Detection of chemically induced renal injury: the cascade of degenerative morphological and functional changes that follow the primary nephrotoxic insult and evaluation of these changes by in-vitro methods

Abstract

A diversity of chemicals cause discrete lesions in the kidney by a number of different mechanisms, and similar types of chemicals may give rise to more than one target cell injury. Screening for these lesions in vivo may be unreliable if a single noninvasive or invasive criterion is used. Instead, evidence of nephrotoxicity must be based on an array of tests, applied over a period of time. These should include biochemical, pathological and histochemical tests conducted in tandem. A primary toxic injury to the kidney may give rise to recovery, to permanently altered functional reserve or to a clinically identifiable effect, such as acute or chronic renal failure or malignancy. These clinical effects occur as a result of a cascade of degenerative changes which are a consequence of a primary lesion but also affect other parts of the kidney. A number of factors can modulate the progression of the primary insult to the end-effect. In-vitro nephrotoxicity screening is also difficult, but a rational approach can be based on current understanding of how chemicals target for and damage cells in anatomically well-defined regions of the kidney. In-vitro techniques can provide answers to specific questions about the mechanisms by which chemicals damage these discrete cell types. It is essential that a number of different in-vitro systems be developed in parallel to address the mechanistic aspects and screening of nephrotoxicity properly. Data generated in vitro must be related to the situation in vivo and used to devise reliable noninvasive tests for assessing nephrotoxicity in man