Krall Paola, Yañez Dominique, Rojo Angélica, Delucchi Ángela, Córdova Miguel, Morales Jorge, Boza Pía, de la Rivera Alonso, Espinoza Natalie, Armijo Natalia, Castañeda Luis E, Farfán Mauricio J, Salas Carolina
Departamento de Pediatría y Cirugía Infantil Oriente, Facultad de Medicina, Universidad de Chile, Santiago de Chile, Chile.
Laboratorio Clínico, Hospital Luis Calvo Mackenna, Santiago de Chile, Chile.
Front Pharmacol. 2021 Apr 22;12:653525. doi: 10.3389/fphar.2021.653525. eCollection 2021.
Tacrolimus (TAC) and mycophenolic acid (MPA) are the main immunosuppressive drugs used in pediatric kidney transplantation. Single nucleotide polymorphisms (SNPs) in metabolizing enzymes and transporters might influence plasma levels of these drugs. Herein, we sought to determine the influence of SNPs on , and genes in Chilean pediatric kidney recipients using TAC and MPA. A prospective study was performed on 104 pediatric kidney recipients that used TAC and MPA for immunosuppression. The median age at the time of transplantation was 8.1 years [Q1-Q3 4.5-11.6 years] and the main clinical diagnosis was a structural anomaly. In a subgroup of patients, a complete steroid withdrawal was made at day 7. The polymorphism (ancestral allele *1; variant allele *3) was determined in the entire cohort, while -24G > A, -275T > A, and -2152C > T polymorphisms were determined in 53 patients. Genotypes were associated with trough drug concentrations (C), dose requirements normalized by weight (TAC-D mg/kg) or body surface (MPA-D mg/m2), trough levels normalized by dose requirements (C/D), and area under the curve in 12 h normalized by dose requirements (AUC/D). The frequencies of the variant alleles , , , and were 76.9, 22.1, 6.6, and 2.9%, respectively. AUC/TAC-D were 1.6-fold higher in patients than in carriers ( and ). When analyzing patients with steroid withdrawal, patients had 1.7-fold higher AUC/TAC-D than the other genotypes. Patients carrying the genotype had higher TAC-C, lower TAC-D and higher TAC-C/D, consistently in a 6-months follow-up. Creatinine clearance was stable during the follow-up, regardless of the genotype. No significant differences between and genotypes were observed in MPA-C, MPA-D or MPA-C/D. However, patients carrying the allele had lower AUC/MPA-D than those carrying the ancestral allele. These results support that and genotyping in pediatric recipients might be useful and advisable to guide TAC and MPA dosing and monitoring in children that undergo kidney transplantation.
他克莫司（TAC）和霉酚酸（MPA）是小儿肾移植中使用的主要免疫抑制药物。代谢酶和转运蛋白中的单核苷酸多态性（SNP）可能会影响这些药物的血浆水平。在此，我们试图确定SNP对智利使用TAC和MPA的小儿肾移植受者中 、 和 基因的影响。 对104名使用TAC和MPA进行免疫抑制的小儿肾移植受者进行了一项前瞻性研究。移植时的中位年龄为8.1岁[第一四分位数 - 第三四分位数 4.5 - 11.6岁]，主要临床诊断为结构异常。在一组患者中，在第7天完全停用类固醇。在整个队列中确定了 多态性（祖先等位基因1；变异等位基因3），而在53名患者中确定了 -24G>A、 -275T>A和 -2152C>T多态性。基因型与谷浓度（C）、按体重标准化的剂量需求（TAC-D mg/kg）或体表面积（MPA-D mg/m²）、按剂量需求标准化的谷水平（C/D）以及按剂量需求标准化的12小时曲线下面积（AUC/D）相关。 变异等位基因 、 、 和 的频率分别为76.9%、22.1%、6.6%和2.9%。 患者的AUC/TAC-D比 携带者高1.6倍（ 和 ）。在分析停用类固醇的患者时， 患者的AUC/TAC-D比其他基因型高1.7倍。在6个月的随访中，携带 基因型的患者始终具有较高的TAC-C、较低的TAC-D和较高的TAC-C/D。随访期间肌酐清除率稳定，与基因型无关。在MPA-C、MPA-D或MPA-C/D中未观察到 和 基因型之间的显著差异。然而，携带 等位基因的患者的AUC/MPA-D低于携带祖先等位基因 的患者。 这些结果支持，对小儿肾移植受者进行 和 基因分型可能有助于并建议用于指导接受肾移植儿童的TAC和MPA给药及监测。
