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1Marija Živković Radojević, 2Marina Marković, 2Aleksandar Dagović
1 Fakultet medicinskih nauka Univeziteta u Kragujevcu
2 Klinički centar Kragujevac, Centar za onkologiju i radiologiju, Odeljenje hemioterapije


• The paper was received on 03.11.2016. / Corrected 12.11.2016 / Accepted on 14.11.2016



Correspondence to:
dr Marija Živković Radojević, MD, PhD student
Janka Veselinovića 82,
34000 Kragujevac
phone: +381-65/83-84-450
e-mail: e-mail:





Cisplatin is one of the most efficient antineoplastic drugs used in the treatment of solid tumors, testicular, head and neck, ovarian, cervical and lung cancer. It's use is often limited by the side effects on the gastrointestinal tract, ototoxicity, nephrotoxicity, neurotoxicity and myelosuppression. Acute kidney damage induced by cisplatin is characterized by a reduction in tubular reabsorption, increase in vascular resistance in the microvasculature of the kidney, increased levels of creatinine and urea in serum, electrolyte imbalance, increase of creatinine clearance and urea, reduced ability to concentrate urine, reduction of glomerular filtration rate, and other parameters. Diagnosis of the kidney damage can not be made at an early stage because the clearance of creatinine little depends on the severity of the damage. By an early identification of risk factors and applying nephroprotective procedures, it is possible to reduce the extent of kidney damage and improve the results of oncological treatment.



Key words

cisplatin, acute kidney damage, mechanism, diagnosis, prevention





  1. Pabla N, Dong Z. Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int 2008;73(9):994-1007.
  2. Kim HJ, Park DJ, Kim JH, Jeong EY, Jung MH, Kim TH et al. Glutamine protects against cisplatin-induced nephrotoxicity by decreasing cisplatin accumulation. J Pharmacol Sci. 2015;127(1):117-26.
  3. Shahbazi F, Sadighi S, Dashti-Khavidaki S, Shahi F, Mirzania M. Urine ratio of neutrophil gelatinase-associated lipocalin to creatinine as a marker for early detection of cisplatin-associated nephrotoxicity. Iran J Kidney Dis. 2015;9(4):306-10.
  4. Maghsoudi O, Mirjalili SH, Dolatabadi M, Joshaghani MF, Zarea M, Yahaghi E et al. Investigations of renal function using the level of neutrophil gelatinase-associated lipocalin associated with single-dose of cisplatin during chemotherapy. Diagn Pathol. 2015;10:98.
  5. Kidera Y, Kawakami H, Sakiyama T, Okamoto K, Tanaka K, Takeda M et al. Risk factors for cisplatin-induced nephrotoxicity and potential of magnesium supplementation for renal protection. PLoS One. 2014;9(7):e101902.
  6. Yoshida T, Niho S, Toda M, Goto K, Yoh K, Umemura S et al. Protective effect of magnesium preloading on cisplatin-induced nephrotoxicity: a retrospective study. Jpn J Clin Oncol. 2014;44(4):346-54.
  7. Yao X, Panichpisal K, Kurtzman N, Nugent K. Cisplatin nephrotoxicity: a review. Am J Med Sci. 2007;334(2):115-24.
  8. Perazella MA. Onco-nephrology: renal toxicities of chemotherapeutic agents.Clin J Am Soc Nephrol. 2012;7(10):1713-21.
  9. Liu HE, Bai KJ, Hsieh YC, Yu MC, Lee CN, Chang JH et al. Multiple analytical approaches demonstrate a complex relationship of genetic and nongenetic factors with cisplatin- and carboplatin-induced nephrotoxicity in lungcancer patients. Biomed Res Int. 2014;2014:937429.
  10. Petrović D. Maligne bolesti i oštećenje bubrega u kliničkoj praksi. Petrović D. Ed. Kragujevac: Fakultet medicinskih nauka; 2015.
  11. Prasaja Y, Sutandyo N, Andrajati R. Incidence of cisplatin-induced nephrotoxicity and associated factors among cancer patients in Indonesia. Asian Pac J Cancer Prev. 2015;16(3):1117-22.
  12. Mousavi SS, Zadeh MH, Shahbazian H, Khanzadeh A, Hayati F, Ghorbani A et al. The protective effect of theophyline in cisplatin nephrotoxicity. Saudi J Kidney Dis Transpl. 2014;25(2):333-7.
  13. Krüger K, Thomale J, Stojanović N, Osmak M, Henninger C, Bormann S et al. Platinum-induced kidney damage: Unraveling the DNA damage response (DDR) of renaltubular epithelial and glomerular endothelial cells following platinum injury.Biochim Biophys Acta. 2015;1853(3):685-98.
  14. Gautier JC, Riefke B, Walter J, Kurth P, Mylecraine L, Guilpin V et al. Evaluation of novel biomarkers of nephrotoxicity in two strains of rat treated with Cisplatin.Toxicol Pathol. 2010;38(6):943-56.
  15. Sahni V, Choudhury D, Ahmed Z. Chemotherapy-associated renal dysfunction. Nat Rev Nephrol. 2009;5(8):450-62.
  16. Ghayyoomi M, Soltani N, Nematbakhsh M, Moslemi F, Talebi A, Shirdavani S et al. The effect of an specific inducible NO synthase inhibitor,S-methylisothiourea hemisulfate on cisplatin-induced nephrotoxicity; gender-related differences. Adv Biomed Res. 2015;4:130.
  17. Arunkumar PA, Viswanatha GL, Radheshyam N, Mukund H, Belliyappa MS. Science behind cisplatin-induced nephrotoxicity in humans: a clinical study. Asian Pac J Trop Biomed. 2012;2(8):640-4.
  18. Kim SY, Sohn SJ, Won AJ, Kim HS, Moon A. Identification of noninvasive biomarkers for nephrotoxicity using HK-2 human kidney epithelial cells. Toxicol Sci 2014;140(2):247-58.
  19. Wilmes A, Bielow C, Ranninger C, Bellwon P, Aschauer L, Limonciel A et al. Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics. Toxicol In Vitro. 2014. pii: S0887-2333(14)00195-7.
  20. Bulacio RP, Torres AM. Time course of organic anion transporter 5 (Oat5)urinary excretion in rats treated with cisplatin: a novel urinary biomarker for early detection of drug-induced nephrotoxicity. Arch Toxicol. 2015;89(8):1359-69.
  21. Bulacio RP, Anzai N, Ouchi M, Torres AM. Organic Anion Transporter 5 (Oat5)Urinary Excretion Is a Specific Biomarker of Kidney Injury: Evaluation of Urinary Excretion of Exosomal Oat5 after N-Acetylcysteine Prevention of Cisplatin Induced Nephrotoxicity. Chem Res Toxicol. 2015;28(8):1595-602.
  22. Nasri H. Cisplatin and renal injury; current concepts. J Renal Inj Prev. 2013;2(3):89-90.
  23. Kimoto Y, Sugiyama A, Nishinohara M, Asano A, Masuda A, Ochi T et al. Expressions of protein oxidation markers, dityrosine and advanced oxidation protein products in Cisplatin-induced nephrotoxicity in rats. J Vet Med Sci. 2011;73(3):403-7.
  24. Osman AM, Telity SA, Damanhouri ZA, Al-Harthy SE, Al-Kreathy HM, Ramadan WS et al. Chemosensitizing and nephroprotective effect of resveratrol in cisplatin- treated animals. Cancer Cell Int. 2015;15:6.
  25. Hagar H, Medany AE, Salam R, Medany GE, Nayal OA. Betaine supplementation mitigates cisplatin-induced nephrotoxicity by abrogation of oxidative/nitrosative stress and suppression of inflammation and apoptosis in rats. Exp Toxicol Pathol. 2015;67(2):133-41.
  26. Yousef MI, Hussien HM. Cisplatin-induced renal toxicity via tumor necrosis factor-α, interleukin 6, tumor suppressor P53, DNA damage, xanthine oxidase,histological changes, oxidative stress and nitric oxide in rats: protective effect of ginseng. Food Chem Toxicol. 2015;78:17-25.
  27. Trujillo J, Molina-Jijón E, Medina-Campos ON, Rodríguez-Muñoz R, Reyes JL,Barrera D et al. Superoxide anion production and expression of gp91(phox) and p47(phox) are increased in glomeruli and proximal tubules of cisplatin-treated rats. J Biochem Mol Toxicol. 2015;29(4):149-56.
  28. Mitazaki S, Hashimoto M, Matsuhashi Y, Honma S, Suto M, Kato N et al. Interleukin-6 modulates oxidative stress produced during the development of cisplatin nephrotoxicity. Life Sci. 2013;92(12):694-700.
  29. Sánchez-González PD, López-Hernández FJ, López-Novoa JM, Morales AI. An integrative view of the pathophysiological events leading to cisplatin nephrotoxicity. Crit Rev Toxicol. 2011;41(10):803-21.
  30. Noroozi J, Zeynali F, Nematbakhsh M, Pezeshki Z, Talebi A. Nonpreventive Role of Aerobic Exercise Against Cisplatin-induced Nephrotoxicity in Female Rats. Int J Prev Med. 2015;6:58.
  31. Liu X, Huang Z, Zou X, Yang Y, Qiu Y, Wen Y. Panax notoginseng saponins attenuates cisplatin-induced nephrotoxicity via inhibiting the mitochondrial pathway of apoptosis. Int J Clin Exp Pathol. 2014;7(12):8391-400.
  32. Fernández-Rojas B, Rodríguez-Rangel DS, Granados-Castro LF, Negrette-Guzmán M, León-Contreras JC, Hernández-Pando R et al. C-phycocyanin prevents cisplatin-induced mitochondrial dysfunction and oxidative stress. Mol Cell Biochem. 2015;406(1-2):183-97.
  33. Zsengellér ZK, Ellezian L, Brown D, Horváth B, Mukhopadhyay P, Kalyanaraman B et al. Cisplatin nephrotoxicity involves mitochondrial injury with impaired tubular mitochondrial enzyme activity. J Histochem Cytochem. 2012;60(7):521-9.
  34. Ju SM, Pae HO, Kim WS, Kang DG, Lee HS, Jeon BH. Role of reactive oxygen species in p53 activation during cisplatin-induced apoptosis of rat mesangial cells. Eur Rev Med Pharmacol Sci. 2014;18(8):1135-41.
  35. Ju SM, Kang JG, Bae JS, Pae HO, Lyu YS, Jeon BH. The Flavonoid Apigenin Ameliorates Cisplatin-Induced Nephrotoxicity through Reduction of p53 Activation and Promotion of PI3K/Akt Pathway in Human Renal Proximal Tubular Epithelial Cells. Evid Based Complement Alternat Med. 2015;2015:186436.
  36. Kim HJ, Park DJ, Kim JH, Jeong EY, Jung MH, Kim TH et al. Glutamine protects against cisplatin-induced nephrotoxicity by decreasing cisplatin accumulation. J Pharmacol Sci. 2015;127(1):117-26.
  37. Zhang W, Zhang L, Chen YX, Xie YY, Zou YF, Zhang MJ et al. Identification of nestin as a urinary biomarker for acute kidney injury. Am J Nephrol. 2014;39(2):110-21.
  38. Rostami B, Nematbakhsh M, Pezeshki Z, Talebi A, Sharifi MR, Moslemi F et . Effect of testosterone on Cisplatin-induced nephrotoxicity in surgically castrated rats. Nephrourol Mon 2014;6(5):e21546.
  39. Xu Y, Ma H, Shao J, Wu J, Zhou L, Zhang Z et al. A Role for Tubular Necroptosis in Cisplatin-Induced AKI. J Am Soc Nephrol. 2015;26(11):2647-58.
  40. Kubala M, Geleticova J, Huliciak M, Zatloukalova M, Vacek J, Sebela M. Na(+)/K(+)-ATPase inhibition by cisplatin and consequences for cisplatin nephrotoxicity. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2014;158(2):194-200.
  41. Ghorbani A, Omidvar B, Parsi A. Protective effect of selenium on cisplatin induced nephrotoxicity: A double-blind controlled randomized clinical trial. J Nephropathol. 2013;2(2):129-34.
  42. Mijuskovic M, Stanojevic I, Milovic N, Cerovic S, Petrovic D, Jovanovic D et al. Urinary KIM-1 and AQP-1 in patients with clear renal cell carcinoma: a potential non-invasive biomarkers. Vojnosanit Pregl. 2016; 73 (3): 266-272. 
  43. Dahal A, Bellows BK, Sonpavde G, Tantravahi SK, Choueiri TK, Galsky MD et al. Incidence of Severe Nephrotoxicity With Cisplatin Based on RenalFunction Eligibility Criteria: Indirect Comparison Meta-analysis. Am J Clin Oncol. 2014. [Epub ahead of print]
  44. McDuffie JE, Ma JY, Sablad M, Sonee M, Varacallo L, Louden C et al. Time course of renal proximal tubule injury, reversal, and related biomarker changes in rats following cisplatin administration. Int J Toxicol. 2013;32(4):251-60.
  45. Sinha V, Vence LM, Salahudeen AK. Urinary tubular protein-based biomarkers in the rodent model of cisplatin nephrotoxicity: a comparative analysis of serum creatinine, renal histology, and urinary KIM-1, NGAL, and NAG in the initiation, maintenance, and recovery phases of acute kidney injury. J Investig Med. 2013;61(3):564-8.
  46. Oc MA, Demir H, Cekmen MB, Isgoren S, Gorur GD, Bilgili U. Correlation of Cystatin-C and radionuclidic measurement method of glomerular filtration rate in patients with lung cancer receiving cisplatin treatment. Ren Fail. 2014;36(7):1043-50.
  47. Montoro-Molina S, Quesada A, Zafra-Ruiz PV, O'Valle F, Vargas F, de Gracia Mdel C et al. Immunological detection of glutamyl aminopeptidase in urine samples from cisplatin-treated rats. Proteomics Clin Appl. 2015;9(5-6):630-5.
  48. Fliedl L, Wieser M, Manhart G, Gerstl MP, Khan A, Grillari J et al. Controversial role of gamma-glutamyl transferase activity in cisplatin nephrotoxicity. ALTEX. 2014;31(3):269-78.
  49. Wadey RM, Pinches MG, Jones HB, Riccardi D, Price SA. Tissue expression and correlation of a panel of urinary biomarkers following cisplatin-induced kidney injury. Toxicol Pathol. 2014;42(3):591-602.
  50. Ashrafi F, Nematbakhsh M, Nasri H, Talebi A, Hosseini SM, Ashrafi M. Vacuolization, dilatation, hyaline cast, debris or degeneration: which one is the most correlated item to score the kidney damage pathologically in Cisplatin induced nephrotoxicity model? Nephrourol Mon. 2013;5(4):918-20.
  51. Nematbakhsh M, Ashrafi F, Nasri H, Talebi A, Pezeshki Z, Eshraghi F et al. A model for prediction of cisplatin induced nephrotoxicity by kidney weight in experimental rats. J Res Med Sci. 2013;18(5):370-3.
  52. Rouse R, Min M, Francke S, Mog S, Zhang J, Shea K et al. Impact of Pathologists and Evaluation Methods on Performance Assessment of the Kidney Injury Biomarker, Kim-1. Toxicol Pathol. 2015;43(5):662-74.
  53. Harpur E, Ennulat D, Hoffman D, Betton G, Gautier JC, Riefke B et al. Biological qualification of biomarkers of chemical-induced renal toxicity in two strains of male rat. Toxicol Sci. 201;122(2):235-52.
  54. Shea K, Stewart S, Rouse R. Assessment standards: comparing histopathology, digital image analysis, and stereology for early detection of experimental cisplatin-induced kidney injury in rats. Toxicol Pathol. 2014;42(6):1004-15.
  55. Jia JB, Lall C, Tirkes T, Gulati R, Lamba R, Goodwin SC. Chemotherapy-related complications in the kidneys and collecting system: an imaging perspective. Insights Imaging. 2015;6(4):479-87.
  56. Lameire N. Nephrotoxicity of recent anti-cancer agents. Clin Kidney J. 2014;7(1):11-22.
  57. Sendur MA, Aksoy S, Yaman S, Arik Z, Tugba Kos F, Akinci MB et al. Administration of contrast media just before cisplatin-based chemotherapy increases cisplatin-induced nephrotoxicity. J BUON. 2013;18(1):274-80.
  58. Ouchi A, Asano M, Aono K, Watanabe T, Kato T. Comparison of short and continuous hydration regimen in chemotherapy containing intermediate- to high-dose Cisplatin. J Oncol. 2014;2014:767652.
  59. Montoya J, Luna HG, Amparo JR, Casasola C, Cristal-Luna G. Renal function of cancer patients "fit" for Cisplatin chemotherapy: physician perspective. Gulf J Oncolog. 2014;1(16):64-72.
  60. Sindhu G, Nishanthi E, Sharmila R. Nephroprotective effect of vanillic acid against cisplatin induced nephrotoxicity in wistar rats: a biochemical and molecular study. Environ Toxicol Pharmacol. 2015;39(1):392-404.
  61. Hosseinimehr SJ, Asadian R, Naghshvar F, Azizi S, Jafarinejad M, Noaparast Z et al. Protective effects of thymol against nephrotoxicity induced by cisplatin with using 99mTc-DMSA in mice. Ren Fail 2015;37(2):280-4.
  62. Rasoulian B, Kaeidi A, Pourkhodadad S, Dezfoulian O, Rezaei M, Wahhabaghai H et al. Effects of pretreatment with single-dose or intermittent oxygen on Cisplatin-induced nephrotoxicity in rats. Nephrourol Mon. 2014;6(5):e19680.
  63. Song KI, Park JY, Lee S, Lee D, Jang HJ, Kim SN et al. Protective effect of tetrahydrocurcumin against cisplatin-induced renal damage: in vitro and in vivo studies. Planta Med. 2015;81(4):286-91.

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PDF Radojević Živković M. et al • MD-Medical Data 2016;8(4): 223-228

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