Electrolyte Blood Press.  2014 Dec;12(2):55-65. 10.5049/EBP.2014.12.2.55.

Cisplatin-induced Kidney Dysfunction and Perspectives on Improving Treatment Strategies

Affiliations
  • 1Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Iksan, Jeonbuk, Korea. jeanso@wku.ac.kr

Abstract

Cisplatin is one of the most widely used and highly effective drug for the treatment of various solid tumors; however, it has dose-dependent side effects on the kidney, cochlear, and nerves. Nephrotoxicity is the most well-known and clinically important toxicity. Numerous studies have demonstrated that several mechanisms, including oxidative stress, DNA damage, and inflammatory responses, are closely associated with cisplatin-induced nephrotoxicity. Even though the establishment of cisplatin-induced nephrotoxicity can be alleviated by diuretics and pre-hydration of patients, the prevalence of cisplatin nephrotoxicity is still high, occurring in approximately one-third of patients who have undergone cisplatin therapy. Therefore it is imperative to develop treatments that will ameliorate cisplatin-nephrotoxicity. In this review, we discuss the mechanisms of cisplatin-induced renal toxicity and the new strategies for protecting the kidneys from the toxic effects without lowering the tumoricidal activity.

Keyword

Cisplatin; Chemotherapy; Nephrotoxicity; NAD+

MeSH Terms

Cisplatin
Diuretics
DNA Damage
Drug Therapy
Humans
Kidney*
Oxidative Stress
Prevalence
Cisplatin
Diuretics

Reference

1. Yao X, Panichpisal K, Kurtzman N, Nugent K. Cisplatin nephrotoxicity: a review. Am J Med Sci. 2007; 334:115–124. PMID: 17700201.
Article
2. Sastry J, Kellie SJ. Severe neurotoxicity, ototoxicity and nephrotoxicity following high-dose cisplatin and amifostine. Pediatr Hematol Oncol. 2005; 22:441–445. PMID: 16020136.
Article
3. Miller RP, Tadagavadi RK, Ramesh G, Reeves WB. Mechanisms of Cisplatin nephrotoxicity. Toxins (Basel). 2010; 2:2490–2518. PMID: 22069563.
Article
4. Ciarimboli G. Membrane transporters as mediators of cisplatin side-effects. Anticancer Res. 2014; 34:547–550. PMID: 24403515.
5. Ciarimboli G. Organic cation transporters. Xenobiotica. 2008; 38:936–971. PMID: 18668435.
Article
6. Urakami Y, Nakamura N, Takahashi K, Okuda M, Saito H, Hashimoto Y, Inui K. Gender differences in expression of organic cation transporter OCT2 in rat kidney. FEBS Lett. 1999; 461:339–342. PMID: 10567723.
Article
7. Ciarimboli G, Deuster D, Knief A, Sperling M, Holtkamp M, Edemir B, Pavenstadt H, Lanvers-Kaminsky C, am Zehnhoff-Dinnesen A, Schinkel AH, Koepsell H, Jurgens H, Schlatter E. Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective interventions. Am J Pathol. 2010; 176:1169–1180. PMID: 20110413.
Article
8. Franke RM, Kosloske AM, Lancaster CS, Filipski KK, Hu C, Zolk O, Mathijssen RH, Sparreboom A. Influence of Oct1/Oct2-deficiency on cisplatin-induced changes in urinary N-acetyl-beta-D-glucosaminidase. Clin Cancer Res. 2010; 16:4198–4206. PMID: 20601443.
9. Pabla N, Murphy RF, Liu K, Dong Z. The copper transporter Ctr1 contributes to cisplatin uptake by renal tubular cells during cisplatin nephrotoxicity. Am J Physiol Renal Physiol. 2009; 296:F505–F511. PMID: 19144690.
Article
10. Townsend DM, Tew KD, He L, King JB, Hanigan MH. Role of glutathione S-transferase Pi in cisplatin-induced nephrotoxicity. Biomed Pharmacother. 2009; 63:79–85. PMID: 18819770.
Article
11. Hanigan MH, Lykissa ED, Townsend DM, Ou CN, Barrios R, Lieberman MW. Gamma-glutamyl transpeptidase-deficient mice are resistant to the nephrotoxic effects of cisplatin. Am J Pathol. 2001; 159:1889–1894. PMID: 11696449.
12. Hanigan MH, Gallagher BC, Townsend DM, Gabarra V. Gamma-glutamyl transpeptidase accelerates tumor growth and increases the resistance of tumors to cisplatin in vivo. Carcinogenesis. 1999; 20:553–559. PMID: 10223181.
13. Townsend DM, Deng M, Zhang L, Lapus MG, Hanigan MH. Metabolism of Cisplatin to a nephrotoxin in proximal tubule cells. J Am Soc Nephrol. 2003; 14:1–10. PMID: 12506132.
Article
14. Zhang L, Hanigan MH. Role of cysteine S-conjugate beta-lyase in the metabolism of cisplatin. J Pharmacol Exp Ther. 2003; 306:988–994. PMID: 12750429.
15. Kuhlmann MK, Burkhardt G, Kohler H. Insights into potential cellular mechanisms of cisplatin nephrotoxicity and their clinical application. Nephrol Dial Transplant. 1997; 12:2478–2480. PMID: 9430835.
Article
16. Pabla N, Dong Z. Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int. 2008; 73:994–1007. PMID: 18272962.
Article
17. Jiang M, Dong Z. Regulation and pathological role of p53 in cisplatin nephrotoxicity. J Pharmacol Exp Ther. 2008; 327:300–307. PMID: 18682572.
Article
18. Lee RH, Song JM, Park MY, Kang SK, Kim YK, Jung JS. Cisplatin-induced apoptosis by translocation of endogenous Bax in mouse collecting duct cells. Biochem Pharmacol. 2001; 62:1013–1023. PMID: 11597570.
19. Ramesh G, Reeves WB. Salicylate reduces cisplatin nephrotoxicity by inhibition of tumor necrosis factoralpha. Kidney Int. 2004; 65:490–499. PMID: 14717919.
20. Strasser A, O'Connor L, Dixit VM. Apoptosis signaling. Annu Rev Biochem. 2000; 69:217–245. PMID: 10966458.
Article
21. Tsuruya K, Ninomiya T, Tokumoto M, Hirakawa M, Masutani K, Taniguchi M, Fukuda K, Kanai H, Kishihara K, Hirakata H, Iida M. Direct involvement of the receptor-mediated apoptotic pathways in cisplatin-induced renal tubular cell death. Kidney Int. 2003; 63:72–82. PMID: 12472770.
Article
22. Seth R, Yang C, Kaushal V, Shah SV, Kaushal GP. p53-dependent caspase-2 activation in mitochondrial release of apoptosis-inducing factor and its role in renal tubular epithelial cell injury. J Biol Chem. 2005; 280:31230–31239. PMID: 15983031.
Article
23. Takeda M, Kobayashi M, Shirato I, Osaki T, Endou H. Cisplatin-induced apoptosis of immortalized mouse proximal tubule cells is mediated by interleukin-1 beta converting enzyme (ICE) family of proteases but inhibited by overexpression of Bcl-2. Arch Toxicol. 1997; 71:612–621. PMID: 9332697.
24. Park MS, De Leon M, Devarajan P. Cisplatin induces apoptosis in LLC-PK1 cells via activation of mitochondrial pathways. J Am Soc Nephrol. 2002; 13:858–865. PMID: 11912244.
Article
25. Peyrou M, Hanna PE, Cribb AE. Cisplatin, gentamicin, and p-aminophenol induce markers of endoplasmic reticulum stress in the rat kidneys. Toxicol Sci. 2007; 99:346–353. PMID: 17567590.
Article
26. Price PM, Safirstein RL, Megyesi J. Protection of renal cells from cisplatin toxicity by cell cycle inhibitors. Am J Physiol Renal Physiol. 2004; 286:F378–F384. PMID: 12965891.
Article
27. Price PM, Yu F, Kaldis P, Aleem E, Nowak G, Safirstein RL, Megyesi J. Dependence of cisplatin-induced cell death in vitro and in vivo on cyclin-dependent kinase 2. J Am Soc Nephrol. 2006; 17:2434–2442. PMID: 16914540.
Article
28. Bassett EA, Wang W, Rastinejad F, El-Deiry WS. Structural and functional basis for therapeutic modulation of p53 signaling. Clin Cancer Res. 2008; 14:6376–6386. PMID: 18927276.
Article
29. Wei Q, Dong G, Yang T, Megyesi J, Price PM, Dong Z. Activation and involvement of p53 in cisplatin-induced nephrotoxicity. Am J Physiol Renal Physiol. 2007; 293:F1282–F1291. PMID: 17670903.
Article
30. Molitoris BA, Dagher PC, Sandoval RM, Campos SB, Ashush H, Fridman E, Brafman A, Faerman A, Atkinson SJ, Thompson JD, Kalinski H, Skaliter R, Erlich S, Feinstein E. siRNA targeted to p53 attenuates ischemic and cisplatin-induced acute kidney injury. J Am Soc Nephrol. 2009; 20:1754–1764. PMID: 19470675.
Article
31. Clark JS, Faisal A, Baliga R, Nagamine Y, Arany I. Cisplatin induces apoptosis through the ERK-p66shc pathway in renal proximal tubule cells. Cancer Lett. 2010; 297:165–170. PMID: 20547441.
Article
32. Dickey DT, Wu YJ, Muldoon LL, Neuwelt EA. Protection against cisplatin-induced toxicities by N-acetylcysteine and sodium thiosulfate as assessed at the molecular, cellular, and in vivo levels. J Pharmacol Exp Ther. 2005; 314:1052–1058. PMID: 15951398.
33. Baliga R, Zhang Z, Baliga M, Ueda N, Shah SV. In vitro and in vivo evidence suggesting a role for iron in cisplatin-induced nephrotoxicity. Kidney Int. 1998; 53:394–401. PMID: 9461098.
Article
34. Davis CA, Nick HS, Agarwal A. Manganese superoxide dismutase attenuates Cisplatin-induced renal injury: importance of superoxide. J Am Soc Nephrol. 2001; 12:2683–2690. PMID: 11729237.
Article
35. Ma SF, Nishikawa M, Hyoudou K, Takahashi R, Ikemura M, Kobayashi Y, Yamashita F, Hashida M. Combining cisplatin with cationized catalase decreases nephrotoxicity while improving antitumor activity. Kidney Int. 2007; 72:1474–1482. PMID: 17898699.
Article
36. Naziroglu M, Karaoglu A, Aksoy AO. Selenium and high dose vitamin E administration protects cisplatin-induced oxidative damage to renal, liver and lens tissues in rats. Toxicology. 2004; 195:221–230. PMID: 14751677.
Article
37. Shiraishi F, Curtis LM, Truong L, Poss K, Visner GA, Madsen K, Nick HS, Agarwal A. Heme oxygenase-1 gene ablation or expression modulates cisplatin-induced renal tubular apoptosis. Am J Physiol Renal Physiol. 2000; 278:F726–F736. PMID: 10807584.
38. Kawai Y, Nakao T, Kunimura N, Kohda Y, Gemba M. Relationship of intracellular calcium and oxygen radicals to Cisplatin-related renal cell injury. J Pharmacol Sci. 2006; 100:65–72. PMID: 16410676.
Article
39. Yilmaz HR, Iraz M, Sogut S, Ozyurt H, Yildirim Z, Akyol O, Gergerlioglu S. The effects of erdosteine on the activities of some metabolic enzymes during cisplatin-induced nephrotoxicity in rats. Pharmacol Res. 2004; 50:287–290. PMID: 15225672.
Article
40. Badary OA, Abdel-Maksoud S, Ahmed WA, Owieda GH. Naringenin attenuates cisplatin nephrotoxicity in rats. Life Sci. 2005; 76:2125–2135. PMID: 15826879.
Article
41. Chirino YI, Hernandez-Pando R, Pedraza-Chaverri J. Peroxynitrite decomposition catalyst ameliorates renal damage and protein nitration in cisplatin-induced nephrotoxicity in rats. BMC Pharmacol. 2004; 4:20. PMID: 15458572.
42. Kelly KJ, Meehan SM, Colvin RB, Williams WW, Bonventre JV. Protection from toxicant-mediated renal injury in the rat with anti-CD54 antibody. Kidney Int. 1999; 56:922–931. PMID: 10469360.
Article
43. Oh GS, Kim HJ, Choi JH, Shen A, Choe SK, Karna A, Lee SH, Jo HJ, Yang SH, Kwak TH, Lee CH, Park R, So HS. Pharmacological activation of NQO1 increases NAD(+) levels and attenuates cisplatin-mediated acute kidney injury in mice. Kidney Int. 2014; 85:547–560. PMID: 24025646.
Article
44. Ramesh G, Reeves WB. TNF-alpha mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. J Clin Invest. 2002; 110:835–842. PMID: 12235115.
45. Kim YK, Choi TR, Kwon CH, Kim JH, Woo JS, Jung JS. Beneficial effect of pentoxifylline on cisplatin-induced acute renal failure in rabbits. Ren Fail. 2003; 25:909–922. PMID: 14669850.
Article
46. 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; 72:37–44. PMID: 17396112.
47. Ramesh G, Reeves WB. p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice. Am J Physiol Renal Physiol. 2005; 289:F166–F174. PMID: 15701814.
Article
48. Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell. 2001; 104:487–501. PMID: 11239407.
49. Ramesh G, Reeves WB. TNFR2-mediated apoptosis and necrosis in cisplatin-induced acute renal failure. Am J Physiol Renal Physiol. 2003; 285:F610–F618. PMID: 12865254.
50. Faubel S, Lewis EC, Reznikov L, Ljubanovic D, Hoke TS, Somerset H, Oh DJ, Lu L, Klein CL, Dinarello CA, Edelstein CL. Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1beta, IL-18, IL-6, and neutrophil infiltration in the kidney. J Pharmacol Exp Ther. 2007; 322:8–15. PMID: 17400889.
51. Lu LH, Oh DJ, Dursun B, He Z, Hoke TS, Faubel S, Edelstein CL. Increased macrophage infiltration and fractalkine expression in cisplatin-induced acute renal failure in mice. J Pharmacol Exp Ther. 2008; 324:111–117. PMID: 17932247.
Article
52. Zhang Y, Yuan F, Cao X, Zhai Z, GangHuang , Du X, Wang Y, Zhang J, Huang Y, Zhao J, Hou W. P2X7 receptor blockade protects against cisplatin-induced nephrotoxicity in mice by decreasing the activities of inflammasome components, oxidative stress and caspase-3. Toxicol Appl Pharmacol. 2014; 281:1–10. PMID: 25308879.
Article
53. Cornelison TL, Reed E. Nephrotoxicity and hydration management for cisplatin, carboplatin, and ormaplatin. Gynecol Oncol. 1993; 50:147–158. PMID: 8375728.
Article
54. Hanigan MH, Deng M, Zhang L, Taylor PT Jr, Lapus MG. Stress response inhibits the nephrotoxicity of cisplatin. Am J Physiol Renal Physiol. 2005; 288:F125–F132. PMID: 15353400.
Article
55. Lynch ED, Gu R, Pierce C, Kil J. Reduction of acute cisplatin ototoxicity and nephrotoxicity in rats by oral administration of allopurinol and ebselen. Hear Res. 2005; 201:81–89. PMID: 15721563.
Article
56. Nisar S, Feinfeld DA. N-acetylcysteine as salvage therapy in cisplatin nephrotoxicity. Ren Fail. 2002; 24:529–533. PMID: 12212833.
Article
57. Deng J, Kohda Y, Chiao H, Wang Y, Hu X, Hewitt SM, Miyaji T, McLeroy P, Nibhanupudy B, Li S, Star RA. Interleukin-10 inhibits ischemic and cisplatin-induced acute renal injury. Kidney Int. 2001; 60:2118–2128. PMID: 11737586.
Article
58. Nagothu KK, Bhatt R, Kaushal GP, Portilla D. Fibrate prevents cisplatin-induced proximal tubule cell death. Kidney Int. 2005; 68:2680–2693. PMID: 16316343.
Article
59. Kitada M, Koya D. Renal protective effects of resveratrol. Oxid Med Cell Longev. 2013; 2013:568093. PMID: 24379901.
Article
60. Catalgol B, Batirel S, Taga Y, Ozer NK. Resveratrol: French paradox revisited. Front Pharmacol. 2012; 3:141. PMID: 22822401.
Article
61. Valentovic MA, Ball JG, Brown JM, Terneus MV, McQuade E, Van Meter S, Hedrick HM, Roy AA, Williams T. Resveratrol attenuates cisplatin renal cortical cytotoxicity by modifying oxidative stress. Toxicol In Vitro. 2014; 28:248–257. PMID: 24239945.
Article
62. Kim DH, Jung YJ, Lee JE, Lee AS, Kang KP, Lee S, Park SK, Han MK, Lee SY, Ramkumar KM, Sung MJ, Kim W. SIRT1 activation by resveratrol ameliorates cisplatin-induced renal injury through deacetylation of p53. Am J Physiol Renal Physiol. 2011; 301:F427–F435. PMID: 21593185.
Article
63. Do Amaral CL, Francescato HD, Coimbra TM, Costa RS, Darin JD, Antunes LM, Bianchi Mde L. Resveratrol attenuates cisplatin-induced nephrotoxicity in rats. Arch Toxicol. 2008; 82:363–370. PMID: 18026934.
Article
64. Kitada M, Kume S, Takeda-Watanabe A, Kanasaki K, Koya D. Sirtuins and renal diseases: relationship with aging and diabetic nephropathy. Clin Sci (Lond). 2013; 124:153–164. PMID: 23075334.
Article
65. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003; 425:191–196. PMID: 12939617.
Article
66. Guarente L. Sirtuins, aging, and metabolism. Cold Spring Harb Symp Quant Biol. 2011; 76:81–90. PMID: 22114328.
Article
67. Hwang JH, Kim DW, Jo EJ, Kim YK, Jo YS, Park JH, Yoo SK, Park MK, Kwak TH, Kho YL, Han J, Choi HS, Lee SH, Kim JM, Lee I, Kyung T, Jang C, Chung J, Kweon GR, Shong M. Pharmacological stimulation of NADH oxidation ameliorates obesity and related phenotypes in mice. Diabetes. 2009; 58:965–974. PMID: 19136651.
Article
68. Kim SY, Jeoung NH, Oh CJ, Choi YK, Lee HJ, Kim HJ, Kim JY, Hwang JH, Tadi S, Yim YH, Lee KU, Park KG, Huh S, Min KN, Jeong KH, Park MG, Kwak TH, Kweon GR, Inukai K, Shong M, Lee IK. Activation of NAD(P)H:quinone oxidoreductase 1 prevents arterial restenosis by suppressing vascular smooth muscle cell proliferation. Circ Res. 2009; 104:842–850. PMID: 19229058.
Article
69. Houtkooper RH, Canto C, Wanders RJ, Auwerx J. The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. Endocr Rev. 2010; 31:194–223. PMID: 20007326.
70. Kim YH, Hwang JH, Noh JR, Gang GT, Kim do H, Son HY, Kwak TH, Shong M, Lee IK, Lee CH. Activation of NAD(P)H:quinone oxidoreductase ameliorates spontaneous hypertension in an animal model via modulation of eNOS activity. Cardiovasc Res. 2011; 91:519–527. PMID: 21502369.
Article
71. Lee JS, Park AH, Lee SH, Kim JH, Yang SJ, Yeom YI, Kwak TH, Lee D, Lee SJ, Lee CH, Kim JM, Kim D. Beta-lapachone, a modulator of NAD metabolism, prevents health declines in aged mice. PLoS One. 2012; 7:e47122. PMID: 23071729.
Article
72. Kim YH, Hwang JH, Noh JR, Gang GT, Tadi S, Yim YH, Jeoung NH, Kwak TH, Lee SH, Kweon GR, Kim JM, Shong M, Lee IK, Lee CH. Prevention of salt-induced renal injury by activation of NAD(P)H:quinone oxidoreductase 1, associated with NADPH oxidase. Free Radic Biol Med. 2012; 52:880–888. PMID: 22227174.
Article
73. Kim HJ, Oh GS, Shen A, Lee SB, Choe SK, Kwon KB, Lee S, Seo KS, Kwak TH, Park R, So HS. Augmentation of NAD(+) by NQO1 attenuates cisplatin-mediated hearing impairment. Cell Death Dis. 2014; 5:e1292. PMID: 24922076.
Article
74. Gaikwad A, Long DJ 2nd, Stringer JL, Jaiswal AK. In vivo role of NAD(P)H:quinone oxidoreductase 1 (NQO1) in the regulation of intracellular redox state and accumulation of abdominal adipose tissue. J Biol Chem. 2001; 276:22559–22564. PMID: 11309386.
Article
75. Gessner DK, Ringseis R, Siebers M, Keller J, Kloster J, Wen G, Eder K. Inhibition of the pro-inflammatory NF-kappaB pathway by a grape seed and grape marc meal extract in intestinal epithelial cells. J Anim Physiol Anim Nutr (Berl). 2012; 96:1074–1083. PMID: 21895782.
76. Pazdro R, Burgess JR. The antioxidant 3H-1,2-dithiole-3-thione potentiates advanced glycation end-product-induced oxidative stress in SH-SY5Y cells. Exp Diabetes Res. 2012; 2012:137607. PMID: 22675339.
Article
77. Moscovitz O, Tsvetkov P, Hazan N, Michaelevski I, Keisar H, Ben-Nissan G, Shaul Y, Sharon M. A mutually inhibitory feedback loop between the 20S proteasome and its regulator, NQO1. Mol Cell. 2012; 47:76–86. PMID: 22793692.
Article
78. Pardee AB, Li YZ, Li CJ. Cancer therapy with betalapachone. Curr Cancer Drug Targets. 2002; 2:227–242. PMID: 12188909.
79. Imai S, Kiess W. Therapeutic potential of SIRT1 and NAMPT-mediated NAD biosynthesis in type 2 diabetes. Front Biosci (Landmark Ed). 2009; 14:2983–2995. PMID: 19273250.
Article
80. Abdellatif M. Sirtuins and pyridine nucleotides. Circ Res. 2012; 111:642–656. PMID: 22904043.
Article
81. Michan S, Sinclair D. Sirtuins in mammals: insights into their biological function. Biochem J. 2007; 404:1–13. PMID: 17447894.
Article
82. Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W, Bultsma Y, McBurney M, Guarente L. Mammalian SIRT1 represses forkhead transcription factors. Cell. 2004; 116:551–563. PMID: 14980222.
Article
83. Ahn BH, Kim HS, Song S, Lee IH, Liu J, Vassilopoulos A, Deng CX, Finkel T. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl Acad Sci U S A. 2008; 105:14447–14452. PMID: 18794531.
Article
84. Li S, Banck M, Mujtaba S, Zhou MM, Sugrue MM, Walsh MJ. p53-induced growth arrest is regulated by the mitochondrial SirT3 deacetylase. PLoS One. 2010; 5:e10486. PMID: 20463968.
Article
85. Abali H, Urun Y, Oksuzoglu B, Budakoglu B, Yildirim N, Guler T, Ozet G, Zengin N. Comparison of ICE (ifosfamide-carboplatin-etoposide) versus DHAP (cytosine arabinoside-cisplatin-dexamethasone) as salvage chemotherapy in patients with relapsed or refractory lymphoma. Cancer Invest. 2008; 26:401–406. PMID: 18443961.
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