Correlation between tacrolimus and diabetes mellitus after kidney transplantation: a single center study
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摘要:
目的 探讨移植后糖尿病(PTDM)的主要危险因素,分析他克莫司与肾移植PTDM发生的相关性。 方法 收集123例肾移植受者的临床资料,分为PTDM组(19例)和非PTDM组(104例)。分析两组受者的临床资料,采用二元logistic回归分析PTDM的危险因素。将24只小鼠分为对照组(生理盐水),他克莫司低剂量组(0.1 mg/kg)、中剂量组(0.75 mg/kg)和高剂量组(1.5 mg/kg),每组各6只,分别每日注射2次。分析他克莫司对小鼠血糖代谢的影响。 结果 肾移植术后1年内PTDM发生率为15.4%(19/123)。受者年龄≥48岁、移植术后3个月他克莫司谷浓度≥9 ng/mL是肾移植术后发生PTDM的危险因素(均为P < 0.05)。低剂量组、中剂量组和高剂量组小鼠给药后的空腹血糖水平低于给药前(均为P < 0.05),但不具有剂量依赖性(P=0.750)。低剂量组、中剂量组和高剂量组小鼠给药后餐后血糖水平高于给药前(均为P < 0.05),且呈现他克莫司剂量依赖性(P=0.012)。 结论 他克莫司与肾移植术后PTDM发生密切相关,受者年龄≥48岁、移植术后3个月他克莫司谷浓度≥9 ng/mL是PTDM发生的独立危险因素。他克莫司以剂量依赖性的方式影响小鼠餐后血糖水平。 Abstract:Objective To explore the major risk factors of post transplantation diabetes mellitus (PTDM) and analyze the correlation between tacrolimus and PTDM after kidney transplantation. Methods Clinical data of 123 kidney transplant recipients were collected. All recipients were divided into the PTDM group (n=19) and non-PTDM group (n=104). Clinical data of all recipients in two groups were analyzed. The risk factors of PTDM were analyzed by binary logistic regression. Twenty-four mice were evenly divided into the control group (normal saline), low-dose tacrolimus (0.1 mg/kg), medium-dose tacrolimus (0.75 mg/kg) and high-dose tacrolimus groups (1.5 mg/kg). The solutions were given twice a day. The effect of tacrolimus on blood glucose metabolism in mice was evaluated. Results The incidence of PTDM was 15.4% (19/123) within 1 year after kidney transplantation. Age≥48 years old and the trough concentration of tacrolimus≥9 ng/mL within 3 months after kidney transplantation were the risk factors for PTDM after kidney transplantation (both P < 0.05). The fasting blood glucose levels of mice after administration in the low-, medium- and high-dose tacrolimus groups were significantly lower than those before administration (all P < 0.05) in a dose-independent manner (P=0.750). In the low-, medium- and high-dose tacrolimus groups, the postprandial blood glucose levels of mice after administration were significantly higher than those before administration (all P < 0.05) in a dose-dependent manner (P=0.012). Conclusions Tacrolimus is intimately correlated with the incidence of PTDM after kidney transplantation. Age≥48 years old and the trough concentration of tacrolimus ≥9 ng/mL within 3 months after kidney transplantation are the independent risk factors of PTDM. Tacrolimus affects the postprandial blood glucose levels of mice in a dose-dependent manner. -
表 1 两组受者一般资料比较
Table 1. Comparison of general data of recipients between the two groups
变量 PTDM组(n=19) 非PTDM组(n=104) 统计值 P值 年龄(x±s,岁) 48±8 40±11 3.17 0.004 性别(男性)[n(%)] 16(84) 72(69) 1.77 0.162 BMI(x±s,kg/m2) 22±4 22±3 0.10 0.730 糖尿病家族史[n(%)] 1(5) 3(3) -① 0.494 丙型病毒性肝炎史[n(%)] 0 1(1) - 1.000 透析类型[n(%)] - 0.901 血液透析 16(84) 79(76) 腹膜透析 2(11) 17(16) 未透析 1(5) 8(8) 术前糖化白蛋白(x±s,%) 14.4±3.3 14.1±2.1 0.35 0.889 术前低密度脂蛋白胆固醇(x±s,mmol/L) 2.3±0.8 2.5±0.8 -1.37 0.376 术前甘油三酯[M(P25,P75),mmol/L] 1.40(1.00,1.67) 1.33(1.00,1.50) 0.42 0.803 注:①-为无数据。 表 2 肾移植术后发生PTDM的危险因素分析
Table 2. Analysis of the risk factors for PTDM after kidney transplantation
变量 PTDM组(n=19) 非PTDM组(n=104) OR①值 P值 年龄(x±s,岁) 48±8 40±11 1.077 0.004 诱导药物[n(%)] 1.201 0.726 抗胸腺细胞球蛋白 7(37) 34(33) 巴利昔单抗 12(63) 70(67) 感染[n(%)] 8(42) 48(46) 0.848 0.744 排斥反应[n(%)] 0 3(2.9) < 0.001 1.000 糖皮质激素累积剂量(x±s,g) 1.9±0.1 1.9±0.1 1.000 1.000 他克莫司谷浓度 首次[M(P25,P75),ng/mL] 5.1(4.0,11.9) 9.7(6.2,12.8) 0.916 0.181 术后1个月(x±s,ng/mL) 9.2±3.3 10.0±2.9 0.910 0.650 术后3个月(x±s,ng/mL) 9.0±1.5 7.1±1.5 2.467 < 0.001 术后6个月(x±s,ng/mL) 7.2±1.6 6.7±1.5 1.167 0.249 术后12个月(x±s,ng/mL) 6.4±1.5 6.2±1.3 1.026 0.869 术前BMI(x±s,kg/m2) 22±4 22±3 1.006 0.917 术前糖化白蛋白(x±s,%) 14.4±3.3 14.1±2.1 1.060 0.894 术前低密度脂蛋白胆固醇(x±s,mmol/L) 2.3±0.8 2.5±0.8 0.611 0.979 术前甘油三酯[M(P25,P75),mmol/L] 1.40(1.00,1.76) 1.33(1.00,1.50) 1.143 0.308 注:①OR为比值比。 -
[1] VALDERHAUG TG, HJELMESÆTH J, JENSSEN T, et al. Early posttransplantation hyperglycemia in kidney transplant recipients is associated with overall long-term graft losses[J]. Transplantation, 2012, 94(7): 714-720. DOI: 10.1097/TP.0b013e31825f4434. [2] PONTICELLI C, FAVI E, FERRARESSO M. New-onset diabetes after kidney transplantation[J]. Medicina (Kaunas), 2021, 57(3): 250. DOI: 10.3390/medicina57030250. [3] JENSSEN T, HARTMANN A. Post-transplant diabetes mellitus in patients with solid organ transplants[J]. Nat Rev Endocrinol, 2019, 15(3): 172-188. DOI: 10.1038/s41574-018-0137-7. [4] HECKING M, SHARIF A, ELLER K, et al. Management of post-transplant diabetes: immunosuppression, early prevention, and novel antidiabetics[J]. Transpl Int, 2021, 34(1): 27-48. DOI: 10.1111/tri.13783. [5] SZILI-TOROK T, SOKOOTI S, OSTÉ MCJ, et al. Remnant lipoprotein cholesterol is associated with incident new onset diabetes after transplantation (NODAT) in renal transplant recipients: results of the TransplantLines biobank and cohort studies[J]. Cardiovasc Diabetol, 2022, 21(1): 41. DOI: 10.1186/s12933-022-01475-y. [6] ZHANG K, ZHENG S. The need for deepened molecular mechanism exploration in new onset diabetes after transplantation (NODAT)[J]. Hepatobiliary Surg Nutr, 2021, 10(6): 896-898. DOI: 10.21037/hbsn-2021-22. [7] 中华医学会器官移植学分会. 中国移植后糖尿病诊疗技术规范(2019版)[J]. 器官移植, 2019, 10(1): 1-9. DOI: 10.3969/j.issn.1674-7445.2019.01.001.Branch of Organ Transplantation of Chinese Medical Association. Technical specification for the diagnosis and treatment of posttransplant diabetes in China (2019 edition)[J]. Organ Transplant, 2019, 10(1): 1-9. DOI: 10.3969/j.issn.1674-7445.2019.01.001. [8] YOUSIF E, ABDELWAHAB A. Post-transplant diabetes mellitus in kidney transplant recipients in Sudan: a comparison between tacrolimus and cyclosporine-based immunosuppression[J]. Cureus, 2022, 14(2): e22285. DOI: 10.7759/cureus.22285. [9] CHEVALLIER E, JOUVE T, ROSTAING L, et al. pre-existing diabetes and PTDM in kidney transplant recipients: how to handle immunosuppression[J]. Expert Rev Clin Pharmacol, 2021, 14(1): 55-66. DOI: 10.1080/17512433.2021.1851596. [10] HWANG H, GHEE JY, SONG JH, et al. Comparison of adverse drug reaction profiles of two tacrolimus formulations in rats[J]. Immunopharmacol Immunotoxicol, 2012, 34(3): 434-442. DOI: 10.3109/08923973.2011.618135. [11] RODRÍGUEZ-RODRÍGUEZ AE, PORRINI E, HORNUM M, et al. Post-transplant diabetes mellitus and prediabetes in renal transplant recipients: an update[J]. Nephron, 2021, 145(4): 317-329. DOI: 10.1159/000514288. [12] DAI C, WALKER JT, SHOSTAK A, et al. Tacrolimus- and sirolimus-induced human β cell dysfunction is reversible and preventable[J]. JCI Insight, 2020, 5(1): e130770. DOI: 10.1172/jci.insight.130770. [13] RODRIGO E, PIÑERA C, DE COS MA, et al. Evolution of tacrolimus blood levels and concentration-dose ratios in patients who develop new onset diabetes mellitus after kidney transplantation[J]. Transpl Int, 2005, 18(10): 1152-1157. DOI: 10.1111/j.1432-2277.2005.00191.x. [14] PIRSCH JD, MILLER J, DEIERHOI MH, et al. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation[J]. Transplantation, 1997, 63(7): 977-983. DOI: 10.1097/00007890-199704150-00013. [15] JOHNSON C, AHSAN N, GONWA T, et al. Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporine (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation[J]. Transplantation, 2000, 69(5): 834-841. DOI: 10.1097/00007890-200003150-00028. [16] WU Y, LEVIS B, RIEHM KE, et al. Equivalency of the diagnostic accuracy of the PHQ-8 and PHQ-9: a systematic review and individual participant data Meta-analysis[J]. Psychol Med, 2020, 50(8): 1368-1380. DOI: 10.1017/S0033291719001314. [17] 周厚地, 郑宏庭, 隆敏. 移植后糖尿病的药物治疗研究进展[J]. 解放军医学杂志, 2020, 45(6): 657-662. DOI: 10.11855/j.issn.0577-7402.2020.06.14.ZHOU HD, ZHENG HT, LONG M. Advances in pharmacotherapy for post-transplant diabetes mellitus[J]. Med J Chin PLA, 2020, 45(6): 657-662. DOI: 10.11855/j.issn.0577-7402.2020.06.14. [18] 夏漫城, 仝煦楠, 双卫兵. 肾移植术后新发糖尿病影响因素的研究进展[J]. 宁夏医科大学学报, 2021, 43(9): 979-984. DOI: 10.16050/j.cnki.issn1674-6309.2021.09.021.XIA MC, TONG XN, SHUANG WB. Research progress on influencing factors of new-onset diabetes mellitus after renal transplantation[J]. J Ningxia Med Univ, 2021, 43(9): 979-984. DOI: 10.16050/j.cnki.issn1674-6309.2021.09.021. [19] AJABNOOR A, NASSER M, KHAN N, et al. Evaluation of tacrolimus trough level in patients who developed post-transplant diabetes mellitus after kidney transplantation: a retrospective single-center study in Saudi Arabia[J]. Transplant Proc, 2020, 52(10): 3160-3167. DOI: 10.1016/j.transproceed.2020.05.014. [20] 周珊, 王雪静, 王子杰, 等. 肾移植术后患者并发糖病的危险因素分析[J]. 长春中医药大学学报, 2021, 37(6): 1415-1418. DOI: 10.13463/j.cnki.cczyy.2021.06.062.ZHOU S, WANG XJ, WANG ZJ, et al. An analysis on the risk factors for diabetes in patients after a renal transplantation surgery[J]. J Changchun Univ Chin Med, 2021, 37(6): 1415-1418. DOI: 10.13463/j.cnki.cczyy.2021.06.062. [21] 张静, 林秋子. 预测肾移植术后新发糖尿病风险的列线图模型的建立与应用[J]. 现代实用医学, 2020, 32(11): 1322-1324, 封3. DOI: 10.3969/j.issn.1671-0800.2020.11.008.ZHANG J, LIN QZ. Establishment and application of nomogram model to predict the risk of new diabetes after kidney transplantation[J]. Mod Pract Med, 2020, 32(11): 1322-1324, cover 3. DOI: 10.3969/j.issn.1671-0800.2020.11.008. [22] KOTHA S, LAWENDY B, ASIM S, et al. Impact of immunosuppression on incidence of post-transplant diabetes mellitus in solid organ transplant recipients: systematic review and Meta-analysis[J]. World J Transplant, 2021, 11(10): 432-442. DOI: 10.5500/wjt.v11.i10.432. [23] CHENG F, LI Q, WANG J, et al. Analysis of risk factors and establishment of a risk prediction model for post-transplant diabetes mellitus after kidney transplantation[J]. Saudi Pharm J, 2022, 30(8): 1088-1094. DOI: 10.1016/j.jsps.2022.05.013. [24] ALBANO L, BANAS B, KLEMPNAUER JL, et al. OSAKA trial: a randomized, controlled trial comparing tacrolimus QD and BD in kidney transplantation[J]. Transplantation, 2013, 96(10): 897-903. DOI: 10.1097/TP.0b013e3182a203bd. [25] SHIHAB FS, WAID TH, CONTI DJ, et al. Conversion from cyclosporine to tacrolimus in patients at risk for chronic renal allograft failure: 60-month results of the CRAF study[J]. Transplantation, 2008, 85(9): 1261-1269. DOI: 10.1097/TP.0b013e31816b4388. [26] 陈雄, 姚斌, 董婷婷, 等. 肾移植术后糖尿病临床特点及相关危险因素分析[J]. 中华内科杂志, 2009, 48(7): 547-551. DOI: 10.3760/cma.j.issn.0578-1426.2009.07.007.CHEN X, YAO B, DONG TT, et al. The characteristics and risk factors for post-transplantation diabetes mellitus[J]. Chin J Intern Med, 2009, 48(7): 547-551. DOI: 10.3760/cma.j.issn.0578-1426.2009.07.007. [27] REDMON JB, OLSON LK, ARMSTRONG MB, et al. Effects of tacrolimus (FK506) on human insulin gene expression, insulin mRNA levels, and insulin secretion in HIT-T15 cells[J]. J Clin Invest, 1996, 98(12): 2786-2793. DOI: 10.1172/JCI119105. [28] MONTORI VM, BASU A, ERWIN PJ, et al. Posttransplantation diabetes: a systematic review of the literature[J]. Diabetes Care, 2002, 25(3): 583-592. DOI: 10.2337/diacare.25.3.583. [29] CHAI YX, JI JL, LI SJ, et al. Efficacy of anti-T-lymphocyte globulin-Fresenius as an induction agent in deceased-donor renal transplantation: a cohort study[J]. Exp Ther Med, 2020, 19(3): 2384-2390. DOI: 10.3892/etm.2020.8451. [30] MAES BD, KUYPERS D, MESSIAEN T, et al. Posttransplantation diabetes mellitus in FK-506-treated renal transplant recipients: analysis of incidence and risk factors[J]. Transplantation, 2001, 72(10): 1655-1661. DOI: 10.1097/00007890-200111270-00014. [31] ØZBAY LA, SMIDT K, MORTENSEN DM, et al. Cyclosporin and tacrolimus impair insulin secretion and transcriptional regulation in INS-1E beta-cells[J]. Br J Pharmacol, 2011, 162(1): 136-146. DOI: 10.1111/j.1476-5381.2010.01018.x. [32] LING Q, HUANG H, HAN Y, et al. The tacrolimus-induced glucose homeostasis imbalance in terms of the liver: from bench to bedside[J]. Am J Transplant, 2020, 20(3): 701-713. DOI: 10.1111/ajt.15665. [33] 关艳春, 唐旖阳, 马骁, 等. 糖皮质激素诱导的高血糖及糖尿病研究进展[J]. 大连医科大学学报, 2022, 44(2): 157-162. DOI: 10.11724/jdmu.2022.02.12.GUAN YC, TANG YY, MA X, et al. Hyperglycemia and diabetes induced by glucocorticoids: a systematic review[J]. J Dalian Med Univ, 2022, 44(2): 157-162. DOI: 10.11724/jdmu.2022.02.12. [34] 叶红英, 李益明. 糖皮质激素对血糖的影响及其处理[J]. 中华糖尿病杂志, 2021, 13(1): 1-4. DOI: 10.3760/cma.j.cn115791-20200819-00519.YE HY, LI YM. Glucose metabolism abonormalities induced by glucocorticoids[J]. Chin J Diabetes, 2021, 13(1): 1-4. DOI: 10.3760/cma.j.cn115791-20200819-00519. [35] LU Y, WANG E, CHEN Y, et al. Obesity-induced excess of 17-hydroxyprogesterone promotes hyperglycemia through activation of glucocorticoid receptor[J]. J Clin Invest, 2020, 130(7): 3791-3804. DOI: 10.1172/JCI134485. [36] STOUT A, FRIEDLY J, STANDAERT CJ. Systemic absorption and side effects of locally injected glucocorticoids[J]. PM R, 2019, 11(4): 409-419. DOI: 10.1002/pmrj.12042.