Objective  To systematically evaluate the effects of tacrolimus (TAC) and cyclosporine A (CsA) on the incidence of post-transplant diabetes mellitus (PTDM) in patients after kidney trans-plantation.

Methods  PubMed, Embrase, The Cochrane Library, CNKI, WanFang Data and VIP data-bases were electronically searched to collect randomized controlled trials (RCTs) about the incidence of PTDM using TAC and CsA from inception to December 31st, 2022. The Chinese Journal of Organ Trans-plantation, Organ Transplantation and Chinese Journal of Nephrology from January 1st to December 31st, 2022 were manually searched to avoid missing the recent research results. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies. RevMan 5.4.1 software was used for Meta-analysis.

Results  A total of 23 RCTs involving 5 269 patients were in-cluded, including 2 681 cases in the TAC group and 2 588 cases in the CsA group. The results of Meta-analysis showed that compared with CsA group, the incidence of PTDM in TAC group was significantly higher (OR=2.15, 95%CI 1.60 to 2.89, P<0.001). Subgroup analysis results showed that, the incidence of PTDM in TAC group was higher than that in CsA group when other diagnostic cri-teria were used (P<0.05), except that insulin treatment was required. The incidence of PTDM induced by TAC at 6 to 60 months was significantly higher than that of CsA, with statistical significance (P<0.05); The incidence of PTDM caused by tachlimus combined with azathioprine (AZA) or myco-phenolate mofetil (MMF) subgroups was significantly higher than that of CsA combined with AZA or MMF (P<0.05). However, there was no statistical difference in the incidence of PTDM between the TAC combined with sirolimus group and the CsA combined with sirolimus group (P=0.91).

Conclusion  Current evidence shows that, at 6 to 60 months after kidney transplantation, the incidence of TAC-induced PTDM is significantly higher. The incidence of PTDM is higher in the TAC combined with AZA or MMF group, but there was no statistical difference in the incidence of PTDM when low-dose TAC or CsA is combined with sirolimus.

1.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.

2.Valderhaug TG, Hjelmesaeth 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.

3.Heit JJ, Apelqvist AA, Gu X, et al. Calcineurin/NFAT signalling regulates pancreatic beta-cell growth and function[J]. Nature, 2006, 443(7109): 345-349. DOI: 10.1038/nature05097.

4.Cotovio P, Neves M, Rodrigues L, et al. New-onset diabetes after transplantation: assessment of risk factors and clinical outcomes[J]. Transplant Proc, 2013, 45(3): 1079-1083. DOI: 10.1016/j.transproceed.2013.03.009.

5.Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration' s tool for assessing risk of bias in randomised trials[J]. BMJ, 2011, 343: d5928. DOI: 10.1136/bmj.d5928.

6.Campos HH, Abbud Filho M, Brazilian Tacrolimus Study Group. One-year follow-up of a Brazilian ran-domized multicenter study comparing tacrolimus versus cyclosporine in kidney transplantation[J]. Transplant Proc, 2002, 34(5): 1656-1658. DOI: 10.1016/S0041-1345(02) 02968-8.

7.Charpentier B, Rostaing L, Berthoux F, et al. A three-arm study comparing immediate tacrolimus therapy with antithymocyte globulin induction therapy followed by tacrolimus or cyclosporine A in adult renal transplant recipients[J]. Transplantation, 2003, 75(6): 844-851. DOI: 10.1097/01.TP.0000056635.59888.EF.

8.Ciancio G, Burke GW, Gaynor JJ, et al. A randomized long-term trial of tacrolimus/sirolimus versus tacrolimus/mycophenolate mofetil versus cyclosporine (NEORAL)/sirolimus in renal transplantation. Ⅱ. Survival, function, and protocol compliance at 1 year[J]. Transplantation, 2004, 77(2): 252-258. DOI: 10.1097/01.TP.0000101495.22734.07.

9.Ciancio G, Gaynor JJ, Guerra G, et al. Randomized trial of 3 maintenance regimens (TAC/SRL vs. TAC/MMF vs. CSA/SRL) with low-dose corticosteroids in primary kidney transplantation: 18-year re-sults[J]. Clin Transplant, 2020, 34(12): e14123. DOI: 10.1111/ctr. 14123.

10.Ekberg H, Bernasconi C, Nöldeke J, et al. Cyclosporine, tacrolimus and sirolimus retain their distinct toxicity profiles despite low doses in the Symphony study[J]. Nephrol Dial Transplant, 2010, 25(6): 2004-2010. DOI: 10.1093/ndt/gfp778.

11.Gaber AO, Kahan BD, Van Buren C, et al. Comparison of sirolimus plus tacrolimus versus sirolimus plus cyclosporine in high-risk renal allograft recipients: results from an open-label, randomized trial[J]. Transplantation, 2008, 86(9): 1187-1195. DOI: 10.1097/TP.0b013e318187bab0.

12.Gonwa T, Johnson C, Ahsan N, et al. Randomized trial of tacrolimus + mycophenolate mofetil or aza-thioprine versus cyclosporine + mycophenolate mofetil after cadaveric kidney transplantation: results at three years[J]. Transplantation, 2003, 75(12): 2048-2053. DOI: 10.1097/01.TP.0000069831.76067.22.

13.Guerra G, Ciancio G, Gaynor JJ, et al. Randomized trial of immunosuppressive regimens in renal trans-plantation[J]. J Am Soc Nephrol, 2011, 22(9): 1758-1768. DOI: 10.1681/ASN.2011010006.

14.Hardinger KL, Bohl DL, Schnitzler MA, et al. A randomized, prospective, pharmacoeconomic trial of tacrolimus versus cyclosporine in combination with thymoglobulin in renal transplant recipients[J]. Transplantation, 2005, 80(1): 41-46. DOI: 10.1097/01.tp.0000162980.68628.5a.

15.Johnson C, Ahsan N, Gonwa T, et al. Randomized trial of tacrolimus (Prograf) in combination with az-athioprine 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.Jurewicz WA. Tacrolimus versus ciclosporin immunosuppression: long-term outcome in renal trans-plantation[J]. Nephrol Dial Transplant, 2003, 18 Suppl 1: i7-11. DOI: 10.1093/ndt/gfg1028.

17.Kim SJ, Lee KW, Lee DS, et al. Randomized trial of tacrolimus versus cyclosporine in steroid withdraw-al in living donor renal transplant recipients[J]. Transplant Proc, 2004, 36(7): 2098-2100. DOI: 10.1016/j.transproceed.2004.08.070.

18.Kim J, Park J, Hwang S, et al. Ten-year observational follow-up of a randomized trial comparing cy-closporine and tacrolimus therapy combined with steroid withdrawal in living-donor renal transplan-tation[J]. Clin Transplant, 2018, 32(9): e13372. DOI: 10.1111/ctr.13372.

19.Lee YJ, Kim B, Lee JE, et al. Randomized trial of cyclosporine and tacrolimus therapy with steroid withdrawal in living-donor renal transplantation: 5-year follow-up[J]. Transpl Int, 2010, 23(2): 147-154. DOI: 10.1111/j.1432-2277.2009.00955.x.

20.Liu LS, Li J, Chen XT, et al. Comparison of tacrolimus and cyclosporin A in CYP3A5 expressing Chi-nesede novo kidney transplant recipients: a 2-year prospective study[J]. Int J Clin Pract Suppl, 2015(183): 43-52. DOI: 10.1111/ijcp.12666.

21.Margreiter R, European Tacrolimus vs Ciclosporin Microemulsion Renal Transplantation Study Group. Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: a randomised multicentre study[J]. Lancet, 2002, 359(9308): 741-746. DOI: 10.1016/S0140-6736(02)07875-3.

22.Neylan JF. Racial differences in renal transplantation after immunosuppression with tacrolimus versus cyclosporine. FK506 Kidney Transplant Study Group[J]. Transplantation, 1998, 65(4): 515-523. DOI: 10.1097/00007890-199802270-00011.

23.Park JB, Kim SJ, Oh HY, et al. Steroid withdrawal in living donor renal transplant recipients using tac-rolimus and cyclosporine: a randomized prospective study[J]. Transpl Int, 2006, 19(6): 478-484. DOI: 10.1111/j.1432-2277.2006.00303.x.

24.Pirsch JD, Miller J, Deierhoi MH, et al. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group[J]. Transplantation, 1997, 63(7): 977-983. DOI: 10.1097/00007890-199704150-00013.

25.Silva HT Jr, Yang HC, Meier-Kriesche HU, et al. Long-term follow-up of a phase Ⅲ clinical trial com-paring tacrolimus extended-release/MMF, tacrolimus/MMF, and cyclosporine/MMF in de novo kidney  transplant recipients[J]. Transplantation, 2014, 97(6): 636-641. DOI: 10.1097/01.TP.0000437669.93963.8E.

26.Torres A, Hernández D, Moreso F, et al. Randomized controlled trial assessing the impact of tacroli-mus versus cyclosporine on the incidence of posttransplant diabetes mellitus[J]. Kidney Int Rep, 2018, 3(6): 1304-1315. DOI: 10.1016/j.ekir.2018.07.009.

27.Vincenti F, Friman S, Scheuermann E, et al. Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus[J]. Am J Transplant, 2007, 7(6): 1506-1514. DOI: 10.1111/j.1600-6143.2007.01749.x.

28.Wang XH, Tang XD, Xu D, et al. Tacrolimus vs CyA Neoral in combination with MMF and steroids after cadaveric renal transplantation[J]. Transplant Proc, 2000, 32(7): 1702-1703. DOI: 10.1016/s0041-1345(00)01408-1.

29.Dai C, Yan H, Shostak A, et al. Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling[J]. J Clin Invest, 2017, 127(10): 3835-3844. DOI: 10.1172/JCI91761.

30.陈孝, 主编. 临床药物治疗学·器官移植[M]. 北京: 人民卫生出版社, 2016: 32-33.

31.Azarfar A, Ravanshad Y, Mehrad-Majd H, et al. Comparison of tacrolimus and cyclosporine for immu-nosuppression after renal transplantation: an updated systematic review and meta-analysis[J]. Saudi J Kidney Dis Transpl, 2018, 29(6): 1376-1385. DOI: 10.4103/1319-2442.248292.