Pharmacogenomic Variants May Influence the Urinary Excretion of Novel Kidney Injury Biomarkers in Patients Receiving Cisplatin

Cara Chang, Yichun Hu, Susan L Hogan, Nickie Mercke, Madeleine Gomez, Cindy O'Bryant, Daniel W Bowles, Blessy George, Xia Wen, Lauren M Aleksunes, Melanie S Joy, Cara Chang, Yichun Hu, Susan L Hogan, Nickie Mercke, Madeleine Gomez, Cindy O'Bryant, Daniel W Bowles, Blessy George, Xia Wen, Lauren M Aleksunes, Melanie S Joy

Abstract

Nephrotoxicity is a dose limiting side effect associated with the use of cisplatin in the treatment of solid tumors. The degree of nephrotoxicity is dictated by the selective accumulation of cisplatin in renal tubule cells due to: (1) uptake by organic cation transporter 2 (OCT2) and copper transporter 1 (CTR1); (2) metabolism by glutathione S-transferases (GSTs) and γ-glutamyltransferase 1 (GGT1); and (3) efflux by multidrug resistance-associated protein 2 (MRP2) and multidrug and toxin extrusion protein 1 (MATE1). The purpose of this study was to determine the significance of single nucleotide polymorphisms that regulate the expression and function of transporters and metabolism genes implicated in development of acute kidney injury (AKI) in cisplatin treated patients. Changes in the kidney function were assessed using novel urinary protein biomarkers and traditional markers. Genotyping was conducted by the QuantStudio 12K Flex Real-Time PCR System using a custom open array chip with metabolism, transport, and transcription factor polymorphisms of interest to cisplatin disposition and toxicity. Traditional and novel biomarker assays for kidney toxicity were assessed for differences according to genotype by ANOVA. Allele and genotype frequencies were determined based on Caucasian population frequencies. The polymorphisms rs596881 (SLC22A2/OCT2), and rs12686377 and rs7851395 (SLC31A1/CTR1) were associated with renoprotection and maintenance of estimated glomerular filtration rate (eGFR). Polymorphisms in SLC22A2/OCT2, SLC31A1/CTRI, SLC47A1/MATE1, ABCC2/MRP2, and GSTP1 were significantly associated with increases in the urinary excretion of novel AKI biomarkers: KIM-1, TFF3, MCP1, NGAL, clusterin, cystatin C, and calbindin. Knowledge concerning which genotypes in drug transporters are associated with cisplatin-induced nephrotoxicity may help to identify at-risk patients and initiate strategies, such as using lower or fractionated cisplatin doses or avoiding cisplatin altogether, in order to prevent AKI.

Keywords: CTR1; GGT1; GST; KEAP1; MATE1; MRP2; NRF2; OCT2; acute kidney injury; cisplatin; nephrotoxicity; pharmacogenomics.

Conflict of interest statement

The authors declared no conflict of interest.

Figures

Figure 1
Figure 1
(A) Comparisons of SLC22A2 (rs596881) genotypes on eGFR in ambulatory cancer patients prescribed cisplatin. Patients carrying a variant allele of rs596881 in SLC22A2 exhibited statistically significant increases in eGFR (p = 0.01). (B,C) Comparisons of SLC31A1 (rs12686377 and rs7851395) genotypes on eGFR in ambulatory cancer patients prescribed cisplatin. Homozygous variant patients for SLC31A1 (rs12686377 and rs7851395) exhibited eGFR protection with cisplatin therapy (p = 0.01 and p = 0.04). Graphs indicate percent changes in eGFR from baseline. Abbreviations: Estimated glomerular filtration rate: eGFR, Wildtype: WT, Variant: VAR.
Figure 2
Figure 2
(A) Comparison of absolute KIM-1 concentrations by SLC22A2 (rs316019) genotype in ambulatory cancer patients prescribed cisplatin. Statistically significant increases of KIM-1 at baseline (p = 0.02), Day 3 (p = 0.03), and Day 10 (p = 0.046) were demonstrated in patients expressing the SLC22A2 rs316019 variant. (B) Comparison of absolute KIM-1 concentrations to ABCC2 (rs2273697) genotype in ambulatory cancer patients prescribed cisplatin. Statistically significant increases of KIM-1 at baseline (p = 0.02), Day 3 (p = 0.03) and Day 10 (p = 0.046) were demonstrated in patients expressing the ABCC2 rs2273697 variant. Error bars represent standard deviations. Abbreviations: Kidney injury molecule 1: KIM-1, Wildtype: WT, Variant: Var.
Figure 3
Figure 3
Comparison of calbindin absolute concentrations to ABCC2 (rs3740066) genotype in ambulatory cancer patients prescribed cisplatin. Absolute concentrations of calbindin were elevated in patients with the variant allele at all time points; statistically significant at baseline (p = 0.047), Day 3 (p = 0.02), and Day 10 (p = 0.02) versus homozygous wildtype patients. Error bars represent standard deviations. Abbreviations: Wild type: WT, Variant: Var.
Figure 4
Figure 4
Variant alleles in KEAP1 (rs11085735) are correlated with increased concentrations of TFF3 and cystatin C. (A) Absolute concentrations of cystatin C showed a statistically significant increase on Day 3 (p = 0.01) and Day 10 (p = 0.03) in patients expressing the variant allele of KEAP1. (B) Absolute concentrations of TFF3 were increased at baseline (p = 0.01), Day 3 (p = 0.03) and Day 10 (p = 0.03) in patients who carried at least one variant copy of KEAP1. Error bars represent standard deviations. Abbreviations: Trefoil factor: TFF3, Wildtype: WT, Variant: Var.

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