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

NCT ID: NCT05247671

Last Updated: 2022-02-21

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 89 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2022-02-15
• Study Completion Date: 2022-12-15

Brief Summary

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).

Detailed Description

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.

Conditions

Cisplatin Adverse Reaction

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Case

All eligible patients will be recruited to the study and will be assessed for SNPs in both ERCC1 and OCT2 and their association with cisplatin-induced nephrotoxicity through the measurement of cystatin C before taking cisplatin and after receiving the second cycle of cisplatin.

ERCC1

Intervention Type: GENETIC

ERCC1 is a rate-limiting enzyme in the nucleotide excision repair pathway that is known to repair cisplatin-induced DNA damage. Polymorphisms in ERCC1 are known to affect response to cisplatin treatment. A mechanism explaining the effect of the ERCC1 polymorphism on the kidney may be that the homozygous carriers of this rs3212986 allele might have a greater capacity to repair cisplatin-induced DNA damage in their kidney epithelia, and thus would be more resistant to cisplatin-induced nephrotoxicity

OCT2

Intervention Type: GENETIC

OCT2 is expressed on the basolateral membrane of Proximal Tubular Epithelial Cell (PTEC) and plays a central role in cisplatin uptake into tubular cells. Genetic variants in the cisplatin uptake transporter OCT2 showed association with the preservation of kidney function. Patients with the CT genotype in OCT2 polymorphism rs596881 exhibited positive changes in eGFR compared to individuals with the wild type CC genotype

Interventions

ERCC1

ERCC1 is a rate-limiting enzyme in the nucleotide excision repair pathway that is known to repair cisplatin-induced DNA damage. Polymorphisms in ERCC1 are known to affect response to cisplatin treatment. A mechanism explaining the effect of the ERCC1 polymorphism on the kidney may be that the homozygous carriers of this rs3212986 allele might have a greater capacity to repair cisplatin-induced DNA damage in their kidney epithelia, and thus would be more resistant to cisplatin-induced nephrotoxicity

Intervention Type: GENETIC

OCT2

OCT2 is expressed on the basolateral membrane of Proximal Tubular Epithelial Cell (PTEC) and plays a central role in cisplatin uptake into tubular cells. Genetic variants in the cisplatin uptake transporter OCT2 showed association with the preservation of kidney function. Patients with the CT genotype in OCT2 polymorphism rs596881 exhibited positive changes in eGFR compared to individuals with the wild type CC genotype

Intervention Type: GENETIC

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ain Shams University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Lamia Elwakeel

Role: STUDY_DIRECTOR

Head of Clinical Department, Faculty of Pharmacy, Ain Shams University

Locations

Faculty of medicine, Ain Shams University

Cairo, , Egypt

Countries

Egypt

Central Contacts

Israa Abdelbar, BSc

Role: CONTACT

israa.aly@bue.edu.eg

00201013138111

Amal Elkholy, PhD

Role: CONTACT

amalanas9@gmail.com

01060355448

Facility Contacts

Diaa Sherif, MD

Role: primary

d6.moussa@yahoo.com

00201221927446

Other Identifiers

PG study on cisplatin

Identifier Type: -

Identifier Source: org_study_id