Иммуносупрессивная терапия как фактор риска посттрансплантационного сахарного диабета
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Allazova S.S., Novikova M.S., Kotenko O.N., Shilov E.M. Immunosuppressive therapy as a risk factor for new-onset diabetes after transplantation. Therapeutic Archive. 2020; 92 (12): 137–141. DOI: 10.26442/00403660.2020.12.200454
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Материалы и методы. В ретроспективный анализ включены данные 1367 реципиентов (755 мужчин и 612 женщин), которые прожили более одного года после аллогенной трансплантации почки и наблюдались в Московском городском нефрологическом центре с января 1989 по декабрь 2018 г. ПТСД установлен 178 (13%) пациентам на основании критериев Всемирной организации здравоохранения и Американской диабетической ассоциации (American Diabetes Association). Оценивались режимы иммуносупрессивной терапии с применением циклоспорина А, такролимуса, ингибиторов mTOR (и-mTOR), глюкокортикоидов у пациентов с ПТСД и без ПТСД. Для оценки влияния факторов риска применялись методы описательной статистики, вычислены отношение шансов (ОШ) и 95% доверительный интервал (ДИ).
Результаты. ПТСД диагностирован у 105 мужчин и 73 женщин. ОШ для мужчин составило 1,19 (95% ДИ 0,87–1,64), ОШ для женщин – 0,84 (95% ДИ 0,61–1,15). На момент трансплантации средний возраст реципиентов почки в группе ПТСД был выше, чем в группе без ПТСД: 51 [43; 57] и 43 [32; 52] года соответственно (р=0,0001). Большая часть больных с ПТСД (82%) старше 50 лет, в то время как в группе без ПТСД доля больных аналогичного возраста составила 48,5% (р=0,0001). Среди пациентов без ПТСД достоверно чаще проводилась трансплантация почки от живого донора по сравнению с группой с ПТСД+ (7,1% против 1,1%; р=0,001). Среди реципиентов, получавших схему с циклоспорином А, сахарный диабет развился у 75 (42,1%), получавших такролимус – у 102 (57,3%; р>0,05). Шанс (риск развития) ПТСД у пациентов, получающих и-mTOR + такролимус, составил 3,2 (95% ДИ 1,47–6,78; р=0,032), а для пациентов, получающих и-mTOR + циклоспорин А, – 1,95 (95% ДИ 0,88–4,35; р=0,044).
Заключение. У 13% реципиентов после аллотрансплантации почки de novo развивался сахарный диабет. Возраст на момент аллогенной трансплантации почки, пол, а также применение такролимуса в сочетании с и-mTOR являются наиболее значимыми факторами риска развития ПТСД.
Ключевые слова: посттрансплантационный сахарный диабет, факторы риска, аллотрансплантация почки, инсулинорезистентность, такролимус, циклоспорин А, глюкокортикоиды.
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Aim. To analyze the modes of immunosuppressive therapy as a risk factor for new-onset diabetes after transplantation (NODAT) in kidney recipients.
Materials and methods. The retrospective analysis included data from 1367 recipients (755 men and 612 women) who lived more than one year after NODAT and were observed at the Moscow City Nephrology Center from January 1989 to December 2018. NODAT was established for 178 (13%) patients based on criteria from the World Health Organization and the American Diabetes Association. The modes of immunosuppressive therapy using cyclosporin A (CSA), tacrolimus (Tac), mTOR inhibitors, glucocorticoids in patients with NODAT and without NODAT were evaluated. To assess the impact of risk factors, descriptive statistics methods were used, the odds ratio (OR) and the 95% confidence interval (CI) were calculated.
Results. NODAT was diagnosed in 105 men and 73 women. The OR for men was 1.19 (95% CI 0.87–1.64), the OR for women was 0.84 (95% CI 0.61–1.15). At the time of transplantation, the average age of the kidney recipients in the NODAT group was higher than in the group without NODAT: 51 [43; 57] and 43 [32; 52] years, respectively (p=0.0001). Most patients with NODAT (82%) were older than 50 years, while in the group without NODAT, the proportion of patients of the same age was 48.5% (p=0.0001). Among patients without NODAT, transplantation of a kidney from a living donor was significantly more often compared with the group with NODAT+ (7.1% vs 1.1%; p=0.001). Among the recipients who received the regimen with CSA, diabetes developed in 75 (42.1%), those who received Tac in 102 (57.3%; p>0.05). The chance (risk of development) of NODAT in patients receiving i-mTOR + Tac was 3.2 (95% CI 1.47–6.78; p=0.032), and for patients receiving i-mTOR + cyclosporin A, the chance of development NODAT was 1.95 (95% CI 0.88–4.35; p=0.044).
Conclusion. 13% of recipients developed de novo kidney diabetes after allograft. Age at the time of allotransplantation, gender, as well as the use of tacrolimus in combination with i-mTOR are the most significant risk factors for the development of NODAT.
Keywords: new-onset diabetes after transplantation, risk factors, kidney allotransplantation, insulin resistance, tacrolimus, cyclosporin A, glucocorticoids.
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3. Ghisdal L, Van Laecke S, Abramowicz MJ, et al. New-onset diabetes after renal transplantation: risk assessment and management. Diabetes Care. 2012;35(1):181-8. doi: 10.2337/dc11-1230
4. Choudhury PS, Mukhopadhyay P, Roychowdhary A, et al. Prevalence and Predictors of "New-onset Diabetes after Transplantation" (NODAT) in Renal Transplant Recipients: An Observational Study. Indian J Endocrinol Metab. 2019 May-Jun;23(3):273-7. doi: 10.4103/ijem.IJEM_178_19
5. Maes BD, Kuypers D, Messiaen T, et al. Posttransplantation diabetes mellitus in FK-506-treated renal transplant recipients: Analysis of incidence and risk factors. Transplantation. 2001;72:1655-61. doi: 10.1097/00007890-200111270-00014
6. Vincenti F, Friman S, Scheuermann E, et al. Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus. Am J Transplant. 2007;7(6):1506-14. doi: 10.1111/j.1600-6143.2007.01749.x
7. Woodward RS, Schnitzler MA, Baty J, et al. Incidence and cost of new onset diabetes mellitus among U.S. wait-listed and transplanted renal allograft recipients. Am J Transplant. 2003;3:590-8. doi: 10.1034/j.1600-6143.2003.00082.x
8. Burroughs TE, Swindle J, Takemoto S, et al. Diabetic complications associated with new-onset diabetes mellitus in renal transplant recipients. Transplantation. 2007;83(8):1027-34. doi: 10.1097/01.tp. 0000259617.21741.95
9. Abdulrahman MM, Idris MA, Elhakimi WF, et al. New-onset diabetes after transplantation among renal transplant recipients at a new transplant center. Saudi J Kidney Dis Transpl. 2018;29(4):863-71. doi: 10.4103/1319-2442.239641
10. Bzoma B, Konopa J, Chamienia A, et al. New-onset Diabetes Mellitus After Kidney Transplantation – A Paired Kidney Analysis. Transplant Proc. 2018;50(6):1781-5. doi: 10.1016/j.transproceed.2018.02.119
11. Special Issue: KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients. Am J Transplant. 2009;9:S1-S155. doi: 10.1111/j.1600-6143.2009.02834.x
12. Cosio FG, Pesavento TE, Osei K, et al. Posttransplant diabetes mellitus: increasing incidence in renal allograft recipients transplanted in recent years. Kidney Int. 2001;59(2):732-7. doi: 10.1046/j.1523-1755.2001.059002732.x
13. Dong M, Parsaik AK, Eberhardt NL, et al. Cellular and physiological mechanisms of new-onset diabetes mellitus after solid organ transplantation. Diabet Med. 2012;29(7):e1-e12. doi: 10.1111/j.1464-5491.2012.03617.x
14. Soleimanpour SA, Crutchlow MF, Ferrari AM, et al. Calcineurin signaling regulates human islet β-cell survival. J Biol Chem. 2010;285(51):40050-9. doi: 10.1074/jbc.M110.154955
15. Ozbay LA, Smidt K, Mortensen DM, et al. Cyclosporin and tacrolimus impair insulin secretion and transcriptional regulation in INS-1E β-cells. Br J Pharmacol. 2011;162(1):136-46. doi: 10.1111/j.1476-5381.2010.01018.x
16. Heisel O, Heisel R, Balshaw R, Keown P. New onset diabetes mellitus in patients receiving calcineurin inhibitors: a systematic review and meta-analysis. Am J Transplant. 2004;4(4):583-95.
17. Vincenti FFS, Scheuermann E, Rostaing L, et al. DIRECT Investi-gators. Results of an international, randomized trial comparing glu-cose metabolism disorders and outcome with cyclosporine versustacrolimus. Am J Transplant. 2008;7:1506-14.
18. Tillmann FP, Schmitz M, Rump LC, Quack I. Impact of low-dose steroids on HbA1c levels and development of pre-diabetes and NODAT in non-diabetic renal transplant recipients on long-term follow-up. Int Urol Nephrol. 2018;50(4):771-7. doi: 10.1007/s11255-017-1754-0
19. Luan FL, Zhang H, Schaubel DE, et al. Comparative risk of impaired glucose metabolism associated with cyclosporine versus tacrolimus in the late posttransplant period. Am J Transplant. 2008;8:1871-7. doi: 10.1111/j.1600-6143.2008.02328.x
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1. [Danovitch Gabriel M. Handbook of kidney transplantation. Moscow: GEOTAR-Media, 2014; p. 227-60 (In Russ.)].
2. Davidson J, Wilkinson A, Dantal J. New-onset diabetes after transplantation 2003 International Consensus Guidelines. Diabetes Care. 2004;27(3):805-12. doi: 10.2337/diacare.27.3.805
3. Ghisdal L, Van Laecke S, Abramowicz MJ, et al. New-onset diabetes after renal transplantation: risk assessment and management. Diabetes Care. 2012;35(1):181-8. doi: 10.2337/dc11-1230
4. Choudhury PS, Mukhopadhyay P, Roychowdhary A, et al. Prevalence and Predictors of "New-onset Diabetes after Transplantation" (NODAT) in Renal Transplant Recipients: An Observational Study. Indian J Endocrinol Metab. 2019 May-Jun;23(3):273-7. doi: 10.4103/ijem.IJEM_178_19
5. Maes BD, Kuypers D, Messiaen T, et al. Posttransplantation diabetes mellitus in FK-506-treated renal transplant recipients: Analysis of incidence and risk factors. Transplantation. 2001;72:1655-61. doi: 10.1097/00007890-200111270-00014
6. Vincenti F, Friman S, Scheuermann E, et al. Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus. Am J Transplant. 2007;7(6):1506-14. doi: 10.1111/j.1600-6143.2007.01749.x
7. Woodward RS, Schnitzler MA, Baty J, et al. Incidence and cost of new onset diabetes mellitus among U.S. wait-listed and transplanted renal allograft recipients. Am J Transplant. 2003;3:590-8. doi: 10.1034/j.1600-6143.2003.00082.x
8. Burroughs TE, Swindle J, Takemoto S, et al. Diabetic complications associated with new-onset diabetes mellitus in renal transplant recipients. Transplantation. 2007;83(8):1027-34. doi: 10.1097/01.tp. 0000259617.21741.95
9. Abdulrahman MM, Idris MA, Elhakimi WF, et al. New-onset diabetes after transplantation among renal transplant recipients at a new transplant center. Saudi J Kidney Dis Transpl. 2018;29(4):863-71. doi: 10.4103/1319-2442.239641
10. Bzoma B, Konopa J, Chamienia A, et al. New-onset Diabetes Mellitus After Kidney Transplantation – A Paired Kidney Analysis. Transplant Proc. 2018;50(6):1781-5. doi: 10.1016/j.transproceed.2018.02.119
11. Special Issue: KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients. Am J Transplant. 2009;9:S1-S155. doi: 10.1111/j.1600-6143.2009.02834.x
12. Cosio FG, Pesavento TE, Osei K, et al. Posttransplant diabetes mellitus: increasing incidence in renal allograft recipients transplanted in recent years. Kidney Int. 2001;59(2):732-7. doi: 10.1046/j.1523-1755.2001.059002732.x
13. Dong M, Parsaik AK, Eberhardt NL, et al. Cellular and physiological mechanisms of new-onset diabetes mellitus after solid organ transplantation. Diabet Med. 2012;29(7):e1-e12. doi: 10.1111/j.1464-5491.2012.03617.x
14. Soleimanpour SA, Crutchlow MF, Ferrari AM, et al. Calcineurin signaling regulates human islet β-cell survival. J Biol Chem. 2010;285(51):40050-9. doi: 10.1074/jbc.M110.154955
15. Ozbay LA, Smidt K, Mortensen DM, et al. Cyclosporin and tacrolimus impair insulin secretion and transcriptional regulation in INS-1E β-cells. Br J Pharmacol. 2011;162(1):136-46. doi: 10.1111/j.1476-5381.2010.01018.x
16. Heisel O, Heisel R, Balshaw R, Keown P. New onset diabetes mellitus in patients receiving calcineurin inhibitors: a systematic review and meta-analysis. Am J Transplant. 2004;4(4):583-95.
17. Vincenti FFS, Scheuermann E, Rostaing L, et al. DIRECT Investi-gators. Results of an international, randomized trial comparing glu-cose metabolism disorders and outcome with cyclosporine versustacrolimus. Am J Transplant. 2008;7:1506-14.
18. Tillmann FP, Schmitz M, Rump LC, Quack I. Impact of low-dose steroids on HbA1c levels and development of pre-diabetes and NODAT in non-diabetic renal transplant recipients on long-term follow-up. Int Urol Nephrol. 2018;50(4):771-7. doi: 10.1007/s11255-017-1754-0
19. Luan FL, Zhang H, Schaubel DE, et al. Comparative risk of impaired glucose metabolism associated with cyclosporine versus tacrolimus in the late posttransplant period. Am J Transplant. 2008;8:1871-7. doi: 10.1111/j.1600-6143.2008.02328.x
1 ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России
(Сеченовский Университет), Москва, Россия;
2 ГБУЗ «Эндокринологический диспансер» Департамента здравоохранения г. Москвы, Москва, Россия;
3 ГБУЗ «Городская клиническая больница №52» Департамента здравоохранения г. Москвы, Московский городской
нефрологический центр, Москва, Россия;
4 ФГАОУ ВО «Российский университет дружбы народов», Москва, Россия
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S.S. Allazova 1, M.S. Novikova 2, O.N. Kotenko 3,4, E.M. Shilov 1
1 Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia;
2 Endocrinology Dispensary, Moscow, Russia;
3 Municipal Clinical Hospital №52, Moscow, Russia;
4 People’s Friendship University of Russia, Moscow, Russia