Hotline Archive - Risk of Renal Failure With Analgesic Use
December 1994
In a recent article referenced by the Washington Post and other popular media, T.V. Perneger et al reported in the New England Journal of Medicine (331:1675-1679) that the use of certain types of analgesics may be associated with end stage renal disease (ESRD). They did a case control study involving 716 patients with ESRD. The patients were age 26-64 years, had a telephone, and were drawn from the general population in three mideastern states and the District of Columbia. The 361 control subjects were selected by random-digit dialing. They found that heavy average intake (more than 1 pill per day) and medium to high cumulative intake (1000 or more pills in a lifetime) of acetaminophen appeared to double the odds of ESRD. These investigators reported that reduced consumption of acetaminophen could decrease the overall incidence of ESRD by approximately 8-10% at a potential savings of $500 million to $700 million in costs for ESRD care each year. They detected no increase in the risk of renal failure among daily users of NSAIDs. On the other hand, they found a steep increase in the odds of ESRD in persons who consumed 5000 or more pills containing NSAIDs during their lifetime, although this finding is based on few observations. Aspirin was not associated with ESRD.
While of considerable interest, this study has a number of significant flaws. The investigators asked only if the patients took acetaminophen before dialysis and did not determine if acetaminophen was taken before they developed renal disease. The case patients and control subjects differed significantly with respect to sex and race. The study did not take into account that acetaminophen is the most common analgesic recommended for patients with renal disease. In addition, memory recall bias is a potentially significant problem when record documentation is not possible. The relationship of acetaminophen to ESRD associated with other diseases (diabetes, hypertension, etc.) was not clearly delineated.
There is no question that drugs can cause renal injury. Drugs cause renal injury by a toxic effect on renal vascularity (leading to vasoconstriction and ischemia), on tubular epithelial cells or non-dose-related immunologic mechanism. In dose dependent toxicity as proposed above, non-immunologic mechanisms are probably important. After administration of acetaminophen, its metabolites, especially p-aminophenol, are concentrated in the hypertonic renal papillae. This accumulation may explain the occurrence of papillary necrosis as a hallmark of analgesic-induced nephropathy. The long-term renal toxicity of NSAIDs may be caused by persistent inhibition of prostaglandin synthesis, leading to renal medullary ischemia or by acute allergic interstitial nephritis.
Another study reported recently by Whitcomb and Block in the Journal of the American Medical Association stated that hepatoxicity due to acetaminophen after greater than recommended doses may be enhanced by fasting and alcohol. None of these patients used the product as recommended (4 grams/day or less). An associated editorial by Brian Strom from the University of Pennsylvania pointed out that acetaminophen is the OTC analgesic and antipyretic associated with the lowest risk of adverse reaction, even in alcoholic and fasting patients, and that if patients switched to salicylates or NSAIDs, the number of cases of acetaminophen induced hepatotoxicity that would be prevented would be dwarfed by the number of excess deaths from gastrointestinal bleeding. It would be helpful to know the rate of renal insufficiency and hepatotoxicity in a large number of patients taking the recommended amount of acetaminophen, NSAIDs and aspirin before concluding that one drug is safer than the other. Furtiler studies are necessary to establish the safest recommendations.
December 29, 1994
Prepared by Robert Thoburn, MD, and Paul Katz,
MD, editors.
This Hotline is provided by the American College of Rheumatology Communications and Marketing Group as an information service for members. This Hotline does not represent a position statement of the College.
