POS-075 ASSOCIATION OF CYP3A5 POLYMORPHISM WITH INFECTIONS IN KIDNEY TRANSPLANT RECIPIENTS

Abstract

Kidney transplant recipients who are non-expressors (CYP3A5*3/*3 genotype) are known to have increased dose-adjusted trough concentrations of tacrolimus as compared with those who are CYP3A5 expressors (CYP3A5*1/*1 and CYP3A5*1/*3 genotypes), possibly delaying achievement of target concentrations. Also, tacrolimus increases the exposure of mycophenolate mofetil by 30%. Both these factors in patients who are non-expressors can increase the risk of infections. However, there is lack of data corelating CYP3A5 polymorphism with infections post-kidney transplant. We retrospectively evaluated 181 out of 260 kidney transplant recipients who were at regular follow up at the transplant clinic of a tertiary referral center in western India from 2018 to 2021. Recipients on tacrolimus for at least 3 months post-transplant were eligible for evaluation. They were categorized into non-expressors (CYP3A5*3/*3) and expressors (CYP3A5*1/*1 and CYP3A5*1/*3 genotype). The infectious burden was evaluated by the incidence of total infections and further classified according to etiologies such as bacterial, viral, parasitic, fungal and mycobacterial and specific system patterns such as diarrhea, urinary tract infections, tropical illnesses, infections of the skin, soft tissue and musculoskeletal system. The incidence of non-infectious diarrhea was evaluated as a measure of increased MMF exposure. Multivariate logistic regression was performed to evaluate the impact of genotype on the risk of infections. Out of 181 recipients, 103 (56.9%) were non-expressors and 78 (43%) were expressors. Mean (SD) age was 35±10 years with 128 (70.7%) being males. Their mean (SD) eGFR at enrollment was 57.72± 23.15 ml/min/1.73m2. Higher number of non-expressors received antibody induction at the time of transplant but this difference was not statistically significant (52.4% vs 42.3%, p= 0.177). New onset diabetes after transplant observed in the non-expressor group was higher, but did not reach statistical significance (37.2% vs 29.1%, p= 0.252). Overall incidence of infections was similar in both groups (85.4% vs 89.7%, p = 0.389), however tuberculosis was significantly more common in non-expressors (16.7 % vs 6.8%, p= 0.036). This association remained significant (p= 0.043) after controlling for factors such as history of tuberculosis before transplant, antibody induction, living vs deceased donor, triple or dual immunosuppression at time of transplant, and anti-rejection therapy. Infectious diarrhea, fungal infections, parasitic infections, were higher in non-expressors, but this difference was not statistically significant. Hospitalization for infectious diarrhea was significantly higher in non-expressors (20.5% vs 7.8%, p= 0.012). Non-infectious diarrhea attributed to MMF was significantly higher in non-expressors (32.1% vs 19.2%, p= 0.035). Viral infections were higher in non-expressors but were statistically insignificant (51.3% vs 40.8%, p= 0.160). Mortality due to infectious causes was higher in non-expressors but was not statistically significant (6.4% vs 3.9%, p= 0.439). Non-expressor CYP3A5 genotype in kidney transplant recipients is associated with a significant burden of infectious complications and a higher incidence of MMF induced diarrhea. A genotype-based approach may help individualizing dosing of tacrolimus in this population.