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INDEX HAEMODIALYSIS ...............................................................1 Assessment of the dialysis patient ......................................2 Haemodialysis prescription ...................................................3 Haemodialysis access and line sepsis.................................5 Intravenous antibiotic dosing...............................................8 Non-infectious access complications.................................9 Dialysing toxins........................................................................10 Renal anemia ............................................................................11 Mineral bone disease: Phosphate, PTH and Calcium.13 Complications of ESRD..........................................................16 Intradialytic hypotension .....................................................19 PERITONEAL DIALYSIS ...............................................21 Peritoneal dialysis prescription..........................................22 Complications of peritoneal dialysis................................23 Peritoneal dialysis peritonitis..............................................24 Renal nutrition .........................................................................26 ACUTE KIDNEY INJURY ..............................................27 Differential diagnosis of acute kidney injury ................28 Management of acute kidney injury................................29 Continuous renal replacement therapy..........................31 CVVH prescription ..................................................................32 RENAL CONSULTS ..........................................................37 Chronic kidney disease .........................................................38 Microscopic haematuria.......................................................39 Kidney disease in the cancer patient ...............................40 Kidney disease in the HIV positive patient.....................41 Kidney disease in the patient with liver disease..........42 Kidney disease in the medical patient.............................43 Acute interstitial nephritis ...................................................45 Hypertension............................................................................46 Recurrent urinary tract infections .....................................50 Nephrolithiasis .........................................................................51 Renal side effects of common medications ..................54 Radiocontrast nephropathy................................................56 Nephrogenic systemic fibrosis ...........................................57 GLOMERULONEPHRITIS ...........................................59 Rapidly progressive glomerulonephritis ........................60 Nephrotic syndrome..............................................................61 Membrano-proliferative injury pattern...........................62 Systemic lupus erythematosus ..........................................63 TTP-HUS TMA syndromes ....................................................65 General treatment of glomerular disease ......................66 Treatment of lupus nephritis ..............................................67 Treatment of ANCA vasculitis .............................................68 Treatment of anti-GBM disease..........................................69

Treatment of cryoglobulinemic glomerulonephritis .70 Treatment of focal segmental glomerulosclerosis......70 Treatment of IgA nephropathy ..........................................71 Treatment of membranous nephropathy ......................72 Treatment of minimal change disease ............................73 Cyclophosphamide dosing..................................................74 Plasma exchange ....................................................................76 Immunosuppression prophylaxis .....................................77

ACID-BASE, FLUIDS & ELECTROLYTES ...........79 Hyponatraemia........................................................................80 Hypernatraemia.......................................................................83 Acid-base disorders................................................................85 TRANSPLANTATION .....................................................91 Evaluation of prospective renal transplant recipient.92 Evaluation of prospective living donor...........................93 Final pre-transplant assessment........................................95 Post-transplant maintenance immunosuppression...96 Induction agents in transplantation ................................97 Beaumont hospital immunosuppression protocol ....98 Antimicrobial prophylaxis....................................................99 Immediate post-operative management ....................100 Transplant clinic ....................................................................101 Allograft dysfunction ..........................................................103 The failing transplant and return to dialysis ...............104 CMV infection.........................................................................105 BK Polyoma virus ..................................................................106 Malignancy in the transplant patient............................107 Vaccinations in the transplant patient..........................108 Neutropenia in the transplant patient..........................108 Transplant rejection.............................................................109 The highly sensitised transplant patient......................112 OBSTETRIC NEPHROLOGY ...................................115 Physiologic changes of pregnancy ................................116 Hypertensive disorders of pregnancy...........................117 Management of kidney disease in pregnancy...........119 Pregnancy in the transplant patient..............................121 Pregnancy in the dialysis patient....................................122 PROCEDURES .................................................................123 Temporary dialysis access..................................................124 Kidney biopsy ........................................................................125 PATHOLOGY AND URINALYSIS .........................127 ADMINISTRATIVE ........................................................133 Division phone numbers and timetable ......................134


Haemodialysis

RENAL HANDBOOK 1


HAEMODIALYSIS

APPROACH TO THE DIALYSIS PATIENT Anticipate (preventive care) ...................................Vaccinate (HBV, flu, pneumococcal, HPV, VZV), fall risk, cancer screening Access.................................................................................Current access, venous pressures, status via recent fistulagram, bleeding, clotting, future plans Adequacy .........................................................................Dialyser type, time, Qb, Qd, URR, spKT/V, eKT/V Adverse effects of dialysis procedure ................Intradialytic HoTN, cramping, fatigue, headache Albumin (nutrition) .....................................................Weight, BMI, B vit, fluid restrict to 500ml/day + output, supplements Anions and cations ......................................................K+ (2 gm K+/day), Na+, HCO3 Anaemia............................................................................EPO, Iron, B12, Fol, Transfusions Antibiotics and medication .....................................Selected and dosed for ESRD, dosed with dialysis Arterial BP and fluid status......................................UF goal, Dry Weight, Anti-Hypertensives Arterial calcification (Ca-PO4-PTH-Vit D) ............PO4 Binders, Vit D, Cinacalcet Allograft............................................................................Evaluated? Listed? Potential living donors? Advance care planning..............................................Pt goals of care, resuscitation status

DRY WEIGHT “That body weight at the end of dialysis at which the pt can remain normotensive without antihypertensive medication, despite fluid accumulation, until the next dialysis.” How much fluid should I remove? Consider: Respiratory symptoms: Oxygen requirement / O2 Saturation PE: BP, HR, oedema, JVP, chest auscultation Weight gain since last dialysis In’s: IVF, TPN, NGT, PO. Out: Urine, stool output, vomiting, NG suction, 3rd Spacing

TIPS ON ACHIEVING DRY WEIGHT IN A HAEMODIALYSIS PATIENT 1. BP should remain in the normal range for the entire interdialytic period. If BP remains high after dialysis, or is elevated before the next session, a patient is above their dry weight by definition. 2. Long dialysis times may be required, particularly when determining the dry weight for the first time. Trying to achieve the necessary ultrafiltration over a short time causes HoTN, cramping and treatment failure. 3. Go slowly! It may take 3 months to achieve dry weight in a new dialysis pt. During this time carefully controlled persistent UF and a strict low salt diet are used, while BP medications are weaned off entirely. 4. It is essential that all BP medications be tapered down and stopped early in the process. Otherwise it will be impossible to achieve dry weight. 5. HoTN and cramping do not indicate a pt has reached dry weight but that they have hit their maximum refill capacity. If a pt remains hypertensive while experiencing such symptoms, longer dialysis times are indicated to achieve dry weight. 6. Be aware of the “lag phenomenon”. BP does not immediately change in response to changes in volume. BP may only normalise a few weeks after ECF volume has returned to normal. 7. Do not wait for obvious signs of volume overload (oedema, hypertension, etc.). Pay attention to small signs such as headache or slight increase BP at the end of a session. 8. Weight falls rapidly after initiating dialysis due to saline removal. However, weight should return to preinitiation levels after 1 year on dialysis due to muscle and fat build up, with BP now controlled. 9. Ambulatory BP monitoring is helpful in difficult cases, as it gives the best estimate of the true interdialytic BP, correlates best with target organ damage, and predicts all-cause mortality better than pre-dialysis BP. 2 RENAL HANDBOOK


HAEMODIALYSIS

INITIATION OF HAEMODIALYSIS IN CKD PATIENTS Timing of dialysis initiation is determined by clinical assessment. Early initiation does not appear to benefit the pt, whereas late initiation affords a mean of 6 months of dialysis independence (Cooper et al. NEJM 2010). However, it’s better to start a month too early than a day too late. In general GFR should be <9 ml/min before initiating, with 75% of pts having symptoms at 7 ml/min. The PEVACK indications below are clearcut indications.

P ericarditis (pericardial rub on examination). E ncephalopathy. V olume overload refractory to medical mgmt, or where treatment results in progressive uraemia. A norexia with nausea, weight loss. C oagulopathy with uremic bleeding. K HyperKalemia.

HAEMODIALYSIS ADEQUACY Measure Urea

URR

Concept

Limitations

Notes

Most abundant nitrogenous waste Time-averaged urea reflects dialytic Urea alone should not be used as product. Surrogate for small, clearance and protein intake, so a measure of adequacy. water-soluble uremic toxins. low values may reflect adequacy or malnutrition. = (Pre-urea – post-urea) x 100 Pre-urea

An underestimate as it ignores urea clearance through UF and urea generation during HD.

Standard measure of adequacy for inpts. Target 70%, minimum 65% unless significant residual function. The most important determinants of URR are Qb and time. Increasing Qd has small effect.

Single pool Kt/V K= urea clearance (ml/min). Not intuitive. T= length of dialysis in minutes. V= Vd of urea. Usually 55% of total body water in men and 50% in women. Kt/V= measure of urea clearance that takes account of pt’s size.

KDOQI target Kt/V 1.4, minimum 1.2 unless significant residual function. HEMO study showed no benefit of 1.7 vs 1.2. In general, dialysis times should not be tapered back to achieve ‘target Kt/Vs’, especially in smaller pts. Increased time and frequency of HD, independent of urea clearance, is probably beneficial.

Equilibrated Kt/V True clearances are actually lower More work than sp Kt/v. than is captured by sp Kt/V due to post-dialytic rebound in urea released from intracellular stores.

Same calculation as sp Kt/V, but posturea is drawn after a delay to allow equilibration of total body urea. This is the measure used in the HD unit to determine adequacy. RENAL HANDBOOK 3


HAEMODIALYSIS

HAEMODIALYSIS PRESCRIPTION Situation

Time

Qd

K

Ca

Notes

Standard

3-41â &#x201E;2 hrs, Min 300 to rarely 5 max 500 ml/min

500-800 ml/min

2 or 3 rarely 1 or 4

1.25 mmol/l, rarely 1.0 or 1.5 mmol/l

Standard dialysis bicarb = 35. Can adjust between 25 and 40.

2 hrs

500ml/min

As per serum K

1.25, 1.5 or 1.75 if pH or iCa low

May use Mannitol 75gms IV for each of 1st 3 runs and dialyse for 3-4 hours Check ionised calcium if pt is acidemic. Heparin-free dialysis.

Initiation

1st:

Qb

2nd: 3 hrs

200ml/min + F6 membrane 250 ml/min

500ml/min

3rd: 4 hrs

300ml/min

800 ml/min

Severe uraemia

Rule out significant pericardial effusion by physical examination by JVP/Pulsus/BP/CXR) prior to beginning. How to check for pulsus paradoxus: See below. If hyperkalemic, use 2K bath but keep Qb and Qd low. 0K baths are dangerous. If acidemic, check ionised Ca at the start and consider increase in dialysate calcium if low, as iCa will fall as bicarbonate increases, lowering seizure threshold. Uremic pericarditis = daily HD without anticoagulation. Follow prescription for initiation, even in ESRD pts.

Hyperkalemia

2 hrs

Highest possible

800

2

1.25 mmol/l

Additional HD may be needed the next day. Investigate cause of high K â&#x20AC;&#x201C; e.g. access recirculation

Isolated UF

2-3 hrs

Highest possible

N/A

N/A

N/A

UF rate up to 2 litres per hour as tolerated

Post-op transplant

2-3 hrs

~300

500

As per serum K

1.25 mmol/l

Must prevent intradialytic HoTN keep MAP >65 mmHg

Hypotensive

2-3 hrs

200-500

500

As per serum K

1.25-1.5 mmol/l

Cooled dialysate, high dialysate Na; pressors; isovolumetric priming; consider CVVH.

HOW TO CHECK FOR PULSUS PARADOXUS Inflate cuff 30mmHg above point at which brachial pulse becomes impalpable. Slowly deflate cuff, focussing solely on the Korotkoff sounds; there is no need to watch the pt's respirations. Note BP of first intermittent Korotkoff sounds, before a continuous heart beat. This corresponds to the higher systemic BP that occurs on expiration. Keep slowly deflating cuff until you reach the highest BP at which you hear a continuous heart beat. The difference between these 2 readings is the "pulsus paradoxus." A >10 mmHg drop suggests cardiac tamponade and an urgent ECHO to r/o effusion is required before initiating dialysis.

4 RENAL HANDBOOK


HAEMODIALYSIS

ANTICOAGULATION DURING INTERMITTENT HEMODIALYSIS Patient

Initial loading dose

Maintenance dose

Target a PTT

Normal bleeding risk

Tinzaparin 3500u

None

Not done

Increased bleeding risk or HD time < 3.5 hours

Tinzaparin 2500u

None

Not done

Very high bleeding risk, active bleeding, severe uraemia or new initiation

Rinse dialyser with 5000 to Intermittently rinse with normal saline. Keep 20,000IU UFH, flush Qb â&#x2030;Ľ250 mL/min if no other contraindication. system with 0.5-2L of saline.

No change from baseline.

HIT type II

Argatroban 250 mg/kg before HD

1.5-3 x mean of normal range

1.7 to 3.3 mcg/kg/ min (normal liver function)

UFH: standard unfractionated heparin

HAEMODIALYSIS ACCESS TYPES Access Type

Advantages

Disadvantages

Arteriovenous fistulae (wrist, elbow, or transposition)

Preferred dialysis access Once mature, excellent long-term primary patency (85% 1 year and 75% 2 year) Minimal infection rate.

Primary nonfunction rate ~30%. Maturation takes 1-4 months.

Polytetrafluoroethylene grafts

Easier to create surgically Maturation time of 2-3 weeks Large cannulation area and are easy to cannulate.

Poor primary patency rate (50% at 1 year and 25% at 2 years). Six fold higher intervention rate vs. AVF.

Cuffed double-lumen catheters

Can be used immediately after placement. Suitable bridge catheters while AVF matures.

Thrombosis and infection common High risk of permanent central venous stenosis or occlusion. Shorter lifespan than AVF or PTFE grafts. Low Qb = inadequate dialysis.

RENAL HANDBOOK 5


HAEMODIALYSIS

HAEMODIALYSIS LINE SEPSIS Frequency: 1-2 episodes/pt/yr for tunnelled catheters (Allon;AJKD 04;44(5):779). May be asymptomatic or atypical (e.g. present with GI bleeding or diarrhoea), so consider blood cultures in all HD pts upon hospital admission. Consider false-negative blood cultures in pts who respond clinically to empiric Ax. All pts with suspected line sepsis should be evaluated clinically for metastatic infection. Investigate specific complaints with imaging (e.g. back pain =MRI) and perform additional workup if bacteremia confirmed (e.g. TOE). Antibiotic lock = instillation of Ax and anti-coagulants into catheter after each dialysis session, as adjunctive therapy along with systemic Ax. Reported success rate ~50-70%. Surveillance blood cultures should be sent 7 days after Ax course is complete.

KEY FACTS REGARDING HAEMODIALYSIS LINE SEPSIS 1.

Fever and chills are highly predictive of positive blood cultures in dialysis pts with tunnelled cuffed catheters: ~75% of episodes=+blood cultures (Krishnasami;KI 02;62:1136). Therefore, empiric antibiotic therapy is required in all febrile dialysis pts with tunnelled catheters.

2.

Although the majority of episodes result from Staph species (~60%, often Methicillin resistant), a significant minority are due to GNRs (30-40%), with the remainder mixed bacterial or fungal. Therefore, empiric antibiotic therapy must include coverage for GPCs and GNRs: e.g., Vancomycin 1-2 gram IV qHD and Gentamicin 1-2 mg/kg IV qHD. For subsequent dosing see page 8.

3.

Over half of pts with confirmed MSSA bacteremia are treated with Vancomycin. However, switching from Vancomycin to Cefazolin qHD once MSSA is confirmed results in a 40% reduction in mortality (Chan et al;JASN September 2012). Flucloxacillin is an alternative, although qHD dosing of Cefazolin makes it preferable. Therefore, adjust therapy in light of index culture results.

4.

Systemic antibiotic therapy without additional catheter mgmt fails to clear infection in ~70% of cases. Marr;AIM 97;127:275. Therefore, catheter management is required: a. Remove catheter and replace at later date; use temporary access in interim. b. Change catheter over guide-wire (Tanriover;KI 00; 57:2151; Beathard;JASN 99;10:1045); c. Attempt catheter preservation with antibiotic â&#x20AC;&#x2DC;lockâ&#x20AC;&#x2122; technique (Krishnasami;KI 02;62:1136).

6 RENAL HANDBOOK


HAEMODIALYSIS

MANAGEMENT OF HAEMODIALYSIS LINE SEPSIS Infection Type Catheter-Related Bacteremia suspected AND pt is haemodynamically stable without signs of systemic infection.

Symptoms/Signs

Management

Fever and Chills.

1. Blood cultures and initial empiric IV Ax: Vancomycin 1-2 gram loading dose, then 1g IV qHD and Gentamicin 1 mg/kg IV qHD. For further details on Vancomycin and gentamicin dosing in ESRD, see next page page 10. 2. Use catheter for dialysis pending culture results. 3. If clinically improved (afebrile within 24-48 hrs of Ax) and low risk organism (Staph Epi), exchange catheter over guide-wire electively 4. If cultures grow high risk organism (e.g. S. Aureus, fungus), or symptoms last >48 hours, remove catheter and replace 3-5 days later. 5. Antibiotic course is for 2-3 weeks. 6. Outpt mgmt if stable; signs/symptoms of systemic infection develop, see below.

Catheter Related Bacteremia suspected AND pt has signs of sepsis

High fever, shaking chills, 1. Blood cultures and stat empiric IV Ax (see above) rigors, HoTN, hypothermia, 2. Remove catheter ASAP. Ongoing dialysis may be completed before hypo- or hyperglycemia, altered removal, based on clinical judgment. Place temporary catheter mental status, lethargy, 3. Replace tunnelled catheter at new site when blood cultures nausea/vomiting. negative x 48 hrs and pt is clinically improved. 4. Antibiotic course: 3 weeks or longer depending on organism/response.

Exit Site Infection

Purulent drainage, erythema, warmth at exit site +/- fever and signs of systemic illness.

1. Send cultures from exit site and blood. Mild infections can be treated with PO or topical Ax. More serious infections require IV Ax x 7-10 d. 2. In pts with fever, signs of systemic infection or persistent local infection, remove catheter and treat for 2-3 weeks

Tunnel Tract Infection

Tenderness between cuff and central vein entry point.

1. Send cultures from exit site and blood. Begin IV Ax with planned 3 week course. 2. Remove catheter, replace at new site when blood cultures are negative x 48 hours.

RENAL HANDBOOK 7


HAEMODIALYSIS

INTRAVENOUS ANTIBIOTIC DOSING IN HAEMODIALYSIS PATIENTS VANCOMYCIN 1.

All pts receive an initial weight-based loading dose:

Weight

Intravenous Vancomycin Loading Dose

<60kg

1000mg in 100mls 0.9% N/S over 60 mins.

60-90Kg

1500mg in 250mls 0.9 % N/S over 90 mins.

>90Kg

2000mg in 250mls 0.9% N/S over 120 mins.

2. 3.

After this loading dose, all pts receive a maintenance dose of 1g in 100mls 0.9% saline over 60 mins in the last hour of each dialysis. Subsequent doses are then adjusted based on levels from the prior dialysis session. All Vancomycin levels are taken pre-dialysis and target levels are 15 â&#x20AC;&#x201C; 20.

Level from prior HD

IV Vancomycin dose to be administered

>25

Omit next dose and review dosage.

20 -25

Reduce dose to 750mg IV Vancomycin.

10-20

Continue routine dose of 1g.

<10

Check timing of levels and confirm dose was given. Increase dose by 500mg.

GENTAMICIN 1.

Pts receive an initial loading dose based on their estimated GFR:

GFR ml/min

Intravenous Gentamicin Loading Dose

>50 ml/min

5mg/kg; total dose not to exceed 500mg.

30-50 ml/min

3mg/kg.

10-30 ml/min

2mg/kg.

ESRD (<10 ml/min)

1-2 mg/kg.

2. 3. 4. 5. 6. 7.

Trough levels must be taken 16 hours after the FIRST dose. Hence the best time to give subsequent gentamicin doses is 4pm, as levels need to be drawn at 8am. Gentamicin is only re-dosed when 16-hour trough < 1mg/L. If 16-hour trough > 1mg/L, follow daily levels until < 1mg/L and then lower the subsequent dose by at least 1 mg/kg. Once a dose has been established that achieves goal 16 hour troughs, repeat levels should be checked twice per week and noted on drug Kardex before re-dosing. Once daily dosing is preferred, as it causes less nephrotoxicity N-acetyl cysteine may prevent, or attenuate, aminoglycoside induced ototoxicity (Feldman Kidney Int. 2007 Aug;72(3):359-63; Tokqoz Nephrol Dial Transplant. 2011 Dec;26(12):4073-8).

8 RENAL HANDBOOK


HAEMODIALYSIS

NON-INFECTIOUS COMPLICATIONS OF HAEMODIALYSIS ACCESS Complication Limb swelling Catheter dysfunction

Mechanism

Notes

Commonly due to central vein stenosis but can Perform a venogram of proximal veins if prior ipsilateral CVC or also be due to venous valvular incompetence. dilated chest wall veins prior to AVF surgery. Fibrin sheath+/- thrombosis. Presents as poor Treat with thrombolysis. Initially use alteplase dwell in ports x 1 flows (<300 ml/min), inability to aspirate hour, repeat x 1. If this fails, use infusion: 2.5mg actilyse in 50ml heparin, high venous pressures at Qb < 0.9% NaCl @ 17ml/hr x 3 hours into each port of the catheter. 200ml/min, frequent alarms.

AVF aneurysm or True aneurysm: contains all layers of vessel wall pseudoaneurysm Pseudoaneurysm: focal disruption of the vessel wall with collection of blood outside the vessel wall contained by fibrous tissue; result from repeated cannulation in the same area.

Pseudoaneurysms a problem with grafts as material deteriorates with time. Obtain urgent evaluation by vascular surgery if: (1) Poor scab formation after needle removal (2) Spontaneous bleeding from access sites (3) Rapid expansion in pseudoaneurysm size (4) Exposed graft.

Neuropathy

Median nerve dysfunction in long-term dialysis Vascular access may contribute to problem by compression of pts due to local amyloid deposition, leading to median nerve due to the extravasation of blood or fluid or by carpal tunnel syndrome. ischemic injury from a steal effect (ischemic monomelic neuropathy)

Limb ischaemia

Reduced perfusion of distal extremity due to steal of arterial blood flow into the AVF. Symptoms often worsen during dialysis sessions. Physical examination alone not accurate: low threshold for duplex ultrasound.

Presents days after graft placement or weeks after AVF placement (matures later). Absent pulse, cold extremity = surgical ligation to prevent permanent injury. Paraesthesias / coolness with retained pulses: improves over weeks as collateral blood flow develops.

Heart failure

(1) increased cardiac output. (2) decreased systemic PVR. (3) increased sympathetic activity contractility, HR and SV. (4) increased blood volume, ANP, BNP and LVEDV. (5) increased pulmonary flow and pressure.

Access-related decompensation rare, even if underlying cardiac dysfunction. In NYHA III / IV HF, consider PD over HD. If PD not possible, forearm AVF (NYHA III) or CVC (NYHA IV) preferred. Before tying off, AVF salvage may be attempted by distalisation of the anastomosis. Banding may be tried, although often leads to access loss.

Thrombosis

Underlying venous stenosis due to neo- Commonest site of stenosis in wrist AVF is the anastomosis; for intimal hyperplasia in >90%. elbow AVF most stenoses occur in a proximal vein. 80% of PTFE graft dysfunction is due to thrombosis superimposed on stenosis. For suspected acute graft thrombosis, arrange urgent Duplex and call IR at 4712.

Access recirculation

Dialysed blood re-enters the extracorporeal circuit through the arterial needle, rather than entering the systemic circulation. Reduces the efficiency of dialysis. Suggests underlying high-grade venous stenosis leading to access thrombosis. % recirculation= ([P-A]รท[P-V]) x 100, where P, A, and V = [urea] peripheral, pre-dialyser arterial and post-dialyser venous blood, respectively.

Errors arise in the determination of the systemic urea concentration d/t AV and VV disequilibrium. Recirculation >10 % abnormal= Fistulography should be performed in these settings. Suspect if discrepancy between prescribed and delivered Kt/V, and/or inadequate URR. Sometimes due to inadequate arterial inflow and improper needle placement. With catheters, recirculation may be caused by reversing the line ports. RENAL HANDBOOK 9


HAEMODIALYSIS

DIALYSING TOXINS Toxin Methanol

Anion Gap* +ve

Osmolar Clinical Gap** ++ Altered MS, visual complaints, N, V.

HD if...

Other

Notes

Metabolic acidosis. MeOH >200500mg/L. Visual Δ’s.

Fomepizole Heparin free HD – cases B vitamins: Thiamine, of basilar infarct Folate, Pyridoxine. progressing to haemorrhage.

Ethylene glycol

+ve

+

Altered MS, HoTN, Acidosis. Fomepizole Urinary calcium oxalate hypocalcaemia, flank Renal Failure. B vitamins: Thiamine, crystals pain, haematuria, AKI EtGly>200 -500mg/L. Folate, Pyridoxine. (see page 128) Urine, mouth or clothing may fluoresce under Wood’s lamp b/c fluorescein added to antifreeze.

Aspirin

+ve

0

Altered MS, hyperventilation, tinnitus, N, V, pulmonary oedema.

Level >1000 mg/L, altered MS, pulm oedema, renal failure (impairs excretion).

Volume resuscitation, Rising levels may alkalinisation, warrant dialysis activated charcoal and regardless of absolute #. glucose.

Lithium

-ve

0

Tremor, ataxia, V, diarrhoea, seizures, coma.

Li > 4 mmol/L or > 2.5 mmol/L with AKI, CNS or cardiac Sx. Lower levels more toxic in chronic users. Large Vd so long HD required (6°).

HD or supportive. Levels should be repeated 6-12 hourly, and HD continued until levels consistently < 1mmol/l.

Theophylline

N

0 0

Seizures, HoTN, arrhythmias.

Sz, low BP, arrhythmia Haemoperfusion more Lower threshold to start >100mg/L (acute) effective than HD dialysis if age >60 or >60mg/L (chronic). (due to >50% protein comorbidities. binding) .

Metformin

+ve

Lactic acidosis.

Severe acidaemia.

Supportive or HD.

Saline can cause hypernatremia if underlying nephrogenic DI; use hypotonic fluids. CNS symptoms can be permanent so low threshold for HD.

Unclear if improvement results from removal of Metformin or correction of acidosis.

FOOTNOTES: *Anion Gap = [Na]-[Cl+HCO3], range 8-12 **Osmolar Gap = Measured – Calculated plasma Osmolarity, normal <15. Haemodialysis: effective for removing small, water-soluble toxins with minimal protein-binding, low lipid solubility and small volumes of distribution. Commonest intoxications requiring HD: Li+ (31% of cases), EG (25%), salicylates (17%), Valproate (6%), paracetamol (6%: despite no efficacy), methanol (5%), ethanol (3.5%), benzodiazepines (3.5%) Non-dialysable toxins: TCAs, CCBs, paracetamol, digoxin, phenytoin.

10 RENAL HANDBOOK


HAEMODIALYSIS

RENAL ANAEMIA Causes of Anaemia in ESRD/CKD (1) relative erythropoietin deficiency; (2) true iron deficiency; (3) hepcidinmediated functional iron deficiency; (3) cytokine mediated functional iron deficiency

IRON DEFICIENCY IN CKD AND ESRD Nearly all CKD and ESRD pts are anaemic and most are iron deficient or functionally iron deficient. Even with an Hgb of 11 mg/dL and adequate iron stores (with normal haemoglobin being 15 g/L), the pt is still 1 g iron depleted. Each unit of blood should raise the haemoglobin by 1 mg/dL and each unit contains approximately 250 mg of iron. True iron deficiency is common in CKD/ESRD due to poor gastrointestinal iron absorption, blood loss from HD and phlebotomy (which accounts for 1.5–2 gm iron lost / year) and the high incidence of GI bleeding. Work-up (e.g. OGD and/or colonoscopy) is indicated for dialysis pts with newly diagnosed Fe deficiency. Functional iron deficiency is also common in ESRD and is associated with infection and inflammation. It appears mediated by Hepcidin, a 24 amino-acid peptide which blocks iron absorption and transport, although this has not emerged as a useful marker clinically. Iron Therapy is indicated in CKD / ESRD pts who qualify for Epo if Fe parameters below goals: Goal TSAT=2050%, goal ferritin >200. If ferritin is >500-800, consider holding iron due to functional RES-iron blockade (KDOQI Anaemia Guide-lines). Vitamin C has also been used to treat functional iron deficiency (Wingard; AJKD 95;25:433; Giancaspro;J Nephrol 2000;13:444). Potential risks of intravenous iron administration include (1) infection (Teehan;CID 04; 38:1090); (2) increased oxidative stress; (3) increased CV disease risk (‘Sullivan Hypothesis’- Hu;JAMA 07;297:639); (4)iron overload--avoid in liver disease; (5) exacerbation of rheumatoid arthritis. If increasing Epo dose requirement or Hb falling despite EPO: Consider dialysis adequacy (see page 3), disease reactivation/inflammation (CRP/ESR), infection (blood cultures), malignancy (Exam +/- radiology), new haemolysis (Film, LDH, Haptoglobin, Coombs), GI loss (OGD/Colonoscopy).

IRON PREPARATIONS Preparation

Notes

Iron sucrose (Venofer)

Mostly used in HD pts. Dose for dialysis: 200 mg IV qHD x 10 doses. Dose for CKD: 3 doses of 300mg / 300mg / 400mg, each over 2.5 hrs.

Ferric carboxymaltose (Ferinject)

Advantage: may be given IV undiluted solution up to 1g iron (up to max 15 mg/kg body weight). For doses of 200 to 500 mg iron, max rate of 100 mg/min. Often used pre-ESRD, in CAPD pts or pre-discharge in recent transplant recipients.

PO Iron

Poorly absorbed in ESRD but nonetheless is the mainstay in peritoneal dialysis pts. Administer on empty stomach. Many breakfast cereals fortified with significant amounts of iron. Do not use oral iron post-transplant as it may bind to Mycophenolate and other drugs, is not very effective, and is associated with gastrointestinal side effects.

RENAL HANDBOOK 11


HAEMODIALYSIS

RENAL ANAEMIA CONTD. ERYTHROPOESIS STIMULATING AGENTS (ESAâ&#x20AC;&#x2122;S) Aspect

Notes

Efficacy

Prior to Epo, iron overload and hepatitis B infections from repeated transfusions were nearly universal among dialysis pts. Epo reduces hospitalisations, length of stay, transfusion rates and LVH, which were commonly seen with severe anaemia prior to ESAs. (Fellner;KI 93;44:1309). However, complications with Epo therapy have emerged (TREAT trial).

Complications

(1) CV events and death: increased risk of fatal or nonfatal CVA from Hgb 13 vs. 9 gm/dL (TREAT Pfeffer NEJM 09;361;2109). (2) HTNâ&#x20AC;&#x201D;including intra-dialytic; dose-dependent. (3) Graft thrombosis. (4) Seizures. (5) Pure Red Cell Aplasia (>300 cases in 1998-2002 from EPREX). Total weekly doses >20,000 units are associated with adverse outcomes, independent of Hgb level.

Resistance

(1) inflammation/infection; (2) blood loss; (3) iron deficiency; (4) bone marrow failure; (5) haemolysis; (6) aluminium toxicity; (7) haemoglobinopathies; (8) Folate/B12 deficiency; (9) Hyperparathyroidism.

Timing of introduction

Must be individualised. Non-dialysis pts with CKD and symptoms attributable to anaemia, consider starting Epo when Hgb <10 g/dL.

Maintenance

Maintain Hgb levels between 10 and 12g/dL. Higher target Hgb levels are associated with adverse outcomes in prospective RCTs.

Preparations

Epoetin beta (Neorecormon). Starting dose 40U/kg qHD. Typical dose 2000-10,000 U qHD Epoetin theta (Eporatio): Can switch from maintenance treatment with epoetin beta to epoetin theta without change in dose. Darbepoetin (Aranesp): Longer T1/2 due to extra glycosylation. Dose conversion: Epo <10K. U/wk=Aranesp 25/wk Epo 11k-18k/wk = Aranesp 40/wk Epo 18k-34k. U/wk=Aranesp 60/wk Epo 34k-90k=Aranesp 100/wk. Epo>90k/wk=Aranesp 200 units/wk.

12 RENAL HANDBOOK


HAEMODIALYSIS

MINERAL BONE DISEASE: PHOSPHATE, PTH AND CALCIUM PHOSPHATE IN KIDNEY DISEASE  Average dietary intake: 300-500 mmol/day. GI absorption is ~60% of intake (increases to 80% with active Vit D). Phosphate from plants is poorly absorbed because it is stored as Phytate, which humans cannot metabolise. Phosphate in meats & processed foods is easily metabolised and absorbed. Serum phosphate in children is 2.26 mmol/l, which falls to adult range during adolescence.  As GFR falls, filtered phosphate falls. Compensatory mechanisms (increased PTH/FGF23) result in less renal phosphate reabsorption, thus hyperphosphataemia is typically not seen until GFR <25-30 ml/min.  Hyperphosphataemia in ESRD likely causes secondary hyperparathyroidism and extraskeletal calcifications and premature vascular disease.  Dialysis removes approximately 250 mmol of phosphate in 4 hours, equivalent to average daily intake. Unlike urea removal, phosphate removal is dependent primarily on dialysis time, not serum phosphate concentration (due to large intracellular stores).  To prevent positive phosphate balance in ESRD pts: (1) dietary phosphate must be reduced even as adequate dietary protein is maintained; (2) phosphate binders are required (see below). K-DOQI treatment goals for serum phosphate in CKD: Stage 3 – 4=~0.9 – 1.5 mmol/l. Stage 5=1.1 – 1.8 mmol/l.  Convert U.S. to S.I. units by multiplying by 0.3229.

ORAL PHOSPHATE BINDERS Complication Calcium carbonate

Mechanism 500-1500mg tds with meals (3-6 tabs)

Notes Cheap.

Results in calcium absorption, extra-osseus calcification. Constipation. PPIs impair phosphate control when given with calcium-containing binders.

Calcium acetate 500mg – 1500mg PO tds Less calcium absorption than CaCO3. As above. with meals. Many avoid doses >1500 mg tds Sevelamer HCl (Renagel)

0.8-3.2g with meals

Sevelamer CO3 (Renvela)

Same; powder available Same.

Expensive; few studies. Less acidosis.

Lanthanum carbonate

0.5-1.25g/meal

Non-calcium; chewable.

Chalky, big tablet. Can be crushed and sprinkled on food. Avidly binds phosphate across pH range. No long term data. Abnormal abdominal plain film.

Mg hydroxide

2 tabs with meals

Cheap.

Hypermagnesaemia. Diarrhoea. 3rd line.

Aluminium hydroxide

30mls TID for max 4 weeks in lifetime

Effective but toxic. Reserve for crises. Aluminium toxicity.

Fe-Mg-hydroxycarb 1-2g TID

Lowers LDL; maybe less vascular calcification.

Non-calcium.

Expensive. Acidosis. PPIs may improve control when given with non-calcium containing binders. Being phased out for Renvela. Binds cholesterol in gut.

In phase 2 trials.

RENAL HANDBOOK 13


HAEMODIALYSIS

MINERAL BONE DISEASE: PHOSPHATE, PTH AND CALCIUM CONTD. PTH IN KIDNEY DISEASE PTH’s major actions are on bone (increases resorption) and kidney (increases Ca reabsorption, Pi excretion and 1-alpha-hydroxylase activity and thus 1,25 Vit D production). PTH does not act on the intestine. The primary regulator of PTH secretion is the ionised Ca level: the lower the iCa, the higher the PTH. Renal failure results in secondary hyperparathyroidism (SHPTH) & parathyroid gland hyperplasia due to: (1) hyperphosphataemia, (2) hypocalcaemia, (3) 1,25 Vit D Deficiency, (4) PTH resistance at level of bone. Tertiary hyperparathyroidism occurs when the parathyroid gland is no longer under the control of the iCa. Typically raised PTH with a high calcium. PTH is an (imperfect) surrogate of bone status in CKD/ESRD:  High PTH (>500) = likely high turnover bone disease (aka Osteitis Fibrosa Cystica): usually low serum calcium and increased risk of fractures.  Intermediate PTH (100-500) = may be high or low turnover or both (‘Mixed Osteodystrophy’)  Low PTH (<100) = low turnover ‘adynamic’ bone disease, decreased bone buffering capacity, higher serum calcium and higher risk of extraskeletal (metastatic) calcification. It is currently the most common ESRD bone disease. Osteomalacia is rarely seen in HD pts anymore; it was more common in the past in association with aluminium toxicity. Regression of parathyroid hyperplasia is a very slow process: parathyroid cells have a very low natural rate of apoptosis (cell t ½ >30 years). Intact PTH assay (iPTH) measures the 1-84 hormone and fragments (7-84 etc) with reduced or even inhibitory biologic activity. The superiority of other assays which measure just 1-84 remains unproven.

MEDICAL MANAGEMENT OF SECONDARY HYPERPARTHYROIDISM (high PTH, low/normal calcium) Name/Type

Use/Mechanism

Typical Dose

Cholecalciferol = Correction of 25(OH) 400-800 U /day. VitD3, animal form Vit D deficiency Calcitriol (Oral 1,25(OH) Vit D3)

Vit D receptor antag 0.25 – 0.5 mcg po daily. (VDRA). Suppress PTH gene transcription.

Paricalcitol VDRA: Suppress PTH PO: 1-2 mcg/day or (Zemplar) = 19-nor- gene transcription. 2-4 mcg qHD IV: Start with 0.04 – 0.1 1,25(OH) Vit D2 mcg/kg IV qHD. Increase by 2-4mcg/HD q 2-4 weeks to achieve PTH 150-300. Cinacalcet (Mimpara) = calcimimetic

14 RENAL HANDBOOK

Increases sensitivity of calcium sensing receptor (CaSR) to Ca and decreases PTH release.

Ca/Pi Levels

Notes

Increase.

Better absorbed than D2 but high doses are not available. (Wanner;NEJM 05;353:595).

Increase.

IV form (Calcijex) different than PO pharmacologically and rarely used.

In IV form has least effect on Ca/Pi of all available compounds.

Plant form of Vit D with 19 Carbon group removed. IV form is associated with mortality benefit in HD pts (Teng;NEJM03;349:446) thus some nephrologists use 1-2 mcgs qHD even when PTH <150. Also in PO form.

30 mg daily. Increase in 30 Decrease Used in tertiary hyperparathyroidism only. mg increments q2 weeks to (monitor calcium, Avoid in early CKD as causes hypercalciuria. 60- 90 mg bd max. increase dose 20% less CV events in EVOLVE RCT in ageslowly). adjusted analysis.


HAEMODIALYSIS

MINERAL BONE DISEASE: PHOSPHATE, PTH AND CALCIUM CONTD. SURGICAL MANAGEMENT OF TERTIARY HYPERPARTHYROIDISM (high PTH, high calcium) Investigations Sestamibi scan. 4 glands light up (if one = parathyroid adenoma â&#x20AC;&#x201C; needs surgical excision). May be negative if already on Cinacalcet. Surgery

Sub-total or total parathyroidectomy is preferred (NICE guidelines due to cost). Give one alfacalcidol 5mcg OD for 5 days prior to surgery to reduce risk of hypocalcaemia from hungry bone syndrome and continue post-operatively until calcium within the normal range.

VITAMIN D IN KIDNEY DISEASE Aspect

Notes

Major actions Major actions of vitamin D are on intestine (increases Ca and Pi absorption), parathyroid gland (decreases PTH gene transcription) and bone (increases sensitivity to PTH). Vit D does not act on the kidney. Review: Holick;NEJM 07;357:266. Deficiency

Common in the general population, especially in northern climates and in the setting of sun-block use.

Receptors

Vitamin D receptors are widely distributed in humans, suggesting a broad physiologic role for Vit D beyond bone health. Epidemiologic data links Vit. D deficiency to autoimmune disease, malignancies, hypertension/RAAS activation and other conditions.

Formulations

Vit D3 (Cholecalciferol) is produced by animals and in the skin of humans in response to UV light. Vit D2 (Ergocalciferol) is produced by plants and used in the U.S. to fortify to milk and other foodstuffs. It is the least expensive and most common form of replacement therapy and substitutes for Vitamin D3. 25(OH) Vit D (D2 or D3) is the storage form of Vitamin D. It has a long half-life and is the best indicator of overall body stores. In large quantities, 25(OH)Vit D can cross react with 1,25 receptors and cause Vit D toxicity. 1,25(OH) Vit D (D2 or D3) is the active form of Vitamin D. Levels vary on diurnal basis and there are few clinical indications to measure 1,25(OH) Vit D levels in ESRD/CKD; in addition, the assay is less reliable than the 25-D assay.

Vitamin D in ESRD

ESRD pts are commonly deficient in both 25(OH) Vit D (due to underlying Vit D deficiency) and in 1,25 (OH) Vit D. 1,25(OH) Vit D deficiency results from (1) reduced 1-alpha hydroxylase activity. Traditionally attributed to low renal mass and hyperphosphataemia but also due to high levels of FGF-23, a phosphaturic hormone (Gutierrez;JASN 05;16:2205); (2) decreased filtration of 25D+binding protein, resulting in less 1,25 production; (3) deficiency of the substrate 25(OH) Vit D. Nephrotic pts lose Vit D binding protein (59 Kd) in urine and may need large supplementation.

RENAL HANDBOOK 15


HAEMODIALYSIS

COMPLICATIONS OF ESRD CARDIOVASCULAR COMPLICATIONS OF ESRD Complication Hypertension

Pathophysiology

Management/Pearls

(1) Hypervolemia (2) adrenergic system / sympathetic amines (3) endothelium derived substances, (4) Hyporenin-Hyperaldo, (5) EPO, (6) SHPTH/high Ca.

>80% of ESRD pts have HTN (Agarwal;Am J Med 03;115: 291). Optimal BP in ESRD is unknown. Mgmt: (1) Meds addressing sympathetic and RAAS; (2) challenge dry weight; (3) hold or reduce EPO dose; (4) life style modifications; (5) Switch to PD.

Sudden death / arrhythmias

LVH, LV dysfunction, electrolyte abnormalities (Bleyer;KI 06;69:2268).

Rate of sudden death X100 times general population. Prevent with Carvedilol (Cice; JACC 03;41:1438) +/- spironolactone (Gross AJKD), ICD devices, beware medications which prolong QT interval.

LV hypertrophy and dilatation

Pressure and volume overload from anaemia, LVH seen in 75% of incident dialysis pts (Foley;AJKD vascular stiffness with resultant pulse wave 98;32(S3):S112) —~½ concentric, ½ eccentric. Both forms reflection. associated with CHF. Mgmt: volume and anaemia control, control ischemia.

CHF

With preserved or reduced EF. Reflects high Most CKD pts excluded from 3 major trials of B-Blockers and CHF. incidence of HTN, CAD and LVH, with resultant Carvedilol associated with improved outcomes in HD/CHF myocardial fibrosis. (Cice;JACC 03; 41: 1438). AVF/AVG can lead to high output CHF.

Atherosclerotic Multifactorial: high incidence of hypertension, vascular disease diabetes plus uremic toxins, lipid abnormalities, endothelial abnormalities, inflammatory state and oxidative stress, high Ca-Pi product.

CAD present in 40% of ESRD pts (Foley;AJKD 98;32(S3):S112). Troponin elevations can reflect reduced GFR but are associated with worse outcome (Havekes;AJKD 06;47:823) 4D and AURORA trials= similar risk reduction in non-fatal CV events to gen. Pop, but no mortality benefit to statins in diabetic ESRD pts (Wanner;NEJM 05;353:238).

Valvular abnormalities (Aortic & mitral calcification)

Ectopic calcification, uremic milieu.

Pericardial effusions

‘Uremic’ (pre-ESRD) or ‘Dialysis Associated’. Anterior and Circumferential effusions associated with tamponade Haemorrhage due to platelet dysfunction, anti- during dialysis. Mgmt: intensify dialysis, avoid anti-coagulants, coagulants. drain, pericardial glucocorticoid injections (Rutsky;AJKD 87;10:2).

Arterial stiffness Medial vascular calcification, HTN.

Incidence and rate of progression of AS increased in CKD/ESRD (London;JASN 00;11:778). Coumadin inhibits matrix – gla protein and may accelerate calcifications. Valvuloplasty outcomes worse. Metal valve preferable to tissue d/t rapid recalcification.

Pulse Wave Velocity is the best single predictor of CV risk in ESRD pts.

Pulmonary artery All causes, plus air emboli from HD circuit, or Compromises transplant candidacy. Must dialyse to true EDW hypertension emboli from AVF procedures. before diagnostic right heart cath (false +ve).

16 RENAL HANDBOOK


HAEMODIALYSIS

COMPLICATIONS OF ESRD CONTD. DERMATOLOGIC COMPLICATIONS OF ESRD Complication

Management / Pearls

Pruritis

Multifactorial. Manage with (1) Phosphate/PTH mgmt (2) Replete IV iron (3) Sun exposure or UVB phototherapy (4) Lanolin cream (5) Anti-Histamines (6) D/c heparin.

Nephrogenic systemic fibrosis (Nephrogenic Fibrosing Dermopathy)

Symmetrical, bilateral fibrotic, indurated papules, plaques or subcutaneous nodules occurring 2 months to 15 years post gadolinium exposure in ESRD and advanced CKD. Lesions start in the hands, feet and ankles and move proximally. Rarely are lesions found on the abdomen and the head is spared. Lesions are oedematous and may look like cellulitis initially. Sharp pain, pruritis and burning are also a feature. Joints lose flexibility due to fibrosis. Mortality of 28%. Case reports of improvement with Imatinib for systemic disease. Avoid gadolinium when GFR < 30 ml/min.

Calciphylaxis (‘Calcific Uremic Ateriolopathy’)

Occurs in 1-4% of dialysis pts. Involves widespread calcification of the small vessels of dermis and subcutaneous tissues (Wilmer;Semin Dial 02;15:172) with subsequent thrombosis, tissue ischaemia and skin necrosis. Presents as very painful , well defined, deep violaceous reticulated plaques, progressing to deep non-healing ulcers that can become gangrenous. Risk factors: Hyperparathyroidism, elevated Ca-PO4 product, DM, female, obesity, warfarin, protein C or S deficiency. Prognosis: 1-year survival is 50% with most dying from sepsis. Treatment: Low phos diet, normalizing Ca and phos with non-Ca binders and low-calcium dialysate. Sodium thiosulphate 25g VI over 30 minutes qHD has been shown to improve lesions and should be continued for 2 months beyond resolution of lesions.

Calcinosis cutis, nodular calcification and tumoural calcinosis

Metastatic calcification syndromes. Ca deposition in skin presenting as painless flexural infiltrating plaques at peri-articular sites, occurring in 1% of dialysis pts. The size and number of plaques correlate with degree of hyperphosphataemia. Unlike calciphylaxis this disorder does not cause skin necrosis. Risk factors include low albumin, high phosphate, high alkaline phosphatase and morbid obesity. Normalisation of Ca and phos can causes regression.

Perforating skin disorders

Includes Perforating Folliculitis, and ‘Kyrle’s Disease.

Bullous disorders

Includes Porphyria Cutanea Tarda and pseudoporphyria.

Beta-2 microglobulin amyloidosis

Clinical triad: Arthritis, Carpal Tunnel Syndrome, Bone Cysts (spares skin). Becoming rare in era of high flux dialysers.

Porphyria Cutanea Tarda (PCT)

Uroporphyrinogen accumulation causes phototoxic rash: fragile skin, blisters, vesicles and bullae in sun exposed, esp. dorsum of the hands, sclerodermoid changes, hypertrichosis, hyperpigmentation and pruritis. Abnormal LFTs distinguishes from pseudoporphyria. RFs in ESRD: Iron overload and inability to excrete porphyrin precursors. Incidence in ESRD 1-18%. Diagnosis: fractional levels of plasma porphyrin precursors. Treatment: phlebotomy and avoid sun. Higher doses of ESA are required to avoid anaemia. Chloroquine may help.

Pseudoporphyria (syn. bullous dermatosis of ESRD)

Same presentation as PCT, but no sclerodermoid changes or hypertrichosis. Normal LFTs distinguishes from PCT (baseline plasma uroporphyrin increased in ESRD). Associated with UV exposure, diuretics, NSAIDS, Ax, antifungals (voriconazole), retinoids, finasteride, imatinib. Treatment: removal of offending drugs and N-acetylcysteine. May take months to improve. RENAL HANDBOOK 17


HAEMODIALYSIS

COMPLICATIONS OF ESRD CONTD. ENDOCRINE COMPLICATIONS OF ESRD Complication

Management / Pearls

Infertility/ Menstrual abnormalities

50% amenorrhoeic and <10% have regular menses. High incidence of anovulatory cycles. Hyperprolactinaemia is also common (Palmer;JASN 99;10:1381).

Pregnancy

Pregnancies difficult to date as urine and serum B-HCG both unreliable.

Erectile dysfunction

Present in as many as 50% of men with ESRD. Responds to PDE inhibitors.

Goitre

TSH & T4 usually normal. T3 reduced due to reduced peripheral conversion.

Slow growth

Growth Hormone (GH) and IGF1 levels elevated but growth delayed responds to exogenous GH administration.

Cushing’s

Can't use 24 hour cortisol to diagnose, use dexamethasone suppression test.

Hypothermia

Very common in ESRD, temperatures >38◦C are suspicious for infection.

NEUROLOGIC COMPLICATIONS OF ESRD Complication

Management / Pearls

Neuropathies

Common, from diabetes and uraemia, manifest as paraesthesias, decreased sensation, sexual dysfunction, presyncope, postural HoTN.

Restless legs

Pt may complain primarily of pain. Mgmt: (1) assess, optimise dialysis adequacy, (2) treat iron deficiency if present, (3) dopamine agonists Ropinirole or Pramipexole, (4) Clonazepam.

Pain

~50% of ESRD pts experience chronic pain, of varying and often unknown etiology, with large impact on quality of life (Kimmel:AJKD 03;42:713). Responds to analgesics in stepped approach (Barakzoy:JASN 06;17:3198). Step 1 paracetamol. Step 2 hydrocodone, Oxycodone, tramadol. Step 3. Fentanyl, hydrocodone, Oxycodone, methadone.

Generalised weakness

Differential diagnosis includes: electrolyte abnormalities, Vit D deficiency, SHPTH, aluminium intoxication, drug toxicity, ? L-Carnitine deficiency (Hedayati;Semin Dial 06;19(4):323).

Sleep apnoea

High prevalence in renal pts.

GASTROINTESTINAL COMPLICATIONS OF ESRD Complication

Management / Pearls

Constipation

Causes: Multifactorial. Consider opiates, dehydration, phosphate binders. Treat with: Lactulose, Colace, PEG. Avoid Sorbitol, Fleets Products (high phosphate load), MagCitrate / MOM (Magnesium).

GI Bleeding

Causes include angiodysplasias in stomach/duodenum/ colon (Zucklerman;AIM 85;102:588). Platelet dysfunction contributes. In pt’s at high risk for infection, (tunnelled catheter), consider occult bacteremia as a cause of GIB. Avoid sucralfate as contains aluminium. Most H2 blockers require dose adjustment in ESRD while PPI’s do not.

Lower transaminases / less Transaminases usually 30-50% lower in ESRD pts. An increase into even the high normal range might reflect aggressive hepatitis C a new Hep C infection or other issue. Gallstones

More common in ESRD. PKD pts can have clinically insignificant CBD dilatation.

H. pylori

Avoid Bismuth which accumulates in ESRD.

18 RENAL HANDBOOK


HAEMODIALYSIS

INTRADIALYTIC HYPOTENSION (IDH) Aspect

Notes (Schreiber;AJKD 01;38 (S4): S1; and Dheenan;KI 01;59:1175)

Background

A common predisposing factor is abnormal CV physiology present in majority of HD pts: left ventricular hypertrophy with preload dependence in >75% (Foley AJKD 98; 32(S3):S112) high cardiac output (25% increase due to AVF) with low peripheral vascular resistance (similar to anaemic pts). Cramping, fatigue and intradialytic HoTN are poor proxies for volume status, and these pts are often above dry weight with large interdialytic gains.

Consider

(1) Cardiac: MI, pericardial effusion, arrhythmia (2) Septicaemia, particularly line sepsis (3) GI bleed, may be first presentation of sepsis in ESRD (4) Excessive or rapid volume removal.

Acute evaluation

(1) Pt: Symptoms, mentation, rhythm, rub, pulsus, volume status, abdomen, BP in legs. (2) Data: Anti-HTN dosing, albumin, haemoglobin, LV function, microbiology. (3) Consider: ECG, cardiac enzymes, blood cultures, urgent ECHO, dialysate culture.

Mgmt

(1) Immediate: Trendelenburg; O2; stop UF, reduce Qb; administer 0.9% or 23.4% NaCl (= 4004 mEq/litre; dose 10 ml); consider empiric Ax; optimise cardiac function/rhythm, manage GI bleed if present. (2) Adjust HD Prescription: Lower UF goal, perform isolated UF, increase HD time, lower dialysate temp. to 36 deg, consider â&#x20AC;&#x2DC;NPOâ&#x20AC;&#x2122; status during dialysis, reassess dry weight. (3) Limit interdialytic weight gain: Reduce dialysate Na (intra-dialytic weight gain associated with gradient between dialysate and serum Na) Reduce dialysate Na to match serum Na. Restrict dietary Na and reduce dry weight. (4) Increase plasma refill rate: Albumin infusion (esp. if SAlb is low), PRBC transfusions if anaemic, adjust Epo/iron; consider Na modelling. (5) Medication adjustments: Adjust dosing schedule of anti-hypertensive medications (except Beta Blockers, which may protect against Bezold-Jarisch reflex); consider addition of Midodrine @ 2.5 mg PO 30 min prior to HD (titrate to 10 mg TID) and give extra dose mid-dialysis, avoid in pts with CAD. Alternative: Sertraline. (Perazella;AJKD 01;38(S4):S26).

RENAL HANDBOOK 19


Peritoneal Dialysis

RENAL HANDBOOK 21


PERITONEAL DIALYSIS

PERITONEAL DIALYSIS BASICS Definitions: CAPD = Continuous Ambulatory Peritoneal Dialysis; CCPD=Continuous Cyclic Peritoneal Dialysis (requires a cycler). Many prescriptions have elements of both. APD = automated peritoneal dialysis. Benefits of PD relative to HD: independence, lack of intravascular infections, preserved native kidney function, better middle molecule clearance. Studies of mortality experience relative to HD (Jarr;AIM 05;143:174) are limited by methodological issues and difficulties randomising pts. Pt requirements: PD requires a motivated, cognitively intact pt with preserved peritoneal anatomy. Contraindications (relative): (1) weight> 200 lbs / 100Kg; (2) No residual renal function (especially if BSA > 2); (3) Diabetes (due to infection, effects on blood glucose/ lipids, possibly higher mortality); (4) ascites; (5) previous intra-abdominal surgery.

THE PERITONEAL DIALYSIS PRESCRIPTION Basic PD orders: specify fluid volume, dextrose % in fluid, and # of exchanges /day. For example, “2 L x 2.5% x 4 exchanges.” Electrolytes: PD solutions do not contain any potassium and use lactate (Daioneal) or bicarbonate (Physioneal) as buffer. Nutrineal contains a 1.36% soln with added amino acids for malnourished. Bicarbonate more physiological and less pain when filling. If pt is hypokalemic, or tends to hypokalemia, potassium chloride (3-5 mmol/L) can be added, to reduce loss. Convert cycler pts to CAPD by calculating their total daily infusion volume at home and dividing by ~4-6 exchanges / day. Ultrafiltration: use daily weights and the flow sheets that show drain volume to assess. Manufacturer’s Platform: Two are available, one from Baxter (‘Ultra-Bag’) and the other from Fresenius. Exchange between the two requires an adaptor.

PERITONEAL DIALYSIS ORDERS Transporter

D/Pcreat

Fill Volume

2 litre, 2.5 litre, 3 litre.

Comments

Fluid Type - Glucose

1.36, 2.27 or 3.86% Glucose. Icodextrin.

CAPD Exchange Frequency

q4, q6, or 5 x / day.

APD Dwell Time

2 hours.

Calcium

‘Low Calcium’ =1.25 mmol/L.

Rarely use Calcium = 1.75 mmol/l.

Heparin

500 - 2000 units per 2 - 2.5L.

Add PRN for haemoperitoneum, peritonitis.

PERITONEAL DIALYSIS FLUIDS Solution

Glucose concentration

mOsm/L

Cap colour

Expected UF

1.36%

1,360 mg/dl

345

Yellow

150ml/exchange

2.27%

2,270 mg/dl

395

Green

250ml/exchange

4.86%

3,860 mg/dl

484

Red

425ml/exchange

Icodextrin (Extraneal)

Mixture of high MW oligopolysaccharides which can prolong UF. Associated with maltose absorption and falsely elevated finger-stick glucose in older glucometers. Skin reactions in ~15%.

22 RENAL HANDBOOK


PERITONEAL DIALYSIS

PERITONEAL EQUILIBRATION TESTING (PET) PET (Twardowski; Perit Dial Bull 87;7:138) is used to define the solute and water transport characteristics of the peritoneum. The results are necessary to write an effective PD prescription. The PET is performed by measuring the dialysate (D) and plasma (P) creatinine concentration and the Dialysate glucose concentration at 0, 2 and 4 hours and comparing the ratios (D/P creatinine and D/D0 glucose) to empiric standards. As a result of the PET, pts’ are characterised as being High, High Average, Low Average or Low Transporters.

INTERPRETATION OF PET TEST RESULTS Transporter

D/Pcreat

Comments

High (10% of pts)

0.82-1.03

Best managed with cycler. Can experience ‘ultrafiltration’ failure and fluid overload — consider Icodextrin during day time dwell. Albumin often low.

High-avg (50%)

0.65-0.81

Can be managed with CAPD or cycler--7.5 to 9 litres/24 hrs.

Low-avg (35%)

0.50-0.64

Standard PD high dose needed for larger pts.

Low (5%)

0.34-0.49

Manage with long dwell CAPD. Can suffer from underdialysis, must achieve drain volume > 9 litres/24 hrs.

COMMON NON-INFECTIOUS COMPLICATIONS OF PD Problem

Details

Management Considerations

Leaks

Typically seen early after cath placement

Inflow issues

Pain can result from low pH of PD solution or from peritonitis. From clots, fibrin, constipation.

Reduce fill volume. Use nocturnal APD with pt horizontal. IP pressure reduction - laxatives. Consider temporary switch to HD. Test for peritonitis. Can slow infusion rate, use Physioneal if pain on infusion or add HCO3 (7-10 ml) or Lidocaine to bag. Treat constipation. Leaving fluid incompletely drained after prior dwell reduces outflow pain. Dx by testing glucose on pleural fluid and/or with radio-labelled albumin or methylene blue. Rx with PD holiday, VATS or open surgery. Reduce fill volume or change to CCPD. PPI’s, low-dose Metoclopromide. Diagnosis is critical to mgmt. Use heparin and frequent exchanges to prevent catheter clotting. Reassure, disturbing for pts.

Outflow issues

From congenital or acquired defects in diaphragm. More common on right side, in women and in PKD pts. Back Pain Mechanical stress from fill volume. GI complaints Nausea, early satiety, GERD. Haemoperitoneum Common in menstruating women. There are many other causes including encapsulating peritoneal sclerosis, splenic infarct, liver cancer, retroperitoneal or iliopsoas haematoma. Ultrafiltration Unable to remove excess fluid. Usually in high failure transporters and those on PD for yrs. PD failure. Encapsulating Disease of visceral peritoneum. Usually > 5yrs peritoneal or multiple peritonitis episodes. UF failure. sclerosis (EPS) Weight loss, failure to thrive, high ESR / CRP but no infection, early satiety, altered bowel habit. Diagnosis by CT abdomen: abdominal cocoon, peritoneal thickening. Pleural effusion

Switch to HD. Some advocate continuing PD for a period after conversion to decrease risk of EPS. Life threatening. Avoid exploratory laparotomies. If early, peritonectomy and enterolysis. Aggresive nutrition. Tamoxifen 20mg OD (anti-TGFbeta).

RENAL HANDBOOK 23


PERITONEAL DIALYSIS

PD ADEQUACY Measure of PD Adequacy = Weekly Kt/V: target =1.8. Weekly Clearance =[daily residual renal clearance (24hr urine creat. clearance) x7] PLUS [daily PD clearance (24hr PD fluid drain vol x creatinine content) x7. Divide by ‘V’ to get Weekly Kt/V. Are higher PD clearances associated lower mortality? CANUSA study (Churchill;JASN 96;7:198) suggested better survival with increased clearance but reanalysis of data (Bargman;JASN 01;12:2158) suggested better survival resulted from higher residual renal function. ADEMEX RCT (Paniagua;JASN 02;13:1307): no mortality benefit of 60 L/week (3 litre x 4-5 exchanges) vs. 45 L/wk (2 litre x 4).

PD PERITONITIS Issue

Notes

Prevention

(1) Proper ‘flush before fill’ technique, hand washing, wearing mask, keeping windows closed and animals out of room; (2) Gentamicin sulphate 0.1% cream or mupirocin ointment daily to exit site (Bernardini;JASN 05;16:539); (3) Co-amoxiclav prophylaxis for colonoscopy or sigmoidoscopy.

Presentation

Pts will report cloudy fluid (ie newsprint can’t be read through it). Examine exit site and catheter tunnel; look for strangulated hernias in the abdominal wall.

Diagnosis

Fluid cell count > 100 with >50% neutrophils. Culture using 5-10 ml of unspun effluent from cloudy bag inoculated into blood culture bottles. Send for gram stain and C&S. If cloudy bag unavailable, infuse bag and wait 1-2 hours (less time may lead to false negative).

Abdominal imaging

Unnecessary except if physical exam is concerning or multiple relapses. If blood cultures are positive, consider a primary abdominal process: e.g. appendicitis, diverticulitis, cholecystitis.

Indications for catheter removal

(1) Fungus; (2) Polymicrobial suggesting bowel perforation; (3) Pseudomonas; (4) Possibly Tuberculous peritonitis; (5) Failure to improve on therapy (especially with GNRs or no improvement by day 5).

Relapsing peritonitis

= recurrence w/in four weeks of prior Rx. Consider (1) poor pt technique especially if S. Epi or Diphtheroids; (2) infected catheter (biofilm) e.g. Stenotrophomonos or similar bacteria.

Empiric antibiotic therapy

Need to cover both Gram positives and Gram negatives. First line: IP Vancomycin and gentamicin, dwell time of the exchange must be a minimum of 6 hours. IP Vancomycin dosing: First dose 2g, subsequent does should 1g unless high clearance predicates 2g intermittent dosing. Target range: 15-20mg/l, repeat dosing when serum level <20mg/l. IP Gentamicin dosing: APD - 0.6mg/kg daily if UO <400mls, 1.0mg/kg daily if UO >400mls (in one >6hr dwell/dy); CAPD - 8mg/L loading dose, 4mg/L maintenance dose each dwell. Give N-Acetylcysteine 600mg BD while treating with gentamicin (Tokgoz NDT 2011).

Antibiotic incompatibility

Amoxicillin / Gentamicin incompatibility: These agents need to be given separately, as they bind in PD fluid necessitating sequential dosing. Gentamicin should be added to dialysate as indicated by serum levels. Adjust for interruption in amoxicillin dosing by increasing the maintenance dose to 100mg/L in the dwell preceding gentamicin dwell. Quinolones: Sevelamer and calcium chelate quinolones, give at least 2 hours after quinolones.

In case of antibiotic allergy

Flucloxacillin/amoxicillin allergy, give Vancomycin. If Vancomycin allergy, contact microbiology.

Ongoing Mgmt

(1) Adjust Ax when organism sensitivities are available (see next table “Guided antibiotic therapy in PD peritonitis”). (2) Use daily cell count to follow response to treatment.

24 RENAL HANDBOOK


PERITONEAL DIALYSIS

GUIDED ANTIBIOTIC THERAPY IN PD PERITONITIS GRAM POSITIVE ORGANISMS Culture Streptococci

Treatment

Amoxicillin sensitive: Loading dose amoxicillin Evaluate for exit site or tunnel 250-500 mg/L, maintenance 50mg/L per exchange infection. Amoxicillin resistant: IP Vancomycin.

Comments

2 weeks

Duration

Enterococci Vancomycin resistant (VRE)

Amoxicillin sensitive: Loading dose amoxicillin Outrule intra-abdominal pathology 250-500 mg/L, maintenance 50mg/L per exchange Evaluate for exit site or tunnel plus gentamicin in a separate bag if clinically infection. unstable or not settling by day 3. Amoxicillin resistant: Discuss with micro.

3 weeks

S. aureus incl. MRSA

IP Vancomycin - If no improvement by day 3, add second agent (check with micro). If no improvement by day 5, remove catheter.

Severe peritonitis. Concurrent exit site or tunnel infection: remove catheter.

3 weeks â&#x20AC;&#x201C; IV Rx for 48-72hrs post resolution of pyrexia

Coagulase negative Staph.

IP Vancomycin.

Evaluate for exit site or tunnel infection.

2 weeks

Corynebacterium IP Vancomycin.

Evaluate for exit site or tunnel infection.

3 weeks

GRAM NEGATIVE AND OTHER ORGANISMS Culture P. aeruginosa

Treatment

Comments

Duration

Check sensitivities with micro before commencing therapy. Use 2 Ax. Consider surgical opinion if unstable.

No improvement after 3 days: Remove catheter Continue Ax for 14 days post removal Consider abdominal CT (?abscess)

3 weeks

Other gram negatives eg: Check sensitivities with micro before E. coli, Proteus spp commencing therapy. Consider surgical opinion if unstable.

No improvement after 3 days: Repeat cell count, gram stain & culture. Consider catheter removal.

2- 3 weeks

Polymicrobial (multiple Check with microbiology re sensitivities gram negative organisms before commencing therapy. and/or anaerobes) Surgical opinion for all.

No improvement after 3 days: Remove catheter. Continue Ax for 14 days post removal. Consider abdominal CT (?abscess).

3 weeks

Fungal

Fluconazole. Stop Ax. Remove catheter. Discuss with microbiology.

2-4 weeks

TB

Discuss with microbiology and respiratory medicine.

Culture negative

If clinical improvement at 3 days, continue Consider catheter removal and unusual IP Vancomycin and gent. aetiologies (see next page).

Consider when pt not responding to antibiotic therapy. Remove catheter if no clinical improvement.

12 months

2-3 weeks

RENAL HANDBOOK 25


PERITONEAL DIALYSIS

DIFFERENTIAL DIAGNOSIS OF STERILE PERITONITIS Complication Neutrophils

Management / Pearls Atypical infection Mycobacteria, fungi Intraperitoneal disease Cholecystitis, appendicitis, SBO, mesenteric ischaemia Retroperitoneal disease Pancreatitis, splenic infarction, abscess, RCC Drugs Amphoterocin B, Vancomycin Contamination Endotoxin, acetaldehyde Eosinophils Allergic reaction Tubing, bags Drugs Vanc, gent, streptokinase, cephalosporins Post-peritonitis Resolution phase Infection Fungal, parasitic Monocytes Icodextrin related Infection Mycobacteria Erythrocytes Haemoperitoneum See haemoperitoneum section below Malignant cells Lymphoma, metastatic disease Acellular Fibrin Starting PD, Post peritonitis Triglycerides Pancreatitis, Neoplasms, Catheter-related trauma, SVC syndrome, Ca channel blockers

RENAL NUTRITION PHOSPHATE CONTENT OF COMMON FOODS (Source: Abbott Labs; Renal Nutrition Forum 04;Vol 23(3)) High Phosphate Foods NUTS POULTRY PUMPKIN SEEDS MEAT SUNFLOWER SEEDS SAUSAGE COLAS CHOCOLATE PEANUT BUTTER ICE CREAM

Lower Phosphate Foods CHEESE MILK YOGURT CREAM SOUP DRIED PEAS/BEANS BISCUITS 100% BRAN CEREAL PIZZA MEAT/FISH/POULTRY LIVER

FISH STRAWBERRIES PASTA POPCORN HAMBURGER CRACKERS CHICKEN CORN FLAKES SIRLOIN STEAK RICE KRISPIES

LETTUCE GREEN BEANS SORBET CABBAGE CREAM CHEESE APPLE GRAPES CRANBERRY JUICE

POTASSIUM CONTENT OF COMMON FOODS (Source: National Kidney Foundation) High Potassium MEAT, POULTRY, FISH APRICOTS AVOCADO BANANA MELON KIWI MILK ORANGES AND ORANGE JUICE POTATOES PRUNES SPINACH TOMATOES /TOMATO JUICE VEGETABLE JUICE WINTER SQUASH 26 RENAL HANDBOOK

Moderate Potassium Foods APPLE JUICE ASPARAGUS BEETS BLACKBERRIES, RASPBERRIES, CHERRIES STRAWBERRIES PEACHES, PEARS, PINEAPPLES, RAISINS CARROTS CORN AUBERGINE GRAPEFRUIT GREEN PEAS LEAFY LETTUCE ONIONS BROCCOLI

Lower Potassium Foods APPLES PEPPERS BLUEBERRIES CABBAGE CRANBERRIES, CRANBERRY JUICE CUCUMBER GRAPES GREEN BEANS ICEBERG LETTUCE MANDARIN ORANGES MUSHROOMS - CANNED PEACHES PINEAPPLES PLUMS


Acute Kidney Injury

RENAL HANDBOOK 27


ACUTE KIDNEY INJURY

DIFFERENTIAL DIAGNOSIS OF ACUTE KIDNEY INJURY PRE-RENAL ACUTE KIDNEY INJURY True volume depletion and shock Incl. ‘relative’ HoTN in pt with hypertension. Effective circulating volume depletion

CHF, Cirrhosis (hepato-renal); Nephrotic syndrome; Sepsis; Severe hypoalbuminaemia of rapid onset; 3rd spacing e.g. pancreatitis or rhabdo.

Altered renal or systemic haemodynamics

Afferent arteriole constriction (Hypercalcemia, NSAIDs, CNIs); Efferent arteriole dilatation: ACEi, ARB.

POST-RENAL ACUTE KIDNEY INJURY Bladder Outlet Obstruction

Incl. Foley catheter problems.

Bilateral ureteric obstruction

Stones, clots; malignancy; compression due to retroperitoneal malignancy; endometriosis; fibrosis; or lymphadenopathy.

Unilateral ureteric obstruction

In pt with single functioning kidney.

Ultrasound negative variants

Early extreme ureteral compression, volume depletion.

INTRINSIC KIDNEY DISEASE ATN (Acute Tubular Necrosis)

Ischemic (cardiogenic, hypovolaemic); SIRS/Sepsis with or without shock; Exogenous nephrotoxins (contrast, aminoglycosides, cisplatin); Endogenous nephrotoxins (myoglobin, haemoglobin).

AIN (Acute Interstitial Nephritis) Medication related; Sarcoidosis; Infectious; Sjogren’s; Tubulointerstitial Nephritis & Uveitis (TINU) syndrome. AGN/RPGN (Acute or Rapidly ANCA Vasculitis; systemic or renal limited; Anti-GBM; Immune Complex Mediated (infectious, Progressive Glomerulonephritis) cryoglobulinemic, SLE); Crescentic IgA / HSP, AGN associated with persistent staphylococcal infection. Acute Vascular Syndromes

Microvascular: Thrombotic Microangiopathy, TTP/HUS, anti-phospholipid syndrome, scleroderma, malignant hypertension, HELLP, atheroemboli. Macrovascular: bilateral RA thromboembolism, dissection, stenosis, renal vein thrombosis; operative cross-clamp.

Crystal Deposition

Acute uric acid deposition (tumour lysis syndrome), Calcium oxalate (ethylene glycol or oxalosis), Calcium phosphate (bowel preps), Medications (acyclovir, methotrexate, indinavir, Septrin).

Associated with paraproteinaemia

Myeloma cast nephropathy; Monoclonal immunoglobulin deposition disease; amyloidosis.

28 RENAL HANDBOOK


ACUTE KIDNEY INJURY

GENERAL MANAGEMENT OF ACUTE KIDNEY INJURY Management Issue

Strategy

Optimise volume status and haemodynamics (systemic and intrarenal)

Administer volume as needed. Use pressors for persistent HoTN, keeping MAP>65. Discontinue ACE/ARB/NSAIDs/CNI. Follow daily weights, I’s & O’s. Use diuretics if volume overloaded and oliguric or anuric (avoid loop diuretics in myelomaassociated ARF).

Manage electrolytes and acid/base disturbances

Eliminate K from diet and IV’s, treat hyperkalaemia with medical mgmt. NaHCO3 if acidaemic/non-oliguric.

Reduce urea production, catabolic state

Reduce dietary protein to ~0.8 gm/kg, use insulin, dextrose infusions to overcome catabolism.

Manage uremic bleeding

DDAVP 0.3 mcg/kg IV x 1-2 (cryoprecipitate adds little to this). For severe bleeding consider conjugated oestrogens (5-30 mg IV or PO daily x 5 days)—take several days to work.

Dose adjust all medicines

If creatinine rising acutely, assume GFR < 10.

Pay close attention to narcotics

Accumulate in renal failure. Metabolites are more potent than parent compound, peak toxicity 24 hours after dose (resp. depression, CNS tox). Hydromorphone, Fentanyl, tramadol or methadone are preferred.

Avoid nephrotoxins

Contrast dye studies, aminoglycoside toxicity.

Erythropoietin replacement

Consider if txp planned (reduce transfusion).

Renal Replacement Therapy

For volume overload (present or anticipated), uraemia, pericardial rub, encephalopathy, refractory hyperkalemia, severe acidosis, uraemia.

RENAL HANDBOOK 29


ACUTE KIDNEY INJURY

SPECIFIC MANAGEMENT OF ACUTE KIDNEY INJURY Category

Type

Key Management Principles

Post-renal

Bladder Outlet Obstruction Bilateral Ureteric Obstruction Abdominal compartment synd.

Foley Catheter, Urology eval, Finasteride/Tamsulosin in men Percutaneous Nephrostomy Tubes (IR) or double J stents (Urology) Bladder press > 25mmHg; effacement IVC and renal veins on CT; causes raised ICP and CVP, so pt appears resuscitated when not; decompressive laparotomy; pt. stays open for a few days.

Pre-renal

Intrarenal haemodynamics Volume depletion/Low BP CHF related

Stop NSAIDs, ACEi/ARB, CNIs, treat hypercalcemia. Optimise volume, optimise haemodynamics keeping MAP>65. Optimise cardiac function, volume status. Elevated venous pressure may be more important than hypoperfusion. Consider albumin infusions. (1) Volume replacement—Albumin / FFP preferred (2) Midodrine-Octreotide (3) consider Vasopressin (4) Dx/Rx infections (5) TIPS (6) Liver Transplant.

Hypoalbuminaemia Hepato-Renal Syndrome Ischemic ATN Nephrotoxins Pigment Nephropathy

Optimise haemodynamics: MAP>65. Treat infections, sepsis. Discontinue nephrotoxin. Can be delayed e.g. Ifosfamide 2 months after exposure. Volume, IV NaHCO3 to keep urine pH =~6 if non-oliguric.

Glomerular

Depends on lesion

See GN section.

Interstitial

Interstitial nephritis

Remove offending agent(s), steroid use assoc. with better outcomes.

Vascular

TTP – HUS

Can occur long after exposure e.g. 8 months post gemcitabine. Possibly PEX, Immunosuppression, aspirin, avoid platelets. ACEi – especially Captopril @ max tolerated dose. Usual mgmt of malignant HTN See page 49. Discontinue anticoagulants, avoid catheterisation, add statins. Delivery of foetus for HELLP/eclampsia; general Rx for acute fatty liver of pregnancy. Anti-coagulation, possibly PEX.

Tubular

Scleroderma Renal Crisis Malignant HTN Atheroemboli Pregnancy related AKI Anti-Phospholipid Antibody Syndrome Crystal deposition Tumour Lysis Ethylene Glycol Acyclovir, Indinavir Methotrexate

Paraprotein

30 RENAL HANDBOOK

Cast Nephropathy, LCDD or HCDD IgM Related Disease Cryoglobulinaemia

Raise urine to neutral pH; worsened by alkalinising urine; Allopurinol 300-400mg; rasburicase; dialysis. Fomepizole (Brent;NEJM 99;340:832), dialysis, pyridoxine, folate, thiamine, alkalinisation (Takeyasu;NEJM 06;354:1065). Discontinue drug, supportive mgmt. Alkalinisation, Dialysis, HD Leucovorin (150mg/m2), thymidine, and Carboxypeptidase-G2 (Wideman;JCO 97;15:2125). Can be fatal due to accumulation and myelosuppression. Manage volume abnormalities, tumour lysis. Avoid loop diuretics (increase cast formation). PEX rarely helpful unless hyperviscosity synd. (Clark;AIM 05;143:777) PEX see ‘Treatment of Glomerular Disease’.


ACUTE KIDNEY INJURY

CONTINUOUS RENAL REPLACEMENT THERAPY BASIC PRINCIPLES  CVVH is the modality primarily used in Beaumont. Blood passes through dialyser and plasma water passes through pores due to a pressure gradient. Solutes are ‘dragged along’ (= ‘convection’). Filtrate is discarded. Replacement Solution (RS) is simultaneously infused into the pt.  CVVHDF = CVVH with dialysate solution run simultaneously, counter current.  Clearance per unit time is lower with CVVH so HD better for hyperkalemia, intoxications, tumour lysis syndrome.  CVVH Blood flow (Qb)~120 - 200 ml/min (compared with HD=300-400 ml/min).  Main indications for using CRRT rather than HD include: (1) hemodynamic instability; (2) significant volume overload; (3) significant acidaemia with ongoing acid production; (4) risk of cerebral oedema from HD (cirrhosis; head trauma). CALCULATING CLEARANCE ON CVVH  Total Clearance = CVVH Clearance + Endogenous Clearance (via urine output).  CVVH Clearance = (Filtrate Volume x Filtrate Creat / Serum Creat).  Qb is low so Filtrate Creat/Serum Creat ~ “1” thus Clearance = Filtrate Volume (L/day). Adjust units to ml/min.  CVVHDF clearance = Filtrate + Dialysate Volume (L/day).  Because RS is given pre-filter (less clotting), actual clearance is lower by ~15%. Actual clearance also reduced when machine is down due to clotting, so getting the anticoagulation right is critical.  Endogenous Clearance = ([UCr] x Uv / [PCr]). Adjust units to ml/min.  Worked example: effluent rate 2L/hr= 33.3 ml/min. Multiply by 0.85 to adjust for pre-filter = clearance (“GFR”) of 28 ml/min.

DOSE OF CVVH  In Beaumont, we use citrate CVVH at 1600 ml/hr RS and 120ml/min Qb as the standard prescription. If higher clearance is needed, use 2400ml/hr RS and 180ml/min Qb.  Optimal ‘dose’ of CVVH appears to be 20-25ml/kg/hr based on the US ATN study [20 vs. 35 mL/kg/hr], the AUS/NZ RENAL study [25 vs. 40 mL/kg/hr] and 2 meta-analyses. Higher intensity dialysis did not improve survival or clinical benefits but was associated with increased complications (e.g. hypotensive episodes, electrolyte disorders).  Note, these results are based on the delivered dose of CRRT, which is significantly less than the prescribed dose. Therefore, the prescribed dose should be 25 to 30ml/kg/hr to deliver 20 to 25 ml/kg/hr.  Clearance with standard citrate Beaumont Hospital protocol = RS @ 1600 ml/hr = 26.7 ml/min, adjusted for pre-filter RS=22.

RENAL HANDBOOK 31


ACUTE KIDNEY INJURY

THE CVVH PRESCRIPTION STEP 1: CHOOSE REPLACEMENT SOLUTION Solution

Contents (mEq/L)

Notes and instructions

Citrate

Na 145, Cl 105, Citrate 40, 0K, 0 Ca, Dex 2 g/L (~glucose 11 mmol/L).

Provides local anticoagulation via chelation of iCa in the circuit. Hepatic metabolism of citrate yields HCO3 (Palsson; KI 99;55:1991). Risk factors for citrate toxicity: liver failure, lactic acidosis. If Lactate>4-5, Anion Gap>20 or advanced liver disease, consider Hemosol instead. Signs of citrate toxicity: (1) Persistent low ionised Ca (<0.9mmol/L) and/or high total adjusted Ca; (2) Metabolic alkalosis; (3) ‘Calcium ratio’ (corrected Ca / ionised Ca) >2.5.

Bicarbonate (Hemosol)

Ca2+ 1.75 Magnesium Mg2+ 0.5 Chloride Cl- 109.5 Bicarbonate HCO3- 32 Lactate 3

Use Hemosol when contra-indication to citrate. Requires heparin or other anticoagulation to prevent clotting; may be unnecessary if coagulopathic. Anticoagulation: Prime with 5000U heparin in 1L NS unless HIT – then use NS alone. Heparin during CVVH given by syringe directly into CVVH system; adjust heparin per standard ITU protocol (target = 1.5-2 x normal but not >100). APTT should be checked in blood outside the CVVH circuit. If heparin and citrate contra-indicated: use no anti-coagulation or argatroban (2mcg/kg/min if normal liver function and change by 0.5mcg/kg/min increments (round dose to nearest 10kg). If no A/C is used, run Qb >200ml/min, if possible.

STEP 2: CHOOSE REPLACEMENT SOLUTION RATES RS Type

Qb

Notes

Citrate Pre-pump replacement at 1600ml/hr. Do not adjust these rates without discussing with consultant on call. (Prismocitrate Post-pump replacement (0.9% NaCl) Must maintain RS:Qb ratio to maintain anti-coagulation and clearance. When 10/2) at 50ml/hr. the RS rate is changed, the Qb must change proportionally (e.g. by 2x or ½). Bicarbonate (Hemosol)

≤50kg: 1200ml/hr 50-60kg: 1600ml/hr 60-70kg: 1800ml/hr 70-80kg: 2000ml/hr 80-90kg: 2400ml/hr ≥90kg: 2600ml/hr

32 RENAL HANDBOOK

Unlike citrate CVVH, RS and Qb can be changed independently of one another. If aggressive treatment reqd (e.g. poisoning) use higher PBP e.g. 3000ml/hr or intermittent HD. Total effluent should be 20-25ml/kg/hr: for average pt = PBP at 2000ml/hr.


ACUTE KIDNEY INJURY

THE CVVH PRESCRIPTION CONTD. STEP 3: CHOOSE BLOOD FLOW RATE RS Type

Qb

Notes

Citrate

120ml/min

Do NOT change this without discussing with consultant on call. After discussion, any changes must maintain RS:Qb ratio to prevent anti-coagulation and clearance problems i.e. the Qb must change proportionally to the RS rate (e.g. x2 or x½ etc).

Bicarbonate

Start at 150ml/min Increase to 200ml/min as tolerated after 10 mins. Faster Qb may reduce clotting. Can be changed independently of RS rate.

STEP 4: CONFIRM OR MODIFY CALCIUM SCALE [USED FOR CITRATE NOT HEMOSOL CVVH] Ensure there is a central line port for infusion of calcium gluconate (by syringe pump). Calcium gluconate 10% solution is delivered UNDILUTED in a 50ML syringe driver into a central line. i Ca (mmol/L) <0.9 0.9-1.0 1.0-1.1 1.1-1.3 >1.3

Replacement 1600 ml/hr 12 ml/hr* 12 ml/hr 10 ml/hr 8.5 ml/hr 8.5 ml/hr and call renal Reg

Replacement 2400 ml/hr 18 ml/hr* 18 ml/hr 15 ml/hr 13 ml/hr 13 ml/hr and call renal Reg

*Give 1 ampoule (=10ml) of IV 10% calcium gluconate and call renal reg.

STEP 5: SPECIFY FLUID REMOVAL GOALS Specify both a 24 hr fluid balance goal (e.g. ‘Minus 2L’) and an hourly goal. If CVP line, consider hourly goal based on CVP. For example: (1) -200 ml/hour if CVP>12; (2) -100 ml/hour if CVP 8-12; (3) 0 ml/hour if CVP < 8. Otherwise use MAP For example: (1) -200 ml/hr if MAP > 70mmHg; (2) -100 ml/hour if MAP 65-70; (3) 0 ml/hour if MAP < 65. STEP 6: SPECIFY ELECTROLYTE MANAGEMENT  Potassium: Added by ICU nurse. KCl is added to each 5L bag of Prismocitrate/Hemosol based on most recent K: if K<3.0, add 40 mmol; if 3.0-3.49, add 30 mmol; if 3.5-5.50, add 20 mmol, if >5.50, add none.  Phosphate: NaPO4 or KPO4: 15 mmol if Pi<2.5 mg/dl; 30 mmol if <1.5 (PRN).  Sodium: Hyponatraemia may develop because RS [Na+] < plasma water [Na+] (154 mEq/L).  Acidosis: If most recent ABG shows pH <7.4 then add 10ml (2 vials) of DURALOCK-C 46.7% citrate to every 5L bag of Prismocitrate 10/2. If pH >7.4: do NOT add extra DURALOCK-C.  Severe acidosis (pH<7.1): May also add isotonic NaHCO3 (3 Amps NaHCO3 1L D5) post-filter @ 50-500 ml/hr, using CVVH machine to remove volume (avoids hypernatremia).  Magnesium: 4.0 mmol of MgSO4 [2ml 50% solution] added to every 5L bag of Prismocitrate 10/2 by ICU nurse. Gives a final Mg concentration of 0.8 mmol/L (1.6meq/L). Do not use MgCl. contd...

RENAL HANDBOOK 33


ACUTE KIDNEY INJURY

WRITING A NOTE ON THE PATIENT RECEIVING CVVH 1. START ALL NOTES WITH... “Pt seen and examined with Dr. XXXX on CVVH , medical notes reviewed and management discussed with multidisciplinary team”. 2. STATE THE WORKING DIAGNOSIS AND DOCUMENT THE FOLLOWING... Example of working diagnosis: Oliguric AKI secondary to ATN.  Document risk factors: e.g. CKD III due to diabetic nephropathy  Document Insults: e.g. Septic shock  Document supporting investigations: Urine dipstick, urine sediment, renal imaging  Document outstanding or additional tests required. 3. DOCUMENT THE CVVH PRESCRIPTION Specify: Qb, replacement rate and solution, UF rate, anticoagulation. 4. DOCUMENT MONITORING AND RECOMMENDATIONS WHILE ON CVVH  Calculate and document delivered CVVH dose (described above). Goal effluent rate 20-25ml/min.  Medications: Document that all meds dosed adequately for delivered clearance or, if not, specify the precise dose adjustments.  Acid-base status: Document ABG okay or, if not, specific measures to correct the acid-base disorder.  Volume: Perform an assessment of volume status supported by documentation of BP, pressor trend, urine output, CVP, CXR. Specify measures to optimise.  Small solute control: Confirm adequate control of K, urea etc. Hypokalemia and hypophosphataemia associated with poor outcomes. Give specific replacement regimens for K, and PO4, including CVVH dose adjustment.  Anticoagulation: i. If on citrate, document that ionised Ca and total Ca okay or, if not, specific measures to correct them ii. If on heparin, argatroban, document platelet count and APTT.

34 RENAL HANDBOOK


ACUTE KIDNEY INJURY

RENAL REPLACEMENT THERAPY IN THE PATIENT WITH ACUTE BRAIN INJURY Pathophysiology: Intracranial pressure increases are buffered by CSF, such that increased ICP leads to increased CSF entry to the spinal cord, increased reabsorption and reduced production. This buffering works best for slowly rising ICP; once this buffering capacity is overcome, the ICP increases steeply, exceeding cerebral perfusion pressure and preventing blood flow. Key question when prescribing dialysis in Neuro ICU: What is the integrity of blood-brain barrier? In vasogenic cerebral oedema (such as is seen in traumatic brain injury (TBI), acute intracerebral haemorrhage, small vessel vascular disease, hypertensive encephalopathy and infection) the BBB is broken down, and substances commonly used in the dialysis prescription such as mannitol and albumin can cross into the brain and worsen cerebral oedema. This may explain the inferior outcomes seen in TBI pts treated with albumin in the SAFE study. Use hypertonic saline instead. The dialysis prescription in the pt with acute brain injury. Modality CVVH

Notes Even stable outpts develop subclinical cerebral oedema during IHD. This can precipitate a catastrophe in a pt with raised ICP. CVVH is first line in TBI as intermittent HD can worsen intracranial hypertension via systemic HoTN (ICP rises when MAP falls), faster removal of urea from plasma than brain and intracellular acidosis (CO2 crosses BBB faster than HCO3).

Intermittent haemodialysis Low blood flow rate and cooled dialysate to minimise HoTN. Small dialyser to slow rate of change of plasma osmolality. only if stable CV, and no High dialysate [Na] (150-160 mmol/l) to minimise cerebral oedema. ICP or midline shift Low [bicarbonate] ~30 mmol/l to prevent worsening of intracranial hypertension. Maintain pre-HD urea 30 mg/dL. Heparin-free dialysis. Peritoneal dialysis

Avoid icodextrin for the same reasons as albumin and mannitol. Low fill volumes to prevent raised intra-abdominal pressure.

RENAL HANDBOOK 35


Renal Consults

RENAL HANDBOOK 37


RENAL CONSULTS

CHRONIC KIDNEY DISEASE Use a systematic approach for all pts (“10 A’s”) CHRONIC KIDNEY DISEASE / LOW CLEARANCE CLINIC Define the pt “Mr. XXX has CKD III secondary to DN, eGFR is 42 ml/min and he has 580mg/g proteinuria per 24 hours. His GFR has fallen 8 ml/min since he was last seen 6 months ago”. Conversion factor for urine protein creatinine ratio is multiply by 0.0088 to convert mg/mmol to g/24 hours. Quick method: divide by 100 = approximation of g/24 hours. Anaemia Check and replete iron stores: ferritin >100 ng/mL, Tsat > 20%. Iron absorption poor in CKD pts; consider course of IV iron. Epo replacement when Hgb 9-10. Goal Hgb controversial following TREAT trial, which showed an excess of CVD in Epo treated pts with CKD. Atherosclerosis Cholesterol: In SHARP trial, Simvastatin and ezetimibe lowered CV events in advanced CKD (Baigent, Lancet 11). Some evidence that statins may slow GFR decline. Target LDL < 1.8 mmol/L in diabetic pts; < 2.6 mmol/L in non-diabetic pts with kidney disease. Other: Low-dose aspirin deemed safe in CKD (Pierrucci; NEJM 89;320:421 and Patrignani;JCI 82;69:1366). Smoking cessation. Albumin (Nutrition) Nutritional assessment: serial weights, albumin. Weight loss and malnutrition are compelling indications to start RRT. Anti-angiotensin Slows decline in GFR, most established in proteinuric CKD. High dose ACEi or ARB for all diabetic and proteinuric pts. therapy Maximise angiotensin blockade in proteinuric renal disease. Acidosis, Anions, Cations (K+ and HC03) Hyperkalemia Target serum K+ level < 5.5 mmol/L. Hyperkalaemia suggests interstitial disease if it occurs when GFR is reasonably preserved. Metolazone is most effective thiazide diuretic when GFR is reduced. Approach (1) Review, adjust Meds (ACE/ARB) (2) Add diuretics (3) low K diet (4) consider chronic calcium resonium. Acidosis Mounting evidence that correcting acidosis slows progression of CKD and improves muscle strength, without causing HTN or vol. overload (Simon et al. CJASN 2013). Symptoms of acidosis can mimic uraemia. Goal HC03 22-24 mmol/L. Increasing fresh fruit and veg in diet as effective as PO NaHCO3, without producing hyperkalemia (Goraya CJASN 2013). May also give NaHCO3 650 bd OR Baking Soda 1/2 - 1 Tsp dissolved in juice bd; treatment can also improve hyperkalemia. Uric acid Gout: Avoid NSAIDs. Use Colchicine (0.6mg every-other-day or daily), possibly Allopurinol (e.g. 100-200 mg/day), and/or short-term prednisolone. Allopurinol toxicity increased with CKD, Thiazide. Do not start during acute flare (Emmerson;NEJM 96;334:445). Consider Losartan (max dose), the only uricosuric ARB. Arterial BP Lower BP: General target is <140/90 mmHg. Some evidence that <130/80 may slow progression of CKD (Parving;Lancet 83;1:1175 and Peterson;AIM 95;123:754). Targeting 120/80mmHg associated with adverse outcomes (ACCORD-BP: NEJM 2010). Arterial Monitor calcium, phosphorous, parathyroid hormone (PTH). Calcification Phosphate binders when Pi abnormal. Consider when eGFR <25 even if Pi normal. Check intact PTH: Rx with Vit D analogue (1alpha 0.25mcg 3/wk) if > 200 pg/mL. Check 25 Vitamin D: If < 15, cholecalciferol 1500 IU/day x 12 wks (e.g. ‘D-Pearls’). Access Counsel pt to protect non-dominant arm for venepuncture. Referral to vascular access surgeon when eGFR or creatinine clearance <20mL/min. Maximise the number of pts with an AV fistula in place. Follow in low clearance clinic. Avoidance of Counsel pts to avoid NSAIDs, minimise exposure to contrast agents. nephrotoxic drugs Adjust the dose of renal-cleared drugs as needed. Allograft Timely referral for transplant evaluation and advocacy for pt during evaluation process. Goal is pre-emptive renal transplantation. Confirm pt has watched all Beaumont educational videos on the website. 38 RENAL HANDBOOK


RENAL CONSULTS

MICROSCOPIC HEMATURIA BACKGROUND  Definition: >2 - 3 RBCs/HPF is considered abnormal (Cohen;NEJM 03;348:2330)  Dipsticks can detect as little as 1 RBC per HPF and are therefore overly sensitive.  When significant proteinuria (>150-300 mg/gm) or renal insufficiency is present, the kidney should be the presumed source of haematuria until proven otherwise.  When proteinuria is absent, haematuria is referred to as “Isolated Hematuria.”  Best data on long-term data on outcomes in young adults with isolated microscopic haematuria is from Vivante et al. (JAMA. 2011;306(7):729-736), using medical data from over 1 million 16-25 year olds assessed for military service: isolated microscopic haematuria present in 0.3%; during 20 years of follow-up, ESRD developed in 0.7% (HR for ESRD = 19.5). Thus, persistent asymptomatic isolated microscopic haematuria significantly increased the risk of ESRD over 22 years, although the incidence and absolute risk are low. This creates a conundrum for following these pts. EVALUATION  Bright Light and Phase Contrast Microscopy to assess for glomerular bleeding.  Helical CT: First without contrast (identifies stones) then with contrast (identifies masses).  Urine Cytology (first morning urine x 3).  Cystoscopy: urology guidelines (Grossfeld;AFP 01;63:1145) = cystoscopy if age > 40 and other work up is neg. Alternative: cystoscopy if age > 50 or bladder cancer risk (smoking, exposure to dyes, CTX, phenacetin, aristolochic acid)--Cohen;NEJM 03;348:2330.  No cause is found in 20-70% of pts with isolated microscopic haematuria. Natural history in these cases appears generally benign (Howard;J Urol 91;145:335).  DDX Haeme + Dipstick without RBCs on microscopy: haemoglobinuria, myoglobinuria, ascorbic acid, Providine iodine contamination. (Chan;NEJM 03;349: 1292).  US nephrologists rarely perform kidney biopsies on pts with isolated glomerular haematuria because therapy is generally not altered by the findings (McGregor;Clin Neph 98;49:345). CAUSES OF GLOMERULAR HEMATURIA (see Cohen;NEJM 03;348:2330 and Steele;NEJM 04;351:2851) IgA Nephropathy

Thin Basement Membrane Disease

Alport’s Syndrome

Other sub-acute GN

NON-GLOMERULAR CAUSES OF HEMATURIA Structural Kidney Diseases Medullary Cystic Disease, PKD, renal trauma or infarction, including emboli, papillary necrosis, sickle cell disease. Kidney Stones

Symptomatic or asymptomatic.

Hypercalciuria or Hyperuricosuria See: Andres;KI 89;36:96. Structural urologic problems

Includes ureteral, urethral or meatal strictures, prostatitis. May occur with or without hydronephrosis.

Cancer or Polyps, benign or malignant

Bladder polyps or cancer, prostate cancer, ureteral transitional cell cancer, renal cell cancer.

Infection

Bacterial cystitis or pyelonephritis, Schistosomiasis, Renal TB.

Menstrual bleeding

Mid-stream specimen collection may reduce contamination.

‘Exercise Hematuria’

Haemoglobinuria if dipstick positive, microscopy negative. RENAL HANDBOOK 39


RENAL CONSULTS

KIDNEY DISEASE IN THE CANCER PATIENT See Humphreys: JASN. 2005 Jan;16(1):151-61 Cause Pre-renal / ATN

Clinical Features and Details

Malignancy associated GN

(1) Minimal change associated with Hodgkin’s and other lymphoproliferative disorders(2) Membranous nephropathy –associated with carcinomas especially lung, GI and other solid tumours (Lafaucheur;KI 2006;70:1510) (3) MPGN.

Tumour lysis syndrome

Medical emergency - hyperkalemia can be severe. Renal failure from (1) uric acid nephropathy— urate usually > 800; (2) phosphate nephropathy (ca-phos deposition). (Rampello;NCP Onc 06;3(8):438). Use high volumes 0.9% saline to keep urine output >200ml/hr; Allopurinol; rasburicase; high dose dialysis.

Hypercalcemia

Causes vasoconstriction of afferent arteriole and volume depletion by inducing nephrogenic diabetes insipidus, which can result in further rise in the calcium.

Chemotherapy toxicity

(1) Cisplatin: tubular toxin also causes Mg wasting--Pabla;KI 08;73:994), (2) ifosfamide: chronic interstitial damage and proximal RTA, (3) methotrexate: crystal induced RF at high doses, manage nephrotoxicity with high dose Leucovorin (150mg/m2 q6) based on MTX levels, HD, thymidine and CPDG2 (4) gemcitabine: HUS/TTP (Humphreys;JASN 05;16:151), (5) avastin: proteinuria and HTN (Zhu;AJKD 07;49:186). See de Jonge;Sem Onc 06;33:68.

Medication toxicity

(1) Aminoglycosides, (2) Bisphosphonates: Pamidronate (collapsing GN) or Zolendronate (ATN), (3) high dose acyclovir (crystal-induced renal failure), (4) amphotericin.

Tumour infiltration of kidney

Associated with myeloma, lymphoma, rarely lung, breast, solid tumours. Rarely severe enough to cause RF.

Urinary tract obstruction

(1) Bilateral ureteric obstruction from retroperitoneal cancer tissue (esp. gynaecological), nodes or fibrosis (2) Bladder outlet obstruction: prostate or bladder ca.

TTP-HUS syndrome

Generally associated with advanced, metastatic (adeno) carcinomas. More common with chemotherapy.

Paraproteinaemia

Cast nephropathy, Monoclonal Ig deposition or amyloid (myeloma/lymphoma).

Renal vein thrombosis

Associated with membranous GN and myeloproliferative disorders and secondary membranous GN.

Contrast nephropathy

Risk higher if volume depletion (e.g. mucositis or poor PO intake) present.

Radiation nephritis

Presentation: rising creatinine, hypertension, disproportionate anaemia several years after XRT. See Cohen;Sem Neph 03;23:486.

VEGF inhibitors

HTN and proteinuria a class effect, Amlodipine best treatment. Cessation of drug not indicated unless PRES.

Stem cell / bone marrow transplant related

Early (1st month): (1) ATN from sepsis / infection / contrast / drugs (amphotericin, CNIs), (2) Sinusoidal obstruction syndrome (similar to hepatorenal syndrome). Later: (1) thrombotic microangiopathy (usually subacute), (2) glomerular disease (membranous GN, minimal change GN) – often associated with GVHD, (3) recurrence of disease e.g. myeloma, (4) CNI toxicity.

40 RENAL HANDBOOK

Very common. Poor PO intake, GI or other losses, sepsis from neutropenia, infections.


RENAL CONSULTS

KIDNEY DISEASE IN THE HIV POSITIVE PATIENT Cause Pre-renal injury or ATN

Clinical Features and Details

Obstruction

Retroperitoneal masses or nodes (TB, MAI, lymphoma) can obstruct ureters.

Ischemic nephropathy (syn. atherosclerotic reno-vascular disease)

Slowly rising creatinine, HTN, low grade proteinuria. Reflects high incidence of atherosclerosis, dyslipidaemia, glucose in tolerance (Friis;NEJM 03;349:1993).

Immune-complex GN

Patterns include (1) SLE-like syndrome; (2) IgAN, (3) Non-specific IC; (4) Hep C GN. Appears to be more common in Caucasians (Fine; AJKD 08;51:504).

Tubulointerstitial nephritis

Appears more common in HIV disease, is associated with TB and with medications such as Ethambutol, Rifampin, and Co-trimoxazole, PPIs, Phenytoin.

Drug toxicity

Clinical Features: slowly rising creatinine, low grade (tubular) proteinuria +/- tubular dysfunction with acidosis, diabetes insipidus. Hematuria and HTN rare. Nucleotide RTIs: Tenofovir (TDF, ‘Viread’; ingredient in Truvada, Atripla) = ARF, proteinuria, Fanconi’s, DI- see Zimmermann;CID 06;42:283. Nucleoside RTIs (lamivudine, zidovudine, emtricitabine, stavudine, abacavir) =ARF/CKD (rare), proximal tubular injury via mitochondrial cytopathy (Daugas;KI 05;67:393). Protease inhibitors: Ritonavir (Norvir; ingredient in Kaletra) may cause ARF in high dose and enhance TDF toxicity by inhibiting P Glycoprotein path. Indinavir causes nephrolithiasis and ARF. Non-nucleoside RTI’s (nevirapine, efavirenz), Integrase inhibitors (Isentress/raltegravir) and CCR5 Entry Inhibitors (Selzentry/maraviroc) have minimal renal toxicity though experience is limited with last 2 classes. Dose reduction is required in CKD for nucleotide, nucleoside RTIs (except Abacavir) or fixed dose combinations (e.g. Trizivir, Atripla, Truvada) (Ahuja;AJKD 03;41:279).

HIV associated TTP/HUS

Clinical Features: Hypertension, MAHA, haematuria, low grade proteinuria (Alpers;KI 03;63:385). Common cause of ARF in some series (Peraldi;NDT 99;14:1578). Rx: consider PEX, IV immune globulin, glucocorticoids.

HIV Nephropathy

Demographic: Black, mixed-race, CD4<200, rarely in pts stable on HAART. Clinical Features: Nephrotic Syndrome, often without oedema due to tubular Na wasting, +/haematuria. Ultrasound: large, echogenic kidneys. Pathology: Collapsing FSGS with microcystic tubular dilatation and lymphocytic infiltrate. Tubuloreticular Inclusions (TRIs) are now less common with HAART. HIV is directly pathogenic to podocytes, which serve as reservoir for infection. Treatment: (1) HAART (Atta;NDT 06;21:2809) (2) ACEi (anti-proteinuric and possibly antiretroviral-Klotman;AJKD 98;31:719). Corticosteroids may be effective by lowering cytokines/NFKB (Eustace;KI 00;58:1253). Recovery from dialysis has occurred following initiation of HAART (Winston;NEJM 01;344:1979).

Baseline sodium wasting (HIV tubulopathy) increases susceptibility to diarrhoea, poor PO intake, IV Contrast, rhabodymyolysis. Sepsis more common.

RENAL HANDBOOK 41


RENAL CONSULTS

KIDNEY DISEASE IN THE PATIENT WITH LIVER DISEASE Cause Pre-renal injury

Clinical Features and Details

Tubular injury (ATN)

Perhaps most common cause of ARF in cirrhosis, precipitated by chronic pre-renal state plus bacterial infections (e.g. SBP) or medications (NSAIDs, ACE/ARB).

Glomerular disease

Hepatic IgA Nephropathy = most common secondary form of IgA nephropathy. Common in ETOH cirrhosis (50-90%) and Hep C (Pouria;NDT 99;14:2279). Hep C associated MPGN Type 1, with or without Cryoglobulinaemia. In [McGuire;AIM 06;144:735], 25 of 30 HCV + pts undergoing liver transplant had MPGN, IgA or other immune complex deposition demonstrated on kidney biopsy. Hep B associated Membranous (usu HepBeAg +). Adefovir to Rx Hep B=nephrotoxic. Rare: HCV-assoc fibrillary / immunotactoid GN, Post-infectious MPGN from SBP, MPGN secondary to AT1 deficiency, ‘Hepatic glomerulosclerosis’= MPGN +/- IgA/IgM dep. (Axelsen;Path 95;27:237)

Hepatorenal syndrome

Types: Type 1 = progresses over ~2 weeks, Type 2 = over weeks to months. Diagnosis= (1) bland urinalysis and proteinuria <0.5 gm/day (2) normal renal u/s (3) absence of shock or active bacterial infection, GI or other fluid loss or exposure to toxic medications (4) no response to 1.5 -2 litre volume challenge (Arroyo;Hepatology 96;23:164). Urine Na < 10 and urine output < 500 ml/day usually present. Reasons to doubt the diagnosis: (1) BP not low (2) absence of ascites/oedema (3) any urinary findings (e.g. proteinuria, pyuria) (4) pt survives without liver transplant. Treatment: colloid +/- crystalloid/frusemide (Peron;Am J Gastro 05;100:2702) to raise MAP 5-10 mmHg, CVP>3; Midodrine & Octreotide (Anjeli;Hepatol 99;29:1690); Vasopressin (requires high dose—Kiser;NDT 05;20:1813); renal replacement therapy, TIPS (Brensing;Gut 00;47:288); liver transplant. Review: Wadei;CJASN 06;1:1066.

Paracetamol toxicity

ATN-like ARF with or without hepatic failure. Risk factors = glutathione deficiency (starvation, ETOH, fasting), anti-convulsants. Value of N-acetyl cysteine for ARF uncertain. Recovery usual but prolonged (7-20 days). Blakely;JASN 95;6:48, Alkhuja;NDT 01;16:190.

Abdominal compartment syndrome

Risk factors=cirrhosis, ascites, abdo surgery, sepsis, obesity, high PEEP, volume overload. Mechanism =SVC + renal vein compression. Intra-abdominal pressure >12 cm/H2O=mild organ dysfunction, >20 cm/H2O + organ dysfunction = abdominal compartment syndrome. Rx: 1. Optimise haemodynamics to keep abdo. Perfusion pressure >50-60 (APP=MAP-IAP); 2. Head down vent/NG Suction; 3. Paracentesis or surgery (Malbrain;Int Care Med 06;3;2:1722).

Cholemic nephrosis

Hyperbilirubinaemia (>400 umol/l) may result in tubular injury and renal failure in absence of portal hypertension (‘Cholemic Nephrosis’) (Betjes;J Neph 06;19:229). Bilirubin-pigmented granular casts are typically present.

Cirrhosis causes chronic ‘pre-renal’ physiology due to: splanchnic vasodilatation, low renal blood flow (Jalan;Gut 97;40:664) and hypoalbuminaemia. Additional pre-renal insults include GI bleeding, over-diuresis, third spacing (e.g. pancreatitis), NG suction, or large volume paracentesis (LVP) esp. without albumin, diarrhoea from lactulose.

FOOTNOTE: Serum creatinine overestimates true GFR in cirrhosis due to extreme cachexia. Bile acids appear to contribute directly to sodium retention in cirrhosis by inhibiting 11 -hydroxy steroid dehydrogenase (Quattropani;JCI 01;108:1299). Hepatitis-B associated Polyarteritis Nodosa can result in renal infarcts. Acute portal vein thrombosis is assoc with renal failure, +/- renal vein thrombosis. 42 RENAL HANDBOOK


RENAL CONSULTS

DIFFERENTIAL DIAGNOSIS OF KIDNEY DISEASE IN THE MEDICAL PATIENT RENAL FAILURE AND LUNG DISEASE  Pneumonia and ATN.  ANCA-Associated Vasculitis.  Anti-Glomerular Basement Membrane Disease.  Cryoglobulinemic Vasculitis - with or without Hep C (Prasad;NEJM 06;355:2468).  Catastrophic Anti-Phospholipid Antibody Syndrome.  Lupus Vasculitis (Bosch;Lupus 1999;8:258).

 Polyarteritis Nodosa.  Infectious pneumonia + infectious-related glomerulonephritis.  Ehler-Danlos (Pulmonary Haemorrhage + Renal Artery Aneurysms).  Sickle Cell Crisis (chest crisis + acute renal failure).  Pulmonary embolus with renal vein thrombosis in membranous nephropathy.

RENAL FAILURE AND EYE DISEASE  Diabetes.  Hypertension.  ANCA-Associated Vasculitis (ocular and orbital inflammation).  Anti-Phospholipid Antibody Syndrome (Magee;NEJM 08;358:274).  Systemic Lupus Erythematosus (choroiditis).  Alport’s (lenticonus/anterior cataracts).  TINU (Tubulointerstitial Nephritis and Uveitis).  Sjogren’s.  Familial Proximal RTA.  Fabry’s Disease (corneal abnormalities).  Dense Deposit Disease.

 Juvenile Nephrosis—Medullary Cystic Disease complex (degeneration of retinal pigmented epithelium).  Von Hippel Lindau (retinal haemangioblastomas).  Uremic optic neuropathy (Korzets;Am J Neph 98;18:240).  Cystinosis (corneal cystine crystal deposition: Servais;CJASN 08;3:27).  Endocarditis (Retinal [Roth spots] + renal emboli or infectious GN).  Red Eyes and Renal Failure (calcium-phosphate deposition in advanced uraemia).  MELAS syndrome (retinal atrophy and deafness).

RENAL FAILURE AND ENT DISEASE  Alport’s.  Distal RTA associated with deafness.  Cocaine.

 Mitochondrial disease (MELAS and other) assoc with deafness, FSGS, diabetes, lactic acidosis  Granulomatous Polyangiitis (Wegener’s granulomatosis)

RENAL FAILURE IN PATIENT WITH ATHEROSCLEROTIC CVD  IV contrast exposure.  Atheroembolic disease (post-cath, spontaneous or anticoagulation-related).  Renal artery thrombosis secondary to HIT.  Macro- or micro-vascular renal artery stenosis.

 Renal vascular occlusion by intra-aortic balloon pump or dissection.  Diabetic nephropathy.  Cardiorenal syndrome.

RENAL FAILURE AND BOWEL DISEASE  Oxalate nephropathy: malabsorption leads to saponification of calcium in small bowel, less calcium to bind oxalate, excessive absorption and hyperoxaluria. Seen in malabsorption states, terminal ileal disease and with use of Orilstat.  Salicylate allergy: e.g. Mesalazine for inflammatory bowel disease.  Mechanical injury to ureter during bowel surgery.

 AA amyloidosis in IBD or cystic fibrosis (also causes nephrolithiasis, DN, GN, chronic interstitial nephritis).  Coeliac disease associated IgAN.  GI lymphoma associated with IgAN.  Polyarteritis Nodosa.  Encapsulating peritoneal sclerosis.

RENAL HANDBOOK 43


RENAL CONSULTS

DIFFERENTIAL DIAGNOSIS OF KIDNEY DISEASE IN THE MEDICAL PATIENT CONTD. RENAL FAILURE AND BLAND URINE  Pre- or post-renal failure.  Vascular diseases, e.g. vascular catastrophe (dissection, thrombosis), atheroemboli, TMA, scleroderma renal crisis.  Myeloma and other paraprotein-related kidney disease.  Hypercalcemia.

 Tubulointerstitial nephritis, sometimes.  ATN, sometimes.  Phosphate nephropathy.  Oxalate nephropathy from enteric oxalosis.

RENAL FAILURE AND PURPURA / RASH  Post-infectious GN.  IgA nephropathy / Henoch Schonlein Purpura.  ANCA-associated vasculitis.  Systemic Lupus Erythematosis.  Cryoglobulinaemia.  Serum sickness (e.g. post monoclonal Ab therapy).  Atheroembolic disease.

 Amyloidosis.  Waldenstrom’s.  TTP-HUS.  DIC.  Parvovirus.  HIV.

RENAL FAILURE AND HEART FAILURE  Decompensated LVF with secondary AKI due to high venous pressures or renal hypoperfusion;  Diuretic-induced AKI in the mgmt of LVF;  Amyloidosis: clue to diagnosis: CCBs, BBs and digoxin are poorly tolerated and cause exacerbation;  Monoclonal immunoglobulin deposition disease;

 Pericardial effusion causing tamponade;  Ischemic cardiomyopathy and renovascular disease;  CKD from any cause plus secondary diastolic HF from LVH;  Fabry’s: CKD, proteinuria, cardiomyopathy, early CAD;  High output HF from AV fistula;  Cor pulmonale from sleep apnoea, frequent in CKD population.

RENAL FAILURE AND ABNORMAL FBC  Low platelets: TTP-HUS, APLS, HIT with renal artery or vein occlusion;

 Eosinophilia: Churg-Strauss, AIN, atheroembolic disease;  Pancytopenia: Malignancy-associated GN, tumour lysis syndrome.

OEDEMA  Cardiac: LVF; tamponade; constrictive pericarditis; restrictive CM; cor pulmonale.  Nephrotic syndrome.  Advanced CKD.  Renal artery stenosis: bilateral severe or in single kidney.  Cirrhosis  Hypoalbuminaemia: difference in oncotic pressures between vascular and interstitial spaces is key. Hypoalbuminaemia of recent onset more likely to be causal than chronic, stable low albumin.

44 RENAL HANDBOOK

 Hypothyroidism  Medications: CCBs, NSAIDs, TZDs, oestrogens, gabapentin, Gleevec  Capillary leak in allergy of critical illness  Venous problems: IVC or iliac vein obstruction; pelvic mass; DVTs;  Sirolimus induced lymphoedema with proteinuria.


RENAL CONSULTS

ACUTE INTERSTITIAL NEPHRITIS Clinical Presentation: Acute kidney injury (oliguric or non-oliguric-- Galpin; Am J Med 1978;65:756) from tubulointerstitial inflammation. Allergic variant=fever, rash, arthralgia, eosinophilia, eosinophiluria occurs in only 15% (Ruffing;Clin Neph 94;41:163). Hypertension, flank pain, enlarged kidneys variably present. (Karras:Am J Emerg Med 94;12:67). FENa>1%. Urinalysis = haematuria (micro or macro) in >90%, WBCs, WBC casts. Proteinuria = 1-2 g/day. NSAIDs = AIN + Minimal Change = Nephrosis. Pathology: Inflammatory interstitial infiltrate of lymphocytes, macrophages, and plasma cells, along with oedema and tubular damage which may be confused with ATN. Blood vessels & glomeruli are spared. Antitubular basement membrane variant: TBM is immunofluorescence positive for IgG and C3 (Neilson;KI 89;35:1257). Pathogenesis: T-cell response to endogenous, infectious, or drug antigen haptens. Mgmt: (1) Withdraw potentially inciting medications and agents and treat relevant infections; (2) Retrospective data indicates less need for long-term dialysis, lower final creatinine with steroids (Gonzalez KI). Consider (a) Prednisolone 1 mg/kg for 2-3 week trial, continue 4-6 weeks if renal function improves (Neilson;KI 89;35:1257); OR IV Methylpred (Pusey;QJM 1983;52:194); OR CYC OR CyA (Shih;KI 88;33:1113). Maintenance with AZA if relapsing.

CAUSES OF ACUTE TUBULOINTERSTITIAL NEPHRITIS Etiology Drug hypersensitivity

Infections

Specific Cause

Comments

Ax: Penicillins, Rifampin, Sulfa NSAIDs PPIs and Cimetidine Diuretics Allopurinol Anti-convulsants including phenytoin

5-6 days of exposure to a drug required but previous exposure to the drug can dramatically accelerate syndrome. Ax and NSAIDs commonest. PPIs also common; tend to present subacutely AIN associated with loop diuretics appears to be extremely rare. Herbs / dietary supplements.

Without kidney infection

Classically seen in association with streptococcal and diphtheria infections. Legionella, Leptospirosis, toxoplasmosis, EBV, mycoplasma, CMV, polyomavirus, measles, TB (Larsen:AJKD 08;51:524).

With kidney infection Systemic disease

Seen in association with SLE, Sjogrenâ&#x20AC;&#x2122;s, Sarcoidosis and ANCA disease.

Other

(1) TINU: Tubulointerstitial nephritis in association with anterior uveitis which can proceed or follow the renal lesions. (2) IgG4 associated: IgG4 +ve plasma cells on renal biopsy.

RENAL HANDBOOK 45


RENAL CONSULTS

HYPERTENSION DIFFERENTIAL DIAGNOSIS OF SECONDARY HYPERTENSION Category Kidney disease

Potential Cause

Renovascular disease

Atherosclerotic renal artery stenosis. Fibromuscular dysplasia. Thrombotic Microangiopathy (SLE or APLAS associated). Takayasu’s Arteritis. Polyarteritis Nodosa (usually with Hep B). Renal artery lesions associated with APLAS. Consider stenoses proximal to renal artery e.g. iliac stenoses in kidney transplant pts.

Endocrine

Hyperaldosteronism (hypokalemia may be absent). Hyperthyroidism (raises SBP) or Hypothyroidism (raises DBP). Pheochromocytoma. Cushing’s Syndrome. Carcinoid. Reninoma (very rare).

Neurologic

Cluster or migraine headaches, CNS lesions, stroke, cerebral oedema, seizures.

Medications (prescription)

OCPs, glucocorticoids, anabolic steroids, CNIs, TCAs, MAO inhibitors, VEGF inhibitors.

OTC medications

NSAIDs, cold remedies incl. decongestants, appetite suppressants.

Lifestyle

High salt diet in ‘salt sensitive’ (African American, age > 60, obese, CKD). Tobacco, alcohol, cocaine, amphetamines, LSD, chewing tobacco. Dietary Supplements-- Ephedra, Liquorice.

Systemic disease

TTP/HUS. Scleroderma. Acute intermittent porphyria. Aortic Coarctation (if age> 40, usually with CV disease; age >50=high mortality). Obstructive Sleep Apnoea (due to hyperadrenergic state).

Psychiatric

Paroxysmal Hypertension (‘Pseudopheochromocytoma’), panic attacks.

Genetic defects in Na handling (generally associated with hypokalemic metabolic alkalosis)

Glucorticoid Remedial Hypertension. Apparent Mineralocorticoid Excess (11 beta steroid dehydrogenase deficiency). Pregnancy Induced Hypertension (progesterone driven). Liddle’s Syndrome (activating mutation of ENaC channel). Gordon’s Syndrome (activating mutation WNK channel; hyperkalemic).

46 RENAL HANDBOOK

CKD / low GFR from any cause. Glomerulonephritis. Polycystic Kidney Disease. Page kidney (compression by hematoma, cyst etc).


RENAL CONSULTS

HYPERTENSION CONTD. EVALUATION OF SECONDARY HYPERTENSION Component History

Check

Physical exam

BP in both arms. HR (tachycardia = elevated sympathetic tone, suggesting thyroid disease, pheo, volume overload -- Graves;Am J Med Sci 89;298:361]. Head and neck: Optic Fundi and thyroid (goitre or bruit). Volume status. Cardiac exam: murmurs, S4. Radial / femoral pulse differences AND radial / radial differences. Abdominal bruits / carotid bruits. Neurologic exam: reflexes, clonus, focal deficits.

Labs

(1) Urinalysis, electrolytes/urea/ creatinine, Ca, Pi, LFTs, Uric Acid, lipids, CBC, TFTs, ANA, anti-phospholipid antibodies, anti-SCL-70. (2) Plasma Aldosterone Concentration and Plasma Renin Activity. (3) 24 hr urine for (a) aldosterone (b) free cortisol (c) protein, (d) sodium, (e) creatinine (use plain container for collection). (4) 24 hr urine for (a) catecholamines (b) metanephrines (use acid-containing container for collection). (5) Plasma metanephrines (drawn from IV placed 20 min earlier). Lenders: JAMA 02;287:1427. Sensitive test; eliminates needs for urinary testing if normal. False +ve if Buspirone, labetolol. Only for equivocal cases based on urine testing at present.

Imaging

Abdominal CT / MRI if testing suggests pheo or hyperaldosteronism. CT / MR angiogram or formal angiography if testing suggests renovascular hypertension. ECHO: assess for LVH, coarctation (Devereux;JAMA 04;292:2350).

Meds / OTCs / ETOH/ Illicits / Supplements. H/o palpitations, sweating, headache, spells. Snoring and/or daytime somnolence. Pregnancy history: pre-eclampsia, pregnancy-induced hypertension, etc. Family history of hypertension including age of onset.

24 hour BP monitoring Exclude â&#x20AC;&#x2DC;white-coatâ&#x20AC;&#x2122; hypertension by 24hr BP monitor.

RENAL HANDBOOK 47


RENAL CONSULTS

HYPERTENSION CONTD. HYPERTENSIVE EMERGENCIES Aspect Hypertensive emergency syndromes

Clinical Features and Details

Pathophysiology

Initial physiological response to HTN is arteriolar vasoconstriction, which prevents pressure transmission to delicate distal vessels. Vasoconstriction is eventually overcome by increasing BP, causing pressure-induced endothelial injury, fibrinoid necrosis, organ dysfunction and the clinical syndromes above.

Importance of clinical assessment

The BP at which fibrinoid necrosis occurs depends upon the baseline BP. Although HTN emergencies usually assoc with BP ≥180/120 mmHg, they can occur at much lower levels (e.g. 140/90mmHg) in children, young women (pre-eclampsia) or athletes. Posterior leukoencephalopathy on MRI (T2-weighted) is helpful in diagnosing such cases. Conversely, DBP > 110 mmHg may be well tolerated in patients with longstanding HTN (e.g. ERSD), and rapid BP lowering is not indicated or even harmful.

Work-up

Obtain MRI for neurologic symptoms (even N, V or restlessness) to exclude CVA (avoid aggressive BP reduction) and diagnose posterior leukoencephalopathy. Defer secondary HTN work-up until stable (page 47).

Treatment

Parenteral in CCU/ITU treatment is generally indicated, see table below.

Goal of therapy

Lower DBP to 100-105 mmHg over 2-6 hrs (max = 25% drop from initial BP). Once this target is reached, switch to oral therapy. Goal BP 140/90 mmHg over 2-3 months. Often associated with worsening renal function that may reverse over subsequent 1-3 mos.

Malignant HTN: marked HTN, retinal hemorrhages, exudates, or papilledema. Hypertensive encephalopathy: insidious onset of headache, N, V, non-localising neurology (restlessness, confusion, seizures, coma). Note, most patients with significant HTN (e.g. DBP ≥120 mmHg) do not have acute, end-organ injury. Rapid lowering of BP may be harmful in such cases. As such, the clinical presentation is essential in the triage and management of such patients.

Management of specific hypertensive emergencies CVA, SAH or ICH

Avoid aggressive BP lowering, as may worsen cerebral ischaemia.

Acute pulmonary oedema

HTN in acute systolic LVF due is treated with vasodilators e.g. GTN and loop diuretic. Avoid hydralazine (increases cardiac work). Caution beta blockers.

Angina pectoris or acute MI

Beta blockers 1st line; IV vasodilators e.g. GTN may reduce mortality in patients with acute MI. Avoid hydralazine (increases cardiac work).

Aortic dissection

IV beta blocker to reduce the HR < 60 beats/min and maintain SBP 100-120 mmHg or the lowest tolerated level. Additional agents only after first controlling HR.

Abrupt cessation of sympathetic blocker

E.g. clonidine or propranolol can lead to severe HTN and coronary ischemia. Reinstitute the drug +/- phentolamine, nitroprusside, or labetalol.

Acute increase in sympathetic activity

E.g. (1) pheochromocytoma; (2) ANS dysfunction, e.g. Guillain-Barré, post-spinal cord injury; (3) drugs, e.g., cocaine, amphetamines, phencyclidine; and (4) tyramine reaction: MAOI and tyramine-containing food (cheese, aged meats, Chianti, champagne, avocados). Beta blockers alone are contraindicated, cause paradoxical worsening of HTN via unopposed alpha-adrenergic vasoconstriction.

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HYPERTENSION CONTD. DRUGS USED IN THE MANAGEMENT OF HYPERTENSIVE EMERGENCIES Drug

Dose

Sodium nitroprusside

0.25-10 μg/kg/ min IV infusion

Nicardipine 5-15mg/h IV hydrochloride Nitroglycerin

5-100 μg/min as IV infusion

Onset of action Immediate

Duration of action 1-2 min

Adverse effects

Special indications N, V, muscle twitching, sweating, Caution if high ICP or thiocynate and cyanide intoxication CKD.

5-10 min

15-30 min, may Tachycardia, headache, flushing, exceed 4 h local phlebitis

2-5 min

5-10 min

Avoid in acute LVF and coronary ischaemia

Headache, V, methaemoglobinemia, Coronary ischaemia tolerance with prolonged use

Hydralazine 10-20mg IV hydrochloride or 10-40mg IM

10-20 min IV 1-4 h IV 20-30 min IM 4-6 h IM

Tachycardia, flushing, headache, V, aggravation of angina.

Eclampsia

Labetalol 20-80mg IV bolus hydrochloride q10min or 0.5-2.0 mg/min IV infusion

5-10 min

3-6 h

Vomiting, scalp tingling, bronchoconstriction, dizziness, nausea, heart block, orthostatic hypotension.

Most hypertensive emergencies except acute heart failure

Phentolamine 5-15 mg IV bolus

1-2 min

10-30 min

Tachycardia, flushing, headache.

Catecholamine excess

MANAGEMENT OF RESISTANT OR DIFFICULT-TO-MANAGE HYPERTENSION Resistant hypertension: uncontrolled HTN despite ≥3 agents, one of which is a diuretic, at best tolerated doses; exclude apparent or pseudo-resistant hypertension by 24hr BP monitor; consider non-compliance and lifestyle factors (above). Typical pt: older (>75 years), high baseline BP, longstanding uncontrolled HTN, target organ damage (LVH), diabetes, obesity and atherosclerotic vascular disease. Aortic stiffening, manifest as a wide pulse pressure, is commonly present. Pts that do not fit this characterisation are more likely to have an identifiable underlying secondary cause of HTN, with underlying kidney disease a common finding. Medical treatment points:  Use drugs with synergistic actions (A+C+D): e.g. ARB (Irbesartan 300-600mg) or ACEi + CCB (Amlodipine 10mg) plus thiazide (chlorthalidone 12.5-25mg is superior to hydrochlorothiazide, although not easily available).  Fixed dose combinations improve compliance e.g. Konverge plus, Exforge plus.  If a 4th drug is required, low dose spironolactone (S) (25-50mg OD if K ≤4.5 mmol/L) is preferred. Substitute amiloride or eplerenone if breast tenderness or gynaecomastia develop, although not as effective.  If K >4.5 mmol/L, double the dose of the thiazide diuretic.  Vasodilating beta blockers (Labetalol, Carvedilol, or Nebivolol), centrally acting agents (clonidine), and direct vasodilators (Hydralazine or Minoxidil) may be added sequentially after (A+C+D+S).  Selective β blockers are not 1st choice antihypertensive agents, and may exacerbate BP variability.  Renal sympathetic denervation therapy is a promising future intervention for resistant hypertension.

RENAL HANDBOOK 49


RENAL CONSULTS

RECURRENT URINARY TRACT INFECTIONS Aspect Definitions

Notes

Presentation

Classic symptoms predictive: dysuria + frequency + haematuria w/out discharge =+ve culture >80%; -ve predictors= nocturia; persistence of symptoms after Rx.

Microbiology

E.coli (80%); S. Sapro (4%); Klebsiella (4%); Proteus (4%). Others= anatomical problem e.g. stone.

Risk factors

Premenopausal: Frequency of intercourse, spermicide use, new partner. Anatomic abnormalities uncommon. Postmenopausal: Oestrogen loss, anatomic RFs common (incontinence, prolapse, raised PVR); DM.

Urine dipstick

Nitrites: +ve result has high specificity (>90%) but low sensitivity (<50%), so –ve result does not rule out infection. Reasons for poor sensitivity: need for urine to be in bladder for >4 hours for reaction to occur and inability of some organisms to reduce nitrates (e.g. S. saprophyticus ). Leukocyte esterase: indicates pyuria. Organisms other than uropathogens can produce, so sensitive (>75%) but not specific (50%).

Urine culture

>100,000 CFU/HPF sensitivity for UTI only 50%; if symptomatic, >1,000 CFU/HPF has sensitivity 80% and specificity 90%. >20 epithelial cells suggests contaminated sample.

≥2 uncomplicated UTIs in 6 months or ≥3 positive cultures in a year; either relapse (same organism despite adequate Rx) or reinfection (more common; different organism or same with interval clearance).

Other investigations Measure post-void residual; screen for diabetes if FHx or obesity. Renal U/S and cystoscopy if unusual organisms on C+S or persistent haematuria. Rx of early recurrence Recurrence within 1 week suggests relapse: send pre-treatment C+S and give 7 day course of fluoroquinolone. Continuous antibiotic prophylaxis

Offer if ≥2 uncomplicated UTIs in 6 months or ≥3 in 12 months. Do not initiate prophylaxis until documented –ve culture 2 weeks post-treatment. Very effective: relative risk for clinical UTI 0.15 (0.08-0.28). Number needed to treat 2.2. No one antibiotic is superior; give for 6-12 months. Can extend to 2-5 years. Most revert to recurrent infections once stopped without additional intervention. Main side effects are nausea and candidiasis. More with nitrofurantoin (aplastic anaemia, polyneuritis, hepatotoxicity and lung toxicity). Give continuous prophylaxis at bedtime e.g. Nitrofurantoin 50-100mg od; Co-trimoxazole 240mg od; cephalexin 125-250mg od.

Postmenopausal women

0.5mg estriol cream vaginally nocte x 2 weeks then x2/week by 8 months. Reduces rate of UTI from 6/year to 0.5/year based on 2 small RCTs. Not = HRT; overall risk from oestrogen appears low.

Pregnant women at Offer continuous or post-coital prophylaxis with nitrofurantoin or cephalexin, except during last 4 weeks of risk for recurrent UTI pregnancy due to potential risk to foetus. Lifestyle modification

Switching from spermicidal contraception may help. Other lifestyle interventions (e.g. changing voiding habits, loose clothing, tights, hot tubs etc.) all unproven.

Cranberries

Appear effective. Meta-analysis of 4 RCTs: RR for UTI 0.66.

50 RENAL HANDBOOK


RENAL CONSULTS

NEPHROLITHIASIS 80% are Ca stones, usually CaOx or, less often, CaP, so reasonable to assume Ca-containing. Rarer types: uric acid (<10%), struvite (Mg-NH4-PO4), cystine (cystinuria: hexagonal crystals and urinary cystine >250 mg/l).

RISK FACTORS FOR CALCIUM-CONTAINING KIDNEY STONES Etiology Urinary

Specific Cause Lower volume Higher Ca Higher oxalate (CaOx stones)

Lower citrate

Higher pH (CaP stones) Hyperuricosuria

Comments

Increases calcium and oxalate concentration. Def: >0.1 mmol/kg/day. Seen in 50% of Ca stone formers. Usually idiopathic, consider primary hyperPTH or chronic acidaemia. Causes haematuria in the absence of stone. Def: > 0.5 mmol/day. Mainly results from reduced intestinal binding by Ca. Seen in enteric oxaluria (malabsorption of fatty acids and bile salts from malabsorption syndromes, Crohn's, bowel resection or diversion, jejunoileal bypass, bariatric surgery, CF). Also low dietary Ca or increased intestinal Ca absorption. Markedly increased levels in primary hyperoxaluria and Vit C toxicity. Def: <2.5 mmol/day. Citrate inhibits stone formation. Consider chronic acidosis from diarrhoea, RTA, carbonic anhydrase inhibitors (topiramate), ureteral diversion. Hypokalemia can trigger hypocitraturia. Alkaline urine (UTI, RTA, high dietary alkali intake) promotes CaP. CaOx stones not pH-dependent in physiologic range. Hyperuricosuria not a risk factor for Ca stones; consider urate stones.

Anatomic

Medullary sponge kidney Marked increase in Ca stones, esp. if hypercalciuria or hypocitraturia. Present in 12-20 % of calcium stone formers, and 20-30 % of women or < 20 years.

Diet

Lower fluid intake

Lower dietary Ca Higher oxalate Lower potassium High animal protein Higher sodium Higher sucrose Lower phytate Medical

Grapefruit juice is associated with an increased risk of stones. Coffee and tea: lower risk by 10 % per cup per day. Beer and wine: lower risk of stone formation. Increases risk, possibly by reduced binding of dietary Ox. Contribution of dietary intake is disputed. Effect of GI disease and intestinal Ca binding may be more NB. Response to dietary restriction variable. Higher dietary K reduces risk by reducing urinary Ca and increasing urinary citrate (K-rich foods often high alkali). DASH diet reduces risk. Increased stone risk in men via hypercalciuria and decreased urine citrate. Enhances excretion of urinary Ca. Increased stone risk in women. Increased dietary phytate (cereal, dark bread, beans) lowers risk.

Primary hyperPTH HyperCa often mild and intermittent. Pts prone to CaP stones. Distal (type 1) renal CaP stones secondary to hypercalciuria, hypocitraturia and high urine pH (>6.0) tubular acidosis Incomplete distal RTA causes hypocitraturia without overt metabolic acidosis. Suspect if urine pH > 5.3 plus low/normal serum tCO2 or nephrocalcinosis. Family history Positive FHx = RR of 2.6 for stones, heritability 50%. Dent's disease: X-linked recessive Cl channel mutation causing hypophosphataemia and hypercalciuria. RENAL HANDBOOK 51


RENAL CONSULTS

NEPHROLITHIASIS CONTD. EVALUATION OF FIRST STONE WITH NO RISK FACTORS FOR RECURRENCE AND NO ADDITIONAL STONES ON NON-CONTRAST HELICAL CT Test History

Notes

Stone composition

Send to lab for analysis

Likelihood of 2nd stone 50% at 10 years. Screen for RFs in previous table and medications (atazanavir, sulfadiazine, triamterene, topiramate, CAI’s).

Urinalysis and culture Urine sediment for crystals Urate, CaP or CaOx, Cystine (hexagonal, diagnostic of cystinuria), Mg-NH4-PO4 (struvite) suggesting upper UTI with urease-producing org (Proteus or Klebsiella). KUB or US at 1, 2 and 4 yrs for detection of new stones.

Monitoring

FULL WORK-UP FOR RECURRENT STONE FORMERS, INCL. THOSE PICKED UP INCIDENTALLY BY CT, OR RISK FACTORS* Test Serum calcium

Notes

Serum chemistry panel

To detect disorders assoc. with nephrolithiasis e.g. hyperuricemia, distal RTA (low/N HCO3).

2 x 24-hour urine collections

Obtain when free of pain, infection and obstruction and pt on "normal routine" wrt diet, fluid intake, and physical activity. Wait 1-2 mos after acute stone episode or intervention (e.g. ESWL). Perform minimum 2 collections and a 3rd if discrepancy between first 2 results.

Screen for primary hyperPTH. Repeat if high-normal (> midpoint of normal range), as primary often not frankly hypercalcaemic. Measure PTH if Ca in high-normal range or if high urine Ca. High index of suspicion in women and CaP stone formers.

Volume pH and acids PH > 7.5 and +ve urine culture are compatible with infection lithiasis, whereas pH < 5.5 favours uric (urate, citrate, oxalate) acid lithiasis. Role of urate, citrate and oxalate discussed below. Calcium Hypercalciuria. Sodium Increased Na increases urinary Ca excretion and blunts response to thiazides for hypercalciuria. Creatinine To assess completeness of collection. Normal 24-hr urinary creatinine: 177-221 μmol/kg (20-25 mg/kg) lean BW in men and 133-177 μmol/kg (15-20 mg/kg) in women. Lower values suggest incomplete collection, except in elderly or decreased muscle mass. Also allows comparison of different collections in same individual. Supersaturation of lithogenic compounds * risk factors for stone recurrence: obesity, diabetes, cystine, struvite, or uric acid stones, chronic diarrheal state or other predisposing medical condition, +ve family history.

52 RENAL HANDBOOK


RENAL CONSULTS

NEPHROLITHIASIS CONTD. PREVENTION OF KIDNEY STONES Test Low urine volume

Notes

Hypercalciuria

Lowering dietary Ca intake should not be recommended, may result in negative Ca balance and osteopenia. Ca supplements increase stone risk as are not taken with food and therefore cannot bind oxalate. Stop if appropriate, or take with meals. Reduce dietary sodium, animal protein, recommend DASH diet. (ref: Borghi et al. NEJM 2002 346:77-84). Consider Thiazide diuretic, but note hypokalemia may increase stone risk by suppressing citrate. Rule out primary hyperPTH, sarcoidosis, and distal RTA.

Hypocitraturia

Supplementing citrate intake (eg, K citrate) effective, but raises urinary pH (metabolised to HCO3) and may accelerate the rate of CaP stone formation. Do not use if urine pH > 6.5 except for pts with RTA, who seem to benefit from despite the alkalinisation.

Hyperoxaluria

Low oxalate diet: avoid spinach, nuts, Vit C supps. Consider increasing dietary Ca, or adding Ca citrate with meals even if urine Ca is high. If diet does not reduce urine oxalate, stop restriction as response very variable. Consider potassium citrate (Urocit-K).

Hyperuricosuria

Lifestyle modification (ie, decreased purine intake and weight loss). If urine pH >6.0, urate not the cause even if hyperuricosuria. If insufficient, consider Allopurinol, which reduces CaOx stone risk in hyperuricosuria, suggesting unsuspected mechanism.

Increase fluid intake to produce > 2L urine/day in all. Fluid should be taken throughout the day and at bedtime, and the volume increased when sweat losses are greater. Reduces risk of recurrent stone by 50%.

No metabolic abnormality These pts often have more Ca, Ox, and/or less citrate in the urine than non-stone formers, although none of the values are clearly "abnormal".

RENAL HANDBOOK 53


RENAL CONSULTS

RENAL SIDE EFFECTS OF COMMON MEDICATIONS Aspect

Notes

ACEi / ARB

AKI, hyperkalemia. Hyponatraemia in setting of chronic volume depletion via impairment of aldosterone response. AKI secondary to crystal deposition and renal tubular obstruction. AKI with features of proximal tubular injury. Anti-GBM disease (Clatworthy; NEJM 08;359;7680). Collapsing FSGS. AIN, ANCA +ve vasculitis. Hyperkalemia, Addisonian picture with normal Synacthen test. Tubular toxicity with AKI, electrolyte wasting. Proteinuria, lysosomal storage disease, phospholipidosis (rare). AKI, CKD, K and Mg wasting. Renal vasoconstriction, AKI, hypomagnesaemia. Chronic CNI nephrotoxicity controversial. Hypokalemia and acquired Fanconi syndrome. High dose therapy associated with membranous nephropathy. MPO ANCA vasculitis, drug-induced lupus. Rarely AKI. Proteinuria, lysosomal storage disease. Nephrotoxicty and proximal tubular damage. AIN, crystal-induced AKI. Tubular injury, AKI, Mg wasting. Increased urea; increases tacrolimus levels. TTP. AIN, ATN. ATN, crystalluria. HUS-TTP. HRT may be associated with CKD progression. AKI, AIN rarely. AKI and CKD. AKI secondary to crystal deposition. ATN. Oedema, hypoglycaemia and neurotoxicity in dialysis pts. HUS-TTP. See aminoglycosides. Hypercalcemia. MPO ANCA vasculitis, drug-induced lupus. Proteinuria from lysosomal storage, hypokalemia. AKI secondary to osmotic nephrosis. AKI secondary to proximal tubular dysfunction. AKI, Fanconiâ&#x20AC;&#x2122;s. AKI secondary to crystal deposition. Collapsing FSGS or TMA. Collapsing minimal change disease or FSGS. AKI with high dose therapy. Contrast nephropathy. MPO ANCA vasculitis, drug-induced lupus. Osmotic nephrosis from sucrose in solution.

Acyclovir Adefovir Alemtuzumab Alendronate Allopurinol Amiloride Aminoglycosides Amiodarone Amphoterocin B Calcineurin inhibitors Capecitabine Captopril Carbamazepine Carboplatin Chloroquine Cidofovir Ciprofloxacin Cisplatin Clarithromycin Clopidogrel Colistin Co-trimoxazole Deoxycoformycin Estrogens Ethambutol Exenatide Felbamate Foscarnet Gabapentin Gemcitabine Gentamicin Growth hormone Hydralazine Hydroxychloroquine Hydroxyethyl starch Ifosfamide Imatinib Indinavir Interferon alpha Interferon beta Interleukin-2 Iodinated contrast Isoniazid (INH) IVIG 54 RENAL HANDBOOK


RENAL CONSULTS

RENAL SIDE EFFECTS OF COMMON MEDICATIONS Aspect

Notes

Ketamine Lithium Lorazepam Mannitol Metformin Methotrexate Methoxyflurane Mitomycin C Moxifloxacin Nafamostat NSAIDs Omeprazole Ondansetron Opiates Orlistat Pamidronate Pancrease Paracetamol Penicillamine Phenacetin Phenytoin

Rhabdomyolysis. Nephrogenic DI, chronic IN, renal cystic change. IV form associated with AG acidosis secondary to propylene glycol. Osmotic nephrosis. Possibly increased risk of lactic acidosis in GFR < 30 ml/min. AKI secondary to crystal deposition. AKI. HUS-TTP. AIN. Hyperkalemia. AIN; MCD; oedema; HTN; AKI. AIN (often subacute); hypomagnesaemia. Hypokalemia. Severe CNS toxicity in dialysis pts with peak effect at 24 hours. Enteric hyperoxaluria and oxalate nephropathy. Collapsing FSGS, esp. in cancer and myeloma pts. Oxalosis if non-compliant. AKI with or without liver injury secondary to ATN, possibly CKD. MPO ANCA vasculitis, drug-induced lupus. Chronic IN. In uraemia always use the free phenytoin level and ignore total level. Causes severe vitamin D deficiency; MPO ANCA vasculitis; drug-induced lupus. MPO ANCA vasculitis, drug-induced lupus. Lactic acidosis. MPO ANCA vasculitis, drug-induced lupus. Proteinuria in high doses, although this may just reflect potency of HMG-CoA inhibition. AKI, proteinuria. Avoid if GFR < 40 ml/min or > 0.5g proteinuria/day. Phosphate nephropathy from bowel prep. Rhabdomyolysis. AKI secondary to crystal deposition. MPO ANCA vasculitis, drug-induced lupus. AKI secondary to crystals, AIN. Progressive CKD with tubular dysfunction. Increased urea without change in GFR. MPO ANCA vasculitis, drug-induced lupus. Hypokalemia by acting as non-resorbable anion if volume depleted. HUS-TTP. See aminoglycosides. Crystal deposition, hyperkalemia. Hyperkalemia. Oedema, avoid in nephrotic pt. Collapsing FSGS. AKI with doses > 4g/day or levels > 15 ug/ml. TMA. AKI secondary to glomerular bleeding and tubular obstruction. Hypokalemia d/t progestin with spironolactone-like effect.

Procainamide Propofol Propylthiouracil Rosuvastatin Sirolimus Sodium phosphate Statins Sulfadiazine Sulfasalazine Sulphonamides Tenofovir Tetracyclines Thioridizine Ticarcillin Ticlodipine Tobramycin Triamterene Trimethoprim Thiazolidinediones Valproate Vancomycin VEGF inhibitors Warfarin Yasmin OCP

RENAL HANDBOOK 55


RENAL CONSULTS

RADIOCONTRAST NEPHROPATHY RISK FACTORS  Major: (1) Pre-existing renal dysfunction (eGFR<50); (2) Diabetes Mellitus.  Other: (1) high contrast dose (dose >(5 ml/kg/serum creatinine)--Freeman;Am J Cardiol 02;90:1068); (2) age >75; (3) volume depletion; (4) CHF; (5) cirrhosis; (6) nephrotic syndrome; (7) HTN; (8) NSAID use; (9) arterial catheterization; (10) IABP in place; (11) urgent/emergency procedure; (12) peripheral vascular disease; (13) myeloma/light chain proteinuria (risk score: Barrett;NEJM 06;354:379 or Bartholomew;Am J Cardiol 04;93:1515). CLINICAL SYNDROME  Characteristic features include: (1) oligoanuria that develops the evening following the procedure (day 1) and is unresponsive to loop diuretics; (2) rapid rise in creatinine; (3) paradoxically low Urine Na and FENa.  Recovery typically begins on day 3 with a rapid increase in the urine output and a creatinine peak. Creatinine returns to baseline by ~day 10. Recovery occurs in most but not all pts.  Due to diuretic-insensitive oligoanuria, elimination of unnecessary IV and PO intake is critical to avoid dialysis. PREVENTION  Volume administration: normal saline @ 1 ml/kg/hr (or 0.5 ml/kg/hr for pts with h/o CHF) x 12 hours before and 12 hours after procedure (Barrett;NEJM 06;354:379) •Use low-osmolar (~600 mOsm/L), non-ionic contrast in smallest volume possible. Iso-osmolar agents (e.g. Iodixanol aka VISIPAQUE~290 mOsm/L) may be useful in high risk pts (Aspelin;EJM 03;348:491) though CONTRAST study failed to show any advantage in high risk pts with CKD and DM. •Discontinue NSAIDs and diuretics 1 day and Metformin 2 days prior to procedure. Little data is available on the utility of discontinuing ACEi/ARBS though some nephrologists hold them prior to contrast study in pts with advanced CKD. •N-Acetyl Cysteine 600-1200 mg po BD beginning ~24 hours prior to procedure and continuing for 24-48 hours after is often given (Marenzi;NEJM 06;354:2773). It is reasonable not to give this therapy, as it is unproven. Furthermore, it should not deflect attention from proven therapies such as volume and choice of contrast agent. •HD and haemofiltration for removal of contrast following administration are ineffective.

56 RENAL HANDBOOK


RENAL CONSULTS

NEPHROGENIC SYSTEMIC FIBROSIS BACKGROUND  A new and debilitating condition marked by scleroderma-like skin changes has been reported in pts with advanced CKD in the last 5-10 years and was initially named Nephrogenic Fibrosing Dermopathy (NFD). •Clinical and autopsy studies revealed that the disease can be rapidly progressive and can involve multiple organ systems including the heart, lungs and muscles. It can cause significant physical disability, pain and increased mortality. It light of these findings, it has been renamed Nephrogenic Systemic Fibrosis (NSF) (Daram;AJKD 05;46:754). •Recent case series have suggested that NSF may result from exposure to gadolinium contrast (Grobner;NDT 06;21:1104 and Marckmann; JASN 06;17:2359). As a result, multiple authorities recommend that gadolinium be avoided in pts with advanced CKD (Kuo;Radiology 07;242:647; Marckmann;JASN 06;17:2359; or www.fda.gov - search gadolinium). In May 2007 the FDA ordered that manufacturers add a black box warning to gadolinium noting the risk of NSF. •Risk for NSF varies with the properties of the gadolinium chelate used: ionic, cyclic chelates bind gadolinium more avidly (and have lower risk) than non-ionic, linear chelates. •Hence, risk with gadoteridol, gadobutrol, or gadoterate is less than with gadodiamide or gadopentate. •Therapy is uncertain. HD immediately after gadolinium exposure results in significant removal: 78, 96, and 99 % in the 1st, 2nd, and 3rd alternate day dialysis sessions, respectively. Whether this affects incidence of NSF is not known. Thalidomide and Gleevec are both under investigation. USE OF GADOLINIUM CONTRAST IN CKD PATIENTS  CKD Stage 1 and 2: No specific precautions recommended.  CKD Stage 3: Avoid gadolinium contrast if possible. If used, assure adequate hydration.  CKD Stage 4: Use gadolinium only when no other imaging options are adequate and the condition under investigation is sufficiently serious. Assure adequate volume status with IV crystalloid. Consider prophylactic dialysis when eGFR < 15-25.  CKD Stage 5 / ESRD: Use gadolinium only for emergency indications and when no other imaging options exist. Perform HD promptly after the procedure and again the following day. PD pts who require gadolinium should be considered for access placement and HD as gadolinium is cleared poorly by peritoneal dialysis.  Acute renal failure or cirrhosis: these pts may be at additionally high risk for NSF and gadolinium should be avoided.  Kidney and other transplant recipients: consult with transplant nephrologist prior to any gadolinium use. Post-transplant status may be an independent RF for NSF, and use of gadolinium is generally avoided.

RENAL HANDBOOK 57


Glomerulonephritis

RENAL HANDBOOK 59


GLOMERULONEPHRITIS

GLOMERULONEPHRITIS Symptoms/signs: Hypertension, oedema. Fatigue, fever, weight loss, joint pains if vasculitis present. Urinalysis: Active urine sediment: RBCs, WBCs, RBC, WBC or granular casts; Proteinuria (>3 g in 10-30%). Use phase contrast microscopy to see acanthocytes and dysmorphic RBCs. Biopsy: LM=diffuse or focal proliferative GN. RPGN has >50% crescents of proliferating epithelial cells, macrophages, fibrin obliterate Bowman’s space, encircles tufts GN Mimics: (1) TTP/HUS (check platelets, LDH, smear for schistocytes); (2) atheroembolism (embolic skin findings, livedo, possibly low complement); (3) plasma cell dyscrasia; (4) malignant hypertension, (5) interstitial nephritis, (6) HIV nephropathy. References: Bosch;Lancet 06;368;(9533):404 and Hricik;NEJM 98;339:888

RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS (RPGN)  Suspect if AKI + active urine sediment (RBC’s plus RBC or WBC casts)  DDx is based on kidney biopsy immunofluorescence, however empiric therapy is usually required before these results available.  If serologic data or kidney biopsy not immediately available, initiate empiric therapy with Methylprednisolone 500-1000mg x 3 days (plus prophylaxis).  Request urgent processing of ANCA / Anti-GBM serologies [call 2650].  Arrange urgent Plasmapheresis (PEX) if pulmonary haemorrhage. Consider plasmapheresis if CNS vasculitis, mononeuritis multiplex or critical organ ischaemia.  Consider early empiric CYC based on serologic data if biopsy results not available (see Page 74).

DIFFERENTIAL DIAGNOSIS OF RPGN Category Anti-GBM disease

Examples Serology, Immunofluorescence, Notes Renal limited or systemic Anti-GBM+, ANCA-; IF: Linear IgG; with pulmonary haemorrhage =Classic Goodpasture’s. disease Rarest but most rapidly progressive GN.

Immune complexmediated

IgA nephropathy Henoch-Schonlein Purpura Cryglobulinaemia SLE Infection Related (‘Post-Infectious’) Idiopathic MPGN

C3, C4 levels typically normal. IF: Granular IgA and C3. Difficult to diagnose without biopsy. Can smoulder or present in fulminant, crescentic form. As above; IgA with systemic findings of rash (biopsy if present), arthralgias, abdominal pain. Also assoc. with prolonged Staph infection. Cryos+, RF +. C4 typically lower than C3. IF: Gran IgG; Check HCV. ANA+, C3 / C4 low. IF = “full house”=IgG, IgM, IgA, C3, C1q; Check ANA, dsDNA, antiSmith. ASO+, Anti-DNAase B+, low C3 / C4. IF=granular IgG; Check blood cultures. Post Group A Strep is prototypic. CNS shunt infection =subacute. Staph Infection (e.g. endocarditis) may cause RPGN via IgA GN. Classically C3 down more than C4, which may be normal. Low C3 / C4. IF: Gran IgG; HCV+: C4 down more than C3; Dense Deposit disease: C3 down more than C4.

Pauci-immune, Renal limited / GPA ANCA+. IF: pauci-immune; Systemic forms associated with flu-like illness, eye lesions ANCA-mediated (Wegener) / MPA / EGPA (episcleritis, orbital lesions) and skin lesions (palpable purpura, non-healing ulcers). (Churg-Strauss) Churg-Strauss associated w/ asthma, eosinophilic granulomas and renal failure only rarely; assoc. with leukotriene inhibitor use. Drug induced ANCA+. IF: pauci-immune; Anti-MPO antibodies (p-ANCA); often very high titres; standard therapy usually reqd. Rash frequent. Usually occurs after years on a drug: Hydralazine, Propylthiouracil, Penicillamine, Minocycline. Double Ab 60 RENAL HANDBOOK

ANCA and Anti-GBM +

IF: Linear IgG. 20% of anti-GBM pts.


GLOMERULONEPHRITIS

NEPHROTIC SYNDROME Presentation: (1) Oedema; (2) Hypoalbuminaemia; (3) Proteinuria (Prot:Creat >300mg/mmol, >3.5 g/d); (4) Hyperlipidaemia. Clinical history/Labs: Pedal or orbital oedema. Often some nephritic feature present. Serum creatinine may be normal though it will overestimate GFR due to increase creatinine secretion with proteinuria. Primary vs Secondary: Primary cases are often sudden in onset, with all features of syndrome. Secondary cases develop slowly and lack key features of syndrome (e.g. oedema) as ‘normal’ nephrons compensate for damaged ones. Biopsy results generally do not distinguish between primary and secondary causes (Orth;NEJM 98;338:1202). Pathophysiology: Effacement (fusion) of podocyte foot processes is the morphologic sine qua non of nephrosis but the extent of effacement does not correlate well with level of proteinuria. Complications: Progressive renal failure, thrombosis, accelerated atherosclerosis, anaemia, infection.

PRIMARY NEPHROTIC SYNDROME Category Idiopathic minimal change disease

Examples Normal light microscopy.

Sudden onset. Hematuria suggests alt. diagnosis. Consider patchy FSGS or early membranous.

Serology, Immunofluorescence, Notes

Primary FSGS

FSGS

Hematuria and HTN often present.

Idiopathic membranous

IgG4 subclass may predominate.

Consider secondary causes if mesangial immune deposits.

IgA Nephropathy

Mesangial deposits or Minimal Change.

Some haematuria usually present.

Immunotactoid/Fibrillary

Deposition disease.

EM is diagnostic.

Congenital Syndromes

Podocytopathies.

Usually paediatric.

Category Hyperfiltration and/or low nephron number

Common Examples

Prior nephrectomy; Obesity Secondary FSGS Chronic Reflux

Foot process effacement patchy. Often no oedema.

Systemic disease

Diabetes Mellitus SLE Cyanotic heart disease Sickle Cell Disease Obstructive Sleep Apnoea Hepatitis C Hepatitis B HIV Parvovirus Amyloidosis; Monoclonal Ig Deposition Disease Cryoglobulinaemia Waldenstrom’s Fabry’s disease Hodgkin’s / Lymphomas Solid tumours – e.g. Colon

Diabetic nephropathy. MPGN or membranous Secondary FSGS

DM >10 yrs, neuropathy, retinopathy

MPGN Membranous/MPGN Collapsing, microcystic tubular changes Collapsing FSGS Amyloid deposition Monoclonal light, heavy chain or both MPGN MPGN MPGN Glycolipid deposition on biopsy Minimal Change Membranous

Hep C-nephrosis is often associated with cryos. Membranous is seen in Hep B pts with E Ag.

SECONDARY PROTEINURIC KIDNEY DISEASES

Hypoxemia

Infection

Paraprotein and other deposition diseases

Malignancy

Pathology

Notes

Foot process effacement patchy. Oedema usually absent.

Amyloid is much more common than MIDD and typically associated with higher levels of albuminuria. Cryoglobulinaemia is typically seen with Hep C. ApoE mutations. Age appropriate cancer screening for all. RENAL HANDBOOK 61


GLOMERULONEPHRITIS

MEMBRANO-PROLIFERATIVE INJURY PATTERN Clinical: haematuria, dysmorphic red cells, occasionally with red cell casts, some proteinuria, creatinine may be normal or elevated. May present like IgAN, with haematuria after an upper respiratory infection. Light microscopy: Key finding is ‘double contour’ or tram-tracks; sign of endothelial injury and repair. DDx based on 3 IF patterns: (1) Immune complex (Ig and C3) (2) complement only (3) IF –ve. Staining Immune complex (Ig and C3)

Complement only

Complement Classic pathway; normal or mildly decreased serum C3 and low C4.

Causes Infection, esp. HCV

Immunofluorescence Viruses: granular IgM, C3; kappa and lambda LC; +/- IgG, C1q ve.

Monoclonal gammopathy

Monotypic kappa or lambda light chains; not both.

Autoimmune disease

"Full house" Ig (IgG, IgM, IgA, C1q, C3, and kappa and lambda LCs).

Alternative Dense deposit pathway; low C3, disease normal C4. C3 may be normal; C3NeF +ve in 80% of DDD.

C3 glomerulopathy

No staining

Normal

62 RENAL HANDBOOK

Electron Microscopy “Fingerprint” cryoprecipitates suggests mixed cryo or LN.

Differential HCV (+ mixed cryo) HBV; chronic bact. Fungal and parasitic infection. MGUS, lymphoma, myeloma or CLL;

Subepithelial deposits; Lupus, Sjögren's Tubuloreticular structures in syndrome, rheumatoid endothelial cells suggest arthritis and thyroiditis lupus.

Bright C3 staining in EM shows characteristic sausage-shaped, wavy, mesangium and densely osmophilic deposits capillary walls. along GBM and mesangium.

Consider monoclonal gammopathies in older adults; drusen on fundoscopy pathognomic in this setting.

Bright C3 staining in EM similar to IC-MPGN no sausage-shaped mesangium and intramembranous and capillary walls. mesangial deposits observed in DDD.

May present as postinfectious GN due to presence of subepithelial “humps”; key is -ve Ig by IF.

Thrombotic No significant Ig or microangiopathy complement in glomeruli.

No electron dense deposits along capillary walls.

TTP-HUS, APLS, BM txp nephropathy, CAN, drug-associated incl. CNI, radiation nephritis, scleroderma and malignant HTN.


GLOMERULONEPHRITIS

SYSTEMIC LUPUS ERYTHEMATOSUS Lupus Nephritis (LN) is among the most dreaded complications of SLE and is associated with significant mortality. 25-50% of SLE pts develop LN early; 60-75% eventually develop it (Fine;JAMA 05;393:3053). 95% of asymptomatic pts have mild LN. Pathophysiology: Immune complexes containing autoantibodies deposit in subendo- and subepithelial spaces, activate complement. (Rahman:NEJM 08;359:929). ‘Extra renal’ manifestations of SLE include malar rash, alopecia, arthralgias, fatigue; accompanied by thrombocytopenia and haemolytic anaemia; less often cardiomyopathy, cerebritis. Pregnancy: SLE often develops or flares during pregnancy or first ~8 wks postpartum. It can mimic preeclampsia / HELLP. Pathology: Diffuse=>50% of glomeruli involved; Focal<50%; Global=lesion involving > ½ glomerular tuft; Segmental= < ½; Necrosis=fragmented nuclei or disruption of GBM usually + Fibrin. 15-40% evolve from one form to another and can do so in a non-sequential way (e.g., Type II to Type IV) Immunofluorescence: staining includes IgG, C3, usually C1q, variably IgA and IgM. All five = full house (three of a kind + a pair). ESRD d/t LN: Extra-renal symptoms become quiescent after ESRD onset, 6-12 months of dialysis. However, mortality for LN pts is x2 that for matched controls. This may relate to coming off hydroxychloroquine, which reduces thrombotic events, or ceasing to attend SLE doctor due to burnout. KIDNEY DISEASES ASSOCIATED WITH SLE Lupus nephritis Classic immune-complex mediated glomerular lesions with haematuria, RBC casts, proteinuria (nephrotic in 45-65% of cases). Anti-Phospholipid antibody associated

Multiple manifestations: (1) renal limited TMA; (2) renal artery or vein thrombosis with infarction, (3) hypertension, (4) livedo reticularis.

Necrotising ANCA+ GN

Pauci-immune lupus GN described in lupus pts with p-ANCA and MPO+(Schwartz:Hum Pathol 83;14:158 and Nasr:CJASN 2008;3:682).

Tubulointerstitial nephritis

Immune complexes fix complement along the tubular basement membranes. Hyperkalemia or hypokalemia may be present.

Podocytopathy

Nephrotic syndrome without immune complexes. May have FSGS or minimal change pattern.

Hydroxychloroquineinduced

Rare complication manifested by proteinuria and renal failure. Bx=cytoplasmic inclusions within podocytes, like Fabry’s (Woywodt;NDT 07; 22:3074 ).

SEROLOGIES USEFUL IN THE DIAGNOSIS OF LUPUS-RELATED KIDNEY DISEASE ANA Very sensitive, non-specific. dsDNA and Anti-Smith

Less sensitive than ANA but specific for LN.

C3 and C4

Useful for diagnosis and tracking course of flare. Also low in SLE pts with skin manifestations and haemolytic anaemia.

Anti-Histone

Suggests drug-induced Lupus. Renal manifestations are rare.

Anti-Ro / La

Suggestive of Sjogren’s. Associated with neonatal heart block.

Anti-RNP

Associated with lupus cerebritis.

Anti-Phospholipid antibody screen

Anti-cardiolipin antibodies, lupus anti-coagulant or B2-Glycoprotein 1 may be associated with renal thrombotic microangiopathy. RENAL HANDBOOK 63


GLOMERULONEPHRITIS

PATHOLOGY OF LUPUS NEPHRITIS Class of LN Class I: Mesangial immune deposits without proliferation

Pathology LM: Nil / normal; IF: Mesangial immune deposits.

No abnormality or mild haematuria/proteinuria

Class II: Mesangioproliferative

LM: Mesangial hypercellularity, matrix expansion. IF: Mesangial deposits, usually IgG and C3.

No abnormality or mild haematuria/proteinuria

Class III: Focal Proliferative Lupus Nephritis

LM: mesangial and endothelial proliferation +subendothelial deposits, involving <50% of gloms in segmental pattern. IF: Diffuse granular staining. Subdivisions: (1) Active vs Chronic and (2) Segmental vs. Global.

Proteinuria and haematuria. Nephrotic syndrome, HTN, renal failure rare.

Class IV: Diffuse Proliferative Lupus Nephritis

LM: mesangial and endothelial proliferation +subendothelial deposits, involving >50% gloms; Special note made of gloms with fibrinoid necrosis and crescents. IF: Diffuse granular staining. Subdivisions: (1) Active vs Chronic and (2) Segmental vs. Global.

Proteinuria, haematuria in all. Nephrotic syndrome, HTN, renal failure are common. Use dsDNA and complements to follow course.

Class V: Membranous Lupus

LM: Diffuse thickening of basement membrane. IF: Granular, Subepithelial Immune Deposits manifestations.

50% will have a negative ANA; many will have no extra-renal.

Class VI

Sclerosed glomeruli without residual activity

64 RENAL HANDBOOK

Clinical Correlate


GLOMERULONEPHRITIS

TTP-HUS-TMA SYNDROMES Thrombotic microangiopathy (TMA) = pattern of vascular kidney injury seen in TTP, HUS, malignant hypertension, scleroderma, radiation injury, preeclampsia, HELLP, paraproteinaemia. Endothelial injury is key to pathophysiology. Review: Ruggenenti;KI 01;60:831). Clinical features: Thrombocytopenia, Coombs negative micro-angiopathic haemolytic anaemia (MAHA) with LDH elevation. Different syndromes may overlap. Mimics: Sepsis (DIC), cancer, pre-eclampsia and malignant hypertension. Pathology: capillary/arteriole thickening, platelet (TTP) or fibrin+platelet (HUS) thrombi, endothelial cell damage. Chronic TMA: hypoperfusion, atrophy, fibrosis. Tests to order: FBC, blood film, retics, coags, fibrinogen, LFTs, amylase, LDH, pregnancy test, DAT, blood gp, Hep/HIV/autoantibody screens, stool culture if diarrhoea. Consider ADAMTS13. Class of LN Acquired TTP

Pathology

Clinical Correlate

IGg autoantibody vs. ADAMTS 13 metalloproteinase

Classic pentad: neurologic findings, fever, thrombocytopenia, MAHA and renal failure. Associated with: Black race, female, obesity, pregnancy, infection, surgery. Treatment: (1) PEX with octaplas: 1.5 PVs x 3, then 1PV/day until platelets >150 x 2 days (2) Prednisolone 1mg/kg (3) Aspirin 325 mg/d if platelets >20-50k (4) Start LMWH when platelets > 50 (5) Platelet transfusion contraindicated unless life-threatening bleeding (6) Rituximab if cardiac or neuro involvement (7) HAART if HIV-related. For recurrences: Rituximab (Yomtovian;Br J Haem 04;124:787), splenectomy, nephrectomies. Congenital ADAMTS Rare, associated with neonatal hyperbilirubinaemia. Frequent relapses. Responds Familial TTP abnormality. to plasma infusion. See Levy;Nature 01;413:488. Classic E coli O157:H7 HUS in children, more common in females, Caucasians. Renal HUS with diarrhoea Shiga toxin damages endothelium. ADAM TS13 involvement common. (D+ HUS) usually normal. Children: Supportive care/avoid Ax. Adults: Supportive care. If unsure, suggest PEX until pathogenic bacterial strain confirmed; immunosuppression unhelpful; Ax may worsen outcomes. Atypical HUS without Alternative complement Often relapsing with overall worse prognosis than D+ disease. If complement factor D (D- HUS) abnormality. H / I deficient, disease will recur post-transplant, whereas MCP mutations will not. Neuraminidase exposes TF Paediatric pts with pneumococcal sepsis. Coombâ&#x20AC;&#x2122;s test +ve. TTP/HUS with Ag. pneumococcus HUS with HIV Unclear May be due to direct viral endothelial injury. TTP/HUS in pregnancy +/- ADAMTS 13 <24 wks gestation: TTP, treat with PEX/Steroids. >34 weeks usually preeclampsia/HELLP, treat with delivery, consider PEX. Post Partum=HUS, PEX uncertain benefit. Predominantly female, young adults with SLE, APLAS, Scleroderma. Treatment = treat underlying disorder, TTP/HUS in autoimmune disorders consider PEX. For APLAS, use anti-coagulation, steroids, ?PEX/IV IgG. Immune-mediated with anti-platelet or anti-ADAMTS13 antibodies. Associated with Quinine, Clopidogrel, TTP/HUS secondary Ticlopidine, others. PEX is indicated, immunosuppression unhelpful. to drugs Dose & duration dependent: Insidious, with progression even after causative agent (CNIs, Cisplatin, Ara-C, Gemcitabine) discontinued. Consider PEX. Risk Factors: unrelated donor, HLA mismatch, GVHD, sepsis, CNIs. Usually renal-limited. ADAMTS13 normal. TTP/HUS after Stem Mortality high, PEX of uncertain value. Cell Tx Cancer assoc. TTP/HUS Typically adenocarcinoma +/- chemo (gemcitabine, cisplatin etc.) PEX not beneficial. RENAL HANDBOOK 65


GLOMERULONEPHRITIS

GENERAL TREATMENT OF GLOMERULAR DISEASE Aspect Hypertension

Measure Treat to goal BP <140/90; lower BP (130/80) may help reduce hyperfiltration and proteinuria. Mgmt of hypervolemia critical for BP control. RAAS blockade with ACEi, ARB

Response ACE or ARB preferred agents if pt is proteinuric (see below).

High dose ARB or ACE reduces proteinuria more than std dose. Combination ACEi/ARB assoc with excess side effects in ONTARGET trial of CVD (not proteinuria). Synergistic with ACEi or ARB (25 mg/day adequate); observe for hyperkalemia. (Chrysotomou:CJASN 2006;1:256). Paricalcitol reduces proteinuria in DM (de Zeeuw, Lancet 10; 376). Moderate restriction (0.8 gm/kg) reduces glomerular pressure and proteinuria. (Ruilope;JASN 92;3:1307). Statins Statins may reduce proteinuria (Douglas;AIM 06;145 :117) and rate of renal function decline (Sandhu;JASN 06;17:2006). Pentoxifylline Phosphodiesterase inhibitor with few side effects (n/v and dizziness) at conventional doses (400 mg bd if GFR < 15-20, dose daily). May reduce proteinuria and attenuate TNF-alpha driven cellular proliferation in diabetic and non-diabetic renal disease (Ducloux;Lancet 01;357:1672 ; Galindo;J Rheum 03;30:2382). Statins Reduce high CVD risk (KI 1993;44:638). Atorvastatin and Rosuvastatin most potent, Simvastatin next. Rosuvastatin 80 mg associated with ARF, proteinuria (Alsheikh;Circulation 05;111:3051). Proteinuria may relate to potency of HMG-CoA inhibition. Diuretics Higher doses of loop diuretics required in nephrosis. Metolazone is preferred Thiazide. Diuretics also reduce proteinuria. Sodium Restriction Restrict sodium to 2-3 gm/day; confirm with 24 hour urine. ARB/ACEi ‘Ted’ Stockings ineffective without Na restriction. Heparin / warfarin or LMWH (Rostoker; Risk factors: (1) Prior thrombosis, (2) Persistent proteinuria > 10 g/day, Nephron 95;69:20) in high-risk (3) Serum alb <20 (4) Other thrombophilias— e.g. Factor V Leiden or individuals APL+, (5) Membranous glomerulopathy, (6) ANCA disease (WGET;NEJM 05;352:351). Warfarin requires intensive monitoring due to urinary Vitamin K losses. Epo and Iron when Hgb <9-10 Anaemia may develop early in the nephrotic syndrome (relative to GFR reduction) due to loss of erythropoeitin in urine.

Proteinuria Apply multiple therapies to maximally reduce Spironolactone proteinuria –see Zoja;JASN 1,25 vitamin D 02;13:2889. Dietary protein restriction

Hyperlipidemia

Oedema

Thrombotic risk

Anaemia Infection risk Other

66 RENAL HANDBOOK

(1) Vaccinate (Pneumovax/flu/etc) during remissions; (2) Use prophylaxis when treating with immunosuppression (See page 77). (1) Replete Vitamin D (D-Binding Protein lost in proteinuria); (2) Check PTH; (3) Smoking Cessation; (4) Review drug dosing as hypoalbuminaemia changes free drug levels (5) In hypothyroidism: follow TSH (thyroxine and TBG lost in urine -- Junglee:J PG Med 06;52:201).


GLOMERULONEPHRITIS

SPECIFIC TREATMENT OF PRIMARY GLOMERULAR DISEASE TREATMENT OF LUPUS NEPHRITIS Disease severity Class I or II Class III (Mild)

Induction treatment

Notes

Adjunctive therapies as indicated.

No consensus on immunosuppression.

Prednisolone ~0.5 mg/kg daily, tapering, for 6 month course. Mod-to-Severe Class Prednisolone 1 mg/kg/day tapering 10-20% per 1-2 III or wks as tolerated. Class IV PLUS or MMF 1g BD, titrating to 1.5g BD as tolerated (D, N, Mod-to-Severe Class V leukopenia). OR CYC IV 500mg every 2 weeks x 3 months (Eurolupus). Necrotising or Pulse Methylprednisolone 1g x 3 IV, then Crescentic Class III or prednisolone 1 mg/kg/day tapering 10-20% per 1-2 IV wks as tolerated. Repeat IV MP 500 mg-1g with each or monthly CYC. otherwise high-risk CYC IV X 1 dose each month x 6 months, and then pts quarterly for 2 years. (NIH regimen: Gourley MF eta l. Ann Intern Med. 1996;125(7):549.); In practice, many nephrologists would transition to MMF after successful induction rather than continue CYC for this duration. For dosing see page 74. Class V (Mild) Observe OR MMF 500mg BD titrating to 1-1.5g BD AND Prednisolone OR CsA ~2.5 mg/kg BD AND Prednisolone OR Tacrolimus 0.05-0.1mg/kg/d AND Prednisolone

Mild =Creat< 100 umol/l and Proteinuria <2 g/day. PEX not beneficial. MMF preferred for black and Asian pts. Eurolupus regimen not tested fully in blacks. Consider adding Rituximab or Belimumab for resistant disease.

Little published experience with MMF induction of necrotising / crescentic SLE. If using MMF induction, aim for dose of 3g/day. Consider adding Rituximab or Belimumab for resistant disease.

Mild =creat <120umol/l and proteinuria <2g/day. For mixed membranous and proliferative lesions (Class V + III /IV): treat as Class III or IV. Regimens containing CsA or CYC are more effective than prednisolone alone in inducing remission of proteinuria (Austin HA, JASN 2009). Weak data in Asians only for MMF and tacrolimus (Yap DY Nephrology 2012 May;17(4):352-7).

Maintenance (following 6 month induction regimens above) Prednisolone 5-10 mg/d and either MMF ~750 – 1500 mg bd for months 6-12 tapering to ~500 mg bd by month 24 and 250 mg bd by month 36 OR AZA 1 – 2 mg / kg daily

MMF/AZA both effective maintenance (Contreras;NEJM 04;350:971). Ref: 18925525 – Adjust doses of AZA to keep WBC >~20002500/uL. If using MMF , switch once successfully induced, beginning 2-4 weeks after last CYC dose when WCC >4x109/L and neutrophil count > 1.5 x109/L

Adjunctive treatments All pts with LN should receive adjunctive hydroxychloroquine (max 6mg/kg) unless contraindicated Consider Rituximab if associated anti-phospholipid antibody syndrome (Limal; Lupus 08;17:69) RENAL HANDBOOK 67


GLOMERULONEPHRITIS

TREATMENT OF ANCA VASCULITIS Situation Standard induction

Treatment

Notes

Prednisone 1mg/kg (max 80mg), taper to 10 mg by 3 months (add Methylprednisolone 500 mg IV x 3 days if organ-threatening disease) AND CYC IV 15mg/kg x 3 doses q2wks then q3wks until remission plus 3 more months (usually 9-10 doses). Reduce dose if older or lower GFR (see page 74). Max 1.2g. See CYCLOPS regimen for further details (see page 74). OR PO CYC 2 mg/kg per day orally. Max dose 100 mg OD if age > 60 years Dose adjust for GFR (see page 74). OR Rituximab 375mg/m2 confirming depletion of CD19+ B cells (<0.005) after 2 weeks; re-treat if inadequate depletion.

Prophylaxis required (see page 77). Give Rituximab if: (1) Fertility concerns (2) High risk of CYC adverse events (GFR <20, age >70) (3) >15g previous CYC exposure (4) Active infection Rituximab is equivalent to CYC in most cases (RAVE, NEJM 2010;336:221 & RITUXVAS, NEJM2010;336:221) Consider MTX if GFR>60ml/min and no organs threatened (NORAM, Arth & Rhem 2005;52:2461). Daily oral CYC if anti-PR3+ and large granuloma load (at especially high risk of relapsing disease).

Induction in critical illness: Standard induction as above plus Give CYC pulse >24hr before PEX to avoid theoretical - creatinine > 500 or dialysis PEx daily or every other day x 5-10 days based loss of drug. - lung haemorrhage on ANCA titre. Give rituximab after PEX course completed. - CNS vasculitis or mononeuritis Relapsing disease (organ threatening)

As per induction therapy with CYC or Rituximab Rituximab may be superior to CYC in relapsing disease (RAVE trial).

Maintenance

AZA ~2 mg/kg daily and Prednisolone 5-10mg od OR Rituximab re-treatment every 6 months.

68 RENAL HANDBOOK

AZA as effective as 1 yr of CYC and more effective than MMF. Anti-Staph Ax (Septrin) reduce relapse of upper airway disease.


GLOMERULONEPHRITIS

TREATMENT OF ANTI-GBM DISEASE (GOODPASTURE’S SYNDROME) Situation Ab+ve with RPGN And / or Pulmonary haemorrhage (incl. DLCO >30% above normal in patient with subclinical disease)

Dialysis dependent, anuric and/or 100% fibrous crescents plus interstitial disease on biopsy (with no extra-renal disease).

Treatment

Notes

Methylprednisolone 500 mg IV x 3 days followed by prednisolone 60mg, taper to 10 mg by 3 months. AND Oral CYC pulse: 200-400 mg po daily x 3-4 days, then PO CYC 2 mg/kg per day orally. Max dose 100 mg OD if age > 60 years. Dose adjust for GFR (see page 74). OR IV CYC 15mg/kg q 2wks x 3 doses then q 3wks until remission plus 3 more months. Reduce dose if older or lower GFR (see page 74). Max 1.2g. See CYCLOPS regimen for further details see page 74. AND PEX daily or every other day x 14 days based on anti-GBM titre. Use 50% FFP replacement initially if recent kidney biopsy or pulmonary haemorrhage.

Prophylaxis required (see page 77). Taper Prednisolone to zero over 3-9 months, beginning after PEX complete. PO CYC may be preferable to IV in this setting (daily PEX). IV reserved for pts who cannot take oral medications, are unreliable, or who have severe renal failure and oliguria, where bladder toxicity of PO CYC is increased. Continue CYC for 3-6 months. Maintenance therapy generally unnecessary as relapses are rare in pure anti-GBM disease. 20% associated with + ANCA (usually MPO) -- see below for Rx of 'Double Antibody' pts. Smoking cessation prevents recurrence. Give CYC pulse >24hr before PEX to avoid theoretical loss of drug.

Renal recovery rare (<10% in these circumstances) and some nephrologists avoid immunosuppression, especially in high risk pts (e.g. elderly / frail). Renal recovery may occur if urine output preserved and little scarring on kidney biopsy; treat as above, reducing immunosuppression rapidly if any adverse events.

Additional considerations: All pts with pulmonary haemorrhage (even sub-clinical diagnosed by DLCO) should be treated with aggressive immunosuppression. In renal transplant candidates, aggressive treatment can clear antibodies and expedite transplantation. “Double antibody” positive Clinical course tends to be fulminant early with later recurrences. Typically ‘double antibody positive’ (ANCA and anti-GBM) pts are treated using anti-GBM induction followed by maintenance therapy used for ANCA disease (Levy;JASN 01;12:113A).

RENAL HANDBOOK 69


GLOMERULONEPHRITIS

TREATMENT OF CRYOGLOBULINEMIC GLOMERULONEPHRITIS Situation Treatment Aggressive renal disease and/or Rituximab 375 mg/m2 IV q week x 4 doses extra renal vasculitis, with or 1000 mg IV q 2 weeks x 2 doses Hepatitis C + OR As per ANCA induction (see page 74). Slow/Smouldering renal disease, no extra renal vasculitis with Hepatitis C +

Treat Hep C with Peg-IFN / Ribavirin. Use CYC/Methylprednisolone for progression OR Rituximab as above.

Notes In aggressive Hep C disease, begin anti-HCV Rx (PegIFN + Ribavirin) when pt is stable on ISDs. Rituximab may worsen HCV replication. Check HBV serologies. Bruet;Am J Med 74;57:775.

Slow/Smouldering renal CTX 3-6 months and MP x 6 months as per Treat underlying lymphoma or lymphoproliferative disease, no extra renal ANCA protocol disease if present. vasculitis without Hepatitis C + OR Rituximab as above. Crescentic GN with intraluminal CYC / Methylpred per ANCA induction thrombi AND AND / OR Cryocrit >~5-8% PEX

PEX, typically one plasma volume, 3 x/ week x 2-3 weeks.

TREATMENT OF PRIMARY FOCAL SEGMENTAL GLOMERULOSCLEROSIS Category Non-nephrotic proteinuria

Treatment

Prednisolone 60 mg daily (or 100-120 mg every other day if age >60 yrs (Nagai;Clin Neph 94; 42:18)) for 4 months followed by 3+ month taper. Nephrotic range proteinuria and CyA ~2.5 mg/kg BD AND Prednisolone steroid resistant or intolerant 0.15 mg/kg (tapering) (e.g. diabetic or obese) or early OR relapse Tacrolimus AND Prednisolone (1 mg/kg x 4 wks, then taper) (Segarra;NDT 02;17:655) OR MMF 750 mg to 1 gm bd AND Prednisolone. Nephrotic range proteinuria

Relapse after 6 months

Repeat initial treatment course

High Risk (proteinuria >10 gm/d or Renal dysfunction or collapsing subtype)

Prednisolone as above AND CyA as above CNI treatment duration: 6 months after complete relapse, 12 months after partial relapse.

Advanced CKD or interstitial fibrosis

Treatment risks may exceed benefits

70 RENAL HANDBOOK

Notes

ACEi and ARB and other adjunctive 10-year renal survival in non-nephrotic FSGS pts is therapies (see page 66). If renal function ~80-90% (Rydel; AJKD 95;25:534). decreased, response to Rx. may be poor. For prophylaxis: see page 77. Spontaneous remission rare (<5%). Need to ‘stay the course’ and persist with treatment:, remission achieved in 20-60% after 4 mos of highdose steroids, with no additional benefit at 6 mos. (Banfi;Clin Neph 91;36:53) Steroids appear more effective than CYC as initial treatment (Ponticelli;AJKD 99;34:618). CyA + low-dose prednisolone effective for steroidresistant pts but associated with frequent relapse (Cattran;KI 99;56:2220). CYC PO may have role in steroid sensitive subjects (Ponticelli; NDT 93;8:1326) but is of limited use in steroid resistance (Korbet:AJKD 1994;23:773). CyA may contribute to progression of FSGS (Meyrier;KI 94;45:1446) if dose >5 mg/kg/d. MMF + Dex similar to Cya in NIH trail (Gipson; KI 11;80:868). Value of PEX in native kidney FSGS unclear.


GLOMERULONEPHRITIS

TREATMENT OF IGA NEPHROPATHY Category Treatment Notes Hematuria, normal GFR and BP No consensus. ARF from macro. haematuria=no immunosuppression. Consider coeliac disease. w/ proteinuria < 1 gm /day

Observe for 3 months before treating. ACE or Some add fish oil = EPA~1.9 gm +DHA 1.4 gm - e.g. ARB to reduce proteinuria and achieve BP < Omacor 2 caps BD. (Donadio;JASN 99;10:1772). 140/90. High dose ARB or addition of spironolactone for persistent proteinuria.

IgA with Minimal Change pattern

Subset with nephrotic syndrome, minimal haematuria, preserved renal function and podocyte effacement on biopsy: treat as per minimal change disease (Barratt:KI 2006;69:1934).

w/ proteinuria >1 gm/day (despite anti-proteinuric Rx) and normal renal function (eGFR > 60 ml/min)

Prednisolone 1mg/kg od x 2 months, tapered over 4 months PLUS ACEi/ARB OR ‘Pozzi’ protocol= Methylprednisolone IV 500 mg-1 gm/day for 3 days at start of months 1, 3, 5, AND Prednisolone 0.5 mg/kg QOD for 6 months (Pozzi;JASN 04 15:157).

Immunosuppression is controversial as study results conflict and Pozzi protocol developed prior to aggressive RAAS blockade. (Appel;CJASN 2006;1:347). MMF and AZA ineffective in most pts. No trial evidence to support steroids if GFR <60ml/min. STOP-IgAN trial should give more definitive answers; reporting end 2013.

‘Progressive’ IgA: Risk of immunosuppression outweighs proteinuria > 1gm/day, benefits based on current data. impaired & declining renal function (<60ml/min) and HTN Crescentic (>10-50%) with progressive renal dysfunction

Treat as per ANCA vasculitis. No PEX.

See Tumlin;Sem Neph 04;24:256. PEX does not appear to change clinical course. Substitute AZA or MMF after CYC (Tumlin;NDT 03;18:1321)

RENAL HANDBOOK 71


GLOMERULONEPHRITIS

TREATMENT OF MEMBRANOUS NEPHROPATHY Category Low risk for progression to ESRD:proteinuria <0.3g/day and GFR normal after 6 months of supportive care

Treatment

Notes

RAS blockade and statins– see page 66.

Clinical course: 1/3 spontaneous complete remission, 1/3 persistent proteinuria, 1/3 slow decline in renal function thus conservative Rx used prior to ISDs. Predictors of progression=(1) Initial GFR, (2) change in GFR over 6 mos, (3) level of proteinuria. See Cattran;KI 97;5:901. Progression is rare in ‘never nephrotic’ pts. Rapid deterioration: consider (1) pre-renal/ATN, (2) AIN especially, from diuretics, (3) renal vein thrombosis, (4) crescentic transformation.

Moderate risk: Preserved renal function (eGFR>50) with PCR 300-600 after observation period of 6 mos or greater despite maximal adjunctive therapy

Modified Ponticelli (Ponticelli;JASN 98;9:444):

Partial responses (50% reduction in proteinuria to level <3.5 gm/d and normal renal function) are associated with improved outcomes (Troyanov;KI 04;66:1199). 30-40% relapse but often reverse with retreatment or treatment with alternative regimen. Some use Cya 1.75 (max 2.5) mg/kg BD PO x 6-12 mos (goal trough 100-200 ng/L, reduce dose 50% for 30% creat rise AND pred ~0.15 mg/kg po od to max 15mg/day x 6-8 mos. However, Howman RCT in high risk pts (below) argues against this approach. Spontaneous remission may be more common than prev thought. Cattran algorithm can predict those at greatest risk of progression: Kidney Int 1992; 42: 960–966 (takes into account drop in GFR over interval >6/12 and lowest level of proteinuria over 6/12 observation). Discontinue CNI if no response after 6/12.

Months 1, 3 and 5: Methylprednisolone 1000 mg IV daily x 3 d then Prednisolone 0.4 mg/kg/d x 27 days. Months 2, 4 and 6: CYC PO daily x 30 days (see page 74 for dose). OR Tacrolimus 0.1mg/kg/d (target level 5-10) AND Prednisolone (0.15mg/ kg) x 12 months, assuming no evidence CNI nephrotoxicity. OR Rituximab 375mg/m2 x 4 doses a week apart.

High risk: Progressive renal dysfunction and/or proteinuria >8 g/day after obs. period despite max adjunctive Rx.

Modified Ponticelli (as above).

Membranous with crescents

Induction as per ANCA vasculitis.

Membranous with rapid deterioration

Consider MGN complicated by anti-GBM disease.

72 RENAL HANDBOOK

Efficacy over adjunctive therapy and CyA confirmed in RCT with 10 years f/u (Howman; Lancet 2013). Authors recommend avoiding CyA in this group. Shorter observation period often used when renal function is declining. Ineffective Rx’s=Steroids alone (Cattran;NEJM 89;320:210), PO CYC alone (Donadio;KI 74;6:431), IV CYC+Steroids (Reichert; AIM 94;121:328) CyA (Howman; Lancet 2013). Consider warfarin for thromboembolism prophylaxis.


GLOMERULONEPHRITIS

TREATMENT OF MINIMAL CHANGE DISEASE Category Initial Therapy

Treatment

Notes

Prednisolone 1mg/kg (max 80mg/d) daily for 4 weeks if remission achieved, max 16 weeks if remission not achieved, then taper over 6 months.

Remission occurs in 50-75% in two years without treatment (Black;Br Med J 70;3:421). Time to remission with steroids greater in adults than children (~6075% in 8 weeks 75 -90% in 16 weeks). Relapses more common in younger pts. (Korbet;AJN; 88;8:291 and Nakayama;AJKD 02;39:503).

1st Relapse

Prednisolone as above -- taper more slowly than during initial taper.

Steroid resistant (no response >12-16 weeks)

CyA 2-5 mg/kg/day to start, then taper AND low dose prednisolone 5-15 mg/d OR Tacrolimus 0.05-0.1mg/kg/d OR CYC PO 2mg/kg x 8 weeks.

Consider repeat biopsy to rule out underlying FSGS or MGN missed by initial biopsy. Partial remissions are rare and should also raise suspicion of underlying FSGS (Mak;NDT 96;11:2192).

Steroid sensitive with frequent relapses (>3 per year) or steroid dependence or toxicity

CYC PO ~2 mg/kg daily x 8-12 weeks (see page 74 for dose adjustment) OR CyA 1 – 2.5 mg/kg BD to start, then taper OR MMF 1 – 1.5 g BD (Choi;KI 02;61: 1098) OR Tacrolimus 0.25 – 0.5 mg/kg BD OR Rituximab 375mg/m2 x 4 doses a week apart OR continuous low dose prednisolone (~15mg od).

Remissions from CYC may be more durable in adults than in kids (Nolasco;KI 86;29:1215) and more durable than CyA. Low doses/levels of CyA effective for maintaining remission. Nephrotoxicity of CyA lowest when dose <5.5 mg/kg and level < 150 (Meyrier;KI 94;45:1446). IV CYC: more frequent relapse than PO (Donia;NDT 03;18:2054). Rituximab appears promising in steroid-dependant relapsing MCD (Munyentwali; KI 2013).

Low-dose prednisolone (~0.15 mg/kg) given concurrently with all options above (CYC, CyA, MMF and Tacrolimus).

RENAL HANDBOOK 73


GLOMERULONEPHRITIS

CYCLOPHOSPHAMIDE Dosing: The dosing recommendations below are only guidelines and must be individualised for particular pts. See sections on specific diseases for additional information on dose frequency, duration and references.

NIH REGIMEN FOR PULSED IV CYCLOPHOSPHAMIDE FOR LUPUS NEPHRITIS Dosing

Interval

eGFR or CrCl Loading dose age <60 yrs > 80 ml/min (round dose up) 1000 mg / m2 40 – 80 ml/min 750 mg / m2 20-39 ml/min 600 mg / m2 < 20 ml/min or dialysis (round down) 500 mg/ m2 Monthly IV pulse x 6 months pulse and then quarterly for 2 years.

Loading dose age >60 yrs 750 mg / m2 575 mg / m2 450 mg / m2 375 mg / m2

CYCLOPS REGIMEN FOR PULSED IV CYCLOPHOSPHAMIDE FOR ANCA VASCULITIS Age (years) Dosing

Interval

Serum creatinine Notes <300 umol/l >300 umol/l Max dose 1.2g < 60 15 mg/kg/pulse IV 12.5 mg/kg/pulse IV to avoid overdose > 60 and < 70 12.5 mg/kg/pulse IV 10 mg/kg/pulse IV in the obese > 70 10 mg/kg/pulse IV 7.5 mg/kg/pulse IV Pulse 1-3 given every two weeks. Thereafter, pulse every three weeks until remission plus 3 more months (usually 9-10 doses).

ORAL CYCLOPHOSPHAMIDE Oral loading dose: Under certain circumstances (e.g. anti-GBM or severe ANCA vasculitis), an oral CYC loading dose may be preferred: e.g. 200-400 mg po daily x 3-4 days, even if poor renal function. This is best accomplished by giving the pt 25 mg sized tablets and having them drink a glass of water with each tablet. Subsequent oral dose following the initial oral loading dose as follows: eGFR or CrCl > 15 ml/min < 15 ml/min or dialysis

Starting dose age <60 yrs 2mg/kg/day 1 mg / kg / day

Starting dose age >60 yrs 1.5 mg / kg / day 0.8 mg / kg / day

COMPLICATIONS OF CYCLOPHOSPHAMIDE Complications N, V, fatigue Alopecia Infection – bacterial or viral Hemorrhagic cystitis Infertility

SIADH Liver dysfunction Malignancy 74 RENAL HANDBOOK

Notes Common at time of IV infusion. Serotonin antagonists (e.g. Zofran) are helpful. Thinning common; total alopecia rare at these doses. Herpes group infection risk increased (including CMV)- see above for antimicrobial and other prophylaxis. Rare with IV doses < 1 g/m2. Women: risk rises with age (<25 yrs=0-15%; >30 yrs=30-45%) and total dose (~25% for <20g; 70% for >30g). Amenorrhea common during Rx. Many CTX-treated women experience earlier menopause. Men: gonadal toxicity for >300mg/kg total dose. A 2-3 month course of 2mg/kg=120-180mg/kg. Refer to HARI in Rotunda hospital for sperm banking. Rare, but can occur within first 24 hours after infusion. Avoid hypotonic IV fluids. Rare hepatocellular injury with transaminitis, elevated bilirubin. Especially bladder cancer. Risk related to dose and duration. Acute Leukaemia can occur with doses >10-25 grams.


GLOMERULONEPHRITIS

Many complications of CYC are rare when the dose=2 mg/kg for 2-3 months e.g. (total dose = 120-180 mg/kg or 8.4-12.6 gm in a 70 kg person). Longer courses (e.g. 6-9 months= 360-450 mg/kg) are associated with significantly more toxicity. Recommended maximum CYC cumulative load 20g. Oncologic CYC doses (~2-3 gm/m2) are associated with alopecia and other acute side effects.

MONITORING, DOSE ADJUSTMENT AND ADJUNCTIVE MEDICATIONS WHILE RECEIVING CYCLOPHOSPHAMIDE Aspect Monitoring

Measure

Response

Baseline 10 and 14 days Pre-next dose

FBC, U&E, CRP, ESR, CK, LDH, LFT’s, bone profile, urate, urine PCR and serology as appropriate (anti-GBM, ANA, dsDNA, ANCA, C3, C4). FBC, U&E, CRP, urine PCR. FBC, U&E, CRP, ESR, LDH, LFT’s, GGT, bone profile, appropriate immune markers and urine PCR. Use WCC to adjust subsequent dose.

Dose adjustment for IV CYC based on FBC (day 0,10,14)

WCC < 4x109/L WCC nadir 2-3 x109/L WCC nadir 1-2x109/L Platelets< 100x109/L

Postpone and check FBC weekly Reduce dose of last pulse by 20% Reduce dose of last pulse by 40% Postpone and check FBC weekly – give when plts ≥100

Dose adjustment for PO CYC

Follow FBC every two weeks for as long as the patient is on CYC. Hold if total WCC < 3.5 x109/L and reduce dose on re-introduction

Adjunctive meds

Ovarian protection Ondansetron

Co-trimoxazole Ranitidine or PPI Vaccination

Nystatin drops or amphotericin losenges Fluconazole TB prophylaxis Osteoporosis prophylaxis

Goserelin 3.6mg monthly, giving first dose as soon as possible. Ondansetron 8mg PO, 30 minutes pre and 12 hours post infusion Consider pre-pulse if anticipatory symptoms are present (alternative: Metoclopramide 10mg TDS / cyclizine 50mg TDS). 480mg nocte (check for allergy). When on prednisolone>10mg/day. If possible prior to immunosuppression: Hib/MenC, pneumococcal polysaccharide and MenACWY conjugate vaccine. Don’t delay therapy waiting for this. To prevent oral candidiasis while corticosteroid dose above 20mg/day. 50mg OD if hx of fungal infection. Isoniazid 300mg OD and pyridoxine 10mg OD if from endemic region, or has had close contact or has unexplained upper lobe fibrosis. Vitamin D3: cholecalciferol 1500 IU/day (e.g. ‘D-Pearls’). Consider Alendronate >65 yrs or post menopausal if GFR >30 ml/min

RENAL HANDBOOK 75


GLOMERULONEPHRITIS

PLASMA EXCHANGE Aspect Rationale

Notes

Technique

Plasma is separated from blood cells with a centrifuge (technique used by blood bank) or a highly permeable filter called a membrane plasma separator installed in a standard dialysis circuit. Plasma is typically replaced with albumin and saline, sometimes with FFP, to avoid volume depletion.

Kinetics

Like urea removal during dialysis, the amount of the macromolecule of interest removed during PEX is directly proportional to its concentration in the plasma, thus the efficiency of antibody removal falls with time. Removing one (1) Estimated Plasma Volume (EPV) reduces intravascular antibody by ~63%; 1.5x=78%; 2x=86%.

Effectiveness depends on...

(1) (2) (3) (4)

The PEX prescription

(1) Estimate plasma volume= (0.065 x weight in kilograms) x (1 - haematocrit). Assuming a normal haematocrit, 1 PV is ~40ml/kg. Use lower volumes for pts with lower haematocrits; (2) Decide plasma removal goal: typically 1 to 1.5 EPVs (~40-60 ml/kg); (3) Specify replacement solutions and amount – typically use 2:1 ratio of 5% albumin + 0.9% saline. Use pure FFP replacement in TTP; (4) Pre-med with paracetamol and Chlorpheniramine if giving FFP (allergic reactions); (5) Bleeding risk: Use 50% FFP replacement if recent/planned kidney biopsy, lung haemorrhage or other bleeding, or prolonged INR; (6) Specify calcium replacement – usually 1g per hour i.e. 5g calcium gluconate in 250ml 0.9% NaCl infused at 50cc/hr). Give extra e.g. 1.5g hr if using FFP replacement; (7) Specify anti-coagulation –typically heparin 2000 units; (8) Hold ACEi for 24-48 hours due to risk of anaphyllactoid reactions; (9) Duration: Usually daily x 3 days, then alt. days to balance risks/benefits, with total dose based on the substance to be removed, the clinical goal of therapy, or both.

Coagulation monitoring

Fibrinogen is more completely removed by PEX than other factors: lose 2/3 per session and regain 1/3 per day. Significant fibrinogen deficiency (<50mg/dL) will elevate the PT/aPTT, so just follow those. Never check a fibrinogen level right after PEX as it will be artificially low. If you do check fibrinogen, consider FFP for levels <100 mg/dL. Remember FFP is ABO typed, and type O thus contains anti-A and anti-B Abs. For ABOi incompatible transplantation, use FFP type that matches the donor to avoid giving back the same Abs removed by pheresis. This does not cause problems for the pt as Ab levels low.

Clinical goals of therapy

RPGN/ABMR: return of urine output / renal function ± Ab clearance. TTP: daily exchanges until the LDH is normal and platelets >150 for 2-3 consecutive days Guillain-Barre: Improved neurological function; it may be necessary after the initial exchanges to perform PEX 1-2 times/week until improvement occurs.

76 RENAL HANDBOOK

Removal of anti-HLA or ABO antibodies that would lead to antibody-mediated rejection. Removal of other pathogenic antibodies (ANCA/anti-GBM) or antigen-antibody complexes (cryoglobulins). Removal of complement e.g. C3, C4. This is likely very important.

Efficiency of antibody removal by PEX; Vd of antibody and its rebound rate through lymphatics; Antibody type: IgM is almost completely removed after 1-2 exchanges; Rate of antibody synthesis. For IgG there is ~35% rebound within 24-36 hours. After the 5th PEX treatment, the concentration will vary from ~10% to 25% of basal levels, after which additional pheresis has little impact other than to maintain these levels.


GLOMERULONEPHRITIS

PLASMA EXCHANGE CONTD. Aspect Antibody clearance goals

Notes

Major complications include:

(1) (2) (3) (4) (5) (6) (7)

Approximately 75% of IgM is intravascular. As a result, only 1-2 procedures are required to effectively reduce IgM levels. Only 45% IgG is intravascular; 48 hours post-PEX, plasma IgG production returns to 40% of the pre-treatment level. A minimum of 5 separate exchanges over 7 to 10 days is required to remove 90 percent of the total initial body immunoglobulin burden. Beware IgG "rebound" phenomenon: cessation of PEX after several procedures can result in pre-treatment or even higher levels of IgG, if the pt is not on ISDs. Symptomatic hypocalcaemia; worse if using FFP due to alkalosis. Give extra IV Ca; Metabolic alkalosis if using a lot of FFP; HoTN; Bleeding from loss of clotting factors; Clearance of highly protein bound drugs; generally give meds afterwards; Line complications; Anaphylactoid rxns on ACEi (hold for 24-48 hours). See Mokrzycki;AJKD 94;23:817.

IMMUNOSUPPRESSION PROPHYLAXIS (for prophylaxis post-kidney transplant, see page 99) PREVENTION OF INFECTIOUS COMPLICATIONS OF IMMUNOSUPPRESSION Type Pneumocystis carinii jiroveci pneumonia

Preferred prophylasix

Alternatives

Notes

Co-trimoxazole 480mg OD

Atovaquone 1500 mg daily OR Dapsone 50-100 mg (must check G6PD).

Co-trimoxazole dosed MWF or everyother-day for GFR <30.

Candida

Nystatin (100,000 Units/ml) 4-6 ml Swish/Spit BD.

HSV and CMV (Herpes) Valacyclovir 500 mg daily. Higher dose (e.g. 1g BD) if CMV IgG positive or prior CMV disease. Lamivudine 100 mg daily (Gastro 2003; 125:1742).

Most problematic with high dose corticosteroids. (Prednisolone>40mg/d). Nystatin preferred for pts on CNIs. CMV induced lung haemorrhage can be confused with recurrent vasculitis.

HBV reactivation

Entecavir 0.5 mg daily

HCV exacerbation

Hepatitis C serology (and viral load / RIBA if high risk) should be checked prior to beginning significant immunomodulatory regimen. If positive, discuss with ID/Hepatology.

Check Hep B serologies / Hep B. DNA if high risk. Fatal reactivation. seen with Rituximab (Dervite;NEJM 01;344:68) and other regimens: Calabrese;ARD 06;65:983.

TB reactivation

CXR pre-treatment, Isoniazid 300mg plus Pyridoxine 10mg OD for 9 months and discuss with ID.

Strongyloides reactivation

Ivermectin 200 mcg/kg x 2 doses (prophylaxis)

Treatment: Ivermectin 300 mcg/kg x 3 days; repeat in 1 wk

Risk=pts from endemic areas (developing world). Send pre/post titres. RENAL HANDBOOK 77


GLOMERULONEPHRITIS

IMMUNOSUPPRESSION PROPHYLAXIS CONTD. PREVENTION OF NON-INFECTIOUS COMPLICATIONS OF IMMUNOSUPPRESSION Type Bone

Consider Preferred prophylasix when using... High dose Vitamin D3 e.g. cholecalciferol corticosteroids 1500 IU/day x 12 wks (e.g. ‘DPearls’)

Alternatives

Alendronate 35 – 70 mg po q Maintain 25(OH) Vit D level >32. week per renal function in those at high prior risk of fragility fracture (more effective than alfacalcidol – see De Nijs ;NEJM06;355:675). Proton Pump Inhibitor Anti-nausea Rx necessary during CYC pulse – e.g. Zofran.

High dose H2 Blocker – e.g. Ranitidine corticosteroids 300 mg po daily adjusted for renal function Bladder Cyclophos-IV CYC: ½ NS or NS 500 ml to 1 litre starting night prior if inpt + 2 litres PO intake/day x 2 days. phamide – For repeated IV CYC dosing over 3 days (e.g. ANCA induction) or for (IV >> PO) high risk pts: add Mesna 400 mg IV 30-60 min prior to CYC and 3 and 6 hours after (for total IV Mesna dose =1200 mg). Mesna PO 800 mg x 1 can be substituted for the last IV Mesna dose each day. – Oral Mesna alternative: Mesna 200 mg po Tid x 4 days. – PO CYC: instruct pt to drink full glass of water with each 25 mg tablet taken. Gonadal CyclophosGNRH analogues (e.g. Goserelin 3.6mg IM qmonth or Leuprolide (women) phamide 3.75mg IM qmonth) (see Cigni;AJKD 08;52:887). Induces oocyte quiescence. Administer mid-cycle. Most effective if given 3-4 wks prior (high dose or prolonged) to 1st CYC dose. Major side effects = Bone loss. GI

Gonadal (men)

78 RENAL HANDBOOK

Sperm banking (contact HARI unit)

Notes

Risk of male infertility with CYC is not well defined.

Mesna use is not routine, reserved for circumstances where dose > 1g/m2 x single dose Mesna ineffective if GFR<20ml/min. Bladder irrigation via 3 way Foley catheter can be used for pts with difficulty voiding. In aggressive GN, many nephrologists are reluctant to delay treatment to allow gonadal protection given the significant risk of worsening renal function, which in turn can worsen pregnancy outcomes.


Acid-Base, Fluids and Electrolytes

RENAL HANDBOOK 79


ACID-BASE, FLUIDS AND ELECTROLYTES

HYPONATRAEMIA COMMON MISTAKES IN THE DIAGNOSIS OF HYPONATRAEMIA 1. Failure to recognise and treat acute, symptomatic hyponatraemia. 2. Over-confidence in physical exam to detect mild volume depletion. 3. Tendency to over-diagnose SIADH. Question this diagnosis if there is a co-existing electrolyte or acidbase disorder of any kind, there is reduced GFR (even if the creatinine is “normal”) or if there is no obvious drug, lung, CNS or endocrine cause, which should be present in >90% cases of true SIADH.

THE IMPORTANCE OF SOLUTE INTAKE IN THE GENERATION OF HYPONATRAEMIA Dietary solutes are required to excrete a water load and the total solute intake limits daily urine output. Once daily solutes have been passed in urine, no further water can be excreted. A normal daily solute intake is 10mOsm/kg/day. A normal adult can generate very dilute urine (50mOsm/kg) if ADH secretion is suppressed. Hence, in a 90kg adult the maximal daily urine output is 18L (90 x 10)/50. However, in an elderly 50kg woman with a solute intake of 3 mOsm/kg/day (e.g. tea and toast diet) and isosthenuria (i.e. reduced ability to maximally dilute urine seen in normal aging and mild kidney disease), may not generate urine below 150 mOsm/kg. Hence, maximal urine output in this setting falls to 1L a day ((50 x 3)/150). Any water intake above this will cause ‘trickle-down’ hyponatraemia. Plasma and urinary features replicate SIADH (low pNa, uNa not <10, uOsm not fully suppressed).

LOW-SOLUTE, “TRICKLE-DOWN” HYPONATRAEMIA Contributing factors: (1) Low total osmolar intake, due to a low protein diet (low plasma urea is a clue) or low NaCl intake (2) low delivery of filtrate to distal nephron (3) low GFR (subclinical) or other cause of enhanced reabsorption of Na in PT (e.g. Thiazide diuretic) (4) isosthenuria: Age-related inability to generate maximally dilute urine. Uosm often 100-300 mOsm/kg in CKD (5) excess non-renal or recent renal NaCl loss (i.e. was taking a diuretic up to recently). Classic presentations: (1) Elderly ladies on a ‘tea and toast’ diet: Contributing factors often include a thiazide diuretic and low-salt diet for HTN, subclinical CKD and isosthenuria (urine specific gravity of protein free plasma – indicates tubular injury). These pts cannot tolerate a water load; (2) Younger women attempting to lose weight: Restrictive diet, large non-renal NaCl loss from sweating through exercise, high water intake; (3) Malnourished male alcoholics with a large beer intake. Beer is low in osmoles, protein and NaCl and full of water. GENERAL PEARLS FOR THE MANAGEMENT OF HYPONATRAEMIA 1. Fluid restriction alone rarely sufficient, outcomes are better with IV NaCl (Ayus JC et al. JAMA 1999). 2. Hyponatraemia only requires treatment when it is hypotonic, so confirm low Posm before treating, unless emergency setting (i.e. acute, symptomatic with altered consciousness, seizures etc). 3. If urine (Na + K) > serum Na, it is not physiologically possible to correct Na using fluid restriction alone. 4. Inadvertent overcorrection is usually due to water diuresis from “switching-off” ADH activity following NaCl and increases the risk of osmotic demyelination syndrome. 5. If overcorrection occurs, re-lower serum Na with 5% dextrose +/- DDAVP (Perianayagam CJASN 08;3:331). 6. Factor in potassium replacement: 20 mmol of KCl is equivalent to 40 mL of 3% NaCl. 7. Know the Na content of the 2 commonly used solutions: 3%NaCl: 513 mmol/l; 0.9% NaCl 154mmol/l. 8. Rule of thumb: 1 ml/kg/hr 3% NaCl corrects Na by ~1 mmol/litre/hr (Berl:NEJM 07;356:2064). 9. Whatever the initial correction goal, the serum sodium should not be increased by more than 12 mmol/L in any 24-hour period and/or 18 mmol/L in any 48-hour period. 80 RENAL HANDBOOK


ACID-BASE, FLUIDS AND ELECTROLYTES

DIAGNOSIS OF HYPONATRAEMIA IS THIS ACUTE, SYMPTOMATIC HYPONATRAEMIA (E.G. ALTERED CONSCIOUSNESS, SEIZURES)? IF SO, PROCEED IMMEDIATELY TO TREATMENT (SEE PAGE 82) AND DEFER DIAGNOSIS. ESSENTIAL DATA 1. Plasma and urine osmolality. Low Posm confirms hypotonicity. Uosm reflects ADH activity: high Uosm = high ADH 2. Plasma and urine sodium: Low Una or FeNa = a ‘salt-avid’ kidney and confirms appropriate ADH release. 3. Plasma and urine electrolytes: K, CL, HCO3, urea, creatinine and urate. Abnormalities argue against SIADH 4. Glucose: Pseudohyponatremia (normal Posm). Na falls 1.6 mmol/L for every 5.5mmol/l above normal. 5. Daily urine volume: Total daily solute intake ÷ urine osmolality 6. Osmolar excretion rate: uOsm x 24 hr urine volume. Normal=10mOsm/kg/day. Identifies low solute intake as a cause of hyponatraemia. 7. Total body water: Watson formula online or smartphone. Otherwise: Weight (kg) x 0.5 (women) or 0.6 (men); If >60 yrs: wt x 0.45 (women) or 0.5 (men) CONSIDER THE 6 POSSIBLE MECHANISMS OF HYPONATRAEMIA BASED ON PHYSICAL EXAM AND ABOVE DATA Mechanism Water intoxication

ECF volume depletion No

Urine Na

Supporting evidence

Causes

Low or normal

Max. dilute urine (30-100 mOsm/kg Primary polydipsia, depending on age). IV fluids.

Yes High Coexisting acid-base or electrolyte disorder suggestive. Low plasma K, metabolic alkalosis, high urinary K, high TTKG (>7), urinary Cl- high. Low plasma K, metabolic alkalosis, high urine pH, Urine Na >20 but low urinary Cl-. High plasma K (in 66%), metabolic acidosis, low TTKG (< 2), low cortisol, low aldosterone, positive Synacthen, although sensitivity poor in secondary adrenal failure. Cerebral Na wasting Polyuria, time course urinary Cl- high.

Renal Na loss Diuretics Vomiting Adrenal insufficiency

Non-renal Na loss

Yes

Very low

Non-gap acidosis if diarrhoea.

Diarrhoea, burns, ileus, pancreatitis.

Low cardiac output or low albumin

No, maybe oedema

Very low

FeNa low, FeUrea low.

Heart, renal or liver failure.

Non-physiologic ADH No release (SIADH)

Not very low

Normal electrolytes and acid-base, low urea and urate, Uosm > POsm by at least 200 mOsm.

Medications. Pituitary, CNS thyroid or lung dis.

No

Low or normal

Low urea, Posm>Uosm. Calculate free water clearance.

See next page.

‘Trickle-down’ hyponatraemia

RENAL HANDBOOK 81


ACID-BASE, FLUIDS AND ELECTROLYTES

MANAGEMENT OF HYPONATRAEMIA TREATMENT OF SYMPTOMATIC OR ACUTE (<48 HRS) HYPOTONIC HYPONATRAEMIA 1. GIVE INITIAL 100ML 3% NACL BOLUS OVER 5 MINS, REPEAT ONCE IF SYMPTOMS PERSIST (e.g. seizures). Rapid initial correction with hypertonic saline is both safe and medically indicated. Factor any boluses into the daily correction volume calculation. 2. CALCULATE THE AMOUNT OF HYPERTONIC (3%) NACL TO ADMINISTER AFTER INITIAL BOLUS Calculate the total amount of 3% saline to increase serum Na by 6 mEq/L using equation below. Subtract any boluses the pt received. This equation is quite accurate, with 95% of pts achieving a serum Na increase of 3-9 mmol/L, allowing a safety margin to keep the total correction under 12meq/day: Volume of 3% saline in litres to increase Na by 6meq/l:

6 x (Total body water (L) +1) (513 – initial serum Na)

E.g. An elderly 60kg woman (TBW: 60 x 0.45 = 27L) with an initial serum Na of 120 mmol/l would require 430 mls 3% NaCl to achieve 6meq correction. 3. CALCULATE THE INFUSION RATE Divide the volume of 3% NaCl by number of hours to get infusion rate. You can vary the rate so long as the total amount given is within target. If hyponatraemia is chronic and symptomatic, correct by ~1-2 mmol/hour for 3-4 hours, or until symptoms resolve. 4. ASSESS RISK FACTORS FOR OSMOTIC DEMYELINATION SYNDROME (ODS) Risk factors: female, hypokalemia, chronic hyponatraemia, alcoholism, cirrhosis, malnourishment. If risk factors present, give DDAVP 2-4 mcg SC q8 when starting 3% saline. This prevents rapid correction from a water diuresis due to “switching-off” of ADH activity by NaCl. (Sood L et al; AJKD. 2013 Apr;61(4):571-8). 5. MONITOR Monitor urine output for signs of water diuresis. Increase DDAVP dose if this occurs. Monitor serum Na concentration every 4-6 hours.

TREATMENT OF ASYMPTOMATIC HYPOTONIC HYPONATRAEMIA ASYMPTOMATIC PTS WITH VOLUME DEPLETION, NA >120MMOL/L AND NO RISK FACTORS FOR DEMYELINATION Give monitored trial of 0.9% saline at 100 ml/hr. CHRONIC, ASYMPTOMATIC HYPONATRAEMIA Fluid restrict all, but if urine (Na + K) > serum Na, it is not possible to correct Na by fluid restriction alone. Loop diuretics + NaCl tablets; Urea pills 30g day; Demeclocycline (600-1200mg/day; takes 8-10 days to work; can cause AIN) Oral Tolvaptan works (Schrier:NEJM 06;355:2099), but prohibitively expensive and FDA warning re: liver toxicity. Rx 15mg titrating to 60mg. Stop fluid restriction after first dose, check Na after 6 hours and before next dose. 82 RENAL HANDBOOK


ACID-BASE, FLUIDS AND ELECTROLYTES

HYPERNATREMIA Excretion of concentrated urine requires: (1) hypertonic medullary interstitium; (2) intact ADH secretion and responsiveness. Problems with either can cause water loss. Thirst prevents hypernatremia in cognitively intact pts with access to water, even if urinary concentrating mechanisms are defective. Hypernatremia is always hyper-osmolar and hypertonic; pseudohypernatraemia is not described (Adrogue; NEJM 00; 342:1493). Sodium overload rarely produces hypernatremia without water loss. Scenarios include: (1) hypertonic fluid administration, particularly NaHCO3 ampoule administration; (2) hypertonic feedings; (3) ingestion of salt or sea water; (4) hypertonic saline enemas; (5) hypertonic dialysis; (6) Primary hyperaldosteronism or Cushingâ&#x20AC;&#x2122;s. Differential diagnosis: The cause of hypernatremia is usually clear from the history, being almost always due to water losses in an elderly pt that are not replaced because of impaired mental status or intubation. Posm >295 mosmol/kg or serum Na >145 mmol/L should stimulate maximal urinary concentration. If both hypothalamic and renal function are intact, Uosm should be >600 mosmol/kg (may be as high as 1400 in younger pts) and DDAVP should not cause a further increase. Thus, if hypernatremia is observed in a wellappearing, alert pt with access to water, a hypothalamic lesion affecting the thirst centre should be strongly suspected.

DIFFERENTIAL DIAGNOSIS OF HYPONATRAEMIA BASED ON URINE OSMOLALITY Urine Osm

Differential Diagnosis

> 600 Consistent with non-renal water loss

GI water loss from NG drainage, vomiting, fistulas, osmotic diarrhoea. Insensible losses. Reduced H2O intake: Primary hypodipsia, reset osmostat, osmoreceptor dysfxn. Water loss into cells from seizures, severe exercise (uNa < 25). Sodium overload -- see above. (uNa > 100).

300-600 (renal water loss)

Partial NDI: (uOsm 300-600) Causes as for complete NDI below. Partial NDI is particularly common in older pts, especially old men with prior obstructive uropathy or psychiatric pts that have received Lithium. Pts will not respond to DDAVP 2-4mcg SC. Osmotic Diuresis (see below).

Uosm~ Posm (~300 and urine output > 3L/day)

Osmotic Diuresis from Glucose, Urea, Mannitol, large volume 0.9% saline administration. The UOsm seen in osmotic diuresis tends to be close to Posm, (~300) may overlap values seen in partial NDI/CDI. Osmotic diuresis from urea is an under recognised cause of free water loss in hospitalised pts. Although urea is an ineffective osmole in plasma ( equilibrates quickly across cell membranes), it is an effective osmole in urine as transitional epithelium is impermeable to it. Diagnosis: Daily solute excretion (uOsm x 24 hour UOP in litres) > 1000 mOsm is consistent with osmotic diuresis. Pts will not respond to DDAVP 2-4mcg SC, as effect already maximal.

Uosm < Posm (usually less than 300 mosmol/kg i.e. renal water loss)

Nephrogenic DI (NDI): Lithium, Ifosfamide, hypercalcemia, hypokalemia, medullary cystic disease, post-obstructive, sickle cell, congenital. Central DI (CDI): Neurosurgery, trauma, Histiocytosis X, granulomas, tumours, ethanol, idiopathic. These are distinguished by the administration of DDAVP 2-4mcg with monitoring of Uosm and volume q 30 mins x2 hrs for evidence of increase in Uosm. Unlike NDI, CDI responds briskly, although the response may be blunted due to washout of the medullary interstitium from longstanding dilute polyuria. RENAL HANDBOOK 83


ACID-BASE, FLUIDS AND ELECTROLYTES

TREATMENT OF HYPERNATRAEMIA STEP 1. CALCULATE THE FREE WATER DEFICIT Free water deficit = (Total body water) x [(Na/140)-1]. Shortcut: (Serum Na – 140) / 3 = ~Free H2O deficit in litres. STEP 2. CALCULATE THE FREE WATER CLEARANCE Electrolyte free water Urine Output (ml/min) clearance (ml/min) x [1 – (uNa + uK) / pNa]

Shortcut: If Uosm is ½ pOsm, then ~½ the urine output is free water. If uOsm > pOsm, the FWC is negative and free water is being retained

Examples: (1) UOP=200 ml/hr; uNa=23; UK=15, SNa=150. EFWC 200*[1-(23+15)/150]=150 ml/hr. EFWC = 150 ml/hr contributing to hypernatremia. (2) UOP=200 ml/hr; uNa=87; UK=55; pNa=150. EFWC =200*1 – (88+59)/150] = 4 ml/hr. Hypernatremia in this case is not from urinary losses. STEP 3. ESTIMATE THE NON-RENAL WATER LOSS Non-renal water loss (stool/insensible) is difficult to quantify. Usually estimate insensible losses at 500 ml H2O per day, more if high fever, increased GI output etc. STEP 4. DECIDE ON THE RATE OF CORRECTION Simple goal: replace ~½ free H2O deficit + ongoing losses in first 24 hours. Do not exceed 12 mmol/day or 0.5 mmol/hour in any one hour in Na shift. STEP 5. SELECT THE FLUID TYPE Use 5% dextrose. If pts can drink safely, allow them to do so and reduce IV repletion by equivalent amount. Concomitant administration of NaCl (as NS or ½ NS) appropriate in volume depleted pts. STEP 6. CONSIDER TREATMENT OF UNDERLYING CAUSE Treatment of Water loss from Central DI: Use DDAVP SQ 1-2 mcg SQ BD. Avoid nasal and oral DDAVP in hospitalised pts. Follow UOP and reduce IV fluids PRN. Treatment of Water Loss from Urea-Driven Osmotic diuresis: Urea production results from (1) feeds, TPN (~50 mOsm urea per 10g dietary protein); (2) catabolism / gluconeogenesis from stress/steroids. Administer free water AND reduce gluconeogenesis with insulin and glucose; reduce catabolism by correcting acidosis and treating hyperthermia and repleting magnesium and phosphorus.

POLYURIA Polyuria and/or polydipsia are common presenting complaints of outpts with diabetes insipidus. Serum sodium typically is high-normal. Primary polydipsia is the other major diagnostic consideration: serum sodium is typically low-normal. Solute diuresis as a cause of polyuria must be excluded esp. in inpts. Solute excretion >1000 mOsm/day = solute diuresis; 600-900 mOsm/day = water diuresis. Differentiating Diabetes Insipidus from vs Primary Polydipsia: 1. If plasma Osm is ≤295 at baseline, restrict access to free water until pOsm >295. 2. When pOsm is >295, check uOsm. a. uOsm > 800 = primary polydipsia; b. uOsm = 300-800=partial DI (possibly with component of polydipsia); c. uOsm <300 =complete DI (central or nephrogenic). 3. Administer DDAVP 2-4 mcg SQ to distinguish Nephrogenic from Central DI. Caution: Pts with primary polydipsia given DDAVP develop hyponatraemia. a. Failure of uOsm to increase by 50% in 1-2 hours=NDI. 84 RENAL HANDBOOK


Renal Handbook 2013 changed_Layout 1 21/05/2013 12:15 Page 85

ACID-BASE, FLUIDS AND ELECTROLYTES

GENERAL APPROACH TO THE PATIENT WITH AN ACID-BASE DISORDER 1. CHECK ABG AND DETERMINE THE PRIMARY ACID BASE DISORDER Acid-base disorder

pH

Primary disturbance

Metabolic acidosis

<7.4

Low HCO3

Metabolic alkalosis

>7.4

High HCO3

Respiratory acidosis

<7.4

High pCO2

Increase HCO3

Respiratory alkalosis

>7.4

Low pCO2

Decrease HCO3

-

-

Compensation

Notes

Decrease pCO2

Note: normal arterial pH is 7.4 (not 7.35-7.45) and is very tightly regulated. The pH is determined by ratio of serum HCO3- to PCO2, not by either one alone. Compensatory responses generally do not fully correct the arterial pH to 7.4. Hence a normal pH plus substantial derangement of serum HCO3- and PCO2 indicates a mixed acid-base disorder, with the exception of chronic respiratory acidosis/alkalosis, which sometimes fully compensate over time.

Increase pCO2 -

-

2. DETERMINE IF THE COMPENSATION IS APPROPRIATE USING ACID-BASE NOMOGRAM Given any 2 of the, Pco2, pH or bicarbonate, the 3rd can be determined from the nomogram. Each acidbase disorder, together with the appropriate compensation, is represented as a band. Acid-base values falling within a band usually represent a single disturbance. However, occasionally such values represent a combination of acid-base disorders, a mixed disturbance. On the other hand, acid-base values falling outside any band almost certainly represent at least two acid base disturbances.

100 60

90

80

70

60

12 10 Arterial blood [H+] (nmol/L) 50 40 30 120 110 100 90

80

6

6

pCO2 in kPa

20 70

60

50

40

56 35 48 Arterial plasma [HCO-3] (nmol/L)

Chronic respiratory acidosis

40

4

Metabolic alkalosis

44

30

36

25 3

32 20

Acute respiratory acidosis

28 24

Normal Acute respiratory alkalosis

20

15

Chronic respiratory alkalosis

16 12

10

Metabolic acidosis

8

2

pCO2 (mmHg)

1

pCO2 curves shown in (mmHg); red scale to convert to kPa

5 52

4 0 7.0

7.1

7.2

7.3

7.4 7.5 Arterial blood pH

7.6

7.7

7.8

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ACID-BASE, FLUIDS AND ELECTROLYTES

3. IN METABOLIC ACIDOSIS, DETERMINE THE ANION GAP (see page 87 for full details) Anion Gap = Na+ – (Cl− + HCO3−) = Unmeasured Anions – Unmeasured Cations. Remember to adjust for hypoalbuminaemia (see page 87). 4. IN NON-ANION GAP ACIDOSIS, DETERMINE URINARY ANION GAP (see page 88 for full details) Urinary Anion Gap = Na+ + K+ − Cl− = Unmeasured Anions – Unmeasured Cations. 5. IN ANION GAP ACIDOSIS, DETERMINE IF THERE IS A PRE-EXISTING METABOLIC ACIDOSIS/ALKALOSIS (see page 88) Delta/delta = to identify pre-existing metabolic acidosis/alkalosis (see page 88 for full details). 6. IN AN UNEXPLAINED ANION GAP ACIDOSIS, DETERMINE IF THERE IS A POISONING USING THE OSMOLAR GAP Osmolar Gap = Measured – Calculated plasma Osmolarity. Calculated plasma Osmolarity = (2 x serum [Na]) + [glucose] + [urea] + 1.25 x [ethanol]. An OG >15 indicates an unmeasured osmole: see page 10 “dialysing toxins”. 7. ESTABLISH THE CLINICAL DIAGNOSIS. Once the acid-base disorder is identified, the underlying cause(s) should be identified and a unifying diagnosis put forward. WORKED EXAMPLE OF A COMPLEX, MIXED ACID-BASE DISORDER Case: "A critically ill patient with septic shock and multiple organ failure on inotropes, mechanical ventilation, antibiotics, and large volumes of normal saline. Na 130, K 3.0, Cl 111, albumin 15 g/L, phosphate 0.7 mmol/l, HCO3= 9, pCO2= 5.1, pH = 7.1." Step-by-step interpretation: 1. Check ABG and determine the primary acid-base disorder: There is a low pH plus a low HCO3-, so the primary derangement is a metabolic acidosis. 2. Determine if the compensation is appropriate: Using the nomogram, the upper limit for pCO2 in a simple acute metabolic acidosis with a pH of 7.1 should be approximately 3.2kPa. The pCO2 is actually 5.1kPa, indicating inadequate compensation i.e. a co-existing respiratory acidosis. 3. In metabolic acidosis, determine the anion gap: The anion gap is 10, which seems normal. However, the AG must be corrected for severe hypoalbuminaemia. As albumin is the main constituent anion in the AG, hypoalbuminaemia effectively lowers the baseline AG by 2.5 per 10g/L decrease in albumin from normal. In this case, serum albumin is 15 g/L so the "baseline" AG should be about 4 (i.e. [(40 -15) x 2.5]). The AG is therefore increased by about 6 and would account for a portion of the fall in HCO3(from 24 to about 18). 4. In anion gap acidosis, determine if there is a pre-existing metabolic acidosis/alkalosis: The corrected AG of 6 does not account for all of the fall in HCO3- of 15 (24 – 9). However, the chloride concentration is also increased relative to sodium, indicating a co-existing non-gap acidosis, which explains the rest of the fall in HCO3- (from 18 to 9). The ‘delta/delta (Δ/Δ)’ gives you the same information: the ratio of rise in AG (6) to fall in bicarbonate (15) is < 1, indicating a combined AG and normal AG acidosis. 5. Establish the clinical diagnosis: An anion gap metabolic acidosis (probably lactic), a non-gap hyperchloremic metabolic acidosis (possibly diarrhoea, renal tubular, and/or "NaCl expansion"), and respiratory acidosis due to lung and/or CNS dysfunction. 86 RENAL HANDBOOK


ACID-BASE, FLUIDS AND ELECTROLYTES

ANION GAP ACIDOSIS – – – – – –

Anion Gap (AG) acidosis results from the overproduction or addition of acid. Principle of electro-neutrality: in body fluids, cations = anions. An exception would create electricity. The AG follows from this principle:  Na + Other Cations = Cl + HCO3 + Other Anions. Rearranging this equation gives:  AG = Na – (Cl + HCO3) = Other Anions – Other Cations Normal AG varies from lab to lab. Pt’s baseline is most useful clinically. AG =11-20 often nonspecific (renal failure, dehydration, hyperphosphataemia). AG>25 usually has a dominant explanation: lactic or ketoacidosis, or an ingestion.

Correcting the Anion Gap: causes of Low or Negative Anion Gap – “Other Anions” fall: Hypoalbuminaemia: the AG must be corrected for severe hypoalbuminaemia by adding 2.5 for each 10g/L decrease in albumin below 40. – “Other Cations” rise: IgG (Polyglonal or Myeloma (if +ve charged IgG), high Ca or Mg, Li intoxication. – Na measurement is spuriously low (high Triglycerides, extreme hypernatremia) or Cl- spuriously high .

CAUSES OF ANION GAP ACIDOSIS: “GOLDMARK” Cause Glycols

Notes Ethylene

Only cause of AG acidosis that also causes renal failure.

Propylene

Used as diluent in lorazepam – consider in pt on infusion for DTs.

Oxoproline

Typically seen in setting of 1. Paracetamol use 2. Glutathione deficiency (malnourishment/ illness) 3. Female gender 4. CKD. Test: 5 ml urine for pyroglutamate. Consider in critically ill with relentless rise in AG in setting of normal lactate and ketones. Treatment: Stop paracetamol, N-Acetyl Cysteine.

L-lactate

Traditionally attributed to overproduction or underutilisation but pathophysiology is complex and excess lactate production can occur even when O2 delivery is adequate. Mitochondrial dysfunction may be important contributor in sepsis as in MELAS syndrome and medicationrelated lactic acidosis (RTI’s, Metformin, linezolid, cyanide).

D-lactate

Results from GI bacterial production of d-Lactate (e.g. in short-bowel syndrome). AG may be 01 as d-Lactate filtered, not absorbed well by L-lactate transporters.

Methanol

Acidosis from Formic Acid. Rx: Fomepizole, Folate, HD.

Aspirin

Respiratory Alkalosis often dominant in adults, while AG acidosis (lactic) predominates in children.

Renal failure

Occurs late in ESRD, after a period of normal-AG acidosis. Due to Pi, SO4, Urate, Hippurate. AG typically < 20-25.

Ketoacidosis

Diabetic

Can produce Normal AG acidosis in settings of high GFR due to loss of ‘potential bicarbonate’ in form of urine ketones (e.g. children and pregnant pts).

Alcoholic/Starvation Due to insulin deficiency, lipolysis, conversion of free fatty acids into ketoacids. Rx: Thiamine, then dextrose and saline. Pay attention to phosphate. Do not give insulin. RENAL HANDBOOK 87


ACID-BASE, FLUIDS AND ELECTROLYTES

ANION GAP ACIDOSIS CONTD... Delta/Delta (Δ/Δ) – Ratio of rise in AG (above normal of 10) to fall in bicarbonate (below normal of 24). – Example: AG 22 is 10 above baseline of 12; HCO3 14 is 10 below baseline of 24. Delta-delta is 1 (10/10), which is the expected value in an uncomplicated AG acidosis. Delta/Delta Interpretation

Possible Explanation in setting of Acidemia

0

AG is zero (not increased above baseline).

Normal AG Acidosis.

<1

Fall in HCO3 exceeds rise in AG from baseline.

AG + Normal AG Acidosis OR AG Acidosis with loss of anions as Na salts in urine.

1–2

Fall in HCO3 is balanced with rise in AG.

Typical value in uncomplicated AG (particularly lactic) acidosis.

>2

Fall in HCO3 is less than AG, suggesting serum HCO3 was AG Acidosis + Metabolic Alkalosis high to begin with.

NON-ANION GAP ACIDOSIS –

– – –

Normal AG (NAG) acidosis results from  HCO3 loss from GI tract or kidney.  Failure of kidney to create new HCO3 required due to protein metabolism.  AG acidosis in which proton is retained but anion is excreted as Na+ salt. Renal Tubular Acidosis is the most common renal cause of NAG acidosis. An alternative explication of RTA = “Recognise the Ammonium Defect,” as all forms of RTA involve a failure of ammoniagenesis. The traditional nomenclature for RTA is outdated: most nephrologists refer to RTA’s as distal, proximal or Type IV. Consider RTA in pts with kidney stones. Nephrolithiasis complicates distal RTA due to (1) alkaline urine; (2) hypocitraturia due to acidified prox. tubule which increases reabsorption of citrate; (3) hypercalciuria from bone buffering of protons.

Urinary Ammonium (NH4) Excretion – In response to acidaemia, the kidney should increase NH4+ excretion. Urine pH reflects only free H+ ions and can be misleading. RTA is a low ammonium excretion condition. – Urine Anion Gap (uAG) is how we estimate NH4+ excretion to diagnose an acidification defect.  Like serum anion gap, it is based on principle of electro-neutrality:  (Na + K)- Cl = Other Anions – Other Cations = uAG.  As with all urine lytes, there is no ‘normal’ UAG as excretion = intake.  In acidaemia, uAG should be < - 40.  If uAG > 0 in acidaemia, kidney has failed to increase NH4+ excretion = RTA. – UAG Pitfalls:  Cannot be used when uNa+ < 25, because H+ secretion in this setting is limited by distal Na delivery, not primary RTA.  In presence of unusual anions such as hippurate or ketones, the uAG is positive despite high NH4 production. – Urine Osm Gap can be used as an alternative to uAG. It is diagnostic even when unusual anions such as hippurate are present. Measured UOsm is compared to calculated UOsm [(2*Na+K) + urea + gluc]. If difference (uOsm gap) is > 80-100, significant NH4+ is present in urine and the kidney is responding appropriately. 88 RENAL HANDBOOK


ACID-BASE, FLUIDS AND ELECTROLYTES

CAUSES OF NON-ANION GAP ACIDOSIS Cause

Details

GI bicarb loss

Diarrhoea from upper tract or fistula contains bicarbonate, which titrates H+ in lower tract, and ‘potential’ bicarbonate (acetate, lactate, citrate) is lost in stool.

Dilutional

0.9% NaCl dilutes serum HCO3; pH of 0.9% NaCl is 5.5.

Renal causes CKD

Decreased NH3 production causes a normal gap acidosis in early CKD.

Proximal RTA

Isolated or with Fanconi’s Syndrome. Urine pH is variable. Acquired: Myeloma, LCDD or Amyloid Vit D deficiency hyperparathyroidism, Ifosfamide, heavy metals, carbonic anhydrase inhibitors (Diamox / Topiramate). Familial: Alport’s, Medullary Cystic Disease.

Distal RTA

‘Classic’ form=defective H+ excretion--urine pH>7, K+ low. Hyperkalemic form= voltage-dependent defect. Acquired causes= analgesic or other tubulointerstitial nephropathy, nephrocalcinosis, amyloid, cryoglobulinaemia, Sjogren’s, primary biliary cirrhosis, SLE, rheumatoid arthritis, amphotericin B, lithium, obstruction. Many familial forms exist.

Type IV RTA

Classically seen in setting of diabetes mellitus, usually with CKD, hyperkalemia and hyporeninism. Also seen with Primary Hypoaldosteronism, ‘Pseudohypoaldosteronism’ including Gordon’s Syndrome, Addison’s, and RAAS inhibitors including CNIs, ACEi, ARB, amiloride, trimethoprim.

Hyperkalemia

Inhibits renal PCT ammoniagenesis and competes with NH3 in Thick Ascending Limb.

Resins and chloride salts Renagel and Cholestyramine result in Chloride – Bicarb exchange in GI tract. Similarly chloride salts for any kind (e.g. CaCl, NH4Cl) result in NAD acidosis. Urinary diversion

Ileal loops, bladder reconstruction and other GU surgical procedures which place urine is in contact with bowel result in Cl and HCO3 exchange and NAG acidosis.

AG acidosis with anion clearance

‘Potential bicarbonate’ anions lost as Na+ salts: (1) Recovery phase of DKA, Na-Ketone salts are lost in urine (2) DKA with high GFR (pregnancy / children) (3) Hippurate (glue sniffing) (4) D-Lactic Acidosis.

Pancreatic Txp

When pancreas allograft is anastomosed to urinary bladder, HCO3 is lost in urine.

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Transplantation

RENAL HANDBOOK 91


TRANSPLANTATION

EVALUATION OF PROSPECTIVE RENAL TRANSPLANT RECIPIENT TWO KEY QUESTIONS To the potential recipient: why do you want a transplant? To the referring physician and primary nephrologist: Is this pt an appropriate transplant candidate? KEY CONTRAINDICATIONS 1) Malignancy (waiting time for h/o cancer=2-5 years --Penn;Transpl 93; 55:742); Active Infection (eg. diabetic foot ulcer, osteomyelitis, TB); (3) Unstable ischemic heart disease; (4) Substance abuse, psychosis, noncompliance or non-adherence to medical and dialysis regimens. ADDITIONAL CONTRAINDICATIONS (1) positive cross match; (2) ABO incompatibility; (3) unacceptable risk of graft loss (persistent anti-GBM antibodies, primary hyperoxaluria, active lupus, active vasculitis, prior graft loss from FSGS or other GN); (4) HIV (transplant only via protocol); (5) BMI>32; (5) life expectancy: 5-year survival <50% (WHO Ethics Statement); may be waived for potential LDKT, when emotional / other considerations may supervene (6) Pulm HTN. Older age is OK (Johnson;Transp 00;69:794). (7) DIABETIC PTS (1) Consider pancreas tx (simultaneous or after); (2) consider pre-emptive transplant given poor outcomes on dialysis; (3) assess for CAD, PVD, gastropathy, foot ulcers/osteomyelitis, orthostasis, bladder dysfunction. TIMING TIMING OF WORK-UP INITIATION AND LISTING Initiate work-up at≤ eGFR 20 ml/min; list at ≤15ml/min. Aspect

Key Points (in addition to standard Hx + Ex) [Kasiske;AJT 01;S1(2);5; Knoll;CMAJ 05;173:S1]

ESRD history

Letter from pt’s nephrologist with BMI, dry weight, up to date medications and copies of all relevant reports; cause of ESRD with prior renal biopsy reports; previous transplants; pregnancies; blood transfusions; dialysis history; access infection/thrombosis; peritonitis; urine output; prior immunosuppression. Sensitisation to HLA: previous transplants, number of blood transfusions, number of pregnancies (inc miscarriages).

General history

Cardiovascular ROS esp. exercise tolerance, claudication, DVT, PE; Malignancies; Abdominal operative reports; International living (h/o + PPD); Psych/alcohol/drug hx; Social supports, compliance, work history. If preserved UO screen for voiding dysfunction or recurrent pyelonephritis.

Exam

Ht & Wt; BMI. Skins cancers. Femoral pulses. Carotid Bruits. Infection search: Skin, feet, PD or HD catheter site, teeth and oropharynx.

Cardiac Screening

All: ECG and CXR at eval and repeated every 2 years; Echo for LV/RV fxn, PA pressure. Age> 65 OR symptomatic: consider cardiac cath. Most diabetics need cardiac cath (Witczak:AJT 06;6:2403).

Cancer Screening

All aged 55-74: BowelScreen: -ve faecal immunochemical test or colonoscopy within 2 yrs. Women: Pap smear within 12 months if aged 25-60 and ever sexually active; Mammogram within 2 years if 50-64 years or high risk. Men: Age >50=PSA; Age < 40=testicular exam. Dialysis pts: US for Renal Cell Cancer (Doublet;J Urol 97;158:42) and gallstones. Diabetics with gallstones require cholecystectomy per-transplant. Prior CYC, history of longterm Foley catheter or self-intermittent catheterisation: check dipstick for blood: if positive then cystoscopy.

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TRANSPLANTATION

EVALUATION OF PROSPECTIVE RENAL TRANSPLANT RECIPIENT CONTD. Aspect

Key Points (in addition to standard Hx + Ex) [Kasiske;AJT 01;S1(2);5; Knoll;CMAJ 05;173:S1]

Vascular

Diminished pulses OR claudication OR high risk for PVD: ABI’s +/- Pelvic CT Angiogram with run off if abnormal. If pre-ESRD, CT scan without contrast AND Non-invasive doppler exam of arterial circulation.

Blood Testing

General: U&E, Ca, Phos, Mg, LFTs, Glucose, HBA1C, Alb, Glob, Lipids, FBC with Diff, INR, APTT, PTH, Urinalysis. Immunology: ABO, HLA typing, PGEN, Crossmatch will be done prior to actual transplant. Serologies: HIV, HepBsAg/sAb, HCV, CMV, VZV, EBV, syphilis, HSV, Hypercoagulable screen if indicated (previous DVT/PE/clotted AVF/recurrent miscarriages).

Need for nephrectomy

Usually done 6 weeks pre-transplant. Consider for: (1) large PKD kidneys, (2) severe HTN, (3) significant proteinuria, (4) recurrent stones, (5) unknown diagnosis.

Other

(1) All – Dentist for routine care, gum disease (2) PKD--consider MRA for cerebral aneurysm though risks of gadolinium in CKD pt must be weighed (3) Ophthalmology for diabetics and those with h/o eye disease (4) Vaccinate for VZV (IgG neg), ?HZV (age >59), HPV (females age 13-26), Hep B, Pneumococcus and Influenza at least 1 month prior to transplant; (5) CXR (6) Hypercoagulable screen (APLAb, V Leiden, PT gene or MTHR mutations, or protein C, S or AT3 deficiencies) if frequent episodes of thrombosis in the dialysis access port, a history of DVTs or miscarriages.

EVALUATION OF PROSPECTIVE LIVING DONOR OUTCOMES Outcomes after donation (Ramcharan; AJT 02;2:959) and uninephrectomy (Narkun;KI 93;43:1110) are excellent but potential donors must be carefully screened. KEY ISSUES (1) Donation voluntary; (2) Surgical risk low; (3) Risk of uninephrectomy status low; (4) Risk of transferring cancer/ infection low; (5) High chance of success in recipient. MAJOR RISKS OF DONATION (1) ~3/10,000 risk of death (2) ~3/10,000 risk of ESRD (3) hypertension (Boudville;AIM 06;145:185); (4) proteinuria. CONTRAINDICATIONS (1) Age<18-25 or >75; (2) BMI>30; (3) diabetes; (4) hypertension not controlled on 2 drugs or with any endorgan damage; (5) malignancy; (6) microalbuminuria / proteinuria; (7) H/o recurrent kidney stones; (8) GFR < 80 ml/min/1.73m2; (9) transmissible infection; (10) certain familial kidney diseases; (11) psychiatric illness; (12) H/o non-compliance or substance abuse; (13) pregnancy. CONTROVERSIAL ISSUES 1) Mild HTN (Textor;Transp 04;78:276); (2) Family h/o diabetes, (3) Isolated haematuria; (4) H/o single kidney stone; (5) Previously ‘cured’ malignancy (if queries, contact Israel Penn tumour registry online).

RENAL HANDBOOK 93


TRANSPLANTATION

EVALUATION OF PROSPECTIVE LIVING DONOR CONTD. Evaluation of Living Donor (Amsterdam;Transp 05;79:S53 and Davis;AJKD 04;43:508) Initial Screen

Phone screen by coordinator and letter from general practitioner.

ABO Testing

If incompatible: consider other donors, paired exchange, ABOi transplant.

History

Relationship with recipient, motivation to donate, potential coercion or payment, medical, surgical, psych history, hobbies (rule out traumatic), employment, intâ&#x20AC;&#x2122;l travel, cigs / alcohol / substance abuse, family support of donation, family medical history. Meds inc NSAIDs, herbal meds.

Physical Exam

BP x 3 <140/90, BMI<30, general medical exam normal.

Basic Labs

U+E, Creatinine, Ca, Phos, Alb, Uric Acid, LFTs, GGT, Fasting Lipids, Fasting Glucose, FBC, Coags.

HLA Testing

Cross match (repeat just prior to tx); HLA typing if sibling or if recipient is sensitised.

Diabetes Screen

Fasting glucose <5.6. If >5.6, repeat and get GTT.

Renal Disease Screen

(1) Normal urine dipstick e; (2) negative MSU; (3) normal spot urine protein / creatinine; (4) 24 hr Urine for creatinine clearance>80 ml/min (if borderline, perform other test of GFR (5) metabolic stone eval if h/o kidney stone (6) Isotopic GFR for all.

Serologies

HIV, HTLV, HBcAg, HbsAg, HBsAb, HCV, CMV, EBV, syphilis.

Cancer screen

All aged 55-74: BowelScreen: -ve faecal immunochemical test or colonoscopy within 2 years. Women: Pap smear within 12 months if aged 25-60 and ever sexually active; Mammogram within 2 years if 40-64 years or high risk. Men: Age >50=PSA; Age < 40=testicular exam.

Cardiac

ECG in all. Consider Echo/Stress test in >65 years or symptoms.

Pre-op assessment Consent/ Counselling

Problems with prior GA; ECG, CXR. Document having watched donor educational videos and having read the donor handbook. Describe risks, describe confidential opt out, obtain consent, advise weight loss if BMI 30-35, advise smoking cessation x 4-8 weeks prior to surgery.

Renal imaging

US. CT angiogram with urogram: assess kidney size, vessels, urinary tract. Split-function renogram where significant size discrepancy.

Surgical Evaluation Optional

Hx + Ex by operating surgeon and anaesthesia. Psychology +/- psychiatry review. Direct psychiatric review if clear history of psych disease.

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TRANSPLANTATION

FINAL PRE-TRANSPLANT ASSESSMENT Living donor recipients General

Seen for the final time 3-5 days before the transplant. History and exam should be performed and the pretransplant evaluation reviewed.

Medication Adjustments ACEi, ARBs and diuretics should be discontinued at least 2 days prior to living donor transplantation and calcium channel blockers or alternative anti-hypertensives substituted. Short acting anti-hypertensives are preferred but short acting nifedipine should be avoided. Goal BP on the morning of surgery: SBP 120-149. Hx of CAD: ensure pt is on: (1) beta-blocker with heart rate <70 and (2) aspirin. Antiplatelet therapy: Discontinue routine aspirin given for primary prevention of coronary disease 5-7 days prior to transplant. If known CV disease or stents – continue aspirin. Anticoagulant therapy: For non-valvular disease atrial fibrillation, warfarin can be discontinued several days before surgery and the INR allowed to drift down. For mechanical valves, admit for INR monitoring and heparin administration. For insulin dependent pts, give usual insulin the night before. At 6am on the morning, start GKI infusion. Immunosuppression

Confirm plans made pre-transplantation. Start tacrolimus 0.05mg/kg BID once final cross-match results are known.

Vascular Anatomy

Multiple renal arteries occur in 15-20% of pts. These increase ‘back table’ surgical preparation, prolong ischemic time, and may put part of kidney at higher risk for ATN and DGF / SGF.

PD Catheter

Ensure this is flagged for removal at time of transplant.

PD Pts

Send PD fluid for cell counts and culture prior to surgery.

Deceased Donor Kidney Recipients (on admission to Beaumont) Consider recent

Infections (access infection, PD peritonitis, foot infections, antibiotic use). Hospitalisations. Cancer diagnosis. Chest pain or exertional symptoms. Outpt dialysis unit and nephrologist should be contacted to update recent medical issues.

Need for dialysis

Need for dialysis pre-op, usually for hyperkalaemia.

Medication Adjustments ACEi, ARBs, diuretics and phosphate binders should be discontinued. Continue beta-blocker or calcium channel blocker. Hx of CAD: ensure pt is on: (1) beta-blocker with heart rate <70 and (2) aspirin. Anticoagulant therapy: If on warfarin, consider FFP based on INR. Mechanical valves will require bridging heparin administration. For insulin dependent pts, give usual insulin the night before. At 6am on the morning, start GKI infusion. Immunosuppression

For protocols see page 98.

Vascular Anatomy

Multiple renal arteries occur in 15-20% of pts. These increase ‘back table’ surgical preparation, prolong ischemic time, and may put part of kidney at higher risk for ATN and DGF / SGF.

PD Catheter

Flag for removal if low likelihood DGF. Routinely removed if peritoneum is opened at time of surgery.

PD Pts

Send PD fluid for cell counts and culture prior to surgery. RENAL HANDBOOK 95


TRANSPLANTATION

POST-TRANSPLANT MAINTENANCE IMMUNOSUPPRESSION Drug

Dose

Adverse effects

Pearls

Tacrolimus (Prograf) CNI

0.15mg/kg bd x 2 doses, then 0.1 mg/kg bd, adjusted by level

All CNI: Nephrotoxicity, TMA, tremor, headache, other CNS toxicity, hyperlipidemia, hypertension, hypomagnesaemia, No need for loading dose if hyperkalemia. live donor, start with 0.05 Tacrolimus: Hair loss, DM (Vicente; mg/kg bd AJT 07;7:1506).

Primarily liver clearance ELITE-Symphony trial: best maintenance regimen is low-dose tacro (trough 3-7 ng/mL), MMF, and lowdose steroids. Goal trough: 8-10ng/mL for 1st month, then... Low risk: 4-8 ng/mL High risk: 8-10 ng/mL

Ciclosporin A (Neoral) CNI

IV: 1.5mg/kg over 4 hours CyA: Hair growth, gum hyperplasia. q12 x 2 doses PO: 3-4 mg/kg bd, adjusted by level.

IV dose=1/3 total daily given slowly (> 4 hours). Follow level. Goal ~100ng/mL after 1yr Generics â&#x2030; equivalent.

Mycophenolate 500mg bd. May give up to Mofetil (MMF; 1g bd if high immunologic Cellcept / Mycolat) risk. antiproliferative

Nausea, diarrhoea, abdominal pain, cytopenias. AEs more common as renal function declines and protein binding changes.

Highly protein bound. Higher doses needed with CyA ( inhibits absorption by 30%50%) and African ancestry (Neylan;Transp 97;64:1277). Need lower doses in steroidfree protocols (Cattaneo KI 02;6;2:1060) and hypoalbuminaemia (Atcheson;Ther Drug Monit 04;26: 284).

Mycophenolic Acid (MPA; Myfortic)

360-720mg bd.

2nd line agent to MMF. Two potential advantages over MMF: (1) Maybe less GI side effects (2) better absorption (~30%) if on PPI as MMF absorption requires acidic stomach.

Azathioprine (Imuran) antiproliferative

3mg/kg 4 hours posttransplant PO/IV 2mg/kg 24 hours posttransplant PO.

Cytopenias, hepatitis, cholestasis, pancreatitis (Raman; JIM 90;228:69). Consider testing TPMT before commencing.

Avoid with Allopurinol. Alternative to MMF if GI symptoms. MYSS trials: no Î&#x201D; in rejection, pt/graft survival or GFR vs. MMF even if no steroids.

Sirolimus (Rapamune) mTor inhibitor

To begin sirolimus, continue CNI until night before, then initiate sirolimus 3mg od the following morning. Check levels a week later. If continuing Tacrolimus, goal combined (Rapa + Tacro) level =8-10.

Oedema, mouth ulcers, hyperlipidemia, cough, pneumonitis, anaemia cytopenias, poor wound healing, rash, Lymphocoele, TTP, GI upset, nephrotoxicity, joint pains, HTN, proteinuria, ARF.

Do not use if GFR <40 or proteinuria >0.5g. Do not use with CyA. Commonest indication is anti-tumour effect (esp. non-melanoma skin ca). Goal trough 6-8 ng/mL in pts >6m post Tx. Switch to alternative agent 2 wks before any surgery to avoid wound healing problems.

Corticosteroids

High dose Methylprednisolone tapering to prednisolone (see page 98).

GI ulceration, insomnia, mood change, weight gain, diabetes, hyperlipidemia, bone loss, dermal thinning, cataracts.

Literature does not support steroid avoidance: x2 rejection rate, same side effects. Late withdrawal less successful than early.

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IMMUNOSUPPRESSIVE AGENTS IN TRANSPLANTATION: INDUCTION Drug

Class

Dose

Adverse effects

Pearls

Depleting Ab

3-5 mg/kg IV x 3-5d, but no maximum total dose. Reduce dose by 50% for WCC 2-3 or platelets 50-75. Stop if WCC <2 or platelets <50.

Severe side effects without pre-medication (due to cytokine release from cell lysis, a sign of efficacy).

Indications: PGEN >95% or LD transplant with significant baseline DSA or kidney-pancreas transplant. Monitoring goals: (1) Absolute CD3, CD4 <0.01 OR (2) Total lymphocyte count <3% of total WCC or < 50 cells/µL. Only re-dose when above these thresholds. Give by I.J. line Give Methypred 250mg IV and Piriton 4mg PO pre-dose. Ensure pt is on Septrin, Valcyte and Nystatin 1mL qds.

Induction agents ATG (anti-thymocyte Ab)

Fever, rash, rigors, low back pain, leukopenia, thrombocytopenia, serum sickness if used without steroids. Give Chlorpheniramine (10 mg IV) 15–60 minutes before administration.

30mg IV x 1 at time of TX

Leucopenia. Possible autoimmunity, suggestion of more C4d+ ABMR.

Efficacy as for ATG, more effective than basiliximab in steroid minimisation regimes (Brennan;NEJM 06;355:1967).

Very few.

More acute rejection episodes, fewer infections than ATG(Brennan;NEJM 06;355:1967).

Alemtuzumab (Campath)

Humanised anti-CD52 Ab

Basiliximab (Simulect)

Anti-IL-2 antibody 20 mg on days 0 and 4.

Rituximab

Anti-CD20 antibody

375mg/m2

Infusion reactions, cytopenias, Not a stand-alone induction agent, oedema. but may be an adjunct in certain situations e.g. desensitisation.

IVIG

Pooled IgG

2g/kg

Rate-related, anaphylaxis in IgA deficient pts,

As above. Started pre-operatively and >30% must be given before unclamping kidney.

IMPORTANT INTERACTIONS WITH IMMUNOSUPPRESSIVE MEDICATIONS Agent

Inhibitors: lower levels or effect

Potentiators: raise levels or effect

CNIs

Anti TB Drugs: Rifampicin, Rifabutin Anti-Convulsants: Barbiturates, Phenytoin Ax: Ciprofloxacin, Imipenem, certain cephalosporins Other: Ticlopidine, Octreotide, St. John’s Wort, Antacids

CCBs: Diltiazem, Verapamil Antifungals: all Azoles. Macrolide Ax, especially clarithromycin, erythromycin. Other: Protease Inhibitors, grapefruit juice

MMF

–CyA inhibits enterohepatic circulation and lowers levels Hypoalbuminaemia raises free levels. –PPIs lower AUC Uraemia changes protein binding, raises free levels.

Sirolimus

Sevelamer lowers levels ACEi + sirolimus leads to high rate of angioedema

Azathioprine

Allopurinol raises levels and toxicity (Raman;JIM 90;229:69). Valgancyclovir, ACEi, Carbamazepine and Co-trimoxazole increase haematologic side effects. RENAL HANDBOOK 97


TRANSPLANTATION

BEAUMONT KIDNEY TRANSPLANT IMMUNOSUPPRESSION PROTOCOLS Transplant Type

Induction

MMF

Steroids

Deceased donor (DDKT)

Basiliximab 20mg 0.15mg/kg bd x 2 doses, then 0.1 mg/kg bd, days 0,4 adjusted by level

Tacrolimus

500mg bd

Protocol

ECD donor*

Basiliximab 20mg 0.15mg/kg bd x 2 doses, then 0.1 mg/kg bd, days 0,4 adjusted by level

500mg bd

Protocol

Monozygotic twins

None

Started pre-transplant at 0.05 mg/kg so no need for 500mg bd loading dose. Give 0.1 mg/kg bd as inpt and follow levels. Stop all immunosuppression at 1 month.

Protocol

HLA-identical living related sibling

None

Started pre-transplant at 0.05 mg/kg so no need for 500mg bd loading dose. Give 0.1 mg/kg bd as inpt and follow levels. Minimise immunosuppression by 6 months.

Protocol

Standard immunologic risk

Basiliximab 20mg Started pre-transplant at 0.05 mg/kg so no need for 500mg bd days 0,4 loading dose. Give 0.1 mg/kg bd as inpt and follow levels.

Protocol

High immunologic risk**

ATG

As above

Protocol

Steroid minimisation

ATG

As above, but keep tacro level ~10 x6 mos, and maintain 500mg bd levels 8-10 long term.

1000mg bd

Protocol

Steroid withdrawal in routine transplantation not supported by the literature, but may be appropriate in low immunologic risk (1st TXP, PRA <20%, no HLA Ab), high medical risk candidates (e.g. HCV, diabetes, obesity, or high skeletal or eye risk from steroids). FOOTNOTES: For low CNI levels despite high doses, add Diltiazem. For African ancestry pts, start MMF at 1 to 1.5g po BD; Sirolimus at 3 mg/day. Reduce MMF for leukopenia, anaemia, GI symptoms (nausea, vomiting, diarrhoea) *ECD donor: >60 years or aged 50-59 and death from CVA, h/o HTN; or Creatinine>130. Living related= Must be a primary relative (Parent, Child, Sibling) **High immunologic risk: Historic +crossmatch, historic /current DSA, repeat transplant esp. if same mismatched HLA, high PGEN, history of severe rejection, positive flow and negative CDC crossmatch.

STANDARD KIDNEY TRANSPLANT CORTICOSTEROID DOSING PROTOCOL Day 0: Methylprednisolone 500 mg IV given pre-op and 12 hours post transplant. Day 1: Prednisolone 20 mg OD from day 1 post-op until discharge. Days 7-30: Prednisolone taper to 5 mg PO daily by 1 month. Higher immunologic risk or higher body weight may need slower taper (5mg by 90 days) or maintenance on 7.5-10mg indefinitely.

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BEAUMONT KIDNEY TRANSPLANT ANTIMICROBIAL PROPHYLAXIS Infection

Transplant Status

Therapy

Pneumocystis carinii jiroveci pneumonia prophylaxis

Standard

Co-trimoxazole 480mg od (alternate days if creat>250) for 6 months. Co-trimoxazole also prevents Nocardia, Listeriosis, Toxoplasmosis, and UTIs.

Sulfa Allergic

Dapsone 50-100 mg daily (check G6PD) or atovaquone 1500 mg po with meals daily or Co-trimoxazole desensitisation.

Prior CMV or generally debilitated Co-trimoxazole daily for life.

Human Herpes Virus (CMV, HSV1 and 2, EBV, VZV, HHV 6,7,8)

Acute rejection

‘Resets the clock’. Co-trimoxazole for 3-6 months following ATG or increase in immunosuppression.

CMV IgG (D+/R-)

Highest risk. Give Valgancyclovir 900mg daily if GFR >60, 450 mg daily if GFR >30 ml/min and M/W/F if <30. Continue for 6 months (Humar: Am J Transplant. 2010;10(5):1228).

CMV IgG (D-/R+) or (D+/R+) Intermediate risk. Give Valgancyclovir 450 mg daily if GFR >30 ml/min or M/W/F if <30. Continue for 3 months. CMV IgG (D-/R-)

Low risk for CMV infection but risk of other herpes virus infection. Consider valacyclovir 500-1000mg od for 3m, adjusted for GFR. Definitely give if pt receives extra immunosuppression e.g. ATG, continue for 6 months.

Status Unknown

Assume high risk and use strategy for CMV IgG positive.

Multiple prior transfusions

Treat as high risk (see above) if >20 units PRBCs given.

Increase in immunosuppression

Typically therapy with either valgancyclovir or valacyclovir is resumed.

Fungal infections

Use if prednisolone >20 mg/d, or Nystatin (100,000 Units/ml) 4-6 ml Swish/Spit BD. Fluconazole 200-400 ATG or Ax mg/day is effective for prophylaxis failures and is standard following pancreas Tx’s; raises CNI levels.

UTIs

All x 6 mos, or indefinite for recurrent UTIs.

Strongyloides

If pt is from an endemic regions (Latin America) or has + serology, administer Ivermectin 200 mcg/kg PO x 2 doses.

Hepatitis B

Consider Lamivudine 100 daily even if HepBsAb +. Discuss with GI (Blanpain;Transp 98;66:883).

TB

Positive PPD or ‘High risk’ (from endemic country or evidence of prior infection). Treat with INH for 9mos prophylactically after discussing with ID.

RENAL HANDBOOK 99


TRANSPLANTATION

PERI- AND IMMEDIATE POST-OPERATIVE MANAGEMENT (DAYS 0 – 3) Infection

Transplant Status

Therapy

Immediately Post-op

Exam: respiratory function, perfusion to lower limbs, urine output. Check the pre-operative urinalysis (and culture) results especially for pyuria. Initial labs are drawn 1 hour and 5 hours post-op. If pt is oliguric, check the 1 hr potassium level as hyperkalemia is common due to reperfusion of ischemic kidney. In absence of oligoanuria, maintain UOP=>50 ml/hr with fluids, frusemide. Standard Beaumont IVF post-transplant: •Anuria: give 30 mls 0.9% saline per hour; •<100ml/hour: give urine output + 50mls per hour; •100-400ml/hour: replace urine output; •400-600 ml/hour: replace 66% of urine output per hour; •>600 ml/hour: replace 50% of urine output per hour.

Assessment of Allograft Function Post-Operatively

Urine output (allowing for pre-op output) is best immediate measure. Any question regarding allograft function: obtain US and/or Mag3 renogram renal flow scan (nuclear medicine).

Bladder Anastomosis and Foley Mgmt

Ureter into bladder (ureteroneocystostomy): remove Foley Catheter on POD 5. Many of these pts get a ‘double-J’ ureteral stent, removed 6 weeks post-op.

Blood Transfusions

All blood is leukocyte depleted. All transplant pts must receive CMV –ve blood.

Diabetes Mgmt

At 6am on the morning, start GKI infusion.

Anti-Coagulation

Kidney transplant pts receiving heparin experience a high rate of bleeding. Clinical experience suggests that bleeding is better than clotting, but nonetheless the indications for anti-coagulation must be discussed in advance.

Hyperkalemia

50% dextrose and 10U Actrapid. Treat co-existing acidosis with NaHCO3 8.4%. Give calcium gluconate 1 vial if > 6.0 or ECG changes. Avoid rectal administration of calcium resonium as high risk of perforation in the setting of ileus. Low dose oral resonium (15 g) is usually acceptable. Consider dialysis if these measures fail. Must d/w Transplant surgeon and nephrologist.

Phosphate

Post-op hypophosphataemia common. Cautious phosphate replacement if possible d/t risk of acute phosphate nephropathy (case reports). Diet best: almonds, nuts, meats and eggs.

Vascular Access

AV fistulas/grafts are used by trained nurses to draw blood and rarely for IV access. Avoid central lines / prolonged IV lines.

Dialysis post-transplant

Higher threshold is used for HD in post-transplant state, especially if urine output is increasing, due to risk of risk of ischemic injury to allograft. Minimal / no heparin, no TPA, avoid HoTN, cautious UF/minimise ultrafiltration.

Suspected Urine Leak

Consider if severe pain over graft or resistant hyperkalaemia. Measure fluid creatinine (=serum) and potassium (higher than plasma).

100 RENAL HANDBOOK


TRANSPLANTATION

TRANSPLANT CLINIC ALLOGRAFT FUNCTION Serum Creatinine

Transplant pts follow their creatinine closely. Addressing it 1st focuses the visit.

INTERVAL HISTORY General Focused systems review Medication toxicity screen

Recent infections, cancer screenings MEDICATIONS Doses, administration, adherence Review new meds Review prophylaxis

Recent hospitalisations? Visits to outside physicians? (1) Home BP < 140/90 mmHg (2) oedema (3) new skin lesions (4) gout. Tac: uncontrolled HTN, insomnia, hair loss, tremors, GI upset. CyA: gum changes or hair growth. Pred: weight gain, rage disorder, warts. MMF/MPA: gastrointestinal complications . Sirolimus: oral ulcers, oedema, pulmonary symptoms, anaemia. Including basal cell and squamous cell ca’s.

Pts should carry written list. Consider potential interactions with ISDs. Ongoing need for Valcyte, Co-trimoxazole (6 months duration) or PPI? See page 99.

PHYSICAL EXAMINATIONS Weight and vitals Early post-transplant, weight may fall due to salt excretion and low intake. Oropharynx Thrush: seen with high dose steroids. Mouth ulcers: sirolimus, HSV infection. Skin Suspicious moles, cushingoid appearance. Lymph nodes Post Transplant Lymphoproliferative Disorder (PTLD). Extremities Oedema: consider nephrotic syndrome, CHF, DVT, sirolimus, CCBs. Tremor: CNI. LABORATORY Creatinine See above. hypomag-, hypophos-, hyperCa,. Check PTH if hyperCa or hypophosp. Ca, Phos, Mg Leukopaenia=Meds (MMF / sirolimus / valgancyclovir/Septrin/PPi) or CMV / B19. Anaemia=MMF / FBC sirolimus / ACEi / iron deficiency. Thrombocytopenia=?TMA. See page 96 for goal levels. CNI/mTOR level Check urine dipstick, Prot:creat ratio. Proteinuria and haematuria usually resolves by 6 weeks post TXP; Urinalysis persistence/recurrence? Consider recurrent disease (e.g. FSGS or IgA or MPGN or TMA). Fasting glucose checked each visit; check HgbA1c if elevated. Blood Glucose Screen months 1, 2, 3, 6, 9, 12 mos (Bohl;CJASN 07;2(S1):S36). Do not check urine BK. BK virus serum PCR BK viraemia seldom occurs before 1 month post-transplant, rapidly increases by month 3 and plateaus by month 6. Sustained viraemia indicates viral urothelial invasion, a precursor to BK-nephropathy. CMV virus PCR EBV virus monitoring Monitoring unnecessary while on prophylaxis with valganciclovir. Check if fever or leucopaenic. If PTLD suspected, or for EBV -ve pts such as diabetics or children, EBV monitoring may allow earlier recognition of a predisposition to PTLD that may be prevented with reduction of ISDs. Send a clotted sample (order as “CYTO”) to H+I lab for antibody screening monthly until three months post Anti-HLA antibodies transplant, then quarterly up to one year, then annually. If any graft dysfunction test DSA (order as “PTXAB”). (1) LDL cholesterol < 1.8mmol/l in high CV risk pts; (2) LFTs for statin-treated pts; (3) PTH. Other Testing RENAL HANDBOOK 101


TRANSPLANTATION

TRANSPLANT CLINIC CONTD... ASSESSMENT AND PLAN Allograft function Immunosuppression Anti-Microbial Prophylaxis Ureteric Stent Cardiovascular Hypertension

If creat> baseline, see page 103 (assessment of allograft dysfunction). If stable, consider ACE/ARB. See page 98 for Transplant Immunosuppression Protocols.

Lipids CK Fever

Use generic Atorvastatin; Pravastatin ineffective, avoid Simvastatin with CyA. Check quarterly if on statin. Routinely admit pts with a fever greater than >38C for pan culture (incl. CMV-PCR and empiric Ax). Avoid Ax that interfere with CNI /mTOR levels (see page 97). For bacterial infections, do not routinely decrease immunosuppression unless they are recurrent or life threatening. However, reduce/stop MMF/AZA for CMV or BK, which are biomarkers of over-immunosuppression. Estimated blood loss over the first three months is 750 mL. Oral iron problematic (binds MMF, not very effective, GI side effects). Anaemia is aggravated by ACEi/ARB. ACEIs and ARBs useful for treating post-transplant erythrocytosis, which usually does not occur in the first three months. Skin review for all with dermatology referral if concerns, plus other age appropriate screenings as per national screening protocols (Breastcheck, Bowelscreen) and annual Cervical screening. Vit D3= standard prophylaxis. Consider low dose bisphosphonate if high risk for fracture, but ensure 25-vitamin D levels are adequate first. Hypercalcemia common early post transplant due to residual FGF-23. Consider Cinacalcet or parathyroidectomy in severe cases (expensive). Check Mg level quarterly: CNIs and mTORs cause Mg wasting. Plan for retransplantation, dialysis access. Reduce immunosuppression. First 30-60 days: discourage crowded places and driving for 2 - 4 weeks post-transplant. Encourage: Sunhat and SPF>50 sunblock, yearly flu vaccine, regular dermatology visits. Pneumovax should be given twice in ptâ&#x20AC;&#x2122;s lifetime. Discourage: Cats, birds, digging in soil, dusty undisturbed environments (e.g. cleaning the attic) due to risk of fungal infection, spore inhalation etc. First 1-2 weeks: Renal Day Ward. Then Renal OPD. After first year, see every 3m depending on stability and medical complexity. And schedule follow up with primary nephrologist (whom pt should see within first 3-6 mos after transplant depending on circumstances). (1) At every visit; (2) One week after change in immunosuppression or addition of ACE/ARB/Diuretic; (3) No less frequently than every 3-6 months in ALL pts regardless of stability. References: Kasiske;JASN 00;1151 and Hariharan;AJKD 06;47:S22.

Anaemia / erythrocytosis Cancer Screening Mineral & Bone Disease

Failing allograft? Counselling and Life Style

Follow-up (approximate) Clinic visits Blood checks

102 RENAL HANDBOOK

Review dosing, necessity. See page 99. Must be removed ~6 weeks after transplantation. Document. BP, Lipids, DM (see Ojo;Transp 06;82:603). CCBs: 1st line is Amlodipine as minimal effects on CNI levels; avoid Diltiazem / verapamil as they raise CNI and mTOR levels (inhibit CYP3A4). BB: Use if any CAD ACEi/ARB: Most pts require an ACEI or ARB (LVH, CVD). Problematic early post transplant (anaemia, hyperkalaemia, allograft dysfunction), delay until after 3 mths.


TRANSPLANTATION

DIFFERENTIAL DIAGNOSIS OF KIDNEY GRAFT DYSFUNCTION Time Frame

Aetiologies

Evaluation

Immediate Ischemic renal injury /ATN i.e. delayed graft function (DGF) (minutes to Arterial or Venous Thrombosis days) Urinary obstruction or leak Hyperacute or Acute ABMR Recurrent Renal Disease Donor induced injury e.g. TMA, DIC

US ± renogram scan ± biopsy at 1 week if no diuresis Emergency US+renogram U/S, Flow Scan Urgent biopsy, DSA (order “PTXAB”) Urine dipstick, biopsy Renal scan ± biopsy

Early Pre Renal Failure (few days to 6 mos post) CNI nephrotoxicity incl. TMA TCMR or ABMR Urinary outflow obstruction Acute graft pyelonephritis Recurrent renal disease Transplant Renal Artery Stenosis BK or CMV Infection

Assess PO intake, d/c ‘dialysis’ diet, minimise opioids, treat ileus LDH, plts, biopsy Biopsy, HLA antibody testing (order “PTXAB”) U/S, urine dipstick, MSU, BK viraemia Urine dipstick, culture. Cover with Ax before biopsy Urine dipstick, Urine PCR US, Angiography best test See below

Late (>6 mos)

Biopsy, HLA antibody testing (order “PTXAB”), Urine prot:creat ratio Clinical, labs, biopsy Ultrasound, Post-Void Residual

TCMR or ABMR (incl. Transplant Glomerulopathy) CNI toxicity: Hemodynamic, Fibrotic, TMA Urinary Tract Dysfunction: BPH, neurogenic bladder, reflux, stones. Recurrent UTI’s or Graft pyelonephritis Recurrent or de Novo Renal Disease Medication Interactions: e.g. rhabdomyolysis BK Nephropathy Transplant Renal Artery Stenosis or Iliac Stenosis PTLD Tubular injury

Urine dipstick, MSU, Post-Void Residual Serologies, Urinalysis, Urine prot:creat ratio, Biopsy Review med list (e.g. CNI + Statin) Blood BK PCR, Biopsy US, Angiography best test Biopsy; EBV PCR, CT scan, FBG-PET Common, often unexplained

RENAL HANDBOOK 103


TRANSPLANTATION

DISTRIBUTION OF HISTOLOGIC DIAGNOSES BY TIME POST-TRANSPLANTATION

(Sellares J et al AJT; 12(2):388-399)

THE FAILING TRANSPLANT AND RETURN TO DIALYSIS Failing transplant: The goal is to wean immunosuppression without precipitating an acute rejection episode. Consider switching to once daily CNI and ignoring trough levels. Another approach is to increase MMF and stop CNI entirely. Sirolimus is contraindicated if GFR < 40ml/min or proteinuria > 0.5g/day, so is generally unsuitable in this setting. Return to dialysis: The goal is to wean off immunosuppression without precipitating need for early transplant nephrectomy for a symptomatic rejection episode. The exception is someone for whom an imminent re-transplant is planned and immunosuppression is continued in such cases. As CNIs are more effective in preventing acute rejection, and the antimetabolite is more likely to increase infection risk on dialysis, generally stop antimetabolite first. Once urine output falls to < 500ml/day reduce to once daily CNI and minimise prednisolone, stopping entirely when pt becomes anuric. Give short steroid burst for rejection episodes.

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INFECTION IN THE KIDNEY TRANSPLANT RECIPIENT GENERAL CONSIDERATIONS REGARDING INFECTION IN THE TRANPLANT RECIPIENT Bacterial infection: Infection is extracellular and easily detected as foreign by the innate immune system. Generally do not need to reduce immunosuppression. The exception is recurrent bacterial infection, which may indicate impaired innate immunity. In a transplant recipient this may be due to an anatomical problem or hypogammaglobulinaemia. Consider reducing AZA/MMF and sometimes give IVIG for severe pneumonia in a transplant recipient. Viral infection: Infection is intracellular and clearance depends on eliminating the infected host cell by means of the innate (NK cells), adaptive (T cell) +/- humoral responses. Response is further limited by infection masquerading as self. Viral infection generally indicates over-immunosuppression; reducing or stopping MMF/AZA is the favoured approach. Viral infections are frequently associated with allograft dysfunction and histology may resemble acute rejection, so the decision to reduce immunosuppression may be difficult.

CYTOMEGALOVIRUS (CMV) INFECTION Aspect

Notes

Background CMV is the most important opportunistic infection post-transplant. Definitions

CMV infection: evidence of CMV replication eg positive blood PCR test – see below. CMV disease: evidence of CMV replication AND tissue damage (leukopaenia, GI involvement, hepatitis, pneumonitis, retinitis, encephalitis, pancreatitis, nephritis, radiculopathy).

Aetiology

Virus has direct and indirect toxicity, raising risk of rejection, graft dysfunction or loss, transplant RAS and death.

Risk factors

High risk: D+/R – (60% such pts develop disease without prophylaxis). D+/R+; Immunosuppression intensity; Higher degree of HLA mismatch.

Diagnosis

Blood CMV viral load / PCR (+ve = >2000 copies/ml).

Prevention

See “Beaumont kidney transplant antimicrobial prophylaxis” see page 99.

Treatment

Reduce immunosuppression; at very least, stop MMF/Aza but consider also reducing CNI. Oral valganciclovir @900mg bd for 21 days (VICTOR study Asberg; AJT 07;7:2106). If severe disease, consider IV ganciclovir 5mg/kg bd, then use oral valgancyclovir. Adjust both for GFR. Avoid underdosing as it leads to Rx failure and resistance. After 21 days and assuming large fall in CMV PCR (>log100.5), reduce valgancyclovir to 900mg od and give for another 28 days, then stop if CMVPCR neg. Check CMV-PCR 2 weeks later. Avoid restarting MMF/Aza.

Pearls

Any pt with CMV disease: restart Co-trimoxazole prophylaxis for 6m.

RENAL HANDBOOK 105


TRANSPLANTATION

BK POLYOMA VIRUS Aspect

Notes

Syndromes

(1) Asymptomatic renal allograft dysfunction, can be severe. Usually > 3-6 mos post transplant; (2) Ureteric stenosis, sometimes with hydronephrosis.

Aetiology

BK Virus, a DNA virus and member of the polyoma virus family. BK is ubiquitous (>80-90%) but quiescent in adults. Replication occurs in setting of immunosuppression (Hariharan:KI 06;69:655).

Risk factors

Studies are conflicting, possibilities include older recipient age, DDKT, BK. D+/R- combination, high intensity immunosuppression (Tacro level > 8 and/or MMF dose>1.5-2gm/day--Bohl;CJASN 07;2(S1):S36), HLA mismatching, CMV disease.

Diagnosis

Kidney biopsy shows tubulointerstitial nephritis and viral inclusions by LM, immunoperoxidase staining of biopsy material positive for viral antigen SV40, 40 nm viral particles by EM. BK is patchy and negative biopsy does not ‘rule out’; medullary parenchyma has higher yield. (Randhawa:AJT 06;6:2000). Non-invasive testing=blood PCR. In (Hirsch:NEJM 02;34:488), all pts with nephropathy had >7,700 copies/ml; a cut off of > 10,000 copies/mL had sensitivity of 98%. Rarely nephropathy is present with lower level (>1000 copies/mL). Urine testing is out of favour due to poor specificity. False +ve in prostatic disease.

Treatment

General Principle: reduce immunosuppression. Most centres discontinue or significantly reduce MMF dose while modestly lowering CNI levels. In refractory or severe cases consider: (1) Leflunomide 100 mg po x 3-5 days then 10-40mg daily. Goal trough of active metabolite A77-1726=50-100 mcg/ml (Williams;NEJM 05;352:1157; Josephson;Transp 06;81:704) and/or (2) IV IgG 2 grams/kg in divided doses over 2-5 days, especially if rejection appears present (Sener:Transp 06;81:117). (3) Switch CNI to sirolimus. (4) Ciprofloxacin.

Pearls

(1) Prevention of BK through routine monitoring of blood PCR in all kidney recipients (e.g., at months 1-6,9 and 12 post transplant—Bohl;CJASN 07;2(S1):S36), with reduction of immunosuppression in face of positive result, is increasingly accepted and may prevent relative over-immunosuppression (Brennan;AJT 05;5:582). (2) Interstitial inflammation can be confused with rejection; BKN indistinguishable from TCMR without SV-40 staining; both can occur concomitantly. (3) As anti-rejection treatment can accelerate graft loss (Hussain;Clin Transp 0216:43), have a high threshold before diagnosing / treating rejection in presence of BK (Randhawa;AJT 06;6:2000). ABMR features (endarteritis, fibrinoid arterial necrosis C4d+glomerulitis) suggest concomitant rejection. (4) Consider re-biopsy +/- treatment if graft function fails to improve or worsens following a reduction in immunosuppression.

PRESENTING THE TRANSPLANT PATIENT ON WARD ROUNDS Key data points to include are brief pre-txp history, intra-operative course and post-operative course e.g. “Mr. W is a 60 year old man with ESRD from IgA nephropathy who was on HD for 3 years using a left forearm AVF. He was under the care of Dr. Plant in Cork prior to receiving an ECD kidney from a 65-year-old man 5 days ago. Intra-operatively, the artery and vein were anastomosed end-to-side to the common iliacs because of recipient atherosclerosis of the external iliac vessels. The ureter was anastomosed to the native ureter because the bladder was small and contracted. A ureteric stent was placed and is due for removal in 2 weeks. The HLA mismatch was 2-11 and the CMV serostatus was D+/R+ and the EBV status D+/R+. The cold ischemia time was 16 hours. Post-operatively, the patient received induction therapy with basiliximab 20mg on days 0 and 4. Maintenance therapy was with tacrolimus, MMF, and a steroid taper as per protocol. The course was complicated by slow graft function and the patient was discharged on post-operative day 5 with a serum creatinine of 320mmol/L.” 106 RENAL HANDBOOK


TRANSPLANTATION

MALIGNANCY IN THE TRANSPLANT PATIENT POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER (PTLD) Background PTLD generally refers to extra-nodal B-cell lymphomas due to Ebstein-Barr virus (EBV). Commonest post-tx cancer in kids, 2nd in adults and commonest fatal post-tx cancer. Syndromes Clinical presentations vary from a benign infectious mononucleosis syndrome to a severe malignant lymphoproliferative disorder. 3 distinct clinical syndromes are described: (1) Polyclonal B-cell proliferation with malignant transformation, widespread disease, and multiorgan involvement. Accounts for 30% of pts and presents within weeks of transplant. (2) Majority (>50%) present as an infectious mononucleosis within a year of transplant due to a benign polyclonal proliferation of B cells. This is easily missed; very responsive to lowering immunosuppression. (3) Minority present with a monoclonal B-cell proliferation, extra-nodal disease, and visceral involvement late posttransplant. NHL > HL. Aetiology B-cell disease caused by iatrogenic T-cell dysfunction: activated T-cells normally regulate B-cell proliferation; pharmacological T-cell inhibition permits proliferation of EBV-infected B-cells. Immunoglobulin (IgH) rearrangements distinguish aggressive monomorphic forms from others. Risk factors Main risk factor is the EBV D+/R- recipient, and they need monitoring for EBV infection. 50% of unmonitored EBV D+/Rrecipients develop PTLD Other risk factors include extremes of age, transplant of an adult kidney into a child, heavier immunosuppression especially ATG and CMV infection, Belatacept in EBV D+/R- pts. Diagnosis Tissue biopsy (preferably excisional biopsy). Diagnosis based on histological, cytological and microbiological evidence: lymphoproliferation that disrupts tissue architecture, oligoclonal or monoclonal cell lines and the presence of EBV in the tissue. LDH elevated in 66%. EBV viral load (>2000 copies has 100% sensitivity; 86% specificity). FBG-PET scan for staging. IgH gene rearrangement studies. Prevention Check EBV in all flu-like illnesses esp. if lymphadenopathy is present and during the first post transplant year. Treatment Early disease often easily managed by lowering immunosuppression (“Preventable with Timely Lowering of Drugs”) e.g. reduce CNI by 50%, d/c MMF/AZA, same or 50% less steroid. Consider sirolimus. Late disease as for standard treatment of lymphoma per oncology e.g. R-CHOP. Antivirals don’t work. EBV does not express thymidine kinase, the target of ganciclovir/acyclovir. Pearls Incidence is highest in 10-14th year post transplant (Morton Tx 2013;(3):470-478). Early onset assoc. with EBV R- status, EBV+ histology and extra nodal disease. Later disease tends to be EBVneg on histology. PTLD originating from the donor (based on HLA-DR analysis) tends to arise in the first year after transplantation in the graft and responds well to lowering immunosuppression, whereas recipient-origin PTLD develops later (75 mos) as a multisystem, invasive disease with a poorer prognosis (Petit Transplantation. 2002 Jan 27;73(2):265-71).

MANAGEMENT OF IMMUNOSUPPRESSION IN MALIGNANCY Malignancy Management Non-melanomatous Switch to sirolimus from CNI if multiple non-melanomatous skin cancers (Euvrard S et al. N Engl J Med skin cancer 2012;367:329-339). Other malignancy Discontinue MMF, consider sirolimus +Tacro targeting combined trough level of ~8 or use sirolimus +Pred or Pred alone. Chemotherapy Discuss expected degree of myelosuppression with Oncologist. If severe neutropenia expected, switch to pred planned only. PTLD As above. RENAL HANDBOOK 107


TRANSPLANTATION

VACCINATIONS IN THE TRANSPLANT PATIENT All pre-transplant vaccinations should be given >30 days prior to transplant in order to be effective. Live vaccines (e.g. MMR, Varicella, shingles) must be given >30 days pre-transplant and transplant should not proceed in the interim. VACCINES TO CONSIDER BEFORE TRANSPLANTATION Yearly. If not received within 3-5 years, check Pneuomoccal Ab titres if vaccinated previously. If not received within 10 years. If non-immune. Requires 3 doses @ 0, 1 and 2-6 mos. Use 40mcg, as opposed to usual adult dose of 10mcg, in advanced CKD. Not mandated if pre-emptive transplant recipient. Measles, mumps, rubella (MMR) If non-immune to measles by serology. Avoid if on immunosuppression. Varicella If non-immune by serology. Avoid if on immunosuppression. Meningococcus Consider in pts at high risk for ABMR, or other condition that may require Haemophilus Influenza splenectomy or Eculizumab. VACCINES TO CONSIDER AFTER TRANSPLANTATION Inactivated Influenza (injection) Pneumovax TDaP (Tetanus, Diphtheria, acellular Pertussis) Hepatitis B

Yearly. Vaccine is safe but may be associated with the production of anti-HLA antibodies (Katerinis AJT 1111:1727). Pneumovax Every 3-5 years for total 2-3 doses. TDaP (Tetanus, Diphtheria, acellular Pertussis) Every 10 years. Inactivated Influenza (injection)

VACCINES CONTRAINDICATED AFTER TRANSPLANTATION Measles, mumps, rubella (MMR), Varicella, Shingles, Flu Mist, Oral Polio, Yellow Fever, BCG.

LEUCOPENIA AND NEUTROPENIA IN THE TRANSPLANT PATIENT Background: Leukopaenia and neutropaenia are common, with peak incidence at 100 days post transplant. Neutropenia is defined as absolute neutrophil count (ANC) <1.5x109/L. Although neutropenia after kidney transplant is not associated with as much fever / sepsis as neutropenia after chemotherapy, it is nonetheless associated with a poorer prognosis (Hurst FP et al, Transplantation. 2011 Jul 15;92(1):36-40.) Aetiology: Causes include medications (valgancylovir, Co-trimoxazole, mycophenolate mofetil, ATG, tacrolimus, AZA, sirolimus, PPi) and infections (mainly CMV). Drug-induced neutropaenia is much more common than CMV-induced neutropaenia, especially if the pt is still on valgancylovir prophylaxis. In the absence of evidence of CMV disease (fever, hepatitis etc.), it is reasonable to assume the cause is medication and to reduce medications as below. Once ANC >2.0, stopped medications can be slowly re-introduced. Bone marrow biopsy is very rarely required. Mgmt: GCSF appears to be safe; usually only 2-3 doses are needed. Absolute neutrophil count Check CMV viral load? Admit Valgancyclovir* Co-trimoxazole MMF# Add GCSF Frequency of FBC checks

Mild 1.0-1.5 x 109/L If evidence of CMV disease Only if unwell Halve or stop Halve or stop Halve or stop No Every 3-4 days

*If high risk of CMV or other herpes virus infection: substitute valacyclovir.

108 RENAL HANDBOOK

Moderate 0.5-1.0 x 109/L If evidence of CMV disease Only if unwell Stop Stop Stop Usually no Every 2-3 days

Severe <0.5 x 109/L Yes Yes Stop Stop Stop Yes Daily

#If rejection a concern, double the dose of prednisolone while MMF stopped.


TRANSPLANTATION

TRANSPLANT REJECTION BANFF SCHEMA FOR THE HISTOLOGICAL DIAGNOSIS OF REJECTION Diagnosis

Frequency Typical onset

Borderline changes TCMR

9% 9%

C4d+ABMR 4% (must be DSA+)

C4d-ABMR 14% (must be DSA+)

Mixed

6%

Presentation

Lesions (see below)

First 6 weeks

Allograft dysfunction; stable but poor function; delayed graft function. First 1-6 months; >1yr As above. Occasionally fever, graft suggests non-adherence pain. >6-12 months Allograft dysfunction; proteinuria; fever, graft pain.

>6-12 months

As above.

>6-12 months; >1yr Allograft dysfunction; proteinuria; suggests non-adherence fever, graft pain.

t>0 and i≥0 (No v lesions) i≥2 and t≥2 OR v>0 1st transplant week: C4d+ and g≥0 or ptc≥0 or v3 or thrombosis or ATN Later: C4d+ and g≥0 or ptc≥0 or cg≥0 or ci and ct≥0, ptcmml >4 or cv≥0 (no deposits on EM) 1st transplant week: No C4d but g≥0 or ptc≥0 or v3 or thrombosis or ATN Later: No C4d but g≥0 or ptc≥0 or cg≥0 (no deposits on EM) Features of both TCMR and ABMR

Avoid the following terms: (1) Type 1a (=TCMR), Type 1b (=TCMR), Type 2 (=TCMR +/- ABMR), Type 3 (=ABMR); (2) ‘Vascular rejection’ as it does not distinguish between TCMR and ABMR; (3) Chronic allograft nephropathy or CAN. Not used anymore.

BANFF GRADING OF TRANSPLANT HISTOLOGY Lesion

Acronym

Score: 0

Interstitial inflammation i 0-9% of cortex Tubulitis t No tubulitis Intimal arteritis v No arteritis Glomerulitis g No gloms Peritubular capillaritis ptc <10% of (in ≥10% of ptcs) cortical ptcs C4d peritubular C4d None capillary staining Transplant cg Double contours in glomerulopathy (most <10% of capillary severely affected glom) loops Interstitial fibrosis ci 0-5% of cortex Tubular atrophy ct No tubular atrophy Arterial fibro-intimal cv None thickening

1

2

3

10-25% of cortex 1-4 cells involving <25% of luminal area <25% of gloms 3-4 cells luminal inflammatory cells 1-9% of biopsy area

26-50% of cortex 5-10 cells involving >25% of luminal area 26-75% of gloms 5-10 luminal inflammatory cells 10-50% of biopsy area

>50% of cortex >10 cells Transmural inflamm. +/arterial fibrinoid necrosis >75% of gloms >10 luminal inflammatory cells >50% of biopsy area

Double contours in 10-25% of capillary loops 6-25% of cortex 1-25% of cortical tubules 1-25% luminal narrowing

Double contours in Double contours in 26-50% of capillary loops >50%of capillary loops 26-50% of cortex >50% of cortex 26-50% of cortical tubules >50% of cortical tubules 26-50% luminal narrowing >50% luminal narrowing RENAL HANDBOOK 109


TRANSPLANTATION

TREATMENT OF TRANSPLANT REJECTION Diagnosis

Treatment

Notes

Borderline changes

Borderline changes in the first 6 weeks post Molecular studies suggest 66% injury 33% TCMR (de transplant in an ECD or DCD kidney may be treated Freitas et al AJT; 12(1):191-201). conservatively. If unsure, low threshold for repeat biopsy. Borderline changes between 3-6 months could be considered to be TCMR and treated as such.

TCMR

Methylprednisolone 500mg IV x 3 days (monitor blood sugars) and Optimise maintenance immunosuppression: adequate CNI levels or MMF dose (at least 750mg bd); add steroids. Consider ATG 1.5mg/kg/day x 7-10 days via CVC.

Early TCMR (before 1yr) has an excellent prognosis and no association with graft failure (Sellares J et al AJT;12(2):388-399) Late TCMR (after 1yr) is suggestive of non-adherence and a risk factor for ABMR Mixed rejection can be treated with steroids but also requires ABMR mgmt (see below) Steroids may be started empirically if a histological diagnosis will take over 24hrs. Improvement in creatinine usually occurs within 72-96 hrs but stabilisation can also be sign of response ATG requires hydrocortisone and anti-histamine preemptively. Requires CMV, PCP and fungal prophylaxis for 3-6months post therapy. Increased risk of PTLD and infection long term. V-lesion does not necessarily require ATG therapy (Sellares et al AJT;11(3): 489-499). In early TCMR (<1yr), consider ATG if V2-3. Also consider ATG in â&#x20AC;&#x153;steroid-resistant rejectionâ&#x20AC;? i.e. persisting biopsy findings of TCMR at day 7 post steroid treatment with no clinical improvement.

Very early ABMR (i.e. PEX (1-1.5 plasma volumes x 5 exchanges) and/or Treatment depends on level of activity (i.e. g or ptc score) high risk transplants Rituximab (375mg/m2) and/or IVIg 2g/kg. and stage (i.e. degree of scarring). in the first week) Severe cases: consider immediate splenectomy Repeat Xmatch after final PEX. (within 24hrs of the diagnosis). ATG. Later ABMR

110 RENAL HANDBOOK

PEX (1-1.5 plasma volumes x 5 exchanges) and/or Rituximab (375mg/m2) and/or IVIg 2g/kg and/or Increase CNI levels (e.g. tacro trough 10-15) and MMF dose (e.g. 1g BD). Switch to MMF if on AZA and/or Eculizumab 900mg qweek x 4 doses, then 1200mg every 2 weeks indefinitely and/or ATG.


TRANSPLANTATION

CROSS MATCHING AND HLA TYPING CROSS MATCH (XM) – A XM tests a specific recipient’s serum for antibodies against a specific donor’s T and B cells. Cytotoxicity XM: donor T or B cells are tested for lysis in response to recipient serum. – T Cell XM: “Anti-Human Globulin–Complement Dependent Cytotoxicity” (AHG-CDC) XM: (1) Recipient serum is added to donor T cells; (2) AHG is added to crosslink bound antibody and increase sensitivity; (3) complement and vital dye are added; (4) the cells are examined for lysis. A positive AHG-CDC XM means recipient has anti-donor HLA Class I antibodies (T cells express only HLA Class I). – B cell CDC XM: Recipient serum is added to donor B cells followed by complement and vital dye. Cells are washed prior to adding complement (Amos method) to increase specificity. B Cells express Class I & II HLA so a positive B Cell XM with negative T Cell XM suggests Class II anti-HLA antibodies. Non-HLA antibodies and auto-antibodies often react with B cells, so B cell XM is less specific than T cell XM. – Flow XM: In lieu of or in addition to the CDC-XM, recipient serum is added to donor T and B lymphocytes followed by a fluorescent anti-human antibody. A Flow cytometer is used to assess antibody binding (a ‘binding’ assay). Rituximab and ATG turn the CDC XM falsely positive, so Flow XM is used instead when these agents have been given. Flow XM may be more sensitive than CDC in some circumstances.

HLA TYPING – Of the 6 major HLA-MHC Loci (Class I=A, B, C; Class II=DP, DQ, DR), A, B and DR are the most important in kidney transplantation (though DQ is also routinely typed). HLA type may be determined using DNA or cytotoxicity techniques. – HLA genes are inherited as single unit (‘haplotype’), one from each parent. Siblings have a 25% chance of being HLA identical by simple Mendelian genetics (½ x ½). Such HLA identical pairs have improved outcomes due to low immunologic risk so their immunosuppresison may be minimised. – Zero mismatch deceased donor kidneys = no mismatch at A, B, DR. However, unlike 0 mismatch siblings, these are assumed not to be matched for minor HLA antigens. – Donor HLA typing is critical when the recipient has pre- or post-transplant anti- HLA antibodies, as it allows the identification of the antibodies as being donor-specific, which are more pathogenic.

HLA ANTIBODY DETECTION AND IDENTIFICATION PANEL REACTIVE ANTIBODY TESTING AND PGEN – The H+I lab uses (Panel Reactive Antibody) PRA testing to identify recipients with HLA antibodies that react to common HLA antigens. PRA = % of HLA antigens to which the recipient serum reacts. – PRA identifies antibodies as Class I or II but may not identify antigen specificity particularly when the PRA is high. Pts with high PRA (>80%) experience long wait times for deceased donor kidneys. – New assays such as ELISA and Luminex can detect anti-HLA antibodies not identified by the CDC assay, as well as non-complement fixing antibodies. Because of these changes in technology, and the limitations of PRA as a measure of transplantability, the term PRA is falling into disuse and is being replaced by generated PRA (Pgen). Pgen is the proportion of unsuitable donors for each potential recipient, calculated using a database of donor HLA types. – The Pgen value is not used to guide immunosuppressive therapy but as an indicator of how difficult it is to find a compatible graft. – The Beaumont matching programme lists acceptably mismatched pts and significantly sensitised pts with a Pgen >50% so as pts with non-complement fixing antibodies are not disadvantaged. RENAL HANDBOOK 111


TRANSPLANTATION

HLA ANTIBODY DETECTION AND IDENTIFICATION CONTD. TECHNIQUE – PRA can be performed using (1) Cytoxicity assays, in which lymphocytes collected from assorted blood donors are assessed for lysis in response to recipient serum and complement; (2) Solid phase binding assays, which detect antibody bound to HLA antigens purified from blood donors. Binding is detected using either (a) ELISA; (b) Luminex, which uses coloured HLA antigen-coated beads, a phycoerythrin labelled anti-human IgG and a laser detection system to detect up to 100 different HLA specificities in one tube; (c) Flow cytometry using HLA-coated beads and fluorescent anti-human IgG.

HLA ANTIBODY IDENTIFICATION – Donor specific antibodies (aka ‘DSA’ = directed against HLA antigen(s) present in donor) are more pathogenic than non-donor specific (‘Third Party’) HLA antibodies. – Pre-Transplant: The specificity of anti-HLA antibodies is determined so they can be compared to the HLA antigens on the prospective donor. – Post-Transplant: Serum from recipients with allograft dysfunction is tested to determine if de novo antiHLA antibody is present and if so whether the antibody is donor specific (DSA) or non-donor specific (‘Third Party’). – Techniques: Antibody specificities are identified using ELISA, Flow Cytometry or Luminex test kits that incorporate purified HLA antigens onto plates or beads. – Non-HLA antibody (MIC-A; anti-endothelial antibody and others) may also be pathogenic but their significance is unclear and they are not routinely tested.

MATCHABILITY SCORES – The H&I Department has a database of over 1,000 HLA types of previous deceased donors from our population. We use this database of donor HLA types to calculate the chance of a pt getting a good match from our donor population. – This data is expressed as a percentage of the population and is made available to the referring clinicians and the Department of Transplantation on the monthly transplant waiting lists. It can be used to accurately discuss the likelihood of a pt getting a very good match, or how unlikely this is, depending on the pt’s HLA type. – The scores from over 2,500 pts analysed to date range from below 0.01 to 16% i.e. ranging from 1 in every 10,000 donors to 16 in every 100 donors being a close genetic HLA match. To use the matchability score, you need to know the pt’s blood group. If the blood group is B or AB, there are very few donors of these blood groups, and therefore, waiting for a close match is inadvisable.

THE HIGHLY SENSITISED TRANSPLANT PATIENT SENSITISED AND ABO-INCOMPATIBLE RECIPIENTS – The presence of ABO incompatibility or a positive CDC-XM (page 90) have traditionally been absolute contraindications to transplantation because of the near certain risk of ABMR. ~14% of pts on the wait list have PRAs>80% but they receive only 7% of the kidneys transplanted each year (Jordan;AT 06;6:459). – Preparative regimens to remove anti-ABO/HLA antibodies (PEX + immunosuppression +/- Rituximab) have allowed these transplants to occur with good short-term results in highly selected pts although long-term outcomes for HLA desensitisation are not great. – Alternative = ‘Paired Kidney Exchange’. ABO incompatible donor-recipient pairs (e.g. A-B) are matched with other incompatible pairs (B-A) to make two (or more) matches (Montgomery;JAMA 05;294:1655). O recipients benefit less frequently because O donors can donate to any ABO group, but they may benefit when HLA sensitisation or altruistic O donor is present. – Alternative =’Kidney Donor Chain’: An altruistic donor catalyses a series of paired kidney transplants. 112 RENAL HANDBOOK


TRANSPLANTATION

THE HIGHLY SENSITISED TRANSPLANT PATIENT

CONTD.

TRANSPLANTATION OF THE HLA SENSITISED PATIENT – Anti-HLA Abs are not naturally occurring (in contrast to anti-ABO Abs). They result from transplantation, pregnancies, transfusions, possibly viral infections. – Two broad approaches have been used to allow these transplants to proceed: (1) High dose IV IgG (~2 gm/kg) monthly x 4 months-– from group at UCLA (Jordan;AJT 06;6:459). In the ‘NIH-IGO2’ RCT (Jordan;JASN 04;15:3256), IV IgG lowered anti-HLA antibody levels and reduced the mean time to DDKT from 10+ years to ~5 years. (2) PEX (to remove antibody) + low dose IV IgG (~100-150 mg/kg) (or CMV IgG) + standard transplant immunosuppression (to reduce antibody production)--from Johns Hopkins Hospital (Sonnenday; Transp Proc 02;34:1614) and Mayo Clinic (Stegall;AJT 06; ;6:346) – Although short-term results for HLA-desensitisation were encouraging, medium-term results have been disappointing. This has lead to increased popularity of paired and donor-chain approaches.

TYPICAL SEQUENCE OF EVENTS FOR HLA INCOMPATIBLE KIDNEY TRANSPLANT POD

HD / PEX

Medications

HLA testing

Meningococcal and pneumococcal vaccines.

2 months – 13 days

HD only

Rituximab 1g after dialysis.

– 11 days

HD only

Start tacrolimus, MMF, Septrin and Valacyclovir as per protocol (see page 98-99). Vitamin K 10mg PO x 1.

– 8 days

HD only

– 5 days

PEX + HD

– 3 days

PEX + HD

– 1 day

PEX + HD

Day 0

Transplant Methylprednisolone as per LUKT protocol (see page 98). ATG (see page 97).

Day 2

PEX

Day 4

PEX

Discharge

Sample to H+I lab pre-dialysis.

Pre- and post- PEX samples to H+I lab Final XM performed using these samples Admit. IVIG 0.4g/kg IV after PEX with pre-medication.

Pre- and post- PEX samples to H+I lab Check fibrinogen pre-PEX and give FFP if <100. For ABOi, use FFP that matches donor type.

Pre- and post- PEX samples to H+I lab Check IgG level. Give IVIG 0.4g/kg IV after PEX if < 400. Give Rituximab 1g prior to going home.

ABO INCOMPATIBILITY – Preparative regimens similar to HLA-desensitisation are used e.g. PEX or column-based immunoadsorption, plus splenectomy or Rituximab (and no splenectomy; Gloor;Transp 05;80:1572). 6+ year follow up in Japan has been favourable: Takahashi ;AJT 04;4:1089. – ‘Accommodation’ can occur in which anti-ABO antibodies return and C4d is + but allograft function remains good. – Because ABO A2 is less completely expressed on kidney endothelial cells than A1, A2 kidneys can be transplanted into B and O recipients without PEX, IV IgG or other preparation if the anti-A titres in the recipient are <8 (Bryan;AJT 07;7:1181). RENAL HANDBOOK 113


TRANSPLANTATION

THE HIGHLY SENSITISED TRANSPLANT PATIENT CONTD. PAIRED KIDNEY EXCHANGE (PKE) Aspect

Notes

Definitions

Exchange of kidneys between 2 sets of donor-recipient pairs in circumstances where direct donation is impossible due to ABO or HLA incompatibility.

Background

30% of donor-recipient pair transplants cannot proceed because of ABO or HLA incompatibility. Always consider PKE in this situation. Remember to ask about family or friends interested in donation who were previously turned down because of ABOi.

Who to consider for PKE

Anyone eligible for transplant with a willing but incompatible LD. Altruistic living donors . Pairs who are compatible but might benefit from a different LD for other reasons (e.g. better matching of donor and recipient size).

Advantages

Allows access to transplant for highly sensitised patients, avoids need for desensitisation and provides a living donor allograft to each recipient.

Disadvantages

Transplant may never happen: Remains difficult for ABO-O or highly sensitised pts to find a match (see rates below). Pairs should be prepared for potential disappointments: e.g. match runs may not be successful or match runs may be successful but transplant does not proceed for other reasons. Poor outcome with 1 of the transplants can be difficult to deal with. Costs of evaluating many potential LDs Preserving anonymity: pairs remain anonymous to one another.

Where

Beaumont currently referring adult pts to 2 UK centres: Coventry (RH), Royal Free (GJ).

The process

1. 2. 3. 4. 5. 6. 7.

What if matchrun not successful?

Try and enroll an ABO-O donor, if possible! Do at least 3 matchruns. If no success after 3, consider expanding number of acceptable mismatches, finding a â&#x20AC;&#x2DC;near perfectâ&#x20AC;&#x2122; rather than perfect donor or direct donation and limited desensitisation if low DSA.

Identify recipient + donor (1 or 2). Obtain HSE approval to fund the transplant abroad. Donor evaluation in Ireland. Donor + recipient details forwarded to UK centre; enrolment in UK-PKE. Successful matchrun. Pre-op review of Donor + Recipient in UK centre. Transplant.

UK PKE TRANSPLANT RATES BY ABO OF REGISTERED PAIRS (as of April 2012) DONOR O DONOR A DONOR B DONOR AB

Recipient O

Recipient A

Recipient B

Recipient AB

21% 16% 17% 0%

53% 23% 38% 0%

33% 31% 9% 0%

67% 0% 25% 0%

% = % transplanted of total pairs listed. 114 RENAL HANDBOOK


Obstetric Nephrology

RENAL HANDBOOK 115


OBSTETRIC NEPHROLOGY

PHYSIOLOGIC CHANGES OF PREGNANCY Anatomic

1 - 1.5 cm increase in kidney length (no change in glomerular number). Decreased bladder tone with increased reflux. Collecting system dilatation with R > L hydronephrosis (with risk of UTI/Pyelo).

Hemodynamic

Decreased vascular resistance (via HCG/Relaxin) with subsequent RAAS activation. Na/H2O retention, increased cardiac output. Initial decline in BP, followed by slow rise to non-pregnant levels near term.

Renal Haemodynamics

Increased plasma volume leads to 80% rise in renal plasma flow and 40-50% increase in GFR. MDRD and other equations underestimate GFR by 25-40ml/min. A creatinine above 70umol/l in pregnancy indicates significant renal dysfunction. Measurement of 24 hour creatinine clearance provides the most accurate assessment of GFR in a pregnant woman. Increased GFR = increased excretion of protein, glucose, amino acids, calcium, uric acid.

Acid-base

Progesterone leads to hyperventilation (average pCO2=30) and alkalosis with compensatory decrease in serum HCO3 (average tCO2=22).

Water

Reset osmostat (mediated by HCG/relaxin) results in 5-10 mmol/L decrease in serum Na.

Minerals

Increased (1,25) Vit D leads to increased Ca absorption and hypercalciuria (>300 mg/d). Urine pH is increased, hypocitraturia and hypomagnesiuria are common.

KIDNEY BIOPSY DURING PREGNANCY As there are limited treatment options in pregnancy (symptom mgmt, BP control, steroids +/- AZA, and termination/delivery), careful consideration must be given to the likely utility of biopsy information at that precise point in the pregnancy. The main indication is to identify an illness requiring immediate treatment. Aetiology

Onset

Notes

1st trimester

Nephrotic range proteinuria, creatinine >135 mmol/l and hypertension.

Biopsy appears as safe in early pregnancy as it is outside of pregnancy. However, RBF is increased, so bleeding post biopsy a concern. Biopsy indicated as a diagnosis of lupus nephritis, scleroderma or crescentic GN requires immediate mgmt.

2nd trimester

Symptoms suggestive of scleroderma For SRC, mother's life is in danger and the condition may worsen in respond renal crisis or active lupus nephritis or to steroids; biopsy required to confirm. Biopsy also needed for suspected newother active, progressive GN. onset diffuse proliferative lupus nephritis, as this must be treated immediately.

3rd trimester

Defer if possible. Risks associated with kidney biopsy are increased; contraindicated after 32 weeks gestation (Kuller; Am J Ob Gyn 01;184:1093).

Biopsy less likely to influence mgmt at this point. Biopsy has to be done with pt lying on her side or sitting because of the gravid uterus. Pts often too hypertensive for biopsy. Based on case reports, the decision to start Methylpred +/â&#x20AC;&#x201C; AZA may often be made empirically: steroids used to buy time before delivery.

ANTICOAGULATION IN KIDNEY DISEASE PATIENTS DURING PREGNANCY Pregnancy= pro-thrombotic state. Nephrotic pts are at increased risk for thrombotic complications. Main RFs are profound hypoalbuminaemia and membranous GN (20x increased risk vs. IgA: 8% vs. 0.4%). Warfarin avoided due to warfarin embryopathy: nasal hypoplasia, epiphyseal stippling and bleeding problems. Unfractionated and LMWH heparins are thought to be safe in pregnancy; reasonable to give to women on bed rest with nephrotic syndrome and either membranous GN and/or severe hypoalbuminaemia (<20). Does not cross placenta. Note LMWH accumulates in CKD, so dose for GFR. 116 RENAL HANDBOOK


OBSTETRIC NEPHROLOGY

HYPERTENSIVE DISORDERS IN PREGNANCY Gestational Hypertension

Complicates 6% of pregnancies, begins in latter part of pregnancy. Diagnosis: (1) Previously normotensive; (2) BP > 140/90; (3) No proteinuria. Prognosis: Benign unless severe (BP > 160/110) or onset before 30 wks.

Essential Hypertension

Prevalence: 3% of pregnancies. Diagnosis: BP > 140/90 before or after pregnancy that persists >12 weeks postpartum.

Pre-Eclampsia

Pre-eclampsia accounts for 50% of pregnancy-related HTN. See page 118.

Secondary Hypertension

(1) Activating mutation of mineralocorticoid receptor; (2) Pheo; (3) RAS; (4) Primary hyperaldosteronism (often stable due to spironolactone-effect of progesterone).

TREATMENT OF HYPERTENSION IN PREGNANCY Background RCTs: conflicting results re: benefit of treating women with history of HTN and BP >160/100 mmHg. No convincing decrease in poor maternal and foetal outcomes with treatment of mild-mod HTN in pregnant pts (SBP 140–169 mmHg; DBP, 90–109 mmHg; Abalos;Cochran Review 07;4) Guidelines from US, Europe, Australia, and Canada recommend starting Rx at higher BP than usual. DBP >110 mmHg during pregnancy associated with increased stroke risk. Severity

Agent

Starting dose

Maximum dose

250-500mg BD PO

2000mg/day in up to 4 divided doses Causes somnolence

100-200mg BD PO

1200mg/day in up to 4 divided doses

Hydralazine

10mg QDS PO

200mg/day in up to 4 divided doses

LA Nifedipine

20-30mg PO QD

120mg/day in single dose

Hydralazine

5-10mg IV/IM q30min OR 10mg IV/IM q30min Infusion 0.5-1mg/hr

Drug of choice for hypertensive crisis in pregnancy.

Labetolol

5-20mg IV q30min OR Infusion 1-2mg/min

2nd choice. Monitor newborn for bradycardia and low BP.

Mild to moderate Methyldopa hypertension* Labetolol

Severe hypertension

80mg IV q30min

Notes

May cause v. low BP when given with Mg

Other anti-hypertensives (1) Diuretics: Some are reluctant to use in pregnancy as may interfere with normal volume expansion of pregnancy. However, meta-analysis of 9 RCTs (n>7000) diuretics found no increase in incidence of adverse foetal effects (Collins R, Br Med J 290: 17–23, 1985) (2) ACEi and ARB: Contraindicated at all stages of pregnancy; cause oligohydramnios, renal dysplasia, pulmonary hypoplasia and anuria in newborn.

RENAL HANDBOOK 117


OBSTETRIC NEPHROLOGY

PRE-ECLAMPSIA/ECLAMPSIA/HELLP PRE-ECLAMPSIA/HELLP Definition

Hypertension and proteinuria after 20 weeks gestation (if no h/o HTN or CKD). Early onset: CKD, HTN, molar pregnancy, APLAS, foetal anomaly, illicit drugs. Diagnosis difficult if pre-existing kidney disease with HTN and proteinuria.

Risk Factors

H/o preeclampsia, diabetes, primigravid, multiple gestations, family history, age >40.

Pathophysiology

New paradigm = placenta produces circulating VEGF inhibitors. PET is characterised by increases in anti-angiogenic factors, soluble fms-like tyrosine kinase 1(sFlt-1), and endoglin, which are thought to play a major role in its pathogenesis. Increase in anti-angiogenic factors is accompanied by a decrease in placental growth factor and vascular endothelial growth factor. May someday be helpful in distinguishing preeclampsia from pre-existing kidney disease.

Signs and Symptoms

(1) HTN > 140/90 or significant increase in baseline BP; (2) proteinuria > 300mg/24 (may be nephrotic; absent in 10%) and oedema (esp. facial); (3) declining GFR (creatinine usually normal); (4) benign urinalysis; (5) uric acid > 300 mmol/l; (6) thrombocytopenia, sometimes MAHA; (7) RUQ pain and elevated LFTs = HELLP; (8) CNS= headaches, blurry vision; (9) pulmonary oedema.

Pathology

Glomerular endotheliosis = endothelial swelling and loss of fenestrations.

Differential

(1) pre-eclampsia; (2) exacerbation of pre-existing CKD/HTN; (3) acute fatty liver of pregnancy; (4) TTP-HUS; (5) SLE flare; (6) gestational thrombocytopenia; (7) cerebral haemorrhage; (8) hepatitis; (9) cholestasis; (10) pancreatitis; (11) migraine.

Management

(1) Hospitalise for maternal/foetal monitoring; (2) bed rest; (3) anti-hypertensives (avoid diuretics); (4) MgSO4 to prevent seizure if severe; (5) antenatal dexamethasone for women at 24-34 weeks gestation; (6) delivery if gestation >38 weeks, plt count < 100,000; elevated LFTs; oliguria; rising creatinine; eclampsia; foetal distress. Prompt improvement in BP and creatinine after delivery typical.

Prevention

Low-dose aspirin in prospective RCTs (n> 20,000): may have some benefit in women at the very highest risk. NICE recommend 75mg aspirin for women at mod-high risk of PET. Pts with CKD would fall into this group. Ca++ supplements may help; anti-coagulation for APLAS.

Maternal consequences

Higher risk of HTN, CAD, CVA, VTE, renal disease (Vikse;JASN 06;17:837). Foetal consequences: IUGR, oligohydramnios, abruption, loss.

ECLAMPSIA Definition

Preeclampsia or gestational HTN AND seizures, coma, stroke.

Differential

CVA; hypertensive encephalopathy; Pheo; CNS mass, infection or vasculitis; metabolic disorders (hypoglycaemia, uraemia, hypo- or hypernatremia); TTP-HUS, illicit drugs; CNS vasculitis; Reversible Posterior Leukoencephalopathy Syndrome (RPLS).

Management

(1) General interventions by Ob/GYN; (2) Treat BP if > 150/95; (3) MgSO4 (reduces recurrence, deathâ&#x20AC;&#x201D;see Lucas; NEJM 95;333;201); (4) Delivery.

Maternal prognosis 70% incur complications including CVA, DIC, AKI, liver injury or rupture, cardiopulmonary arrest, pneumonia. Foetal prognosis

118 RENAL HANDBOOK

9-23% mortality due to premature birth, placental abruption, asphyxia. Prognosis improves with greater gestational age.


OBSTETRIC NEPHROLOGY

MANAGEMENT OF KIDNEY DISEASE IN PREGNANCY ACUTE KIDNEY INJURY AND PREGNANCY Aetiology

Onset

Notes

Pre-Renal /ATN

12 - 18 weeks gestation

Precipitants: hyperemesis gravidarum or septic abortion.

Preeclampsia (+/- HELLP)

>20wks (usually late 3rd trim, to 1-2d postpartum)

Classic syndrome: (1) Renal failure is rare except with bleeding or DIC; (2) Afebrile; 3) ADAMTS13 normal or mildly depressed. Mgmt: see page 118.

TTP predominant TTP-HUS

1st or early 2nd trimester

Fever, neurological symptoms, MAHA, thrombocytopenia, ARF less common. DIC and increase in LFTs rare. ADAMTS13 levels typically decreased significantly. Mgmt: PEX (40% recover). Spontaneous recovery rare.

HUS predominant TTP-HUS

Usually postpartum

ARF, with MAHA and thrombocytopenia. DIC and elevated LFTs rare. Mgmt: same as early TTP-HUS (=PEX).

Acute Fatty Liver of Pregnancy

Second half, usually 3rd trimester

Symptoms: anorexia, nausea, vomiting, abdominal pain. HTN, proteinuria, signs of liver disease (increased LFTs, coagulopathy, hypoglycaemia), acute renal failure in 60%. Mgmt: supportive or early delivery. Prognosis: good with early diagnosis.

Bilateral Renal Cortical Necrosis (severe ATN)

Post-Delivery

Symptoms: HoTN, anuria/oliguria, haematuria, flank pain. +DIC. Imaging: hypoechoic (U/s) or hypodense (CT) renal cortices. Associated with: placental abruption, amniotic fluid embolism, haemorrhage. Mgmt: No specific therapy. 20-40% = partial recovery.

Nephrolithiasis

2nd/3rd trimester

Symptoms/signs: Flank pain, haematuria, rarely causes ARF. Diagnosis: CT contraindicated. Alternatives: pelvic ultrasound (60% sensitive), transvaginal ultrasound, ureteroscopy, MRI. Mgmt: 75+% pass spontaneously. Nephrostomy. For persistent sepsis: ureteroscopy or laser lithotripsy. ESWL contraindicated.

Severe AKI requiring dialysis

Any time

Early and frequent dialysis as uremic toxins cross placenta (goal urea <17). Avoid intradialytic HoTN which reduces placental perfusion and can induce premature labour. After mid-pregnancy, intradialytic foetal monitoring is indicated. HD and PD are both used. PD is associated with less intradialytic HoTN and premature labour. Gravid uterus is not a contraindication to PD.

Acute GN

Any time

Most important indicators of acute GN are changes in creat/proteinuria during 1-2 weeks after initial detection. Delivery or termination will not reverse decline in function unless d/t PET, so biopsy may be required to confirm. RENAL HANDBOOK 119


OBSTETRIC NEPHROLOGY

MANAGEMENT OF SPECIFIC CHRONIC KIDNEY DISEASES DURING PREGNANCY Outcomes are generally good if BP and renal function normal and proteinuria is absent. If creatinine >133, 47-86% risk of foetal complications (prematurity, intrauterine growth retardation) and 25-53% risk of CKD progression (Imbasciati;AJKD 07;49;729). Proteinuria often worsens during pregnancy, regardless of its cause. Aetiology

Onset

Notes

Diabetic nephropathy

Best outcomes when creatinine and BP are normal and glucose is optimal at conception. Screen for nephropathy, CAD. Change ACEi/ARB to dihydropyridine CCB pre-conception. Early HTN treatment reduces proteinuria and preterm delivery. Low dose aspirin reduces preeclampsia (Duley;Cochrane Review 04;1). Pre-eclampsia risk is proportional to 1st trimester proteinuria.

SLE

Pre-conception: (1) Pregnancy safest if lupus quiescent for 6 mos before conception (2) Early screening for APLAS. See Kong; NDT 06;21:268. Lupus flare during pregnancy: HTN, proteinuria, decreased GFR, thrombocytopenia. Syndrome easily confused with PET: low complement (C3, C4 usually elevated in pregnancy, borderline levels suspect). Normal LFTs, onset <20 wks supports SLE flare. Diffuse proliferative lupus nephritis requires prompt Rx regardless of renal function as risk for rapid, irreversible loss of GFR and life-threatening extra-renal complications. Other Complications: (1) Foetal loss from APLS, lupus anticoagulant; (2) Preeclampsia (without lupus flare); (3) Thrombotic events (DVT, PE, MI, CVA's); (4) foetal heart block due to passive transfer of antibodies from anti-Ro/La + mother. Mgmt: (1) If APLS titre >40 GPL, daily aspirin recommended; (2) Heparin + aspirin for h/o thrombotic events; (3) Immunosuppression with Prednisolone 30-60 mg daily or AZA; (4) Early delivery if needed. Outcomes: Maternal = Pre-eclampsia (13 -66%), thromboembolism, worsening renal function, post partum haemorrhage. Foetal = Preterm delivery (3x more common), IUGR, foetal loss (17%).

Chronic GN (IgAN, FSGS, IgAN, FSGS (also reflux nephropathy and PKD) may be diagnosed first during pregnancy because women MCD, MPGN, MGN) may have their first urine dipstick test as adults at this time. Polycystic Kidney Disease

Key points: (1) Liver cysts enlarge due to oestrogen; (2) must rule out cerebral aneurysms before labour if positive FHx; (3) increased chance of UTI during pregnancy.

Chronic pyelonephritis

Exacerbated due to urinary stasis in pregnancy. Encourage high fluid intake and frequent bacteriuria screen, treat particularly if reflux nephropathy present.

120 RENAL HANDBOOK


OBSTETRIC NEPHROLOGY

PREGNANCY IN THE TRANSPLANT PATIENT Trimester

Issue

Notes

Preconception

Allograft function

At least 1 year post transplant. BP controlled, creatinine < 133 umol/l and <0.5g proteinuria. No recent rejection or pyelonephritis.

Immunosuppression Switch MMF to AZA x 3 months before conception. Switch sirolimus to tacrolimus x 3 months before conception. Other meds

Stop ACE / ARB x 3 months before conception. See page 117 for alternatives. Folate 5mg OD and consider aspirin 75mg in ‘higher risk’.

Education

Early meeting with Renal Consultant to discuss the pregnancy with pt and partner. Outcomes good if creatinine < 133 umol/l and <0.5g proteinuria.

First and Second Monitoring

The pt should be reviewed by pre-natal team every four weeks. A foetal ultrasound should be performed to assess foetal growth and amniotic fluid. Referral to Rotunda high risk clinic (Drs. Magee/ O’Seaghdha). First prenatal visit and ultrasound should be arranged as soon as possible (e.g. 8 weeks).

BP

Should be less than 140/90. Use Methyldopa, Labetolol and Amlodipine (see page 117). Watch levels if using nifedipine.

UTIs

Occur in 42% of pts. Low threshold for prophylaxis (nitrofurantoin 50mg nocte until 4 weeks pre-delivery).

Third

Monitoring

Pre natal visits increased to once weekly.

Peri-partum

Delivery

Dexamethasone may be given for foetal lung maturity in the event of premature labour. At delivery give IV hydrocortisone 100mg IV plus usual steroid dose. Peri-partum tacrolimus goal trough 8-10; levels will drop post-partum. Vaginal delivery okay. Avoid NSAIDs. Discuss contraception plans; Mirena coil preferred.

RENAL HANDBOOK 121


OBSTETRIC NEPHROLOGY

PREGNANCY IN THE DIALYSIS PATIENT Trimester

Issue

Notes

First

Education

Early meeting with Renal Consultant, Dialysis Registrar, CNM to discuss the pregnancy with pt and her partner. Significant risks to mother and foetus are outlined: spontaneous abortion, hypertension, PET, polyhydraminios, premature birth, foetal abnormalities. First prenatal visit and ultrasound should be arranged as soon as possible.

HD

Most pts require >20 hrs HD per week to maintain pre-dialysis urea < 17, as uremic toxins cross placenta. Consider daily 3 hour dialysis. Avoid intradialytic HoTN, which reduces placental perfusion and can induce premature labour.

Medications

Only calcium acetate or calcium carbonate binders should be used. Lanthanum carbonate (Foznol), Sevelamer (Renagel) and aluminium based binders should be avoided. Calcitriol can be used. ACEi’s, Statins and ARBs are contraindicated. Heparin should be changed to LMWH. Additional water based vitamins should be added: 5mg Folic acid OD, Orovite & “Pregnance & Vit D” (15mg zinc, 2.5ug Vit D). Increase calcium as needed to keep serum calcium levels normal. Likely to need more IV iron.

Monitoring

Weekly labs: Urate, Alk phos, Alt, LFT’s, CBC, U/E, CPM, Tco2. Monthly labs: Ferritin and TIBC. Folate, Vit B12, Urine culture monthly. Weekly review of volume status by renal doctor.

HD

HD dose may be increased during 2nd trimester and 3rd trimester to daily to maintain volume control and pre-dialysis urea <17. After mid-pregnancy, intradialytic Foetal monitoring is indicated. Weekly review of pt’s volume status by renal team is vital.

Medications

BP should be less than 140/90 and the drugs of choice to control hypertension are Methyldopa, Labetolol, nifedipine and Amlodipine (see page 117). Anaemia: The anaemia of ESRD can worsen significantly during pregnancy with expected plasma volume expansion and the limited ability to increase RBC production. EPO dose may need to be significantly increased to meet target Hgb 10.5-12.0 g/dl. IV Venofer may be given as per standard guidelines.

Monitoring

The pt should be reviewed by pre-natal team every two weeks. A foetal ultrasound should be performed to assess foetal growth and amniotic fluid.

HD

Increase hours as necessary (see above). Weekly volume status assessment critical. Transfer to Beaumont for HD post delivery.

Monitoring

Pre natal visits increased to once weekly.

Delivery

C-section preferred. Dexamethasone may be given for foetal lung maturity in the event of premature labour.

Second

Third

122 RENAL HANDBOOK


Procedures

RENAL HANDBOOK 123


PROCEDURES

COMMON RENAL PROCEDURES DIALYSIS CATHETER PLACEMENT Preparation

Relative contraindications: bleeding diathesis, untreated bacteremia. Obtain consent for placement and re-placement; for all sites; CVVH and HD. Necessary supplies: ACD flush; two extra sterile 10 ml syringes, sterile blue bowl and 4 x 10ml sterile saline flushes to flush needles and line once placed; extra syringe for finder needle; extra catheter kit.

Technique

Real time ultrasound provides higher success, lower complication rates (Hind;BMJ03;327(7411):361). Ultrasound the site prior to sterile prep to identify anatomy. Avoid subclavian position due to high incidence of subclavian stenosis. Dilating is important and difficult step as HD catheters are bigger than other central lines. Tricks: (1) a skin nick can help but is not always necessary, depending on size of catheter; (2) reproduce angle that needle took; hold traction on skin to prevent wire bending; pull wire back as you advance dilator; if you meet resistance, reposition or nick skin with scalpel; (3) discard dilator if irregularities develop at tip; (4) for bent wire: advance wire forward or backward to get kink out of way of advancing dilator.

Removing, changing or reinserting lines

Replace a line over a wire only if it was recently placed and is acutely malfunctioning; otherwise remove and replace with a fresh stick, preferably after line free interval. Removing lines: use Trendelenburg for IJ’s; Bed flat for Fems; hold x 5-20 mins or more; notify nurse so site can be monitored for hematoma. Nurses on St. Peter’s will remove lines after HD. The frequency with which lines should be replaced depends on location and on the pt’s activity level.

CHOICE OF TEMPORARY DIALYSIS CATHETER Femoral

Internal jugular

Catheter length

24 cm (no shorter, needs to reach central circulation).

15 cm (Right IJ). 20 cm (Left IJ).

Advantages

– No risk of pneumothorax. – Possibly fewer insertion complications.

– – – – –

Disadvantages

Bed rest required. Caution if IVC filter. Appears to have higher infection risk.

Uncomfortable. Need X-ray before use. Risk of carotid puncture. Do not place if PPM or ICD without d/w cardiology.

Tricks

– Positioning: Abduct leg. Alternative is to bend knee, inwardly rotate hip. – Move caudally or avoid site if artery lies over vein despite good abduction. – If vein can’t be located, insert finder needle medially and march laterally, with- drawing each time until vein is located. – No need to suture line if it will be removed the same day.

– ALWAYS use real time US. – Positioning: Trendelenberg. – Have sense of pt’s CVP and O2 Sat to help assess venous vs arterial stick. – Use 25 g needle as finder needle. – Usually needle at point where 2 heads of SCM meet.

124 RENAL HANDBOOK

Lasts longer. Pt is mobile. Pt can go home with one in certain circumstances. Posterior approach most comfortable. Low insertion risk.


PROCEDURES

KIDNEY BIOPSY Major Indications

(1) RPGN; (2) SLE; (3) Nephrotic Syndrome; (4) AKI/CKD of unknown etiology; (5) Kidney allograft dysfunction.

Contraindications

Bleeding risk: INR>1.5; aspirin or clopidogrel in the last 1 week; platelet count < 100, creatinine > 250 umol/l. Other medical or renal issues: (1) Uncontrolled hypertension—SBP>160; (2) UTI especially if upper tract involved; (3) Hgb < 8 g/dL; (4) renal mass; (5) possibly solitary kidney; (6) hydronephrosis; (7) cystic kidney disease (8) inability to lie flat on stomach x 20-40 minutes or hold breath.

Pt Preparation

Check vitals, perform focused H&P, explain procedure in detail (including need for multiple needle passes) and obtain written consent which includes Benefits (“Diagnosis and Possibly Treatment”) and Risks (“Pain, infection, bleeding including ~10% risk of gross haematuria, requirement for blood transfusions, requirement for surgery or other treatment to stop bleeding, obstruction and requirement for urinary catheter, loss of kidney, failure to obtain kidney tissue or make diagnosis”). have IV line placed, check coags, confirm recent negative urine culture, send Urine prot:creat ratio in nephrotic pts; DDAVP 0.3 mcg/kg if creatinine >250umol/L.

Checklist

Consent. Normal coags. Platelets > 100. Type and screen sent. No Aspirin or clopidogrel.

Performing the Procedure

Positioning: place pillows under stomach (native) or back (allograft). ‘Fire’ the biopsy needle/gun into the air so the pt hears what it sounds like. Before prepping, perform ultrasound to select kidney and mark biopsy site. Apply lignocaine to capsule. After pass, perform a u/s to look for hematoma / AVM.

Post Biopsy Mgmt

Transport the pt back to his or her room personally. Orders: (1) Lie flat x 6 hours; (2) Vitals q15 min x 1hr; q30 min x 2hrs; q 1 hr x 4 hrs; (3) Check FBC 6 hours post and next AM; (4) Notify Dr for SBP < 100 or >160; HR> 100; gross haematuria; failure to void or severe pain. For gross haematuria: administer DDAVP; begin IV fluids, check US next day. For severe flank or abdominal pain: stat CT scan (higher sensitivity than US). HoTN or Hb drop >2g/dl: IV fluids, consider transfusion, notify IR or Surgery. Pt should avoid heavy lifting (>5-10 lbs) and excessive exertion for one week.

RENAL HANDBOOK 125


Pathology and Urinalysis

RENAL HANDBOOK 127


PATHOLOGY AND URINALYSIS

URINALYSIS STANDARD (“BRIGHT FIELD”) MICROSCOPY  Technique: Lower the condenser completely to maximise contrast. Start with the x10 lens and slowly scan slide. Change to x40 lens to examine formed elements. PHASE CONTRAST MICROSCOPY  Low-contrast cells and casts in urine refract light differently. Phase Contrast Microscopy translates refractile differences into contrast differences.  Technique: Focus using the x40 lens; move the condenser up high and turn up the light source. Rotate the condenser annulus (built into the condenser) to 40.  Bright RBCs contain haemoglobin and suggest lower urinary tract bleeding. Dark RBCs are without haemoglobin, which is more consistent with glomerular bleeding.  Acanthocytes (ring-form RBCs with vesicle-shaped protrusions) identified using phase and present in a high fraction (>20%) suggest glomerular bleeding (Mohammad;J Clin Path 93;46:642.) Other forms of RBC dysmorphism are less helpful in identifying glomerular bleeding (Kohler;KI 91;40:115). Crenated RBCs (multiple spicules) form in concentrated urine and are not helpful diagnostically (Cohen;NEJM 03;348:2330). POLARISED LIGHT MICROSCOPY  White light vibrates in many directions, polarised light vibrates in one. Crystals with organised structure appear bright, refractile (“birefringent”) under polarised light.  Technique: Requires a polarising lens above and below the specimen. One polariser is built into many microscopes. The 2nd polariser (a piece of film) is held manually over the condenser and rotated until the field is black (indicating the polarisers are at right angles). The polariser is then rotated back slightly while the urine is examined.  Positive birefringence= uric acid, Ca-Ox Monohydrate, Triple Pi, Ca-Pi, methotrexate, acyclovir, indinavir, sulphonamide, triamterene, primidone (Fogazzi NDT 96;11:379). Urinalysis Findings Bland RBCs WBCs Tubular Cells Hyaline Granular Casts WBC Casts RBC Casts URINE CRYSTALS

128 RENAL HANDBOOK

Possible Meanings / Diagnosis Consider pre-renal, post-renal, or vascular causes of renal insufficiency Upper or lower tract, from trauma, tumours, stones, or glomerular lesions. Suggests cystitis, pyelonephritis, allergic process (eg. AIN) or glomerulonephritis Suggests tubular damage but can be a normal finding CastsSuggests pre-renal injury but can be normal finding if present in small numbers Suggests tubular injury (ATN) particularly if dark (‘muddy brown’). Suggests pyelonephritis, allergic process or glomerulonephritis. Most specific finding for glomerulonephritis. Sensitivity is moderate.


PATHOLOGY AND URINALYSIS

RENAL PATHOLOGY Lesion

Features

Minimal change disease

LM: Normal. IF: No immune complexes. EM: Podocyte foot process effacement.

FSGS

Notes

GFR usually not normal, mean creatinine 130 mmol/l. Mean proteinuria ~10g/day. ~20% have AKI. LM: Segmental glomerular scarring, glomerular adhesions to Absence of foot process effacement and normal Bowman’s capsule. gloms by LN suggests secondary FSGS. IF: Non-specific trapping of IgM, C3 in scarred glomerular areas. EM: Podocyte foot process effacement, scarred GBM (thick, wrinkled).

Collapsing FSGS

LM: As above but with proliferation of overlying podocytes Same features seen in HIV nephropathy. forming pseudocrescents. IF: as above. EM: as above.

Membranous GN

LM: Thickened GBM (H&E); GBM with spikes (PAS, silver), GBM deposits (trichrome). IF: Granular IgG,C3 along GBM. EM: Subepithelial deposits +/- intervening GBM “spikes” depending on stage.

Amyloidosis

LM: Pink and glassy (H&E), pale pink (PAS) or blue (trichrome) material in gloms, tubular BMs, vessels, interstitium. Silver stain –ve. Congo red +ve, apple green birefringence. IF: Usually light chain predominant in AL. EM: Non-branching randomly arranged fibrils 8-10nm.

LCDD, LHCDD, HCDD

LM: Mesangial hypercellularity (>3 cells per mesangial area). May be nodular. IF: Light and/or heavy chain restriction of deposits along GBM, tubular BM, mesangium. EM: Deposits in mesangium, GBM, TBM.

Diabetes

LM: Mild DN: thick GBM. Mod DN: mesangial. hypercellularity. Severe: KW nodules, arteriolar hyalinosis. IF: Linear IgG similar to anti-GBM disease. EM: Thick GBM.

IgA nephropathy

LM: Mesangial hypercellularity; may be crescentic. Concurrent IgAN and membranous occurs in IF: IgA dominant, but mesangium often stains for other Ig and (1) HBV (2) allografts (3) Asians. complement. EM: mesangial deposits.

MPGN

LM: Lobular glomeruli with endocapillary proliferation (cells Polyclonal Ig suggests immune complex occluding capillaries), thick GBM, double contours (PAS, silver), disease, monoclonal suggests paraprotein. No red GBM deposits (trichrome); may be crescentic. Ig suggests C3GN, DDD or TMA. IF: See page 62 May be Igs and complement, complement alone or non-staining. continued next page  EM: Subendothelial deposits and GBM duplication.

Features suggesting secondary MGN include (1) non-subepithelial deposits, (2) “full-house” IF staining, (3) endothelial tubo-reticular inclusions and (4) mesangial or endocapillary proliferation. Membranous in allograft: 75% de novo, 25% recurrent, occas. donor derived Membranous with AKI, think renal vein thrombosis. Consider early MGN if glomeruli are not proliferative but not quite normal.

Acute post-infectious GN occurring on a background of DN has a very poor prognosis: 80% progress to ESRD. Usually due to Staphylococcus and usually IgA staining.

RENAL HANDBOOK 129


PATHOLOGY AND URINALYSIS

RENAL PATHOLOGY CONTD... Lesion

Features

Notes

Cryoglobulinaemia LM: MPGN pattern. Intraluminal IC pink hyaline pseudothrombi Note: Ig and complement indicates classical (H&E); may be crescentic. pathway activity, isolated complement IF: Type 1: IgM with LC restriction; Types 2 and 3: IgM, IgG and indicates alternative pathway. polyclonal LC. EM: Microtubular substructure in cryoglobulins. HCV disease

LM: MPGN +/- intraluminal IC pink hyaline pseudothrombi (H&E) ; may be crescentic. IF: granular IgG, C3 along GBM. EM: Subendo deposits, GBM duplication, endothelial tubuloreticular inclusions.

C3 nephropathy

LM: MPGN pattern, thick GBMs. DDD/MPGN type II. IF: Pseudolinear C3 only along GBM. Check C3Neph Factor. EM: confluent intramembranous electron dense deposits in GBM.

Fibrillary GN

LM: MPGN pattern; may be crescentic. IF: Pseudolinear IgG, C3 along GBM. EM: 12-24 nm fibrils.

Immunotactoid GN

LM: MPGN pattern; may be crescentic. IF: Pseudolinear IgG, C3 along GBM. EM: 48-72 nm fibrils.

Anti-GBM disease

LM: Crescentic GN with necrotic glomeruli. IF: Linear IgG. EM: No immune complexes.

Pauci-immune (ANCA) GN

LM: Crescentic GN with necrotic glomeruli. IF: Negative. EM: No immune complexes.

Alport syndrome

LM: Normal. Possibly interstitial foam cells. IF: Variable loss of alpha 3,4,5 chains of type IV collagen. EM: Wrinkled GBM, thick or thin, scalloped, “basket-weave substructure”.

Thin BM disease

LM: Normal. IF: Normal alpha collagen IV staining. EM: Normal but thin (<200nm or 2-3 foot processes).

Post-infectious GN

LM: diffuse endocapillary hypercellularity, endothelial and mesangial proliferation, neutrophils and monocytic infiltrate. May be crescentic. IF: 3 patterns (1) starry sky (commonest) (2) garland (3) mesangial (resolving). EM: predominantly subepithelial deposits, electron dense subepithelial "humps". LM: Interstitial inflammation (lymphocytes +/- plasma cells), eosinophils. IF: negative. EM: normal.

Allergic IN Pyelonephritis

130 RENAL HANDBOOK

LM: Neutrophils with tubular lumina. IF: negative. EM: normal.

Predictors of relapse include PR3 positivity, lung or ENT disease.

1/3 staph, 1/3 strep, 1/3 Gr –ve. S. Epi associated MPGN typically presents with nephrotic syndrome. S. aureus associated PIGN presents with proliferative, IC-GN. S- Aureus superantigen-associated presents with IgA/HSP.


PATHOLOGY AND URINALYSIS

RENAL PATHOLOGY CONTD... Lesion

Features

TMA pattern

LM: Arteriolar +/- intraglomerular thrombi, intramural arteriolar schistocytes, mucoid intimal change. Medial hypertrophy of SM with “onion-skinning” IF: Thrombi stain for fibrin EM: Fibrin (tactoids with periodicity), endothelial cell oedema, subendothelial electron-lucent space

Notes

TRANSPLANT RENAL PATHOLOGY Lesion

Features

Antibody-mediated rejection (ABMR)

LM: ATN or TMA (v. early ABMR), glomerulitis, peritubular capillaritis, rarely interstitial haemorrhage, transplant glomerulopathy. IF: 50% will have C4d in peritubular capillaries. EM: No deposits (NB, if present = GN).

T cell-mediated rejection (TCMR)

LM: Tubulitis, interstitial inflammation, endarteritis. IF: negative. EM: Normal.

Acute CNI toxicity (diagnosis of exclusion)

LM: Isometric vacuolisation of tubular epithelial cells (very non-specific finding), TMA if severe. IF: negative; fibrin thrombi if TMA. EM: TMA: endothelial cell swelling, subendothelial electon-lucent material, fibrin.

Chronic CNI toxicity (diagnosis of exclusion)

LM: Interstital fibrosis and tubular atrophy (typically striped pattern), Arteriolar hyalinosis, transplant glomerulopathy if chronic TMA. IF: negative. EM: No deposits. Chronic TMA: double contours (transplant glomerulopathy).

BK nephropathy

LM: Identical to TCMR: Tubulitis, Interstitial inflammation (?plasma cell enriched), intranuclear “glassy” viral inclusions. IF: Immunohistochemistry +ve for SV-40. EM: Normal.

CMV or adenovirus infection

LM: Interstitial inflammation with “owl eye” large pink viral nuclear inclusions and small cytoplasmic basophilic inclusions. IF: negative. EM: normal.

PTLD

LM: striking interstitial inflammation, in-situ hybridisation often EBV +ve. IF: negative. EM: normal. RENAL HANDBOOK 131


Administrative

RENAL HANDBOOK 133


ADMINISTRATIVE

BEAUMONT RENAL DIVISION PHONE NUMBERS (PREFIX (01) 809 FROM OUTSIDE HOSPITAL) NEPHROLOGY CONSULTANTS Prof. Peter Conlon..................................................086-225 1790 Dr. Declan de Freitas .............................................085-870 6429 Dr. Mark Denton ...................................................086-772 5955

Prof. Mark Little ....................................................086-609 6068 Dr. Colm Magee ....................................................083-345 1039 Dr. Conall O’Seaghdha ..........................................087-927 1244

NEPHROLOGY CONSULTANT SECRETARIES Claire Kavanagh (Prof. Conlon) ...........................................2747 Catherine Mulcahy (Dr. de Freitas) ......................................2727 Joan Long (Dr. Denton) ......................................................3080

Louise Cawley (Dr. Magee /Prof. Little) ...................01-797 4701 Anne Moloney (Dr. O’Seaghdha) .........................................2567

UROLOGY CONSULTANT SECRETARIES Mr. Thomas Creagh ..............................................................3310 Ms. Mary Donovan...............................................................2935 Ms. Molly Eng......................................................................2339 Mr. David Hickey..................................................................3135 Miss Dilly Little....................................................................2935

Mr. Ponnusamy Mohan........................................................3346 Mr. Richard Power ...............................................................3046 Mr. Kashif Siddiqui ..............................................................3485 Mr. Gordon Smyth ...............................................................2339

RENAL PATHOLOGY Dr. Tony Dorman (Pathology) ..............................................2644 Margaret Moran Senior Medical Scientist .............................2630 Maria O’Grady Medical Scientist ..........................................2630

Paula Gillic Renal Pathology Secretary ................................2008 Histopathology Laboratory ..................................................2353

USEFUL RENAL WARD NUMBERS Renal Day Care Unit.............................................................3144 St. Teresa's Transplantation Unit.................................2294/2761 St. Peter's Dialysis....................................................01-797 4805 St. Martin's Dialysis ...................................................2730/2731 St. Peter's..................................................................2290/2285

St. Damien’s Urology.................................................2293/2292 St. Damien’s Nephrology ...........................................2323/2324 Home HD:............................................................................8363 PD / Home Therapies:..............................................8152 / 3146 Intensive Therapy Unit (ITU).......................................2769/2494

TRANSPLANT, UROLOGY AND NEPHROLOGY NURSING AND SUPPORT STAFF Transplant Nurses: Louise McSkeane, Ruth O’Malley, Olive McEnroe: ...8395 / 2321 Transplant Co-ordinators: (Phyllis/Aileen) ................3119 / 2759 Patient Care Co-ordinator: Mary T Murphy .................754 / 2834 Renal Counsellor: Margaret Hanna ............................828 / 3931 Renal Dietician:...............................................2357 / 792 / 497 Renal Pharmacist: Martin Ferguson........................................749 Ultrasound ..........................................................................3430

Interventional Radiology......................................................4712 H + I (James / Trish) ...............................................3238 / 2651 Mircera Nurse.........................................................086-8372850 Divisional Nurse Manager: Petrina Donnelly ...........8340 / 2297 CNM III HD Programme: Veronica Francis ................8606 / 2729 CNM II St. Peter’s: Maureen McNulty ........................8116 / 2286 Vascular Access: Fiona Auguste .................................8111 / 3144 Renal IT: Cathal Collier .............................................338 / 2758

HELPDESKS IT Helpdesk: ........................................................................2550 PIPE helpdesk:.....................................................................3047 PACS helpdesk: ....................................................................2169 134 RENAL HANDBOOK

Postgraduate Education: ......................................................2573 Salaries:..............................................................................2250 Security:...............................................................................2110


ADMINISTRATIVE

BEAUMONT RENAL DIVISION PHONE NUMBERS (PREFIX (01) 809 FROM OUTSIDE HOSPITAL) CLINICAL SUPPORT AREAS Audiology: ...........................................................................2760 Angiography (room 12): ..................................................... 2776 Blood Pressure Uni:................................................... 2160/3041 Death Certificates:............................................................... 2182 Diabetic Day Centre:...................................................2744/2745 Neurophysiology: ................................................................2735 Pallative Care: .....................................................................2820 Poisons Information:............................................................2566

Pharmacy: ...........................................................................2144 Physiotherapy: ..........................................................2956/2526 Patient Enquiries (Main Reception): ...........................2530/3385 Social Work Department: .....................................................3290 Speech Therapy: ..................................................................2956 Theatre (Main Reception): ...................................................2954 Transport (Main Reception) (Patient):...................................2141

LABORATORIES Blood Test Appointments: .....................................................2674 Chemical Pathology/Biochemistry Results:...........................2669 Coagulation:....................................................................... 2656 Laboratory Results:..............................................................2669 Endocrine Labs: .........................................................2684/2688 Flow Cytometry:...................................................................2763 Haematology:............................................................2703/2663

Histopathology Results: .............................................2632/2636 Immunology Results: .......................................2669/2674/2658 Microbiology: ......................................................................2646 Pathology: ...........................................................................2674 Phlebotomy / Blood Test: ....................................................2325 Renal Laboratory:................................................................3034 Toxicology: ......................................................................2673/5

X-RAY MRI Radiologists:.................................................................3099 MRI Scan Appointments:.......................................................3100

X-Ray & Scan Appointments: ................................................3001

WARDS, UNITS, AND EMERGENCY DEPARTMENT A.B. Cleary:................................................................2310/2316 Adams McConnell: ......................................................2402/2417 Banks:.................................................................................2306 Cardiology Day Unit: ...........................................................2063 Corrigan: .............................................................................2438 Critical Care Unit:.................................................................2436 Emergency Department - GP Liaison:....................................2708 Emergency Department - Reception: ...........................2714/2720 Emergency Department - Triage Nurse: ................................2722 Endoscopy (Stephen Doyle Unit):..........................................3194 Hamilton Transit: ...........................................01-797 4877/4878 Hardwicke:................................................................2350/2825 High Dependency Unit (HDU):..............................................2363 Intensive Therapy Unit (ITU):......................................2769/2494 Oncology Day Ward:............................................................2362 Phoenix:....................................................................2331/2329 Renal Day Care Unit:............................................................3144 Richmond I.T.U.:.........................................................2418/2420

Richmond:.................................................................2432/3085 St. Anne's E.N.T.:........................................................2395/2401 St. Brigid's:..................................................................425/2431 St. Clare's:...........................................................................2360 St. Damien’s Urology:................................................2293/2292 St. Damien’s Nephrology: ..........................................2323/2324 St. Finbar’s Day Ward:.........................................................2823 St. John's (Wed/Friday Day Care Centre): ............................2168 St. Laurence's:...........................................................2388/2394 St. Martin's Dialysis Unit:...........................................2730/2731 St. Mary's:...........................................................................2398 St. Michael's:.......................................................................3288 St. Patrick's:.........................................................................2490 St. Paul's:..................................................................2381/2383 St. Peter's:.................................................................2290/2285 St. Peter's Dialysis (Isolation Unit): ..........................01 797 4805 St. Raphael's: ......................................................................2502 St. Teresa's Transplantation Unit:................................2294/2761 RENAL HANDBOOK 135


ADMINISTRATIVE

BEAUMONT RENAL DIVISION PHONE NUMBERS (PREFIX (01) 809 FROM OUTSIDE HOSPITAL) ADMISSIONS Renal Admissions:................................................................2988

Urology/Renal Admissions: .................................................2295

MANAGEMENT / ADMINISTRATION Creditors / Accounts: .......................................3296/2246/2247 Clinical Services:..................................................................2937 Communications 2867 Finance:...............................................................................2107 Fundraising (Beaumont Hospital Foundation):......................2161 Human Resources:...............................................................2253 Hygiene and General Services: .............................................2612 IT: .......................................................................................2550 Medical Administration: .......................................................2189

Nursing Administration:.......................................................3381 Patient Accounts: .................................................................3499 Planning & Development:....................................................2933 Project and Estates: .............................................................2268 Smurfit Building (R.C.S.I.):...................................................3700 Stores:.................................................................................3030 Supplies Department:.................................................2122/2143 Technical Services: ...............................................................2333

FAX NUMBERS Main Hospital Fax (General Office): .........................01-837 6982 Renal Unit: ..........................................................................2802 St. Martin’s (Renal): ............................................................2728 St. Peter’s (Renal:................................................................3944 Histology (Pathology):.........................................................2955 Immunology:.......................................................................3933

Tissue Typing: ......................................................................3145 Transplant Co-ordinator:...........................................01-797 4870 Urodynamics:.......................................................................3018 Urology:..............................................................................3962 Medical Administration:.......................................................2953

BEAUMONT RENAL DIVISION CONFERENCES Mon Sign-out

8am

Tues

Weds

Thurs

Fri

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Meeting Walsh library (Rota below)

Renal J Club

Teaching / Tx J Club*

8-9am 11:30-14:30

OPD O'Seaghdha

OPD Conlon / Magee Renal pathology**

13:00

OPD Denton / Rotunda

13:00-17:00 15:00-18:00

OPD Conlon / De Freitas

Research Meeting

OPD Magee / Little

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17:00

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Weds

Meeting

Time

Regs to Attend

1st of month

Renal M+M

0815-0900

All

2nd of month

Living Donor

0715-0800

Tx

3rd of month

Tx M+M

0800-0900

All

4th of month

Living Donor

0800-0900

Tx

136 RENAL HANDBOOK

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*Tx J Club is every 2nd Fri, 0900-1000. Teaching is every week and lead by the on-call nephrologist. **Every 2nd Tue.


INDEX HAEMODIALYSIS ...............................................................1 Assessment of the dialysis patient ......................................2 Haemodialysis prescription ...................................................3 Haemodialysis access and line sepsis.................................5 Intravenous antibiotic dosing...............................................8 Non-infectious access complications.................................9 Dialysing toxins........................................................................10 Renal anemia ............................................................................11 Mineral bone disease: Phosphate, PTH and Calcium.13 Complications of ESRD..........................................................16 Intradialytic hypotension .....................................................19 PERITONEAL DIALYSIS ...............................................21 Peritoneal dialysis prescription..........................................22 Complications of peritoneal dialysis................................23 Peritoneal dialysis peritonitis..............................................24 Renal nutrition .........................................................................26 ACUTE KIDNEY INJURY ..............................................27 Differential diagnosis of acute kidney injury ................28 Management of acute kidney injury................................29 Continuous renal replacement therapy..........................31 CVVH prescription ..................................................................32 RENAL CONSULTS ..........................................................37 Chronic kidney disease .........................................................38 Microscopic haematuria.......................................................39 Kidney disease in the cancer patient ...............................40 Kidney disease in the HIV positive patient.....................41 Kidney disease in the patient with liver disease..........42 Kidney disease in the medical patient.............................43 Acute interstitial nephritis ...................................................45 Hypertension............................................................................46 Recurrent urinary tract infections .....................................50 Nephrolithiasis .........................................................................51 Renal side effects of common medications ..................54 Radiocontrast nephropathy................................................56 Nephrogenic systemic fibrosis ...........................................57 GLOMERULONEPHRITIS ...........................................59 Rapidly progressive glomerulonephritis ........................60 Nephrotic syndrome..............................................................61 Membrano-proliferative injury pattern...........................62 Systemic lupus erythematosus ..........................................63 TTP-HUS TMA syndromes ....................................................65 General treatment of glomerular disease ......................66 Treatment of lupus nephritis ..............................................67 Treatment of ANCA vasculitis .............................................68 Treatment of anti-GBM disease..........................................69

Treatment of cryoglobulinemic glomerulonephritis .70 Treatment of focal segmental glomerulosclerosis......70 Treatment of IgA nephropathy ..........................................71 Treatment of membranous nephropathy ......................72 Treatment of minimal change disease ............................73 Cyclophosphamide dosing..................................................74 Plasma exchange ....................................................................76 Immunosuppression prophylaxis .....................................77

ACID-BASE, FLUIDS & ELECTROLYTES ...........79 Hyponatraemia........................................................................80 Hypernatraemia.......................................................................83 Acid-base disorders................................................................85 TRANSPLANTATION .....................................................91 Evaluation of prospective renal transplant recipient.92 Evaluation of prospective living donor...........................93 Final pre-transplant assessment........................................95 Post-transplant maintenance immunosuppression...96 Induction agents in transplantation ................................97 Beaumont hospital immunosuppression protocol ....98 Antimicrobial prophylaxis....................................................99 Immediate post-operative management ....................100 Transplant clinic ....................................................................101 Allograft dysfunction ..........................................................103 The failing transplant and return to dialysis ...............104 CMV infection.........................................................................105 BK Polyoma virus ..................................................................106 Malignancy in the transplant patient............................107 Vaccinations in the transplant patient..........................108 Neutropenia in the transplant patient..........................108 Transplant rejection.............................................................109 The highly sensitised transplant patient......................112 OBSTETRIC NEPHROLOGY ...................................115 Physiologic changes of pregnancy ................................116 Hypertensive disorders of pregnancy...........................117 Management of kidney disease in pregnancy...........119 Pregnancy in the transplant patient..............................121 Pregnancy in the dialysis patient....................................122 PROCEDURES .................................................................123 Temporary dialysis access..................................................124 Kidney biopsy ........................................................................125 PATHOLOGY AND URINALYSIS .........................127 ADMINISTRATIVE ........................................................133 Division phone numbers and timetable ......................134

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