Drug-Induced Nephrotoxicity Aetiology, Clinical Features and Management

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Abstract
There is a growing number of hospitalised patients who develop a drug-induced renal problem because increasing numbers of potent drugs have been added to the therapeutic arsenal in recent years. The 3 clinical syndromes that can be recognised in drug-induced nephropathy are acute renal failure, chronic interstitial nephritis and the nephrotic syndrome. The first can be caused by prerenal problems, acute interstitial nephritis, acute tubular necrosis and intratubular obstruction. The most important drugs that cause prerenal failure are NSAIDs, captopril and cyclosporin. NSAIDs inhibit the synthesis of prostaglandins, and consequently vasoconstriction of the afferent arteriole leads to lowering of the glomerular filtration rate (GFR); captopril blocks the formation of angiotensin II (which also leads to a lower GFR), and should be used with caution in patients with stenotic renal arteries; cyclosporin causes vasoconstriction of the afferent arteriole, which is probably mediated by the sympathetic system. Combinations of these drugs result in increased nephrotoxicity. The drugs most likely to cause acute interstitial nephritis are antibiotics and NSAIDs. Normally, signs of an allergic reaction are also present. Acute interstitial nephritis is usually self-limiting, but in some studies it is claimed that steroids may promote recovery. Four important causal agents of acute tubular necrosis are aminoglycosides, amphotericin B, radiocontrast agents and cyclosporin. Approximately half of the cases of drug-induced renal failure are related to the use of aminoglycosides: generally, 10 days after start of treatment a non-oliguric renal failure develops, with recovery after withdrawal of the drug in almost all cases. The aminoglycosides are particularly nephrotoxic when combined with other nephrotoxic drugs. 80% of amphotericin B-treated patients develop renal insufficiency, a percentage that increases as the cumulative dose exceeds 5g. It is because of its unique antifungal properties that there are still some indications for the use of this highly nephrotoxic drug; the high percentage of nephrotoxicity can probably be prevented in part by sodium loading. The nephrotoxicity of radiocontrast agents is largely dependent on renal function: from 0.6% in patients with normal renal function to 100% in patients with a serum creatinine above 400 μmol/L. Diabetes mellitus does not add greatly to the risk of radiocontrast nephrotoxicity. The nephrotoxicity of cyclosporin is dose-dependent and reversible, although there are some reports of irreversibility after long term use. Cyclosporin can also result in nephrotoxicity in combination therapy. Two mechanisms may be involved: some drugs increase the concentration of cyclosporin (e.g. ketoconazole), and careful monitoring is recommended; other drugs have an additive nephrotoxic effect and these combinations should not be used. Intratubular obstruction is often associated with chemotherapy, resulting in precipitation of urate, but can also be caused by precipitation of the drug itself (e.g. methotrexate). Chronic interstitial nephritis is also called analgesic nephropathy, and was formerly caused by phenacetin; paracetamol (acetaminophen), particularly in combination with other analgesics, can cause the same disease. Chronic nephritis can also be caused by cyclosporin. Drug-induced nephrotic syndrome is mostly immunologically mediated; membranous glomerulonephritis and minimal change glomerular disease are the most frequently encountered histological abnormalities. Drugs that can cause membranous glomerulonephritis are gold salts, penicillamine, captopril and mercury compounds, but after cessation of these drugs renal function recovers rapidly. Minimal change glomerular disease can be caused by NSAIDs and lithium. Nephrotic syndromes, not related to membranous glomerulonephritis or minimal change glomerular disease, can be caused by several other drugs, of which antiepileptic agents and heroin are well known. It is important to keep in mind that every renal failure of unknown origin may have been caused by drugs.