Prevalence and Risk Factors of Post-Transplantation Diabetes Mellitus in Patients after Kidney Allotransplantation in Moscow Volume 1 - Issue 2

Novikova Maria*, AllazovaSona, Kotenko Oleg and Shilov Eugene

• PhD, Department of nephrology, First Moscow State Medical University (Sechenov University),Russia

Received: July 05, 2018;   Published: July 11, 2018

Corresponding author: Novikova Maria, PhD, Department of nephrology, First Moscow State Medical University (Sechenov University), Russia, Moscow, 11/4 Rossolimo str

DOI: 10.32474/JUNS.2018.01.000108

Abstract PDF

Purpose:To find out the prevalence, and the risk factors conducive to the development of post-transplantation diabetes mellitus (PTDM) after kidney allotransplantation (KAT).

Methods: The medical histories of 146 recipients of kidney allotransplants received between 1989 and 2014 were reviewed in retrospect. Diabetes mellitus diagnosed before KAT was a criterion for exclusion from the study. Analysed as risk factors were: sex, age, KAT time, and the use of glycocorticoids (GCs), tacrolimus (Tc), and/or cyclosporine A (CcA). The veritability of their influence was assessed using the step-wise linear regression analysis method.

Results:The recipients’ average age was 42.9 +/- 20.2 (х±σ) years at the time of the study. PTDM prevalence in the general group was 21.9% (n=32). Age and the use of calcineurin inhibitors (CNIs) and GCs had the greatest impact on PTDM development (р=0,01).

keywords: Post-Transplantation Diabetes Mellitus, Kidney Allotransplantation, Glycocorticoids, Calcineurin Inhibitors, Tacrolimus, Cyclosporine

Abbrevations: KAT: Kidney Allotransplantation, PTDM:Post-Transplantation Diabetes Mellitus, GCs: Glycocorticoids, Tc: Tacrolimus, CcA:Cyclosporine A, CNIs: Calcineurin Inhibitors, NODAT: New Onset Diabetes After Transplantation, IGT: Impaired Glucose Tolerance, WHO: World Health Organisation, ADA:American Diabetes Association

The principles of the diagnosis and treatment of PTDM, or new onset diabetes after transplantation (NODAT), are based on the criteria of diabetes mellitus and impaired glucose tolerance (IGT) adopted by the World Health Organisation (WHO) and the American Diabetes Association (ADA) in 2003 [1]. PTDM is associated with a bad prognosis due to an increased risk of cardiovascular catastrophe, graft loss, death from graft loss and the recipient’s death [2-4].

Statistical Analysis:

We used step-wise linear regression analysis to predict our target variable (PTDM) using the AICC information criterion. The statistical data were processed using the IBM SPSS Statistics 22.0 software.

PTDM Prevalence Among Recipients after KAT:

Retrospective analysis found PTDM in 32 (21,9%) of the 146 recipients who lived longer than one year after KAT. Diabetes mellitus diagnosed before KAT was a criterion for exclusion from the study. The male-to-female ratio was 46.6% and 53.4%. The average age of the KAT recipients who developed PTDM was 42,9 +/- 20,2 (х±σ) years at the time of the study. PTDM development probability increased with the recipients’ age (r=0.345 with р≥0,01) and was inversely correlated to time after KAT. PTDM probability was the highest in the first five and ten years after KAT: 34.4% (n = 11) and 40.6 % (n = 13) respectively and would decrease in the following years: 11 to 15 years after KAT, PTDM prevalence was 12.5% (n=4), and 9,4% (n=4) after 15 years.

The Influence of Immunosuppressive Therapy Regimen on PTDM Prevalence:

The immunosuppressive therapy protocol included the following preparations: CcA+ MMF/ AZA + GCs and Тс + MMF/AZA + GCs. CcA and Тс concentrations in plasma were kept within their therapeutic values throughout the observation period. After CcA to Тс conversion, an increase of PTDM prevalence from n=11 (18.6%) to n=21 (26%) was noted but made no statistically veritable difference. GCS was used in all the kidney transplant recipients.

PTDM Development Risk Factors (Linear Modelling):

The following predictors were analysed: sex, age, KAT time, and the use of GC, Тс, and/or CcA immunosuppressive therapy. The frequency fields of the patients’ gender and KAT time were not included in the model for lack of those predictors’ effect. The importance of using CcA , GCs, age and Тс for generating the PTDMdevelopment prognosis was 52.8%, 17.4%, 15%, and 14.8% respectively.

Older patients have more chances of developing PTDM than younger ones at the time of transplantation [4,5].Besides age, CNI use in combination with GCs increases the PTDM development risks [6-16]. Differences inPTDM prevalence between CcA and Тс immunosuppressive regimens may partially be attributable to difference of PTDM definition and CNI dose and concentration [17-20]. Therapy including GCs remains disputable until now, but, according to clinical studies of the kidney graft, it is generally recognized that short-time ‘pulse’ therapy and low maintenance doses of GCs are not only safe but may reduce the PTDM development risk [21-25]. These data are of special interest in connection with the latest studies that demonstrate possibly varying, particularly autoimmune, PTDM genesis [26-30].

1. Davidson J, Wilkinson A (2004) New-onset diabetes after transplantation 2003 International Consensus Guidelines. Transplantation 27(3): 805- 812.
2. Burroughs TE, Swindle J, Takemoto S, Lentine KL, Machnicki G, et al. (2007) Diabetic complications associated with new-onset diabetes mellitus in renal transplant recipients. Transplantation 83(8): 1027- 1034.
3. Hjelmesaeth J, Hartmann A, Leivestad T, Holdaas H, Sagedal S, et al. (2006) The impact of early-diagnosed new-onset post-transplantation diabetes mellitus on survival and major cardiac events. Kidney Int 69: 588-595.
4. Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ (2003) Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 3(2): 178-185.
5. Cosio FG, Pesavento TE, Osei K, Henry ML, Ferguson RM (2001) Posttransplant diabetes mellitus: increasing incidence in renal allograft recipients transplanted in recent years. Kidney Int 59(2): 732-737.
6. Heit JJ, Apelqvist AA, Gu X, Winslow MM, Neilson JR, et al. (2006) Calcineurin/NFAT signalling regulates pancreatic beta-cell growth and function. Nature 443: 345-349.
7. Tamura K, Fujimura T, Tsutsumi T, Nakamura K, Ogawa T, et al. (1995) Transcriptional inhibition of insulin by FK506 and possible involvement of FK506 binding protein-12 in pancreatic beta-cell. Transplantation 59(11): 1606-1613.
8. Øzbay LA, Smidt K, Mortensen DM, Carstens J, Jørgensen KA, et al. (2011) Cyclosporin and tacrolimus impair insulin secretion and transcriptional regulation in INS-1E β-cells. Br J Pharmacol 162(1): 136-146.
9. Polastri L, Galbiati F, Bertuzzi F, P Fiorina, R Nano, et al. (2002) Secretory defects induced by immunosuppressive agents on human pancreatic beta-cells. Acta Diabetol 39(4): 229-233.
10. Duijnhoven EM, Boots JM, Christiaans MH, Wolffenbuttel BH, Van Hooff JP, et al. (2001) Influence of tacrolimus on glucose metabolism before and after transplantation: a prospective study. J Am Soc Nephrol 12(3): 583-588.
11. Fernandez LA, Lehmann R, Luzi L, Rattazzi A, Angelico MC, et al. (1999) The effects of maintenance doses of FK506 versus Cyclosporin A on glucose and lipid metabolism after orthotopic liver transplantation. Transplantation 68(10): 1532-1541.
12. Maffi P, Bertuzzi F, De Taddeo F, Magistretti P, Nano R, et al. (2007) Kidney function after islet transplant alone in type 1 diabetes: impact of immunosuppressive therapy on progressive of diabetic nephropathy. Diabetes Care 30: 1150-1155.
13. Neumayer HH, Färber L, Haller P, Kohnen R, Maibücher A, et al. (1996) Substitution of conventional cyclosporine with a new microemusion formulation in renal transplant patients: result after 1 year. Nephrol Dial Transplant 11(1): 165-172.
14. Mathew JT, Rao M, Job V, Selvakumar Ratnaswamy, Chakko K Jacob, et al. (2003) Post-transplant hyperglycaemia: a study of risk factors. Nephrol Dial Transplant 18(1): 164-171.
15. Cotovio P, Neves M, Rodrigues L, Alves R, Bastos M, et al. (2013) Newonset diabetes after transplantations: assessment of risk factors and clinical outcomes. Transplant Proc 45(3): 1079-1083.
16. Davidson JA, Wilkinson A (2004) New-onset diabetes after transplantation 2003 international consensus guidelines: an endocrinologist’s view. Diabetes Care 27: 805-812.
17. Webster AC, Woodroffe RC, Taylor RS (2005) Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data. Br Med J 331(7520): 810.
18. Heisel O, Heisel R, Balshaw R, Keown P (2004) New onset diabetes mellitus in patients receiving calcineurin inhibitors: a systematic review and meta-analysis. Am J Transplant 4(4):
19. Ekberg H, Tedesco-Silva H, Demirbas A (2007) Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 357(25): 2562-2575.
20. Luan FL, Zhang H, Schaubel DE (2008) Comparative risk of impaired glucose metabolism associated with cyclosporine versus tacrolimus in the late posttransplant period. Am J Transplant 8: 1871-1877.
21. Tillmann FP, Schmitz M, Rump LC, Quack I (2018) 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 50(4): 771-777.
22. Luan FL, Steffick DE, Ojo AO (2011) New-onset diabetes mellitus in kidney transplant recipients discharged on steroid-free immunosuppression. Transplantation 91(3): 334-341.
23. Hjelmesaeth J, Hartmann A, Kofstad J (2001) Tapering off prenisolone and cyclosporine the first year after renal transplantation: the effect on glucose tolerance. Nephrol Dial Transplant 16(4): 829-835.
24. Hjelmesaeth J, Hartmann A, Kofstad J (1997) Glucose intolerance after renal transplantation depends upon prednisolone dose and recipient age. Transplantation 64(7): 979-983.
25. Knight SR, Morris PJ (2010) Steroid avoidance or withdrawal after renal transplantation increases the risk of acute rejection but decreases cardiovascular risk. A Meta-Analysis. Transplantation 89(1): 1-14.
26. Aasebo W, Midtvedt K, Valderhaug TG (2010) Impaired glucose homeostasis in renal transplant recipients receiving basiliximab. Nephrol Dial Transplant 25(4): 1289-1293.
27. Yoshiko Matsuda, Minnie M Sarwal (2016) Unraveling the Role of Allo- Antibodies and Transplant Injury. Front Immunol 7: 432.
28. Ei Wafai RJ, Chmaisse HN, Makki RF, Fakhoury H (2011) Association of HLA class II alleles and CTLA-4 polymorphism with type 1 diabetes. Saudi J Kidney Dis Transpl 22(2): 273-281.
29. Tivol EA, Borriello F, Schweitzer AN (1995) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3(5): 541-547.
30. Gribben JG, Freeman GJ, Boussiotis VA (1995) CTLA4 mediates antigenspecific apoptosis of human T cells. Proc Natl Acad Sci USA 92(3): 811- 815.