert scale consisting of 15 items. 1st, 5th, 9th, 10th, 11th and 14th items are the expression of positive attitude, while 2nd, 3rd, 4th, 6th, 7th, 8th, 12th and 13th items are the expression of negative attitude. Positive expressions are scored as “I totally agree=5”, “I agree=4”, “I do not agree=3”, “I disagree=2”, “I totally disagree=1”.

Negative attitudes are subject to reverse scoring. Scoring ranges from 15-75. Cronbach’s alpha was found as 0.897 according to the sub-scales of the scale. Developed by Diamond et al, this scale was applied to an adult group (n= 322), and they found Cronbach’s alpha value of subgroups as 0.90 for center of control, 0.91 for self-awareness, 0.91 for certainty and 0.82 for importance of health (21).

Kadıoğlu et al (2012) found that Cronbach’s alpha value varied between 0.60 and 0.76 in nursing students (center of control 0,76; Self-Awareness 0,63; Certainty 0,71; Importance of Health 0,60) and between 0.53 to 0.73 in students’ families (center of control 0.67; self-awareness 0.53; certainty 0.73; importance of health 0.54) in the Turkish version The patients in the center where the research was conducted were informed about the research. Data collection forms were applied by the investigator for 1520 minutes in the form of a question-answer form after patients, who volunteered to participate in the study, filled out the consent forms.

Ethical issues The study was conducted in accordance with the Declaration of Helsinki. Prior to the study, necessary permissions were obtained from the Ethics Committee of Non-Interventional Clinical Investigations Ethics Committee decision date: 26.02.2018 (number#2018-01/ 22).

Data analysis SPSS 22.0 software was used for statistical evaluation of the data. The Kolmogorov-Smirnov test was used for the evaluation of the normality of data, and in the analysis of the descriptive properties of individuals mean ± standard deviation were used for figures, percentages and continuous variables if the data provide parametric conditions, independent t test was used for two independent groups, and the Kruskal-Wallis test was used for more than two independent groups. The statistical significance level was taken as 0.05.

Results Around 50.9% of the study sample were female, 54.5% were between 46-65 years of age, 48.2% were graduated from primary school. 56.4% had been receiving hemodialysis treatment for 1-4 years, 82.7% had a chronic disease other than CKD, and hypertension ranks first with 60% among the patients as one of the chronic diseases. The characteristics of participants are presented in Table 1.

When the mean scores of patients’ health literacy are examined, the mean score was 77.40 ± 12.94 and the appraisal has the highest value, with and the mean score of 26.83 ± 4.60 from the scale sub-dimension (Table 2).

According to health literacy (item mean score: 3.09) scale mean scores of individuals, it is seen that the level of health literacy is between having little difficulty and having some difficulty.

Table 3 shows patients’ perception of health levels.

Perception of health scale (PHS) mean score was found as 47.56 ± 4.10 (min: 15.00 max: 75.00). According to scores, patients’ health perceptions were moderate. The scores of the patients from the scale sub-dimensions, respectively center of control 13.96 ± 2.73, certainty 11.50 ± 2.41, selfawareness 12.00 ± 1.08 importance of health 10.61 ± 1.92.

Health perception scale was obtained from the subdimensions and the highest score was obtained from the self-control sub-dimension.

In Table 4, comparison of the scale scores in terms of the sociodemographic characteristics indicated that the males (83.57 ± 10.67), those within the age range of 26-35 (106.50 ± 26.1) and those who work as officer (95.8 ± 17.06) were found to have significantly higher mean scores of health literacy. Similarly, as education level, duration of hemodialysis treatment and duration of CKD disease increased, health literacy scale score was higher (P < 0.005). There was no statistically Journal of Renal Endocrinology, Volume 7, 2021

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Mollaoğlu M et al Table 1. Sociodemographic and medical characteristics of patients Characteristics

Number ()

Age range (y)

Subscales

HLI Mean Scores Mean ± SD

Min-Max

14.87 ± 3.85

5.00-25.00

18-25

2 (1.8)

Access

26-35

2 (1.8)

Understanding

18 ± 5.28

7.00-35.00

36-45

9 (8.2)

Appraisal

26.83 ± 4.60

8.00-40.00

46-65

60 (54.5)

Application

17.69 ± 2.41

5.00-25.00

65 and upper

37 (33.6)

Total

77.40 ± 12.94

25.00-125.00

Abbreviation: HLI, Health Literacy Scale; SD, standard deviation.

Gender Female

56 (50.9)

Male

54 (49.1)

Marital status Married

82 (74.5)

Single

28 (25.4)

Officer labourer Retired House wife

HLI Mean Scores Min-Max

13.96 ± 2.73

5.00-25.00

5 (4.5)

Certainty

11.50 ± 2.41

4.00-20.00

6 (5.5)

Self-awareness

12.00 ± 1.08

3.00-15.00

37 (33.6)

Importance of health

10.61 ± 1.92

3.00-15.00

53 (48.2)

Total

47.56 ± 4.10

15.00-75.00

8 (7.3)

Student

1 (0.9)

Educational degree Illiterate

15 (13.6)

Literate (no school)

23 (20.9)

Primary school

53 (48.2)

High school

13 (11.8) 6 (5.5)

Hemodialysis vintage (y) 1-4

62 (56.4)

5-9

29 (26.4)

10-14

8 (7.3)

≥15

11 (10)

Comorbidities Diabetes Mellitus

Subscales Center of control

Self-employment

University

Table 3. Patients’ perception of HLI mean scores

Mean ± SD

Occupation

56 (50.9)

Hypertension

66 (60)

Hearth Failure

31 (28.2)

Coronary artery disease

3 (2.7)

Other (COPD, gastritis etc. )

11 (10)

significant relationship between perception of health and sociodemographic characteristics.

When the relationship between health literacy and health perception was examined, a significant positive correlation was found between two scales (Table 5). As health perception of patients increases, health literacy levels also increase.

Discussion Health literacy affects decisions made by people to improve their quality of life, maintain their health and prevent diseases (30). The health literacy is important in chronic cases requiring active participation and compliance of the patient with the treatment process, like hemodialysis treatment (19). When the literature is 4

Table 2. Hemodialysis patients’ HLI and subscales mean scores

Journal of Renal Endocrinology, Volume 7, 2021

Abbreviation: HLI, Health Literacy Scale; SD, standard deviation.

reviewed, it is observed that the health literacy level of hemodialysis patients is low (31). In our study, according to health literacy (item mean score; 3.09) scale mean scores of individuals, it is seen that the level of health literacy is between having little difficulty and having some difficulty. Patients received the highest score in the appraisal sub-dimension and the lowest score in access to information dimension. When we look at the status of health literacy in the world, in the United States, which is one of the developed countries, 50% of adults do not have basic health literacy. In a study in which health literacy was assessed in patients with CKD, more than 40% of the patients had inadequate health-related attitudes (32). In the study with hemodialysis patients, roughly one third (32.3%) of participants had inadequate health literacy (33). It can be considered that individuals in the study evaluate the information they have acquired about health, and are competent to determine which medical information is appropriate for them. On the other hand, it is seen that they are lacking in accessing information, obtaining information from the health personnel and using visual literary tools such as the internet and television. This situation can be interpreted to be related to the low education level of the sample group.

Health literacy levels in various chronic diseases were examined. In a study with diabetic patients, health literacy levels were found to be sufficient (34). This result is thought to be related to continuous education of diabetic patients. In a study conducted in Nepal, 51.8% of hypertension patients and 77.2% of patients with chronic obstructive pulmonary disease (COPD) were found to have insufficient health literacy (35).

It has been observed that the education of the patients to learn about diseases may prevent the development

Health literacy in HD Table 4. Comparison of sociodemographic characteristics and mean scores of the scale HLI Mean ± SD

Features

Statistical test

PHS Mean ± SD

Statistical test

47.08 ± 4.00

t: -1.23, P = 0.219

Gender Female

71.46 ± 12.20

Male

83.57 ± 10.67

t: -5.53, P = 0.00

48.05 ± 4.19

Age (y) 18-25

72.50 ± 23.3

26-35

106.50 ± 26.1

46.5 ± 9.19

36-45

81.77 ± 9.03

46-65

78.63 ± 11.9

48.0 ± 3.70

65 and upper

73.05 ± 12.01

46.9 ± 4.05

Officer

95.8 ± 17.06

49.8 ± 6.01

Laborer

86.0 ± 12.85

46.66 ± 5.57

Retired

82.9 ± 11.9

House wife

70.0 ± 9.30

Self-employment

81.5 ± 5.04

48.2 ± 3.7

Student

89.00 ± 0.00

53.0 ± 0.00

Illiterate

65.87 ± 10.1

46.3 ± 3.93

Literate (no school)

69.27 ± 8.4

Primary school

79.75 ± 9.6

High school

85.76 ± 12.18

46.4 ± 4.6

University

99.16 ± 13.7

50.5 ± 5.61

54.5 ± 7.77 KW: 10.25, P = 0.036

45.33 ± 3.84

KW: 6.38, P = 0.172

Occupation

48.08 ± 4.35

KW: 37.56, P = 0.00

46.88 ± 3.56

KW: 2.60, P = 0.625

Educational degree 47.5 ± 3.6 KW: 44.7, P = 0.000

47.8 ± 3.9

KW: 4.44, P = 0.349

Hemodialysis vintage (y) 1-4

74.75 ± 12.38

5-9

80.34 ± 14.1

46.9 ± 3.9

10-14

79.00 ± 12.11

48.6 ± 2.5

≥15

83.45 ± 10.79

48.0 ± 2.7

1-4

73.48 ± 12.4

46.7 ± 3.7

5-9

75.36 ± 11.8

10-14

84.0 ± 14.0

≥15

83.0 ± 10.17

KW: 7.48, P = 0.058

48.3 ± 5.05

KW: 2.93, P = 0.402

CKD vintage (y) 47.3 ± 4.4

KW: 13.7, P = 0.003

49.6 ± 4.0

KW: 6.83, P = 0.077

47.5 ± 3.9

Abbreviations: HLI, Health Literacy Scale; PHS, perception of health scale.

Table 5. Relationship between health literacy and health perception Health Perception Scale

Health Literacy Index Information access Information understand Information appraise Information apply Total score of HLI

Center of Control

Certainty

Self- awareness

Importance of health

r

0.351

0.378

0.097

-0.164*

Total score of HPS 0.405

P

0.001a

0.001a

0.157

0.044

0.001a

r

0.272

0.346

0.086

-0.170*

0.328

P

0.002

0.001a

0.186

0.038

0.001a

r

0.315

0.440

0.097

-0.162*

0.418

P

0.001a

0.001a

0.157

0.046

0.001a

r

0.090

0.358

0.247

0.083

0.374

P

0.175

0.001a

0.005a

0.194

0.001a

r

0.344

0.477

0.145

-0.160*

0.473

P

0.001a

0.001a

0.066

0.047

0.001a

Abbreviations: HLI, Health Literacy Scale; PHS, perception of health scale. a P < 0.05

of symptoms related to disease or dialysis, and that individuals can manage the symptoms more effectively and their adaptation to the disease can be better achieved, thereby improving the quality of life (36,37). Education of the patient receiving dialysis in Turkey are provided by

the medical staff. In every dialysis session, the necessary information is given by the visit and controller and other healthcare professionals, especially nurses.

Chronic diseases adversely affect individuals’ perception of health. CKD is a chronic condition and necessitates Journal of Renal Endocrinology, Volume 7, 2021

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Mollaoğlu M et al

the individual to re-define the definition of health and to ensure the intrinsic motivation in adapting to the disease (38). As a result of the study, the overall total score of PHS was found as 47.56 ± 4.10. It can be said that patients’ health perceptions are moderate. In the study performed

by Yanmış and Ergüney with hemodialysis patients, the patients’ perceptions of health levels were similar to that of our study (39). The patients received the highest score from the subscales of health perception in the dimension of self-awareness. It can be interpreted as that people are aware that protecting their health is in their own hands. In a study conducted by Jansen et al, positive perception of disease and treatment was found to be related to the higher sense of self-determination and autonomy (40). Again, in another study conducted by Jansen, it was concluded that hemodialysis treatment significantly affected their daily lives and that their personal controls were at a low level (41). And another study with diabetic patients found that significant direct pathways were determined from empowerment perceptions to health literacy from selfefficacy to self-care behaviors (10).

In our study, health literacy scale scores of male patients, young people, officers and those with high education levels were found to be higher when health literacy and sociodemographic characteristics were compared.

Similarly to our study, in the study conducted by Çimen and Temel, health literacy scores increased as age decreased and education level increased (18). In the study conducted

by Toci et al with elderly individuals, it was found that health literacy scores decreased with increasing age (27).

This result can be explained by the low level of education of elderly individuals in our country. Because, according to 2015 data the proportion of illiterate individuals is 7.9 in Turkey (42). Health literacy rates of patients increase with the increase of education level. As a result, patients’ awareness against diseases is increasing.

Similarly to our study, Özdemir et al reported that women had lower health literacy in their study with 456 people using preventive health services (43). It can be interpreted that the result we obtained could be related to the low education level of women in our sample. On the other hand, in some studies, women’s health literacy levels were found to be higher (9,18).

In the studies, it was found that the level of knowledge increased as the patients’ kidney disease progressed and the interviews with health professionals increased (44).

In the present study, health literacy scale scores increased as the duration of CKD and hemodialysis treatment increased. Increasing knowledge about CKD in relation to health literacy can increase the self-care capacities of patients, ensure the effective use of the health system and improve the quality of health personnel-patient relations (16). As the duration of diagnosis increases, patients need to solve their own health problems with experience. For this reason, patients’ health perceptions and information increase in order to improve their health.

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Health literacy is associated with perceived health status.

Because people with the adequate health literacy are more likely to take action to solve their health problems if they actively learn about their health and feel that their health is deteriorating (45). In our study, a positive correlation was found between the health literacy and the perception of health. Health literacy scale scores of those with the high perception of health were also high. When the literature is examined, it has been shown that there is a relationship between the health literacy and the perception of health (46-48).

Conclusion In our study, examining the findings, it was concluded that there is a relationship between the health literacy and the perception of health. Additionally, the levels of health literacy and health perception of hemodialysis patients in the study were found to be moderate level. When the data were evaluated, it was concluded that the patients had difficulty in accessing the information but had no difficulty in applying the information about their health. Studies have shown that there is a relationship between compliance with dialysis treatment and health literacy and perception of health. The health literacy and health perceptions of the patients should be increased in order for the hemodialysis treatment process to be effective. At this stage, it is seen that nurses and health personnel interacting with the patient have an important role in evaluating the patients and providing education and information when necessary.

Moreover, the development of health literacy can be achieved through the joint efforts of different parties such as education sector, non-governmental organizations, academic environment, media and communication sector, as well as the health sector.

Within the limits of this study was to be performed in only one dialysis unit. The number of patients in the sample is small. However, very few studies have been conducted in our country. Therefore, this study is one of the pioneering studies. In the larger population it will be a guide for further studies.

Limitations of the study Within the limits of this study was to be performed in only one dialysis unit. The number of patients in the sample is small. However, very few studies have been conducted in our country. Therefore, this study is one of the pioneering studies. In the larger population it will be a guide for further studies.

Acknowledgements We would like to extend our sincere thanks to all the hemodialysis patients for their invaluable contributions to the study.

Authors’ contribution MM, EB and FC were the principal investigators of the study. MM and EB were included in preparing the concept and design. MM and FC revisited the manuscript and critically evaluated the intellectual

Health literacy in HD contents. All authors participated in preparing the final draft of the manuscript, revised the manuscript and critically evaluated the intellectual contents. All authors have read and approved the content of the manuscript and confirmed the accuracy or integrity of any part of the work.

Conflicts of interest The authors declare that they have no competing interests.

15.

16.

Ethical considerations Ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the authors.

17.

Funding/Support The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Open Access Journal of

Renal Endocrinology

Case Report J Renal Endocrinol 2021;7:e12. http://www.jrenendo.com

Nickan

doi: 10.34172/jre.2021.12

Research Institute

What about NSAID and secondary minimal change disease in adult’s people? A case report and review of the literature Erica E Faure1 ID , Jorge H. Mukdsi1*

ID

Abstract Non-steroidal anti-inflammatory drugs (NSAIDs) have been used in the management of inflammatory disease for decades. The spectrum of nephrotoxicity attributed to NSAIDs includes mainly acute tubulointerstitial nephritis. However, much less attention has been given to drug-induced glomerular injury. NSAIDs treating patients presenting with nephrotic syndrome may have a variety of glomerular changes indistinguishable from those found in idiopathic minimal change disease (MCD), for example. The clinical presentation is typically abrupt with nephrotic syndrome while in the elderly it can present as acute renal failure from the beginning. We present an MCD-NSAID induced in elderly patient and discuss possible pathogenic mechanism, thinking about on the indiscriminate use of NSAIDs. Here we report the case of a 66-year-old woman with a history of nephrotic syndrome and hypertension without an apparent secondary etiology. However, an exhaustive history showed and indiscriminate use of NSAIDs. Renal biopsy showed a MCD with a mild interstitial nephritis. To our knowledge the morphology of drug-induced diseases often does not differ from the primary forms, making the distinction difficult. There are subtle clues, although the dialogue between clinician and pathologist is essential to reach an etiological diagnosis. Physicians should suspect glomerulonephritis in patients who receive drugs and its management must be determined based on the histological characteristics of the disease. Although corticosteroid therapy seems to be of value, the effectiveness of this approach must still be tested in randomized and multicentric clinical trials.

Keywords: Non-steroidal anti-inflammatory drugs, Minimal change disease, Adult Citation: Faure EE, Mukdsi JH. What about NSAID and secondary minimal change disease in adult’s people? A case report and review of the literature. J Renal Endocrinol. 2021;7:e12. doi: 10.34172/jre.2021.12.

Copyright © 2021 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction The kidneys are a frequent target by many drugs used in clinical practice that can exert significant damage in their structure and, therefore, in the function (1). The incidence of acute renal injury related to drugs can be greater than 60%, which can be very expensive and require multiple interventions, including hospitalization (2).

The drug injury could present 4 possible phenotypic forms: acute renal failure, glomerular lesion, tubular lesion or nephrolithiasis. The clinical presentation includes increased creatinine, proteinuria, glomerular hematuria, electrolyte abnormalities and ultrasonographic findings of nephrolithiasis, respectively (3). The spectrum of nephrotoxicity attributed to non-steroidal anti-inflammatory drugs (NSAIDs) includes acute tubular necrosis, acute tubulointerstitial nephritis, glomerulonephritis, papillary necrosis, chronic renal failure, sodium and water retention, hypertension, hyperkalemia and hyperreninemic hypoaldosteronism (4).

The most common is tubular or interstitial damage, resulting in acute tubular necrosis or acute interstitial

nephritis, which are dose-dependent processes (5), although there are reports of subclinical renal dysfunction and, chronic renal insufficiency (4). Much less attention has been given to drug-induced glomerular injury (6,7).

NSAIDs patients treated presenting with nephrotic syndrome may have a variety of glomerular changes indistinguishable from those found in minimal change disease (MCD), membranous glomerulonephritis (MG), focal segmental glomerulosclerosis (FSGS). These complications have almost occurred in association with acute interstitial nephritis (8). The mechanisms of NSAIDs induced nephropathies have not been explained. Most authors consider that each of them is a separate entity with own mechanisms. Considering increasing use of these drugs, nephropathy is a rare complication. One possible explanation is that they have a common cause and that the pathogenic processes are modulated by secondary factors that can vary from one patient to another (9).

Case Presentation A 66-year-old woman, with hypertension of 15 years of evolution, hearing loss and ex-smoking, begins in 2018

Received: 4 February 2021, Accepted: 23 March 2021, ePublished: 16 April 2021 Universidad Nacional de Córdoba, Facultad de Ciencias Médica, Centro de Microscopía Electrónica, Córdoba, Argentina. *Corresponding Author: Jorge Mukdsi; Email: mukdsijorge@gmail.com, jorge.mukdsi@unc.edu.ar 1

Faure EE et al

Implication for health policy/practice/research/ medical education Association between drugs and glomerulopathies is not uncommon. Minimal change disease induced by nonsteroidal anti-inflammatory drugs is not different from idiopathic minimal change disease. The dialogue between clinician and pathologist is essential to reach an etiological diagnosis.

May with ankles and thighs edema and blood pressure values higher than usual. She is hospitalized in 2018 September due to edema and dyspnea, and she was studied for nephrotic syndrome without diagnosis. She received antiproteinuric drugs. Another nephrologist, requests a renal biopsy for nephrotic syndrome. An exhaustive history showed and indiscriminate use of NSAIDs The laboratory showed: total cholesterol 405 mg/dL, triglycerides 267 mg/dL, proteinuria 5.5 g/24 h, albumin 2.2 g/dL, creatinine 3 mg/dL, HbA1c 5.5%. HBV viral serology negative. Autoimmune serology: ANCAc, ANCAp: negative. ANA 1/20. Urinary sediment without particularities. On the other hand, renal ultrasonography reported right and left kidney, both of 10x5x5 cm, with preserved corticomedullary relationship and without dilatation. The fundus showed a grade I hypertensive retinopathy.

The high-resolution optical microscopy showed three glomerular structures without major alterations, with slightly hypertrophic podocytes (Figure 1). The interstitium exhibited mild edema and few eosinophilic polymorphonuclear leukocytes, highlighting the presence of several of these in peritubular capillary lumens. Focal fibrosis and slight tubular atrophy, were observed.

The ultrastructural study reveals normal glomerular basement membranes with paramesangial folds by sectors.

Podocytes exhibit very extensive and severe pedicel fusion with microvillus transformation and vesicularization of

Figure1. High-resolution optical microscopy showed normal glomerulus with prominent podocyte (p). M: mesangium; e: endothelium. Original magnification ×400.

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their cytoplasm (Figure 2). No tubulo-reticular inclusions are identified in cytoplasm of endothelial cells or clear deposits of immune complex type.

Discussion The drug-induced glomerular disease is a poorly defined and recently reported entity (10) and, although is a rare condition, causes significant morbidity and mortality, with most of the drugs that cause it associated with MCD or MG (6).

Drug exposure glomerular lesion can be classified into two specific forms: direct cell toxicity and immunemediated injury (11).

The immune-mediated injury includes antibodies formation induced by haptens, toxins against visceral epithelium or T cells with cytokine secretion and glomerular endothelial cells injury, contribute to glomerular disease after drug exposure (5).

Some NSAIDs can produce severe proteinuria and nephrotic syndrome associated with glomerular lesions identical to those seen in the MCD. In most, but not in all cases, there is a concomitant acute interstitial nephritis characterized by the influx of polyclonal B and T cells.

Although interstitial inflammation could predict a drugrelated MCD, some reports have indicated that the drugs can produce it without inflammation (12).

Secondary MCD accounts for 10% of all cases, mainly in adults, with only a few recognized causes, including drugs and Hodgkin’s lymphoma. The primary defect in MCD and FSGS appears to be related to podocyte dysfunction with diffuse slough of pedicel processes and absence of immune deposits, as the main diagnostic features. The clinical presentation is typically abrupt with nephrotic syndrome and, rarely with hematuria or hypertension, while in the elderly it can present as acute renal failure from its beginning, as in our patient, presumably due to the existence of previous vascular disease. Warren et al reported that 5 of 55 cases of adult MCD were due to NSAIDs and interstitial nephritis was common in these

Figure 2. Electron microscopy shows diffuse foot process effacement.

GBM: glomerular basement membrane; e: endothelium; L: capillary lumen. Original magnification ×7500.

NSAID and minimal change disease

biopsies (13).

Regarding physiopathogenic mechanism, a drug can directly affect a cell type, modifying the immune system or cell metabolism resulting in a specific pattern of glomerular injury. The glomerular drug-induced injury can primarily affect the immune system and lead to the production of autoantibodies, resulting in several druginduced glomerulopathies (6).

The drugs that cause FSGS are, for the most part, similar to those that cause MCD. The systemic release of factors that increase the capillary perm-selectivity may be the basis for the association between drug exposure and MCD (5). However, Ravnskov consider that a toxic effect on the podocyte is unlikely because in other NSAIDs treated patients is not followed by proteinuria, and on contrary sometimes they have been used to reduce the nephrotic syndrome (9).

Although Markowitz et al argues that the available data do not support a relationship between NSAIDs and FSGS, many publications claim that drug-induced podocytopathies consist of MCD and FSGS, including both NOS and collapsing type. Although the relationship between MCD and FSGS has been a debate area and most patients with MCD do not progress to FSGS or vice versa, multiple therapeutic agents are associated with both conditions (6). Both diseases are associated with nephrotic syndrome and share diffuse changes in podocytes in the absence of immune deposits (1). Risk factors and mechanisms of NSAID-induced nephrotic syndrome have not been characterized, but it is known that the inhibition of cyclooxygenase by these drugs can result in vascular permeability increase in glomerular and peritubular capillaries and, consecutively, in proteinuria.

Similarly, by the same mechanism, activated T cells secrete cytokines that can cause podocyte injury and increase glomerular permeability (1).

The classic renal findings of MCD are the presence of normal glomeruli without tubulointerstitial inflammatory changes (7). On the other hand, Feinfeld et al postulate that his patients represent the second case of nephrotic syndrome associated with NSAIDs with a pattern of MCD and absence of interstitial nephritis, suggesting that glomerular and interstitial lesions can occur independently (14).

The NSAID-induced MCD can be independent of the dose and can resolve spontaneously without medical intervention (7). The fact that the lesion appears only in a small proportion of patients, makes it unlikely that it is only due to a direct pharmacological effect of the drug. The glomerular changes are indistinguishable from those of the idiopathic “minimal change”. Proteinuria of the nephrotic range has only been rarely reported in association with acute interstitial nephritis induced by drugs, caused by other drug classes than NSAIDs. Most cases of acute interstitial nephritis do not have concomitant glomerular proteinuria. The nephrotic syndrome of MCD, with or

without associated interstitial nephritis, can probably be a complication of therapy with any NSAID. In the case of MG, immune complexes would be formed secondary to the increase in glomerular patency due to hyperactivity of the immune system (15,16). Since this drug-associated injury usually decrease spontaneously and rapidly in a few weeks (which is an unlikely event in a large number of patients with nephrotic syndrome due to idiopathic MCD), corticosteroid therapy in this adult population is probably not indicated initially. The withdrawal of the agent is usually associated with complete resolution, but corticosteroids can accelerate the rate of return to normal renal function and disappearance of proteinuria. However, a clear beneficial effect of steroids in the course of NSAIDinduced MCD has not yet been established (5). If renal failure or nephrotic syndrome persists, corticosteroid therapy could be justified (14).

A drug-induced etiology should be considered in all forms of kidney disease. Careful attention to the timing of adverse events and a clinic-pathological correlation can provide insights into new and important patterns of druginduced nephrotoxicity (5).

Despite of hypothesis about how some drugs can cause glomerular disease, there are no definitive biomarkers to distinguish between a patient with an idiopathic disease and a drug-induced disease (10).

Clinical, laboratory and pathological variations are more likely determined by the type and strength of the immune response and the magnitude of exposure to the drug (9).

It is important to highlight that these drugs, which are widely used due to their easy access, are a group of drugs that produce a number of alterations at the renal level, which confirms the importance of both health professionals and patients, know more in depth about the adverse effects that can be generated at this level, as well as in other organs and systems. In the same way, it is important to make all health personnel aware of the high susceptibility of the kidney as a potential target of drug and other xenobiotic toxicity, especially when it represents the main mechanism for the elimination of drugs and other substances from the body. The early recognition of patients with a particularly high risk of developing such events, will result in the optimal use of medications in terms of dosage schemes, possible combinations and monitoring, in order to minimize the impact of this frequent adverse effect and potentially serious (1), remembering that potentially offensive drugs should be discontinued before attributing the lesion to the “idiopathic” category (12).

Conclusion To our knowledge the morphology of drug-induced diseases often does not differ from the primary forms, making the distinction difficult. There are subtle clues, although the dialogue between clinician and pathologist is essential to reach an etiological diagnosis.

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Faure EE et al

Physicians should suspect glomerulonephritis in patients who receive drugs and who develop renal failure, proteinuria or active urinary sediment and its management must be determined based on the histological characteristics of the disease. The drug responsible should be discontinued immediately if glomerulopathy is suspected. Treatment modalities that are sometimes effective in other forms of glomerulopathies have been used empirically. Although corticosteroid therapy seems to be of value, the effectiveness of this approach must still be tested in randomized and multicentric clinical trials.

4.

5.

6.

7.

8.

Authors’ contribution EEF have drafted the initial manuscript which was further modified

by JHM. All authors have reviewed and agreed on the final version of this manuscript prior to submission.

9.

Conflicts of interest There is no conflict of interest in this case report.

10.

Ethical considerations Ethical issues including plagiarism, double publication, and redundancy have been completely observed by the authors. The patient has provided informed consent to publish as a case report.

11.

Funding/Support None.

13.

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Dixit M, Doan T, Kirschner R, Dixit N. Significant acute kidney injury due to non-steroidal anti-inflammatory drugs: inpatient setting. Pharmaceuticals. 2010;3:1279-85.

Izzedine H, Launay-Vacher V, Bourry E. Drug-induced glomerulopathies. Expert Opin Drug Saf. 2006;5:95-106.

Open Access

Original J Renal Endocrinol 2021;7:e13.

Journal of

Renal Endocrinology

http://www.jrenendo.com

Nickan

doi: 10.34172/jre.2021.13

Research Institute

Frailty at the beginning of dialysis; is it a prognostic factor?

ID

Santiago Silva1* , Cristina Milano1 ID , Gonzalo García1 ID , Anabel Abib1 ID , Carlos Díaz1 ID , Gustavo Laham1 ID Abstract Introduction: Frailty (F) refers to the cumulative organic damage caused by aging, as a consequence of a diminished physiological reserve.

Frailty’s prevalence is 73% in dialysis.

Objectives: Our aim was to identify the prevalence of F in patients starting hemodialysis (HD) or hemodiafiltration online (HDF) treatment to asses change in frailty during a six-month period of dialysis.

Patients and Methods: This prospective cohort study evaluated 67 incident patient starting-HD or HDF at one year, with a follow-up period of at least six months. The frailty was assessed by the Fried frailty method. According to this test, we divided the population in two groups: Pre-frail (0-2) and frail (3-5).

Results: Mean age was 64 years, 64% were male and 92% were treated with HD. A total of 35.8% of the patients were admitted to dialysis with a prosthetic or native fistula. The prevalence of F at the beginning of dialysis was 65.7%. The mean value of Charlson index (CHI) was 5.2 ± 2. There was a significant correlation between CHI and frailty test (P < 0.0001). Basal F score (n=67) improved after 6 month (n=52): 3 (2-4) versus1 (1-2) (P < 0.0001). Hematocrit (28 versus 32% P = 0.05) and calcium levels (8.6 and 8.9 mg/dL, P < 0.002) also increased after sixth-month. Global mortality was 7.5%. In the multivariate analysis CHI (P < 0.001) and albumin (P = 0.003) were frailty predictors.

Conclusion: The prevalence of F in patients who start dialysis therapy is high. There was an improvement in F score after six-month of dialysis treatment. Patients with higher F score had higher mortality with higher CHI. Keywords: Dialysis, Sarcopenia, End-stage chronic renal disease Citation: Silva S, Milano C, García G, Abib A, Díaz C, Laham G. Frailty at the beginning of dialysis; is it a prognostic factor? J Renal Endocrinol. 2021;7:e13. doi: 10.34172/jre.2021.13.

Copyright © 2021 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction Historically, knowledge concerning aging was established upon the different biological mechanisms that lead to it, casting aside other matters unrelated to biology such as the psychosocial sphere (1). Following this new approach two principal syndromes where described, disability and comorbidity, which are now known to modify significantly quality of life (1). Disability in senile population was explained exclusively as a consequence of the underlying disease, without finding a physiopathological mechanism that accounted for it, in the absence of an established disease or its relationship with the process of aging itself (1). For this reason, over the past ten years, a new term has emerged, conceptualizing a new characteristic or phenotype, called frailty (1). This new phenotype or frailty syndrome, was first embraced by geriatricians to describe cumulative damage in multiple organic systems, produced by the process of aging itself (1-4). This leads to a state of diminished physiological reserve and tolerance to stressful insults, both internal and external (1-4). Therefore, frailty syndrome is defined as the cumulative damage of multiple organs and systems secondary to the mere process of

aging, which results in a diminished physiological reserve (30%) leading to an inadequate tolerance to internal and external insults (1-9). Woods et al describe four main risk factors for the development of frailty: physiological, comorbidity, socio-demographic and physiological (10). Frailty syndrome in chronic kidney disease (CKD) patients, without the need of renal replacement therapies (RRTs), account for the physiological dysfunction secondary to organic aging among other comorbidities (2,11). Furthermore, patients who require RRT, other factors such as uremic syndrome and pro inflammatory states are added alongside conditions characteristic to hemodialysis (HD) (vascular access type, dialysis dose (Kt/V), anemia, bone mineral metabolism etc.) (2,10).

This syndrome affects a number of physiological areas such as the cognitive, emotional, nutritional, functional, strength, equilibrium, mobility and sleep. Moreover, it also has an impact in social aspects. This leads to the development of different diagnostic scores, to prevent and improve outcomes in patients suffering from frailty, which are now a new area of investigation (1). Overall, the Fried Frail test, is the most tested and applied, using five

Received: 23 January 2021, Accepted: 17 April 2021, ePublished: 18 May 2021 Department of Internal Medicine, Neprhology Section, Centro de Educación Medica e Investigaciones Clinícas (CEMIC), Buenos Aires, Argentina. *Corresponding Author: Santiago Silva, Email: sdst1986@gmail.com, sasilva @cemic.edu.ar 1

Silva et al

Implication for health policy/practice/research/ medical education Frail is an undervalued condition associated with great mortality on dialysis. A lot of studies evaluated frail in cross sectional analysis. We studied incident patients admitted to dialysis. We assessed the frailty prevalence of patients starting hemodialysis or hemodiafiltration and followed these patients prospectively for 6 months. To our knowledge, there is a lack of prospective studies in this area.

different variables to score a patients as non-frail (0), pre frail (score 1-2) or frail (>3) (1,2,5,12-14). The prevalence of F accounts for 7% to 12% of general population and CKD at early stages and the incidence stands between 7% and 15%, accounting for different ethnic groups and methods applied to quantify the frailty (1,2). Frailty in population over forty years or older, varies between 42 and 73% with a frailty risk being 4 or 5 times greater than general population (2).

Objectives Our aim was to identify the prevalence of frailty in patients starting HD or hemodiafiltration online (HDF) treatment. To asses change in frailty during a six-month period of dialysis Patients and Methods Study design The study was designed as a single-centered prospective cohort study evaluating 67 incident patients starting HD or HDF between December 2017 and December 2018 with a follow up period of at least six months.

Inclusion criteria • Incident patients (>18 years) starting HD or online high volume HDF. Exclusion criteria • Patients treated with other forms of RRT (peritoneal dialysis or kidney transplant) • Patients denial to perform the frailty test Variables The quantitative and qualitative variables for each patient where obtained from the EUCLID (European Clinical Database) database, an online program for data recollection of patients admitted for chronic RRT of Fresenius dialysis centers. Demographic data such as age, gender, cause of renal insufficiency, comorbidities, cardiovascular disease (considered as coronary artery disease, peripheral artery disease or the presence of aortic aneurysm), Charlson index (CHI) adjusted by age and validated for dialysis, RRT modality (HD or HDF), type of vascular access at entry (graft or native fistula or catheter, either permanent 2

Journal of Renal Endocrinology, Volume 7, 2021

or transient). The weight taken into account was measured with BCM (Body Composition Monitor) after two weeks of treatment trying to account for the possible bias of fluid overweight or malnutrition. Blood sample analysis [albumin, creatinine, urea, PCR, ferritin, ferremia, transferrin, transferrin saturation percentage, hematocrit, calcium, phosphorus, intact parathyroid hormone (iPTH) and vitamin D were measured at the beginning and after six months of treatment.

Fragility measurement Frailty was measured by the Fried Frail method which considers five physical variables (Table 1).

The test was first performed in the examination room before the first dialysis session and at month six. According to the obtained score the study population was divided into two groups: 1. Pre-frail: 0 to 2 points 2. Frail: 3 to 5 points Non-frail patients were included in the pre-frail group to facilitate the statistical analysis at baseline due to the small number of patients (2 non-frail patients younger than 24 years).

Ethical issues The research followed the tenets of the Declaration of Helsinki. The Ethics Committee of CEMIC University Institute of Medical Sciences approved this study.

Accordingly, written informed consent was taken from all participants before any intervention.

Statistical analysis The qualitative variables are described as percentages; the quantitative variables are expressed in means and medians with their standard deviation (SD) or interquartile range (IQR) as appropriate. Frailty was considered as a quantitative discrete variable for significance analysis with a minimum score of 0 and a maximum score of 5 points, distributed in two groups according to the score, pre-frail (0-2 points) and frail (3-5 points). This was considered at enrolment and at month six. The descriptive variables considered for each group where included according to clinical criteria and literature review, considering mortality and morbidity predictors in patients with RRT. Adjusted risk indices and confidence intervals of 95% (IC of 95%) with a P value <0.05 were used to establish statistical significance. For the analysis of comparison of continuous quantitative variables between admission and sixth month for the two groups, the Wilcoxon nonparametric test was used.

Results A total of 67 patients initiated RRT. At month six, 52 patients (77.6%) completed the study. Five patients died (7.5%), four were transferred to other dialysis center (6%), one patient recovered renal function and five (7.5%)

Frailty at the beginning of dialysis Table 1. Frailty test according to Fried frail (Cardiovascular Heart Study) Score

Component

Physical Method

Yes

No

Low weight

Unintentional weight loss ≥4.5 kg in the past year.

1

0

Exhaustion

According to CES-D 2 parameters: How often did you feel exhausted?

0. Rarely or not (less than 1d), 1. With certain frequency (1-2 d), 2. Moderate frequency (3-4 d) 3. Most of the time.

2-3 in the score, it is positive.

1

0

Physical Activity

Short version of the Minnesota Leisure Time Activity questionnaire 2011,* stratified by sex: <383 kcal/wk men <270 kcal/wk women

1

0

1

0

1

0

Based on a 4.5 m walking distance; stratified by sex and height.

Walking time

Men Height: ≤173 cm: >173 cm: Women Height ≤159 cm >159 cm

Grip strength

≥7 s ≥6 s

By men/women BMI: Men BMI Dynamometer** ≤24 kg/m2 ≤ 29 kg 24.1-26 kg/m2 ≤ 30 kg 26.1-28 kg/m2 ≤ 31 kg >28 kg/m2 ≤ 32 kg Women: ≤23 kg/m2 23.1-26 kg/m2 26.1-29 kg/m2 >29 kg/m2

Results

walking time ≥7 s ≥6 s

≤ 17 kg ≤17.3 kg ≤18 kg ≤ 21 kg

0: No frail 1-2: Pre Frail 3 -5: Frail

Modified from: Johansen et al.4 CESD-2: Epidemiological Center for Depression Studies, BMI: Body Mass Index, MET: unit of measure for metabolic index defined as the amount of heat emitted by a person at rest per square meter of skin equivalent to 50 kcal/ h/m² *Calculation by METS (resting metabolic unit) for each physical activity with the formula: kcal/week: METS × KG × Time in hours × days a week of the activity.

The activities carried out 3 months prior to admission to hemodialysis were considered, ruling out baseline activities (dressing, personal hygiene, sleeping, physiological functions) and taking into account those that imply moderate light intensity (1-1.5 METS) (1.6-3 METS). and great intensity (more than 6 METS) ** Instrument to measure force, based on the deformation capacity of elastic bodies.

received a kidney transplant (Figure 1).

Mean age was of 67 ± 17 years, 43 (64%) were male.

The follow-up period since RRT until end of study, death, renal transplant or transfer to other dialysis facility was 5.9

months (5.7-6.4). Considering patients with two or more renal risk factor (being hypertension the most prevalent in our cohort) as multifactorial etiology for renal insufficiency, this accounted for the leading cause of CKD with 48% of the patients (n=32). Regarding comorbidities, 26.8% of the patients where diabetic, 88% had hypertension and 32.8% presented with some extent of cardiovascular disease. Prior to enrolment 5 patients were treated with ketoanalogues supplements and diet. Thirty-five patients did not have prior nephrological care (late referral) and 32 had nephrological care and received erythropoiesis stimulator agents and secondary hyperparathyroidism treatment such as calcium and vitamin D supplements. We did not find statistical difference in frailty (3.0 ± 1.3 vs 3.2 ± 1.3, P = 0.48) and CHI (5.03 ± 1.8 versus. 5.52 ± 2.1, P = 0.31) between patients according to prior nephrological care (Table 2).

The median estimated glomerular filtration rate (eGFR) at entry was 6.9 (5-10) mL/min/ 1.73 m2. The median value of hematocrit and serum albumin were 28% (17-33%) and 3.7 g/dL (2.4-4.9 g/dL) respectively. HD accounted for the most common renal replacement modality with 62 patients (92%) and transient catheters were the most common vascular access n= 37 (55%). The median body mass index was 26 kg/m2 (14.8-40 kg/m2). The median for CHI at enrolment was 5.2 (2-10). We found a significant improvement in hematocrit and serum calcium at month six. Regarding treatment modalities, 29% of the patients (n = 15) remained in HD and 71% changed to HDF during the study. In contrast with the data presented at enrolment at the end of the trial prothesis and native fistulas were the most common vascular access accounting for 86.5% of the patients while 13.5% had a permanent catheter.

The median score of frailty at dialysis entry was of three (2-4) versus one (1-2) at month six (P < 0.0001). The prevalence of F at the beginning of the study accounted for 65.7% of the population, in contrast in the 52 patients who remained in the study until completion, the frailty prevalence descended to 19% with a corresponding increase to 81% of pre-frail patients (P < 0.0001).

No patient with involuntary weight loss was observed.

The respective medians for each frail parameter at month six where: Walking speed 5.5 (3-9), grip strength 23 (10-50), exhaustion 0.3 (0-3) and physical activity 1734 (197.6-7159) kcal/wk. Walking for leisure was the physical activity most commonly observed in the study.

After dividing the population into frail (FR) and pre-frail (PF) groups, we stratified age in three groups from 18 to 39; 40 to 61 and 62 years or older and observed that patients in the last group had more prevalence of frailty (P < 0.0001). We did not find significant differences between genders. Median eGFR in the FR group 8.1 mL/ min (1.5-17) was greater than in the PF group: 7.1 mL/ min (2-14) (P < 0.0001). CHI median in the FR group was higher six (2-10) than PF group: 2 (4-7) (P < 0.0001).

Serum albumin levels were lower in FR group (P < 0.03).

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Silva et al

67 patients

1 Kidney function recovered

5 kidney transplant

4 transferered to other dialysis center

3 LDKT

5 deaths: 3 sepsis 2 cardiovascular

2 CDKT

52 patients at Month six Figure 1. Follow up at six months. LDKT: living donor kidney transplant, CDKT: cadaveric donor kidney transplant.

We observed five (11.4 %) deaths in the FR group compared with no deaths in PF group (P < 0.01). Causes of death were cardiovascular (n= 2) and infectious (n=3).

The frail group also had a lesser number of kidney transplants (P = 0.02; Tables 3 and 4).

The frailty test had a significant statistical correlation with the CHI, (r = 0.54; P < 0.0001) suggesting that patients with greater number of comorbidities are more frailty (Figure 2). In the linear multivariate analysis, CHI (P < 0.0001) and serum albumin (P < 0.003) were the only predictors of frailty (Table 5).

Discussion In the present study, the prevalence of frailty in patient’s incident in RRT was 67.5% using the Fried frail score by the physical method. This data is similar to the prevalence reported in Bao et al (73%) counting with a population of 1576 patients who initiate dialysis from Comprehensive Dialysis Study (CDS) using the Fried Frail score criteria by the self-reported method (15). The prospective study by Bárbara et al including 95 patients on pre-dialysis, showed a prevalence of F for patients over 65 years of 44% using the Groningen Frailty Indicator (GFI) test, the Identification of Seniors at Risk-Hospitalized Patients (ISAR-HP) and the Veiligheids management system (VMS). This prevalence compared with the Fried Frail self-report test had lower sensitivity and specificity (GFI 89% / 57%, ISAR-HP 83% / 77% and VMS 77% / 67% respectively) (16). Several studies report that the prevalence of F is modified according to the method used to measure it, as well as gender, age, and comorbidities. Leaving aside these variations, the Fried Frail test by the physical method has a high sensitivity and specificity compared to other techniques in the incident population on dialysis, especially in patients older than 40 years. Based on the above, we have chosen this method to 4

Journal of Renal Endocrinology, Volume 7, 2021

evaluate our patients. A significant improvement in frailty status, hematocrit and calcemia was observed during the follow-up. We believe it was due to better medical control (monthly control), therapeutic compliance, improvement in nutritional status and physical state which we think accounts for the optimization of the internal environment and the elimination of blood toxins, hence we do not consider that this finding represents a selection biases.

We also observed that frailty increases proportionally to age (group 40-61 years, 18% and >62 years 82%), as occurred in the cross-sectional study by Johansen et al with incidents in HD that are part of the longitudinal Dialysis Morbidity and Mortality Study (DMMS), where the prevalence in those under 40 years of age was 44.4%, in those aged 60 to 70, 74.2% and 80 or more 78.8% (12). The high prevalence of frailty in patients requiring dialysis compared to the healthy population over 50 years (7 to 17%) according to cross-sectional CHS studies (Cardiovascular Health Study and SHARE STUDY (Study, Survey of Health, Aging and Retirement in Europe), is an important observation with potential clinical benefits its diagnosis and early prevention (1). The cohort of patients with a score for FR had a mortality of 11.4% compared to 0% in the pre-frail patients. It is reasonable to expect that mortality could increase with a longer period of observation, as demonstrated by the prospective study by McAdams-DeMarco et al in 146 HD patients in whom mortality was 40% at 3 years of follow-up, also associating a 3-fold higher risk of death independently compared to non-frailty patients in HD (RR: 2.6; 95% CI: 1.046.49, P = 0.04) (17). In the present study, the F measured by the Fried Frail physical method test had a significant correlation with the age-adjusted CHI at the start of RRT (r = 0.54, P < 0.0001). However, a retrospective study

by Kim et al using the claim frailty index (CFI) test in

Frailty at the beginning of dialysis Table 2. Characteristics at baseline and at month 6 Baseline n = 67 (%)

Variables

Month 6 n = 52 (%)

P

Demographics Age

64 ± 17

Male, n (%)

43 (64)

Causes of CKD Glomerulonephritis

9 (13.4)

Hypertension

14 (20.8)

Multiple myeloma

4 (6)

Multifactorial*

32 (48)

Polycystic renal disease.

5 (7.4)

Obstructive uropathy**

3 (4.4)

Laboratory values CKD-EPI, mL/min/1.73 m2

6.9 (5-10)

Albumine, mg/dL

3.7 (2.4-4.9)

3.9 (3-7.9)

0.2

Urea, mg/dL

197 (43-654)

135 (84.4-214)

0.04

PCR, mg/dL

1.1 (0.2-3.4)

5.3 (0.1-33)

0.01

Transferrin, ng/dL

183.7 (105-272) 192 (128-331)

0.1

Transferrin saturation, %

24.8 (9-69)

27.3 (6-83)

0.3

25-OH, mg/dL

18 (11.7-27.7)

Not measured

Calcium, mg/dL

8.6 (6.9-10.7)

8.8 (7.3-10)

<0.002

Phosphorus, mg/dL

5.5 (1.2-10.5)

5.8 (1.5-9.6)

0.9

Hematocrit, %

28 (17-33)

32.7 (19.3-44.8)

0.05

Hemodialysis

62 (92)

15 (29)

<0.001

Online hemodiafiltration

5 (8)

37 (71)

Dialysis modality, n (%)

Vascular access, n (%) Transient catheter

37 (55)

Permanent catheter

6 (9)

7 (13.5)

Prosthetic or native fistula

24 (36)

45 (86.5)

<0.01

Other BMI (kg/m2)

26 (14.8-40)

Charlson Index

5.2 (2- 10)

Kt/V***

3642 volunteer older adults with different comorbidities showed that this was significantly higher than the CHI to predict disability (0.62-0.72 viruses. 0.58-0.66, P ≤ 0.01) and morbidity (0.58 viruses. 0.66, P ≤ 0.01), not so to predict mortality (0.68 vs. 0.68; P = 0.5) or hospitalization (0.58 vs. 0.54, P = 0.07) (14). In our study there was a decrease in the percentage of patients with F after sixth month of RRT (65.7 vs. 19%), improvement in walking speed time (5.5 versus 6 m/s) and in the exhaustion (0.3 vs. 2.5 points), increased physical activity (1734 vs. 493 kcal/wk) and increased grip strength (23 versus 20 kg).

The vast majority of studies on F in dialysis patients evaluate this population with cross-sectional studies; however, a study by Lee et al showed similar data to our work (18). Forty-six incident patients older than 65 years undergoing HD were evaluated with a comprehensive geriatric assessment (CGA) frailty score, obtained a 32,6% of frailty (defined as a CGA >10). This group observed that in the CGA index carried out in 29 (60.4%) patients at 12 months they showed an improvement in the median score, being at baseline 8 versus 6 a year (P < 0.001) (18).

To our knowledge, there is no literature on other studies showing the prevalence of F at the start of dialysis with a follow-up after 6 or 12 months. We find important to state the idea that the manifestations of the uremic syndrome can overlap with the frailty syndrome, sharing several of its symptoms, such as exhaustion, weight loss and decrease in muscle mass. This could support the fact that in the first months a significant improvement is evident in the initiation of RRT patients with uremic symptoms.

This would not be the case in frail patients for whom RRT may worsen, improve slowly or maintain their symptoms (19). That is why, in view of the false positives that can occur for the diagnosis of F at the beginning of RRT, we consider necessary to evaluate more diagnostic tools of greater specificity and, in the same way highlight the need of prospective studies with longer times.

Table 4. Variables in frail and Pre-frail groups 1.5 (0.9-2.2)

* It was considered multifactorial with 2 or more comorbidities at the same time, except that the cause of CKD was evidenced by imaging methods, renal biopsy or bone marrow. ** Prostatic hypertrophy, there was no other related cause. *** Kt/V dialysis quality and efficacy measurement parameter K: urea clearance in dialysis process, T: dialysis time and V: urea distribution volume.

Variable Age

Frail n= 44

Pre-Frail n= 23

P

74 (40-91)

48 (18-77)

<0.001

Groups by age 18-39

0

7 (30.5%)

40-61

8 (18 %)

11(47.8%)

>62

36 (82%)

5 (21.7%)

Male gender

28 (63.6 %)

15(65.2%)

0.36

Table 3. Parameters of frailty at admission and sixth month

eGFR, mL/min

8.1 (1.5-17)

7.1(2-14)

<0.0001

Frailty test

Admission n= 67

Sixth month n= 52

P

Charlson Index

6 (2-10)

2 (4-7)

<0.0001

3.6 (2.4-4.5)

4 (2.8-4.9)

0.03

Frailty (median)

3 (2-4)

1 (1-2)

<0.0001

1.15

2.7

0.05

Frail, n (%)

44 (65.7%)

10 (19%)

Kidney transplant

0

5

0.02

Deaths

5

0

0.01

Pre-frail, n (%)

23 (34.3%)

42 (81%)

<0.0001

Albumin PCR

Journal of Renal Endocrinology, Volume 7, 2021

<0.0001

5

Silva et al Table 5. Multivariate linear regression (Dependent variable: fragility) Variable

OR

P

Sex

0.70

0.472

3.62

2.72

Charlson Index

0.479

<0.0001

0.19

0.45

Albumin

- 0.319

<0.003

-1.47

-0.32

CKD-EPI

0.117

0.309

-0.44

0.13

Calcium

0.345

0.520

0.25

1.22

Phosphorus

- 0.92

0.440

-0.26

0.11

0.47

0.701

-0.003

0.005

Urea

95% CI

Correlation Charlson and Frailty index

12

Charlson index

10 8 6

4 2 0

0

2

Frailty

4

6

Figure 2. Correlation histogram between Frailty Index and Charlson (r= 0.54, P < 0.0001).

Conclusion The prevalence of frailty in patient’s incident starting two different dialysis modalities was 67.5%. There was an improvement in frailty test after six months of dialysis.

Mortality in patients with frailty was related with lower levels of albumin and an increased CHI. Limitations of the study The main limitation of this study is the number of patients at the beginning of the trial, which was not sufficiently representative for extracting conclusive results. The follow up period was only of six months, which limits the observations on the long-term behavior of frailty. It may be argued that the loss of 22 % of data (n = 15) may affect this study validity, but we think that the results would not be much different with lesser loss of data. Nevertheless, the strength of this study resides in the follow up and reevaluation of the majority of patients after six months of having initiated a dialysis therapy Availability of data and materials The datasets generated and/or analyzed during the current study are not publicly available due was generate by the authors in an excel program, but are available from the corresponding author on reasonable request.

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Authors’ contribution SS created and recollected the data of all participants, wrote the manuscript. CM, AA and CD reviewed some results. GG translated to English. GL and SS analyzed the statistics data.

Conflicts of interest The authors declare that they have no competing interests.

Ethical considerations Ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the authors.

Funding/Support We want to confirm that this study was an investigator initiated studies (IIS) and did not received any research funding.

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10. Woods NF, LaCroix AZ, Gray SL, Aragaki A, Cochrane BB, Brunner RL, et al. Women’s Health Initiative. Frailty: emergence and consequences in women aged 65 and older in the Women’s Health Initiative Observational Study. J Am Geriatr Soc. 2005;53:1321-30. doi: 10.1111/j.1532-5415.2005.53405.x.

Erratum in: J Am Geriatr Soc. 2017;65:1631-1632.

11. Roshanravan B, Khatri M, Robinson-Cohen C, Levin G, Patel KV, et al. A prospective study of frailty in nephrology-referred patients with CKD. Am J Kidney Dis. 2012;60:912-21. doi: 10.1053/j.ajkd.2012.05.017 .

Frailty at the beginning of dialysis 12. Johansen KL, Chertow GM, Jin C, Kutner NG. Significance of frailty among dialysis patients. J Am Soc Nephrol.

2007;18:2960-7. doi: 10.1681/ASN.2007020221.

13. Nixon AC, Bampouras TM, Pendleton N, Woywodt A, Mitra S, Dhaygude A. Frailty and chronic kidney disease: current evidence and continuing uncertainties. Clin Kidney J. 2018;11:236-245. doi: 10.1093/ckj/sfx134.

14. Kim DH, Glynn RJ, Avorn J, Lipsitz LA, Rockwood K, Pawar A, et al. Validation of a Claims-Based Frailty Index Against Physical Performance and Adverse Health Outcomes in the Health and Retirement Study. J Gerontol A Biol Sci Med Sci. 2019;74:1271-1276. doi: 10.1093/gerona/gly197.

15. Bao Y, Dalrymple L, Chertow GM, Kaysen GA, Johansen KL. Frailty, dialysis initiation, and mortality in end-stage renal disease. Arch Intern Med. 2012;172:1071-7. doi: 10.1001/ archinternmed.2012.3020.

16. van Munster BC, Drost D, Kalf A, Vogtlander NP. Discriminative value of frailty screening instruments in end-stage renal disease.

Clin Kidney J. 2016;9:606-10. doi: 10.1093/ckj/sfw061.

17. McAdams-DeMarco MA, Law A, Salter ML, Boyarsky B, Gimenez L, Jaar BG, et al. Frailty as a novel predictor of mortality and hospitalization in individuals of all ages undergoing hemodialysis. J Am Geriatr Soc. 2013;61:896-901. doi: 10.1111/jgs.12266.

18. 18.Lee SW, Lee A, Yu MY, Kim SW, Kim KI, Na KY, et al. Is frailty a modifiable risk factor of future adverse outcomes in elderly patients with incident end-stage renal disease? J Korean Med Sci. 2017;32:1800-6. doi: 10.3346/jkms.2017.32.11.1800.

19. Johansen KL, Delgado C, Bao Y, Kurella Tamura M. Frailty and dialysis initiation. Semin Dial. 2013;26:690-6. doi: 10.1111/ sdi.12126.

Journal of Renal Endocrinology, Volume 7, 2021

7

Open Access

Original J Renal Endocrinol 2021;7:e14.

Journal of

Renal Endocrinology

http://www.jrenendo.com

Nickan

doi: 10.34172/jre.2021.14

Research Institute

Outbreak and impact of coronavirus disease 2019 (COVID-19) on dialysis patients; Al Khezam dialysis center experience, Kuwait ID

Emad Abdallah* , Bassam Al Helal, Reem Asad, George Nessim, Shaikha Al-Bader, Yasser Elsharkawi, Ahmed Elmasry, Mohamed Abdelgelil, Essam Allam, Sahar Abdelkareem, Mohammad Kamal, Mohamed Hemida, Yasser Shaaban, Zeinab Zeid, Amr Saad, Abuhashem Ahmed Abstract Introduction: Coronavirus disease 2019 (COVID-19) is an outbreak due to SARS-CoV-2, declared by the World Health Organization (WHO) as a global pandemic in March 2020. Patients with underlying diseases, such as those with end-stage kidney disease (ESKD) on dialysis, are at greater risk.

Objectives: The aim of our study to assess the outbreak and impact of COVID-19 on dialysis patients.

Patients and Methods: Our study prospectively assessed and followed 442 patients with ESKD undergoing dialysis [390 patients on maintenance hemodialysis (HD) and 52 patients on peritoneal dialysis (PD)] for outbreak and impact of COVID-19 on these patients during the period from April 22, 2020 until March 23, 2021 in Al Khezam dialysis center, Kuwait. Age, gender, nationality, original kidney disease, history of hypertension (HTN), diabetes mellitus (DM), ischemic heart disease (IHD), congestive heart failure (CHF), bronchial asthma (BA), chronic obstructive pulmonary disease (COPD), history of pulmonary embolism (PE) and source of infection were analyzed. Symptoms as fever, fatigue, cough, loss of smell and taste and chest pain were recorded, the need for ICU admission, mechanical ventilation (MV), extracorporeal membrane oxygenation (ECMO), medications were recorded. The need to shift to continuous renal replacement therapy (CRRT) and outcomes (complications and mortality) were analyzed.

Results: Our study reported that 102 out of 442 (23%) dialysis patients [97 out of 390 (24.8%) HD patients and 5 out of 52 (9.6%) PD patients] got infected with COVID-19 and reinfection reported in 4 out of 97 (4%) COVID-19 HD patients. Around 27% of COVID-19 HD patients had fever, 19% had fatigue, 8% had cough, 4% had loss of smell, 4% had loss of taste, 4% had chest pain and 40% of COVID-19 PD patients had fever. Fifteen out of 97 (15 %) COVID-19 HD patients needed ICU admission, 12 out of 97 (12 %) COVID-19 HD patients needed MV. A 33 out of 97 (34%) COVID-19 HD patients and 4 out of 5 (80%) COVID-19 PD patients needed to switch to CRRT. Mortality was 17 (15 HD and 2 PD) out of 102 (16.6 %) COVID-19 dialysis patients and common causes of death were sepsis, myocardial infarction (MI), heart failure and PE. Conclusion: Outbreak and mortality of COVID-19 infection is high in ESKD patients undergoing dialysis compared with general populations. Strict protocol for prevention of COVID-19 should be undertaken in dialysis centers and encourage of home dialysis and highly protective COVID-19 vaccination priority for dialysis patients.

Keywords: COVID-19, Hemodialysis, Peritoneal dialysis Citation: Abdallah E, Al Helal B, Asad R, Nessim G, Al-Bader SH, Elsharkawi Y, Elmasry A, Abdelgelil M, Allam E, Abdelkareem S, Kamal M, Hemida M, Shaaban Y, Zeid Z, Saad A, Ahmed A. Outbreak and impact of coronavirus disease 2019 (COVID-19) on dialysis patients; Al Khezam dialysis center experience, Kuwait. J Renal Endocrinol. 2021;7:e14. doi: 10.34172/jre.2021.14.

Copyright © 2021 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction Coronavirus disease 2019 (COVID-19) is an outbreak due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a new virus of Coronaviridae family, emerged in China in December 2019 and declared by the World Health Organization as a global pandemic in March 2020. COVID-19 infection causes an atypical flu that often leads to severe acute respiratory syndrome with high mortality rate. Patients with underlying diseases, such as those with end-stage kidney disease (ESKD) on dialysis, are at greater risk (1).

In particular, COVID-19 is a real challenge for patients on HD, whose high susceptibility to COVID-19 is only partially explained by their average old age, frequent comorbidities, and impaired immune function. In fact, those receiving maintenance hemodialysis (HD). These patients cannot be isolated at home completely because they require routine treatment in the HD center, usually 3 times a week, the need of physical presence at health care facilities, the mobility to HD centers, and the high aggregation for the continuous physical proximity of patients during HD session strongly increase the risk of

Received: 11 January 2021, Accepted: 15 April 2021, ePublished: 7 May 2021 Al Khezam Dialysis Center, Al Adan Hospital, Kuwait. *Corresponding Author: Professor Emad Abdallah, Email: drabdallah96@gmail.com

Abdallah E et al

Implication for health policy/practice/research/ medical education Our study prospectively assessed and followed 442 patients with endstage kidney disease (ESKD) undergoing dialysis [390 patients on maintenance hemodialysis (HD) and 52 patients on peritoneal dialysis (PD)] for outbreak and impact of COVID-19 on these patients during the period from April 22, 2020 until March 23, 2021 in Al Khezam dialysis center, Kuwait. Our study reported that 23% of dialysis patients [24.8% HD patients and 9.6% PD patients] got infected with COVID-19 and reinfection reported in 4% of COVID-19 HD patients. Mortality was 16.6% of COVID-19 dialysis patients and common causes of death were sepsis, myocardial infarction, heart failure and pulmonary embolism.

contamination with SARS-CoV-2, the virus that causes COVID-19 (2). Surprisingly, first available data suggest that although HD patients’ infection rate in the COVID-19 epidemic is much higher than in other populations, the disease course is rarely fatal and less severe, both compared with kidney-transplanted patients and general population (2).

2.

3.

4.

5.

6.

Objectives The aim of our study is to assess outbreak and impact of COVID-19 on dialysis patients in Al Khezam dialysis center, Kuwait during the period from April 22, 2020 until March 23, 2021.

7.

Patients and Methods Study design Our study prospectively assessed and followed 442 patients with ESKD undergoing dialysis [390 patients on maintenance HD and 52 patients on peritoneal dialysis (PD)] for outbreak and impact of COVID-19 on these patients during the period from April 22, 2020 until March 23, 2021. Age, gender, nationality, original kidney disease, history of hypertension (HTN), diabetes mellitus (DM), ischemic heart disease (IHD), congestive heart failure (CHF), bronchial asthma (BA), chronic obstructive pulmonary disease (COPD), history of deep venous thrombosis (DVT) and pulmonary embolism (PE) and source of infection were analyzed. Symptoms as fever, fatigue, and cough, loss of smell and taste and chest pain were recorded. The need for intensive care unit (ICU) admission, mechanical ventilation (MV), extracorporeal membrane oxygenation (ECMO), inotropes, and medications were recorded. Angiotensinconverting enzyme inhibitor (ACEI)/angiotensin receptor blockers (ARBs) use prior to COVID-19 and ACEI/ ARBs held were analyzed. The need to shift to continuous renal replacement therapy (CRRT) and outcomes (complications and mortality) were also analyzed.

9.

Protocol for prevention of COVID-19 in Al Khezam dialysis center 1. HD patients confirmed to have COVID-19 were transferred to the HD center specifically set up for 2

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8.

10.

11.

12.

confirmed COVID-19 cases in Jaber hospital, Kuwait for conducting dialysis.

HD patients in the primary HD center who had made contact with the patient were listed as close contacts and doing dialysis in isolation rooms for 14 days.

HD patients in the primary HD center who were on the same shift of dialysis remained in their initial hospital for dialysis and arrangements were made for them to receive dialysis in the same shift.

Patients were asked to isolate at home during the nondialysis period, and they were not allowed to take public transport to the hospital on the day of dialysis.

After patients arrived at the hospital, their body temperature and the epidemiological form (including whether there are any COVID-19 symptoms, suspected contact history and recent travel history) were recorded and verified by the physician.

HD patients under quarantine (history of contact to COVID-19 positive or recent returning from travel) continue their dialysis sessions during quarantine period at their usual center in isolation rooms.

Until the previous shift of dialysis patients left completely, the patients could not enter the dialysis treatment room.

PD patients should stay at home and hospital visits should be minimized for only urgent indications (e.g. suspected peritonitis).

PD patients with mild or moderate COVID-19 disease can continue PD treatment as usual and isolation at home.

PD patients with severe or critical cases can be temporarily transferred to HD and isolated in the hospital.

Medical masks were required for all patients during the entire dialysis treatment.

At the same time, the medical staff implemented strict hand hygiene policies and all members were required to use protective equipment, including surgical masks, face shields/goggles, protective gowns, medical caps, and gloves (3).

Ethical issues The research followed the tenets of the Declaration of Helsinki written and informed consent taken from all participants before any intervention.

Statistical analysis The mean and standard deviation and percentage of the results and paired t tests to compare outbreak and mortality in diabetic, hypertensive, IHD and CHF patients with outbreak and mortality in patients with none DM, HTN, IHD and CHF were conducted. All statistical analyses were performed using MedCalc software (version 5, 2019 MedCalc, San Diego, CA, USA). P value of 0.05 was used as a significance level.

COVID-19 and dialysis patients

Results Our study reported that 102 0ut of 442 (23%) dialysis patients [97 out of 390 (24.8%) HD patients and 5 out of 52 (9.6%) PD patients] got infected with COVID-19 and reinfection reported in 4 out of 97 (4%) COVID-19 HD patients during the period from April 22, 2020 until March 23, 2021 compared with 5.1% in general population in Kuwait (Figure 1). Mean age, gender, nationality, original kidney disease, history of HTN, DM, IHD, CHF, BA, COPD, history of DVT and PE, source of infection and medications are shown in Table 1. Around 27% of COVID-19 HD patients had fever, 19% had fatigue, 8% had cough, 4% had loss of smell, 4% had loss of taste, 4% had chest pain (Figure 2) and 40% of COVID-19 PD patients had fever. Fifteen out of 97 (15 %) COVID-19 HD patients needed ICU admission, 12 out of 97 (12 %) COVID-19 HD patients needed MV. Twenty-two out of 97 (22.6 %) COVID-19 HD patients and 1 out of 5 (20%) COVID-19 PD patients were on ACEI/ARBs prior to COVID-19 and 1 out of 97 (1%) COVID-19 HD patients held ACEI/ ARBs. A 33 out of 97 (34%) COVID-19 HD patients and 4 out of 5 (80%) COVID-19 PD patients needed to switch to CRRT. Complications including developed myocardial

24.80%

23%

9.60% 5.10%

General population with COVID-19

PD patients with COVID-19

HD patients with COVID-19

Total dialysis patients (HD&PD) with COVID-19

Figure 1. Outbreak of COVID-19 in hemodialysis (HD) and peritoneal dialysis (PD) patients in Al Khezam dialysis center and general population in Kuwait.

infarction (MI), PE and developed sepsis/acute respiratory distress syndrome (ARDS) were seen in 1 out of 97 (1%) COVID-19 HD patients, 1 out of 97 (1%) COVID-19 HD patients and 7 out of 97 (7%) COVID-19 HD patients, respectively. Mortality was 17 (15 HD and 2 PD) out of 102 (16.6 %) COVID-19 dialysis patients compared with 0.56% in general population with COVID-19 infection in Kuwait (Figure 3) and common cause of death was sepsis, MI, heart failure and PE (Table 1).

Table 1. Demographic, clinical characteristics and outcomes of COVID-19 positive dialysis patients Variables

COVID-19 HD patients (97/390)

COVID-19 PD patients (5/52)

Age (years)

55.6182 ±17.2632

58.5±9.1

Gender (M/F)

46 (47%)/51 (53%)

4 (80%)/1 (20%)

Nationality (KWT/Non KWT)

83 (86%)/14 (14%)

3 (60%)/2 (40%)

DM/HTN/DM+HTN

61 (63%)/89 (92%)/62 (63%)

4 (80%)/5 (100%)/4 (80%)

IHD/CHF

47 (48%)/11 (11%)

3 (60%)/0

Bronchial asthma/COPD

3 (3%)/2 (2%)

0/0

Original kidney disease (DN, HTN/GN/Aeropathy/APKD/ Myeloma/cryo/LMBS/unknown

55 (57%)/21 (22%)/6 (6%)/3 (3%)/5 (5%)/1 (1%)/1 (1%)/1 (1%)/4 (4%)

4 (80%)/1 (20%)/0/0/0/0/0/0

Source of infection (Dialysis center/word/other hospital/ family member/unknown

8 (8%)/2 (2%)/3 (53%)/38 (39%)/46 (47%)

0/0/0/1 (20%)/4 (80%)

Fever/fatigue/cough/loss of smell/loss of taste/chest pain

27 (28%)/18 (19%)/8 (8%)//4 (4%)/4 (4%)/4 (4%)

2 (40%)/0/0/0/0/0

ICU/MV/ECMO/ Inotropes

15 (15%)/12 (12%)//0/2 (2%)

0/0/0/0

Azithromax/clostin/meronem/vancomycin/meropenem/ tazocin/teicoplanin/klacid

18 (18.5%)/20 (21%)/18 (18.5%)/12 (12%)/16 (16%)/10 (10%)/2 (2%)/2 (2%)

4 (80%)/1 (20%)/4 (80%)/2 (40%)/0/0/0/0

MI//CHF/Arrhythmias/PE

1 (1%)/1 (1%)/0/1 (1%)

0/0/0/0

Sepsis/ARDS

7 (7%)

0

ACEI/ARBS prior to COVID-19/Held

22 (22.6%)/1 (1%)

1 (20%)/0

Need to switch to CRRT

33 (34%)

4 (80%)

COVID-19 Reinfection

4 (4%)

0

Heparin/clexane/fondaparinux/none

67 (69%)/ 12 (12%)/2 (2%)/ 16 (16%)

0

Mortality

15 (15.4%)

2 (40%)

With DM/HTN/DM+HTN

12 (80%)/14 (93%)/12 (80%)

2 (100%)/2 (100%)/2 (100%)

With IHD/CHF/IHD+CHF

11 (73%)/3 (20%)/1 (7%)

2 (100%)/0/0

Sepsis/MI/PE

7 (47%)//1 (7%)//2 (14%)

0/0/1 (100%)

HD, hemodialysis; PD, peritoneal dialysis; DM, diabetes mellitus; HTN, hypertension; IHD, ischemic heart disease; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; DN, diabetic nephropathy; GN, glomerulonephritis; APKD, adult polycystic kidney disease; LMBS, Laurance-Moon-BiedleSyndrome; ICU, intensive care unit; MV, mechanical ventilation; ECMO, extra corporeal membrane oxygenation; MI, myocardial infarction; PE, pulmonary embolism; ARDS, acute respiratory distress syndrome, ACEI/ARBS, angiotensin converting enzyme inhibitors/A receptor blockers; CRRT, continuous renal replacement therapy.

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Abdallah E et al

Loss of smell 4%

Chest pain 4%

Loss of tast 4%

Cough 8%

Asymptomatic dialysis patients with COVID-19 34%

Fatigue 19%

Fever 27%

Figure 2. Symptoms of COVID-19 in dialysis patients in Al Khezam dialysis center, Kuwait.

The outbreak of COVID-19 in diabetic patients was comparable with non-diabetic patients (95% CI -6.5143% to 42.8959%, P = 0.1495) while the outbreak of COVID-19 in hypertensive patients was high compared with nonhypertensive patients (95% CI 32.8048% to 82.6231%, P < 0.0001). Mortality in diabetic and hypertensive patients was high compared with mortality in nondiabetic and non-hypertensive patients (95% CI 24.3824% to 78.3175%, P = 0.0012; 95% CI 53.1278% to 94.0754%, P < 0.0001 respectively). There was a significant difference in mortality between IHD and non-IHD patients (95% CI 21.0204% to 77.3188%; P = 0.0026). The presence of DM, HTN and IHD increased mortality, while the presence of, BA and COPD, use or holding of ACEI/ARBS and age did not increase the incidence of COVID-19 or mortality (P > 0.05).

Discussion In our study, the outbreak of COVID-19 among dialysis patients was 23% compared with 5.1 % in general population in Kuwait and our study reported that mortality rate among dialysis patients with COVID-19 was 16.6% compared with 0.56% in general population with COVID-19 infection in Kuwait. Reinfection was reported in 4% of COVID-19 HD patients in our study.

Couchoud et al (4) revealed that among dialysis facilities, the COVID-19 prevalence was 6% during the initial 7-week surge in France as reported from the French Renal Epidemiology and Information Network Registry of patients receiving maintenance dialysis (4). About 3.3% of patients receiving dialysis nationwide developed COVID-19, with a nearly 2-fold greater risk among patients receiving in-center HD as compared to patients receiving home dialysis compared with COVID-19 incidence estimates of 0.2% in the general population (4). In our study, the outbreak of COVID-19 among HD patients (24.8%) was high compared with PD patients (9.6%). Critically, the regional incidence of COVID-19 among patients treated with dialysis mirrored the regional 4

Journal of Renal Endocrinology, Volume 7, 2021

Figure 3. Mortality among dialysis patients with COVID-19 in Al Khezam dialysis center and general population in Kuwait.

incidence in the general population, suggesting a major role in the impact of community spread on infection in patients treated with dialysis.

Among patients receiving dialysis who have COVID-19 mortality was approximately 20% (4).

This mortality rate is confirmed by Jager et al (5) who, reporting from the European Renal Association— European Dialysis and Transplant Association Registry, revealed an approximately 20% mortality rate due to COVID-19 among both patients receiving dialysis and kidney transplant recipients, a rate that is dramatically higher than the estimated 4% mortality rate overall in Europe among people diagnosed with COVID-19 (6).

Additionally Ng et al (7) demonstrated the experience of a health system in New York at the height of the first COVID-19 surge, showing that among 419 patients receiving maintenance dialysis who were hospitalized with COVID-19, mortality was 32%, with a 37% higher adjusted risk of death among patients receiving dialysis who were hospitalized than other patients who were hospitalized with COVID-19. Taken together, these studies revealed the high COVID-19 risk for patients requiring maintenance dialysis, both for acquiring infection and, especially, for poor outcomes once infected, with shortterm mortality that is likely to be 20% or higher.

In our study, the mortality rate was approximately 16.6 % among patients receiving dialysis in Kuwait. In Europe and much of Asia including Kuwait, aggressive protocols were taken to control the spread of COVID-19 in the general population, with institution of mandatory physical distancing policies in times of high community spread, implementation of mandatory masking policies, and broad availability of contact tracing and testing, including among asymptomatic individuals, with resultant substantial reductions in mortality. In the United States, implementation of and adherence to public health measures have been inconsistent, with the result that the United States still averaged more than 40,000 new cases per day and 750 deaths per day due to COVID-19 in

COVID-19 and dialysis patients

September 2020, six months after the initial surge in New York (6).

In centers providing dialysis services, particularly dialysis providers and patients receiving dialysis, must remain vigilant. Interventions to mitigate the impact of COVID-19 among the dialysis population apply to three key settings; the dialysis center, transportation to and from the dialysis center, and the communities in which patients who are treated with dialysis live (8).

Within dialysis facilities, reasonable precautions can decrease the risk of transmission and facilitate care of patients receiving dialysis who have COVID-19, thereby reducing the need for hospitalization and the burden on hospital systems (9).

These include universal mask use among patients and dialysis staff, screening and triage to help identify and rapidly cohort patients with symptoms of or exposure to COVID-19, reduced crowding in HD facilities including in waiting rooms and staff break rooms, specified treatment areas and protocols for providing HD to patients under investigation for or with COVID-19, and, in times of higher community prevalence, testing asymptomatic patients requiring maintenance dialysis as well as dialysis staff for COVID-19. Critically, dialysis facilities should anticipate a continued need for increased physical space and staffing capacity while the pandemic persists, particularly in areas of ongoing community transmission.

Patients need education that the easing of physical distancing poses greater risk to them. Transportation to and from dialysis varies greatly around the world; nevertheless, reducing shared rides and mandating sanitation protocols can reduce infection. Lastly, many patients requiring maintenance dialysis reside in high-risk communities, such as densely populated urban areas or congregate residences such as nursing facilities; awareness of the risk posed in these settings and expanded testing of individuals residing in high-risk settings can reduce the threat of COVID-19 both to these patients and to the broader dialysis population (10,11).

Conclusion Outbreak and mortality of COVID-19 infection is high in ESKD patients undergoing dialysis compared with general populations. Strict protocol for prevention of COVID-19 should be undertaken in dialysis centers and encourage of home dialysis and highly protective COVID-19 vaccination priority for dialysis patients.

Limitations of the study The limitation of the study is that our study is a single center study with few numbers of HD and PD patients. We need a big study including all dialysis centers in Kuwait.

Acknowledgements Many thanks to all my colleagues in Al Khezam dialysis center for following, caring and management and helping in collecting data of dialysis patients infected with COVID-19.

Authors’ contribution EA was the principal investigator of the study. EA, BA, and RA were included in the preparation of concept and design. EA, GN, SA, and MH revisited the manuscript and critically evaluated the intellectual contents. All authors participated in preparing the final draft of the manuscript, revised the manuscript and critically evaluated the intellectual contents. All authors have read and approved the contents of the manuscript and confirmed the accuracy or the integrity of any part of the work.

Conflicts of interests The authors declare that they have no competing interests.

Ethical considerations Ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the authors.

Funding/Support The authors received no financial support for the research, authorship, and/or publication of this article References 1. Pisani A, Rizzo M, Angelucci V, Riccio E. COVID-19 experience in hemodialysis patients: a cue for therapeutic heparin-based strategies? Nephron. 2020;144:383-5.

2. Ikizler TA. COVID-19 and dialysis units: what do we know now and what should we do? Am J Kidney Dis. 2020;76:1-3. doi: 10.1053/j.ajkd.2020.03.008.

3. Yun Tang, BS , Yi Li, PhD , Yi Xin, BS , Fei Deng, MBBS. Prevention and Management of COVID-19 in Hemodialysis Centers. Am J Manag Care. 2020;26:e237-8.

4. Couchoud C, Bayer F, Ayav C. Low incidence of SARS-CoV-2, risk factors of mortality and the course of illness in the French national cohort of dialysis patients. Kidney Int. 2020;98:151929. doi: 10.1016/j.kint.2020.07.042.

5. Jager KJ, Kramer A, Chesnaye NC. Results from the ERA-EDTA Registry indicate a high mortality due to COVID-19 in dialysis patients and kidney transplant recipients across Europe.

Kidney Int. 2020;98:1540-8. doi: 10.1016/j.kint.2020.09.006 6. World Health Organization. WHO coronavirus disease (COVID-19) dashboard. 2020. https://covid19.who.int/.

Accessed October 2, 2020.

7. Ng JH, Hirsch JS, Wanchoo R. Outcomes of patients with endstage kidney disease hospitalized with COVID-19. Kidney Int. 2020;98:1530-9. doi: 10.1016/j.kint.2020.07.030.

8. Weiner D.E. Watnick S.G. Hemodialysis and COVID-19: an Achilles’ heel in the pandemic health care response in the United States. Kidney Med. 2020;2:227-30.

9. Centers for Disease Control and Prevention. Interim additional guidance for infection prevention and control recommendations for patients with suspected or confirmed COVID-19 in outpatient hemodialysis facilities. https://www. cdc.gov/coronavirus/2019-ncov/hcp/dialysis.html. 2020.

10. Bhayani S, Sengupta R, Markossian T. Dialysis, COVID-19, poverty, and race in greater Chicago: an ecological analysis.

Kidney Med. 2020;2:552-558.

11. Liu CK, Ghai S, Waikar SS, Weiner DE. COVID-19 infection risk among hemodialysis patients in long-term care facilities.

Kidney Med. 220;2:810-1. doi: 10.1016/j.xkme.2020.07.005.

Journal of Renal Endocrinology, Volume 7, 2021

5

Open Access Journal of

Renal Endocrinology

Original J Renal Endocrinol 2021;7:e15. http://www.jrenendo.com

Nickan

doi: 10.34172/jre.2021.15

Research Institute

The relation between vitamin D status and anemia in patients with end stage renal disease on regular hemodialysis Essam Nour el Din Afifi1, Ahmed Mohamed Tawfik1, Essam Eldin Rashad Saeed Abdulkhalek2, Lina Essam Khedr1*

ID

Abstract Introduction: Anemia is a common complication in end-stage renal disease (ESRD) patients on regular hemodialysis (HD). There has been a lot of interest recently in the non-classical effects of 25(OH) vitamin D (calcidiol), including its association with erythropoiesis and anemia pathogenesis.

Objectives: To study the relation between anemia and vitamin D status in patients on regular HD. Patient and Methods: This study is a cross-sectional study that included 90 patients on regular HD. Vitamin D status was classified into deficient (<20 ng/mL), insufficient (20-30 ng/mL) and sufficient (>30 ng/mL).

Results: The level of vitamin D measured in the patients ranged between 3.5 to 66 ng/mL with median of 16.35 ng/mL. There were statistically significant positive correlations between vitamin D levels and the level of hemoglobin (P < 0.001), serum calcium levels (P < 0.001) and serum PO4 levels (P = 0.023). Higher hemoglobin levels were statistically related to both higher vitamin D values (P < 0.001) and higher serum calcium concentration (P < 0.001). Meanwhile, a significant negative correlation was found between hemoglobin levels and serum PTH values (P < 0.001).

Conclusion: There was a significant association between the status of vitamin D and the level of hemoglobin in dialysis population who were studied, independent from iron status. other associations with hemoglobin levels included PTH level and calcium.

Keywords: Vitamin D, Calcidiol, Anemia, Dialysis, End-stage renal disease Citation: Nour el Din Afifi E, Tawfik AM, Abdulkhalek EERS, Essam Khedr L. The relation between vitamin D status and anemia in patients with end stage renal disease on regular hemodialysis. J Renal Endocrinol. 2021;7:e15. doi: 10.34172/jre.2021.15.

Copyright © 2021 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction Anemia is a complication that is commonly encountered when caring for patients with chronic kidney disease (CKD). Moreover, the severity of the anemia worsens as the glomerular filtration rate (GFR) declines, with a prevalence reaching approximately 90% in patients with a GFR less than 30 mL/min (1).

Previous studies have found anemia to be associated with significant morbidity and mortality in end-stage renal disease (ESRD) patients on hemodialysis (HD). Anemia leads to progression of left ventricular hypertrophy with increased risk of myocardial infarction and heart failure (2,3). Anemia has also been associated with depression, cerebrovascular stroke, and fatigue and reduced exercise tolerance (4).

The pathogenesis of anemia in CKD is multifactorial.

The fall in GFR is typically accompanied by a decrease in erythropoietin production. However, several other factors contribute including absolute and functional iron deficiency, folate and vitamin B12deficiencies and suppression of erythropoiesis by uremia (5).

Among patients with CKD or those on dialysis, vitamin D deficiency and insufficiency are increasingly common (6). Diet restrictions and decreased sunlight exposure are factors that affect vitamin D levels in dialysis patients.

Del Valle et al reported inadequate sunlight exposure in approximately 84% of HD patients with vitamin D deficiency (7). Furthermore, uremia has a negative effect on the activation of plasma vitamin D in response to ultraviolet B (UVB) irradiation (8). One of the most common cutaneous manifestations in patients undergoing HD is hyperpigmentation, which too can impair the activation of vitamin D (9). Understanding vitamin D physiology has sparked interest in recent studies searching for other functions beyond its role in mineral and bone metabolism (10). It has been proven that activation of vitamin D can occur in several tissues, in addition to the kidneys (11). Several studies have shown that an increased risk of cardiovascular, musculoskeletal and autoimmune diseases, cancer and increased risk of infections can be associated with vitamin D deficiency (12,13). The study to evaluate early kidney disease and the third national health

Received: 11 January 2021, Accepted: 15 April 2021, ePublished: 5 June 2021 Department of Internal Medicine and Nephrology, Ain Shams University, Cairo, Egypt.

Cairo University, Cairo, Egypt. *Corresponding Author: Lina Essam Khedr, Email: linakhedr@med.asu.edu.eg 1 2

Nour el Din Afifi E et al

Implication for health policy/practice/research/ medical education In a cross-sectional study that included 90 patients on regular hemodialysis, we found a statistically significant positive correlation between vitamin D levels and the level of hemoglobin.

and nutrition examination survey showed that vitamin D deficiency was significantly and independently associated with anemia in patients with CKD who do not require dialysis (14,15).

Objectives This study aimed to evaluate the relation between anemia and vitamin D status in patients on regular HD Patients and Methods Study design This is a cross-sectional study involving 90 patients in El Agouza hospital, Giza, Egypt, with ESRD on regular HD treatment for more than six months with age over 18 years.

This study excluded patients with hepatitis B or hepatitis C infection, patients with malignancies, patient with hemolytic anemia, patients with malabsorption syndromes (Celiac disease and inflammatory bowel disease), patients with active or chronic infections, patients with active bleeding and renal transplant recipients. All patients were on fixed dose of erythropoietin 4000 units twice weekly, except those with hemoglobin more than or equal to 11 g/dL. The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) guidelines (2012) recommended that Hb targets should be in the range of 10.0–11.5 g/dL, regardless of whether the patients were receiving dialysis (16). Therefore, we defined anemia as an Hb level of <11 g/dL. All patients were subjected to full history and physical examination with emphasis on demographic data age, gender, duration of HD, cause of renal failure, comorbidities, and medications. Laboratory tests included serum calcium, phosphorus, 25(OH) D and intact parathyroid hormone (iPTH) levels, hemoglobin level, ferritin level, serum iron, total iron binding capacity (TIBC) and calculation of transferrin saturation (TSAT).

Serum 25(OH) vitamin D level was measured by ELISA (Cal biotech. USA, REF: VD2208), serum samples were collected and centrifuged and separated as soon as possible, stored at -20°C, all specimens were allowed to come to room temperature before use. Vitamin D deficiency was defined as serum levels < 20 ng/dL, insufficiency 20-30 ng/dL and sufficiency >30 ng/dL. Ethical issues The research followed the tenets of the Declaration of Helsinki. This study was approved by Ain Shams University ethical committee (Ref# FWA000017585).

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Journal of Renal Endocrinology, Volume 7, 2021

Informed consent was taken from all participants.

Statistical analysis IBM SPSS statistics (V. 25.0, IBM Corp., USA, 2017-2018) was used for data analysis. Data were expressed as median and percentiles for quantitative non-parametric measures.

The following tests were conducted: (a) Comparison between two independent groups for non-parametric data using Wilcoxon rank sum test; (b) Comparison between more than 2 patient groups for non-parametric data using Kruskal-Wallis test; and (c) Ranked Spearman’s correlation test to study the possible association between each two variables among each group for non-parametric data. The probability of error at 0.05 was considered significant, while at 0.01 and 0.001 are highly significant.

Results This study recruited 90 patients with ESRD, maintained on regular HD in El Agouza hospital HD unit. Table 1 shows the demographics of the study population with the mean age of 51.13 ± 10.44 years consisted of 68 males and 22 females with median duration of HD of 9.50 (6-2) years.

Around 32 (35.6%) of patients were diabetic while 86 (95.6%) of them were hypertensive. As regards the etiology of ESRD the majority of the patients listed hypertension and diabetes 37 (41.1%) and 32 (35.6%) patients respectively.

The level of vitamin D measured in the patients ranged between 3.5 to 66 ng/mL with median of 16.35 ng/mL (834 ng/mL). About 24 patients had vitamin D deficiency (vitamin D levels <20 ng/dL) (Table 2). Accordingly, patients with insufficient levels (vitamin D levels 20Table 1. Demographic data of the study population N = 90 Gender Age (y) Dialysis duration (y) Diabetic HTN

Etiology of ESRD

Female Male Mean ± SD Range Median (IQR) Range

22 (24.4%) 68 (75.6%) 51.13 ± 10.44 24–66 9.50 (6–12) 1–21

No

58 (64.4%)

Yes

32 (35.6%)

No

4 (4.4%)

Yes

86 (95.6%)

Hypertension

37 (41.1%)

Diabetic nephropathy

32 (35.6%)

Lupus nephritis

4 (4.4%)

Chronic glomerulonephritis

4 (4.4%)

Chronic tubulointerstitial nephritis

2 (2.2%)

ADPKD

1 (1.1%)

Hereditary nephritis

1 (1.1%)

Amyloidosis

1 (1.1%)

Unknown

8 (8.9%)

ESRD, end-stage renal disease; ADPKD, autosomal dominant polycystic kidney disease.

Vitamin D and anemia in ESRD

there was highly significant negative correlation between vitamin D3 levels and serum iPTH (intact PTH) levels P < 0.001) and TSAT (P = 0.003).

There were no significant correlations between vitamin D3 levels in all three groups of patients and age of the patients, duration of HD, serum phosphorus levels, serum iron levels, TIBC, serum ferritin levels or serum albumin levels (Table 6).

Table 7 shows highly significant positive relation between hemoglobin levels of all patients and their vitamin D3 levels (P < 0.001). Meanwhile, no significant relationship between hemoglobin level and presence of diabetes (P = 0.533) or hypertension (P = 0.748), etiology of ESRD (P = 0.302) and type of dialysis access (P = 0.960) was detected.

Additionally, highly significant positive correlations between plasma hemoglobin concentration with both vitamin D3 (P < 0.001) and serum calcium levels (P < 0.001) were seen. Meanwhile, a highly significant negative correlation between hemoglobin levels and serum iPTH levels was seen (P < 0.001).

There were no statistically significant correlations between hemoglobin levels and age of the patients, duration of HD, serum phosphorus levels, serum iron, TIBC, serum ferritin levels, TSAT or serum albumin levels (Table 8).

Table 2. Classification of the patients according to vitamin D3 levels (ng/dL) Vitamin D3

No. (%)

Deficient

24 (26.7%)

Insufficient

32 (35.6%)

Sufficient

34 (37.8%)

Median (IQR)

16.35 (8–34)

Range

3.5–66.3

30 ng/dL) were 32 individuals, while patients with sufficient (>30 ng/dL) levels were 34 cases. Table 3 shows no statistically significant relations between vitamin D levels and the gender of the patients (P = 0.536), their age (P = 0.973), duration of HD (P = 0.600), diabetes mellitus (P = 0.064) and hypertension (P = 0.249).

There were statistically significant positive correlations between vitamin D levels and the value of hemoglobin (P < 0.001), serum calcium levels (P < 0.001) and serum PO4 levels (P = 0.023). However, significant negative correlations of vitamin D levels with serum iPTH levels (P < 0.001), serum iron (P = 0.019) and TSAT (P = 0.012) were detected. There was no statistically significant relation between vitamin D levels and type of dialysis access (P = 0.437), TIBC (P = 0.193), serum ferritin levels (P = 0.125) or serum albumin concentration (P = 0.541) (Table 4).

In Table 5, using Spearman’s correlation coefficient, highly significant positive correlation between vitamin D3 levels and both hemoglobin levels (P < 0.001) and serum calcium levels (P < 0.001) were detected. Meanwhile,

Discussion Observational studies have reported that vitamin D deficiency worsens with progression of CKD stage (17).

Table 3. Vitamin D levels in the 3 groups and demographic data Vitamin D3 levels (ng/dL)

Gender Age Dialysis duration Diabetic HTN

Etiology of ESRD

Deficient

Insufficient

Sufficient

n = 24

n = 32

n = 34

Female

5 (20.8%)

10 (31.2%)

7 (20.6%)

Male

19 (79.2%)

22 (68.8%)

27 (79.4%)

51.33 ± 10.18

50.78 ± 10.61

51.32 ± 10.76

24–63

24–65

26–66

9.5 (6.5–11.5)

10 (7–12)

8 (5–11)

2–18

1–21

1–17

No

14 (58.3%)

17 (53.1%)

27 (79.4%)

Yes

10 (41.7%)

15 (46.9%)

7 (20.6%)

Mean ± SD Range Median (IQR) Range

No

0 (0.0%)

1 (3.1%)

3 (8.8%)

Yes

24 (100.0%)

31 (96.9%)

31 (91.2%)

Hypertension

11 (45.8%)

7 (21.9%)

19 (55.9%)

Diabetic nephropathy

10 (41.7%)

15 (46.9%)

7 (20.6%)

Lupus nephritis

1 (4.2%)

2 (6.2%)

1 (2.9%)

Chronic glomerulonephritis

0 (0.0%)

0 (0.0%)

4 (11.8%)

Chronic tubulointerstitial nephritis

0 (0.0%)

2 (6.2%)

0 (0.0%)

ADPKD

0 (0.0%)

1 (3.1%)

0 (0.0%)

Hereditary nephritis

0 (0.0%)

0 (0.0%)

1 (2.9%)

Amyloidosis

0 (0.0%)

0 (0.0%)

1 (2.9%)

Unknown

2 (8.3%)

5 (15.6%)

1 (2.9%)

Test value

P value

Sig.

1.246

0.536

NS

0.028

0.973

NS

1.021

0.600

NS

5.505

0.064

NS

2.783

0.249

NS

27.089

0.041

S

ESRD, end-stage renal disease; ADPKD, autosomal dominant polycystic kidney disease.

P value < 0.05: Significant; P-value < 0.01: Highly significant.

Journal of Renal Endocrinology, Volume 7, 2021

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Nour el Din Afifi E et al Table 4. Vitamin D level in 3 groups in relation to clinical parameters including Vitamin D3

Arteriovenous fistula Dialysis access

Serum calcium (mg/dL) Serum phosphorus (mg/dL) PTH (pg/mL) Hemoglobin (g/dL) Serum iron (µg/mL)

TSAT (%) Serum albumin (g/dL)

Sufficient

n = 32

n = 34

23 (95.8%)

29 (90.6%)

33 (97.1%)

1 (4.2%)

1 (3.1%)

1 (2.9%)

Permanent HD catheter

0 (0.0%)

2 (6.2%)

0 (0.0%)

8.57 ± 1.07

8.43 ± 0.67

9.32 ± 0.68

7.6–11.9

6.9–9.7

8.6–12

4.63 ± 0.81

4.52 ± 0.92

5.32 ± 1.67

2.9–7.2

2.6–8.1

2.7–11

Mean ± SD Range Mean ± SD Range Median (IQR)

669.5 (468.5–782.5)

528.5 (380–666.5)

157.5 (112–213)

Range

230–1197

46.7–1107

28–444

Mean ± SD

8.73 ± 0.83

9.24 ± 1.43

11.24 ± 1.83

6.6–10.1

6.7–14.3

7–14.3

65.33 ± 20.36

66.38 ± 18.88

53.06 ± 22.16

28–94

27–109

16–98

185.46 ± 47.19

204.94 ± 58.36

216.56 ± 77.32

105–303

112–311

112–390

471.54 ± 139.92

399.62 ± 158.78

374.94 ± 216.51

236–764

15.9–720

16–782

35.16 ± 8.12

33.12 ± 7.90

26.87 ± 14.66

9–47

8–46

5–56

3.93 ± 0.39

3.94 ± 0.31

3.84 ± 0.48

3.4–4.9

3.5–4.7

3.1–5.1

Range Mean ± SD Range Range

Ferritin (ng/mL)

Insufficient

n = 24 Arteriovenous graft

Mean ± SD

TIBC

Deficient

Mean ± SD Range Mean ± SD Range Mean ± SD Range

Test value

P value

Sig.

3.774a

0.437

NS

11.646b

0.000

HS

3.935b

0.023

S

50.646c

0.000

HS

24.660b

0.000

HS

4.159b

0.019

S

1.676b

0.193

NS

2.131b

0.125

NS

4.670b

0.012

S

0.618b

0.541

NS

P value > 0.05: Non-significant (NS); P value < 0.05: Significant (S); P value < 0.01: Highly significant (HS). a Chi-square test; b One Way ANOVA test; c Kruskal-Wallis test.

However, there was no difference in prevalence of vitamin D deficiency between CKD patients and the general population in a cross sectional study by Guesseous et al (18). Low 25-hydroxy vitamin D levels have been associated with secondary hyperparathyroidism, decreased bone mineral density and high bone turnover in CKD and patients receiving chronic dialysis treatment (19,20). Moreover, it has been associated with a decrease in muscle power and an increased fall risk (21). It has been Table 5. Correlation of vitamin D3 levels with the other studied parameters using spearman correlation coefficient Vitamin D3 R

P value

-0.027

0.798

Disease duration

-0.064

0.550

Hemoglobin

0.569**

0.000

Serum calcium

0.537**

0.000

0.173

0.103

Intact PTH

-0.733**

0.000

Serum iron

-0.197

0.062

TIBC

0.184

0.082

Ferritin

-0.180

0.090

-0.305**

0.003

-0.129

0.226

Age

Serum phosphorus

TSAT (%) Serum albumin

P value < 0.05: Significant; P value < 0.01: Highly significant.

4

Journal of Renal Endocrinology, Volume 7, 2021

suggested in studies conducted on bone marrow red cell precursor cells that the active form of 25OH vitamin D, calcitriol is associated with upregulating erythropoietinreceptors. Additionally, the active form of 25OH vitamin D also increases cell membrane permeability to calcium stimulating and proliferation of pre-erythroid cell series along with erythropoietin (22).

Our study is cross-sectional that recruited 90 ESRD patients on regular HD in Al Agouza hospital HD center.

In the current study, 66% of patients had vitamin D levels below 30 ng/mL. Several studies have shown a high prevalence of vitamin D deficiency and insufficiency in CKD patients sometimes reaching over 80% (23). There are various causes of 25(OH)vitamin D deficiency in dialysis and CKD population like deficient sunlight exposure (24), impaired vitamin D synthesis and metabolism (25), uremic gastritis and dietary restrictions (26).

In our study, we divided our participants according to their vitamin D status into deficient, insufficient and sufficient groups. We found a highly significant relation between 25(OH) vitamin D levels and hemoglobin levels of our patients (P < 0.001). The patients with sufficient 25(OH) vitamin D levels had higher mean hemoglobin levels than those with insufficient 25(OH) vitamin D levels and subsequently than those with deficient 25(OH) vitamin D levels (mean 11.24 ± 1.83, 9.24 ± 1.43, and 8.73 ± 0.83 ng/dL, respectively). Similarly, Patel et al, found

Vitamin D and anemia in ESRD Table 6. Relationship between vitamin D3 levels in all patients and the other demographic parameters Vitamin D3

Gender Diabetic HTN

Etiology of ESRD

Dialysis access

Median (IQR)

Range

Female

15.95 (11–32)

3.8–51

Male

16.85 (8–34.5)

3.5–66.3

No

19.5 (10–36)

4–66.3

Yes

14.3 (6.8–24.5)

3.5–57

No

35.2 (25.35–41.7)

17.7–46

Yes

16 (8–33.8)

3.5–66.3

Hypertension

30.7 (8–37)

4–51

Diabetic nephropathy

14.3 (6.8–24.5)

3.5–57.0

Lupus Nephritis

13.4 (9.25–24.9)

5.5–36

Chronic glomerulonephritis

32 (31.5–35.5)

31–39

Chronic tubulointerstitial nephritis

17.85 (17.7–18)

17.7–18

ADPKD

13 (13–13)

13–13

Hereditary nephritis

46 (46–46)

46–46

Amyloidosis

37.4 (37.4–37.4)

37.4–37.4

Unknown

12.65 (9–18.85)

6.7–66.3

Arteriovenous fistula

16 (8–34)

3.5–66.3

Arteriovenous graft

22 (8.3–34)

8.3–34

Permanent HD catheter

20 (18–22)

18–22

Test value

P value

Sig.

-0.521a

0.602

NS

-1.691a

0.091

NS

-1.831a

0.067

NS

9.119b

0.332

NS

0.230b

0.891

NS

ESRD, end-stage renal disease; ADPKD, autosomal dominant polycystic kidney disease; HD, hemodialysis.

P value > 0.05: Non-significant (NS); P value < 0.05: Significant (S); P value < 0.01: Highly significant (HS). a Mann-Whitney test; b Kruskal-Wallis test.

Table 7. Hemoglobin level in relation to demographics data and vitamin D status Hemoglobin

Gender Diabetic HTN

Etiology of ESRD

Dialysis access

Vitamin D3 (ng/dL)

Mean ± SD

Range

Female

9.38 ± 1.62

6.6–12.3

Male

10.02 ± 1.88

7–14.3

No

9.95 ± 1.92

6.6–14

Yes

9.7 ± 1.68

7.9–14.3

No

10.15 ± 2.22

7.6–12.3

Yes

9.85 ± 1.83

6.6–14.3

Hypertension

10.19 ± 2.07

6.6–14

Diabetic nephropathy

9.69 ± 1.68

7.9–14.3

Lupus nephritis

8.78 ± 1.44

6.7–10

Chronic glomerulonephritis

11 ± 1.73

8.4–11.9

Chronic tubulointerstitial nephritis

8 ± 0.57

7.6–8.4

ADPKD

8.5 ± 0

8.5–8.5

Hereditary nephritis

9±0

9–9

Amyloidosis

12.3 ± 0

12.3–12.3

Unknown

9.4 ± 1.17

8.2–11.9

Av fistula

9.86 ± 1.86

6.6–14.3

Av graft

9.67 ± 1

8.7–10.7

Permanent HD catheter

10.15 ± 2.47

8.4–11.9

Deficient

8.73 ± 0.83

6.6–10.1

Insufficient

9.24 ± 1.43

6.7–14.3

Sufficient

11.24 ± 1.83

7–14.3

Test value

P value

Sig.

-1.431•

0.156

NS

0.626•

0.533

NS

0.322•

0.748

NS

1.213••

0.302

NS

0.041••

0.960

NS

24.660

0.000

HS

ESRD, end-stage renal disease; ADPKD, autosomal dominant polycystic kidney disease; HD, hemodialysis.

P value > 0.05: Non-significant (NS); P value < 0.05: Significant (S); P value < 0.01: Highly significant (HS).

that 25 (OH) vitamin D deficiencies were significantly associated with anemia in patients with early CKD (14).

However, most patients in that study were CKD stage 3 and none were on dialysis.

Furthermore, it was clear that higher levels of vitamin

D were significantly associated with lower PTH levels.

Serum PTH levels in patients with deficient and insufficient 25(OH) vitamin D levels were higher than those with sufficient 25(OH) vitamin D levels with median values (669.5, 528.5 and 157.5 ρg/mL respectively; Journal of Renal Endocrinology, Volume 7, 2021

5

Nour el Din Afifi E et al Table 8. Correlation of hemoglobin level with the other parameters using Spearman’s correlation coefficient Hemoglobin R

P value

0.569**

0.000

Age

0.033

0.758

Disease duration

-0.171

0.107

Serum calcium (mg/dL)

0.410**

0.000

Vitamin D3

Serum phosphorus (mg/dL)

0.109

0.308

-0.477**

0.000

Serum iron (µg/mL)

-0.004

0.972

TIBC

0.022

0.835

Ferritin (ng/mL)

0.047

0.663

T.SAT (%)

-0.005

0.962

Serum albumin (g/dL)

-0.198

0.061

PTH (pg/mL)

P < 0.001). Similarly, several studies detected also negative correlation between 25(OH) vitamin D and serum PTH levels, establishing the role of vitamin D in suppressing secondary hyperparathyroidism along with calcitriol (19,20).

High PTH levels were significantly associated with lower hemoglobin levels in our study. Bone marrow fibrosis can occur in high PTH levels leading to both anemia and erythropoietin resistance in CKD and dialysis patients (27). However, in the studies that examined the relation between hyperparathyroidism and anemia, 25(OH) vitamin D levels were not routinely measured (28).

Vitamin D has an anti-inflammatory action, reducing interleukin 6 and hepcidin levels leading to improved erythropoietin hyporesponsiveness (29). In our study, ferritin levels were higher in patients with deficient levels of vitamin D, however, this was not found to be statistically significant. A significant negative relation between vitamin D level and serum iron (P = 0.019) and transferrin saturation (%) (P = 0.012) was clear in our study. Patients with vitamin D deficiency had higher serum iron level and higher transferrin saturation levels compared with those with sufficient vitamin D levels. This finding, together with higher levels of ferritin in patients with deficient vitamin D may suggest that inflammation may play a role in the pathogenesis of anemia in those patients. Our study also supports the findings of Patel et al who found no evidence of iron deficiency in vitamin D deficient CKD patients (14).

Anemia was defined as hemoglobin level less than 11 g/dL. Risk factors associated with lower hemoglobin levels in this study included deficient vitamin D levels, high parathyroid hormone levels and high calcium levels.

There was no statistically significant association between hemoglobin and duration of dialysis, age of patients, original kidney disease and type of vascular access.

However, several studies including Madore et al have found age, race, gender erythropoietin (EPO) dose and frequency that EPO was administered, iron status (serum iron, transferrin saturation and ferritin), serum albumin, 6

Journal of Renal Endocrinology, Volume 7, 2021

and the efficiency of dialysis by urea reduction ratio , were all found to be significantly associated with hemoglobin concentration (30). In the current study, all patients were on erythropoietin twice weekly, except those with hemoglobin over 11 g/dL, during the time of the study.

Conclusion This study has found a statistically significant relation between the patients’ vitamin D status and hemoglobin concentration. There was a correlation between vitamin D deficiency and anemia in our studied population. Further studies are needed to establish a causal relationship between 25 hydroxy vitamin D deficiency and anemia.

Limitations of the study A few limitations should be noted. First, this was a single-center study; hence, additional studies with larger numbers of participants are needed to further establish the relationship between vitamin D deficiency and anemia.

Second, it is difficult to establish a causal relationship between vitamin D deficiency and anemia as the current cross-sectional study design. Lastly more factors related to anemia in ESRD were not available as C-reactive protein, hepcidin and dialysis adequacy.

Authors’ contribution EN and LK conceived the idea, AT and ER contributed to the data collection and analysis. LK wrote the manuscript. All authors participated in preparing the final draft of the manuscript, revised the manuscript and critically evaluated the intellectual contents. All authors have read and approved the content of the manuscript and confirmed the accuracy or integrity of any part of the work.

Ethical considerations Ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the authors.

Conflicts of interest The authors declare that they have no competing interests.

Funding/Support No funding was provided for this study.

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Guessous I, McClellan W, Kleinbaum D, Vaccarino V, Zoller O, Theler JM, et al . Swiss Survey on Salt Group. Comparisons of serum vitamin D levels, status, and determinants in populations with and without chronic kidney disease not requiring renal dialysis: a 24-hour urine collection population-based study. J

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19. Mucsi I, Almási C, Deák G, Marton A, Ambrus C, Berta K, et al. Serum 25(OH)-vitamin D levels and bone metabolism in patients on maintenance hemodialysis. Clin Nephrol.

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20. Milinković NLJ, Majkić-Singh NT, Mirković DD, Beletić AD, Pejanović SD, Vujanić ST. Relation between 25(OH)-vitamin D deficiency and markers of bone formation and resorption in haemodialysis patients. Clin Lab. 2009;55:333-9.

21. Boudville N, Inderjeeth C, Elder GJ, Glendenning P. Association between 25-hydroxyvitamin D, somatic muscle weakness and falls risk in end-stage renal failure. Clin Endocrinol (Oxf).

2010;73:299-304.

22. Alon DB, Chaimovitz C, Dvilansky A, Lugassy G, Douvdevani A, Shany S, et al . Novel role of 1,25(OH)(2)D(3) in induction of erythroid progenitor cell proliferation. Exp Hematol.

2002;30:403-9.

23. Ngai M, Lin V, Wong HC, Vathsala A, How P. Vitamin D status and its association with mineral and bone disorder in a multiethnic chronic kidney disease population. Clin Nephrol.

2014;82:231-9.

24. Del Valle E, Negri AL, Aguirre C, Fradinger E, Zanchetta JR. Prevalence of 25(OH) vitamin D insufficiency and deficiency in chronic kidney disease stage 5 patients on hemodialysis.

Hemodial Int. 2007;11:315-21.

25. Cuppari L, Garcia-Lopes MG. Hypovitaminosis D in Chronic Kidney Disease Patients: Prevalence and Treatment. J Ren Nutr.

2009;19:38-43. doi: 10.1053/j.jrn.2008.10.005.

26. Vaziri ND, Hollander D, Hung EK, Vo M, Dadufalza L. Impaired intestinal absorption of vitamin D3 in azotemic rats.

Am J Clin Nutr. 1983;37:403-6.

27. Neves PL, Triviño J, Casaubon F, Santos V, Mendes P, Romão P, et al. Elderly patients on chronic hemodialysis with hyperparathyroidism: increase of hemoglobin level after intravenous calcitriol. Int Urol Nephrol. 2006;38:175-7.

28. Kalantar-Zadeh K, Lee GH, Miller JE, Streja E, Jing J, Robertson JA, et al. Predictors of hyporesponsiveness to erythropoiesisstimulating agents in hemodialysis patients. Am J Kidney Dis. 2009;53:823-34.

29. Türk S, Akbulut M, Yildiz A, Gürbilek M, Gönen S, Tombul Z, et al. Comparative effect of oral pulse and intravenous calcitriol treatment in hemodialysis patients: the effect on serum IL-1 and IL-6 levels and bone mineral density. Nephron.

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Journal of Renal Endocrinology, Volume 7, 2021

7

Open Access

Original J Renal Endocrinol 2021;7:e16.

Journal of

Renal Endocrinology

http://www.jrenendo.com

Nickan

doi: 10.34172/jre.2021.16

Research Institute

Effect of oral vitamin C on serum hepcidin level, iron status and inflammation among hemodialysis patients with functional iron deficiency anaemia ID

Maha A. Behairy1* , Ahmed Gharib1, Mahmoud Zaki1, Reem El Sharabasy1

ID

Abstract Introduction: Hepcidin is a key regulatory peptide in iron homeostasis, the pathogenesis of functional iron deficiency (FID) anemia and erythropoiesis-stimulating agent (ESA) resistance is contributed to the inflammatory mediated increase in the serum hepcidin levels among prevalent hemodialysis (HD) patients.

Objectives: To test the reducing therapeutic effect of oral vitamin C supplements on hepcidin levels and iron status among HD patients with FID anemia.

Patients and Methods: This study is an interventional prospective cohort study; 48 prevalent HD patients were enrolled. Group one: 31 patients who received the conventional treatment of erythropoietin stimulating agents together with oral supplementation of vitamin C 500 mg every other day dose for 3 months. Group two: 17 patients who received only the conventional therapy of erythropoietin stimulating agents. Patients with hemoglobin level <11 g/dL, ferritin level >200 ng/mL and transferrin saturation (TSAT) >20 % were included.

Laboratory parameters: serum hepcidin, high-sensitivity C-reactive protein (hs-CRP) titre, CBC, and iron indices were measured at baseline and after 3 months.

Results: On comparing the two groups, oral vitamin C in group 1 resulted in a statistically significant reduction in hepcidin levels [mean 2506.456 ± 1320.53 pg/mL to 1748.396 ± 1432.28 pg/mL (P = 0.03)], and a significant reduction in hs-CRP level [mean 8603.236 ± 2547.77 ng/mL to 5611.296 ± 2829.27 ng/mL] (P = 0.001) after three months of treatment in comparison to control group. A decrease of EPO requirement and elevation of hemoglobin level were observed in a study group with oral vitamin C. Conclusion: Oral vitamin C may be a promising therapy in decreasing serum hepcidin and inflammatory markers among prevalent HD patients with FID anemia.

Keywords: Vitamin C, Hemodialysis, Hepcidin, Iron deficiency, Anaemia Citation: Behairy MA, Gharib A, Zaki M, El Sharabasy R. Effect of oral vitamin C on serum hepcidin level, iron status and inflammation among hemodialysis patients with functional iron deficiency anaemia. J Renal Endocrinol. 2021;7:e16. doi: 10.34172/jre.2021.16.

Copyright © 2021 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction Functional iron deficiency (FID) is a major cause of persistent anemia in hemodialysis (HD) patients. It was vaguely detected to be caused by chronic inflammatory status and renal dysfunction until the discovery of hepcidin, which described a large part of the pathophysiologic mechanism (1). Hepcidin, a peptide hormone synthesized by the liver, is the central regulatory module for systemic iron homeostasis by decreasing iron absorption from the duodenum, iron release from the macrophages involved in recycling senescent red blood cells, and iron release from iron-storing hepatocytes. The net consequence of elevated hepcidin is decreased iron transfer into the blood plasma, leading to FID (2).

Hepcidin is partially removed from the body by nephron filtration and degradation in the proximal tubule.

With diminishing renal function, the renal excretion and degradation of hepcidin are reduced while its hepatic

production is increased by the inflammatory stimuli marked by elevated interleukin 6 (IL-6). As a result, the blood hepcidin level is elevated in dialysis patients causing FID (2). Iron metabolism, including de novo and recycled iron, is under the functional control of a recently discovered peptide, designated hepcidin (3,4). Vitamin C can reduce ferric iron (Fe3+) into the readily absorbable ferrous form (Fe2+), iron exits enterocytes by ferroportin located in the basolateral membrane of enterocytes (4).

Larger erythropoietin (EPO) doses and parenteral vitamin C were used to improve renal anemia in uremic patients.

While the mechanistic relationship between EPO and hepcidin expression was known recently, the relationship between vitamin C and serum hepcidin levels among HD patients is still unclear and there are limited studies about the clinical therapeutic value of oral vitamin C among HD patients with FID.

Received: 17 June 2021, Accepted: 2 August 2021, ePublished: 14 August 2021 Internal Medicine and Nephrology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt. *Corresponding Author: Maha Abdelmoneim Behairy, Email: mahabehairy@med.asu.edu.eg, Mahabehairy80@gmail.com 1

Behairy MA et al

Implication for health policy/practice/research/ medical education The appropriate management of anemia is crucial for improving quality of life as well as mortality in chronic kidney disease patients.

This clinical research observed the therapeutic impact of low doses of oral vitamin C on the inflammation-mediated hepcidinferroportin pathway, the main contributing factor in the pathogenesis of functional iron deficiency anemia among chronic kidney disease patients on regular hemodialysis in clinical practice. The effective dose of vitamin C, which has also a beneficial anti-inflammatory effect, with low hazards, needs further clinical trials.

Objectives We aimed to study the short-term effect of oral vitamin C therapy on serum hepcidin level and iron indices among HD patients Patients and Methods Study design This study is an interventional prospective cohort study.

Forty-eight prevalent HD patients participated in the study who were randomly assigned into two groups; a study group who received oral (ascorbic acid) vitamin C 500 mg every other day after HD sessions together with erythropoiesis-stimulating agents (ESAs) and IV (intravenous) iron therapy, and a control group who received only ESAs together with IV iron therapy. Patients’ eligibility criteria; patients were eligible to participate in the study if they were clinically stable chronic HD patients maintained on three sessions per week using bicarbonate dialysate and heparin as an anticoagulant, patients’ age

≥18 years with FID anemia defined as hemoglobin level <11 g/dL, ferritin level >200 ng/mL and transferrin saturation (TSAT) >20% (5). Patients excluded from the study were patients with non-renal causes of anemia other than iron deficiency, patients with evidence of active or occult bleeding, patients who received a blood transfusion within the last four months, patients with end-stage liver disease, or chronic hypoxia, or those with history of recent hospitalization or infection requiring antibiotics within the last four weeks, patients with chronic inflammatory states and patients with known sensitivity to vitamin C. CONSORT flow diagram of the study was illustrated in Figure 1. The objectives of this prospective study to evaluate the clinical value of oral vitamin C doses in reducing high serum hepcidin levels in HD patients and the impact of vitamin C as adjuvant therapy on inflammatory markers as high-sensitivity C-reactive protein (hs-CRP) titer reduced erythropoietin resistance, raised hemoglobin level, and impact of oral vitamin C low doses on iron profile parameters.

Patients were subjected to detailed history taking and thorough clinical examination. Laboratory investigations included CBC, reticulocyte count, iron indices, creatinine, Ca, Po4, parathyroid hormone (PTH), urea reduction ratio -Post BUN (URR) = Pre BUN ×100 together with hs-CRP titer and Pre BUN serum hepcidin level by the human hepcidin-25 ELISA kit E3096Hu, manufactured by Bioassay technology laboratory, Shanghai Korean Biotech Co., Ltd. These were drawn at baseline and after three months of oral vitamin C therapy.

The hepcidin kit is an enzyme-linked immunosorbent assay (ELISA). HEPC25 present in the sample was added

Assessed for eligibility (n=210) chronic hemodialysis patients

Enrolment

Excluded (n= 155)  Not meeting inclusion criteria (n=125)  Declined to participate (n=17 )  Other reasons (n= 13 ) Randomized (n= 55) chronic HD patients with FID anemia

Allocation Allocated to control (n= 20) received erythropoietin stimulating agents  Received allocated intervention (n=20 )  Did not receive allocated intervention (n=0 )

Lost to follow-up (died in accident) (n=1)

Allocated to intervention with oral vitamin C 500 mg every other day plus erythropoietin stimulating agents (n=35)  Received allocated intervention (n= 35 )  Did not receive allocated intervention (n= 0 )

Follow-Up for 3m m

Lost to follow-up (patient transferred to another hospital) (n=1)

Discontinued intervention (non-compliant to treatment) (n=2)

Analysed (n= 17)  Excluded from analysis (give reasons) (n=0)

Discontinued intervention (non-compliant) (n=3)

Analysis Analysed (n= 31)  Excluded from analysis (give reasons) (n=0)

Figure 1. CONSORT Flow diagram of the study.

2

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Oral vitamin C in hemodialysis

to the wells and bound to human HEPC25 antibodies pre-coated on the wells. Then biotinylated human HEPC25 antibody was added and bound to HEPC25 in the sample. Streptavidin-HRP was then added and bound to the biotinylated HEPC25 antibody. After incubation, unbound streptavidin-HRP has washed away during a washing step. Substrate solution was then added, and color developed in proportion to the amount of human HEPC25. The reaction was terminated by the addition of acidic stop solution and absorbance was measured at 450 nm. Response to therapy was defined as patients with an increase in hemoglobin at least 1.0 g/dL during the followup of 3 months. EPO resistance index was calculated, defined as average weekly EPO dose per kg body weight (wt) per average hemoglobin (Hgb) (ERI = (EPO/wt)/ Hgb).

Statistical methods Analysis of data was conducted using SPSS program version 23. Quantitative data were presented as mean and standard deviation. Qualitative data were presented as count and percentage. The student t test was applied to compare quantitative data between two groups and one-way ANOVA was used when more than two groups were to be compared. Mann-Whitney U test was used to compare non-parametric quantitative data between two groups. Paired samples t test was applied to compare paired observations of quantitative data for the same group and the Wilcoxon signed ranks test was used for non-parametric data. Repeated measure ANOVA test was used to compare the change in quantitative data over time.

The chi-square (χ²) test was used to compare qualitative

data between different groups, Pearson’s correlation test was used to compare the correlation between different continuous variables. P value < 0.05 was considered statistically significant.

Results The present study included 13 (41.9%) males and 18 (58.1%) females in the study group with a mean age ± SD 46.48 ± 15.57 years versus 8 (47.1%) males and 9 (52.9%) females in the control group with mean age ± SD 46.82 ± 16.74 years. The mean of time on dialysis in the study group and control group was 4.12 ± 1.10 and 3.28 ± 2.03 years respectively. Among the study group, the most common causes of renal failure were hypertension (32.3%) and diabetes mellitus (12.9%) among others, while in the control group; the most common causes were hypertension (47.1%), diabetes mellitus (11.8%), glomerulonephritis (11.8%) and unknown causes (11.8%).

Adequate dialysis was ensured in both groups as assessed by mean URR of 68% and 64% in the study and control groups, respectively. The baseline studied laboratory investigations were described in Table 1, with no statistically significant differences regarding the baseline studied parameters between the two groups of patients.

Hepcidin levels showed a statistically significant reduction in the study group after three months of oral vitamin C therapy (P = 0.03), while hepcidin levels showed no significant reduction in the control group after three months (P = 0.46) as shown in Table 2.

For hepcidin levels, there was no significant “withinsubjects” effect regarding time indicating an insignificant change in the mean hepcidin level over time alone

Table 1. Comparison between the two groups regarding lab investigations before intervention Study group Mean

Control group SD

Mean

SD

t*

P value

Hemoglobin (g/dL)

9.69

0.82

9.81

0.87

0.47

0.64 NS

Iron (ug/dL)

72.17

26.22

67.64

28.27

0.56

0.58 NS

Ferritin (ng/mL)

971.96

526.34

1159.25

481.90

01.21

0.23 NS

TIBC (ug/dL)

213.59

33.02

221.75

33.35

0.82

0.42 NS

T Sat (%)

0.29

0.14

0.31

0.12

1.00

0.32 NS

Retic count

1.39

0.65

1.25

0.55

0.75

0.46 NS

EPO resistance index

11.53

7.97

11.63

5.93

0.04

0.97 NS

PTH (pg/mL)

475.97

345.03

643.35

489.05

1.38

0.17 NS

Ca (mg/dL)

8.54

1.10

8.64

0.84

0.33

0.74 NS

PO4 (mg/dL)

4.37

1.23

4.49

1.29

0.32

0.75 NS

Urea 1 (mg/dL)

100.42

36.17

92.76

27.11

1.12

0.83 NS

Urea 2 (mg/dL)

32.19

18.94

26.59

10.23

1.33

0.19 NS

Urea reduction ratio (%)

0.68

0.13

0.64

0.11

1.17

0.25 NS

K (mmol/L)

5.30

0.72

5.29

0.89

0.01

0.99 NS

Hepcidin (pg/mL)

2506.45

1320.53

3161.76

1034.48

-1.767

0.084 NS

hs-CRP (ng/mL)

8603.23

2547.77

7044.12

2778.37

1.964

0.056 NS

TIBC, Total iron-binding capacity; T Sat, transferrin serum iron saturation; PTH, parathormone; Ca, calcium; PO4, phosphorus; Urea 1, urea pre-dialysis; Urea 2, urea post-dialysis; K, potassium; hs-CRP, highly sensitive C-reactive protein; EPO, erythropoietin. * Student t test.

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Behairy MA et al Table 2. Comparison between studied variables before and after intervention among patients’ groups Study group (Vitamin C)

Variables

Control group

Before (Mean ±SD)

After (Mean ±SD)

P value*

Before (Mean ±SD)

After (Mean ±SD)

P value*

Hepcidin (pg/mL)

2506.4±1320.53

1748.3 ± 1432.28

0.03

3161.76 ±1034.48

3195.88 ± 998.91

0.46

hs-CRP (ng/mL)

8603.2± 2547.77

5611.2 ± 2829.27

0.001

4061.7 ± 2880.62

2158.8 ± 1736.76

0.001

9.69 ± 0.82

10.18 ± 1.24

0.09

9.81± 0.87

10.19 ± 1.36

0.12

Hemoglobin (g/dL) Iron (ug/dL)

72.17 ± 26.22

57.28 ± 30.01

0.02

67.64 ± 28.27

59.59 ± 26.53

0.29

Ferritin (ng/mL) ≠

869.60 ± 793.30

546.20 ± 874.30

0.01

1159.2 ±481.90

635.54 ± 436.16

0.001

TIBC (ug/dL)

213.59 ± 33.02

192.63 ± 25.85

0.001

221.75± 33.35

189.70 ± 33.06

0.01

35 ± 14

30 ± 15

0.12

0.31 ± 0.12

0.32 ± 0.14

0.82

T Sat (%) Retic counts EPO dose (IU) (average/week) EPo resistance index

1.39 ±0.65

0.84 ± 0.52

0.001

1.25 ± 0.55

0.78 ± 0.72

0.05

7142.8 ± 3147.18

6229.7 ± 3218.44

0.26

8000.0 ± 3023.72

5666.4 ± 2807.45

0.06

11.53 ± 7.97

9.75 ± 7.34

0.14

11.63 ±5.93

8.88 ± 5 .79

0.11

TIBC, Total iron-binding capacity; T Sat, transferrin serum iron saturation; hs-CRP, highly sensitive C-reactive protein; EPO, erythropoietin. * Paired Samples t test; *Significant P value <0.05.

(P = 0.09). The “between subjects’ effect” was statistically significant (P = 0.029) indicating that the mean hepcidin level differed significantly between the two groups. The interaction between time and group variables (P = 0.04) illustrates that vitamin C together with time resulted in a significant reduction of hepcidin levels in the study group as shown in Table 3 and Figure 2.

Highly sensitive CRP levels showed a highly significant reduction in the study group (P < 0.01) as shown in, while hs-CRP levels also showed a highly significant reduction in the control group (P < 0.01) as shown in Table 2. For hsCRP, there was a highly significant “within-subjects” effect indicating a significant change in the mean hs-CRP level over time (P < 0.01) as shown in Table 4. The “betweensubjects effect” was statistically highly significant (P < 0.01) indicating that the mean hs-CRP level differed significantly between the study groups. There was a highly significant correlation between baseline hepcidin levels and baseline hs-CRP levels (P < 0.01).

Regarding ferritin, as shown in, the study group showed a highly significant reduction in ferritin levels (P = 0.01), among the control group also showed a highly significant reduction in ferritin levels (P < 0.01) as shown in (Table 2). Comparison between two groups during the follow-up revealed that for serum ferritin, there was no significant “within-subjects” effect indicating an insignificant change in the mean serum ferritin level over time (P > 0.05). The “between-subjects effect” was statistically insignificant (P > 0.05) indicating that the mean serum ferritin level did

not differ significantly between the study groups. There was no interaction between time and group variables.

Regarding other iron indices, the study group showed a statistically significant reduction in iron levels (P<0.05).

Total iron binding capacity (TIBC) and reticulocyte count showed highly significant reductions (P < 0.01) as shown in Table 2. The control group showed a highly significant reduction in TIBC (P = 0.01) and a significant reduction in Retics (P = 0.05) as shown in Table 2. There were no significant reductions in iron levels and TSAT after three months.

There was no statistically significant difference between the study and control groups regarding hemoglobin response to therapy, defined as an elevation in hemoglobin

Figure 2. Comparison between the two groups regarding changes in Hepcidin levels during follow-up.

Table 3. Comparison between the two groups regarding changes in hepcidin levels during follow up Hepcidin level (pg/mL)

Study group Mean

Control group SD

Mean

Within subject effect

Between subject effect

SD

Time

Time*group

Group

0.04

0.029

Before

2506.4

1320.5

3161.76

1034.48

0.09

After

1748.3

1432.2

3195.88

998.91

NS

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Oral vitamin C in hemodialysis Table 4. Comparison between two groups regarding change in hs-CRP levels during follow up Hepcidin level (pg/mL)

Study group

Control group

Mean

SD

Mean

SD

Before

8603.2

2547.7

4061.7

2880.6

After

5611.2

2829.2

2158.8

1736.7

Within subject effect

Between subject effect

Time

Time*group

Group

<0.001

0.33

<0.001*

* Significant P value <0.05

level ≥1 g/dL (χ²=0.202, P>0.05). In the study group, 13 (41.9%) patients showed elevation ≥1 g/dL while 18 (58.1%) patients did not show elevation. In the control group, 6 (35.3%) patients in the control group showed elevation ≥1 g/dL while 11 (64.7%) patients did not show elevation.

There were no significant reductions in erythropoietin dose or hemoglobin levels in the study group after three months of oral vitamin C therapy. The control group showed no significant reduction in erythropoietin dose or hemoglobin levels. The erythropoietin resistance index showed a reduction in the study and control groups after intervention but was not statistically significant (P > 0.05).

There were no significant correlations between baseline hepcidin levels and gender, cause of renal failure, age, weight, body mass index, erythropoietin dose, hemoglobin levels, iron indices, reticulocyte count, or serum electrolytes. The study group showed nonsignificant changes in other studied parameters as PTH, potassium (K), calcium, and phosphate (PO4) in both groups after three months.

Discussion This study found that hepcidin levels were higher in both the study and control groups of prevalent HD patients compared to the normal reference ranges which are in agreement with multiple studies as Xu et al (6), Kuragano et al (7), and Peters et al (8), who found high levels of hepcidin among HD patients compared to healthy controls. High hepcidin levels are contributed to increased production resulting from the chronic inflammatory status seen in end-stage renal disease patients and due to its reduced renal clearance. In the current study, we observed that oral vitamin C therapy resulted in a significant reduction in hepcidin levels in the study group; while, the control group showed a non-significant reduction.

In agreement with our study, when Chiu et al (9), cultured hepcidin-producing HepG2 cells from the liver with 50-100 mg/mL vitamin C for six hours with reverse transcription PCR (polymerase chain reaction) quantitative hepcidin measurements, he found a depression in hepcidin production and an improvement in the utilization of stored iron and concluded that vitamin C directly inhibits hepcidin expression within HepG2 cells, additionally may correct the downregulating EPO receptor. Limited clinical studies are examining the link between serum hepcidin and vitamin C among chronic

kidney disease and HD patients.

The significant reduction in hs-CRP levels among HD received oral vitamin C supplementation in the present study agreed with Biniaz et al (10), who confirmed that among the 151 HD patients involved, hs-CRP levels decreased more obviously in the intravenous vitamin C supplemented group than in the control group (P=0.028).

In comparison, our study showed a highly significant reduction in the control group as well.

Our study reported a highly significant correlation between baseline hepcidin levels and baseline hs-CRP levels. There were no other significant correlations between baseline hepcidin levels and gender, cause of renal failure, age, weight, body mass index, erythropoietin dose, hemoglobin levels, iron indices, reticulocyte count, or serum electrolytes. In contrast to our study, Kuragano et al (7), found a highly significant correlation between hepcidin and iron indices (iron, transferrin, TSAT and ferritin). Fujita et al (11), demonstrated a strong positive correlation between serum ferritin and hepcidin mRNA expression. This can be explained by the fact that hepcidin primarily regulates the liver iron content, which would, in turn, regulate serum ferritin levels via hepatic iron content because hepatocytes and Kupffer cells also express ferroportin. In agreement with our study, Kuragano et al (7), found that hepcidin level was not correlated with age, gender, gender, hemoglobin levels, erythropoietin dose or serum electrolytes.

The present study showed that vitamin C therapy resulted in a highly significant reduction in ferritin levels after intervention in the study group but this was also observed in the control group. In agreement, Sultana et al (12), showed a significant reduction in ferritin after oral vitamin C therapy in the ascorbate group. In contrast, Deved et al (13), assessed the effect of ascorbic acid on iron indices in five trials (14-18) and showed a small non-significant decrease in ferritin concentration in intravenous-ascorbic acid supplemented users over controls, although this result did not achieve statistical significance.

The current study showed that oral vitamin C therapy resulted in a non-significant reduction in TSAT and a significant reduction in TIBC; in contrast, six trials (1419) showed a statistically significant increase in TSAT for the intravenous-ascorbic acid group compared with controls. In agreement with our study, Atallah et al (15), showed that the intravenous-ascorbate supplemented Journal of Renal Endocrinology, Volume 7, 2021

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Behairy MA et al

group was associated with a decrease in TIBC, an indicator of improved iron delivery to tissues.

The present study showed no statistically significant difference between the study and control groups regarding hemoglobin response to therapy, defined as an elevation in hemoglobin level ≥1 g/dl, which may be attributed to the short-term period of the present study. In contrast to our study, a systematic review by Deved et al (13), examining the effects of intravenous ascorbic acid on hemoglobin concentration in HD patients included three trials (n = 125) with baseline hemoglobin levels <11 g/dL and reported mean changes in hemoglobin concentration 0.8-1.8 g/dL in the ascorbic acid groups and -0.1 to 1.1 g/dL in the control groups. The change in hemoglobin concentration was statistically significant, with ascorbic acid use resulting in a 0.9 g/dL increase in hemoglobin level compared with controls.

Our study showed that oral vitamin C resulted in a decrease in EPO dose in the study group (12 U/kg/wk) but was less than in the control group (34 U/kg/wk). In contrast, Atallah et al (15), showed that intravenous vitamin C decreased EPO doses significantly greater among HD patients in the experimental ascorbate patients (48 U/kg/wk) than in control patients (27 U/kg/wk). It may be attributed to the variability of EPO doses available used by patients in different studies and also oral vitamin C has different pharmacokinetics than intravenous vitamin C. Other contrasting studies as Sultana et al (12), demonstrated a significant decrease in EPO dose requirements with low-dose oral vitamin C in anemic HD patients with FID over three months. David et al (13), also showed a mean change in recombinant human erythropoietin (rHuEPO) dose ranging from -48 to 1 U/ kg/wk in the ascorbic acid groups and -27 to 10 U/kg/ wk in the control groups in six trials (14-19) including (n=303) patients. The use of ascorbic acid was associated with a significant decrease in rHuEPO dose compared with controls. In our study, the erythropoietin resistance index showed a non-significant reduction in the study and control groups after intervention.

Vitamin C is known for its strong anti-inflammatory role and its antioxidant nature that may explain its effects on the inflammatory mediators as hepcidin and hs-CRP but it is used requires caution as it is metabolized into oxalic acid, and excess oxalate accumulation leads to the formation of oxalate crystal deposits in tissues and systemic oxalosis (20). Therefore, most of the previous studies were designed to be a short duration of administration of intravenous vitamin C for limitation of estimation serum oxalate and to minimize the risk of oxalosis among HD patients. Our study was designed with a low dose of oral ascorbic acid (vitamin C) which has the advantage of easy availability and cost-effectiveness over the moderate duration.

Conclusion There is a direct relationship between ascorbic acid 6

Journal of Renal Endocrinology, Volume 7, 2021

(vitamin C) and serum hepcidin level among chronic kidney disease patients. Oral vitamin C may be a promising therapy in decreasing serum hepcidin levels and inflammatory markers as hs-CRP and ferritin levels in prevalent HD patients with FID anemia. For further larger cohort studies to investigate the long-term effect of vitamin C low doses as adjuvant therapy on hepcidin level and reducing erythropoietin requirement or improving hyperferritinemia among HD patients.

Limitations of this study The limitations of this study are; this it is a pilot study with small sample size. Serum vitamin C and oxalate levels were not measured.

Authors’ contribution MB has made substantial contributions to the conception and design of this study, revised and analyzed the patient data, involved in drafting of the manuscript and revising it for important intellectual content and has given final approval of the version to be published.

MZ made substantial contributions to conception and design, revised and analyzed the patient data and has given final approval of the version to be published. AH made substantial contributions to acquisition of data, writing the manuscript and has given final approval of the version to be published. RE made substantial contributions to conception and design, analysis and interpretation of data, and drafting the manuscript. All authors read and approved the final manuscript file Conflicts of interest The authors declare that there is no conflict of interest.

Ethical issues All the procedures conducted in the study followed the ethical standards of Ain Shams University Hospital Research Committee (Ethics Committee reference number: 000017585) and the ethical standards laid down in the 1964 Declaration of Helsinki. Informed written consent was obtained from all the patients enrolled in the study. Accordingly, ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the authors.

Funding/Support No funding was received.

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2010;142:24-38. doi: 10.1016/j.cell.2010.06.028.

2. Handelman GJ. New insight on vitamin C in patients with chronic kidney disease. J Ren Nutr. 2011;21:110-2. doi: 10.1053/j.jrn.2010.11.003.

3. Malyszko J, Mysliwiec M. Hepcidin in anemia and inflammation in chronic kidney disease. Kidney Blood Press Res. 2007;30:15-30. doi: 10.1159/000098522.

4. Shike H, Lauth X, Westerman ME, Ostland VE, Carlberg JM, Van Olst JC, et al. Bass hepcidin is a novel antimicrobial peptide induced by bacterial challenge. Eur J Biochem.

2002;269:2232-7. doi: 10.1046/j.1432-1033.2002.02881.x.

5. Thomas DW, Hinchliffe RF, Briggs C, Macdougall IC, Littlewood T, Cavill I, et al. Guideline for the laboratory diagnosis of functional iron deficiency. Br J Haematol. 2013;161:639-48. doi: 10.1111/bjh.12311.

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Xu Y, Ding XQ, Zou JZ, Liu ZH, Jiang SH, Chen YM. Serum hepcidin in haemodialysis patients: associations with iron status and microinflammation. J Int Med Res. 2011;39):19617. doi: 10.1177/147323001103900542.

Kuragano T, Shimonaka Y, Kida A, Furuta M, Nanami M, Otaki Y, et al. Determinants of hepcidin in patients on maintenance hemodialysis: role of inflammation. Am J Nephrol.

2010;31:534-40. doi: 10.1159/000312381.

Peters HP, Laarakkers CM, Swinkels DW, Wetzels JF. Serum hepcidin-25 levels in patients with chronic kidney disease are independent of glomerular filtration rate. Nephrol Dial Transplant. 2010;25:848-53. doi: 10.1093/ndt/gfp546.

Chiu PF, Ko SY, Chang CC. Vitamin C affects the expression of hepcidin and erythropoietin receptor in HepG2 cells. J Ren Nutr. 2012;22:373-6. doi: 10.1053/j.jrn.2011.09.007.

Biniaz V, Sadeghi Shermeh M, Ebadi A, Tayebi A, Einollahi B. Effect of Vitamin C Supplementation on C-reactive Protein Levels in Patients Undergoing Hemodialysis: A Randomized, Double Blind, Placebo-Controlled Study. Nephrourol Mon. 2013;6:e13351. doi: 10.5812/numonthly.13351.

Fujita N, Sugimoto R, Takeo M, Urawa N, Mifuji R, Tanaka H, et al. Hepcidin expression in the liver: relatively low level in patients with chronic hepatitis C. Mol Med. 2007;13:97-104. doi: 10.2119/2006-00057.Fujita.

Sultana T, DeVita MV, Michelis MF. Oral vitamin C supplementation reduces erythropoietin requirement in hemodialysis patients with functional iron deficiency. Int Urol Nephrol. 2016;48:1519-24. doi: 10.1007/s11255-016-13099.

Deved V, Poyah P, James MT, Tonelli M, Manns BJ, Walsh M, et al. Ascorbic acid for anemia management in hemodialysis

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Sezer S, Ozdemir FN, Yakupoglu U, Arat Z, Turan M, Haberal M. Intravenous ascorbic acid administration for erythropoietinhyporesponsive anemia in iron loaded hemodialysis patients.

Artif Organs. 2002;26:366-70. doi: 10.1046/j.15251594.2002.06888.x.

Attallah N, Osman-Malik Y, Frinak S, Besarab A. Effect of intravenous ascorbic acid in hemodialysis patients with EPOhyporesponsive anemia and hyperferritinemia. Am J Kidney Dis. 2006;47:644-54. doi: 10.1053/j.ajkd.2005.12.025.

Chan D, Irish A, Dogra G. Efficacy and safety of oral versus intravenous ascorbic acid for anaemia in haemodialysis patients. Nephrology (Carlton). 2005;10:336-40. doi: 10.1111/j.1440-1797.2005.00424.x. PMID: 16109077.

Deira J, Diego J, Martínez R, Oyarbide A, González A, Díaz H, Grande J. Comparative study of intravenous ascorbic acid versus low-dose desferroxamine in patients on hemodialysis with hyperferritinemia. J Nephrol. 2003;16:703-9.

Giancaspro V, Nuzziello M, Pallotta G, Sacchetti A, Petrarulo F. Intravenous ascorbic acid in hemodialysis patients with functional iron deficiency: a clinical trial. J Nephrol.

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Keven K, Kutlay S, Nergizoglu G, Ertürk S. Randomized, crossover study of the effect of vitamin C on EPO response in hemodialysis patients. Am J Kidney Dis. 2003;41:1233-9. doi: 10.1016/s0272-6386(03)00356-1.

Handelman GJ. New insight on vitamin C in patients with chronic kidney disease. J Ren Nutr. 2011;21:110-2. doi: 10.1053/j.jrn.2010.11.003.

Journal of Renal Endocrinology, Volume 7, 2021

7

Open Access Journal of

Renal Endocrinology

Mini Review J Renal Endocrinol 2021;7:e17. http://www.jrenendo.com

Nickan

doi: 10.34172/jre.2021.17

Research Institute

Congestive kidney failure; recent knowledge and new trends ID

Mehrdad Rabiee Rad1 ID , Ghazal Ghasempour Dabaghi1 , Shakiba Hassanzadeh2* ID Abstract One of the possible causes of renal failure due to heart failure is congestive kidney failure (CKF). Venous congestion has a key role in the development of renal dysfunction and damage in patients with heart failure. This condition is named congestive nephropathy. In this mini-review the common causes of congestive kidney failure, its pathophysiology, histopathological changes and treatment are discussed.

Keywords: Renal failure, Congestive kidney failure, Venous congestion Citation: Rabiee Rad M, Dabaghi G, Hassanzadeh S. Congestive kidney failure; recent knowledge and new trends. J Renal Endocrinol.

2021;7:e17. doi: 10.34172/jre.2021.17.

Copyright © 2021 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction One of the possible causes of renal failure due to heart failure (HF) is congestive kidney failure (CKF) or congestive nephropathy, a neglected disorder caused by increased renal venous pressure. Venous congestion is a strong predictor of worse symptoms and hospitalization requirements. Since the congestion usually occurs several weeks before the presentation of the symptoms, early detection and treatment may improve renal and cardiac outcomes (1). Nevertheless, cardiac disorders are not the only cause of high venous blood pressure. For example, Winton et al (2) reported kidney dysfunction in a dog model that was caused by kidney vein thrombosis.

Additionally, increased intra-abdominal pressure (IAP) is reported to be another possible cause of renal congestion (3). Since CKF may be reversible and has a critical role in renal failure, special attention to this disorder seems crucial. Herein, we review the common causes of CKF, its pathophysiology, histopathological changes and treatment.

Pathophysiology The pathophysiology of renal failure caused by congestion is multifactorial and complex. Studies have shown a strong association between increased renal venous pressure and reduced renal arterial flow to maintain the glomerular arteriovenous gradient (4). The congestion triggers biochemical stress that causes the endothelial cells, as the largest endocrine paracrine organ of the body, to switch their synthetic profile to an activated state. This activated

state of the endothelial cells has pro-inflammatory and vaso-constricting characteristics (5,6). This situation may lead to a reduction in nitric oxide (NO) bioavailability.

NO is a key factor in sustaining the compensated state of HF through vaso-dilatory, anti-inflammatory, and antioxidant processes. Consequently, the reduction of NO leads to vasoconstriction of the renal arteries (7). On the other hand, other vasoactive and bioactive molecules such as prostaglandins and cytokines also have a role in vasoconstriction and reduced glomerular filtration rate (GFR) in renal congestion (7). Moreover, reduced renal atrial pressure to less than 80 mm Hg impairs the renal auto-regulatory function (8). Decreasing the arterial blood flow may lead to hypoxia and lower glomerular filtration. Shimada et al (9) showed that in a rat model with renal congestion, the venous congestion caused tubulointerstitial and glomerular injury via pericyte detachment because of hypoxia, physical stress, and compression of the peritubular capillary.

Heart failure HF is a rapidly growing disorder that occurs when the heart is incapable of maintaining adequate blood flow through body organs. Due to the increase in the mean population age, the prevalence of HF is rising and it is estimated that over 37.7 million individuals suffer from HF globally (10).

Patients with congestive HF have multiple complications such as pulmonary edema or cardio-renal syndrome (11).

Renal failure is one of the most critical complications of HF. For example, in patients with acute decompensated HF,

Received: 11 July 2021, Accepted: 19 August 2021, ePublished: 26 August 2021 School of Medicine, Isfahan University of Medical Science, Isfahan, Iran.

Nickan Research Institute, Isfahan, Iran. *Corresponding Author: Shakiba Hassanzadeh, Email: shak.hassanzadeh@gmail.com 1 2

Rabiee Rad et al

Implication for health policy/practice/research/ medical education Given that congestive kidney failure is a reversible condition, early detection and treatment of congestion are associated with improved renal outcomes.

decreasing renal function one year after hospital discharge is a mortality and morbidity risk factor (12). Cardio-renal syndrome is a disorder that has worsening renal function and medication resistance to diuretics caused by HF. There are multiple similar pathophysiological mechanisms between HF and renal failure, such as inflammatory and cellular reactions of the immune system, hemodynamic changes, stress reactions, acid-base status, neurohormonal responses, and fluid status (13). HF patients that have preserved ejection fraction commonly have renal failure. This may be due to the inflammatory mechanism and endothelial damage caused by renal failure that can lead to stiffening, hypertrophy, and interstitial fibrosis in cardiomyocytes (14). In HF patients, renal blood flow reduces not only because of the incapability of the heart pump and anti-vasopressin therapy but also because of the congestion. In addition, increased central venous pressure leads to congestion. Consequently, the pressure of the renal perfusion decreases to less than 80 mmHg resulting in pressure-dependency of the renal perfusion. Neurohumoral activation and pre-glomerular vasoconstriction are the possible pathways for this condition (15). However, Dupont et al reported that increased central venous pressure did not affect worsening renal failure, but lower mean blood pressure was associated with worsening renal failure (16).

Intra-abdominal pressure In 2008, Mullens et al demonstrated that reducing the IAP improves the renal function in patients with an elevated IAP baseline independently to any hemodynamic parameters. This situation is correlated to direct extensive fluid compression on the kidney, which causes ischemia (3). One of the possible mechanisms is compression of the vessels and tubules due to the rise in renal interstitial pressure. Compression leads to reduced reabsorption and tubular secretion leading to decreased GFR (17).

Histopathological findings Understanding the renal pathological changes in CKF is crucial for improving our knowledge about the disease.

Most of the renal histopathological examinations associated with venous congestion were performed on rats rather than humans, to prevent the unwanted side effects of kidney biopsy in humans. A recent experimental study compared two groups of animal models consisted of a group of rats that had constricted inferior vena cava and a group of sham-operated (SHAM) on male Sprague Dawley rats. There were increases in the width and surface 2

Journal of Renal Endocrinology, Volume 7, 2021

area of the Bowman’s capsule and glomeruli, respectively, in the group of rats that had constricted inferior vena cava.

A positive association was also reported between the abdominal venous pressure and the glomerular surface area 21 weeks after surgery (18). This enlargement may be due to the vasodilation of the afferent artery in response to decreased GFR leading to intra-glomerular hypertension (19). Moreover, these studies showed increasing interstitial edema and inflammation, casts formation, and collapsing renal tubular lumen in the mice with elevated IAP and kidney congestion. In addition, by increasing IAP from 5 to 10 cmH2O, higher interstitial inflammation was observed (20). Other studies have also reported the involvement of pericyte detachment, impaired slit diaphragm, podocyte effacement, and tubular injury. For example, pericyte detachment might lead to impaired renal circulation, hypoxia, and tubular necrosis (9).

Congestive kidney failure diagnosis Unfortunately, there is no specific examination or laboratory test for diagnosing CKF. Most of the frequent signs and symptoms of CKF are also observed in several other diseases. Moreover, many individuals with CKF could have normal cardiac function and the signs of volume overload may improve rapidly after the administration of diuretics (21). Therefore, diagnosing CKF is difficult.

The clinical signs and symptoms that are caused by volume overload may be also associated with CKF such as weight gain, edema, and pleural effusion. No response to treatment with high doses of diuretic and jugular vein distension due to HF may also be associated with CKF. If the initial assessment included the above signs and symptoms, further evaluation and testing may be required to determine the underlying cause (21).

Doppler ultrasound is an effective tool for assessing intra-renal blood flow. Previous studies have found that the patterns of intra-renal venous flow are associated with venous congestion and are independent risk factors of acute kidney failure following cardiac surgery (22).

Moreover, they showed that these patterns are associated with renal and right heart functions and the outcome of patients with pulmonary hypertension (23). Therefore, Doppler ultrasound could be an instant and non-invasive test for evaluating renal congestion and treatment response.

In addition to clinical and imaging assessments, altered laboratory biomarkers may be useful in the diagnosis.

Elevated renin, angiotensin, and aldosterone hormones lead to increased blood urea nitrogen-to-creatinine ratio and hypokalemia (24). Decreased serum creatinine and GFR indicate kidney injury and reduced renal function in these patients. However, renal function may not be influenced by venous congestion, particularly at the early stage of the disease (25). Moreover, some antihypertensive drugs may impact hormonal concentration.

Consequently, although renal dysfunction and changes of

Congestive kidney failure

fluid-regulatory hormones increase the accuracy of the diagnosis, the absence of these abnormalities does not exclude congestive kidney injury.

Treatment There are several therapeutic options for congestive renal failure. Generally, these treatments aim at reducing the excess fluid volume and renal venous pressure. It has been shown that reducing central venous pressure to the normal range results in complete resolution of renal congestion findings in animal experiments. The degree of improvement in the renal function depends on the period and extent of the venous congestion (26). Consequently, early diagnosis and treatment of renal congestive failure may improve the outcomes and prognosis in patients. The major challenge in treating congestive nephropathy is to increase water excretion and sodium level without causing adverse effects on renal function. Loop diuretics, such as furosemide, increase sodium levels in the tubules by blocking the sodium transporter in the tubular cells of the loop of Henle. Elevated tubular sodium reduces the GFR and increases the risk of hyponatremia (27). Furthermore, it has been reported that there is a coloration between higher doses of loop diuretics and poor renal outcomes in HF patients (28). Therefore, although loop diuretics are effective and common treatments for HF, they may be associated with worsening renal function. Previous studies have found that peritoneal dialysis had a positive effect on an HF patient with refractory congestion. They demonstrated significant improvement in the cardiac and renal functions after peritoneal dialysis during a longterm follow-up (29). Their results suggest that peritoneal dialysis could be an alternative treatment in medicationresistant patients.

Sildenafil, a blocker of phosphodiesterase 5, has been used in the treatment of pulmonary arterial hypertension (PAH). A randomized controlled study showed that sildenafil is associated with increased GFR, decreased serum creatinine, and improved renal function in patients with PAH. This improvement was associated with better outcomes and reduced mortality (30). In addition, it has been shown that vasopressin levels increase significantly in patients with HF especially in patients with severe HF (31). Vasopressin type 2 receptor antagonists, such as tolvaptan, may be beneficial in renal congestion by inhibiting the activation of neuro-humoral pathways and increasing excess water excretion. Animal studies in rats with HF have shown that long-term treatment with tolvaptan is associated with improving cardiac and renal histopathological changes and increasing urine volume. Additionally, the overall survival of the rats with HF increased with tolvaptan (32). A ventricular assist device (VAD) is another option for the treatment of renal congestion. Implantation of VAD in patients that had severe HF has been associated with significantly higher GFR and improvement of renal function (33).

Additionally, VAD implantation was related to the rapid reduction of serum creatinine in HF patients (34).

Conclusion Venous congestion has a key role in the development of renal dysfunction and damage in patients with HF. There are also some other conditions associated with congestive nephropathy including elevated IAP and pulmonary hypertension. Although the exact mechanisms and pathophysiology are not yet fully understood, there are useful medical and interventional therapies in the management of this disease. Given that CKF is a reversible condition, early detection and treatment of congestion are associated with improved renal outcomes. Further studies are required to find additional and useful clinical and laboratory tests for the diagnosis and treatment options of CKF. Authors’ contribution MRR and GGD conducted the primary draft. SH conducted the secondary edit. All authors read and signed the final paper.

Conflicts of interest The authors declare that they have no competing interests.

Ethical issues Ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the authors.

Funding/Support None.

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7. Gimbrone MA Jr, Nagel T, Topper JN. Biomechanical activation: an emerging paradigm in endothelial adhesion biology. J Clin Invest. 1997;99:1809-13. doi: 10.1172/JCI119346.

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Open Access

Review J Renal Endocrinol 2021;7:e18.

Journal of

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http://www.jrenendo.com

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doi: 10.34172/jre.2021.18

Research Institute

Post-COVID–19 complication and its effect on acute kidney injury ID

Vinit Singh Baghel1 , Sapnita Shinde1, Vibha Sinha1, Sanjay Kumar Pandey2, Sudhakar Dwivedi2, Nikita Singh2, ID ID ID Atul Kumar Tiwari3, Saurabh Saxena4, Naveen Kumar Vishvakarma1* , Dhananjay Shukla1* , Prashant Bhatt5* Abstract The novel coronavirus outbreak has become a global health emergency. The common symptoms of COVID-19 disease which have affected a large population are common cold, fatigue, headache and fever. However, complications such as multiple organ failure, acute respiratory syndrome and septic shock are seen in about 5% of patients with persisting severe symptoms and post-COVID syndrome.

The COVID-19 acute kidney injury in patients displays damage in the kidney, proteinuria, hematuria and elevated serum creatinine. The symptoms of acute kidney injury vary from mild to severe, which necessitates proper clinical management and renal replacement therapy (RRT). Therefore, it is necessary to understand the pathophysiology of acute kidney injury involving infiltrated immune cells, thrombosis, and cytokine regulation. There is no definite treatment for acute kidney injury; the strategy for preventing the complications will only come through clinical experience. Therefore, more studies are needed for the proper understanding of the disease etiology in acute kidney injury patients with COVID-19. New strategies, International collaboration and multi-disciplinary research are needed to be implemented for the proper management.

Keywords: Post-COVID–19 complications, Acute kidney injury, Clinical management, Pathophysiology Citation: Singh Baghel V, Shinde S, Sinha V, Pandey SK, Dwivedi S, Singh N, Tiwari AK, Saxena S, Vishvakarma NK, Shukla D, Bhatt P. Post-COVID–19 complication and its effect on acute kidney injury. J Renal Endocrinol. 2021;7:e18. doi: 10.34172/jre.2021.18.

Copyright © 2021 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction Ever since the severe acute respiratory coronavirus-2 (SARS-CoV-2) and the resultant COVID-19 disease were first reported in the Wuhan province of China, it has emerged to be a global pandemic with more than 210 million cases and more than 4.49 million deaths as of August 24, 2021. As observed worldwide the disease resulted in a massive surge in hospitalizations and deaths from respiratory failure (1,2). In hospital settings, it was observed that the patients succumbed to death not only by the primary infection of the disease but also due to secondary infections. Early information on secondary infections as the consequence of COVID-19 showed an alarming figure of patients developing acute kidney injury (AKI) (3). Reports from Italy and China showed the incidence rate of AKI due to COVID-19 in a wide range of 0.5-29%, with most of the patients on the lower side of the range (4–6). While the initial reports from the U.S.A. showed an incidence of 28% to 46% (3,7).

These cases for the incidence of AKI in the COVID-19 infected patients have been possibly reported due to the fact that angiotensin-converting enzyme 2, vastly

expressed in podocytes and proximal tubule cells, is also recognized as the binding site for coronavirus SARSCoV-2 (4-6). This puts the kidney as a target organ for the infection and injury caused by COVID-19. The biopsy reports have shown clear renal injuries in the patients (8).

In addition, collapsing focal segmental glomerulosclerosis has been also reported in Black patients (9,10).

In this review, we have discussed the current understanding of the post-COVID-19 complications and involvement of the kidney with special emphasis on the AKI, its clinical features, pathophysiology and clinical management with the potential use of various therapies.

Post-COVID-19 complications and AKI SARS-CoV-2 is a novel coronavirus that has webbed the world with COVID-19 disease. The major symptoms of the disease include fever, cough, tiredness, difficulty in breathing and loss of taste with the smell. Although, the symptoms have variations in patients, ranging from mild symptomatic to asymptomatic; whereas few show acute respiratory distress syndrome (ARDS) which could be fatal (11). Symptoms, in the patients with COVID-19,

Received: 8 August 2021, Accepted: 11 September 2021, ePublished: 29 September 2021 Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, India. 2MDRU, Shyam Shah Medical College, Rewa, Madhya Pradesh 486001 India. 3Department of Zoology, Dr. Bhanvar Singh Porte Govt. College, Pendra, CG, India. 4Next Gen Invitro Diagnostics Pvt Ltd, Gurugram, Haryana, India. 5State Forensic Science Laboratory, Sagar, Madhya Pradesh, India. *Corresponding Authors: Dhannajay Shukla, Email: sdhannu@gmail.com, Naveen Kumar Vishvakarma, Email: naveenvishva@gmail.com and Prashant Bhatt, Email:drbatt.p@gmail.com 1

Singh Baghel V et al

Implication for health policy/practice/research/ medical education It is necessary to understand the pathophysiology of acute kidney injury involving infiltrated immune cells, thrombosis, and cytokine regulation.

that subdue within four weeks are considered as acute COVID-19 symptoms, while patients who do not recover even after negative COVID-19 PCR reaction test and experience no symptoms of COVID-19 are considered as patients experiencing “post-COVID-19 syndrome” which may cause life-threatening severity. The National Institute for Health and Care Excellence (NICE) defines the post-COVID-19 syndrome as, “the symptoms or signs in patients that have developed due to COVID-19 and lasted for approximately three months, which could not be explained by an alternative diagnosis” (12).

The most common symptoms associated with the postCOVID-19 syndrome are headache, fatigue, body pain, anxiety and dyspnea. Evidence from studies has shown post-COVID-19 complications in patients associated with cardiac and pulmonary systems, including cardiac manifestations such as arrhythmia, ischemia and myocarditis; whereas pulmonary complications procuring pneumothorax, pleural effusion, and pneumonia are associated with bacteria (3). The most common reason for patients’ admission to intensive care unit (ICU) with COVID-19 is mainly respiratory failure necessitating the need for mechanical ventilation or vasopressor support.

Though the data on complications related to AKI is limited, the recent report for AKI has shown a 15% of incidence rate (13). The clinical and autopsy reports of patients with COVID-19 confirm the pulmonary infarction, intravascular coagulation, thrombosis, procuring to

increased D-dimer level, and decrease in platelet counts.

Also, the organ system manifests the microangiopathy, splenic infarction, joint pain, and hematuria or proteinuria indicating the renal infarction (14,15). The analysis of kidney function in COVID-19 patients has found an increased level of blood urea and serum creatinine (16). A recent cohort study has defined COVID-19 AKI with the higher levels of proteinuria (ratio of protein to creatinine more than 0.5, 1+ or more than 30 mg/dL on urinalysis), hematuria (1+ or higher urinalysis) (17).

COVID-19 patients with comorbidities including old age, chronic renal insufficiency, cardiac-related problems, and hypertension are at higher risk of poor outcomes. Also, patients diagnosed with chronic kidney disease (CKD) are identified to be at an elevated risk of developing upper respiratory tract infection as a consequence of continuous pro-inflammatory cells from faults in innate and adaptive immunity.

Acute kidney injury Being a health concern worldwide AKI has been associated with high mortality, healthcare expenses, and morbidity. AKI is estimated to impact around 13.3 million people per year with 1.7 million deaths (18). Though the direct relationship between AKI and death has been controversial the progression of AKI to CKD and endstage renal disease (ESRD) further increases the human burden.

Being a multifactorial disease the etiology of AKI is complex (Figure 1). Some of the factors include renal injury due to the surgery, adverse response to the medications, sepsis, toxins, dehydration, acute illness, and inflammation (19). This etiological diversity and complexity together with the heterogeneous patient group present unique challenges in the treatment of the patients.

Figure 1. Acute kidney injury being a multifactorial disease is influenced by various factors such as age, ethnicity of the population, genetic and epigenetic modifications and several other conditions such as respiratory syndrome, viral infections, cardiovascular diseases and diabetes. These factors contribute towards the development of AKI. The development of AKI is further influenced by the duration and stage of the disease and may progress to chronic kidney disease and end-stage renal disease

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Post COVID-19 complication

As of the current scenario, no other medical intervention other than dialysis has been shown to effectively improve the survival rate, fasten the recovery process and limit the injury. Even among the patients who may survive AKI, several long-term outcomes such as progression of CKD, ESRD have been frequently observed (20,21). Thus, the AKI, previously considered to have a gentle course in the recovered patients, can lead to the deterioration of the quality of life and finances (20,22).

Pathophysiology of AKI Post COVID-19 complications and their manifestation as kidney disease can be attributed to various factors such as sepsis, nephrotoxicity, and hypovolemia along with cardiovascular comorbidity (Figure 2) (23). AKI can be a consequence of kidney congestion caused due to the failure of the right ventricle in cardiorenal syndrome, secondary to coronavirus infection.

The autopsy (24) data indicates the affected endothelium of the lungs and kidney, which is a probable cause of proteinuria. Moreover, the viral particles have also been reported to be present in the cells of the renal endothelium, suggesting the potential role of viremia in damaging the renal endothelial layer and subsequently leading to kidney injury. Furthermore, the SARS-CoV-2 can directly cause infection in podocytes and renal tubular epithelium by utilizing an angiotensin-converting enzyme 2-dependent pathway leading to protein leakage in Bowman’s capsule, acute tubular necrosis, protein reabsorption vacuoles’ formation, mitochondrial dysfunction, and collapsing glomerulopathy (8,9).

Another proposed mechanism for the pathogenesis of AKI as a consequence of post-COVID-19 infection involves the dysfunction of immune responses, as observed in cytokine storm and lymphopenia (6,23).

The other factors which have the potential to contribute towards AKI are macrophage activation syndrome, rhabdomyolysis and development of microthrombi and microemboli with reference to endotheliitis (endothelial injury) and hypercoagulability (24,25).

Management of post-COVID-AKI Kidney injury in COVID-19 patients is closely linked to the disease’s severity. In the paucity of specific treatment alternatives, the care strategy for patients with COVID-19 in the ICU remains largely supportive. Considering the high frequency of kidney involvement in COVID-19, all known therapeutic strategies for supporting kidney function should be explored. For reducing the occurrence and severity of AKI in critically ill patients of COVID-19, the patient should implement the Kidney Disease; Improving Global Outcomes (KDIGO) supportive care guideline. This guideline includes avoiding nephrotoxins, avoiding non-steroidal anti-inflammatory drugs, regularly checking serum creatinine and urine output, and considering hemodynamic monitoring (26).

Adjust fluid balance Adjusting the fluid balance is an essential option for managing the risk of acute renal failure, according to the volume responsiveness and tolerance assessment test.

The major goal of this strategy is to return to the normal volume status to avoid volume overload and the danger of pulmonary edema, right ventricular overload, congestion, and AKI. Fluid deprivation at the time of admission may be common in COVID-19 patients since they frequently appear with fever and pre-hospital fluid resuscitation is rarely used. To avoid AKI, hypovolemia should be managed in these patients. Recruitment approaches and procedures with a relatively high positive end-

Figure 2. Multiple pathways initiated upon the COVID-19 infection lead to acute kidney injury. The probable effect of various immune dysfunction such as cytokine storm, hypercoagulability and lung infection on renal function has been shown. The edema caused due to the above factors may lead to increased renal interstitial pressure and further contribute to the progression of acute kidney injury. The release of pathogen-associated molecular patterns (PAMPs) and damageassociated molecular patterns (DAMPs) may elicit an immune response and lead to immune-mediated thrombosis

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expiratory pressure have been used in ARDS subsequent to COVID-19 (27,28).

Extracorporeal treatment AKI has been linked to an increased risk of death in people who have SARS. Approximately 1.5-9 percent of patients who got AKI as a result of COVID-19 infection required RRT in the form of continuous renal replacement therapy (CRRT). With severe infection, the number of cases who needed RRT jumped to 5.2-25 percent. If conventional care fails, early commencement of RRT and sequential extracorporeal organ support may provide sufficient organ support and limit the advancement of disease severity in patients with COVID-19 and AKI (29,30). However, future clinical trials should examine this technique.

In the treatment of coronavirus-associated pneumonia such as SARS and MERS, CRRT has been widely employed. Because SARS and COVID-19 are so similar, it’s practically possible that CRRT will help COVID-19 sufferers (31,32). CRRT is a method that resembles the physiological glomerular filtration process by injecting arteriovenous blood through a semipermeable membrane filter that eliminates overexpressed pro-inflammatory and anti-inflammatory molecules from the blood circulation non-selectively through convection and diffusion. CRRT plays a pivotal role in inhibiting inflammatory signaling pathways, regulate water-electrolyte instability and acidbase balance. It also reduces the peak inflammatory factor concentration, reduces body inflammation and prevents unnecessary activation of inflammatory signaling molecules. Theses actions of CRRT lead to stable and balanced body internal environment (26,33). Early CRRT treatment for patients with severe COVID-19 can help prevent the condition from progressing to critical illness or mortality, as well as minimize the incidence of AKI. In one trial, the combined CRRT/blood perfusion group surpassed the blood perfusion treatment alone in terms of disease efficacy, hospitalization time, platelet count, activated partial thromboplastin time, blood oxygen saturation, mean arterial pressure, urea nitrogen, and serum creatinine. The former had a lower mortality rate (34). Due to the high frequency of clotting in CRRT filters and catheters, patients undergoing CRRT must have systemic anticoagulation therapy.

Further investigation into the therapeutic impact and evaluation of CRRT in severe COVID-19 patients is still needed (35). Xiao et al (36), in their observational analysis of 287 individuals observed that maximum number of patients recovered from stage 1 AKI. On the contrary, the death rates were high for the patients who advanced to stage 2 or 3 of AKI (3). COVID-19’s effect on patients’ long-term kidney function should be studied further.

Furthermore, larger, multi-center studies are required to acquire a better understanding of AKI in COVID-19 patients, as well as how to prevent and manage it.

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Conclusion and future prospects Regardless of very limited data present on the correlation between the incidence of AKI and COVID-19 infection, it is plausible that the AKI may be a consequence of complex process mediated by infection of the virus, dysregulation of immune pathways, cytokine storm and hypercoagulation and their interaction with other risk factors of AKI. The data on clinical characteristics of AKI is very scarce and hence more study on the underlying mechanism needs to be done. Also, the data that are available lack detailed analysis of parameters indicating the kidney functions such as, urine microscopy, urine electrolytes and kidney injury markers. The markers of the immune system such as macrophage activation markers, complement activation markers, coagulation markers and kidney imaging are some of the important data needed for the deep insight into underlying COVID-19 associated physiopathology of AKI. Also, the clearer picture painted by the elaborate data will help us in designing better prevention and intervention strategies against COVID-19 associated AKI. Authors’ contribution VSB, SS, VS, SKP and SD conducted the primary draft. NS, AKT and SSa completed the paper. NKV, DS and PB finalized the paper. All authors read and signed the final paper.

Conflicts of interest The authors declare that they have no competing interests.

Ethical issues Ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the authors.

Funding/Support None.

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Open Access

Mini-Review J Renal Endocrinol 2021;7:e19.

Journal of

Renal Endocrinology

http://www.jrenendo.com

Nickan

doi: 10.34172/jre.2021.19

Research Institute

Vitamin D and COVID-19 infection; recent findings ID

Alireza Pouramini1 , Fatemeh Kafi1 ID , Shakiba Hassanzadeh2* ID Abstract COVID-19 infection increases the risk of death in patients with chronic conditions such as diabetes or obesity. The exact role of vitamin D in COVID-19 infection is unknown and controversial. Furthermore, the exact prevalence of vitamin D deficiency is still unknown but it affects individuals worldwide regardless of ethnicity and age. Herein, we give an overview of vitamin D deficiency as a global public health problem, the role of vitamin D in COVID-19 infection, and the proper approach to treating vitamin D deficiency.

Keywords: COVID-19, Vitamin D, SARS-CoV-2, Immune system, Vitamin D Citation: Pouramini A, Kafi F, Hassanzadeh S. Vitamin D and COVID-19 infection; recent findings. J Renal Endocrinol. 2021;7:e19. doi: 10.34172/jre.2021.19.

Copyright © 2021 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction The severe acute respiratory syndrome coronavirus type2 (SARS-CoV-2) coronavirus disease 2019 (COVID-19) has rapidly spread worldwide. The severity of COVID-19 infection ranges from asymptomatic to severe and may lead to acute respiratory distress syndrome or multi-organ failure. Therefore, the interest in improving the immune system to avoid COVID-19 infection in this devastating pandemic has increased (1).

COVID-19 infection exacerbates the inflammatory response and increases the risk of death in patients with chronic conditions. For example, in diabetic patients, which causes systemic inflammation, worse infectionrelated respiratory symptoms are more likely to develop (2). Obesity and central adiposity are also significant risk factors for COVID-19-related complications, especially in those with compromised heart and lung functions (3). The risk of COVID-19-associated thrombotic complications is also increased due to common vascular damages in diabetic and hypertensive patients (4).

Several preventive measures for general public health have been recommended to limit the risk of SARS-CoV-2 transmission including hand and respiratory cleanliness (5). A healthy lifestyle and proven-effective nutraceutical supplements may help combat some aspects of the infection. Currently, it is critical to provide preventative health measures to lower the risk of COVID-19 infection including proper vaccine distribution and/or effective antiviral medicine.

Adequate nutrition and eating habits have been widely discussed during the COVID-19 pandemic, since underestimating the importance of nutrition in COVID-19 patients will significantly impact their

prognosis. This is because of their impact on noncommunicable diseases (such as diabetes and obesity) that can result in more severe infections and also their role in the improvement of the patients’ inflammatory state (6). In addition, vitamins C and D and zinc (7) have been reported to possibly have an important role in the susceptibility to the disease and the function maintenance of the immune system (8). C-reactive protein (CRP) and other inflammatory markers, including inflammatory cytokines and chemokines, are commonly high in patients with COVID-19 (9, 10). Therefore, any nutritional method that can regulate the immune function may be advantageous both early on, when an adequate immune response is critical, and later on, when a cytokine storm may cause hyper-reactive immune responses.

In this review, we give an overview of vitamin D deficiency as a global public health problem, the role of vitamin D in COVID-19 infection, and the proper approach to treating vitamin D deficiency.

Search strategy For this mini-review, we searched PubMed/Medline, Web of Science, Scopus, DOAJ (Directory of Open Access Journals), Embase, and Google Scholar, using keywords including; COVID-19, vitamin D, SARS-CoV-2 and immune system Vitamin D as a global public health problem Vitamin D, a fat-soluble vitamin, is essential in calcium homeostasis and bone health. It has also been associated with different disorders such as hypertension, diabetes, metabolic syndrome, cancer, autoimmune, and infectious illnesses (11). These conditions have a significant impact

Received: 16 July 2021, Accepted: 15 September 2021, ePublished: 7 October 2021 School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. 2Nickan Research Institute, Isfahan, Iran. *Corresponding Author: Shakiba Hassanzadeh, Email: shak.hassanzadeh@gmail.com 1

Pouramini A et al

Implication for health policy/practice/research/ medical education COVID-19 infection increases the risk of death in patients with chronic conditions such as diabetes or obesity. The exact role of vitamin D in COVID-19 infection is unknown and controversial.

on global public health.

The exact prevalence of vitamin D deficiency is still unknown but it is estimated that it affects around one billion people worldwide regardless of ethnicity and age.

Interestingly, vitamin D deficiency may be seen in some low-latitude or industrialized countries. Traditionally, in low-latitude countries, it was considered that the ultraviolet B radiation is sufficient to prevent vitamin D deficiency and in industrialized countries, fortification of vitamin D has been performed for several years (11).

Vitamin D role in COVID-19 Our lungs have about a 70 m2 surface area that is in contact with air, so it is a significant target for viruses like SARS-CoV-2. Vitamin D may have several roles in COVID-19 infection. For example, vitamin D deficiency can impair innate cellular immunity and trigger cytokine storms, which contribute to the development of ARDSassociated COVID-19. Additionally, vitamin D promotes the production of antimicrobial peptides in the respiratory epithelium, which makes viral infections and COVID-19 symptoms unlikely. Vitamin D may also have an antiinflammatory effect on the body when it is exposed to SARS-CoV-2 infection (12, 13). Covid-19 is characterized by the dysregulation of this response, particularly the renin-angiotensin system, and the level of over-activation of this system is associated with a poorer prognosis.

The CYP27B1 enzyme converts vitamin 25 (OH) D to its active form in antigen-presenting cells (APCs) such as dendritic cells (DCs) and macrophages (14). Similar to macrophages and DCs, endothelial cells display major histocompatibility complex class I and II antigens and may function as APCs (15). They play an important role in vitamin D function in innate and adaptive immunity.

Treatment of vitamin D deficiency The amount of vitamin D is measured by the blood vitamin D. However, we are unsure about the optimal doses of vitamin D. Some evidence support 50 nmol/L vitamin 25(OH)D levels because parathyroid hormone does not significantly decrease in individuals with vitamin D baseline levels more than 50 nmol/L. A study with 365,530 participants found that the 45-60 nmol/L range is an excellent target for decreasing mortality and premature death (16, 17). A 2017 meta-analysis found that individuals who took vitamin D daily or weekly without bolus doses had higher protective effects than those who took one or more bolus doses (18). Similarly, a placebocontrolled study of 3046 infants given 100 000 IU vitamin 2

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D bolus doses every three months found no reduction in the incidence of pneumonia and there were even increased incidences in certain cases (19). Bolus vitamin D3 supplements, or even high doses of 4000 IU/day or 10 000 IU/day, may have produced worse results in bone mineral density than 400 IU/day because the transiently high level of vitamin D activated the 24-hydroxylase enzyme, resulting in the production of 24, 25 (OH) 2D, an inactive form of vitamin D (20,21).

Even in obese individuals, regular doses of 800 IU are sufficient to achieve the target of a minimum concentration of 50 nmol/L vitamin D, and since doses up to 4000 IU/ day are safe and vitamin D capsules are typically sold in 1000 IU capsules forms, the use of one 1000 IU capsule per day is sufficient and safe for all adults (22).

Meta-analysis regarding vitamin D association with COVID-19 disease A meta-analysis of 373 critical COVID-19 patients that was published in 2020 found that patients with worse prognoses had significantly lower serum levels of vitamin D compared to those with favorable prognoses (23). In addition, another meta-analysis that included 532 patients from two randomized controlled trials (RCTs) and one retrospective case-control research found that patients who took vitamin D supplements required less intensive care unit (ICU) admission (24). On the contrary, Rawat et al conducted a meta-analysis of three randomized controlled trials and two quasi-experimental studies to determine the effect of vitamin D supplementation in COVID-infected individuals. They reported that vitamin D supplementation did not significantly reduce the mortality and ICU admission rates, or the need for invasive ventilation (25).

The key reasons for the various findings may be as the followings; 1) Currently, there are limited available clinical trials and inadequate information about the influence of the various doses of vitamin D as well as the proper duration of therapy on the outcome. 2) Additionally, the current studies lack the sufficient information to examine the effect of vitamin D therapy in patients with severe vitamin D deficiency at baseline. 3) The characteristics of the participants of these studies that had comorbid conditions were heterogeneous making the evaluation of vitamin D effect in these individuals impossible due to insufficient available evidence.

As a result, more RCTs with enough sample sizes are required to fill these limitations.

Authors’ contribution AP and FK wrote the draft. SH conducted the English and scientific edit. All authors read and signed the final draft.

Conflicts of interest The authors declare that they have no competing interests.

Ethical considerations Ethical issues (including plagiarism, data fabrication, double

Vitamin D and COVID-19 publication) have been completely observed by the authors.

Funding/Support None.

References 1. Watkins J. Preventing a covid-19 pandemic. BMJ. 2020;368:m810. doi: 10.1136/bmj.m810.

2. Gupta R, Hussain A, Misra A. Diabetes and COVID-19: evidence, current status and unanswered research questions.

Eur J Clin Nutr. 2020;74:864-70. doi: 10.1038/s41430-0200652-1.

3. Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention.

JAMA. 2020;323:1239-42. doi: 10.1001/jama.2020.2648.

4. WHO Coronavirus (COVID-19) Dashboard -- WHO Coronavirus (COVID-19) Dashboard With Vaccination Data [Internet]. Available from: https://covid19.who.int/.

5. Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, et al.

Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N Engl J Med. 2020;382:1199-207. doi: 10.1056/NEJMoa2001316.

6. Chaplin DD. Overview of the immune response. J Allergy Clin Immunol. 2010;125:S3-23. doi: 10.1016/j.jaci.2009.12.980.

7. Zabetakis I, Lordan R, Norton C, Tsoupras A. COVID-19: The Inflammation Link and the Role of Nutrition in Potential Mitigation. Nutrients. 2020;12. doi: 10.3390/nu12051466.

8. Maggini S, Beveridge S, Sorbara PJP, Senatore G. Feeding the immune system: the role of micronutrients in restoring resistance to infections. Cab Reviews: Perspectives in Agriculture, Veterinary Science, Nutrition and Natural Resources. 2008;3:1-21.

9. Herold T, Jurinovic V, Arnreich C, Lipworth BJ, Hellmuth JC, von Bergwelt-Baildon M, et al. Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J Allergy Clin Immunol. 2020;146:128-36.e4. doi: 10.1016/j. jaci.2020.05.008.

10. Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020;180:934-43. doi: 10.1001/jamainternmed.2020.0994.

11. Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr.

2008;87:1080s-6s. doi: 10.1093/ajcn/87.4.1080S. 12. Daneshkhah A, Agrawal V, Eshein A, Subramanian H, Roy HK, Backman V. Evidence for possible association of vitamin D status with cytokine storm and unregulated inflammation in COVID-19 patients. Aging Clin Exp Res. 2020;32:2141-58. doi: 10.1007/s40520-020-01677-y.

13. Mitchell F. Vitamin-D and COVID-19: do deficient risk a poorer outcome? Lancet Diabetes Endocrinol. 2020;8:570.

doi: 10.1016/s2213-8587(20)30183-2.

14. Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol. 2014;21:319-29. doi: 10.1016/j.chembiol.2013.12.016.

15. Virzì GM, Zhang J, Nalesso F, Ronco C, McCullough PA. The Role of Dendritic and Endothelial Cells in Cardiorenal Syndrome.

Cardiorenal Med. 2018;8:92-104. doi: 10.1159/000485937.

16. Griffin G, Hewison M, Hopkin J, Kenny R, Quinton R, Rhodes J, et al. Vitamin D and COVID-19: evidence and recommendations for supplementation. R Soc Open Sci. 2020;7:201912. doi: 10.1098/rsos.201912.

17. Fan X, Wang J, Song M, Giovannucci EL, Ma H, Jin G, et al.

Vitamin D Status and Risk of All-Cause and Cause-Specific Mortality in a Large Cohort: Results From the UK Biobank.

J Clin Endocrinol Metab. 2020;105. doi: 10.1210/clinem/ dgaa432.

18. Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and metaanalysis of individual participant data. BMJ. 2017;356:i6583. doi: 10.1136/bmj.i6583.

19. Manaseki-Holland S, Maroof Z, Bruce J, Mughal MZ, Masher MI, Bhutta ZA, et al. Effect on the incidence of pneumonia of vitamin D supplementation by quarterly bolus dose to infants in Kabul: a randomised controlled superiority trial. Lancet.

2012;379:1419-27. doi: 10.1016/s0140-6736(11)61650-4.

20. Ketha H, Thacher TD, Oberhelman SS, Fischer PR, Singh RJ, Kumar R. Comparison of the effect of daily versus bolus dose maternal vitamin D(3) supplementation on the 24,25-dihydroxyvitamin D(3) to 25-hydroxyvitamin D(3) ratio.

Bone. 2018;110:321-5. doi: 10.1016/j.bone.2018.02.024.

21. Burt LA, Billington EO, Rose MS, Raymond DA, Hanley DA, Boyd SK. Effect of High-Dose Vitamin D Supplementation on Volumetric Bone Density and Bone Strength: A Randomized Clinical Trial. JAMA. 2019;322:736-45. doi: 10.1001/ jama.2019.11889.

22. Griffin G, Hewison M, Hopkin J, Kenny RA, Quinton R, Rhodes J, et al. Preventing vitamin D deficiency during the COVID-19 pandemic: UK definitions of vitamin D sufficiency and recommended supplement dose are set too low. Clin Med (Lond). 2021;21:e48-e51. doi: 10.7861/clinmed.2020-0858.

23. Munshi R, Hussein MH, Toraih EA, Elshazli RM, Jardak C, Sultana N, et al. Vitamin D insufficiency as a potential culprit in critical COVID-19 patients. J Med Virol. 2021;93:733-40. doi: 10.1002/jmv.26360.

24. Shah K, Saxena D, Mavalankar D. Vitamin D supplementation, COVID-19 and disease severity: a meta-analysis. Qjm. 2021;114:175-81. doi: 10.1093/qjmed/hcab009.

25. Rawat D, Roy A, Maitra S, Shankar V, Khanna P, Baidya DK. “Vitamin D supplementation and COVID-19 treatment: A systematic review and meta-analysis”. Diabetes Metab Syndr.

2021;15:102189. doi: 10.1016/j.dsx.2021.102189.

Journal of Renal Endocrinology, Volume 7, 2021

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Open Access

Mini Review J Renal Endocrinol 2021;7:e20.

Journal of

Renal Endocrinology

http://www.jrenendo.com

Nickan

doi: 10.34172/jre.2021.20

Research Institute

Renal complications of sickle cell disease ID

ID

ID

ID

Sara Bahadoram1 , Bijan Keikhaei1 , Mohammad Bahadoram1,2 , Mohammad-Reza Mahmoudian-Sani1,2 , ID Shakiba Hassanzadeh3* Abstract The nephropathy and renal complications of sickle cell disease are associated with various events such as hypoxic or ischemic conditions and reperfusion injury. Erythrocyte sickling occurs following these events and renal medullary acidosis.

Keyword: Sickle cell disease, Renal failure, Nephropathy, Erythrocyte, Hemoglobin SS Citation: Bahadoram S, Keikhaei B, Bahadoram M, Mahmoudian-Sani MR, Hassanzadeh S. Renal complications of sickle cell disease. J Renal Endocrinol. 2021;7:e20. doi: 10.34172/jre.2021.20.

Copyright © 2021 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction The incidence rate of sickle cell disease (SCD) is estimated at 300 000 births per year. In SCD patients, at the sixth amino acid position of the β-globin gene, valine is substituted for glutamine. The β-globin gene is located on the short arm of chromosome 11. Additionally, the sickle cell trait is caused by inheriting a copy of the mutation (1). Hemoglobin SS (HbSS) disease is the most common type of SCD and approximately one-third of SCD patients are heterozygous for hemoglobin SD (HbSD) (2). SCD is an inherited disorder that leads to defective hemoglobin production that creates erythrocytes with damaged membranes. This process occurs following cellular dehydration, chronic hemolytic disease, and episodes of vascular occlusion (3).

Search strategy For this mini-review, we searched Directory of Open Access Journals (DOAJ), PubMed/Medline, Web of Science, Scopus, Embase and Google Scholar, using keywords including; sickle cell disease, renal failure, nephropathy, erythrocyte and hemoglobin SS Nephropathy in sickle cell disease patients The pathophysiology of renal failure and nephropathy in SCD patients is not yet fully understood. However, it has been associated with hypoxic or ischemic conditions, reperfusion injury, and changes in vascular reactivity. Hypoxia and renal medullary acidosis cause erythrocyte sickling which leads to glomerular microinfarction and hyper-filtration. Subsequently, progressive

glomerulosclerosis and chronic kidney disease (CKD) occur (4). In addition, it has been reported that the TGFβ/ BMP pathway is involved in the development of kidney diseases in SCD patients (5).

A study reported that 4.2% and 2.4% of HbSS and HbSC patients develop renal failure, respectively. Additionally, kidney failure is a progressive disorder and common in SS and SB phenotypes of SCD (5). Severe early anemia and hemoglobin levels less than 8 g/dL are the most important symptoms in SCD patients with HbSS and HbSβ0 subtypes that develop microalbuminuria (6). On the other hand, EPO (erythropoietin) synthesis is impaired in cases with renal dysfunction and reduced glomerular filtration rate (GFR) (5).

Renal complications in sickle cell disease SCD patients are at risk for renal complications and in most cases, SCD-induced nephropathy occurs gradually.

Renal complications vary from glomerular hypofiltration to microalbuminuria or occasionally macroalbuminuria, and finally leads to CKD (5). However, fewer pain attacks and stable hemoglobin levels are less likely to lead to proteinuria and kidney failure (7).

Renal manifestations include low-medullary blood flow rate during the first decade of life, hyposthenuria, renal papillary necrosis, proteinuria, hematuria, focal segmental glomerulosclerosis (FSGS), and finally, renal medullary carcinoma. Furthermore, hyper-filtration is the first sign of renal dysfunction with an increased risk of progression to end-stage renal disease (ESRD) (3). In addition, chronic hemolysis causes iron deposition in

Received: 23 August 2021, Accepted: 2 October 2021, ePublished: 17 October 2021 Thalassemia and Hemoglobinopathy Research Center, Research Institute of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. 2Chronic Renal Failure Research Center, Ahvaz Jundishapur University of Medical, Sciences, Ahvaz, Iran. 3Nickan Research Institute, Isfahan, Iran. *Corresponding Author: Shakiba Hassanzadeh, Email: shak.hassanzadeh@gmail.com 1

Bahadoram S et al

Implication for health policy/practice/research/ medical education The renal complications of sickle cell disease are associated with various events such as hypoxic or ischemic conditions. Erythrocyte sickling occurs following these events and, in turn, may lead to renal complications and chronic kidney disease. Early diagnosis, regular screening and monitoring, preventive measurements, and immediate treatment may slow the progression to renal failure.

the kidney leading to mesenchymal cell proliferation and glomerular fibrosis (8). On the other hand, recurrent pain attacks cause ischemic renal injury and lead to the loss of kidney function and decrease the levels of prostaglandin and GFR (7).

The role of cardiac output in renal diseases Cardiac output increases in SCD patients due to various reasons. These patients experience endothelial nitric oxide synthase (eNOS) deficiency due to chronic hemolysis.

Therefore, the arteries do not have a proper hemodynamic response and there is an increased risk of developing acute kidney injury (AKI) (8).

The role of micro-infarction in developing hematuria and renal diseases Hematuria in SCD patients is due to micro-infarction in the renal papilla, which is often self-limiting but may lead to renal necrosis and clot formation (1, 5).

Hematuria often occurs at an older age and there is no difference in the incidence of both genders (7). Papillary necrosis secondary to vascular occlusion episodes leads to macroscopic hematuria (8). Hematuria may develop due to medullary carcinoma which may occur even at the age of 2 years (5).

Urine concentrating inability The inability to increase urinary concentration to 450 mmol/kg is a common finding in SCD patients (5). Urine concentrating ability in SCD patients is associated with the deletion of the α-globin gene; deletion of two genes reduces urine concentration (1).

The role of blood pressure level in developing kidney disease Blood pressure (BP) is usually low in SCD patients due to the hemodynamic response to the extensive systemic vasodilation induced by nitric oxide (NO) and prostacyclin production (2). The mean BP is lower than normal compared to healthy individuals of the same age and race.

In the cases that have hypertension, the diastolic pressure increases which is associated with increased creatinine and pulmonary hypertension (5). High BP and elevated heart rate are both important in increasing the risk of morbidity caused by kidney disease in SCD patients (2).

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Microalbuminuria and proteinuria Microalbuminuria occurs at an early age and progresses to proteinuria and, eventually, kidney failure with increased age and anemia severity (4). Microalbuminuria is associated with decreased plasma hemoglobin and increased reticulocyte counts (4). The prevalence of microalbuminuria and increased β2 microglobulin levels are higher in SS patients compared to AS patients (9). In addition, albuminuria is more common in SS patients than AS patients (2).

The prevalence of proteinuria in SS patients has been reported to be 17 to 33% (8). Proteinuria may occur alone or in combination with renal vein thrombosis, foot ulcer, hematuria, and acute or chronic glomerulonephritis (7).

Proteinuria and progression to kidney failure increase in the severe phenotype of SCD that is associated with multiple episodes of acute coronary syndrome and stroke (4).

Renal glomerular diseases Nephromegaly due to glomerular hypertrophy is detected on ultrasound in infants aged 7 to 18 months. Under light microscope, the most common finding is FSGS (8).

Renal tubular disorders and acute renal injury SCD is associated with distal and proximal renal tubular disorders. Most patients experience hyperphosphatemia and, commonly, have elevated uric acid and creatinine.

Distal renal tubular disorder presents with incomplete type IV RTA (renal tubular acidosis) symptoms and occurs in critically ill patients with hyperkalemia and acidosis (5).

AKI may occur due to episodes of vascular occlusion following a decrease in hemoglobin level and ketorolac consumption (8).

Other manifestations of kidney diseases Nocturia is also prevalent in SS patients. The incidence of enuresis is severe in SS, moderate in hemoglobulin SA (HbSA), and less in SB (10). Concurrent α-thalassemia delays microalbuminuria. Low levels of hemoglobin F (HbF) predispose a person to kidney disease; therefore, an HbF level of ˃20% indicates a reduced risk of kidney failure (5). The pain attacks that lead to anemia and require blood transfusions are associated with low GFR levels (7).

Screening Screening for glomerular injury with dipstick test should start at the age of 10 years (4). In addition, monitoring should be performed for patients with persistent microscopic hematuria, GFR <60 mL/min/1.73 m2, and proteinuria with a Pr/Cr (protein/creatinine) ratio of 50 mg/mmol (5). These patients should be followed up with annual urinalysis (4).

Prevention Prevention of anemia (caused by pain attacks) through

Complications of sickle cell

prophylactic blood transfusion could reduce glomerular hyperfiltration and slow the progression to kidney failure (7). The lowest acceptable hemoglobin level in ESRD patients is 8-9 g/dL (8). Hyposthenuria can be reversed at a young age by blood transfusions (5).

Biomarkers The diagnosis of nephropathy in asymptomatic SCD patients is of particular importance (7).

Increased nephrin levels in SCD patients with persistent hyperfiltration indicate glomerular injury. Age as well as systolic and diastolic BPs are important factors in determining the GFR levels of the patients (3). The ratio of cystatin-C to creatinine is another key marker for assessing renal function in children and adults (5).

Treatment In addition to treatment with hydroxyurea, stimulants of erythropoiesis can be administered to prevent anemia in these patients. Grade 3-4 of patients with chronic renal disease require high doses of erythropoiesis stimulants.

However, chronic transfusion therapy does not affect the prevention of proteinuria (5). In children aged between 9 to 18 months, hydroxyurea helps increase urine concentration and reduce hyper-filtration. Angiotensinconverting enzyme inhibitors can be prescribed to reduce proteinuria in SCD adults that have normotension and microalbuminuria (11). Renal replacement therapy is required in cases when the GFR declines to less than 40 ml/min/1.73 m2 (5).

Conclusion The nephropathy and renal complications of SCD are associated with various events such as hypoxic or ischemic conditions and reperfusion injury. Erythrocyte sickling occurs following these events and renal medullary acidosis. Subsequently, renal complications and CKD may occur. Therefore, early diagnosis, regular screening and monitoring, preventive measurements, and immediate treatment may slow the progression to renal failure.

Authors’ contribution Primary draft by MB, MRMS and SB. Scientific edit by BK. English edit by SH and MB. All authors read and signed and approved the final paper.

Conflicts of interest The authors declare that they have no competing interests.

Ethical considerations Ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the authors.

Funding/Support This study was supported financially by the Vice Chancellor of Research of Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

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6. Aban I, Baddam S, Hilliard LM, Howard TH, Feig DI, Lebensburger JD. Severe anemia early in life as a risk factor for sickle-cell kidney disease. Blood. 2017;129:385-7. doi: 10.1182/blood-2016-09-738104.

7. Nnaji UM, Ogoke CC, Okafor HU, Achigbu KI. Sickle Cell nephropathy and associated factors among asymptomatic children with sickle cell anaemia. Int J Pediatr.

2020;2020:1286432. doi: 10.1155/2020/1286432.

8. Olaniran KO, Eneanya ND, Nigwekar SU, Vela-Parada XF, Achebe MM, Sharma A, et al. Sickle cell nephropathy in the pediatric population. Blood Purif. 2019;47:205-13. doi: 10.1159/000494581.

9. Sesso R, Almeida MA, Figueiredo MS, Bordin JO. Renal dysfunction in patients with sickle cell anemia or sickle cell trait. Braz J Med Biol Res. 1998;31:1257-62. doi: 10.1590/ s0100-879x1998001000004.

10. Raynal G, Bracq A, Tillou X, Limani K, Petit J. Les complications rénales de la drépanocytose [Renal complications of sicklecell anaemia]. Prog Urol. 2007;17:794-5. doi: 10.1016/ s1166-7087(07)92294-0.

11. Roy NB, Fortin PM, Bull KR, Doree C, Trivella M, Hopewell S, et al. Interventions for chronic kidney disease in people with sickle cell disease. Cochrane Database Syst Rev. 2016:CD012380. doi: 10.1002/14651858.Cd012380.

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