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Published on: November 8, 2015
Association of CYP3A5, ABCB1, and CYP2C8 Polymorphisms with Renal Function in Kidney Transplant Recipients Receiving
Zühal Kaltuş1, Nuşin Harmancı2, Garip Şahin3
1Department of Medical Pharmacology, Eskisehir City Hospital, Çavdarlar street. No:144/A, Odunpazari, Eskisehir, 26080, Turkey. zuhalkaltus@gmail.com.
Background/Objectives:
Tacrolimus (TAC, FK-506) is a calcineurin inhibitor commonly used to prevent organ rejection in transplant patients. It has a narrow therapeutic index and nephrotoxic effects, characterized by interindividual dose variability. TAC is metabolized by the CYP450 (CYP3A5, CYP3A4) enzyme system and transported by P-glycoprotein (ABCB1). Additionally, the CYP2C8 enzyme has been suggested to play a protective role against both graft rejection and drug-induced toxicity. Genetic polymorphisms in these pathways may influence the risk of tacrolimus-related nephrotoxicity. This retrospective cohort study was conducted to evaluate the association between CYP3A5, ABCB1, and CYP2C8 gene polymorphisms and renal function in kidney transplant recipients METHODS: This study investigated the impact of CYP3A5, ABCB1 and CYP2C8 polymorphisms on blood TAC level and kidney function in renal transplant patients. Genotyping was conducted to determine allele frequencies for CYP3A5 (6986A>G), ABCB1 (13435C>T), and CYP2C8 (A1196G) polymorphisms. Renal function was assessed by measuring serum creatinine, estimated glomerular filtration rate (eGFR), and protein/creatinine ratios at 3, 6, and 12 months post-transplantation.
Result:
At 12 months post-transplant, the median serum creatinine level was significantly higher in patients with CYP2C8 (*1/*3 and *3/*3) genotypes compared to those with the CYP2C8*1/*1 genotype (p = 0.021). Additionally, the increase in creatinine from the 3rd to the 12th month was significantly greater in the CYP2C8 (*1/*3 and *3/*3) group (p = 0.036). No significant differences were observed in TAC dosage, blood concentration, or renal function between ABCB1 genotype groups. Although daily TAC doses differed significantly between CYP3A5 genotypes, renal function did not significantly vary.
Conclusion:
In light of these data, CYP2C8 gene polymorphism has been associated with an increase in serum creatinine, one of the key markers of renal function. ABCB1 gene polymorphism showed no association while CYP3A5 gene polymorphism influenced TAC dose; however, further studies with larger cohorts are required to clarify these associations.
Insights
Genetic variations in CYP2C8 influence kidney function in transplant patients taking tacrolimus (TAC). CYP2C8 gene polymorphism is linked to increased serum creatinine, a marker of renal function, in kidney transplant recipients.
Area of Science:
- Pharmacogenomics
- Transplantation Medicine
- Nephrology
Background:
- Tacrolimus (TAC) is crucial for preventing organ rejection but has a narrow therapeutic index and nephrotoxic potential.
- Interindividual variability in TAC response is influenced by genetic factors affecting its metabolism and transport.
- CYP2C8 is implicated in a protective role against graft rejection and drug toxicity.
Purpose of the Study:
- To investigate the association between CYP3A5, ABCB1, and CYP2C8 gene polymorphisms and renal function in kidney transplant recipients.
- To evaluate the impact of these polymorphisms on tacrolimus blood levels and kidney function post-transplantation.
Main Methods:
- Retrospective cohort study analyzing kidney transplant recipients.
- Genotyping for CYP3A5 (6986A>G), ABCB1 (13435C>T), and CYP2C8 (A1196G) polymorphisms.
- Assessment of renal function via serum creatinine, eGFR, and protein/creatinine ratio at 3, 6, and 12 months post-transplant.
Main Results:
- CYP2C8 (*1/*3 and *3/*3) genotypes were associated with significantly higher serum creatinine levels at 12 months post-transplant compared to CYP2C8*1/*1.
- A greater increase in creatinine from 3 to 12 months was observed in patients with CYP2C8 (*1/*3 and *3/*3) genotypes.
- No significant associations were found between ABCB1 polymorphisms and renal function or TAC levels. CYP3A5 genotypes affected TAC dose but not renal function.
Conclusions:
- CYP2C8 gene polymorphism is associated with increased serum creatinine, indicating an impact on renal function.
- ABCB1 gene polymorphism showed no association with renal function.
- CYP3A5 gene polymorphism influences TAC dosage, but further research with larger cohorts is needed to clarify these associations.
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