In common clinical usage nonsteroidal anti-inflammatory drugs infrequently produce adverse effects on the kidney.

Abstract

EACH DAY, well over 5 million people are exposed to various nonsteroidal antiinflammatory drugs (NSAIDs) in the United States. This figure derives from data on naproxen, sulindac, indomethacin, ibuprofen, benoxaprofen, piroxicam and other nonsteroidal drugs. 1 The number is clearly an underestimate since it does not include aspirin. Moreover, we know that about one percent of the population have rheumatoid arthritis (2.3 million) while another one percent has spondylarthritis. 2 Of the several million more who have degenerative joint disease, many are receiving daily NSAIDs. To these must be added the many individuals who regularly take aspirin for poorly defined reasons, ingesting, together, hundreds of tons per year. In one recent survey, some ten percent of patients admitted over a one-week period to a Veterans Administration Hospital were taking NSAIDs.3 How many of these individuals are at risk for nephrotoxicity from these agents? Opinion is roughly divided between those who assume the risk is virtually nil (they divide the vast denominator at risk by the tiny number of case reports) and those who consider that nonsteroidals are guilty, (they rememeber the anecdotes and have a particularly sensitive appreciation of renal physiology) until proved innocent! Few people take the middle ground. In this debate, we are more fortunate than in many other biomedical discussions. We do have the facts. It is now well-recognized that prostaglandins are important modulators of the hemodynamic and excretory functions of the kidney. These unsaturated fatty acids are synthesized from arachidonate precursors, a process regulated by intrarenal factors, circulating angiotensin II, catecholamines, vasopressin, bradykinin and, no doubt, other chemicals (4). Salt and water excretion is modified by the effects of prostaglandins on glomerular filtration rate, proximal tubal fluid reabsorption, medullary solute gradients, and the water and ion reabsorptive properties of distal nephron segments. Likewise, prostaglandins mediate renin release under normal conditions and, particularly, in response to intravascular volume depletion. In a variety of clinical disorders, renal prostaglandins are considered to be abnormal. These processes include hypertension, ureteral obstruction, Bartter's syndrome, hypokalemic nephropathy, and drug-induced disorders of water metabolism. Nevertheless, it should be stressed that there is not a consensus concerning the physiologic importance of the prostaglandin system on renal function. This results from the technical and physiological problems in defining the role of renal prostaglandins. 5 At issue is the role of prostaglandins in the maintenance of normal renal function in normal individuals, as compared to their action to maintain renal function in individuals with renal compromise. Most investigators agree that the prostaglandins become progressively more active with deteriorating renal function. What role do NSAIDs have in complicated clinical situations? The renal effects of drugs that inhibit prostaglandin synthesis have been debated for several years. It must be remembered that it is dangerous to extrapolate from the in vitro situation to the in vivo condition, or from extrarenal location to the kidney. For example, acetylsalicylic acid acetylates platelet cyclooxygenase irreversibly, resulting in inhibition for the life of the cell. By contrast, renal cyclooxygenase turnover, is rapid and aspirinmediated inhibition disappears within 48 hr. fi The other NSAIDs inhibit cyclo-oxygenase reversibly and disassociate from the cyclooxygenase molecule resulting in inhibitory effects that are progressively attenuated over