Nephrotoxicity of nonsteroidal anti-inflammatory drugs: Focus on selective cyclooxygenase-2 (COX-2) inhibitors

Steven G. Coca, Mark A. Perazella

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

Abstract

Traditional (non-selective) NSAIDs cause nephrotoxicity through inhibition of cyclooxygenase (COX) activity and prostaglandin formation in the kidney. Patients with prostaglandin-dependent disease states are the group at most risk for this adverse effect. It has become apparent that the COX-2 enzyme isoform is constitutively expressed and upregulated in the human kidney during states of renal stress. COX-2 derived prostaglandins importantly modulate renal blood flow and glomerular filtration rate as well as sodium, potassium and water excretion by the kidney. As a result, clinical renal syndromes induced by the selective COX-2 inhibitors are quite similar to those described with the traditional NSAIDs, suggesting that COX-2 derived prostaglandins are important in maintaining normal renal function. Inhibition of prostaglandins causes a reduction in renal blood flow and acute renal failure in patients with predisposing conditions. These include true volume depletion from nausea/vomiting, diarrhea and excessive diuretic therapy. Effective volume depletion from clinical disease states such as heart failure, cirrhosis, and nephrotic syndrome as well as diseases such as chronic kidney disease and renal artery stenosis also portend risk of acute renal failure from prostaglandin inhibition. Prostaglandins also modulate renal potassium excretion through stimulation of the renin-angiotensin-aldosterone system. Inhibition of prostaglandins can result in hyperkalemia when co-existent conditions such as renal failure, diabetes mellitus and therapy with certain medications (ACE inhibitors, angiotensin receptor blockers, potassium-sparing diuretics) are also present. The classic syndrome of hyporeninemic hypoaldosteronism with a type-4 renal tubular acidosis (RTA) picture (hyperkalemic metabolic acidosis) can be observed when selective COX-2 inhibitor therapy is superimposed. Inhibition of prostaglandins is associated with decreased renal sodium and water excretion and all NSAIDs, including the selective COX-2 inhibitors cause some degree of sodium retention. All patients suffer from this effect, but only patients with certain clinical conditions develop obvious edema, hypertension or heart failure. Patients with underlying hypertension (especially those on antihypertensive medications), heart disease and other salt-retentive disease states (cirrhosis, nephrosis, renal failure) are at highest risk for these complications. Hypertension is a particularly important complication of these drugs as small changes in blood pressure are associated with increased cardiovascular events. Hyponatremia from impaired water excretion also complicates therapy. Less commonly, acute interstitial nephritis (with or without a glomerulopathy) has been described with these drugs. To reduce adverse renal effects from NSAIDs, including all of available the selective COX-2 inhibitors, identification of patients with renal risk should be undertaken. Defining patient risk profiles based on level of kidney function (stage of chronic kidney disease) as well as on the presence of certain co morbidities (hypertension, heart failure, diabetes mellitus, liver disease/cirrhosis, electrolyte imbalance, old age, certain medications) is one simple approach that can be taken. Based on the renal risk, recommendations for therapy and monitoring can be utilized in a rational fashion.

Original languageEnglish
Title of host publicationCox-2 Inhibitor Research
PublisherNova Science Publishers, Inc.
Pages145-180
Number of pages36
ISBN (Electronic)9781616681142
ISBN (Print)9781594549946
StatePublished - 1 Jan 2006
Externally publishedYes

Keywords

  • Acute interstitial nephritis
  • Acute renal failure
  • Cyclooxygenase (COX)
  • Edema
  • Hyperkalemia
  • Hypertension
  • Hyponatremia
  • Nonsteroidal anti inflammatory drugs (NSAIDs)
  • Selective COX-2 inhibitors

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