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Review Article

Drug-induced Kidney Diseases


NP Singh*, A Ganguli**, A Prakash***

Abstract
Drug-induced kidney disease constitutes an important cause of acute renal failure and chronic kidney disease in present day clinical practice. Different classes of drugs, by virtue of immunological mechanisms or direct toxicity initiate certain stereotyped renal responses. For most patients suffering from druginduced nephropathy common risk factors which precipitate the adverse effects include: old age, volume -depleted state, pre-existing renal dysfunction and coexisting use of other nephrotoxins. Although it is impossible to present all the drugs causing renal disease, a few prototype drugs are mentioned. In a case of undiagnosed renal disease a possibility of drug-induced renal failure should be kept as the prompt removal of the drug and supportive management can reverse the renal dysfunction to a large extent.

INTRODUCTION
he incidence of drug-induced nephrotoxicity has been increasing with the ever increasing number of drugs and with easy availability of over-the-counter medication viz. nonasteroidal anti-inflammatory drugs (NSAIDs). Antibiotics, NSAIDs, angiotensin converting enzyme inhibitors (ACEI) and contrast agents are the major culprit drugs contributory to kidney damage. Drug-induced acute renal failure (ARF) accounted for 20% of all ARF in an Indian study;1 of which aminoglycosides accounted for 40% of total cases. A. Syndromes of drug-induced nephropathies Table 1 delineates common syndromes associated with drug-induced kidney diseases. Other syndromes include Acute glomerulonephritis (rarely seen with drugs like rifampicin)- Associated with generalized anasarca, hypertension, oliguria; blood urea nitrogen (BUN) and serum creatinine (SCr) elevated; urine microscopy reveals proteinuria (> 2 g/24 hr) and RBC casts with > 80% dysmorphic RBCs. Renal biopsy may be indicated to assess the pathology and to gauge the severity of inflammatory response. Syndrome of inappropriate ADH secretion- seen with phenothiazines, vincristine, chlorpropamide, cyclophosphamide, tricyclic antidepressants, vasopressin analogues. Nephrogenic diabetes insipidus- seen with lithium,

demeclocycline, aminoglycosides, amphotericin B. The summary of management of drug-induced kidney diseases is mentioned in Table 2. Table 3 outlines dose adjustments for kidney disease patients. B. Individual classes of drugs 1. Aminoglycosides (AMG) AMG are prototype drugs having nephrotoxicity as major side effect. Number of patients developing nephrotoxicity increases with duration of therapy reaching 50% with 14 days2 or more of therapy. Clinical features - Classically it presents as acute tubular necrosis which is generally milder than oliguric ARF. Features include: non-oliguric ARF, proximal tubular dysfunction, enzymuria, proteinuria, glycosuria, hypokalemia, hypocalcemia, hypomagnesemia. In over 50%, renal functions decline after completion of therapy. Recovery is slow and requires 4-6 weeks. Recovery is incomplete3 if pre-existing renal insufficiency exists. Some patients may progress to chronic interstitial nephritis. Mechanisms2 - The drug is actively concentrated in the renal cortex and proximal tubular cells achieve maximum concentration. After entering the cortical cells AMG bind to lysosomes with formation of myeloid bodies/secondary lysosomes. Thereafter mechanisms are unclear. It is believed that the release of AMG into cytoplasm interferes with the phosphatidyl-inositol pathway. The transport system is a low affinity high capacity system that is not easily saturable. Thus momentary high drug concentrations as achieved immediately after intravenous injection result in saturation of the uptake mechanism. Hence, multiple dosing is more deleterious than single dosing bolus injection.

*Professor; **Postgraduate Student; ***Senior Resident; Nephrology Division, Department of Medicine, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi - 110 002. Received : 3.4.2003; Revised : 22.5.2003; Accepted : 1.9.2003

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Table 1: Syndromes of drug-induced kidney disease


Syndrome Pre-renal failure/ functional renal failure Clinical features Drugs

Acute tubular necrosis

Acute interstitial nephritis

Druginduced

Caused by reduced blood delivery NSAIDs, ACEOliguria, anasarca, acute fluid inhibitors, retention with or without amphotericin-B, hypotension. Investigations reveal cyclosporine, - BUN/Cr > 20:1 norepinephrine, - decreased urinary volume diuretics, - FeNa < 1% interleukin-2 - Urinary Na < 10 mMol/L - Urine sediment is bland Casts : RBCs or white blood cells Seen with drugs secreted by kidneys. AMG, Toxicity may be effect of the drug cephalosporins per se or the physiological conse(cephaloridine, quence as in rhabdomyolysis or by cephalothin) the added toxicity of two drugs e.g. Am-B, cisplatin with AMG. Mostly nonrifampicin, oliguric renal dysfunction detected pentamidine, biochemically first or with patients NSAIDs, developing overt signs of dehydration contrast media, and electrolyte loss. Oliguria may cyclosporine, occur if drug is continued. cisplatin, OKT3 BUN/SCr=10 or 15 Fractional excretion of Na (Fe Na) > 2% Urinary sodium content > 20 mmol/d Represents systemic manifestation Methicillin, of a hypersensitivity reaction with ampicillins, fever, rash and arthralgias rifampicin, Onset after drug exposure variable NSAIDs, Systemic signs and symptoms allopurinol, dominate but associated with non- sulfonamides, oliguric renal failure thiazides. Urine R/M erythrocytes, leucocyturia (mainly eosinophiluria), WBC casts Urinary proteinuria usually < 2 g/day but > 2/day seen with NSAIDs Fe Na > 1% Proximal tubulopathy seen with glycosuria, bicarbonaturia, phosphaturia, aminoaciduria, proximal RTA Distal tubulopathy Hyperkalemia, Na+ washing, distal RTA Medullary and interstitial defects Na+ wasting, defect in urine concentration (nephrogenic DI) AIN usually has overlap of different tubular dysfunctions. Eosinophilia and eosinophiluria seen in > 75% of AIN. NSAIDs induced AIN is remarkable in that eosinophiluria is usually absent and associated with heavy proteinuria (> 2 g/d) Renal biopsy required for diagnosis Histology show evidence of tubular edema with interstitial inflammation with or without interstitial fibrosis or glomerular involvement. High degree of interstitial fibrosis is a strong predictor of decline in GFR and progression to chronic kidney disease. Syndrome due to outflow tract Sulfadiazine, obstruction due to crystal methotrexate,

formation in tubules or ureter or methoxyflurane, Due to retroperitoneal fibrosis as acyclovir, with methysergide indinavir, Associated with volume depleted nelfinavir, states or bolus drug administration acetazolamide, Typical history of renal colic triamterine or lumbar pain followed by hematuria and/or oligoanuria of sudden onset Characteristic findings in urine microscopy Showing gross hematuria with RBC or crystals Acyclovir needle-shaped crystals Indinavir reactangular plates or rosettes Hypersensit- Rare Penicillin G, ivity angiitis Associated with vasculitis of small ampicillin, vessels, can cause ARF sulfonamides, Extrarenal manifestations present; thiazides, systemic complaints of vasculitis with metolazone hematuria, hypertension, proteinuria and modest elevation of SCr with abdominal pain, joint involvement or pulmonary changes Kidney biopsy - fibrinoid necrosis of intima and media of small medium sized renal vessels with cell infiltration Thrombotic Rare syndrome Mitomycin-C, microangio- Associated with fever, hemolytic cyclosporine, pathy/ anaemia, thrombocytopenia and renal contraceptives, hemolytic dysfunction and CNS disease (diffuse) OKT3, 5-FU, uraemic Suspect drug as the cause in cases of quinine, cocaine, syndrome Coomb's negative hemolytic anaemia ticlopidine, with thrombocytopenia and renal clopidogrel failure with a known nephrotoxin. Limited form of disease is the hemolytic uraemic syndrome Isolated Associated with edema, proteinuria Gold, heroine, proteinuria (> 3.5 g/day) with hypoalbuminuria. captopril, with Renal biopsy necessary to confirm NSAIDs, IFNnephrotic pathology and prognosis, mostly alpha, Dsyndrome membranous glomerulopathy or penicillamine minimal change disease (no light microscope finding); rarely FSGS Chronic Symptoms of uraemia with occasional Heroine glomerulo- fluid overload states and hypertension pathy Urine may show moderate proteinuria (subnephrotic) or glomerular hematuria Chronic History suggestive of tubular defects NSAIDs, tubulointer- in early stage with polyuria and Thiazides, stitial nocturia Lithium, disease Renal insufficiency develops slowly Chinese herb Glomerular dysfunction seen at late nephropathy, stage germanium Renal histology - Interstitial fibrosis, Mononuclear cell infiltration, tubular atrophy and glomerular sclerosis Drugs implicated for AIN may cause CIN if given longer. Excessive consumption of calcium carbonate and alkalis in antacids may cause alkalosis, hypercalcemia and renal tubular acidosis (Milk-alkali syndrome). Retroperito- Unexplained uremia, polyuria, Methysergide, neal fibrosis Ultrasonography of the urinary tract hydralazine, shows hydroureteronephrosis with methyldopa no apparent sign of calculi

crystalluria

Risk factors for AMG toxicity include Na+ and K+ depletion, renal ischemia, increasing age, liver disease, diuretic use and concomitant use of nephrotoxic agents. Rising trough
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levels may indicate impending nephrotoxicity. Relative toxicites (in decreasing order) Neomycin > Gentamycin > Tobramicin > Netilmicin > Amikacin > Streptomycin
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Table 2 : Summary of management of drug-induced nephropathy


Drug-induced kidney disease may be immunological or nonimmunological toxic reaction Special risk groups include - Age (elderly), volume-depleted state, concomitant use of other nephrotoxic drugs, Pre-existing renal disease and risk factors specific to each drug class Patients need be monitored for - Symptoms, blood pressure, urine volume, SCr, [GFR (predicted), urine Na+, FeNa] urine microscopy, serum electrolytes, serum levels (trough) of certain drugs (cyclosporine, aminoglycosides, vancomycin) Kidney biopsy in drug-induced renal disease; is indicated for* Suspected glomerular disease i.e. proteinuria > 2 g/day or gomerular hematuria * Drug-induced tubulopathies, to establish nature of tubulointerstitial disease * Post-renal transplant renal dysfunction to distinguish rejection from CS-A toxicity. * In patients of suspected microthrombotic angiopathies, to rule out pre-renal cause. Treatment - Adequate fluid administration and treatment of hypertension Steroid use is controversial as long-term trials lacking, but may be used for * Glomerular proteinuria with intake of NSAIDs, gold, penicillamine not responding to cessation of drug * All patients of hypersensitivity vasculitis due to drugs * AIN unresponsive to drug cessation with granulomatous reaction (biopsy proven) * In patients of cisplatin toxicity * Prednisolone in a dose of 1 mg/kg/day or methylprednisolone has been used. Role of dialysis in drug nephrotoxicity * Persistent azotemia after drug withdrawal. Indications are same as usual CKD patients. * Removal of certain drugs may be easily accomplished due to their high sieving coefficient. These are acyclovir, gentamicin, tobramicin, amikacin and cyclosporine. * Modalities like CAVH, CVVH and CVVHD are especially useful in the ICU setting for hemodynamically unstable patients. * Plasmapharesis may be of help in HUS, but prognosis is usually poor. * Drug removal by peritoneal dialysis may be effective for drugs which are highly protein-bound e.g. Cisplatin, cyclosporine, beta-lactams; but the disadvantage is the relatively slow dialysate flow rate (7 ml/min) which is seen with CAPD. In most cases renal function may return to normal. However in patients already in chronic stages chances of recovery are less. In such cases only renal replacement therapies (dialysis of transplant) many help.

electrolyte therapy with specific emphasis on K+ and NaCl as well as Ca2+ and Mg2+ replacement. 2. b-Lactams and vancomycin True nephrotoxicity is rare. Acute interstitial nephritis (AIN) may be seen especially with methicillin. Early formulations of vancomycin had substantial nephrotoxic potential due to impurities4,5 but current preparations are free from adverse effect. AMG + vancomycin combination may have synergistic toxicity. 3. Sulfonamides Use of sulfonamides has increased with advent of AIDS. Sulfadoxine + pyrimethamine combination is used in malaria. Spectrum of nephrotoxicity includes6 1. 2. 3. Acute interstitial nephritis (not common) Necrotizing arteritis ARF due to massive haemolytic anaemia in G-6-PD deficient patients 4. ARF due to crystalluria (seen only with long-acting agents like sulphadiazine) Sulfadiazine: prototype drug causing crystalluria and ARF. The overall incidence is 6%. Renal dysfunction starts after three weeks of commencing treatment in AIDS patients and is related to the cumulative dose (> 84g), the acetylated byproduct is toxic. Sulphadiazine has low solubility in acidic urine. Crystals of sulfadiazine and acetylsulfadiazine are typically recognized by examining the urine sediment where they resemble sheaves of wheat. As the crystals transmit through tubular lumen they cause local abrasion and chemical irritation of collecting duct epithelium followed by peritubular haemorrhage, tubular necrosis and obstruction at any level from collecting duct to bladder. Patient manifests with asymptomatic crystalluria and microhematuria, gross hematuria, oliguria to anuria and post-renal ARF. Risk factors especially in AIDS patients are: 1. 2. 3. Prolonged duration of therapy than in community acquired pneumonia Oral fluid intake may be prevented by toxoplasma encephalitis for which it is used Concurrent diarrhoea and volume depletion

Prevention and management Use total dose as once daily dosing;3 and for shortest possible time in empirical therapy Mostly subclinical toxicity and beyond detection as electrolyte imbalances are subtle Routine monitoring of SCr daily with calculation of dose on basis of GFR/creatinne clearance especially in elderly. Daily monitoring of serum Na+ and K+. If SCr > 1.5 mg/dl stop the drug and consider alternate therapy. Monitor urine output and start adequate fluid and

4. Associated presence of HIV associated nephropathy Prevention and treatment Maintain adequate hydration (~3L/day) Urinary alkalinization with 6-12 g/day of sodium bicarbonate to ensure urine pH > 7.5. Routine urine microscopy 2-3 times a week, to detect gross/microscopic hematuria. Perform ultrasonography in all patients of hematuria. Treatment is reduction or omission of sulfadiazine dose; stoppage causes resolution. Maintain hydration and alkalinization. Ureteral stents may be placed or dialysis may be resorted
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Table 3 : Dose adjustments for patients of renal dysfunction


Drugs Acetazolamide Acetaminophen Acyclovir Allopurinol Alprazolam Aminoglycosides Amiodarone Amoxy/Ampicillin Amphotericin B Analgesics-NSAIDs Analgesics-opioids Antidepressants Aspirin Atenolol Azathioprine Azithromycin Aztreonam Benazepril Benzylpenicillin Beta-blockers Bumetanide Captopril Carbamazepine Carbenicillin Carbenoxolone Cefadroxil Cefazolin Cefixime Cefoperazone Cefotaxime Cefpodoxime Ceftazidime Ceftizoxime Ceftriazone Cefuroxime Cephalexin Cetrizine Chloramphenicol Chlorpromazine Cisapride Cisplatin Clarithromycin Clofibrate Clonidine Colchicine Co-trimoxazole Cyclophosphamide Cycloserine Diazepam Digoxin Dipyridamole Disopyramide Domperidone Doxazosin Enalapril Ergotamine Ethambutol Ethosuximide GFR (mL/min) < < < < 10 50 50 50 Dosage recommendations Avoid Reduce dose frequency Reduce dose frequency Reduce dose No change Reduce dose frequency No alteration, hepatic metabolism Decrease frequency Use only if no alternative No alteration Decrease dose Mainly hepatic excretion Avoid Decrease dose Reduce dose No change Reduce dose Reduce dose Reduce dose Reduce dose No dose alteration; at low GFR may require high doses Reduce dose Reduce dose to 75% Reduce dose Avoid Reduce dose frequency Reduce dose frequency Reduce dose No alteration Reduce dose frequency Reduce dose frequency Reduce dose frequency Reduce dose frequency Reduce dose frequency Reduce dose frequency Reduce dose frequency Reduce dose No dose alteration No change No alteration Avoid No change Reduce dose frequency No change Reduce dose by half Reduce dose frequency Reduce dose Avoid No change Reduce dose frequency No change Reduce dose Reduce dose by half No change Reduce dose hy half Avoid Reduce dose frequency Reduce dose to 75%

Erythromycin Famotidine Finasteride Fluconazole Flucytosine Foscarnet Furosemide Ganciclovir Gemfibrozil Glibenclamide Gliclazide Glipizide Glucorticoids Gold salts Haloperidol Heparin Hydralazine Hydroxy-chloroquine Imipenem Indapamide Insulin Isoniazid Itraconazole Ketoconazole Labetolol Lisinopril Lithium Lovastatin Magnesium salts Melphalan Mercaptopurine Metformin Methocarbomol Methotrexate Methyldopa Metoclopramide Metolazone Metoprolol Metronidazole Mezlocillin Miconazole Misoprostol Morphine Nicardipine Nifedipine Nitrates Nitrofurantoin Nitroprusside Omeprazole Penicillamine Pentamidine Pentoxiphylline Phenobarbitone Phenytoin Piperacillin Potassium salts Pravastatin Prazosin Primidone Probenecid

< 10 < 50 < 50 < 50 < 50 < 50

< 50 < 50 < 50 < 50 < 10 < 50 < 10 < < < < 50 50 50 10

< 50

< 10 < 50 < 10

< 10

< < < < < < < < < < < < < < <

10 10 50 10 50 50 50 50 50 50 50 10 50 10 50

< 50 < 50 < 20 < 20 < 20 < 50 < 50 20-50 < 20 < 50 < 50

< 10 < 50

< 50 < 50 < < < < 10 50 20 50

< 50

< 50

< 50 < 10 < 10 < 50 < 20 < 10 < 50 < 10

< 50 < 50 < 10 < < < < 10 50 50 10

No change Reduce dose by half No change Reduce dose Reduce dose frequency Reduce dose No change Reduce dose frequency Reduce dose No changes; but increased risk of hypoglycemia No changes; but increased risk of hypoglycemia No change but hypoglycemia may occur, although it is short-acting No change Avoid No change No change Reduce dose frequency Reduce dose Reduce dose No change May need dose reduction as insulin requirement falls. No change Reduce dose by half No change No change Reduce dose Reduce dose No change Avoid or reduce dose Reduce dose Reduce dose Avoid Avoid Reduce dose Avoid Reduce dose frequency Reduce dose frequency No change No change Reduce dose by half Reduce dose frequency No change No change Reduce dose frequency No change No change No change Avoid No change No change Avoid if possible, or reduce dose Dosing interval 24-48 hrly No change Reduce dose frequency No change Reduce dose frequency Avoid routine use Reduce dose to half No change Reduce dose frequency Avoid

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Procainamide Propranolol Propylthiouracil Pyrazinamide Quinolones Ramipril Ranitidine Rifampicin Simvastatin Spironolactone Sucralfate Sulphadiazine Sulphasalazine Terazosin Theophylline Thiazide diuretics Ticlopidine Tolbutamide Trimethoprim Tubocurarine Valproic acid Vancomycin Warfarin Zidovudine

< 50 < < < < < 50 10 50 50 50

< 10 10-50 < 10 < 10 < 10

< 10

< < < <

50 20 10 50

Reduce dose frequency No change Reduce dose Reduce dose by half Reduce dose frequency Reduce dose Reduce dose frequency No change Reduce dose to half Reduce dose frequency Avoid No change Avoid Ensure high fluid intake No change No change Avoid No change No change Reduce dose frequency Reduce dose Reduce dose to 75% Reduce dose frequency No change No change

allowing it to easily mingle with cellular membranes, disrupting them and increasing their permeability.11 Disruption of cell membranes leads to endothelial damage with vasoconstriction of afferent and efferent arterioles, causing an acute fall in GFR and an initial oliguric ARF in some patients. Tubular toxicity is related to direct effect on cellular membrane and also medullary ischaemia caused by sudden vasoconstriction. Recent studies show protective effect of pentoxiphylline which is a vascular decongestant and antagonist to TNF-, IL-1.12 Am-B typically causes distal tubular dysfunction. Clinical spectrum of amphotericin nephrotoxicity Azotemia : It is almost universal with Am-B. GFR falls to 40% in first 2-3 weeks and stabilizes at 20-60% of normal throughout course of treatment; normalizing on cessation of therapy. Cumulative doses of 3-4g have greater risk; implying a greater incidence with longer duration of therapy and greater chances of irreversibility as well. 2. Inability to concentrate urine occurs universally within 1-2 weeks of therapy even in absence of decrease in GFR and is not related to occurrence of azotemia. It occurs due to failure of arginine-vasopression (AVP) response on medullary collecting tubule. 3. Electrolyte disturbance occurs as a consequence of distal tubulopathy with predominantly- Mg2+ and K+ loss is important as it may cause worsening of renal function with impairment of concentration ability, urinary acidification, renal insufficiency. 4. Renal tubular acidosis can occur at cumulative doses of 0.5-1 g but is reversible. Management of a case of amphotericin toxicity Prevention is the key with risk factors for Am-B toxicity remain the same as for any toxic nephropathy but sodium deficiency is important especially in patients on diuretics. Novel measures to reduce amphotericin nephrotoxicity Dopamine agonists - may exert protective role.13 Salt supplementation - is the most effective measure in reducing incidence.14 A titre of normal saline infused prior and post Am-B significantly lowers incidence of nephrotoxicity. Liposomal amphotericin-B15 - Liposomal compounds and lipid complexes reduce Am-B toxicity. The lipid complex is rapidly taken up by the reticuloendothelial system thereby significantly increasing the tissue concentration in the liver, spleen and lymphoid tissues. A higher total dose of 5 mg/kg/day compared to a maximum of 0.5 to 1.5 mg/kg/day with Am-B can be achieved without risking the renal tissue; and the efficacy is similar. High cost is the disadvantage. Liposomal preparations should be used in patients with pretreatment renal dysfunction (SCr > 3 mg/dl) and where use of alternative antifungals is not feasible. Age - important risk factor and careful use of CCR for dose titration is necessary for elderly. Frequency of dosing - alternate day administration
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1.

Reduce dose frequency means that the frequency of administration that is the dosing intervals have to be increased; Reduce dose means that the dose being administered to the patient has to be decreased by half if the GFR is between 10-50 ml/ min, and to one-fourth when the GFR is 10-50 ml/min

to, if surgical option not available. Cotrimoxazole - The trimethoprim component achieves more concentration in renal cortex than in serum and in the process impairs the tubular secretion of creatinine resulting in increase in its serum concentration with decline in creatinine rate (CCR) calculated from Cockroft-Gault equation but GFR measured by radio-labeled isotope is normal.7 It is important as it may cause false diagnosis of renal failure in a case of AIDS. Sulfamethoxazole as good urinary solubility compared to sulfadiazine but rare reports of crystalluria8 can be eliminated with adequate hydration. AIN due to the sulfa component is far more common. Hyperkalemia due to trimethoprim inhibition of the apical sodium channels of distal tubule is known and is a dose-related side effect.9 4. Acyclovir Doses > 500 mg/m2 given i.v. leads to nephrotoxicity.10 Its low solubility leads to intratubular precipitation with symptoms of obstructive uropathy and hematuria. Urine analysis reveals birefringent needle-shaped crystals. Interstitial inflammation is seen adjacent to areas of intratubular obstruction. Oliguria is very rare. Risk factors include: volume depletion, pre-existing renal insufficiency and rapid bolus infusion. Treatment is prompt withdrawal of therapy, which restores near normal renal function within 1014 days. However severe renal failure may occur necessitating hemodialysis. 5. Amphotericin-B (Am-B) It contains hydrophilic as well as lipophilic regions;
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reduces incidence of nephrotoxicity. 6. Rifampicin Incidence of rifampicin nephrotoxicity varies from 1.8% to 16% of all ARF. Most cases of rifampicin-related renal failure are secondary to drug-induced haemolytic anaemia. However, AIN, rapidly progressive glomerulonephritis presenting as proteinuria with acute onset deterioration of renal functions and light-chain proteinuria constitute the remaining. Duration of therapy seems important and cases have been reported after two months of therapy; although reactions as early as 13 days have also been seen. Intermittent regimens carry greater risk. The possibility of toxic interaction between isoniazid and pyrazinamide also exists. In most cases prompt withdrawal of therapy and supportive management leads to recovery within three weeks.16-18 Poor prognostic factors19 are- longer duration of anuric phase, severity of immunological abnormalities on renal biopsy; associated hemolysis, leucocytosis and hyperglobulinemia. The Indian experience is less known.16,20 Overall incidence of rifampicin-induced ARF was 1.8% and mortality was 18%. AIN was the most common pathology followed by ATN. Higher incidence of ARF was observed with intermittent therapy. 7. NSAID-induced renal diseases Overall incidence is 3%; but over-the-counter availability of these drugs puts a large population at risk. Conditions causing NSAID-induced hemodynamic deterioration of renal function - Higher than usual dose, volume depletion due to flow loss diarrhoea, congestive heart failure, nephrotic syndrome, cirrhosis particularly with ascites, preexisting renal disease, third space fluid sequestration, diuretic therapy, age > 65 years. Syndromes of NSAID nephrotoxicity Acute effects 1. ARF - usually oliguric 2. Acute interstitial nephritis (AIN) - Associated with heavy proteinuria (> 3 g/24 hr); usually non-oliguric; rarely without proteinuria; takes weeks or months to resolve 3. 4. 5. Hyperkalemia Sodium and water retention Hypertension

NSAID-induced tubulointerstitial nephritis- clinical features Usually subacute to chronic course Mostly seen with fenoprofen but all NSAIDs till date observed to cause Mean period of development 5.4 months Associated with heavy proteinuria (> 3.0 g/d) in 83% of cases Fever, rash, eosinophilia rare (<19%) Renal biopsy characteristically shows tubulo-interstitial infiltrate with some fibrosis. Immunofluorescence shows variable staining for IgA, IgM and C3. Proposed mechanism is occurrence of delayed hypersensitivity response with shunting of arachidonic acid metabolites to lipoxygenase pathway. Leukotrienes mediate chemotaxis for WBCs leading to cellular infiltrates (T-cell and eosinophils).

Effects of NSAIDs on blood pressure21-23 - Modest increase of mean arterial pressure (~6-8 mmHg) in all patients with increase more in patients already hypertensive. Most vulnerable are patients on diuretics and/or -blocker especially patients on propanolol; but less vulnerability seen with calcium channel blockers, direct vasodilators and clonidine. Effects in combinatin with ACE inhibitors are controversial and may cause deterioration of renal function. Most vulnerable are patients with low renin hypertension i.e. elderly and blacks.
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Isolated proteinuria - Isolated reports of proteinuria in absence of tubulointerstitial damage occur; proteinuria reaching nephrotic range; and minimal change disease on biopsy.24 Concept of renal sparing NSAIDs Sulindac was previously considered as reno-protective since its hepatic metabolite sulindacsulfoxide has shown to be least affecting the renal cyclooxygenase system whereas the sulfide metabolite is active as a vasoconstrictor. Present views suggest that kidney can activate the prodrug and lead to vasoconstrictive renal failure usually after days or weeks. Chronic kidney disease (CKD) and NSAIDs - also known as analgesic nephropathy. It is chiefly a chronic interstitial nephritis associated with capillary sclerosis of the vessels of renal pelvis and renal papillary necrosis followed by calcification. It is due to medullary ischaemia induced by loss of vasodilatory effects of prostaglandins on vasa recta. Long term toxicity of individual drugs are unknown and so are incidence and prevalence in view of most drugs available over-the-counter. Classically seen with consumption of any NSAID for over 20 years. The potential of CKD exists with use of analgesic mixture and is most well studied with aspirincodeine. Incidence is higher in females and in patients suffering from rheumatic disorders and migraine. Diagnosis is difficult as there is lack of a simple non-invasive test that reliably implicates analgesics as a cause of renal injury. Clinico-radiological criteria25 - History of analgesic abuse (i.e. daily use of mixture of analgesic drugs for a period not less than five years) with non-contrast CT scan of abdomen showing the following 1. 2. 3. Bumpy contour of the kidneys Decreased length of both the kidneys Papillary calcification 1 or 2 with 3 carries maximum specificity (100%) and sensitivity (94%) in diagnosis.

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Prevention and management: It is one of the few CKDs which can be prevented and early intervention can prevent its progression. Stop NSAIDs if patients develop any evidence of renal insufficiency. Appropriate legislation to limit accessibility of all analgesics is required. COX-2 selective inhibitors - the final answer to nephrotoxicity?26 COX-2 selective inhibitors were designed to counteract the gastrointestinal toxicity considering COX-1 as a constitutive enzyme and COX-2, an inducible enzyme (induced by inflammatory and mitogenic stimuli). COX-2 is now known to exist constitutively in renal tissue especially the cells of the thick ascending loop of Henle and macula dense in humans as well as in renal medulla interstitial cells and medullary collecting duct cells. Prostaglandins generated by COX-2 are involved in tubuloglomerular feedback mechanism leading to afferent arteriolar vasoconstriction. In medulla COX-2 promotes diuresis and natriuresis. Expression of COX-2 is enhanced in low salt diet in the cortex while it is increased in medulla with high salt diet. The former preserves renal function in volume depletion whereas the latter promotes natriuretic and diuretic response during volume expansion. Given the role of COX-2 in renal function; same precautions need to be taken with COX-2 inhibitors; as is necessary for non-selective NSAIDs. In patients with chronically salt depleted state e.g. hypertensive or CHF on diuretics the risk of ARF is the same as with conventional NSAIDs. However, further studies are necessary to assess long-term outcomes. 8. Gold and D-penicillamine Penicillamine - 7% develop nephrotic syndrome with kidney biopsy demonstrating membranous nephropathy. Proteinuria may occur at six months to six years. Gold - Proteinuria occurs in 30% of patient with renal pathology in most being membranous glomerulopathy and minimal change disease in few cases. Proteinuria is usually less than 3.5 g/d. Parenteral gold is more likely to cause proteinuria. At present, genetic predisposition to development of proteinuria both with gold and penicillamine is shown to be in HLA-B8 and HLD-DRW3 patients. Cases of rapidly progressive renal failure due to crescentic GN have been seen otherwise KFTs are maintained. Proteinuria stops on cessation of the drug. Treatment is supportive with withdrawal of the drug. 9. Anti-neoplastic agents Cisplatin - Major side effects is nephrotoxicity and is irreversible in most cases. Toxicity is cumulative and dose-related (> 25-33 mg/m2/ wk predisposes to nephrotoxicity). Nephrotoxicity is by acute tubular necrosis or tubulointerstitial process with symptoms of azotemia and fluid loss. Biochemical tests usually show tubular proteinuria with prominent tubular casts. High BUN and SCr and low
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serum Na+, K+, Mg2+, Ca2+, PO43- occur due to proximal tubular damage. Hypomagnesemia is severe. Damage typically occurs at the S3 portion of proximal tubule. Free radicals may play an important role. Prevention of toxicity is by avoidance of other nephrotoxic drugs like AMG. Begin diuresis after drug administration; maintaining urine output of 100 mL/hr can decrease nephrotoxicity. Mannitol may also be helpful. Administration is better tolerated if given by hypertonic saline which is also be given 12 hours prior and 12 hours post-cisplatin dose. Sodium-thiosulfate i.v. has been tried with some success. It should be added if > 200 mg/m2 of cisplatin is used. Some other measures to reduce nephrotoxicity are methylprednisolone, N-acetylcysteine and antioxidants. Cyclophosphamide - Although primarily a myelotoxic drug, nephrotoxicity is known. At daily doses of more than 50 mg/kg hyponatremia is seen. Hyponatremia occurs due to impaired water excretion by antidiuretic effect on distal nephron. The effect is transient and dissipates after 24 hrs of discontinuation of therapy. Hemorrhagic cystitis is a more common side effect of cyclophosphamide and occurs in 9% of cases. Methotrexate - Effective chemotherapeutic agent Nephrotoxicity seen at doses greater than 1.5 g/m2/week. Mainly due to intratubular deposition of 7hydroxymethotrexate leading to crystalluria and features of non-oliguric renal failure. Element of direct tubular toxicity are ameliorated with folinic acid. High doses of methotrexate need routine monitoring of KFT for casturia and tubular dysfunction. Rapid discontinuation reverses the abnormality. In patients with overt nephrotoxicity, anion binding resin and hemoperfusion therapy have been tried with some success. High dose folinic acid at 200-400 mg i.v. four hourly has been shown also to revert nephrotoxicity. 10. Antihypertensives ACE inhibitors - Most common syndrome is reversible ARF seen in cases of hypertension and congestive heart failure and is related to action of angiotensin II on efferent arterioles for maintenance of GFR at time of low perfusion pressure with increasing filtration fraction. Hence ACEI cause a sudden decline in GFR due to loss of efferent arteriolar tone. In bilateral obstruction of renal arteries (> 70%); efferent arteriolar tone is necessary for maintaining GFR. Therefore, ACEI in such cases can cause renal failure. Clinical features are associated with a sudden onset of oliguria with fluid retention, deranged renal functions and decreased FeNa (< 1%). Membranous nephropathy was earlier seen with captopril; characterized by isolated glomerular proteinuria without derangement of renal functions. Acute tubular necrosis and interstitial nephritis have also been reported.
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Approach to ACE inhibitors should therefore be careful. Recognition of risk factor, vigilant monitoring and volume management is necessary. A drug holiday of agents as furosemide may be necessary before starting the therapy. Serial SCr measurements are recommended especially if higher than 1.6 mg%. Transient deterioration in SCr may be seen on the 3rd day in most patients but derangement persisting beyond the 7th day of therapy needs active intervention to rule out sub-clinical renal stenosis. Angiotensin receptor blockers (ARBs) - ARBs reduce BP to a degree comparable to ACE inhibitors but propensity to cause renal disease is believed to be less, especially with regard to functional renal failure. However, the issue is largely unresolved. 11. Immunosuppressants Cyclosporine A (CS-A) - Two forms of cytotoxicity are known (a) acute reversible nephrotoxicity (b) chronic irreversible nephrotoxicity Acute form : Most transplant recipients manifest one or more episodes of acute renal failure. Usually due to vasoconstriction induced in systemic circulation; secondary to vasospastic products of arachidonate metabolism specially thromboxane-A2. Manifests as sudden onset hypertension occurring within weeks of transplant. Preoperative conditions may have a role in nephrotoxicity as prolonged cold ischemia time, donor hypotension and advanced age of the donor may increase the risk. Manifests with preserved urine volume and Na+ excretion but GFR and renal plasma flow are decreased with no change in the filtration fraction along with hypertension. Rapid improvement upon reduction of cyclosporine dose is seen. GFR progressively rises to baseline as blood levels of CS-A fall to trough levels. Ideal dose: 9-20 mg/kg/day; ideal trough levels of CS-A 150-400 ng/ml Renal biopsy: shows vacuolization in proximal tubules and microcalcification with or without interstitial fibrosis. Treatment: Calcium channel blockers provide protection and ameliorate early cyclosporine toxicity in humans. Large prospective studies now show that they can decrease long-term cyclosporine toxicity and improve graft survival.27 Prostaglandin analogue misoprostol has shown some benefit in reversal of vasoconstrictive effects. Chronic CS-A nephrotoxicity - Typically manifests after one year; mimics chronic rejection. Presents as hypertension, mild proteinuria, rarely hematuria, with marked decline in GFR. Renal biopsy : shows CS-A associated obliterative arteriolopathy, tubular atrophy and interstitial fibrosis; may be seen as early as six months after therapy. Tubular atrophy with diffuse fibrosis may appear as stripes

(striped interstitial fibrosis- characteristic of CS-A). Progression of interstitial fibrosis is dose-dependent with more several lesions in patients with cumulative dose of more than 1.8 g/kg over six months. Hemolytic uraemia syndrome is a rare arteriopathy with severe renal impairment associated with thrombosis in renal microcirculation along with thrombocytopenia and hemolytic anaemia. Prognosis for patients is poor. Plasmapheresis may be of some benefit. Prevention of CS-A toxicity Start CS-A on 5th day post-surgery as lowest dose with upward titration to reach ideal trough concentration in 1-2 months. Meticulous SCr and BP monitoring. Calcium channel blockers are beneficial in initial stages of acute hypertension. Avoid drugs which raise CS-A levels and hence cause nephrotoxicity. These include cimetidine, ranitidine, diltiazem, verapamil, erythromycin, metoclopramide, anabolic steroids and oral contraceptives.

Micronized forms of CS-A are beneficial as total dose is less and lower nephrotoxicity also. In cases of proven CS-A toxicity strategies available include the Triple therapy Prednisolone+CS-A (at lowest dose) + azathioprine. Newer therapies using non-calcineurin inhibitors like the mycophenolate mofetil (MMF) + azathioprine regime or MMF + micronized CS-A have shown some benefit in avoiding nephrotoxicity and ensuring graft survival. 12. Diurectics These cause reduction in GFR by extracellular fluid volume contraction. Other renal diseases induced by the duretics Hypokalemia nephropathy : all the diuretics expect the potassium sparing diuretics. Polyuria and abnormal concentrating ability : All diuretics (except potassium-sparing) due to chronic hypokalemia. Interstitial nephritis : thiazides and furosemide Vasculitis : Thiazides Nephrolithiasis : Acetazolamide at low pH can precipitate in urine leading to renal colic and obstructive uropathy. Hyperuricemia induced by thiazides by inhibition of urate excretion and the ECF volume contraction which enhances proximal tubule uptake induced increase in serum urate levels. Hyperuricaemia predisposes to uric acid nephrolithiasis. Treatment is withdrawal of the offending agent and volume and electrolyte support. Conditions which are immunologicalmediated may respond to steroids. Alkalinization of urine normally used in prophylaxis of obstructive uropathy may be detrimental in case of acetazolamide as it enhances calcium phosphate stones.
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13. Contrast-induced nephropathy It is a condition with impairment in renal function defined as an increase in SCr by more than 25% within three days following intravenous administration of a contrast medium in the absence of an alternative etiology. Incidence varies from 5-12% of those undergoing contrast administration. Risk factors include renal failure, diabetic nephropathy, severe congestive heart failure, amount of contrast media (> 150 ml) and volume depletion. Clinical features - Characteristically acute and progressive rise in SCr within 24 hours of i.v. contrast administration is seen. Oliguria is present in 95% of cases and pre-renal failure is typically seen with FeNa < 1%. Outcome of patients varies with the presentation. Three syndromes have been identified28- oliguria with decreased GFR (77%), reduced GFR without oliguria (12%) and normal GFR without oliguria (11%). It was observed that 32% had permanent renal damage with one out of every five dying of uraemia or requiring renal replacement therapy. The residual renal impairment is maximum with the acute oliguric renal failure group. Prevention and management High risk patient must be identified Monitor SCr on 2nd and 4th day post-procedure in all high-risk patients. Adequate hydration with 0.45% saline at (1.5 ml/kg/hr) starting 12 hours prior to the procedure and after the procedure. Patient should be hemodynamically stable Minimize amount of contrast administered (< 2 ml/kg or max of 150 mL) Use of non-ionic contrast iso-osmolar solution for high risk patients is recommended. In a recent meta-analysis of 31 trials over last 20 years, it was concluded that low osmolar contrast media like ioversal is less nephrotoxic than high osmolar/ionic contrast in existing renal failure but no significant benefit in patients with normal renal functions.29 No benefit of mannitol and furosemide in preventing ARF but may increase risk of ARF. Calcium blockers prevent renal ischemia during initial renal vasoconstrictor phase. Gadolinium30 is also nephrotoxic; more nephrotoxic than iodinated contrast medium dose to dose and hence to be avoided in patients at risk for contrast-induced nephropathy. Doses of < 0.3 mmol/mg/BW of gadolinium is recommended. If patient develops ARF, manage on conservative lines. Most of the times it is reversible but in irreversible cases not improving on hydration, temporary dialysis may be required. 14. Drugs causing hemolysis and myoglobinuria Characteristic drugs are sulfonamides, dapsone, rifampicin which have been already discussed. The mechanism of renal damage resulting in acute tubular necrosis has been
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mentioned in Table 1. Other agents include methyldopa, phenacetin, quinidine, procainamide, melphalan, isoniazid, penicillins and cephalosporins. Hemolysis may result in genetically predisposed patients with G-6-PD deficiency. Aminosalicylic acid, antimalarials e.g. primaquine, aspirin, chloramphenicol, co-trimoxazole, dapsone, nalidixic acid, nitrofuration, probenecid, phenacetin, sulfonamides, procainamide and quinidine can cause hemolysis in these patients, and possibly renal failure too. 15. Poisons masquerading as drugs Various contaminants may find their way in drugs viz. ethylene glycol, heavy metals (especially in bhasmas and bhabhutis given by quacks). Ethylene glycol contamination is recognized by a picture of ethanol-like intoxication, elevated serum osmolality followed by increased anion-gap metabolic acidosis and oxalate crystals in urine. Acute tubular necrosis manifested by proteinuria, oliguria and anuria becomes evident in 12 to 24 hours following ingestion. Heavy metals like lead, cadmium, mercury and arsenic are constituents of medicines given by quacks; and are selectively retained by bone, liver and kidneys for years together. Besides, the kidneys are the major route of their elimination. Chronic administration of these medicines results in subclinical exposure to these toxic agents resulting in interstitial nephritis, tubular damage, decline in GFR and chronic kidney failure. Nephrotic syndrome is another manifestation of heavy metal poisonings and arsenic exposure may result in cancer of the bladder and kidneys.

CONCLUSION
Given the large armamentarium of drugs available today judicious use of such drugs is required to prevent untoward side effects especially on such a vital organ as the kidney. Identifying high risk patients and quick recognition of druginduced injury-related syndrome with prompt cessation of the offending drug are the key to managing such a case before the injury causes permanent damage to the renal tissue.

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1. 2. Jha V, Chugh KS. Drug induced renal disease. J Assoc Physicians India 1995;43:407-21. Luft FC. Clinical significance of renal changes engendered by aminoglycosides in man. J Antimicrob Chemother 1984;13(suppl A):23-30. Gilbert DN. Once-daily aminoglycoside therapy. Antimicrob Agents Chemother 1991;35:399-405. Farber BF, Moellering RC Jr. Retrospective study of toxicity of preparations of vancomycin from 1974 to 1981. Antimicrob Agents Chemother 1983;23:138-41. Sorrell TC, Collignon PJ. A prospective study of adverse reactions associated with vancomycin. J Antimicrob Chemother 1985;16:235-41. Weinstein L, Madoff MA, Samet CM. The sulfonamides. N Eng J Med 1960;263:793-800 and 952-7. Beyhand F, et al. Effect of TMP-SMZ on renal secretion of creatinine in man. J Urol 1975;114:802-8. JAPI VOL. 51 OCTOBER 2003

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Transplant 1998;13:924-9. 20. Agnihotri MS, Bansal S, Kumar A. Acute renal failure due to rifampicin. Indian J Chest Dis Allied Sci 1990;32:125-8. 21. Beckmann ML, Gerber JG, Byyny RL, Loverde M, Nies AS. Propranolol increases prostacyclin synthesis in patients with hypertension. Hypertension 1988;12:582-8. 22. Seelig CB, Maloley PA, Campbell JR. Nephrotoxicity associated with concomitant ACE inhibitor and NSAID therapy. South Med J 1990;83:1144-8. 23. Pope JE, Anderson JJ, Felson DT. A meta-analysis of the effect of nonsteroidal anti-inflammatory drugs on blood pressure. Arch Int Med 1993;153:477-84. 24. Morgenstern SJ, Bruns FJ, Fraley DS, Kirsch M, Borochoitz D. Ibuprofen-associated lipoid nephrosis without interstitial nephritis. Am J Kidney Dis 1989;14:50-2. 25. Elseviers MM, De Schepper A, Corthouts R, et al. High diagnostic performance of CT scan for analgesic nephropathy in patients with incipient to severe renal failure. Kidney Int 1995;48:1316-23. 26. Komers R, Anderson S, Epstein M. Renal and cardiovascular effects of selective cyclooxygenase-2 inhibitors. Am J Kidney Dis 2001;38:1145-57. 27. Feehally J, Walls J, Mistry N, et al. Does nifedipine ameliorate cyclosporin A nephrotoxicity? Br Med J 1987;295:310. 28. Mudge GH. Nephrotoxicity of urographic radiocontrast drugs. Kidney Int 1980;18:540-52. 29. Barrett BJ, Carlisle EJ. Meta-analysis of the relative nephrotoxicity of high- and low-osmolality iodinated contrast media. Radiology 1993;188:171-8. 30. Morcos SK, Thomsen HS, Webb JA. Contrast media induced nephrotoxicity: a consensus report. Contrast Media Safety Committee, European Society of Urogenital Radiology (ESUR). Eur Radiol 1999;9:1602-13.

10. Krieble BF, Rudy DW, Glick MR, Clayman MD. Case report : Acyclovir neurotoxicity and nephrotoxicity - a role for hemodialysis. Am J Med Sci 1993;305:36-9. 11. Androcoli TE, Mohahan M. The interaction of polyene antibiotics with thin lipid membranes. J Gen Physiol 1968;52:300-25. 12. Wasan KM, Vadiei K, Lopez-Berestein G, Verani RR, Luke DR. Pentoxyphylline in amphotericin B toxicity rat model. Antimicrobial Agents Chemother 1990;34:241-4. 13. Reiner NE, Thompson WL. Dopamine and saralasin antagonism of renal vasoconstriction and oliguria caused by amphotericin B in dogs. J Infect Dis 1979;140:564-75. 14. Ohnishi A, Ohnishi T, Stevenhead W, et al. Sodium status influences chronic amphotericin-B nephrotoxicity in rats. Antimicrob Agents Chemother 1989;33:1222-7. 15. Hiemenz JW, Walsh TJ. Lipid formulations of amphotericin B: recent progress and future directions. Clinical Infect Dis 1996;22 (Suppl 2):S133-44. 16. Prakash J, Kumar NS, Saxena RK, Verma U. Acute renal failure complicating rifampicin therapy. J Assoc Physicians India 2001;49:877-80. 17. DeVriese AS, Robbrecht DL, Vanholder RC, Vogelaers DP, Lameire NH. Rifampicin-associated acute renal failure: pathophysiologic, immunologic and clinical features. Am J Kid Dis 1998;31:108-15. 18. Power DA, Russell G, Smith FW, et al. Acute renal failure due to continuous rifampicin. Lin Nephrol 1983;20:155-9. 19. Covic A, Goldsmith DJ, Segall L, et al. Rifampicin-induced acute renal failure: a series of 60 patients. Nephrol Dial

Announcement
Following are the office bearers of API-Hisar, Haryana Chapter elected for the year 2003-2004. Chairman Secretary Vice Chairman Treasurer Joint Secretary Executive Members : : : : : : : : : : AK Singh A Mahajan B Bhushan S Singh K Kishore MP Kamboj BS Jain AK Gupta S Suri A Bhatia Sd/A Mahajan Hon. Secretary,

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