The impact of pharmacogenetic polymorphisms in tacrolimus-based immunosuppressive therapy on clinical outcomes, expenditures and quality of life in kidney transplant recipients

Abstract

Successful kidney transplant required appropriate use of immunosuppressive drugs. Even so, there is no guarantee of an optimal outcome free from transplant-related complications. Hence, personalized pharmacotherapy based on unique genetic data may enhance clinical outcomes and reduce complications. This study aimed to identify clinical efficacy, adverse drug reactions (ADRs) and clinical outcomes and to determine the impact of CYP3A5 and MRP2/ABCC2 polymorphisms on clinical outcomes, expenditures and health-related quality of life (HRQOL) among kidney transplant recipients (KTRs) receiving tacrolimus-mycophenolic acid (MPA)-prednisolone immunosuppression in Malaysia. Patient and graft survival rates were 99.6% and 97.7% respectively at 1-year and 99.2% and 96.1% at 2-years. Leukopenia was a risk factor associated with decreased graft survival (hazard ratio [HR], 5.49; 95% confidence interval [CI], 1.19 –25.35; P=0.03). There was a significant difference in patient survival among patients with or without acute tubular necrosis (ATN), had history of hospitalization for infection or not and among the different dialysis modalities. We examined the impact of CYP3A5*3, ABCC2 -24C>T and ABCC2 3972C>T polymorphisms on clinical outcomes. Compared to CYP3A5 non-expresser group (CYP3A5*3/*3), the tacrolimus dose was 1.8-fold higher at month 1, 2.3-fold at month 3 and month 6 and 2.2-fold at month 12 (p <0.001). We also found significantly more KTRs with ABCC2 -24C>T C wildtype allele experienced infection-related ADRs (59.7% vs. 31.3%; p =0.04). Analysis revealed that factors associated with increased risk of developing graft survival with acute graft rejection and/or ATN were wildtype ABCC2 -24C>T C allele (adjusted Odd Ratio [aOR]: 27.68, 95% CI: 1.20, 636.15), presence of delayed graft failure (aOR: 49.21, 95% CI: 2.37, 1023.73) and cytomegalovirus infection (aOR: 18.10, 95% CI: 2.04, 160.87). This is the first report on the impact of ABCC2 -24C>T genetic polymorphism on clinical outcomes in Malaysian KTRs. The final study verified that CYP3A5*3 spending was 24.8% higher than CYP3A5*1 spending (MYR 60,257.67 vs. MYR 48,281.61; p <0.001). The ICER for achieving graft survival without acute graft rejection and/or ATN was more costeffective among CYP3A5*1 wildtype allele and variant allele of ABCC2 -24C>T T and ABCC2 3972C>T T. The EQ-5D-5L QOL scores were not significantly different by CYP3A5 and MRP2/ABCC2 polymorphism status. We conclude the potential benefits of ABCC2 -24C>T genotyping for risk identification and improving overall transplant outcome in potential KTRs.