腎移植供腎MDR1基因多態(tài)性對他克莫司腎毒性和血藥濃度的影響
發(fā)布時間：2018-09-08 15:36
【摘要】：研究目的： 了解腎移植術后供腎MDR1基因外顯子26（exon26）及外顯子21（exon21）的基因多態(tài)性對于CNI類藥物他克莫司急、慢性腎毒性和血藥濃度的影響程度，探討服用FK506的腎移植受者中供腎MDRl基因多態(tài)性的意義，從而指導臨床醫(yī)師在臨床中對他克莫司的使用劑量的調整，減少他克莫司的毒副作用。通過供者與受者的合理配型減輕他克莫司在長期服用過程中對移植腎的慢性毒副作用，延長移植腎壽命。 研究內(nèi)容： 選取50例2012年7月至2013年2月期間在我院首次接受同種異體腎臟移植手術并術后常規(guī)使用FK506+MMF+Pred三聯(lián)免疫抑制用藥方案移植腎受者的臨床資料。提取供者血液或組織并分離出少量DNA樣本后進行聚合式酶聯(lián)反應（PCR）擴增，所得擴增產(chǎn)物采用sanger測序流程在3730XL測序儀上進行基因組測序，確定標本基因型。根據(jù)患者臨床資料，比較供腎MDR1exon21和exon26上不同基因型的患者FK506的日服用量、血藥濃度/劑量比和急、慢性腎毒性的差異。 結果： 通過基因測序，，測定供腎MDR1exon26基因型分為CC型、CT型、TT型，exon21基因型分為低表達型（TT型）和高表達型（GG/GT/GA/AT型）。本次實驗中共檢測50例基因組DNA樣本，其中MDR1exon21測得TT型7例、GG型9例、GT型20例、GA型4例、AT型10例；MDR1exon26測得CC型18例、TT型9例、CT型23例。MDR1exon26的變異型基因T為41%，野生型基因C為59%；MDR1exon21的變異型基因T為44%，野生型基因G為42%，少見型基因A為14%。在比較術后1周、1月、3月、6月及12月的受者FK506的日服用量和血藥濃度/劑量比時，exon26的CC型、CT型、TT型之間和exon21的低表達型（TT型）和高表達型（GG/GT/GA/AT型）之間未有顯著性差異（P0.05）。 在比較腎移植術后1月、3月、6月時的移植腎受者內(nèi)生肌酐清除率時，exon26的CC型、CT型、TT型之間未有顯著性差異（P0.05）,exon21的低表達型（TT型）和高表達型（GG/GT/GA/AT型）之間也未有顯著性差異（P0.05）。但在比較術后1年的移植腎受者內(nèi)生肌酐清除率時，在exon26中，TT型的內(nèi)生肌酐清除率（58.29+8.52ml/min）明顯低于CC型（66.89+15.21ml/min）和CT型（73.92+12.61ml/min）（P0.05），CC型和CT型之間的差異未有統(tǒng)計學意義。在exon21中，低表達型（TT型）的內(nèi)生肌酐清除率（58.29+8.52）明顯低于高表達型（GG/GT/GA/AT型）的內(nèi)生肌酐清除率（69.94+14.40）（P0.05）。 在比較術后1月內(nèi)的移植腎急性藥物性腎中毒發(fā)生率時，exon21中低表達型（TT型）大于高表達型（GG/GT/GA/AT型）（P0.05），exon26各基因型之間未有顯著性差異（P0.05）。 結論： 1、移植供腎MDR1exon26和exon21的各類基因型對于移植腎受者的FK506血藥濃度/劑量比未有顯著相關性。 2、在保護移植腎功能，減少FK506的急性和慢性腎毒性上，exon26的CC/CT型和exon21的高表達型明顯優(yōu)于exon26的的TT型和低表達型。
[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.
【學位授予單位】：第二軍醫(yī)大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R699.2
[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.
【學位授予單位】：第二軍醫(yī)大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R699.2
【共引文獻】
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