Cis-diamminedichlorplatinum-induced acute renal failure in the rat

Abstract

Our micropuncture studies examined the pathophysiology of the maintenance phase of cis-diamminedichlorplatinum induced (CP) acute renal failure (ARF) in rats. Nonoliguric ARF developed in 75% of the rats 96 hr after CP, 10 mg/kg i.p. Whole animal glomerular filtration rate (GFR) decreased by 88% from control; micropuncture studies of superficial proximal single nephron GFR (SNGFR) indicated a reduction of only 38% 96 hr after CP. A significant tubular fluid 'backleak' of 3H-inulin was demonstrated beyond the sites of micropuncture, resulting in the disproportionate suppression of SNGFR as compared to GFR. The morphologic basis for the failure of lissamine green to appear in distal tubules, after an i.v. or proximal intratubular injection, and for the demonstration of 'backleak' appears to be CP-induced cell injury and necrosis in the P3 segment of the proximal tubule. Loss of brush border, swollen endoplasmic reticulum, loss of intercellular junctional complexes, and epithelial cell sloughing into the tubular lumen were observed. Light and electronmicroscopic examination failed to demonstrate any abnormalities in P1 and P2 segments of proximal tubules in 7 of 9 animals. The remaining two animals had limited involvement of distal P2 segments. The increase in superficial proximal tubule fluid to plasma inulin concentration ratio (2.56 ± 0.1, as compared to 1.78 ± 0.09 in control; P<0.001) in association with a decreased tubule flow rate after CP, suggests that these nephron segments, corresponding to P1 and P2 of morphologic studies, were physiologically intact. Comparable SNGFR obtained in early and late superficial nephron segments is also evidence against significant 'backleak' in these segments. Although intratubular casts were observed in morphologic studies, intratubular hydrostatic pressure (IP) after CP was not different from control values. Intravascular volume depletion resulting from a urinary concentrating defect and decreased fluid intake was also present 96 hr after CP. Acute volume expansion with 5% Ringer's solution, adequate to return the packed red blood cell volume of the post-CP group (53 ± 1.8%) toward control values (48.8 ± 1.9%), failed to significantly increase superficial SNGFR, although whole animal GFR increased from 12 to 23% of control values. CP-induced ARF in the maintenance phase has a multifactorial pathogenesis. Tubular fluid 'backleak' and a primary decrease in glomerular filtration contribute to the decrease in GFR. The possible role of intratubular obstruction cannot be excluded. Volume expansion may more significantly affect deep nephrons after CP than superficial nephrons.