Thishya Kalluri, Sreenu Boddupally, Raju Sree B, Kutala Vijay Kumar
Department of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences (NIMS), Hyderabad, Telangana, India.
Department of Nephrology, Nizam's Institute of Medical Sciences (NIMS), Hyderabad, Telangana, India.
Curr Drug Metab. 2021;22(5):342-352. doi: 10.2174/1389200222666210114123349.
Graft acceptance against immunity is one of the major 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.
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.
A total of 255 renal transplant recipients were analyzed for the pharmacogenetic determinants of tacrolimus (CYP3A53 ABCB1 1236 T>C ABCB1 2677 G>A/T ABCB1 3435 T>C) and mycophenolate (UGT1A83 UGT1A9 IMPDH I IMPDH II c.787C>T ABCC2 -24 C>T and c.3972C>T) using Sanger sequencing.
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.
Genetic variants in tacrolimus and mycophenolate metabolic pathways were found to influence the morbidity and mortality in renal transplant recipients.
移植物对免疫的接受是实体器官移植中的主要挑战之一。免疫抑制药物有效地改善了移植后的结果，然而，它有其自身的局限性。药物代谢酶中的基因多态性已被确定为制定药物遗传学策略的潜在靶点，以实现药物剂量个体化并预防不良事件。
本研究的基本原理是探索他克莫司和霉酚酸代谢途径中的多态性，这些多态性会影响肾移植受者的不良临床结局。
使用桑格测序法对总共255名肾移植受者进行了他克莫司（CYP3A53、ABCB1 1236 T>C、ABCB1 2677 G>A/T、ABCB1 3435 T>C）和霉酚酸（UGT1A83、UGT1A9、IMPDH I、IMPDH II、c.787C>T、ABCC2 -24 C>T和c.3972C>T）的药物遗传学决定因素分析。
5.88%的移植受者发生了急性排斥反应（AR），而在维持期早期，7.45%的患者发生了急性肾小管坏死（ATN）。11.37%和12.16%的患者发生了诸如尿路感染（UTI）和巨细胞病毒（CMV）感染等感染。感染风险增加的患者中霉酚酸的曲线下面积（AUC）显著更高。ABCC2 -24 C>T、c.3972C>T多态性和ABCB1 3435 C等位基因与感染风险降低相关。ABCC2 rs3740066与全因死亡风险增加2.06倍相关。CYP3A5 AG基因型和UGT1A9 -440 CC基因型显示风险增加，而ABCC 3972C>T CC基因型对不良事件具有保护作用。
发现他克莫司和霉酚酸代谢途径中的基因变异会影响肾移植受者的发病率和死亡率。
