Cisplatin nephrotoxicity: experimental and clinical studies

Abstract

Cisplatin is currently one of the most used agents in the treatment of cancer and it is essential in the treatment of germ cell cancer. The use of the drug is hampered by side effects - especially renal toxicity which is dose limiting. The present work was undertaken to elucidate the pathophysiological mechanisms involved in cisplatin induced nephrotoxicity. Immediately after administration of cisplatin to dogs, renal blood flow (RBF) and glomerular filtration rate (GFR) remained unchanged, while proximal reabsorption rates decreased significantly. The cisplatin induced nephrotoxicity is thus initiated by an acute, mainly proximal tubular impairment, preceding alterations in renal hemodynamics. These data were confirmed in a micropuncture study in rats. At 48 to 72 hours after administration of cisplatin depressed renal function could be attributed to impairment of proximal as well as distal tubular reabsorptive capacities, now associated with increased renal vascular resistance. After administration of 4 cycles of 20 mg cisplatin/m2 d. for 5 days in humans, a small but significant decrease in 51Cr-EDTA clearance was observed. In the high-dose cisplatin group (40 mg/m2 d. for 5 days) a severe progressive decrease in GFR was observed during treatment and GFR remained decreased for up to 2 years after termination of treatment. The observation of an acute increase in N-acetyl-beta-D-glucosaminidase and beta-2-microglobulin indicates a primary tubular effect of cisplatin also in humans. A marked reduction of proximal tubular reabsorptive capacities of sodium and water was also observed in this group, together with a decrease in distal tubular function. These changes persist for at least 6 months after treatment. In the high-dose group proteinuria developed. This was mainly of tubular origin during cisplatin infusion and of glomerular origin between treatment cycles. Cisplatin remains one of the most potent antineoplastic agents ever developed. Further work should be performed to reduce its potential for renal toxicity.