The progression of cisplatin-induced tubulointerstitial nephropathy in rats

Abstract

We have previously shown that administration of cisplatin to rats leads to chronic nephropathy with many atubular glomeruli. Using unbiased stereological and histochemical methods our purpose was to investigate the progression of renal structural changes, specifically the events preceding and following the formation of atubular glomeruli in rats after increasing total doses of cisplatin. After administration of cisplatin (2 mg/kg body weight i.p. once weekly) the animals were sacrificed 10 days, three, six, 10 and 20 weeks later. After 4 mg/kg the distal part of most proximal S3 segments appeared necrotic with a negative reaction for enzymes characteristic of brush border and mitochondria. After larger doses, atrophy (and possibly necrosis) was observed in clusters of cortical proximal and distal nephron segments corresponding to an increasing amount of non-functioning nephrons. Hypertrophy/hyperplasia of remaining uninjured nephrons and collecting ducts was observed. The stereological investigations showed an increasing number of atubular glomeruli with open capillaries or glomeruli connected to atrophic tubules with the total dose of cisplatin (30% and 40%, respectively, after 20 mg/kg). The percentage of glomeruli with damaged tubules was significantly higher in the juxtamedullary cortex compared with the superficial cortex. Sclerotic glomeruli were not observed. The findings suggest that a toxic destruction of most S3 segments leads to atrophy or disappearance of the corresponding nephrons with formation of atubular glomeruli, and that the remaining hypertrophic nephrons are connected to the few surviving or regenerated S3 segments.