Cis-Diamminedichloroplatinum (II)-induced Acute Renal Failure in the Rat: Enzyme Histochemical Studies

Abstract

Enzyme histochemical techniques were utilized to examine the progression and extent of proximal tubular injury during the development of cis-diamminedichloroplatinum (II) (CDDP)-induced acute renal failure. Acute renal failure was induced in male rats by the intraperitoneal administration of 10 mg CDDP/kg body weight. At 6, 24, 48, 72, and 96 hr following treatment, renal function was assessed and tissue was collected for renal morphologic and enzyme histochemical studies. The enzymes examined were gamma-glutamyl transpeptidase, alkaline phosphatase, sodium-potassium ATPase (nitrophenyl phosphatase), acid phosphatase, glucose-6-phosphatase, succinic dehydrogenase, alpha-glycerophosphate dehydrogenase, and lactic dehydrogenase. By 24 hr, the activity of acid phosphatase was reduced throughout the proximal tubule, with the greatest decrease occurring in the P3 segment of the proximal tubule located in the outer stripe of the outer medulla. Changes in the histochemical staining of the remaining enzymes were not consistently observed until 48 or, in some cases, 72 hr. These alterations involved all portions of the proximal tubule with the most severe changes involving P3. The results of the enzyme histochemical studies along with the morphologic findings indicating that the initiation of CDDP-induced acute renal failure, first apparent at 48 hr in this model, is associated with cell injury throughout the proximal tubule. The majority of the histochemical changes did not become apparent until late in the course of tubular injury. This suggests that most of the changes in enzyme activity represent nonspecific effects of CDDP-induced tubular injury, as opposed to direct enzyme inhibition by the drug.

Participation of Different Macrophage Populations and Myofibroblastic Cells in Chronically Developed Renal Interstitial Fibrosis after Cisplatin-induced Renal Injury in Rats

“…21,46 Thus, CDDP-induced lesions are characterized by necrosis or degeneration or both of renal tubular epithelial cells in the corticomedullary junction and subsequent dilatation of the affected tubules. 21,46 The present study confirmed our previous report 42 of progressive renal interstitial fibrosis in the corticomedullary junction at the early stages in this model. However, more interestingly, all renal damages were repaired during the long-term observation period of 19 weeks after the cessation of CDDP injection by a reduction in fibrotic tissues and by replacing regenerated renal tubules.…”

Isoliquiritigenin Inhibits Tumor Growth and Protects the Kidney and Liver Against Chemotherapy-Induced Toxicity in a Mouse Xenograft Model of Colon Carcinoma

“…Despite its profound chemotherapeutic properties, the clinical use of cisplatin is frequently limited by severe nephrotoxicity (3,4). Cisplatin-induced nephrotoxicity is associated with increased renal vascular resistance and morphological damage to the intracellular organelles, including cellular necrosis, loss of microvilli, changes in the number and size of lysosomes, and mitochondrial vacuolization (5). Other less frequently observed toxic effects, including hepatotoxicity, occur and adversely affect patients to whom high doses of cisplatin were administered (6).…”

Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumour activity

“…Creatinine is filtered in the glomerulus, but tubular backleak of creatinine, following, for example, tubular obstruction, can also occur. However, backleak does not play a role in this early stage of nephropathy in the animal model studied (Jones et al, 1985). Excretion of the tubular enzyme alanine-aminopeptidase (AAP) served as an indicator of proximal tubular function (Pfleiderer et al, 1980;Fels et al, 1994).…”

“…The effects of DDP on renal function have been extensively studied in animal models. In a rat model the type of DDP nephrotoxicity seems similar to humans, affecting different segments of the nephron, such as the tubular apparatus and the glomerulus (Jones et al, 1985;Safirstein et al, 1981). Impaired transport processes occur at the luminal and to a lesser degree at the contra-luminal side of the proximal tubular membrane and morphological examinations have revealed necrotic cells in the proximal tubules (Ammer et al, 1993;Field et al, 1989).…”