Mechanisms in the development of analgesic nephropathy

Abstract

Clinical and epidemiologic evidence indicates that analgesic nephropathy results from the excessive consumption of combination analgesics, especially those containing paracetamol (acetaminophen) or its analog, phenacetin. The most common analgesic combination currently producing the disease in Australia contains aspirin and paracetamol. To elucidate the mechanism of the disease, a systematic series of studies have been undertaken to examine the renal excretory mechanisms, intrarenal concentration and distribution, and renal metabolism of these drugs. Paracetamol undergoes glomerular filtration and is passively reabsorbed by the tubules. The drug becomes concentrated in the renal medulla during antidiuresis, achieving a concentration approximately five to seven times that achieved in the renal cortex or plasma. Phenacetin does not achieve a concentration in the medulla greater than that in the renal cortex or the plasma. Aspirin and salicylate undergo proximal renal tubular secretion by the organic anion secretory system. Both are reabsorbed by the distal nephron by nonionic diffusion and become concentrated in the medulla during antidiuresis. In the case of aspirin, paracetamol, and salicylate, all three, in addition to becoming concentrated in the medulla in antidiuresis, are distributed within the intracellular compartment of that region. Many of the biochemical events that could lead to papillary necrosis have been defined. Salicylate depletes cellular glutathione in the kidney, but the mechanism producing this change is, as yet, unclear. Paracetamol becomes metabolized to a highly reactive intermediate by both a NADPH-dependent and a NADPH-independent mechanism, and this intermediate (or intermediates) subsequently covalently binds to tissue proteins when glutathione concentrations are reduced. In addition, aspirin directly acetylates kidney proteins but the consequences of this reaction are not known as far as nephrotoxicity is concerned. Thus, the combination of salicylate and paracetamol may be synergistic in increasing covalent binding. This process, if repeated daily, could lead to sufficient covalent binding to produce cell death and the disease state of analgesic nephropathy.