Multiple Analytical Approaches Demonstrate a Complex Relationship of Genetic and Nongenetic Factors with Cisplatin- and Carboplatin-Induced Nephrotoxicity in Lung Cancer Patients

Abstract

Background. Cisplatin and carboplatin cause nephrotoxicity by forming platinum-DNA adducts and lead to cell death. Methods. One-hundred and sixteen Taiwanese lung cancer patients who received cisplatin or carboplatin more than twice were recruited, and their genotypes were determined. The risk of renal dysfunction, injury to the kidney, failure of kidney function, loss of kidney function, and end-stage kidney disease (RIFLE) criteria were used to evaluate the occurrence of nephrotoxicity. A logistic regression, multiple regression with a classification and regression tree (CART), and the Framingham study risk score were used to analyze interactions between genetic and nongenetic factors in producing platinum-induced nephrotoxicity. Results. ERCC1 118C and TP53 72Arg polymorphisms were associated with increased risks of platinum-induced nephrotoxicity. Other risk factors found included the platinum type, baseline serum creatinine (Scr), coadministration of vinorelbine, and the number of chemotherapy cycles. The overall prediction rate of the CART was 82.7%, with a sensitivity of 0.630 and specificity of 0.896. The Framingham study risk prediction model contained 7 factors. Its prediction rate was 84.5%, with a sensitivity of 0.643 and specificity of 0.909. Conclusions. Genetic polymorphisms of ERCC1 and TP53 are risk factors for nephrotoxicity. The CART analysis may provide a clinically applicable model to predict the risk of cisplatin- and carboplatin-induced nephrotoxicity.

Genetic Variations and Cisplatin Nephrotoxicity: A Systematic Review

“…In contrast to the aforementioned results, 11 other studies, mostly underpowered, reported no statistically significant association between the ERCC1 polymorphisms and cisplatin nephrotoxicity (Goekkurt et al, 2009 ; Chen et al, 2010 ; KimCurran et al, 2011 ; Erculj et al, 2012 ; Khrunin et al, 2012 , 2014 ; Windsor et al, 2012 ; Khokhrin et al, 2013 ; Liu et al, 2014 ; Hattinger et al, 2016 ; Powrozek et al, 2016 ). Thus, further studies to disclose molecular mechanisms of ERCC1-mediated cisplatin nephrotoxicity are needed as a scientific basis for a future clinical study.…”

“…The first observational study through genome-wide association and whole-genome sequencing studies to investigate drug-induced kidney disease—the DIRECT study is currently ongoing but the results are still pending (Awdishu et al, 2016 ). Because of patient heterogeneity, any genetic associations must take clinico-epidemiologic and demographic variations into account [e.g., performance status, regular use of NSAIDs, hypoalbuminemia, cardiac disease; (Kidera et al, 2014 ; Liu et al, 2014 ; Bhat et al, 2015 ; Miyoshi et al, 2016 ; Sato et al, 2016 )], through proper documentation, prospective data collection, and appropriate adjustments during the statistical genetic analyses. Alternatively, population pharmacokinetic and/or pharmacodynamic modeling can be used as the basis of additional pharmacogenetic evaluations.…”

“…There is a growing interest in the role of genetic variation in the development of cisplatin nephrotoxicity (Liu et al, 2014 ; Skinner, 2017 ). Variations in organic transporter molecules genes (Yonezawa and Inui, 2011 ; Zhang and Zhou, 2012 ), DNA repair enzyme genes (Khrunin et al, 2010b ; Zhang et al, 2012 ; Xu et al, 2013 ), tumor suppressor genes (Liu et al, 2014 ) and metabolic enzymes involved in platinum detoxification (Barahmani et al, 2009 ; Khrunin et al, 2012 ) have been associated with the risk of nephrotoxicity. Although several genetic variants have been identified to influence cisplatin-induced nephrotoxicity in oncology patients, a comprehensive overview on which genetic variations are consistently associated with nephrotoxicity-induced cisplatin-based chemotherapy is lacking.…”

Pharmacogenetic analysis of irreversible severe cisplatin‐induced nephropathy: a case report of a 27‐year‐old woman

“…In particular, polymorphism in genes involved in cisplatin cellular uptake such as the organic cation transporter 2 ( OCT2 ); metabolism, i.e. glutathione S‐transferases 1 ( GST1 ); DNA repair, like the excision repair cross‐complementation groups ( ERCC1 , ERCC2 ); and other pharmacodynamic candidate genes such as catechol‐O‐methyltransferase ( COMT ), have shown to be associated with nephrotoxicity . Although cisplatin toxicity is in most cases largely reversible, this report describes a young patient with persistent severe nephropathy after three doses of low‐dose cisplatin therapy.…”

Baicalein and its underlying mechanism as a protector against liver injury induced by cisplatin in mice

“…In spite of its considerable clinical benefit, cisplatin therapy is accompanied with undesirable side effects, which has been an increasing concern to clinical doctors. Cisplatin has been documented to cause toxicity in animals and humans [3,4]. It has been elucidated that one of the main target organs of cisplatin toxicity is the liver [5], and that cisplatin intake could cause severe liver injury, including hepatocytic vacuolation, centrilobular necrosis, lymphocyte infiltration and so on [6,7].…”