15 Nephrology

SECTION 15

Nephrology 124.

Microalbumunuria - A Risk Factor for CVD Mritunjay Kumar Singh

587

125.

Management of Anemia in Chronic Kidney Disease: Revisited Narinder Pal Singh, Neena Garg

590

126.

Kidney Injury in Tropical Infections HK Aggarwal, Deepak Jain, Pulkit Chhabra

597

127.

Contrast Associated Acute Kidney Injury: Nephrologist’s Perspective Dinesh Khullar

600

128.

Chronic Kidney Disease of Unknown Etiology Sudhir Kulkarni, Kshitija Gadekar

603

129.

Complicated Urinary Tract Infection Dipankar Bhowmik, Sudeep Singh

607

130.

My Diet Plan for Diabetic and CKD Sanjay Dash

610

C H A P T E R

124 INTRODUCTION

Microalbumunuria A Risk Factor for CVD Mritunjay Kumar Singh

MAU AND MORTALITY

CVD is a leading cause of morbidity and mortality among non communicable diseases(NCD).Prevalence of coronary heart disease(CHD) is between 7-13% in urban and 2-7% in rural India. A conservative estimate indicates that there could be 30 million CHD patients in India of which 14 millions are in urban and 16 million in rural areas. If the current trend continues by the year 2020, the burden of CVD in India will surpass other regions of the world. The country wise statistics of the WHO on non communicable disease estimates that NCD accounts for 53% of the total deaths in India, out of which CVD have a major share of 24%. It is the first among top five causes of deaths in India.

The association between MAU and mortality was apparent from studies, like Heart Outcome Prevention Evaluation (HOPE) that involved high risk patients (> 55 yr. of age with CVD or DM plus at least one CV risk factor). This study show that all cause mortality was 9.4% among patients without MAU and 18.2% among patients with MAU. There is a linear relationship between MAU level and CV events extending below the traditional MAU threshold. MAU among patients with T2DM was associated with a 2.4-fold increased risk of CV death as compared with normoalbumunuria, as reported in a systemic review by Dinneen and Gerstein.

CVD has many established risk factors, with the residual variance in CHD may be attributable in part to unknown factors. This indicates that non established CHD risk factors might be operational in CHD incidence and mortality. Microalbumunuria (MAU) may be one of these independent risk factors other than established one. According to steno-hypothesis (exist since 1989) albuminuria in insulin dependent diabetes mellitus is not only a indication of renal disease but a new independent risk marker of proliferative retinopathy and macroangiopathy.

The presence of MAU is associated with increased all cause mortality in general population. The Prevention of renal and vascular end stage disease (PREVEND) study showed a direct linear relationship between albuminuria and risk of CV death in the general population even at levels of albumin excretion extending below the traditional MAU threshold or “normal� range (15-29 mg/ day) and was increased more than 6 fold when albumin excretion exceeded 300 mg/day.

MICROALBUMUNURIA: DEFINITION AND PREVALANCE

MAU is defined as urinary albumin excretion (UAE) of 20-200mcg/min or 30-300 mg/24 hours. MAU can also be defined in terms of the urinary albumin to creatinine ratio (UACR). A UACR > 30mg/gm in the first voided, clear and midstream morning urine sample is considered abnormal and persistent MAU is defined as the presence of MAU in two or three consecutively collected samples preferably within a period of six months.

In different cross-sectional studies, the prevalence of MAU is 20-40% in patients with diabetes, 40% in poorly controlled hypertension and 10-15% in middle age general population. The prevalence of MAU is associated with the duration and severity of hypertension.

MICROALBUMUNURIA AND CLINICAL OUTCOMES

Data from various clinical studies show that MAU is associated with an increased risk of all cause and cardiovascular mortality, cardiac abnormalities, cerebrovascular disease and peripheral arterial disease.

Relationship between urinary albumin excretion and adverse clinical outcome is continuous one and starts below the threshold for definition of MAU.

MAU AND CARDIAC DISEASE

Cardiac abnormalities like left ventricular dysfunction, left ventricular hypertrophy, ECG abnormalities and coronary heart disease are well associated with MAU. The Strong Heart Study demonstrated a significant association between microalbumunuria and echocardiographic parameters of LV systolic and diastolic function in a cohort study. The larger Losartan Intervention for Endpoint reduction in hypertension (LIFE) study demonstrated increased UACR resulted in increasing risk of CV morbidity and mortality among hypertensive patients with left ventricular hypertrophy. PREVEND study in nondiabetic patients demonstrated a positive relationship between MAU and ECG changes (major ischemia vs. minor ischemia). Urinary albumin excretion (UAE) is as good as ultrasound (US) evaluation of cardiac and carotid structure for predicting cardiovascular risk in hypertensive patients and UAE in combination with US is very much accurate in detecting target organ damage as compared to routine examination. The presence of MAU in hospitalized patients with acute myocardial infarction is a strong prognostic marker of in hospital mortality and long term mortality. MAU is a marker of target organ damage and cardiovascular changes in patients with primary hypertension. The HARVEST study (hypertension and ambulatory recording Venetia

588

study) demonstrated that a 24hr. systolic blood pressure profile was higher in patients with MAU than in those with normoalbumunuria.

chronic, low grade inflammation (measured by CRP/IL-6/TNF alpha). Impaired endothelial NO synthesis plays an important role in the association of MAU with CVD risk, with or without diabetes mellitus.

MAU AND CEREBROVASCULAR DISEASE

NEPHROLOGY

MAU is common finding among patient with cerebrovascular disease. EPIC-norflok study demonstrated that MAU was independently associated with a 50% increased risk of stroke. MAU is an independent risk factor for recurrence of stroke in older population with previous ischemic stroke, as shown in Portland study.

MAU AND PERIPHERAL ARTERIAL DISEASE (PAD)

Studies to correlate MAU with PAD are very limited and needs additional investigation to clarify the relationship.

HOW MAU-CVD LINKED TO EACH OTHER?

There are 4 possibilities: 1.

MAU causes CVD

2.

CVD causes MAU

3.

MAU and CVD caused by common risk factors

4.

MAU and CVD have common pathos physiological process

1.

MAU causes CVD: As per this hypothesis, MAU is caused by glomerular capillary leakage, so it may be associated with diffuse endothelial injury, causes leakage of macromolecules other than albumin leading to cascade of inflammatory responses which in turn start the atherosclerotic process. BUT no evidence/data suggest that MAU directly causes CV events.

2.

CVD causes MAU: To test this hypothesis a study has been designed where association between MAU and CVD has been compared with Peripheral Arterial Disease (accepted marker of atherthrombosis) and CVD. 631 individuals (age/ gender/glucose tolerance stratified sample) were followed up for 5 years .This study showed that both MAU and CVD were strongly associated with 5 yr. risk of CV events. However, only approximately 25% of individuals with MAU also had PAD and vise versa. So the clear evidence for this hypothesis is lacking.

3.

Common underlying risk factor for MAU and CVD: Many cross sectional studies indicate that MAU is associated with many CV risk factors (Age, Male gender, Hypertension, Diabetes, Smoking, Obesity, and Dyslipidemia). At first glance it appears that MAU- CVD link can be explained by common underlying risk factor, but many studies have investigated and found that common risk factor explain only small part of association between MAU and CVD.

4. MAU and CVD linked by a common pathophysiological process: An early event for CVD (atherthrombosis) as currently understood is endothelial dysfunction (measured by NO) and

WHOM TO SREEN FOR MAU

The national kidney foundation guidelines recommend front-end UAE screen in all patients who are at risk for renal disease, including those with diabetes, hypertension, and family history of chronic kidney disease, age > 60yr, and racial and ethnic minorities. The American Diabetes Association (ADA) recommends an annual UAE test in all patients with type 1 diabetes of > 5 yr duration and in all patients with type 2 diabetes starting at time of diagnosis as a prognostic indicator of CVD risk.

The European society of hypertension 2007 guidelines considers MAU as one of the cost effective tools to diagnose target organ damage in hypertensive patient.

There is no evidence to support screening of general population for UAE at present.

TREATMENT OF MAU

Renal targeted therapy designed to reduce proteinuria not only slow the progression of CKD, but also reduce CV risk as well. (PREVEND IT) is the only randomized trial to study the effect of albuminuria lowering in microalbuminuric, otherwise healthy individuals. It reported a 40% reduction in CV events over 4 year, who are treated with ACEI. Controlling blood pressure is the most important strategy to reduce UAE. The Steno-2 trial demonstrated that intensified BP, cholesterol, and glycemic control in patients with type 2 diabetes was associated with decreased risk for cardiovascular mortality. Based on these trials, summary of recommendation for patients with MAU is following: 1.

ACEI/ARBs for renoprotection in diabetic patients.

2.

Target BP for general population < 140/90, for diabetic < 130/80.

3.

HBAIC < 7%.

4.

Target LDL < 70mg/dl in CVD patients, for renal disease and diabetic < 100mg/dl.

Correction of triglyceride, HDL and non HDL cholesterols level

5.

Smoking cessation

6.

Weight reduction and exercise.

7.

Anti platelet therapy

8.

Dietary salt restriction

CONCLUSION

MAU is a risk marker of both renal and cardiovascular disease. MAU and CVD linked by a common pathophysiological process (generalized endothelial dysfunction). MAU is most effective tool to measure target organ damage in hypertensive patients. Risk of

adverse clinical outcomes start below the traditional MAU threshold. It is a treatable marker, and blood pressure control is most effective means to reduce MAU.

REFERENCES

1. Shraddha Chauhan, PhD Scholar; Bani T. Aeri, PhD, The rising incidence of cardiovascular diseases in India:Assessing its economic impact J Preventive Cardiology 2015;4.

2. Samad Ta, Haque WMMb, Microalbumin: Urinary Biomarker of Cardiovascular Risk Assessment, Birdem Medical Journal 2015;5.

Matthew R. Weir, Microalbuminuria and Cardiovascular Disease, Clin J Am Soc Nephrol 2007;2:581-590.

5.

Faical Jarraya, Rim Lakhdar, Khawla Kammoun,Hichem Mahfoudh, Habiba Drissa, Samir Kammoun,Mohamed Abid, Jamil Hachicha, Microalbuminuria A Useful Marker of Cardiovascular Disease, Iranian Journal of Kidney Diseases | Volume 7 | Number 3 | May 2013

6.

Stehouwer CD, Henry RM, Dekker JM, Nijpels G, Heine RJ, Bouter LM. Microalbuminuria is associated with impaired brachial artery, flow-mediated vasodilation in elderly individuals without and with diabetes: further evidence for a link between microalbuminuria and endothelial dysfunction--the Hoorn Study. Kidney Int Suppl 2004; S42-S44.

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3.

4. Stehouwer CD, Smulders YM: Microalbuminuria and risk for cardiovascular disease: Analysis of potential mechanisms. J Am Soc Nephrol 2006; 17: 2106â&#x20AC;&#x201C;2111.

Management of Anemia in Chronic Kidney Disease: Revisited

C H A P T E R

125

Narinder Pal Singh, Neena Garg

INTRODUCTION

Chronic Kidney Disease (CKD) leads to a wide range of systemic derangements. Anemia is a common complication among CKD patients.1 Anemia begins to manifest when GFR falls below 60ml/min/1.73 m2 (Stage III).2 In our previous review published in 1999,3 we did an effort to explain the basic pathophysiology and elaborate various treatment modalities for treatment of anemia.

Management of anemia in these patients has undergone a significant evolution resulting in wide variety of treatment protocols. Hence, this chapter is under taken to compare various modalities available for the management of anemia such as EPO, Iron therapy (oral versus injectable) and briefly elaborate the newer therapies with their rationale.

EPIDEMIOLOGY

The prevalence of CKD in India is escalating and is being presumed that CKD represents a major public health problem in India, at least in urban cities. However, in view of an overburdened health setup and absence of national registries, the true magnitude of CKD has largely been controversial.4 There is a progressive increase in the incidence and severity of anemia with declining renal function. Anemia is twice as prevalent in people with CKD (15.4%) as in the general population (7.6%). The prevalence of anemia increases with each stage of CKD, from 8.4% in stage 1, followed by 14.6% in stage 2, 26.4% in stages 3-4 and 53.4% in stage 5. In India, it has been

recently estimated that incidence of CKD is 785 per million population,5 with prevalence of 78% in Delhi and 16% in Chennai. A cross-sectional registry involving 52,273 CKD patients showed that about 85% patients reported to the nephrologist at Stage-3 and beyond.Â

PATHOPHYSIOLOGY

Anemia in CKD is typically normocytic, normochromic and hypo-proliferative. When a patient develops CKD, anemia occurs as a result of any one or the combinations of multiple factors (Table 1).

ROLE OF ERYTHROPOIETIN (EPO)

EPO is produced by cells of Proximal Convoluted Tubule (PCT). The role of erythropoietin is to control red blood cell production by regulating the differentiation and proliferation of erythroid progenitor cells in the bone marrow. In CKD patients, EPO levels are normal to low with inappropriate erythropoiesis resulting in decreased hemoglobin levels, as found in non-renal anemias. Studies elucidating the regulation of EPO expression led to the identification of the hypoxia inducible factor-hypoxia responsive element system (Figure 1).

ROLE OF IRON DEFICIENCY

1.

Absolute iron deficiency: It is often present in patients initiating hemo-dialysis and replenishing iron stores is crucial in the management of their anemia. It develops in CKD patients due to multiple factors including decrease in intestinal absorption of iron, occult gastrointestinal bleeding

Table 1: Mechanisms of anemia in CKD Mechanism

Outcome

Renal Impairment

Decreased erythropoietin production

Uremia

Bone marrow suppression Decreased RBC life span

Nutritional deficiency

Deficiency of Vitamin B12, folate or Iron

Secondary Hyperparathyroidism

Fibrosis of bone marrow Failure of erythropoiesis

Chronic Inflammation Increased inflammatory cytokines Increased hepcidin

Abnormal iron homeostasis and erythroid progenitor proliferation

Aluminium Toxicity Hypothyroidism

Reduced GFR Increased peripheral vascular resistance

Fig. 1: Pathophysiology of anemia in CKD

due to platelet malfunction, increased incidence of arterio-venous malformation and blood loss from repetitive laboratory testing. Furthermore, the initiation of ESA treatment requires large amounts of stored iron6 (Figure 1).

Functional iron deficiency (ineffective erythropoiesis): It is characterized by the presence of adequate iron stores but a slow iron mobilization rate into the site of erythropoiesis when ESA is started. In other terms, iron transporters fail to keep up with the increased rate of erythropoiesis6 (Figure 1).

3.

Iron deficiency in CKD patients on dialysis: In addition to the usual causes of iron deficiency, patients on hemo-dialysis experience routine iron loss due to the dialysis treatment, frequent blood draws for laboratory testing, surgical procedures, accidental blood loss (vascular access) and gastrointestinal blood loss. As a consequence, patients on hemo-dialysis lose approximately 1000 mg of iron per year.7

Anemia in CKD is a multifactorial disorder. Management of these patients involves dietary improvement, prevention and treatment of blood loss and pharmacological measures in form of iron supplements, ESA etc.

1.

Dietary management: Dietary lack of iron with impaired iron absorption and utilization is important nutritional factor which contribute to high prevalence of anemia in CKD patients.

Rich sources of heme iron in the diet include lean meat, red meat and sea food, whereas sources of non-heme iron are nuts, beans, vegetables and fortified grain products. Milk and milk products, tannins and caffeine inhibit iron absorption and should be avoided with iron rich sources of food.

Vitamin C can improve iron absorption and can be administered concomitantly with iron rich foods.

2.

Chronic blood loss: Elderly population with CKD is at a higher risk of gastritis and peptic ulcers leading to chronic gastrointestinal blood loss and malena.

Long term use of NSAIDs can aggravate GI bleed and deteriorate renal function. Hence, presence of malena warrants Upper GI endoscopy and further intervention as necessitated.

Anemia in itself is an independent clinical identity.

Its occurrence in CKD patient need not always imply their correlation. Hence, other causes of anemia like Vitamin B12, folic acid deficiency, worm infestations, chronic infection, malignancy or hemolytic diseases should be addressed.

3.

Erythropoiesis Stimulating Agents (ESA): Anemia management was revolutionized in the late 1980s with the introduction of recombinant human erythropoietin. EPO and ESAs greatly benefited patients by improving their debilitating

ROLE OF INFLAMMATION AND HEPCIDIN

It is well known that CKD is a low-grade chronic inflammatory state due to imbalance of pro-oxidants and antioxidants.8 Hepcidin is a small peptide produced primarily by hepatocytes. It has antimicrobial properties and regulates iron absorption and metabolism. Hepcidin expression is up regulated by variety of stimuli including inflammation and iron overload. The decreased renal clearance of hepcidin due to failing kidneys further increases its serum level. This increase in hepcidin levels contributes to EPO resistance and iron restriction. Elevated serum hepcidin levels contribute to the dis-regulation of iron homeostasis in CKD patients (Figure 1).

Table 2: Recommended dose of ESA ESA

Dosage recommendation

Route

Remarks

(SC) or IV

• EPO alfa-serum albumin

(SC) or IV

• 2 amino acid substitutions

Side Effects

First Generation Epoetin-alfa or epoetinbeta

50-100 IU/kg thrice a week.

More common: Blurred vision, • EPO beta- polysorbate 20, Body aches, breathlessness, along with urea, calcium Dizziness, Fever. chloride and five amino Less common: Bladder pain, acids Difficult, burning, or painful urination.

Second Generation Darbepoetin- 0.45 mcg/kg once alfa weekly 0.75 mcg/kg once every 2 weeks

SC

• greater metabolic stability

Increases the risk of cardiovascular problems.

• increases the elimination half-life

Third Generation CERA

0.6 mg/kg once every 2 weeks

SC - CKD ND

1.2 mg/kg once every 4 weeks

SC - CKD ND

IV - CKD 5D

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• additional large polymer Hypertension, Diarrhea, chain.

Headache and Upper • half-life is approximately Respiratory Tract Infection.

130 hours.

CHAPTER 125

2.

TREATMENT OF ANEMIA IN CKD

NEPHROLOGY

592

symptoms and freeing them from dependence on blood transfusions with their associated complications (secondary iron overload, infections and sensitization impeding transplantation).

After diagnosing anemia in a patient with CKD all correctable causes should be treated before considering ESA therapy. Above all, this recommendation is based on the observation that iron supplementation given to CKD patients with proven iron deficiency or impaired iron availability generally leads to an increase in Hemoglobin.9 Commonly used ESA agents are Epoetin-alfa, Epoetin-beta, Derbepoetin-alfa and CERA as shown in Table 2.

Although relative EPO deficiency may contribute to the anemia of CKD, it is not the sole cause. Indeed, anemia of CKD is resistant to ESAs in approximately 10-20% of patients.10 It seems likely that supra-physiologic doses of ESAs, especially at very high doses or in patients resistant to treatment, have off-target effects in other tissues. These findings have renewed interest in understanding the molecular mechanisms of anemia in CKD, with the hope of developing new therapies that more closely target the underlying pathophysiology of low hemoglobin.

RESISTANCE OF EPO

‘EPO resistance’ has been introduced to define the patients who fail to attain the target despite a higher than usual dose of ESA or who continuously need this higher dose in order to maintain it. Although there is no consensus about the definition for EPO resistance, the evaluation of resistance is recommended if there is an increase ≥25% in erythropoietin dose or <1 mg/dL gain in hemoglobin levels after 2–4 weeks of treatment.

Causes of inadequate response to EPO includes

Hemolysis, Aluminium toxicity, Osteitis fibrosis (Secondary Hyperparathyroidism), Hemoglobinpathies (Thalessemia, sickle cell anemia), Multiple myeloma, Use of ACE-1/ARB agents, Low effectiveness of molecule. In the absence of detectable abnormalities of any one of the conditions - marrow examination is indicated including hematologist reference.

4.

Iron Supplementation: Iron deficiency is a commonly encountered reversible cause of CKD related anemia and ESA hypo-responsiveness.

Correction of iron deficiency with therapeutic supplementation can reduce the severity of anemia in CKD patients. It is important to diagnose iron deficiency and its cause, because its treatment can readily correct the associated anemia (Table 3). Iron administration is appropriate in patients who are likely to have a clinically meaningful erythropoietic response, when bone marrow iron stores are depleted.

Oral Iron Supplementation

Oral iron is the simplest and most physiological means of administering iron. It is also by far the cheapest therapy in terms of drug acquisition costs. Unfortunately, in CKD settings, it is often ineffective. This was recognized by nephrologists nearly 20 years ago, even prior to the discovery of hepcidin. It is, however, now very apparent that up regulation of hepcidin resulting from inflammation is the explanation for this clinical finding at a molecular level.11 Thus, although many patients may religiously take elemental iron per day via iron tablets or syrup, often negligible or no iron is absorbed. The bioavailability of oral iron sources has been a major concern for the treatment of anemia. Iron is absorbed in the intestine in a highly regulated metabolic cycle.

Table 3: Current Guidelines for Anemia treatment Guidelines

Hemoglobin Level ESA Recommendation

Iron Recommendation

KDIGO (2012)

Hb<13 g/dL (men >15 yr); Hb<12 g/dL (women >15 yr)

Initiate ESA therapy in those with Hb<10 g/ 1-3 months trial of oral iron dL (rule out all other correctable causes of or iv iron, if TSAT <30% and anemia) ferritin<500 mg/L or ESA therapy is to be avoided or decreased (if already on ESA therapy).

KDOQI (2015)

Hb<13.5 g/dL (men); Hb<12.0 g/dL (women)

Initial ESA dose and further adjustments are determined by the patient’s baseline Hb level, target Hb level, rate of increase in Hb level and clinical response.

NICE (2015)

Hb<11.0 g/dL or symptomatic patient(tiredness, shortness of breath, and palpitations)

ESA therapy should not be initiated in the Oral or iv iron to maintain presence of absolute iron deficiency without hypochromic RBC, reticulocyte also managing the iron deficiency; ESAs or TSAT and ferritin targets. not recommended in the presence of comorbidities or a prognosis that is likely to negate the benefits of correcting the anemia

ERBP (2004)

Hb<13.5 g/dL (men ≤70 yr); Hb<13.2 g/dL (men >70 yr); Hb<12.0 g/dL (women)

In low-risk patients or those in whom a clear benefit in quality of life can be foreseen, ESA therapy can be considered at Hb<12.0 g/dL; in high-risk patients, ESA therapy should be initiated at Hb values between 9.0- 10.0 g/dL.

Oral or iv iron administered to maintain ferritin>100 mg/L and TSAT>20% during ESA treatment.

Oral or iv iron if TSAT<20% and ferritin<100 mg/L or if Hb increases without ESA therapy, TSAT<25%, and ferritin<200 mg/L; in patients on ESA therapy in whom increase in Hb or decrease in ESA dose is desired.

Dosage regimen

Oral iron therapy is usually best carried out in 3-4 divided doses per day, with a total of 150-200 mg of elemental iron for adults or 6 mg iron/kg body weight in children. It has also been suggested that attempts be made to individualize treatment and get patients more involved in determining the most tolerable daily iron dose, its formulation and its schedule12 (Table 4).

Oral iron therapy should not be considered for patients on hemo-dialysis receiving ESA.

Intravenous Iron supplementation

At present times, it is clear that intravenous iron is generally superior over oral iron. The only exception to this is that some patients with early CKD may derive some benefits from oral iron albeit with more side effects.

The greater efficacy of intravenous is almost certainly a result of limiting action of hepcidin on absorption of iron from the gut in CKD patients.

Various randomized studies on ND-CKD patients have shown a significantly greater erythropoietic response in the intravenous iron treatment groups as compared to oral iron.15-16 Whereas, in ESA-treated hemodialysis and peritoneal dialysis patients with anemia several randomized trials have shown greater efficacy and safety of intravenous iron preparation.17-18 A question of particular interest is whether iron supplementation alone can produce an adequate increase in hemoglobin without ESA therapy, a situation that would be desirable both in terms of cost and the avoidance of ESA-related side effects.

Schematic representation of treatment of anemia in CKD is illustrated in figure 2.

5.

However, in some cases, the adverse effects of iron are unrecognized because of the non-specific nature of the reactions and the overlap between iron-related

Table 4: Commonly used oral iron supplements S. No. Compound

Dose

1

Ferrous sulphate

200 mg 20-32% iron

2

Ferrous gluconate 300 mg 12 % elemental iron

3

Ferrous fumarate

200 mg 33% iron

4

Colloidal ferric hydroxide

200 mg 50% iron

Iron Content

Vitamin B12 and Folic Acid Supplements: Vitamin B12 and Folate deficiency has been implicated as a contributory factor in renal anemia and hyporesponsiveness to EPO treatment. Deficiency of Vitamin B12 and folic acid causes megaloblastic anemia with neural symptoms. Although folate loss through dialysis is greater than by urinary excretion, these losses are easily balanced by a normal mixed diet containing 60 g protein/day.

Thus, unless patients show significant folate depletion, additional supplementation of folic acid does not appear to have a beneficial effect on erythropoiesis. High-dose folate therapy (515 mg/day) has been shown to reduce plasma homocysteine levels by 25-30% and appears to be

Table 5: Characteristics of intravenous iron supplements Characteristics

Ideal

Iron Sucrose

Dextran

Ferric carboxy-maltose

pH

Neutral

High

Neutral

Neutral

Osmolality

Isotonic

High

Isotonic

Isotonic

Antigenicity

Low

Low

High (risk of anaphylactic reactions)

Low

Time required for administration

Short

Long (3.5 Hrs for 7 mg Fe/kg BW)

Long (6 Hrs for 20 mg Fe/kg BW)

Short

Maximum Dose (mg High Iron)

500 mg/week

20 mg Fe/kg BW

1000 mg/week

Half Life

6 Hrs

3-4 days

16 Hrs

As a 2-minute bolus or as a short infusion in doses up to 300 mg, When higher doses are administered, even with infusions lasting 2 hours, hypotension, nausea.

As an IV bolus or TDI, infusions of 1g over 1hour.

May require weekly or more frequent visits, in short infusions.

As an infusion of 5001500 mg in 15 minutes; however, only doses up to 1000 mg are currently approved. No test dose is required.

Administration

4-24 Hrs

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The treatment of choice for repleting iron stores in hemodialysis patients is intravenous (IV) iron therapy. Although research shows IV iron is more efficacious for restoring iron status compared to oral iron supplements, it should be used judiciously due to risk of adverse events.13 Three intravenous iron products are commercially available: Iron dextrose, Iron sucrose and Ferric carboxy-maltose (Table 5). Intravenous iron therapy is now the standard modality of iron supplementation in hemodialysis patients, but its role in pre-dialysis chronic renal failure patients is less well established. We carried out a study in 2002 to evaluate the efficacy of IV iron dextran administered as total dose infusion in pre-dialysis patients. It showed that IV iron dextran is an effective method to replenish iron stores in pre-dialysis patients.14

adverse effects and dialysis-related adverse effects, such as dizziness, dyspnea, cramps, pruritus, nausea, constipation, diarrhea and hypotension (Table 6).

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Table 6: Characteristics of Oral versus Intravenous Iron Therapy Characteristic

Oral Iron

Intestinal absorption

• Impaired by concomitant food (depending • Parenteral administration on formulation)

Intravenous Iron

• Impaired by concomitant medication (eg, phosphate binders, gastrointestinal medications that reduce acidity)

NEPHROLOGY

• Iron uptake and export of iron from enterocytes via ferroportin inhibited by elevated hepcidin levels Iron bioavailability

• May be inadequate during ESA therapy • Generally high (accelerated erythropoiesis)

Safety

• Gastrointestinal adverse events affect a high • Good safety profile. proportion eg, constipation, dyspepsia, • Risk of (rare) anaphylaxis with dextranbloating, nausea, diarrhea, heartburn containing formulations • Most frequent with ferrous sulfate • Risk of (rare) hypersensitivity reactions

Oxidative stress

• Can saturate the iron transport system • only observed with less stable preparations if the iron is rapidly released (eg, ferrous which can release some more “weaklybound” sulfate), resulting in oxidative stress iron (eg, sodium ferric gluconate, iron sucrose similars) than stable (robust) iron complexes (eg, ferric carboxymaltose, originator iron sucrose)

Compliance

• Pill burden: usually 3 tablets per day

• Administered by health care professional

• Affected by gastrointestinal intolerance Convenience

• Administered at home

• Requires clinic visits

Cost

• Inexpensive

• More expensive per dose but fewer doses required

Fig. 2: Treatment and follow-up algorithm in iron deficiency anemia (Abbreviations: TID- Total infusion dose; FCM- ferric carboxymaltose; LMWID- low molecular weight iron dextra,; ESA- erythropoiesis stimulating agent)

cholesterol in the liver. As mentioned above, cytokines play a role in inhibition of erythropoiesis.

Statins have been evaluated as an adjuvant to EPO with the thought that they have anti-oxidant and anti-inflammatory properties.

well tolerated provided the patient has adequate vitamin B12 stores.19 6.

L-carnitine: L-carnitine is derived from dietary products, mainly red meat and milk. L-carnitine has been shown to improve anemia in uremic patients by stabilizing erythrocyte membrane function or erythropoiesis. This could be a contributing factor of anemia requiring higher dose of EPO. Thus, it has been used therapeutically in dialysis patients with and without concomitant EPO. Most studies have involved hemodialysis patients with IV carnitine administration.19 Androgens: There is no literature available in NDCKD patients. Before EPO was available, androgens were used regularly in the treatment of anemia in dialysis patients. Their use for anemia in dialysis patients has declined markedly since EPO was approved. Various studies were carried out which shows that patients receiving androgen in addition to EPO had a significantly greater increase in HCT values with treatment. These data show that androgen therapy significantly augments the action of exogenous EPO such that lower doses of EPO may be sufficient for an adequate hematopoietic response.20

8.

Ascorbic acid: Ascorbic acid has been studied in the metabolism of iron and anemia management.

It was found that ascorbic acid deprivation increased the total non-haem iron concentration in the spleen and reduced it in the liver, and in both organs ferritin was diminished and haemosiderin increased. Repleting the ascorbic acid restored the normal distribution of iron between the two storage compounds. In spleen, the total storage iron concentration returned to control levels within 24 hours. Another important property of ascorbic acid is its ability to increase the availability of storage iron to chelators. Development of resistance to EPO with “functional iron deficiency”, can be overcome by giving Vitamin C instead of iron, thus avoiding hemosiderosis.21

9.

10.

Pentoxifylline (PTX): Pentoxifylline (PTX) is a methyl xanthine derivative, which is approved for use in peripheral vascular disease and may also have anti-inflammatory effects. Benbernou and coworkers22 studied pentoxifyline and examined its regulatory effect on T-helper cell-derived cytokines in human whole blood and peripheral blood mononuclear cells stimulated with phytohemagglutinin and phorbolmyristate acetate.

The results showed that PTX at the appropriate concentrations could induce selective suppression of interleukin (IL) -2 and interferon (INF) -gamma, whereas at high concentrations this drug could act as a suppressive agent of both TH1- and TH2derived cytokines.

Statins: Statins (HMG-CoA reductase inhibitors) are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of

The data suggest that statin therapy may benefit patients with ESA hypo-responsiveness. This benefit in ESA hypo-responsiveness is associated with the effects of statins on inflammation.These preliminary studies may justify future studies to use statins as an EPO dose reducing adjuvant in patients with inflammation-mediated EPO resistant anemia of CKD.23

11.

Red cell transfusion: Before the mid-1980s, there were no effective therapies for the treatment of anemia in patients with CKD. Anemic patients were managed primarily by regular blood transfusions performed every 2 to 3 weeks. Red cell transfusion has a limited role in patients with CKD. These are severely anemic patients with hemoglobin less than 5g/dl and hypo-responsive to EPO therapy with chronic blood loss. The benefits of red cell transfusions may outweigh the risks in patients in whom ESA therapy is ineffective (e.g., hemoglobinopathies, bone marrow failure, ESA resistance). Repeated transfusions or use of ESA are treatment options for anemia in CKD patients.

Risks associated with blood transfusion include transfusion errors, volume overload, hyperkalemia, citrate toxicity (leading to metabolic alkalosis and hypocalcemia), hypothermia, coagulopathy, immunologically-mediated transfusion reactions, including transfusion-related acute lung injury (TRALI) and iron overload, all of which are uncommon.

NEWER THERAPIES

•

Soluble ferric pyrophosphate (SFP): It is used for treatment of iron deficiency in hemodialysis patients. SFP delivers iron via dialysate slowly during dialysis treatment and replaces 5-7 mg of iron lost during each treatment to maintain iron balance. SFP enters the blood and immediately binds to apo-transferrin, then goes directly to the bone marrow. Recent studies show that SFP delivers iron and maintains hemoglobin concentration without increasing serum ferritin and reduces ESA usage by 35%. There have also been no reported cases of anaphylaxis.24

•

Hypoxia-inducible factor prolyl hydroxylase inhibitor (Roxadustat): A novel class of drug is under investigation that selectively inhibits hypoxia inducible factor prolyl hydroxylases (HIFPH) and stabilizes HIF. HIF is a key regulatory protein which stimulates endogenous erythropoietin (EPO) production, increases transferrin production and decreases hepcidin. Increasing HIF activity through inhibition of HIF-PH may provide an alternative treatment for anemia and may protect against damage related to ischemia-reperfusion.25

•

Erythropoietin mimetic peptides: These are in the

CHAPTER 125

7.

595

development stages for the treatment of anemia in CKD. One agent in this class, hematide, is in the phase 2 of clinical development. In-vitro studies have shown that hematide binds the erythropoietin receptor, triggers intracellular signaling, and causes cell proliferation and differentiation. In vivo, studies have shown that hematide is well tolerated and stimulates erythropoiesis in multiple species to produce a sustained increase in hemoglobin level.26

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NEPHROLOGY

CONCLUSION

Anemia occurs early in CKD and can begin in some people who have a GFR as high as 60 ml/min/1.73 m2.

Though, only a few patients of CKD with anemia receive iron or ESA therapy before their kidney function declines enough to require dialysis. Both currently approved ESAs – Epoetin alfa and derbepoetin alfa can effectively treat the anemia in CKD. Although, controversies regarding target iron levels and in the absence of reliable markers of iron deficiency, but importance of correcting iron deficiency in patients with CKD remains indisputable.

Oral iron therapies offer safe and effective options to treat iron deficiency anemia in patients with CKD in a physiologic way. In contrast to iv iron therapies, oral iron treatments require few resources for administration and are not associated with potential serious adverse events.

However, traditional oral iron treatments are not optimal because of increased gastrointestinal side effects, lack of patient adherence, and very often, lack of efficacy in patients with stage 5 CKD. Overall, treatments currently under development for iron deficiency anemia may represent an improvement in therapeutic options to treat iron deficiency anemia.

REFERENCES

Babitt JL, Lin HY. Mechanisms of Anemia in CKD. J Am Soc Nephrol 2012; 23:28PMC3458456.

2. Weil EJ, Curtis JM, Hanson RL, Knowler WC, Nelson RG. The impact of disadvantage on the development and progression of diabetic kidney disease. Clin Nephrol 2010; 74:32-38.

3. Singh NP, Aggarwal L, Singh T, Anuradha S, Kohli R. Anemia, Iron Studies and Erythropoietin in patients of Chronic Renal Failure. JAPI 1999; 47:284-290.

4. Singh NP, Ingle GK, Saini VK, Jami A, Beniwal P, Lal M, Meena GS. Prevalence of low glomerular filtration rate, proteinurea and associated risk factors in North India using Cockcroft-Gault and Modification of Diet in Renal Disease equation: an Observational, cross-sectional study.

BMC Nephrol 2009; 10:4.

5. Robinson BE. Epidemiology of chronic kidney disease and anemia. J Am Med Dir Assoc 2006; 7:3-6.

6. Fernández-Rodríguez AM, Guindeo-Casasús MC, MoleroLabarta T, et al. Diagnosis of iron deficiency in chronic renal failure. Am J Kidney Dis 1999; 34:508.

7. Locatelli F, Vecchio LD. Erythropoiesis-Stimulating Agents in Renal Medicine. The Oncologist 2011; 16:19-24.

8. Sundaram SPM, Nagarajan S, Devi AJM. Chronic Kidney Disease-Effect of Oxidative Stress. Chinese J Biology 2014; 2014:1-6.

9. Macdougall IC, Eckardt KU. Novel strategies for stimulating erythropoiesis and potential new treatments for anemia. Lancet 2006; 368:947-953.

1.

10. Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med 1987; 316:73-78.

11. Schroder CH. The management of anemia in pediatric peritoneal dialysis patients. Pediatr Nephrol 2009; 18:805809.

12. Besarab A, Coyne DW. Iron supplementation to treat anemia in patients with chronic kidney disease. Nat Rev Nephrol 2010; 6:699-710.

13. Provenzano R, Schiller B, Rao M, Coyne D, Brenner L, Pereira BJ. Ferumoxytol as an intravenous iron replacement therapy in hemodialysis patients. Clin J Am Soc Nephrol 2009; 4:386-393.

14. Anuradha S, Singh NP, Agarwal SK. Total dose infusion iron dextran therapy in predialysis chronic renal failure patients. Ren Fail 2002; 24:307-313.

15. Agarwal R, Kusek JW, Pappas MK. A randomized trial of intravenous and oral iron inchronic kidney disease. Kidney International 2015; 88:905-914.

16. Qunibi WY, Martinez C, Smith M, Benjamin J, Mangione A, Roger SD. A randomized controlled trial comparing intravenous ferric carboxymaltose with oral iron for treatment of iron deficiency anaemia of nondialysisdependent chronic kidney disease patients. Nephrol Dial Transplant 2011; 26:1599-1607.

17. Li H, Wang SX. Intravenous iron sucrose in peritoneal dialysis patients with renal anemia. Perit Dial Int 2008; 28:149-154.

18. Provenzano R, Schiller B, Rao M, Coyne D, Brenner L, Pereira BJ. Ferumoxytol as an intravenous iron replacement therapy in hemodialysis patients. Clin J Am Soc Nephrol 2009; 4:386-393.

19. Hurot JM, Cucherat M, Haugh M, Fouque D. Effects of L-carnitine supplementation in maintenance hemodialysis patients: a systematic review. J Am Soc Nephrol 2002; 13:708714.

20. Singh NP, Ganguli A, Singh T, Agarwal SK, Ahuja N. Long term Effect of Anemia Correction on Progression of Renal Disease and Cognitive Function Using Erythropoietin and Androgenic Steriods. JAPI 2003; 51.

21. Bridges KR, Hoffman KE. The effects of ascorbic acid on the intracellular metabolism of iron and ferritin. J Biol Chem 1986; 261:14273-14277.

22. Benbernou N, Esnault S, Potron G, Guenounou M. Regulatory effects of pentoxifylline on T-helper cellderived cytokine production in human blood cells. J Cardiovas Pharmacol 1995; 25:75-79.

23. Tangdhanakanond K, Raja R. Effect of statins on EPO responsiveness in Type 2- diabetic versus non-diabetic hemodialysis patients. Clinical Nephrology 2010; 73:1-6.

24. Lin VH, Gupta A, Farmer TM, et al. Soluble ferric pyrophosphate (SFP) administered via dialysate reduces ESA and IV iron requirements while maintaining hemoglobin in CKDHD patients. J Am Soc Nephrol 2013; 24:215.

25. Brigandi RA, Johnson B, Oei C, Westerman M, Olbina G, Singh NP. A Novel HIF-prolyl Hydroxylase Inhibitor (GSK1278863) for Anemia in CKD: A 28-Day Phase IIA Randomized Trial. AJKD 2016; 67:861-871.

26. Rastogi A, Nissenson AR. New approaches to the management of anemia of chronic kidney disease: beyond Epogen and Infed. Kidney Int Suppl 2006; 104:14-16.

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Kidney Injury in Tropical Infections

The tropics encompass almost one third of earth’s landmass and are characterized by a hot and humid climate, usually throughout the year. The tropics display a vast number of health problems, which are related to the warm climate, overcrowding and socioeconomic factors. Kidney Injury in the tropical areas has been always an important health related concern. Acute kidney injury (AKI) in tropics is influenced by number of factors like infections, use of unsafe drinking water, exposure to environmental toxins, poverty and inadequate sanitation. Tropical AKI is also influenced by a relative state of hypovolemia due to excess sweating and peripheral vasodilatation due to hot and humid climate. Heavy rainfall creates a favourable environment for survival of organisms causing and transmitting infections like malaria, dengue etc.

The main causes of kidney injury in tropics are due to bacterial, viral or parasitic infections like malaria, dengue, leptospirosis, scrub typhus, acute gastroenteritis etc.

Though these infections have been typically considered as a cause of AKI, the residual damage which may be subclinical can lead to chronic kidney disease. In a recent study from a large tertiary care hospital in South India, AKI was seen in 41.1% of patients with tropical infections, the most common causes being scrub typhus, malaria, salmonellosis, dengue and leptospirosis. Various infections causing tropical nephropathy are as under.

MALARIA

Malaria is a protozoal disease of extreme epidemiological concern because of its greater prevalence in tropical areas.

Renal involvement is more frequently associated with infection by P. falciparum and P. malariae. AKI is a very devastating manifestation of malaria reported in about 3% cases of malaria. The incidence is particularly high in cases of severe P. falciparum malaria where it can be seen in up to 60% patients.

The parasite inhabitates red blood cells (RBC) and alters their morphology and metabolism. It induces formation of membrane protuberances or “knobs” on the erythrocyte surface. P. falciparum infected cells adhere to the vascular endothelium and uninfected RBCs to form rosettes. This promotes cytoadherence between RBCs, platelets and endothelium leading on to microcirculatory failure and organ dysfunction. Immune system activation also leads to endothelial injury and immune complex deposition.

Proinflammatory cytokines, reactive oxygen species and vasoactive mediators lead to haemodynamic changes causing decreased renal blood flow and glomerular filtration rate. The most common manifestation of

HK Aggarwal, Deepak Jain, Pulkit Chhabra

kidney injury in malaria is acute tubular necrosis (ATN).

Acute tubulointerstitial nephritis, diffuse proliferative glomerulonephritis and mesangioproliferative glomerulonephritis are other important manifestations.

Acute malarial nephropathy and chronic malarial nephropathy are two major clinical syndromes associated with kidney involvement in malaria. Acute malarial nephropathy presents as AKI seen in falciparum malaria while chronic malarial nephropathy, also known as quartan malarial nephropathy is actually a glomerulopathy usually seen in children. It is mostly caused by P. malariae.

AKI in malaria is usually seen by the end of first week and is non-oliguric in 50-75% of cases. The laboratory diagnosis can be established by the demonstration of sexual forms of the parasite in peripheral blood smears.

Rapid diagnostic immunological tests are currently available. Urinalysis can reveal microalbuminuria, mild to moderate proteinuria and hyaline & cellular casts.

Renal histology shows ATN predominantly affecting the distal tubules. Tubular changes include haemosiderin granular deposits, haemoglobin casts, interstitial oedema and mononuclear cell interstitial infiltrates. Mortality from malarial AKI varies between 15% and 50%. Dialysis when initiated early in the course of treatment has a very good outcome.

DENGUE

Dengue is a viral haemorrhagic fever caused by a dengue flavivirus and transmitted by aedes aegypti mosquitoes.

The South East Asia and Western Pacific regions in tropics bear about 70% of the total global burden of this disease.

Dengue virus infection may manifest as undifferentiated fever, dengue fever, dengue haemorrhagic fever (DHF), or dengue shock syndrome (DSS). Renal involvement is a well-known complication of dengue fever and can manifest as AKI, proteinuria, glomerulonephritis and haemolytic uraemic syndrome. DHF and DSS are more commonly associated with renal injury and AKI is an independent predictor of mortality. The reported frequency of dengue associated AKI is extremely variable, ranging from 1% to approximately 30%. The main causes of AKI include shock secondary to haemorrhage or dengue shock syndrome and rhabdomyolysis leading to acute tubular necrosis. Renal failure can also occur due to the direct involvement of the kidneys without shock and rhabdomyolysis. Diagnosis mainly depends upon the serological tests available. There is no specific treatment and drugs available for dengue fever. Therefore prompt

598

identification of complications and supportive therapy are the mainstay of management.

LEPTOSPIROSIS

NEPHROLOGY

Leptospirosis is a worldwide distributed zoonotic disease caused by spirochetes of the genus Leptospira. Human infection occurs through contact of abraded skin or mucous membrane with infected tissue or urine of animal host or indirectly through contaminated water, soil or vegetation.

Leptospirosis has a wide spectrum of clinical presentation ranging from asymptomatic condition to a severe multisystem disease. Its clinical presentation may occur as: (i) a non-jaundice, febrile, auto-limited disease (ii) Weil’s syndrome with triad of jaundice, AKI and haemorrhages.

The acute leptospiremic phase is characterized by fever of 3-10 days and the immune phase occurs after a relative asymptomatic period of 1-3 days during which nephropathy occurs. AKI associated with leptospirosis is non oliguric. Incidence of renal involvement in severe leptospirosis varies from 40% to 60%.

There are various factors responsible for AKI seen in severe leptospirosis. The pathogenic mechanisms suggested include bacterial invasion, inflammatory processes, hemodynamic alterations, and the direct toxicity of bacterial products. Tubulointerstitial nephritis due to direct infection of the kidneys is the predominant mechanism of renal involvement.

The diagnosis is possible during the initial febrile period by visualizing leptospira by direct examination of blood, or by its culture. During the immune phase serological tests may be helpful. Renal biopsy reveals interstitial oedema and infiltration with mononuclear cells and few eosinophils. Acute tubular necrosis primarily affecting the proximal tubules is present and glomeruli are usually spared.

The treatment of severe leptospirosis mainly involves the use of antibiotics and haemodialysis. Early dialysis and treatment of leptospira associated renal injury seems to be helpful in reducing mortality.

SCRUB TYPHUS

Scrub typhus is an acute febrile illness and zoonosis caused by orientia Tsutsugamushi, transmitted to humans by the bite of the larva of trombiculid mites. The disease is widely spread all over India and has been reported in several parts of the country.

Scrub typhus is mostly seen during and after the rainy season, mainly affects people who work outside and are exposed to shrubs and vegetation, on which the vector thrives. Presence of a primary papular lesion which enlarges undergoes central necrosis, and crusts to form a flat black eschar is a classical presentation of the disease.

This is associated with regional and later generalized lymphadenopathy. The reported incidence of renal failure caused by scrub typhus varies from 10.5% to 42.6%. In the Indian subcontinent AKI has been reported in about 30 to 60% of the patients of scrub typhus.

There are various explanations behind the pathophysiology of AKI in scrub typhus. Vasculitis of the small blood vessels, DIC, hypovolemia and shock causing renal hypoperfusion, injury to vascular endothelium are main mechanisms of renal involvement. Diagnosis of scrub typhus can be made by a number of tests like Weil Felix test, ELISA, western blot along with renal biopsy. Indirect Immunofluoroscence remains the golden standard. Renal failure caused by scrub typhus is commonly known to be reversible with the appropriate antibiotic therapy, and rarely requires maintenance haemodialysis.

DIARRHOEAL DISEASES

Diarrhoeal diseases are widely prevalent in the tropical developing countries due to factors like poor socioeconomic conditions and lack of clean water supply. Causative organisms include bacterias including Escherichia coli, Compylobacter, Salmonella, Shigella & Vibrio Cholera, viruses like Rotavirus, Norovirus, Adenovirus & Astrovirus and parasites like Giardia lambia, Entamoeba histolytica & Cryptosporidium. Diarrhoeal diseases account for most cases of AKI in children in India. Acute tubular necrosis is the commonest cause of renal injury mainly due to hypovolemia and shock. AKI is usually of oliguric type and have metabolic acidosis out of proportion to renal injury. Management approach includes adequate hydration and correction for intra and extravascular volume deficit produced by fluid losses in diarrhoeas.

OTHER INFECTIONS

Some other bacterial, fungal, parasitic and viral infectious diseases are needed to be mentioned which are associated with significant renal involvement. Renal injury in HIV infected patients in the form of acute tubular necrosis is usually secondary to sepsis, hypotension, dehydration and nephrotoxins. Clinically renal involvement may manifest as acute kidney injury, HIV associated nephropathy, HIV related immune complex diseases, nephropathy secondary to ART and diseases related to common comorbidities.

Kidney involvement has been demonstrated with chronic diseases like leprosy and tuberculosis. Renal injury in these diseases can lead to AKI and further progress to CKD and manifests as proteinuria, haematuria, urinary concentration and acidification defects, acute tubular necrosis, diffuse proliferative lesion and amyloidosis.

Haemolytic uraemic syndrome (HUS) is another common cause of kidney injury in children in most tropical countries.

In India, HUS is responsible for 35-41% of all cases of AKI in children. Schistosomiasis is another important tropical parasitic infection that can involve the kidneys in the form of immune complex glomerulonephritis, also known as schistosomal nephropathy. Fungal infections like renal mucormycosis caused by zygomycetes fungi can lead to kidney injury. It produces organ involvement through vascular invasion and thrombosis resulting in infarction and necrosis of the affected organ. Mostly it involves bilateral kidneys and present with anuric AKI and the outcome is usually fatal.

Visceral leishmaniasis also known as kala azar is a chronic lethal parasitic disease, caused by Leishmania parasite.

Kidney involvement in chronic leishmaniasis is frequent, and associated with increased mortality. Patients usually present with proteinuria, microscopic haematuria and leukocyturia. Renal involvement manifests in various forms like AKI, urinary concentration and acidification defect, nephritic syndrome or nephrotic syndrome.

CONCLUSION

REFERENCES

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Githeko AK, Ototo EN, Guiyun Y. Progress towards understanding the ecology and epidemiology of malaria in the western Kenya highlands: Opportunities and challenges for control under climate change risk. Acta Trop 2012; 121:19­25.

Jayakumar M, Prabahar MR, Fernando EM, Manorajan R, Venkatraman R, Balaraman V. Epidemiologic trend changes in acute renal failure-A tertiary centre experience from south India. Ren Fail 2006; 28:405–10.

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Kaushik R, Kaushik RM, Kakkar R, Sharma A, Chandra H. Plasmodium vivax malaria complicated by acute kidney injury: experience at a referral hospital in Uttarakhand, India. Trans R Soc Trop Med Hyg 2013; 107:188-94.

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Lima EQ, Nogueira ML. Viral haemorrhagic fever induced acute kidney injury. Semin Nephrol 2008; 28:409­15.

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Mehra N, Patel A, Abraham G, Reddy YNV, Reddy YNV. Acute kidney injury in dengue fever using Acute Kidney Injury Network criteria: incidence and risk factors. Trop Doct 2012; 42:160-2.

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Toliver HL, Krane NK. Leptospirosis in New Orleans. Am J Med Sci 2014; 347:159­63.

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Aggarwal HK, Jain D, Kaverappa V, Mittal A, Yadav S, Gupta A. Emergence of Scrub typhus in Northern India: Experience from tertiary care hospital. Klimik Dergisi 2014; 27: 6-11.

8.

Mathew AJ, George J. Acute kidney injury in the tropics.

Ann Saudi Med 2011; 31:451-6.

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Silva GB Jr, Daher EF. Tropical disease associated kidney injury. Rev Bras Clin Med 2013; 11:155-64.

10. Hotez PJ. The world’s great religions and their neglected tropical diseases. PLoS Negl Trop Dis 2016; 10:e0004544.

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CHAPTER 126

Kidney involvement in tropical countries is a challenging problem. The late presentation of patients to health care facilities and the lack of resources in developing countries further make the situation worse. Coordinated and integrated approach from the primary to tertiary health care facilities is very crucial and can reduce the disease burden. Monitoring to assess renal injury, control of preventable risk factors and timely intervention with appropriate antibiotics & early use of renal replacement therapy once kidney injury have proven effective in preventing the long term complications.

2.

C H A P T E R

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Contrast Associated Acute Kidney Injury: Nephrologist’s Perspective

INTRODUCTION

The numbers of procedures requiring contrast media, one of the most important and modifiable causes of acute kidney injury (AKI) are increasing. Over 30 different definitions of AKI have been used in published literature.

According to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines, AKI is defined by any of the following criteria; rise in serum creatinine by at least 3 mg/dl within 48 hours or at least more than 1.5 times the baseline level within 7 days or urine volume less than 0.5 ml/kg/hr for six hours.

The term “contrast induced AKI” is preferred over other terms such as “contrast induced nephropathy”,” acute renal failure” or “worsening of renal failure” because “injury” reflects wide pathological spectrum which includes subclinical injury with preserved renal function.

The incidence of contrast induced AKI is about 2% in general population; however, presence of risk factors increases the rates of contrast induced AKI. Presence of both chronic kidney disease and diabetes mellitus significantly increases the risk and the incidence may reach as high as 50% if there are multiple risk factors.

Contrast media can cause acute renal failure, increase in hospital stay, increase incidence of cardiovascular events and mortality. Even transient renal dysfunction after contrast induced AKI can have adverse impact on the prognosis. Considering serious consequences, better preventive strategies are required for improving clinical outcomes in patients who have high risk of developing AKI.

Table 1: Biomarkers for early detection of AKI Renal region

Biomarker

Glomerulus

Total protein, urinary cystain C, beta 2-microglobulin, alfa 1-microglobulin, albumin

Proximal tubule

Kim-1, Clusterin, NGAL, GSTalfa, beta2-microglobulin, alfa 1 microglobulin, NAG, Osteopontin, Urinary cystain C, Netrin-1, HGF, Cyr61, NHE-2, Exosomal feutin-A, L-FABP, Albumin

Loop of Henle

Osteopontin, NHE-3

Distal tubule

Osteopontin, Clusterin, NGAL, H-HABP, Calbindin D28

Collecting duct

Calbindin D28

Dinesh Khullar

CHALLENGES IN TH E DIAGNOSIS OF AKI

Age, gender, race, muscle mass, diet and nutritional status can affect production of creatinine. Similarly, tubular secretion of creatinine can be affected by bilirubin toxicity or use of certain drugs like cimetidine. Laboratory variability due to differences in assay calibration and factors affecting extra-renal elimination of creatinine can affect creatinine level. These are the limitations for use of definition of AKI based on serum creatinine level. Moreover, glomerular filtration rate (GFR) levels can be sustained by renal functional reserve despite kidney injury. It is therefore important to recognise the possibility of acute renal deterioration without changes in serum creatinine. Renal functional reserve is lost with repeated renal injury. The process should be considered as a continuum from the increased risk to the final stages of kidney damage. Considering the limiations of serum creatinine in AKI continuum, biomarkers (table 1) of early injury could help in early identification of AKI diagnosis and timely intervention.

Biomarkers can be combined with functional criteria in THE definitions of AKI. This might help in early diagnosis, timely intervention and better prognosis.

Wide availability of facilities to perform these tests and cost are the limitations for use of biomarkers. Moreover, the current evidence for use of biomarkers for staging is insufficient.

TYPES OF CONTRAST MEDIA

The profile of contrast media differs based on their pharmacological properties such as structure, ionicity, iodine content and osmolality. Based on the osmolality, the contrast media can be classified as “high osmolar”, “low osmolar” and “iso-osmolar” agents. The examples of high osmolar agents are diatrizoate, iothalamate and ioxithalamate. Iohexol, ioversol and iopamidol are low osmolar agents while iodixanol is an iso-osmolar agent.

Although the exact mechanism of contrast induced AKI is not completely understood, several factors have been suggested to mediate the impact of hyperosmolality on renal function. Diuretic effect stimulating a tubuloglomerular feedback mechanism resulting in reduced GFR, decreased renal blood flow due to alterations in vasoconstriction mediated by adenosine, endothelin and nitric oxide and altered erythrocyte morphology affecting capillary perfusion can potentially affect renal functions.

CONTRAST INDUCED AKI

The risk of AKI risk may be procedure dependent.

The rates of contrast induced AKI following coronary angiography have been reported to be higher than those following contrast-enhanced computed tomography which might be related to more co-morbidities in patients requiring coronary angiography and larger dose of contrast media during angiography. However, the risk of contrast induced AKI cannot be ignored in patients undergoing contrast-enhanced computed tomography procedures, considering their widespread and increasing use.

The management of patients receiving iodinated contrast media should at least be based on eGFR. Patients with eGFR less than 30 ml/min need hospitalization. Adequate hydration should be maintained and plans be made in case dialysis is required. In patients with eGFR more than 60 ml/min (if receiving intra-arterial) or more than 45 ml/ min if receiving intravenous contrast media, may require withdrawal of metformin. For patients with eGFR between these limits, nephrotoxic drugs and metformin should be stopped, adequate hydration should be maintained.

CHOICE OF CONTRAST AGENT

Studies consistently show a benefit of using low-osmolar contrast media over high-osmolar contrast media in terms of rates of contrast induced AKI. Iodixanol is associated with lower risk as compared with iohexol. Iso-osmolar or low osmolar contrast agents are generally used for diagnostic/interventional procedures. Iso-osmolar or low osmolar contrast agent other than iohexol can be used for percutaneous coronary intervention.

MEASURES TO PREVENT CONTRAST INDCUDED AKI

The general principles of contrast-induced AKI management are similar to the management of other causes of AKI. Prevention of AKI is the key.

Dose of Contrast Media

Dose of contrast media should be used based on the renal function and interventional or diagnostic requirements.

Lowest possible dose of contrast media should be used to avoid risk of severe AKI.

Hydration

Adequate hydration especially intravenous fluids are the key for prevention of contrast induced AKI, hence it is important to ensure adequate hydration. Isotonic intravenous fluids should be given before and continued for several hours after contrast administration. For outpatients the fluids can be administrated at the rate of 3 mL/kg over one hour pre procedure and 1 -1.5 mL/kg/ hr during and for 4-6 hrs post procedure (min 6 ml/kg post procedure) whereas for hospitalized patients, the rates can be1 mL/kg/hour for 6 -12 hrs before, during and after procedure Hydration with sodium bicarbonate is associated with a significant decrease in the incidence of contrast induced AKI compared with normal saline, but there is no

601

Left ventricular end-diastolic pressure can be useful guide for fluid replacement. Renal guard system is a device which can guide fluid replacement in setting of forced dieresis.

Avoid Nephrotoxic Medicines

Nephrotoxic drugs such as non-steroidal antiinflammatory drugs, aminoglycosides, ciclosporin, tacrolimus, and amphotericin B should be avoided. Loop diuretics should be stopped at least two days before the intervention, if possible, while chemotherapies (especially platinum-based) should be stopped at least seven days before. The risk associated with angiotensin-convertingenzyme inhibitors and angiotensin II receptor blockers is not clear. Metformin is not directly nephrotoxic, but due to the risk of accumulation of lactic acidosis, it should be stopped at least two days before administration of contrast media.

Pharmacological Prophylaxis

There is no convincing evidence to support use of pharmacological agents for prophylaxis of contrast induced AKI. Some agents (e.e. iloprost, N-acetylcysteine, statins) have shown preliminary evidence of prophylactic benefit, but further investigation in large-scale clinical trials are required before recommending them for the prevention of contrast induced AKI. Acetylcysteine is an antioxidant having vasodilatory properties. There are cconflicting results with use of aceylcysteine. Acetylcysteine (1200 mg BD orally) may be administrated orally a day before and on the day of procedure in high risk patients considering it’s potentially benefits, well tolerated safety profile and cost. However, it should always be used with hydration and iso-osmolar agents. Intravenous acetylcysteine, mannitol or other diuretics should not be used for the prevention of contrast nephropathy

Hemodialysis/Hemofiltration

These procedures do not provide significant benefit versus standard medical therapy in reducing the incidence of contrast-induced AKI. However, some centres perform hemodialysis within 24 hours post contrast administration.

Remote Ischemic Preconditioning

Induction of transient nonlethal ischemia of an organ can protect against subsequent ischemic injury. Methods of induction of ischemia include intermittent arm ischemia by blood pressure cuff inflation and inflation and deflation of balloon during percutaneous coronary intervention.

Larger studies required before such procedures are recommended.

SUMMARY

Use of contrast media for various procedures is common and is rising. Contrast induced AKI is associated with significant burden on patients because of its hospital complications and increased mortality. The risk of AKI is affected by the quantity and type of contrast media

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MANAGEMENT OF PATIENTS RECEIVING IODINATED CONTRAST MEDIA

significant difference in the rates of post-procedural death or the requirement for renal replacement therapy.

NEPHROLOGY

602

used and concomitant conditions. The measures to reduce risk of AKI include identification of patients at risk, use alternative imaging methods, selection of dose of contrast media based on renal functions and diagnostic/interventional need, selecting iso-osmolar or low-osmolar contrast media, discontinuation of nephrotoxic drugs and ensuring adequate hydration.

If there is no contraindication, use isotonic intravenous fluids before and continue for several hours after contrast administration. Acetylcysteine (1200 mg BD orally) may be administrated a day before and on the day of procedure. Intravenous acetylcysteine, mannitol or other diuretics should not be used for the prevention of contrast nephropathy. Prophylactic hemofiltration or hemodialysis in stage 3 or 4 CKD has no role in prevention of contrast associated AKI. Similarly, there is no role of early dialysis post contrast exposure in CKD stage 5.

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9.

Nejat M, Pickering JW, Devarajan P, Bonventre JV, Edelstein CL, Walker RJ. Some biomarkers of acute kidney injury are increased in pre-renal acute injury Kidney International 2012; 81:1254â&#x20AC;&#x201C;1262

10. McCullough PA, Brown JR. Effects of intra-arterial and intravenous iso-osmolar contrast medium (Iodixanol) on the risk of contrast-induced acute kidney injury: A metaAnalysis. Cardiorenal Med 2011; 1:220-234

C H A P T E R

128 Chronic kidney disease (CKD) is emerging as an importing chronic disease globally. This is equally true about India with it’s huge population more than 1.25 billion, CKD is going to be an important non communicable disease in future. It has been recently estimated that age adjusted incidence rate of ESRD in India will be 229 per million populations1 and more than 1 lack new CKD patients need renal replacement therapy annually in India.2 Although diabetes and hypertension are the important causes of CKD, a large number of patients develop CKD due to unknown etiology. This form of CKD recently labeled as CKD of unknown etiology (CKDu) is found frequently and studied extensively in Shri Lanka, El Salvador, Guatemala, Nicaragua, Bulgaria, Croatia and Serbia. In India more studies are required to find out the extent and etiology of this new entity.

The endemic nature of chronic kidney decease of unknown etiology (CKDu) was first observed in 1999 and over the past 15 years the prevalence of the disease within certain geographical locations has increased dramatically. This disease is characterized by it’s disassociation with the well-known risk factors such as diabetes, hypertension or chronic glomerulonephritis. The disease remains asymptomatic, and usually presents as end stage kidney disease.3 Couser et al4 in his review of CKD in developing countries mentioned that the percentage of CKDu is considerably higher in developing countries than developed ones.

International Society of Nephrology –sponsored screening program in China, Mongolia and Nepal revealed that 43% of people with CKD did not have diabetes or hypertension.5 ISN has released a position statement on the epidemics of chronic kidney disease stating that CKDu has become a worldwide concern 6. These epidemics typically affect poor agricultural communities, adults of working age affecting individual’s social and economic aspect of, frequently leading to death even when renal replacement therapy is available. CKDu imposes a formidable challenge to local health systems due to high-cost. There is a need to understand the cause of the problem, so that appropriate preventative measures can be implemented 6.

DEFINITION

Various authors have defined CKDu differently. While there is no internationally accepted case definition, common characteristics across studies include the following:

Chronic Kidney Disease of Unknown Etiology Sudhir Kulkarni, Kshitija Gadekar

1.

Asymptomatic and progressive CKD

2.

Absent or sub-nephrotic proteinuria

3,

Absence of hematuria

4.

Absence of diabetes, chronic or severe arterial hypertension, HIV, snake bite, glomerulonephritis or other urinary tract disease

5.

Normal glycosylated hemoglobin (<6.5%)

6.

Blood pressure

<160/100 mmHg in untreated patients

<140/90 mm Hg in patients receiving up to 2 antihypertensive drugs 7

PATHOLOGY

The main pathology is seen in proximal tubules and interstitium. Clinically the disease is characterized by tubular proteinuria usually β2 – microglobulinuria and the absence of hypertension and edema. The histological appearance of the disease reveals tubulointerstial pathology that is similar to toxic nephropathies 8. To date, there is no unequivocal evidence to a recognizable possible environmental causative factor responsible for the CKDu .9

CKDU IN SHRILANKA

A retrospective, descriptive hospital cohort study carried out during the period 2001-2002 in clinics in Anuradhapura and Kandy found that the majority of patients seeking renal care were CKDu patients.8 Recent investigation from community based study in Shri Lanka report significantly higher rate (12.9 %). The most number of CKDu patients have been reported from three provinces that in NCP, UP, EP in Shri Lanka.2 CKDu in Shri Lanka is more prevalent among men (ratio of 3:1), around the age of 40 to 60 years and who are engaged in agriculture. The suspected causes are episodic dehydration, smoking and consumption of illicit liquor.10 The causal factors that have been suggested that may contribute to the development of the disease include heavy metals like cadmium, arsenic various nucleotides, including uranium, elevated levels of fluoride in ground water, the specific composition of groundwater, aluminum and Aflotoxin.. Although there is not sufficient evidence to state that cadmium is likely to play a significant role in the development of the disease, high levels of fluorides present in their ground water may interact with other constituents that are present namely

604

Table 1: Attack rates per 1000 workers by occupation at a large sugar estate in Chichigalpa, Nicaragua, 2010–201416

NEPHROLOGY

Occupation

Attack rate per 1000 workers

Shrimp farm worker

109.1

Irrigation and drainage worker

61.8

Cane collector/harvester

35.7

Cane cutter

35.5

Weed control worker

34.0

All other occupations

11.7

calcium, sodium and possibly magnesium. This has still to be confirmed. Although it is suggested that aluminum vessels may have a role to play in the development in the disease but there is no supporting evidence. This is also true about Aflotoxin contamination as a significant causal factor responsible for development of the disease in Shri Lanka. Role of genetic link may be responsible as the disease appears to be familial.3 The number of CKDu was likely to reach over 2000 by the end of 201311. These patients are concentrated in the dry regions of the country affecting both men and women, between the ages of 30 and 60 years. The majority of patients are poor farm workers. Multiple factors may be linked in combination like environmental factors, diet practices and genetics11.

The research conducted in Shri Lanka by Ministry of Health (MOH) and WHO, tested blood, urine, hair, and nail from both CKDu patients and controls. They tested a number of environmental samples including water, rice, fish, tobacco, and selected root crops. Exposure to sun, heat, stress and dehydration were thought to be potential contributing factors to CKDu and populations at lower elevation may be at lower risk. These patients work in hot dry zones and spent hours in the fields with limited water intake and are not over weight and hypertensive2.

Exposures from pesticide or fertilizer which contain cadmium can enter the environment through repeated agricultural applications. This is also true about phosphate fertilizers which contain traces of cadmium and heavy metals. The pesticides may also be a cause of concern. The high level of minerals may also be seen in hard water that is fluoride or heavy metals like cadmium, uranium and led in ground water wells. However, the environmental risk factors do not consistently show elevated throughout the endemic area. 8, 12 The MOH/WHO in Shri Lanka estimates that 15 % or more of the population in certain endemic area are at risk of developing CKDu. There are certain things which are not clear from this study.

•

Although previous studies showed that men were more prone to CKDu this study showed more women affected by CKDu.

•

The results of this study indicate that cadmium

exposure is a risk factor for CKDu which is not seen in previous studies.

•

Cadmium was below the permissible limit in rice.

Although cadmium was high levels in tobacco and lotus roots it was found that people rarely get to consume these seasonable vegetables.

•

The water sources had cadmium, led and uranium in permissible limits which does not explain the source of element in the food chain

•

Although the cadmium was found in the urine of these patients drinking water cadmium was within normal limits.

To resolve these discrepancies more research is necessary.13

MESOAMERICAN NEPHROPATHY

Central America has recently gained international attention due to an outbreak of unexplained and severe kidney disease. This is labeled as “Mesoamerican Nephropathy.” This is mostly found in young male sugarcane workers in Central America and was reported in late 1990.14 Pan American health organization and WHO (PAHO/ WHO) highlighted the urgent need for research to discover the cause of this nephropathy. The highest kidney related mortality in the world is reported by O Ramirez 14 in Nicaragua and L. Salvador. L.K. O’ Donnel15 found that in Nicaragua the disease affects primarily young men from poor, rural areas who are mainly agricultural workers.

In the sugar estate the role of Leptospira has been suspected in the transmission of disease. Run-off water from the fields, to which workers were exposed, is likely contaminated with urine from rodents.

As shown in table 1 the attack rate is more seem in workers in irrigation and drainage, as well as shrimp farmers at the sugar estate compare to other occupations like Cane cutters. These workers come in contact with contaminated water through breaks in the skin contact with mucous membranes, or by ingestion. 16 Although identified since 2 decades the etiology of Mesoamerican Nephropathy remains unknown.

CKD U IN INDIA

Agarwal SK17 reported that the epidemiology of CKD in India is different from that in European and western world. Indian patients are younger and present with small kidneys and do not have known etiology of CKD. He concludes that a nationwide reporting system or registry is a necessary to determine the true incidence and prevalence.

Indian Society of Nephrology published the Indian CKD registry 18. The data collected from 2005 showed that 16 % of the adult CKD patient had CKDu. These patients belong to low income group. CKDu was found to be the second biggest cause next to diabetes.

The type of water consumed was from either well water or ground water.

Ajay K. Sing et al.19 studied the epidemiology and risk factors of Chronic Kidney Disease in India. The results were published as SEEK study (Screening and Early Evaluation of Kidney Disease). This study included patients from urban area with high school diploma and from higher income group who were mostly over weight.

The risk factors were hypertension 64.5 %, diabetes 31.6%.

As this study was from urban area did not get cases of CKD of unknown origin due to selection bias. Hargovindsing Trivedi20 from IKDRC Ahmedabad found diabetes in 9.79 %, hypertension 26.87%, obesity 18%, over weight 32.85%, stone disease 17.19%. Urine albumin was present 13.79 % of patients. As this study was from semi urban population there were no patients of CKDu.

A key note address by Dr. Shanthi Mandis in 2013 summarizes the present state of research in CKDu.21 The prevalence of CKDu is 12.9% to 16.9% in various studies. A male to female ratio is variable. There is no definite etiology for CKDu. The suspected factors in the etiology in CKDu are low levels of cadmium exposure through the food chain, exposures to heavy metals and selenium deficiency. The genetic susceptibility is likely cause of CKDu as the disease is seen in families. The use of Sapsand in Herbal Medicine may be responsible for CKDu. Fluoride and calcium in water may aggravate cadmium toxicity. Enalapril can be used to reduced albuminuria in CKDu.

The study carried out in Odisha by Social Human Action for Rural Poor (SHARP) which included villages including Rautabhuin found 100 new cases of CKDu. ICMR and RMRC in Bhubaneswar carried out a survey in Nursingpur. It was found that 8-12% people suffer from CKDu. Such findings are also observed in Cuttack, Bhubaneswar, Jaipur, Balangir, Kalahandi, Jharsuguda and Koroput. ICMR has now identified Odisha as 1 of the two CKD hot spots the other being Andhrapradesh.13

1.

Supply clean drinking water (pipe borne) to mitigate contributing factors that may aggravate the effect of nephrotoxins including high calcium, fluoride and heat /dehydration related harmful effects on kidney.

2.

Explore the use of rock phosphate and regulate Cd, As, Pb in phosphate fertilizers and indiscriminate use of synthetic fertilizers.

Preliminary data from the research carried out form Andhra Medical College, Tatapudi and Harward Medical School found high levels of silica in water samples from Shrikaculam. Although Gangadhar found high levels of strontium and silica in water samples from Prakasam.

He suggests that only silica may be responsible for the disease. WHO India and National Geophysical Research Institute (NGRI), however ruled out silica as the cause of problems in Shrikakulam in Parkas. D.V Reddy of NGRI and A.Gunasekar of WHO India found that ground water in Shrikakulam is less mineralized than that in Prakasam. Concentration of inorganic chemicals were within permissible limits for drinking water. State of Andhrapradesh including costal Uddanam and inland of Chimakurthy Mandal reported CKDu in younger males from rural costal area from low socio economic group.

They are involved in cultivation of coconuts, rice, Jackfruit and cashews. 13

3.

Strengthen tobacco regulations to further protect people including children from exposure to Cd through passive smoking.

4.

Advice people to avoid use of lotus roots from the endemic area (avoid exceeding PTWI)

5.

Further research e.g. explore methods to reduce the intake of Cd by plants by maintaining soil at neutral pH and other affordable measures.

6.

Ensure appropriate disposal of Nickel Cadmium batteries , plastics, bottle lids .

7.

Diazinion, Propanil, Paraquat, Chlotpyriphos, Carbaryl-monitor the ban in the NCP. Regulate the use of pesticides.

8.

Create the awareness (public/doctors) of the danger of inappropriate use of nonsteroid analgesics.

10.

Provide facilities for early diagnosis and ACEI for treatment.

11.

Health education to safeguard the health of the general population including farmers.

12.

Provide social welfare support to affected families.

CKD U IN MAHARASHTRA

We carried out hospital based pilot (unpublished) study at Marathwada region of Maharashtra including 560 patients of CKD over 2 years period between 2014 and 2015. We found 40% of patients had CKDu while diabetes and hypertension were present in 14% and 28% respectively.

Males predominated, male to female ration being 5:2. 52% of patients belonged to age group of 21- 40 years, active age group. 95% of patients had BMI <24.5 Kg/per square meter and 60% patients had proteinuria. Majority patients presented in stage IV and V with shrunken kidneys. 90% of patients were agricultural farm workers or laborers.

45% of patients were illiterate. 39% used tobacco and 15% consumed alcohol. NSAIDs use was seen in 25% and smoking and alcohol both were present in 17% of patients.

WHO RECOMMENDATIONS21

Joint efforts by clinicians, scientist, health organizations and politicians are required to control the epidemic of CKDu in developing countries. This will reduce the financial burden of treating end stage renal disease in poor population mainly affected by CKDu.

REFERENCES

1.

Modi GK, Jha V. The incidence of end-stage renal disease in India: A population-based study. Kidney Int 2006; 70:21313.

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CHAPTER 128

The study published in Lancet July 2013 shows that India contributes to about 20% of CKDu cases worldwide.13

606

2. Jayatilake, N.; Mendis, S.; Maheepala, P.; Mehta, F.R. Chronic kidney disease of uncertain aetiology: prevalence and causative factors in a developing country. BMC Nephrology 2013; 14:180

NEPHROLOGY

3. Noble, Andrew; Amerasinghe, Priyanie; Manthrithilake, Herath; Arasalingam, Sutharsiny. 2014.Review of literature on chronic kidney disease of unknown etiology (CKDu) in Sri Lanka.Colombo, Sri Lanka: International Water Management Institute (IWMI). (IWMI Working Paper 158) 4. Couser WG, Remuzzi G, Mendis S, Tonelli M. The contribution of chronic kidney disease to the global burden of major non communicable diseases. Kidney Int 2011; 80:1258–70. 10.1038/ki.2011.368.

5. Sharma SK, Zou H, Togtokh A, Ene-Iordache B, Carminati S, Remuzzi A, et al. Burden of CKD, proteinuria, and cardiovascular risk among Chinese, Mongolian, and Nepalese participants in the International Society of Nephrology screening programs. Am J Kidney Dis 2010; 56:915–.

6. Sally Horspool (ISN Position Statement on CKDu) http:// www.theisn.org/news/item1904-isn-position-statementonckdu 7. https://ajkdblog.org/2016/03/10/nephmadness-2016international-nephrology-region/ 8. Athuraliya, T. N.C.; Abeysekera, D.T.D.J.; Amerasinghe, P.H. 2011. Uncertain etiologies of proteinuric-chronic kidney disease in rural Sri Lanka. Kidney International 2011 (Advance online publication August 10, 2011; doi: 10.1038/ ki.2011.258.

9.

Chandrajith, R.; Nanayakkara, S.; Itai, K.; Aturaliya, T.N.C.; Dissanayake, C.B.; Abeysekera, T.; Harada, K.; Watanabe, T.; Koizumi, A. 2011a. Chronic kidney diseases of uncertain etiology (CKDue) in Sri Lanka: Geographic distribution and environmental implications. Environ. Geochem.

Health. DOI 10.1007/s10653-010-9339-1

10. Wanigasuriya, K.P.; Peiris, H.; Ileperuma, N.; Peiris-John, R.J.; Wickremasinghe, R. Could ochratoxin a in food commodities be the cause of chronic kidney disease in Sri Lanka? Transactions of the Royal Society of Tropical Medicine and Hygiene 2008; 102:726—728.

11. Myles F. Elledge, Jennifer Hoponick Redmon, Keith E. Levine, Rajitha J. Wickremasinghe, Kamani P. Wanigasariya, and Roshini J. Peiris-John, research brief Chronic kidney Disease of unknown etiology in Shrilanka:

quest for understanding and global implications, RTI international may 2014.

12. Bandara, J.M.R.S.; Senevirathna, D.M.A.N.; Dasanayake, D.M.R.S.B.; Herath, V.; Bandara, J.M.R.P.; Abeysekara, T.; Rajapaksha, K.H. Chronic renal failure among farm families in cascade irrigation systems in Sri Lanka associated with elevated dietary cadmium levels in rice and freshwater fish (Tilapia). Environ Geochem Health 2008; 30:465–478.

13. Richard Mahapatra, Vibha Varshneyand M. Suchtra, December 2013. Kidney Conundrum: 14. O. Ramirez-Rubio, M.D. Mcclean, J.J. Amador, D.R. Brooks.

An Epidemic Of Chronic Kidney Disease In Central America: an overview. J Epidemiol Community Heal 2012; 67:1-3.

15. Prevalence of and risk factors for chronic Kidney disease in rural Nicaragua J.K. O’ Donnel, M Tobey, D.E. Weiner, L.A. Stevens, S. Johnson, P. Stringham, et al. Nephrol Dial Transpl 2011; 26:2798-2805.

16. Mesoamerican nephropathy: a neglected tropical disease with an infectious etiology? Kristy O. Murray, Rebecca S.B. Fischer, Denis Chavarria, Christiane Duttmann, Melissa N. Garcia, Rodion Gorchakov, Peter J. Hotez, William Jiron, doi:10.2016/j.micinf.2015.08.005 17. Agarwal SK. Chronic kidney disease and its prevention in India. Kidney Int Suppl 2005; 68:S41–5. 10.1111/j.15231755.2005.09808.x [PubMed] [Cross Ref] 18. Rajapurkar MM, John GT, Kirpalani AL, Abraham G, Agarwal SK, Almeida AF, et al.What we know about chronic kidney disease in India: first report of the Indian CKD registry. BMC Nephrol 2012; 13:10. PubMed CentralView ArticlePubMed 19. Epidemiology and risk factors of Chronic Kidney disease in India – results from the SEEK (Screening and early evaluation of Kidney Disease) study. Ajay K. Singh, Youssef M.K. Farag, Bharti V. Mittal et al. BMC Nephrologt 2013; 14:2-114.

20. High prevalence of chronic kidney disease in a semi-urban population of Western India Hargovind Trivedi,1 Aruna Vanikar,2 Himanshu Patel,1 Kamal Kanodia,2 Vivek Kute,3 Lovelesh Nigam,2 Kamlesh Suthar,2 Umang Thakkar,4 Harsh Sutariya,5 and Shruti Gandhi5 21. Dr. Shanthi Mendis - Keynote Address. Chronic Kidney Disease; Global and Sri Lankan Perspectives. Aug 29, 2013.

C H A P T E R

129

Complicated Urinary Tract Infection

INTRODUCTION

Urinary tract infection (UTI) is defined as an inflammatory response of the urothelium to microorganism (usually bacterial) invasion. UTIs are one of the most common bacterial infections affecting men and women of all ages.

It is the third most common infection after respiratory and gastro-intestinal infections1. UTI can be classified in various ways: community or hospital acquired, cystitis or pyelonephritis and uncomplicated or complicated. In this article we will review the various aspects of complicated urinary tract infection (cUTI).

DEFINITION OF COMPLICATED URINARY TRACT INFECTION (CUTI)

In general any UTI except that in a young, otherwise healthy, immunocompetent, non-pregnant female with an anatomically and functionally normal urinary tract

Table 1: Clinical syndromes of uncomplicated and complicated UTI Uncomplicated UTI •

Acute uncomplicated cystitis in young women

•

Recurrent acute uncomplicated cystitis in young women

•

Acute uncomplicated pyelonephritis in young women

•

Acute uncomplicated cystitis in adults with other complicating factors

Male sex, Elderly, Pregnancy, Diabetes mellitus, Recent urinary tract instrumentation, Childhood UTI

•

Asymptomatic bacteriuria

Complicated UTI •

Structural abnormality/obstruction

•

Functional abnormality: neurogenic bladder, vesicoureteral reflux

•

Foreign bodies: indwelling catheter (AUTI), ureteral stent, nephrostomy tube.

•

Others conditions Renal failure, renal transplantation, immunosuppression, multidrugresistant uropathogens, health care-associated (includes hospital-acquired/nosocomial place) infection, prostatitis-related infection, upper tract infection in an adult other than a healthy young woman, other functional or anatomic abnormality of urinary tract)

Dipankar Bhowmik, Sudeep Singh

should be considered a cUTI. A detailed classification of the clinical syndromes of uncomplicated and cUTI is given in Table 12.

It may be noted that UTI in males, elderly, childhood, pregnancy, diabetes mellitus, recent urinary instrumentation may actually only be acute uncomplicated cystitis, and not necessarily always cUTI.2 However, one must always have a high index of suspicion in these cases. The anatomical site of infection per se is not the deciding factor. In fact even pyelonephritis may be uncomplicated if it satisfies the factors mentioned above.

RISK FACTORS FOR CUTI

The risk factors for cUTI can be divided under host and organism related factors.

HOST RELATED

Male sex

Males are generally resistant to UTI. This is because of the presence of an elongated urethra, and the antibacterial nature of prostatic secretions.3 Hence UTI in a male should raise the doubt of some underlying abnormality.

Age

Infections in childhood suggest certain abnormalities of the genitourinary tract. Vesicoureteral reflux, urethral valves, ureteropelvic obstruction, or ureterovesical obstruction are all conditions where there is a tendency for an increased incidence of urinary tract infections, andalso increased severity4. Postmenopausal women with recurrent urinary infection are also more likely to have increased residual urine volume, cystoceles and prior genitourinary surgery thus making them more prone to cUTIs.

Cannulated urinary tract

Patients with indwelling catheters (urethral, suprapubic, nephrostomy) or a ureteral double J stentare prone to infection with resistant organisms.It is difficult to distinguish benign colonization from frank infection.

Diabetes

Diabetics are more susceptible to cUTI. Also complications such as perirenal, intra renal abscesses, carbuncles, lobar nephronia, emphysematous pyelonephritis and secondary obstruction due to renal papillary necrosis are more common in diabetics.

Chronic kidney disease

CKD patients have reduction in renal blood flow, urinary volume and reduced immune response. There is also decrease in concentrating ability of urine, reduction

608

of substances in urine inhibiting bacterial growth and decreased delivery of antibiotics in the urinary tract all of which predispose them to cUTI5.

Urolithiasis

Stones cause injury to the urothelium and give bacteria a place to establish colonization. Certain stones are a direct result of infection especially magnesium ammonium phosphate or calcium carbonate and these stones themselves promote persistence of infection.

NEPHROLOGY

Pregnancy

Factors in pregnancy predisposing to cUTI are gravid uterus causing relative obstructive uropathy, high progesterone levels leading to reduced ureteral/bladder motility, voiding dysfunction and venous congestion.

Hence UTI during pregnancy is considered as cUTI unless proved otherwise 6. Appropriate treatment of UTI in pregnancy is imperative to prevent IUGR and pre-term labour. Screening of urine during pregnancy for pyuria and bacteriuria is done to detect UTI early.

Voiding dysfunction

Conditions like neurogenic bladder, spinal cord injury, myogenic atony, spina bifida, sacral agenesis lead to incomplete emptying of the bladder and encourage bacterial growth. These conditions lead to high pressure voiding which cause a reduction in blood supply to the urinary tract, impairing immune response of the host.

Hospital acquired UTI

Hospital acquired (nosocomial)UTIis always considered complicated, because of multiple factors like indwelling catheters, antibiotic overuse, selectivity of multidrug resistant uropathogens, skin break down, loss of urinary or bowel control and cross contamination from patient to patient7.

Immunosuppression

Immunosuppressant drugs including corticosteroids, calcineurin inhibitors, monoclonal antibodies, azathioprine, MMF suppress the immune system and predispose to cUTI.

PATHOGEN RELATED

E coli accounts for most of the infectionsin uncomplicated UTI. In cUTI apart from E coli, several other organisms may be causative.

These include Klebsiella spp., Proteus spp., Enterobacter cloacae, Serratia marcescens, Acinetobacter species, Pseudomonas aeruginosa; and Gram-positive organisms such as Enterococci, coagulasenegative staphylococci and Staphylococcus aureus8.

Candida species are commonly associated with urosepsis in urologic patients with hospital-acquired UTIs. Elderly patients and patients with cannulated urinary tract often have polymicrobial bacteriuria. Occasionally the patient has a focus of sepsis elsewhere, and the infection is hematogenously transported to the urinary system.

CLINICAL FEATURES

cUTI has a varied clinical presentation ranging from mild lower tract irritative symptoms such as frequency, urgency, dysuria, suprapubic discomfort, new or increased incontinence to severe systemic manifestations,

such as bacteremia, sepsis, septic shock and death. Acute pyelonephritis presents with fever, costovertebral angle tenderness and variable urinary tract symptoms. The initial step is to obtain a thorough medical historykeeping in mind the factors associated with cUTI (Table 1) followed by a thorough physical examination.

MANAGEMENT

Investigations

Investigations play a vital role in the diagnosis of cUTI. The simple dipstick examination of the urine, which can be easily done in the clinic or bedside, is the first test.A positive leucocyte esterase dipstick test is a highly sensitive marker for the presence of pus cells in the urine.

Presence of nitrites, which is indicative of bacteruia, has a high positive predictive value of 94% for the diagnosis of UTI.9 In catheter associated UTI, clinical correlation is required along with the laboratory findings. Subsequently samples must be sent to the laboratory for urine-routine and microscopy examination and culture and sensitivity.

As far as possible urine culturesshould be collected prior to administration of antibiotics to maximize the diagnostic yield and avoid false-negative results. Traditionally a growth ofâ&#x2030;Ľ 105colony-forming units (CFUs)/mL of an uropathogenin a midstream, clean-catch urine is indicative of significant bacteriuria. However, a growth as low as 102CFU/mLshould be considered indicative of infection in the presence of suggestive symptoms of UTI. A count of at least 102 CFU/mL is sufficient for a microbiological diagnosis in urine specimens obtained by intermittent catheterization. When the urine is collected by suprapubic aspiration any quantitative count is considered significant for the diagnosis of UTI.10 In addition hematological profiles and serum chemistries including urea, creatinine, electrolytes and liver functions must be done. Blood culture is indicated when infection at distant sites is suspected.

Imaging of the urinary tract is mandatory in cUTI. Ultrasonography is a simple, non-invasive and easily available investigation. It should preferably be performed immediately in the clinic or in the casualty. It can diagnose obstruction of the urinary tract, and can raise the suspicion of pyelonephritis and or abscess formation in the renal parenchyma. Ultrasonography often needs to be supplemented with other imaging modalities.

Contrast enhanced CT scan of the kidneys and urinary tract is the investigation of choice, since it provides maximum information. However, if the patient has renal dysfunction, even plain (non-contrast) CT is useful since it can identify calculi, hemorrhage, obstruction and gas in the urinary tract 11. Urological assessment such as cystoscopy, retrograde pyelography or urodynamic testing may also be indicated.

Treatment

The basic principles which guide the treatment of cUTIs are discussed below. The first of these is to minimize the effects of obstruction or any other anatomic abnormality.

Second, aggressive use of antibiotics is mandatory.

This means appropriate use of broad-spectrum drugs in appropriate dosages. Some patients may have renal

Table 2: Sequelae of Complicated UTI • Urosepsis • Acute kidney injury • Structural damage to the kidney - Abscess: intrarenal or perinephric - Emphysematous pyelonephritis - Acute papillary necrosis • Pregnancy: IUGR, preterm delivery • Rare long term renal complications - Malakoplakia impairment and the drug doses need to be adjusted accordingly. It is always necessary to not only cover Gram-positive and Gram-negative bacteria, but also to choose the specific drugs based upon the culture and sensitivity patterns available in the given hospital or area.A delay in initiating appropriatebroad spectrum antimicrobial agent for severe cUTI is associated with increased mortality. Empiric anti-fungal therapy with azoles or amphotericin may be indicated in diabetics or patients with indwelling urinary catheter. Once the cultures and sensitivities are available, appropriate adjustments must be made. A very effective modality is to use combination therapy. This is especially true when antibiotics from different classes are used together, because they work on different sites in the bacterium. Oral antimicrobial therapy is often appropriate for treatment.

Parenteral therapy is indicated if patients are unable to tolerate oral therapy, have impaired gastrointestinal absorption, have hemodynamic instability, or if the infecting organism is known or suspected to be resistant to oral agents. The duration of therapy should be seven days for individuals with lower tract symptoms, and 10 to 14 days for individuals presenting with upper tract symptoms or sepsis syndrome. Patients with chronic urological devices should receive as short a duration of therapy as possible to limit antimicrobial pressure leading to resistance emergence.

The diagnosis of renal abscess needs drainage of the pus.

Emphysematous pyelonephritisis an emergency. It occurs almost exclusively in diabetics, and is characterized by the finding of air in the renal parenchyma, identified by CT, ultrasound, or abdominal radiographs. Intervention is always required, and even if instituted in a timely fashion there is a high mortality rate.

Sequelae of cUTI

Unless treated appropriately in time, cUTI can have many serious sequelae (Table 2). The most worrying is urosepsis.

This is more likely in immunocompromised patients though all patients are at risk. In fact many patients may present with urosepsis. It more common with Gramnegative organisms and may be associated with multiple organ failure and death. Another serious sequela of cUTIs is renal failure. This may be acute kidney injury or acute kidney injury superimposed on pre-existing chronic

609

Xanthogranulomatous pyelonephritis and malakoplakia are relatively uncommon late complications, but almost always result in renal loss.

PREVENTION

Since cUTI has a high morbidity and sometimes mortality one must take steps to prevent its occurrence.

Training of the nursing staff for appropriate care of the indwelling urinary catheter is mandatory. Prolonged urinary catheterisation must be avoided. Wherever possible, underlying genitourinary abnormalities should be diagnosed and corrected. Chemoprophylaxis is indicated to prevent recurrent symptomatic infection or deterioration in renal function for selected patients with persistent genitourinary abnormalities.

CONCLUSION

Complicated UTI is an important health problem, because of an increase in the number of patients who are at risk. The average age of citizens is increasing, as is the likelihood of contacting those diseases that are associated with aging. Hence it is important for the medical community to diagnose this condition early, and to treat aggressively to not only shorten the disease course, prevent the occurrence of harmful sequelae and also to minimize antimicrobial resistance.

REFERENCES

Laupland KB, Ross T, Pitout JDD, et al. Community-onset urinary tract infections: a population-based assessment.

Infection 2007; 35:150–3.

2. Hooton T. Urinary tract infection in adults. In: Comprehensive clinical nephrology Fifth Ed. Eds. Johnson RJ, Feehally J, Floege J, Saunders, an imprint of Elsevier Inc. 632–43.

3. Fair WR, Couch J, Wehner N. Prostatic antibacterial factor.

Identity and significance. Urology 1976; 7:169–77.

4. Koff SA. Clues to neonatal genitourinary problems.

Postgrad Med 1977; 62:93–101.

5. Kamińska W, Patzer J, Dzierzanowska D. Urinary tract infections caused by endemic multi-resistant Enterobacter cloacae in a dialysis and transplantation unit. J Hosp Infect 2002; 51:215–20.

6. McLaughlin SP, Carson CC. Urinary tract infections in women. Med Clin North Am 2004; 88:417–29.

7. Gaynes R, Edwards JR. Overview of nosocomial infections caused by gram-negative bacilli. Clin Infect Dis 2005; 41:848–54.

8. Nicolle LE. Complicated urinary tract infection in adults.

Can J Infect Dis Med Microbiol 2005; 16:349–60.

9. Lammers RL, Gibson S, Kovacs D, et al. Comparison of test characteristics of urine dipstick and urinalysis at various test cutoff points. Ann Emerg Med 2001; 38:505–12.

10. Nicolle LE. Urinary tract infections in adults. In: Brenner and Rector’s The Kidney 1356–82.

11. Craig WD, Wagner BJ, Travis MD. Pyelonephritis: radiologic-pathologic review. Radiographics 2008; 28:255– 277; quiz 327–328.

1.

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- Xanthogranulomatous pyelonephritis

kidney disease. This deterioration in renal function may improve or may persist requiring renal support therapy.

Pre-existing renal insufficiency (including post-transplant cases) and urinary tract obstruction are predisposing conditions.

C H A P T E R

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My Diet Plan for Diabetic and CKD Sanjay Dash

INTRODUCTION

essential amino acids are included in the diet to synthesize protein while avoiding the accumulation of unexcreted, potentially toxic ions and compounds arising from the breakdown of foods rich in protein.

Chronic Kidney disease is common in India and worldwide. The Screening and Early Evaluation of Kidney Disease (SEEK) study estimates the prevalence of CKD in India at 17.2%2. Diabetes Mellitus is the commonest cause of CKD in India (31%)3 and globally.

A severely deficient diet can lead to muscle mass loss, although more commonly as complications of CKD such as acidosis or inflammation which activate the enzymes that breakdown protein to cause loss of protein stores.

Catabolism will not be halted by prescribing an excess of protein in diet, instead it will lead to accumulation of unexcreted, potentially toxic ions like phosphates and potassium. The outcome is an increasing risk of developing acidosis, hyperkalaemia, hyperphosphatemia, edema, a high serum urea and BUN but no increase in muscle mass.

Globally the number of people with Diabetes is increasing rapidly and the latest data1 reveal there are 415 million adults with Diabetes (India 69.2 million).

Dietary adjustments are an important part of the care plan for Diabetic CKD. Dietary indiscretion in a patient with diabetic nephropathy contributes to the severity and rapid progression of CKD. Conversely the timely and right kind of dietary intervention plays a significant role in controlling the progression of CKD. Among CKD patients, over nutrition results in sodium and volume overload, hyperkalaemia, hyperphosphatemia and accumulation of toxic metabolites of protein degradation.

Undernutrition, on the other hand, exacerbates the risk of malnutrition. As GFR decreases, the nephron is less able to handle potassium, phosphorous, sodium and acid levels. The optimal diet for individual DKD patients varies depending upon the eGFR, proteinuric or nonproteinuric status, and the presence of other co-morbidities such as hypertension or heart failure.

DIETARY PROTEIN

Both quantity and quality of protein and amino acids have been identified to be important for maintenance of adequate nutritional status in diabetic CKD. Identification of optimal dietary protein intake is complicated because it is known that kidney disease confers unique metabolic abnormalities that can include alterations in mineral metabolism, metabolic acidosis, anaemia, vitamin D deficiency, loss of lean muscle mass and susceptibility to malnutrition. Studies that have examined protein restriction have yielded inconsistent results, but the balance of evidence suggests a benefit of moderate dietary protein restriction. The NKF KDOQI4 recommends a target protein intake of 0.8 g/kg/d for non-dialysis DKD. KDIGO5 also suggests a dietary protein intake of 0.8 g/kg/d in diabetic adults with eGFR <30 ml/min/1.73 m2. The ADA6 recommends â&#x20AC;&#x153;usualâ&#x20AC;? (not high) dietary protein intake. In patients with moderately severe and more severe CKD once protein intake is reduced by 0.2 gm of protein/kg/d for one year the baseline values of serum bicarbonate, phosphorus and urea nitrogen are remarkably lower7.

The benefits will compound if enough essential and non-

Besides reducing waste products, benefits of a protein restricted diet include suppressing proteinuria, improved control of 1) blood glucose 2) hyperlipidaemia 3) BP 4) renal bone disease and 5) metabolic acidosis. Decreased albuminuria is associated with slower progression of diabetic CKD. As eGFR declines, appetite decreases and malnutrition may manifest. Body weight and serum albumin is used to monitor nutritional status. Hypoalbuminemia may result from reduced protein and/or calorie intake, uraemia, metabolic acidosis, albuminuria, inflammation, or infection. However, a properly monitored diet prevents malnutrition even when eGFR is below 10 ml/min.

Avoidance of malnutrition is especially important in CKD stages 4 and 5 due to their susceptibility to infections.

Patients with better nutritional status during dialysis have better outcome.

What about the progression of CKD? The conclusions from MDRD8 study suggest that low protein diet did not significantly slow down the loss of GFR. However, it was subsequently observed that those patients who reduced the dietary protein by 0.2 gm/kg/d had a reduced loss of GFR of 29%, which translated into a 41% increase in time to dialysis or death9. The probable reason for this is that a low protein diet can reduce proteinuria which has been proposed as a major factor in progressive loss of GFR. Diet rich in protein from plant sources may be beneficial among CKD patients. Such a diet may reduce proteinuria, slow the progression of CKD, decrease the production of uremic toxins, lower phosphorus intake, and potentially decrease mortality risk. In patients with nephrotic syndrome protein restriction is not recommended.

So the various recommendations suggest that in

diabetic CKD, dietary proteins should be limited to 0.81.0 g protein/kg/day to prevent accumulation of acid, phosphorous and uric acid. However, patients on dialysis will need more protein intake. A high-protein diet (KDOQI recommendation of 1.2 gm/kg/day for haemodialysis and 1.3 gm/kg/d for peritoneal dialysis patients) with fish, poultry or eggs at every meal may be recommended. This will prevent malnutrition.

calorie intake in obese DKD will delay the progression of DKD.

1.

There is no dietary restriction for patients with eGFR>60 ml/min/1.73m2.They should follow the diet of diabetic populations.

CARBOHYDRATES AND FATS

2.

Milk and non-fat dairy products (like yogurt, cheese) less than half litre a day.

3.

Incorporate vegan protein sources into meal plan like pulses 4tsp (raw weight) per day, dried beans and peas, legumes, nuts and seeds.

4.

For non-vegetarian patients, avoid intake of fatty animal protein sources like red meat, poultry with skin and shellfish. Fish or chicken 30-50gms/day can be substituted.

5.

Include high-fibre, wholegrain products (whole/ mixed-grain breads, pastas, cereals; brown rice), avoid refined white flour based products (noodles, maida).

6.

Fresh fruits and vegetables of choice, fresh cooked vegetables are ideal. If potassium is to be restricted citrus fruits, peaches, sapota etc. are to be avoided along with vegetables like avocado, potatoes, tomatoes, pumpkin and spinach.

Cabbage, carrots, cauliflower, celery and cucumber can be substituted. To reduce potassium content, vegetables need to be leached (wash, peel, cut in small pieces, soak in water for sufficient time and the water discarded). To minimize sodium content of diet, provide freshly cooked food. Avoid tinned and canned readymade food, sauces, cheese, soups, popcorn, commercial salad, salted pickles which has high sodium content. Sources rich in inorganic phosphate such as highly processed foods should be avoided because inorganic phosphate has much higher bioavailability.

7.

Diet needs to be enriched with olive oil, fish oil, and vegetarian sources of omega-3 fatty acids.

Finally approaches to incorporating diet patterns for diabetic CKD patient (50kg weight) will be as follows:

SODIUM AND POTASSIUM

1 g of salt contains 0.4 g (17 mEq) of Na ion. Sodium plays a large role in blood pressure control in CKD as a result of alterations in sodium excretion by the kidneys. Sodium intake should be limited to 2,300 mg a day or less. The approach for patients with reduced eGFR who do not have hypertension, volume overload, or increased protein excretion is not clear.

Among CKD patients, the benefits of salt restriction might include the following: ●

Lower blood pressure (BP)

●

Slower progression to end-stage renal disease (ESRD)

●

Improved cardiovascular outcomes

Hyperkalaemia usually occurs when eGFR is less than 20 ml/min/1.73 m2. KDOQI recommends potassium intake between 2 to 4 g/day (51-102 mEq/day) for patients with CKD stages 3 to 4, while recommending no restriction for those in earlier stages of CKD. In stages 4 and 5 CKD fluid restriction is also required.

Phosphorous retention can lead to metabolic bone disease and cardiovascular disease. Dietary phosphorus intake is restricted to a maximum of 0.8 to 1 g/day to normalize the serum levels in patients with an eGFR <60 mL/min/1.73 m2.

Decreased vitamin D production in Diabetic CKD can lead to hypocalcemia. Maintaining a calcium intake of 1.0 to 1.2 g daily will help prevent hypocalcemia.

CALORIE INTAKE

Weight loss leads to improved BP, better glycaemic control, reduction of hyperfiltration and proteinuria11.

Since HTN, Proteinuria, hyperfiltration are all risk factors for progression of DKD, this suggests that reduction of

SUMMARY AND RECOMMENDATIONS

Low protein, low potassium, low phosphorous, moderate carbohydrate and high fibre diet have been recommended to DKD patients in order to control blood sugar levels and delay progression of CKD. The diet of every patient needs to be individualized depending on the tendency to retain or lose salt and the serum levels of protein, potassium, phosphorus and lipids and finally the overall nutritional status and daily urine output of the patient. For most DKD patients, the optimal diet is one similar to the Dietary Approaches to Stop Hypertension (DASH) diet, consisting of fruits, vegetables, legumes, fish, poultry, and whole grains.

A skilled dietician will incorporate a patient’s food preferences, adequate calories and a proper distribution

CHAPTER 130

Whole-grain carbohydrates and fibre and fresh fruits and vegetables are recommended as part of a healthy diet for individuals with DKD. The number of portions and specific food selections from these food groups often need to be limited in advanced stages of CKD due to the potassium and phosphorus loads imposed by these foods.

Literatures suggest beneficial effects of omega-3 fatty acids on albuminuria in DKD10. The general recommendation for DKD is to include omega-3 and omega-9 fatty acids as part of total dietary fat intake while decreasing intake of saturated fats and food sources of trans fatty acids.

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of foods while encouraging compliance. Fortunately, the majority of CKD patients accept dietary changes.

REFERENCES

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Brussels, Belgium: International Diabetes Federation, 2015.

NEPHROLOGY

2. Ajay K. Singh, Youssef MK Farag, Bharati V Mittal, Kuyilan Karai Subramanian, Sai Ram Keithi Reddy, Vidya N Acharya, et al. Epidemiology and risk factors of chronic kidney disease in India â&#x20AC;&#x201C; results from SEEK (Screening and Early Evaluation of Kidney Disease) study. BMC Nephrology 201314:114 DOI:10.1186/1471-2369-14-114 3. M.M. Rajapurkar, George T John, Ashok L Kirpalani, Georgi Abraham, S.K. Agarwal, Alan F. Almeida et al.

What do we know about chronic kidney disease in India: first report of the Indian CKD registry. BMC Nephrology 201213:10 DOI: 10.1186/1471-2369-13-10.

4. The National Kidney Foundation- Kidney Disease Outcomes Quality InitiativeTM (NKF-KDOQITM) Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney disease. Am J Kidney Dis 2001; Feb 49(Suppl. 2) S12-S154.

5. KDIGO (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 2013; 3: S1-S150).

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8. Klahr S, Levey AS, Beck GJ, Caggiula AW, Lawrence Hunsicker, Kusek JW et al. The Effects of Dietary Protein Restriction and Blood-Pressure Control on the Progression of Chronic Renal Disease. (for the Modification of Diet in Renal Disease Study Group). NEJM 1994; 330:878-884.

9. Levey AS, Adler S, Caggiula AW, England BK, Greene T, Hunsicker LG, et al. Effects of Dietary Protein Restriction on the Progression of Advanced Renal Disease in the Modification of Diet in Renal Disease Study. Am J Kidney Dis 1996; 27:652-63.

10. Shapiro H, Theilla M, Attal-Singer J, Singer P. Effects of polyunsaturated fatty acid consumption in diabetic nephropathy. Nat Rev Nephrol 2011; 7:110-121.

11. Ezequiel, D.G., Costa, M.B., Chaoubah, A., de Paula, R.B. Weight loss improves renal hemodynamics in patients with metabolic syndrome. J Bras Nefrol 2012; 34:36-42.