肾移植供肾MDR1基因多态性对他克莫司肾毒性和血药浓度的影响

发布时间：2018-09-08 15:36

【摘要】：研究目的：了解肾移植术后供肾MDR1基因外显子26（exon26）及外显子21（exon21）的基因多态性对于CNI类药物他克莫司急、慢性肾毒性和血药浓度的影响程度，探讨服用FK506的肾移植受者中供肾MDRl基因多态性的意义，从而指导临床医师在临床中对他克莫司的使用剂量的调整，减少他克莫司的毒副作用。通过供者与受者的合理配型减轻他克莫司在长期服用过程中对移植肾的慢性毒副作用，延长移植肾寿命。研究内容：选取50例2012年7月至2013年2月期间在我院首次接受同种异体肾脏移植手术并术后常规使用FK506+MMF+Pred三联免疫抑制用药方案移植肾受者的临床资料。提取供者血液或组织并分离出少量DNA样本后进行聚合式酶联反应（PCR）扩增，所得扩增产物采用sanger测序流程在3730XL测序仪上进行基因组测序，确定标本基因型。根据患者临床资料，比较供肾MDR1exon21和exon26上不同基因型的患者FK506的日服用量、血药浓度/剂量比和急、慢性肾毒性的差异。结果：通过基因测序，，测定供肾MDR1exon26基因型分为CC型、CT型、TT型，exon21基因型分为低表达型（TT型）和高表达型（GG/GT/GA/AT型）。本次实验中共检测50例基因组DNA样本，其中MDR1exon21测得TT型7例、GG型9例、GT型20例、GA型4例、AT型10例；MDR1exon26测得CC型18例、TT型9例、CT型23例。MDR1exon26的变异型基因T为41%，野生型基因C为59%；MDR1exon21的变异型基因T为44%，野生型基因G为42%，少见型基因A为14%。在比较术后1周、1月、3月、6月及12月的受者FK506的日服用量和血药浓度/剂量比时，exon26的CC型、CT型、TT型之间和exon21的低表达型（TT型）和高表达型（GG/GT/GA/AT型）之间未有显著性差异（P0.05）。在比较肾移植术后1月、3月、6月时的移植肾受者内生肌酐清除率时，exon26的CC型、CT型、TT型之间未有显著性差异（P0.05）,exon21的低表达型（TT型）和高表达型（GG/GT/GA/AT型）之间也未有显著性差异（P0.05）。但在比较术后1年的移植肾受者内生肌酐清除率时，在exon26中，TT型的内生肌酐清除率（58.29+8.52ml/min）明显低于CC型（66.89+15.21ml/min）和CT型（73.92+12.61ml/min）（P0.05），CC型和CT型之间的差异未有统计学意义。在exon21中，低表达型（TT型）的内生肌酐清除率（58.29+8.52）明显低于高表达型（GG/GT/GA/AT型）的内生肌酐清除率（69.94+14.40）（P0.05）。在比较术后1月内的移植肾急性药物性肾中毒发生率时，exon21中低表达型（TT型）大于高表达型（GG/GT/GA/AT型）（P0.05），exon26各基因型之间未有显著性差异（P0.05）。结论： 1、移植供肾MDR1exon26和exon21的各类基因型对于移植肾受者的FK506血药浓度/剂量比未有显著相关性。 2、在保护移植肾功能，减少FK506的急性和慢性肾毒性上，exon26的CC/CT型和exon21的高表达型明显优于exon26的的TT型和低表达型。
[Abstract]:Objective: to investigate the effect of gene polymorphisms of donor kidney MDR1 gene exon 26 (exon26) and exon 21 (exon21) on the renal toxicity and serum concentration of tacrolimus in patients with CNI. To explore the significance of donor kidney MDRl gene polymorphism in renal transplant recipients taking FK506, so as to guide clinicians to adjust the dosage of tacrolimus and reduce the toxic side effects of tacrolimus. The chronic side effects of tacrolimus on kidney graft were alleviated by reasonable matching of donor and recipient, and the life span of transplanted kidney was prolonged. Content: the clinical data of 50 patients who received the first renal allograft transplantation in our hospital from July 2012 to February 2013 and were routinely treated with FK506 MMF Pred triple immunosuppressive regimen after operation were selected. The donor blood or tissue was extracted and a small amount of DNA samples were isolated and amplified by polymerase chain reaction (PCR). The amplified products were sequenced by sanger sequencing process on 3730XL sequencer to determine the genotypes of the samples. According to the clinical data of the patients, the difference of daily dosage, blood concentration / dose ratio, acute and chronic nephrotoxicity of patients with different genotypes on MDR1exon21 and exon26 were compared. Results: the MDR1exon26 genotypes of donor kidney were divided into CC type, CT type, TT type and TX on21 genotype by gene sequencing. They were divided into low expression type (TT type) and high expression type (GG/GT/GA/AT type). A total of 50 genomic DNA samples were detected in this experiment. Among them, 7 cases of TT type GG type 9 cases of GT type 20 cases of GA type 4 cases of AT type 10 cases of MDR1exon26 detected the variant gene T of CC type 18 cases of TT type 9 cases of CT type 23 cases. MDR1exon26 gene T was 41B and the wild-type gene C was 595.00%. The variant gene T of MDR1exon21 was 44%, that of wild-type gene G was 42%, and that of rare type gene A was 14%. There was no significant difference between the daily dosage of FK506 and the blood concentration / dose ratio of CC type CT type TT and exon21 low expression type (TT type) and high expression type (GG/GT/GA/AT type) of the recipients at 1 week, 1 month, 3 months, 6 months and 12 months after operation (P0.05). There was no significant difference between the CC / CT / TT type (P0.05) and the low expression type (TT type) and the high expression type (GG/GT/GA/AT type) of exon21 in renal transplant recipients at 1 month, 3 months and 6 months after renal transplantation (P 0.05). However, in the comparison of endogenous creatinine clearance rates in exon26 recipients 1 year after operation, the endogenous creatinine clearance rates of TT type (58.29 8.52ml/min) were significantly lower than those of CC type (66.89 15.21ml/min) and CT type (73.92 12.61ml/min) (P0.05). There was no significant difference between CC type and CT type in exon26. In exon21, the clearance rate of endogenous creatinine in low expression type (TT type) (58.298.52) was significantly lower than that in high expression type (GG/GT/GA/AT type (69.94 14.40) (P0.05). In comparing the incidence of acute drug-induced renal poisoning within 1 month after transplantation, there was no significant difference among the genotypes of low expression type (TT type) and high expression type (GG/GT/GA/AT type) (P0.05). Conclusion: 1. There is no significant correlation between the genotypes of MDR1exon26 and exon21 in renal graft recipients and the ratio of serum drug concentration / dose of FK506 to renal allograft recipients. 2. The CC/CT type and the high expression type of exon21 in reducing acute and chronic nephrotoxicity of FK506 were significantly better than those of TT and low expression in exon26.
【学位授予单位】：第二军医大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R699.2

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