Abstract
BackgroundCisplatin is a widely used chemotherapeutic agent for multiple indications. Unfortunately, in a substantial set of patients treated with cisplatin acute kidney injury (AKI) occurs. A recent case report suggested single nucleotide polymorphisms (SNPs) in the COMT gene might be associated with increased cisplatin-induced nephrotoxicity (de Jong et al., BJCP, 2017). Here, we assessed the association of 3 SNPs in this gene with cisplatin-induced nephrotoxicity in our patient population. MethodsWhole blood samples and serum creatinine concentrations (Scr) of 556 patients who received cisplatin between 2005-2019 were available. The 1947G>A (Val158Met, rs4680), c.615 + 310 C>T (rs4646316) and c.616 – 367 C>T (rs9332377) SNPs were associated with AKI (CTCAE v4.03) using Fisher’s exact test and difference in Scr up to 2 weeks prior to and up to 6 weeks after cisplatin treatment was described. ResultsMedian Scr at baseline was 70μmol/l (inter quartile range (IQR) 59-81). Up to six weeks after the start of cisplatin treatment the median increased to 81μmol/l (IQR 69-96). The presence of a variant of c.615 + 310C>T was associated with an increased occurrence of AKI ≥ grade 3 toxicity in patients carrying a homozygous variant (Var) compared to wildtype (WT) patients. AKI grade ≥ 3 occurred in 4 out of 31 (13%) homozygous variant patients against 6 out of 317 (2%) patients carrying wildtype alleles (p=0.005) after correction for age in a multivariable model. Dehydration occurred in 14 of the 16 patients with AKI grade 3 (3 of 4WT, 6 of 6 HT and 5 of 6 Var) and likely is a confounding factor. The remaining SNPs were not significantly associated with AKI or difference in Scr. ConclusionsThis study showed that variation in COMT c.615+310 C>T (rs4646316) potentially affects the development of AKI grade ≥3, although these results appear to be confounded by dehydration. Therefore, the value of this finding for daily practice is currently unclear and needs to be explored in a prospective setting. Legal entity responsible for the studyR.H.J. Mathijssen. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.
Highlights
Cisplatin is a widely used cytostatic agent that interferes with DNA replication by binding within DNA strands resulting in the inhibition of protein synthesis and DNA replication
In 25 out of 27 patients that had acute kidney injury (AKI) grade 3, dehydration could not be excluded as a potential cause of AKI (Table 3)
We found a significant association b dehydration could not be excluded as a potential cause of AKI
Summary
Cisplatin is a widely used cytostatic agent that interferes with DNA replication by binding within (and between) DNA strands resulting in the inhibition of protein synthesis and DNA replication. Genes 2020, 11, 358 candidate genes, of which two are SNPs in COMT, were genotyped in a young woman who developed severe irreversible cisplatin-induced nephropathy Both COMT polymorphisms were already known to be associated with cisplatin induced ototoxicity [4,5] and were homozygous polymorphic in this patient (c.615 + 310C>T (rs4646316) and c.616-367C>T (rs9332377)) [3]. This theory is supported by data from a mouse model study where cisplatin toxicity was 3- to 6-fold increased when SAM and cisplatin were administered concomitantly, compared to cisplatin administration alone [6] The association between these two COMT polymorphisms and cisplatin-induced nephrotoxicity has not been validated in further clinical research. We studied the association between these three COMT polymorphisms and cisplatin-induced nephrotoxicity in a large cohort of cancer patients in order to assess the clinical relevance of these SNPs and their potential use as predictor in this context
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