Evaluation of the Effect of Genetic Polymorphisms in ERCC1 and OCT2 on the Occurrence and Severity of Cisplatin-induced Nephrotoxicity

Evaluation of the Effect of Genetic Polymorphisms in ERCC1 and OCT2 on the Occurrence and Severity of Cisplatin-induced Nephrotoxicity

Approximately one-third of all patients treated with cisplatin develop renal dysfunction after a single dosage of cisplatin. Germline genetic polymorphisms may cause variations in cisplatin pharmacokinetics and in the ability of epithelial kidney cells to take up cisplatin and repair cisplatin-induced Deoxyribonucleic Acid (DNA) damage. Knowledge concerning which genotypes 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, to prevent Acute Kidney Injury (AKI).

Approximately one-third of all patients treated with cisplatin develop renal dysfunction after a single dosage of cisplatin. Germline genetic polymorphisms may cause variations in cisplatin pharmacokinetics and in the ability of epithelial kidney cells to take up cisplatin and repair cisplatin-induced DNA damage. Knowledge concerning which genotypes 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, to prevent AKI.

Patient written informed consent will be taken prior to study conductance

1. Full laboratory evaluation before and after cisplatin administration including:

   (Complete Blood Count) CBC, liver and renal functions. glomerular filtration rate (GFR), and estimated glomerular filtration rate (eGFR) Serum electrolytes. Marker of nephrotoxicity: Cystatin C.

2. Sample Collection and single nucleotide polymorphism (SNP) Genotyping:

Venous blood (2 mL) will be collected from each subject into tubes containing 50 mmol of Ethylenediamine tetraacetic acid (EDTA) per liter and genomic DNA will be isolated with the GeneJET Whole Blood Genomic DNA purification Mini kit, according to manufacturer's instructions. Polymorphisms will be assessed using the TaqMan based real-time polymerase chain reaction (PCR) assay.

This study aims to assess the influence of single nucleotide polymorphisms in the DNA repair gene Excision Repair Cross Complementation group 1 (ERCC1) and Cisplatin uptake transporter gene Organic Cation Transporter 2 (OCT2) on cisplatin-induced nephrotoxicity by assessment of the following:

1. Occurrence of nephrotoxicity.
2. Degree of renal impairment.
3. Changes in traditional and novel protein biomarkers for AKI.

Inclusion Criteria:

• Males or females aged >18 years receiving cisplatin-containing chemotherapy.
• A Cisplatin dose starting from 75 mg/m2
• Various cancer types
• No history of organ transplantation or kidney dialysis.
• Patients with normal renal function

Exclusion Criteria:

• Co-administration of ifosfamide with cisplatin, because of the known risk of nephrotoxicity.
• Pregnant or lactation.
• Infection with the human immunodeficiency virus (HIV).
• Prior administration of cisplatin.
• Intraperitoneal chemotherapy.
• Inadequate liver function (bilirubin > 1.5 times upper normal limit (UNL) and alanine transaminase (ALT) or aspartate transaminase (AST) > 3.0 UNL or up to 5.0 UNL in the presence of hepatic metastases).
• Inadequate renal function (creatinine > 1.25 times UNL, creatinine clearance < 50 mL/min).
• Serious comorbid systemic disorder incompatible with the study (uncontrolled diabetes mellitus (DM) or hypertension (HTN), myocardial infarction within the last 6 months).
• Patients diagnosed with kidney cancer.
• Exposure to any nephrotoxic drugs or agents.