The responsible analgesics often included a mixture of different substances, including phenacetin, acetaminophen (phenacetin’s major metabolite), and other agents such as NSAIDs, codeine, aspirin, and caffeine. Although there was no direct evidence that phenacetin was the main agent responsible for disease, multiple case series aroused enough suspicion to cause this substance to be banned in Europe in the 1970s and in the United States in 1983. Following this ban, the incidence of analgesic nephropathy has been reported to have decreased; however, variable reporting and difficulties in diagnosis have made this hard to confirm. Moreover, experimental models and clinical case series have illustrated the toxic potential of other analgesics, including acetaminophen, NSAIDs, and aspirin.

Analgesic nephropathy (AN) can serve as a model for the pathogenesis of CTIN. Although the exact mechanism remains incompletely understood, it appears that toxic metabolites are reabsorbed by tubular cells and accumulate. When there is an inadequate supply of reducing agents, these metabolites cause oxidative injury. This injury is most pronounced in the renal papilla, where blood flow and oxygen tension are low. When analgesic combinations include an inhibitor of prostaglandin synthesis, such as aspirin, the resulting renal vasoconstriction can predispose the papilla to ischemia and ultimately necrosis. Although papillary necrosis is characteristic of analgesic nephropathy it is not specific because it can also occur in diabetes (see Plate 4-45), sickle cell anemia, urinary tract obstruction (see Plate 6-1), and renal tuberculosis (see Plate 5-10).