RESUMO
Objective To investigate the clinical efficacy of cyclosporine injection in subclinical or critical treatment of renal transplant patients，and to establish an individualized dosage regimen of cyclosporine injection by studying the effects of nine single nucleotide polymorphisms related to the pharmacokinetics of cyclosporine on the dose-adjusted trough concentration (C0/D′) of cyclosporine injection. Methods Blood samples and clinical data of 144 adult renal transplant patients who used cyclosporine injection were collected and recorded, then, their genotypes of CYP3A4*18B, CYP3A5*3, ABCB1 (C1236T, G2677T/A, C3435T), POR*28, PXR (C5705T, C39823T) and NFKB1-94 ins/del ATTG were determined by Sequenom MassARRAY® SNP methods. Then, the discrepancies of cyclosporine injection’s C0/D′ among the patients with different genotypes was compared and an individualized dosage regimen based on gene polymorphism of cyclosporine injection was established by using multivariate regression analysis. Results Cyclosporine injection improved serum creatinine level by 68.8% in renal transplant patients with subclinical or critical rejection, and the steady-state plasma concentration was (189.50±38.56) ng/ml. The CYP3A4*18B gene polymorphism was significantly correlated to C0/D' of cyclosporine injection, and the C0/D' of patients with *1/*1 genotype was significantly higher than patients of *18B/*18B genotype; but CYP3A5*3, ABCB1(C1236T, G2677T/A, C3435T), PXR C5705T, PXR C39823T, NFKB1-94 ins/del ATTG and POR*28 gene polymorphisms were not significantly correlated to C0/D' of cyclosporine injection. In the final regression model, hemoglobin and CYP3A4*18B gene polymorphisms were significantly correlated to C0/D' of cyclosporine injection. Conclusion Cyclosporine injection can effectively improve the serum creatinine level in patients with subclinical or critical rejection; CYP3A4*18B gene polymorphism is significantly correlated to C0/D' of cyclosporine injection.
RESUMO
OBJECTIVE： To investigate the relationship between ATP-binding cassette subfamily B member 1 （ABCB1） polymorphism and tacrolimus-related adverse drug reactions in renal transplant patients during perioperative period. METHODS： Totally 170 patients who underwent renal transplantation from Nov. 2014 to Mar. 2018 in our hospital as well as were tested for their ABCB1 C1236T （rs1128503）， ABCB1 G2677T/A （rs2032582） and ABCB1 C3435T （rs1045642） genotype were selected in this study. χ2 test was used to compare the incidence of tacrolimus-related ADR among patients with different genotypes. The related adverse reactions included digestive tract reaction， pulmonary infection， renal dysfunction， abnormal liver function， elevated blood sugar， elevated blood lipid and decreased white blood cells. Logistic regression model was used to analyze the unit point risk. The main haplotypes of the above genes were analyzed by PHASE software， and their correlation with tacrolimus-induced ADR was analyzed. RESULTS： Among 170 patients， 21 cases （12.3％） of CC type， 78 cases （45.9％） of CT type and 71 cases （41.8％） of TT type were detected by ABCB1 C1236T （rs1128503）. ABCB1 G2677T/A （rs2032582） test showed that 25 cases （14.7％） were GG type， 95 cases （55.9％） were GA+GT type and 50 cases （29.4％） were AA+AT+TT type. ABCB1 C3435T （rs1045642） test showed that 57 cases （33.5％） were CC type， 82 cases （48.2％） were CT type and 31 cases （18.3％） were TT type. There was no significant difference in the incidence of digestive tract reaction， pulmonary infection， renal dysfunction， elevated blood sugar， elevated blood lipid and decreased white blood cells among patients with different ABCB1 genotypes （P＞0.05）. However， there was significant difference in the incidence of abnormal liver function between ABCB1 C1236T （rs1128503） and ABCB1 C3435T （rs1045642） genotypes （P＜0.05）. There was no significant difference in the incidence of abnormal liver function among ABCB1 G2677T/A （rs2032582） genotypes （P＝0.069）， but P was lower than 0.1. Logistic regression analysis showed that ABCB1 C1236T （rs1128503） CC genotype [OR＝4.959， 95％CI （1.700， 14.468）， P＝0.003]， ABCB1 G2677T/A （rs2032582） GG genotype [OR＝3.500， 95％CI （1.164， 10.524）， P＝0.026] and ABCB1 C3435T （rs1045642） CC genotype [OR＝3.033， 95％CI （1.012， 9.095）， P＝0.048] were risk factors for tacrolimus-related abnormal liver function. ABCB1 CGC haplotype was the main haplotype. There was significant difference in the incidence of abnormal liver function caused by tacrolimus between ABCB1 CGC haplotype and non-ABCB1 CGC haplotype （P＝0.002）， and it was also a risk factor for tacrolimus-related liver dysfunction [OR＝3.173， 95％CI（1.512， 6.656）， P＝0.002]. CONCLUSIONS： The abnormal liver function of ABCB1 CGC haplotype kidney transplantation patients is more likely to occur when tacrolimus is administered during the perioperative period.