- Didier Portilla, MD
Didier Portilla, MD
- Professor of Medicine
- University of Virginia
- A Mazin Safar, MD
A Mazin Safar, MD
- Associate Professor of Medicine
- University of Arkansas for Medical Sciences
- Melissa L Shannon, MD
Melissa L Shannon, MD
- Staff Physician
- Catholic Health Initiatives
- St Vincent Health System
- Richard T Penson, MD, MRCP
Richard T Penson, MD, MRCP
- Associate Professor of Medicine
- Harvard Medical School
Cisplatin is a potent and valuable chemotherapy agent used to treat a broad spectrum of malignancies. Renal tubular dysfunction and a cumulative impairment in renal function, as manifested by a decline in the glomerular filtration rate (GFR), can be dose limiting. The laboratory observation that forced hydration and diuresis may prevent nephrotoxicity facilitated the subsequent clinical development of cisplatin [1-3].
Cisplatin-induced renal toxicity is reviewed here. The use of cisplatin in patients with pre-existing renal dysfunction and the renal effects of the platinum analogs, carboplatin and oxaliplatin, are discussed elsewhere. (See "Chemotherapy-related nephrotoxicity and dose modification in patients with renal insufficiency".)
Multiple mechanisms contribute to renal dysfunction following exposure to cisplatin. These include tubular epithelial cell toxicity, vasoconstriction in the renal microvasculature, and proinflammatory effects.
Cellular toxicity — Cisplatin is a potent cellular toxin, particularly in a low-chloride environment. In the interior of cells, chloride atoms in cisplatin are replaced by water molecules. This hydrolysis product is believed to be the active species, reacting with glutathione in the cytoplasm and DNA in the nucleus . In tumors and other dividing cells, cisplatin-DNA intrastrand crosslinks result in cytotoxicity . These molecular events are thought to be responsible for arresting cancer cell proliferation. More than 50 percent of the drug is excreted in the urine in the first 24 hours following cisplatin administration, and the concentration of platinum achieved in the renal cortex is several-fold greater than that in plasma and other organs [6,7]. Cisplatin primarily injures the S3 segment of the proximal tubule, causing a decrease in the glomerular filtration rate (GFR) .
Experimental studies suggest that basolateral drug transporters play a role in cisplatin uptake . Changes in expression of proximal tubule organic cation transporter-2 (OCT2) have been shown to mediate the accumulation of cisplatin in proximal tubular epithelial cells, which suggests a key role for OCT2 in the development of cisplatin-mediated nephrotoxicity [10-12].
- Cvitkovic E, Spaulding J, Bethune V, et al. Improvement of cis-dichlorodiammineplatinum (NSC 119875): therapeutic index in an animal model. Cancer 1977; 39:1357.
- Gonzales-Vitale JC, Hayes DM, Cvitkovic E, Sternberg SS. The renal pathology in clinical trials of cis-platinum (II) diamminedichloride. Cancer 1977; 39:1362.
- Hayes DM, Cvitkovic E, Golbey RB, et al. High dose cis-platinum diammine dichloride: amelioration of renal toxicity by mannitol diuresis. Cancer 1977; 39:1372.
- Boulikas T, Vougiouka M. Cisplatin and platinum drugs at the molecular level. (Review). Oncol Rep 2003; 10:1663.
- Galea AM, Murray V. The interaction of cisplatin and analogues with DNA in reconstituted chromatin. Biochim Biophys Acta 2002; 1579:142.
- Litterst CL, Torres IJ, Guarino AM, et al. Plasma levels and organ distribution of platinum in the rat, dog, and dog fish following intravenous administration of cis-DDP (II). J Clin Hematol Oncol 1977; 7:169.
- Safirstein R, Miller P, Guttenplan JB. Uptake and metabolism of cisplatin by rat kidney. Kidney Int 1984; 25:753.
- Dobyan DC, Levi J, Jacobs C, et al. Mechanism of cis-platinum nephrotoxicity: II. Morphologic observations. J Pharmacol Exp Ther 1980; 213:551.
- Urakami Y, Okuda M, Masuda S, et al. Functional characteristics and membrane localization of rat multispecific organic cation transporters, OCT1 and OCT2, mediating tubular secretion of cationic drugs. J Pharmacol Exp Ther 1998; 287:800.
- Yokoo S, Yonezawa A, Masuda S, et al. Differential contribution of organic cation transporters, OCT2 and MATE1, in platinum agent-induced nephrotoxicity. Biochem Pharmacol 2007; 74:477.
- Filipski KK, Loos WJ, Verweij J, Sparreboom A. Interaction of Cisplatin with the human organic cation transporter 2. Clin Cancer Res 2008; 14:3875.
- Choi MK, Song IS. Organic cation transporters and their pharmacokinetic and pharmacodynamic consequences. Drug Metab Pharmacokinet 2008; 23:243.
- Luke DR, Vadiei K, Lopez-Berestein G. Role of vascular congestion in cisplatin-induced acute renal failure in the rat. Nephrol Dial Transplant 1992; 7:1.
- Winston JA, Safirstein R. Reduced renal blood flow in early cisplatin-induced acute renal failure in the rat. Am J Physiol 1985; 249:F490.
- Ramesh G, Reeves WB. TNF-alpha mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. J Clin Invest 2002; 110:835.
- Ramesh G, Reeves WB. p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice. Am J Physiol Renal Physiol 2005; 289:F166.
- Kelly KJ, Meehan SM, Colvin RB, et al. Protection from toxicant-mediated renal injury in the rat with anti-CD54 antibody. Kidney Int 1999; 56:922.
- Li S, Gokden N, Okusa MD, et al. Anti-inflammatory effect of fibrate protects from cisplatin-induced ARF. Am J Physiol Renal Physiol 2005; 289:F469.
- Liu M, Chien CC, Burne-Taney M, et al. A pathophysiologic role for T lymphocytes in murine acute cisplatin nephrotoxicity. J Am Soc Nephrol 2006; 17:765.
- Ramesh G, Reeves WB. TNFR2-mediated apoptosis and necrosis in cisplatin-induced acute renal failure. Am J Physiol Renal Physiol 2003; 285:F610.
- Faubel S, Ljubanovic D, Reznikov L, et al. Caspase-1-deficient mice are protected against cisplatin-induced apoptosis and acute tubular necrosis. Kidney Int 2004; 66:2202.
- Zhang B, Ramesh G, Norbury CC, Reeves WB. Cisplatin-induced nephrotoxicity is mediated by tumor necrosis factor-alpha produced by renal parenchymal cells. Kidney Int 2007; 72:37.
- Portilla D, Kaushal GP, Basnakian AG. Recent progress in the pathophysiology of acute renal failure. In: Principles of Molecular Medicine, 2nd ed., Runge MS, Patterson C (Eds), Humana Press, Totawa, NJ 2006. p.643.
- Xu EY, Perlina A, Vu H, et al. Integrated pathway analysis of rat urine metabolic profiles and kidney transcriptomic profiles to elucidate the systems toxicology of model nephrotoxicants. Chem Res Toxicol 2008; 21:1548.
- Townsend DM, Deng M, Zhang L, et al. Metabolism of Cisplatin to a nephrotoxin in proximal tubule cells. J Am Soc Nephrol 2003; 14:1.
- Baliga R, Ueda N, Walker PD, Shah SV. Oxidant mechanisms in toxic acute renal failure. Drug Metab Rev 1999; 31:971.
- Davis CA, Nick HS, Agarwal A. Manganese superoxide dismutase attenuates Cisplatin-induced renal injury: importance of superoxide. J Am Soc Nephrol 2001; 12:2683.
- Masuda H, Tanaka T, Takahama U. Cisplatin generates superoxide anion by interaction with DNA in a cell-free system. Biochem Biophys Res Commun 1994; 203:1175.
- Tanaka-Kagawa T, Kitahara J, Seko Y, et al. Reduced sensitivity of HeLa cells to cis-platinum by simultaneous overexpression of copper, zinc-superoxide dismutase and catalase. Biochem Pharmacol 1999; 57:545.
- Appenroth D, Fröb S, Kersten L, et al. Protective effects of vitamin E and C on cisplatin nephrotoxicity in developing rats. Arch Toxicol 1997; 71:677.
- Lieberthal W, Triaca V, Levine J. Mechanisms of death induced by cisplatin in proximal tubular epithelial cells: apoptosis vs. necrosis. Am J Physiol 1996; 270:F700.
- McGinness JE, Proctor PH, Demopoulos HB, et al. Amelioration of cis-platinum nephrotoxicity by orgotein (superoxide dismutase). Physiol Chem Phys 1978; 10:267.
- Nowak G. Protein kinase C-alpha and ERK1/2 mediate mitochondrial dysfunction, decreases in active Na+ transport, and cisplatin-induced apoptosis in renal cells. J Biol Chem 2002; 277:43377.
- Portilla D, Li S, Nagothu KK, et al. Metabolomic study of cisplatin-induced nephrotoxicity. Kidney Int 2006; 69:2194.
- Abdel-Gayoum AA, El-Jenjan KB, Ghwarsha KA. Hyperlipidaemia in cisplatin-induced nephrotic rats. Hum Exp Toxicol 1999; 18:454.
- Li S, Wu P, Yarlagadda P, et al. PPAR alpha ligand protects during cisplatin-induced acute renal failure by preventing inhibition of renal FAO and PDC activity. Am J Physiol Renal Physiol 2004; 286:F572.
- Nagothu KK, Bhatt R, Kaushal GP, Portilla D. Fibrate prevents cisplatin-induced proximal tubule cell death. Kidney Int 2005; 68:2680.
- Negishi K, Noiri E, Sugaya T, et al. A role of liver fatty acid-binding protein in cisplatin-induced acute renal failure. Kidney Int 2007; 72:348.
- Wittes RE, Brescia F, Young CW, et al. Combination chemothereapy with cis-diamminedichloroplatinum (II) and bleomycin in tumors of the head and neck. Oncology 1975; 32:202.
- Vasey PA. "Dose dense" chemotherapy in ovarian cancer. Int J Gynecol Cancer 2005; 15 Suppl 3:226.
- Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York 2001. p.120.
- Kim SW, Lee JU, Nah MY, et al. Cisplatin decreases the abundance of aquaporin water channels in rat kidney. J Am Soc Nephrol 2001; 12:875.
- Ciarimboli G, Ludwig T, Lang D, et al. Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2. Am J Pathol 2005; 167:1477.
- Jackson AM, Rose BD, Graff LG, et al. Thrombotic microangiopathy and renal failure associated with antineoplastic chemotherapy. Ann Intern Med 1984; 101:41.
- Schilsky RL, Anderson T. Hypomagnesemia and renal magnesium wasting in patients receiving cisplatin. Ann Intern Med 1979; 90:929.
- Lam M, Adelstein DJ. Hypomagnesemia and renal magnesium wasting in patients treated with cisplatin. Am J Kidney Dis 1986; 8:164.
- Sutton RA, Walker VR, Halabe A, et al. Chronic hypomagnesemia caused by cisplatin: effect of calcitriol. J Lab Clin Med 1991; 117:40.
- Lajer H, Kristensen M, Hansen HH, et al. Magnesium depletion enhances cisplatin-induced nephrotoxicity. Cancer Chemother Pharmacol 2005; 56:535.
- Goldstein RS, Mayor GH, Rosenbaum RW, et al. Glucose intolerance following cis-platinum treatment in rats. Toxicology 1982; 24:273.
- Goldstein RS, Mayor GH, Gingerich RL, et al. The effects of cisplatin and other divalent platinum compounds on glucose metabolism and pancreatic endocrine function. Toxicol Appl Pharmacol 1983; 69:432.
- Oeffinger KC, Hudson MM. Long-term complications following childhood and adolescent cancer: foundations for providing risk-based health care for survivors. CA Cancer J Clin 2004; 54:208.
- Koch Nogueira PC, Hadj-Aïssa A, Schell M, et al. Long-term nephrotoxicity of cisplatin, ifosfamide, and methotrexate in osteosarcoma. Pediatr Nephrol 1998; 12:572.
- Hartmann JT, Fels LM, Knop S, et al. A randomized trial comparing the nephrotoxicity of cisplatin/ifosfamide-based combination chemotherapy with or without amifostine in patients with solid tumors. Invest New Drugs 2000; 18:281.
- Hutchison FN, Perez EA, Gandara DR, et al. Renal salt wasting in patients treated with cisplatin. Ann Intern Med 1988; 108:21.
- Cao L, Joshi P, Sumoza D. Renal salt-wasting syndrome in a patient with cisplatin-induced hyponatremia: case report. Am J Clin Oncol 2002; 25:344.
- Wood PA, Hrushesky WJ. Cisplatin-associated anemia: an erythropoietin deficiency syndrome. J Clin Invest 1995; 95:1650.
- Reece PA, Stafford I, Russell J, et al. Creatinine clearance as a predictor of ultrafilterable platinum disposition in cancer patients treated with cisplatin: relationship between peak ultrafilterable platinum plasma levels and nephrotoxicity. J Clin Oncol 1987; 5:304.
- Hartmann JT, Kollmannsberger C, Kanz L, Bokemeyer C. Platinum organ toxicity and possible prevention in patients with testicular cancer. Int J Cancer 1999; 83:866.
- Siegert W, Beyer J, Strohscheer I, et al. High-dose treatment with carboplatin, etoposide, and ifosfamide followed by autologous stem-cell transplantation in relapsed or refractory germ cell cancer: a phase I/II study. The German Testicular Cancer Cooperative Study Group. J Clin Oncol 1994; 12:1223.
- Kemp G, Rose P, Lurain J, et al. Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer. J Clin Oncol 1996; 14:2101.
- de Jongh FE, van Veen RN, Veltman SJ, et al. Weekly high-dose cisplatin is a feasible treatment option: analysis on prognostic factors for toxicity in 400 patients. Br J Cancer 2003; 88:1199.
- de Jongh FE, Verweij J, Loos WJ, et al. Body-surface area-based dosing does not increase accuracy of predicting cisplatin exposure. J Clin Oncol 2001; 19:3733.
- Stark JJ, Howel SB. Nephrotoxicity of cis-platinum (II) dichlorodiammine. Clin Pharmacol Ther 1978; 23:461.
- Castiglione F, Dalla Mola A, Porcile G. Protection of normal tissues from radiation and cytotoxic therapy: the development of amifostine. Tumori 1999; 85:85.
- Capizzi RL. Amifostine reduces the incidence of cumulative nephrotoxicity from cisplatin: laboratory and clinical aspects. Semin Oncol 1999; 26:72.
- Schuchter LM, Hensley ML, Meropol NJ, et al. 2002 update of recommendations for the use of chemotherapy and radiotherapy protectants: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2002; 20:2895.
- Hensley ML, Hagerty KL, Kewalramani T, et al. American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J Clin Oncol 2009; 27:127.
- Ries F, Klastersky J. Nephrotoxicity induced by cancer chemotherapy with special emphasis on cisplatin toxicity. Am J Kidney Dis 1986; 8:368.
- Howell SB, Pfeifle CL, Wung WE, et al. Intraperitoneal cisplatin with systemic thiosulfate protection. Ann Intern Med 1982; 97:845.
- Wu YJ, Muldoon LL, Neuwelt EA. The chemoprotective agent N-acetylcysteine blocks cisplatin-induced apoptosis through caspase signaling pathway. J Pharmacol Exp Ther 2005; 312:424.
- Heidemann HT, Müller S, Mertins L, et al. Effect of aminophylline on cisplatin nephrotoxicity in the rat. Br J Pharmacol 1989; 97:313.
- Benoehr P, Krueth P, Bokemeyer C, et al. Nephroprotection by theophylline in patients with cisplatin chemotherapy: a randomized, single-blinded, placebo-controlled trial. J Am Soc Nephrol 2005; 16:452.
- Heyman SN, Spokes K, Egorin MJ, Epstein FH. Glycine reduces early renal parenchymal uptake of cisplatin. Kidney Int 1993; 43:1226.
- Sengupta P, Basu S, Soni S, et al. Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity. Proc Natl Acad Sci U S A 2012; 109:11294.
- Bundy JT, Connito D, Mahoney MD, Pontier PJ. Treatment of idiopathic renal magnesium wasting with amiloride. Am J Nephrol 1995; 15:75.
- Hansen SW, Groth S, Daugaard G, et al. Long-term effects on renal function and blood pressure of treatment with cisplatin, vinblastine, and bleomycin in patients with germ cell cancer. J Clin Oncol 1988; 6:1728.
- Brock PR, Koliouskas DE, Barratt TM, et al. Partial reversibility of cisplatin nephrotoxicity in children. J Pediatr 1991; 118:531.
- Georgaki-Angelaki HN, Steed DB, Chantler C, Haycock GB. Renal function following acute renal failure in childhood: a long term follow-up study. Kidney Int 1989; 35:84.
- Brenner BM. Nephron adaptation to renal injury or ablation. Am J Physiol 1985; 249:F324.
- Cellular toxicity
- Proinflammatory effects
- Effects on the proximal tubule
- CLINICAL MANIFESTATIONS
- Renal impairment
- Thrombotic microangiopathy
- Fanconi-like syndrome
- Salt wasting
- RISK FACTORS FOR ACUTE RENAL FAILURE
- Lower doses of cisplatin
- Intravenous saline
- Cisplatin analogs
- Other chemopreventive agents
- - Sodium thiosulfate
- - N-acetylcysteine
- - Theophylline
- - Glycine
- - Polymeric cisplatin nanoparticles
- General approach to renal dysfunction or failure
- Discontinuation of cisplatin
- Thrombotic microangiopathy
- SUMMARY AND RECOMMENDATIONS