Renal toxicity of the nonsteroidal anti-inflammatory drugs

M. D. Murray, D. C. Brater

Research output: Contribution to journalReview article

252 Scopus citations


NSAIDs pose little threat of renal insult in normal, healthy persons at therapeutic dosages. However, NSAID administration to susceptible persons may cause decrements in renal plasma flow and glomerular filtration rate within hours. Such acute noxious renal effects are mediated by products of arachidonic acid metabolism. Precipitous decrements in glomerular filtration and renal ischemia, manifested by increased serum creatinine and urea nitrogen, are possible. However, these effects are usually fully reversible with prompt discontinuation of the offending NSAID. Risk factors for the development of these acute renal effects are known. Acute interstitial nephritis with or without nephrotic syndrome is a rare form of renal toxicity that typically occurs between 2-18 months of use. Renal impairment may be so severe as to require temporary hemodialysis; however, renal function usually returns to normal upon discontinuation of the NSAID. The mechanism of acute interstitial nephritis is presumed to be of allergic origin but could also be caused by a reactive metabolite. Fenoprofen use appears to be associated with a much higher risk for its development. In contrast to the acute effects of NSAIDs, irreversible, analgesic-associated nephropathy manifested by papillary necrosis and chronic interstitial nephritis may occur following months to years of high doses of analgesic mixtures. The mechanism by which combination analgesics produce this form of renal injury is unknown and could be either a result of medullary ischemia or a direct effect of a reactive metabolite. An important issue to be resolved is the relationship between the acute, reversible, prostaglandin-mediated renal effects of the NSAIDs and chronic, irreversible destruction, if such a relationship exists. Theoretically, continual or repeated decrements in renal function in patients with predisposing risk factors could cause or contribute to progressive deterioration in renal function. Elevations in blood pressure or interference with the effects of antihypertensive medications could theoretically also contribute to long-term deterioration. In addition to renal syndromes caused by NSAIDs that result in renal impairment, other transient effects on electrolyte and water metabolism may also occur. Reduced secretion of sodium may result in formation of edema, exacerbation of heart failure, or increased blood pressure. Hyporeninemic-hypoaldosteronism may produce hyperkalemia. Finally, reduced excretion of water has rarely caused hyponatremia. It has been suggested that NSAIDs may be renoprotective in patients with nephrotic syndrome. Other have suggested that sulindac is 'renal-sparing' because of a unique metabolic pathway that supposedly limits the exposure of the kidney to the active sulfide metabolite. The detrimental effects on renal function for the patient presented in Figure 6 are not dependent on the appearance of sulindac sulfide in the urine. Instead, this effect is presumably caused by the hemodynamic effect of active drug as it traverses the glomerular vasculature. Because of such conflicting information, clinicians and patients alike are uncertain about the use of these drugs and fear renal impairment from their use. These conflicting data have also left the clinician in a quandary about the safest NSAID to prescribe for patients with diseases that predispose them to renal toxicity. This creates a major dilemma: on one hand, NSAIDs have an established record of versatility in the palliative treatment of a wide variety of painful disorders with a wide margin of safety compared to the alternative therapy such as opiate derivatives; on the other is their potential for renal toxicity. Since the mechanisms for the commonest forms of acute nephrotoxicity are understood, patients at risk can be prospectively defined. These patients can in turn benefit from closer monitoring of renal function when a NSAID is started. The therapeutic margin of these drugs can thereby be enhanced.

Original languageEnglish (US)
Pages (from-to)435-465
Number of pages31
JournalAnnual Review of Pharmacology and Toxicology
StatePublished - Apr 27 1993


  • Analgesic-associated nephropathy
  • Anti-inflammatory agents
  • Interstitial
  • Kidney failure, acute
  • Kidney failure, chronic
  • Nephritis
  • Nonsteroidal

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

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