In vitro systems for nephrotoxicity studies

Abstract

A variety of in vitro systems, including the perfused kidney, microperfused nephron(s), cultured renal slices, renal tubule suspensions/cultures, isolated nephron components (glomeruli and tubule segments) and renal cell suspensions/cultures can be utilized to evaluate chemicals for their potential nephrotoxicity and mechanisms of action. These systems have varying degrees of relevance to the intact kidney or portions thereof; which model to use depends on the specific question asked. If maintenance of physiological flow conditions is important then only the perfused kidney (or tubule) can be used. If the toxicity can be studied in the absence of normal fluid flow, then the other systems may be utilized. Kidney subfractions also have the advantage of multiple biological units that can be examined simultaneously and separately. Closely defined renal slice systems allow for enrichment and evaluation of multiple target cells within the slice. Suspensions or cultures of nephron subfractions are now frequently used to assess the potency and/or mechanism of renal toxins. Disadvantages include the utilization of collagenase, which scars cell and basement membranes and affects membrane transport proteins, which leads to inadequate maintenance of transport mechanisms. Isolation of tubule segments (P 1, P 2, P 3), allows site-specific toxicity studies. Lastly, there has been a dramatic increase in renal cell culture to study toxic events in the kidney. Because of the multiple cell types, minimal availability of specific cell markers, and de-differentiation phenomena, this technique should be used with caution. These in vitro systems have allowed us to examine the role of transport and biotransformation, and to compare potency and mechanism of nephrotoxic chemicals. Although in vitro systems cannot totally duplicate or replace in vivo toxicity studies, they are a very useful and valuable complement.