COMBINATION ANALGESIC-INDUCED KIDNEY-DISEASE - THE AUSTRALIAN EXPERIENCE

Analgesic nephropathy is a unique drug-induced kidney disease characte rized pathologically by renal papillary necrosis and chronic interstit ial nephritis, and is the result of excessive consumption of combinati on antipyretic analgesics, The clinical features of the disorder relat e mainly to the papillary necrosis, renal colic, and obstructive uropa thy and the development of chronic renal failure in a small percentage of patients, There are significant geographic variations in the clini cal features that may be related to the differing combinations of anal gesics. The pathogenesis of the disease is in part related to the kidn eys' ability to concentrate drugs in the papillae. The following seque nce of events presents a plausible explanation for the evolution of th e disease, If a combination of phenacetin and aspirin is ingested, the following steps occur, Phenacetin is converted in the gut and liver t o acetaminophen by first-pass metabolism. Acetaminophen is then taken up by the kidney and excreted, During its excretion, acetaminophen bec omes concentrated in the papillae of the kidney during physiologic deg rees of antidiuresis, the concentration being up to five times the int racellular concentration of other tissues, Acetaminophen undergoes oxi dative metabolism by prostaglandin H synthase to a reactive quinoneimi ne that is conjugated to glutathione, If acetaminophen is present alon e, there is sufficient glutathione generated in the papillae to detoxi fy the reactive intermediate, If the acetaminophen is ingested with as pirin, the aspirin is converted to salicylate and salicylate becomes h ighly concentrated in both the cortex and papillae of the kidney, Sali cylate is a potent depletor of glutathione. The mechanism is not compl etely understood; however, the inhibition of the production of NADPH v ia the pentose shunt is a possible explanation, With the cellular glut athione depleted, the reactive metabolite of acetaminophen then produc es lipid peroxides and arylation of tissue proteins, ultimately result ing in necrosis of the papillae. (C) 1996 by the National Kidney Found ation, Inc.