Different classes of drugs, by virtue of immunological mechanisms or direct toxicity initiate ... increases with duration of therapy reaching 50% with 14 days2 or more of ...... effects. Chronic CS-A nephrotoxicity - Typically manifests after one year ...
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
demeclocycline, aminoglycosides, amphotericin B.
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-
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
T
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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,
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*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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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.
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Table 1: Syndromes of drug-induced kidney disease Syndrome
Clinical features
Pre-renal failure/ functional renal failure
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,
Acute tubular necrosis
Acute interstitial nephritis
Druginduced
Drugs
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 JAPI • VOL. 51 • OCTOBER 2003
crystalluria
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
levels may indicate impending nephrotoxicity. Relative toxicites (in decreasing order) Neomycin > Gentamycin > Tobramicin > Netilmicin > Amikacin > Streptomycin 971
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.
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. •
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Monitor urine output and start adequate fluid and
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
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 JAPI • VOL. 51 • OCTOBER 2003
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) < < <
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 978
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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Announcement Following are the office bearers of API-Hisar, Haryana Chapter elected for the year 2003-2004. Chairman Secretary
: :
AK Singh A Mahajan
Vice Chairman Treasurer Joint Secretary Executive Members
: : : : : : : :
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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