The Mechanistic Basis of Chemical- and Drug-Induced Nephrotoxicity

Abstract

Nephrotoxicity is a costly health problem (CEC/IPCS, 1989) that arises from exposure to environmental pollutants, industrial chemicals and a broad array of therapeutic agents (see Porter, 1982; Bach and Lock, 1987, 1989; Bach et al., 1988, 1990). These clinical nephropathies have, therefore, been studied extensively in animal models with a view to understanding their molecular basis. All too often in the past, however, lesions of clinical relevance have been documented in terms of gross functional changes (such as elevated serum creatinine, blood urea nitrogen, etc.), and advanced morphological degeneration, i.e. end-stage renal disease, using relatively non-specific histological staining such as Haematoxylin and Eosin. Such information is of little value in understanding renal lesions because mechanistic studies need subtle, early effects to be documented. Many nephrotoxic affect discrete anatomical regions of the kidney, while some of these substances damage only specific renal cell types. This concept of target cell toxicity is important to study the mechanisms of nephrotoxicity, as the basis of such discrete injury suggests that there are biochemical characteristics which predispose these cells to the toxic effects of certain chemicals, while the properties of the unaffected cells protect them or make them less susceptible. Sensitive and highly selective methods are necessary to study the molecular basis of injury to the affected region of the kidney and the time-course of injury and recovery.