Temporal and Dose Specific Changes in the Morphology of Kidneys with Cisplatin Induced Nephrotoxicity in Rats

Abstract
Cisplatin, an antineoplastic drug is known nephrotoxic in both rodents and human. The efficacy is driven by adduct formation with nuclear and mitochondrial DNA and the cytotoxicity by formation of phospholipids adducts to RNA and thiol bearing proteins accumulation in tubular epithelial cells at the corticomedullary zone of kidneys. Changes in both serum renal specific markers and histology of kidneys is reported due to cisplatin administration in rats. However, scanty reports available demonstrating early and late changes of cisplatin induced nephrotoxicity evaluation using scanning electron microscope and its diagnostic importance. In this study, cisplatin was administered at 2.5 and 5 mg/kg (single dose, intraperitoneal) to male Sprague Dawley rats. On day 4 and 8 post treatment, serum samples were analyzed for clinical chemistry parameters and kidneys were observed for histology and scanning electron microscopy. Changes in serum blood urea nitrogen and creatinine were minimal on day 4 and less than 3 fold increase on day 8. Histological changes seen on day 4 and 8 were of minimal to mild and moderate to severe in nature at both doses, respectively. Scanning electron microscopic evaluations revealed increased periglomerular space, shrunken glomeruli, wrinkled surface of tubules and presence of minimal cast at 2.5 mg/kg; edematous and degenerated glomeruli with increased periglomerular space, wrinkled surface area, presence of granular material and degenerated tubules at 5.0 mg/kg on Day 4. On day 8, the changes seen were tubular degeneration, increased periglomerular area, shrunken tubules, inflammatory cell infiltration, presence of cellular debris at 2.5 mg/kg; severe tubular degeneration, increased periglomerular area, glomerular degeneration, diffuse presence of cellular debris and cast at 5.0 mg/kg. In conclusion, scanning electron microscopic changes have better diagnostic importance in evaluating changes in certain anatomic structures (e.g., glomeruli) at an early damage to kidneys caused by low dose of cisplatin, which was not detected through traditional serum biomarkers or histology. Scanning electron microscopy is comparable to traditional serum markers or histology in late stage damage induced by cisplatin in rats at the tested dose levels in this study.