Cisplatin-induced alterations in renal structure, ammoniagenesis and gluconeogenesis of rats

Cisplatin [cis-diamminedichloroplatinum (II): CDDP] is a widely used cancer chemotherapeutic agent which has been shown to cause dose-related acute renal failure. The kidney damage is histologically characterized by widespread tubular necrosis, predominantly found in the third segments (S3) of the proximal tubules. To identify the intranephron targets of CDDP more precisely, we examined alterations in ammoniagenesis (AMG) and gluconeogenesis (GLG) using rat kidney slices (for AMG and GLG), tubule suspensions (for GLG), and microdissected nephron segments (for AMG). Ultramicroassay of AMG was carried out using the enzymatic cycling method, and GLG was measured by the HK/G6PHD method. GLG obtained from kidney slices and tubule suspensions on day 3 and day 7 following CDDP treatment did not change significantly from levels in control rats. In contrast, AMG increased on day 3 in the first and third kidney slices cut from the surface inward and decreased significantly on day 7 in the third and fourth slices. Microdissected nephron segments examined on day 7 showed decreased AMG in the second segments (S2; 20.3 +/- 7.7 pmol/mm/15 min vs. 78.7 +/- 9.7 for control, P less than 0.005) and the third segments (S3; 26.3 +/- 14.4 pmol/mm/15 min vs. 79.2 +/- 7.8 for control, P less than 0.005) of the proximal tubules. Additionally, we observed morphological changes under light microscopy to examine the relationship between metabolism and morphology. On day 3 following the CDDP treatment, typical acute tubular necrosis was seen primarily localized in the outer stripe of the outer medulla, while on day 7 the lesion appeared to be recovering. Our data imply a prominent dissociation between renal metabolic and morphologic changes induced by CDDP.