Kalluri Thishya, Boddupally Sreenu, Shree Bhushan Raju and Vijay Kutala*
Background: Graft acceptance against immunity is one of themajor challenges in solid organ transplant. Immunosuppressive medications have effectively improved the post-transplantation outcome; however it has its own limitations. Genetic polymorphisms in drug-metabolizing enzymes have been identified as the potential targets in developing a pharmacogenetic strategy, to individualize drug dose and also in preventing the adverse events.
Objective: The rationale of the study was to explore polymorphisms in tacrolimus and mycophenolate metabolic pathways that influence the adverse clinical outcomes in renal transplant recipients.
Methods: A total of 255 renal transplant recipients were analyzed for the pharmacogenetic determinants of tacrolimus (CYP3A5*3, ABCB1 1236 T>C, ABCB1 2677 G>A/T, ABCB1 3435 T>C) and mycophenolate (UGT1A8*3, UGT1A9, IMPDH I, IMPDH II c.787C>T , ABCC2 -24 C>T and c.3972C>T) using Sanger sequencing.
Results: Acute rejection (AR) was observed in 5.88% of the transplant recipients, whereas, acute tubular necrosis (ATNs) was observed in 7.45% of the patients, within early stage of the maintenance phase. Infections, such as urinary tract infection (UTI) and cytomegalovirus (CMV) infection were observed in 11.37% and 12.16% of the patients. The AUC of mycophenolate was significantly higher in patients with increased risk for infections. ABCC2 -24 C>T, c.3972C>T polymorphisms and ABCB1 3435 C-allele, were associated with reduced risk for infections. ABCC2 rs3740066 was associated with 2.06-fold all-cause mortality risk. CYP3A5 AG- and UGT1A9-440 CC-genotypes showed increased risk, and ABCC 3972C>T, CC-genotype showed protection against adverse events.
Conclusion: Genetic variants in tacrolimus and mycophenolate metabolic pathways were found to influence the morbidity and mortality in renal transplant recipients.
Tacrolimus, mycophenolate, renal transplant, acute rejection, adverse events, CYP3A5, ABCB1, UGT1A9, IMPDH.
Nizam's Institute of Medical Sciences, Clinical Pharmacology& Therapeutics, Nizam's Institute of Medical Sciences, Clinical Pharmacology& Therapeutics, Nizam's Institute of Medical Sciences, Nephrology , Nizam's Institute of Medical Sciences, Clinical Pharmacology& Therapeutics