Incidence and Risk Factors for Post–Renal Transplant Diabetes Mellitus I. Hadj Ali, E. Adberrahim, K. Ben Abdelghani, S. Barbouch, N. Mchirgui, K. Khiari, M. Chérif, M. Ounissi, N. Ben Romhane, N. Ben Abdallah, T. Ben Abdallah, H. Ben Maiz, and A. Khedher ABSTRACT Introduction. Posttransplant diabetes mellitus (PTDM) is a common, serious complication of renal transplantation. The aim of this retrospective study was to estimate the incidence and to identify potential factors predisposing to PTDM. Patients and methods. We evaluated 296 adult nondiabetic patients who underwent kidney transplantation at our center. PTDM was defined according to 2003 international consensus guidelines. Potential factors predisposing to PTDM were analyzed individually and simultaneously using a logistic regression model. Results. Over 2054.5 years of cumulative follow-up, 51 patients (17.2%) developed diabetes corresponding to an annual incidence of 2.5%. PTDM was diagnosed after a median of 2.9 months (range: 0.2–168). The mean age of affect individuals was 33.3 ⫾ 7.4 years. Patients with PTDM were significantly older (P ⬍ .0005) and showed an higher body mass index (BMI; P ⬍ .004). Univariate analysis revealed that age, BMI, family history of diabetes, vascular nephropathy, and hepatitis C infection were associated with PTDM. Multivariate analysis rescaled the roles of age (relative risk [RR] ⫽ 1.046/y; P ⬍ .04), BMI (RR ⫽ 1.107/kg/m2, P ⬍ .05), vascular nephropathy (RR ⫽ 7.06, P ⬍ .03), and hepatitis C infection (RR ⫽ 2.72, P ⬍ .03) as independent factors predisposing to PTDM. Conclusion. Among our relatively young kidney transplant recipients, in whom only 8% received tacrolimus, PTDM was a frequent complication. We suggest that the use of oral glucose tolerance tests to screen patients identifies those predisposed to develop this complication. EW-ONSET DIABETES MELLITUS after transplantation or posttransplant diabetes mellitus (PTDM) is a common, serious complication after renal transplantation.1–3 PTDM is defined as a fasting plasma glucose ⱖ 1.26 mg/dL (7 mmol/L) or 2-hour postload glucose (75 g anhydrous glucose) ⱖ200 mg/dL (11.1 mmol/L). The incidence varies from 7% to 45%.4 – 6 To date, many risk factors have been associated with the occurrence of PTDM, such as advanced age,7 some races, obesity,8 family history of type 2 diabetes mellitus, hepatitis C virus infection,7 and some immunosuppressive drugs. The aim of the present retrospective study was to estimate the incidence and to identify potential factors predisposing to PTDM among Tunisian renal transplant patients.
PATIENTS AND METHODS We evaluated 296 adult nondiabetic patients who underwent kidney transplantation at our center. PTDM was defined according 0041-1345/11/$–see front matter doi:10.1016/j.transproceed.2011.01.032 568
to 2003 international consensus guidelines. We excluded patients with early graft loss. Epidemiological and clinical data have suggested predisposing factors to include age at surgery, gender, body mass index (BMI), first degree family history of diabetes mellitus, number of human leukocyte antigen mismatches, initial cause of nephropathy, pretransplant hypertension, pretransplant hyperlipidemia, renal replacement therapy (RRT), and duration of RRT (years). From Medicine Interne A Department (I.H.A., E.A., K.B.A., S.B., N.M., K.K., M.C., M.O., N.B.R., N.B.A., T.B.A., H.B.M., A.K.), Charles Nicolle Hospital, Tunis, Tunisia; Laboratory of Kidney Pathology (E.A., S.B., M.C., M.O., T.B.A., H.B.M., A.K.), (LR00SP01) Charles Nicolle Hospital, Tunis, Tunisia; Research Laboratory of Immunology (M.C., T.B.A.), (LR03SP01) Charles Nicolle Hospital, Tunis, Tunisia. Address reprint requests to Insaf Hadj Ali, Medicine Interne A Department, Charles Nicolle Hospital, 1006 BS Tunis, Tunisia. E-mail: [email protected]
© 2011 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 43, 568 –571 (2011)
POST–RENAL TRANSPLANT DIABETES MELLITUS We analyzed potential factors predisposing to PTDM individually and simultaneously using a logistic regression model.
Over 2054.5 years of cumulative follow-up, 51 patients (17.2%) developed diabetes, corresponding to an annual incidence of 2.5%. Diabetes was diagnosed during the first year in 33/51 patients (64.7%) demonstrating the early onset of this complication, corresponding to a diabetes incidence of 11.8% during the first year after transplantation. PTDM was diagnosed at a median of 2.9 months (range: 0.2–168). Fig 1 shows the risk of developing diabetes during the first 15 months after renal transplantation, comprising 66.7% of all diabetes cases. The mean age of affected recipients was 33.3 ⫾ 7.4 years. Patients with PTDM were significantly older (P ⬍ .0005) and had higher BMI (P ⬍ .004). In fact, the risk of PTDM increased to 5.7% per year of age (P ⬍ .001) and an increase of 1 kg/m of BMI multiplied the risk of PTDM by 1.34 (P ⬍ .004). Univariate analysis revealed that age, BMI, family history of diabetes, vascular nephropathy and hepatitis C infection were associated with PTDM (Table 1). The multivariate analysis noted the roles of age (relative risk [RR] ⫽ 1.046/y, P ⬍ .04), of BMI (RR ⫽ 1.107/kg/m2, P ⬍ .05), vascular nephropathy (RR ⫽ 7.06, P ⬍ .03), and hepatitis C infection (RR ⫽ 2.72, P ⬍ .03) as independent factors predisposing to PTDM (Table 2). DISCUSSION
The incidence of new-onset diabetes mellitus is extremely variable among studies, ranging from 2% to 50%,9 depending on the diagnostic criteria, the therapeutic protocol, and the prevalence of diabetes in the general population.10,11 Seifi et al3 reported an incidence of 9.9% at 12 months following transplantation; Eckhard et al,12 19.9%. Maldonado et al7 reported frequencies of 7.5%, 13%, and 23% at
1, 5, and 10 years, respectively. Veroux et al13 observed a mean time of emergence of PTDM of about 8 ⫾ 5.2 months after transplantation. Our data showed an 11.8% incidence of diabetes during the first year after transplantation, the median time to diagnose diabetes was 2.9 months. Numerous studies have established the risk factors associated with PTDM, but the heterogeneity of diagnostic criteria has resulted in diverse results. Previous observations have confirmed that older age is an important risk factor in the progressive increased frequency of diabetes mellitus among transplanted patients,7 which may relate to the greater frequency of type 2 diabetes at older ages. Obesity is also considered a risk factor for developing diabetes. Considering that obesity is a growing problem in various countries and that the weight of transplant patients increases markedly in the first 2 years, PTDM will likely become an even more common problem in the future.3,5,10 Other studies have confirmed an association of traditional risk factors prior to transplantation other than age, including family history of type 2 diabetes, presence of pretransplant obesity, and pretransplant elevated triglyceride concentrations in the development of PTDM.14 Given the known correlation of increased PTDM risk with the presence of a positive family history for PTDM, some studies have postulated that predisposition to PTDM may also be governed by genetic variants known to increase the risk for type 2 diabetes development.15,16 Other workers have observed that hepatitis C positivity increases the risk of PTDM.17 The type of immunosuppression has the strongest impact on PTDM incidence; it may be responsible for more than two-thirds of PTDM cases.13 In contrast, Valderhaug et al18 recently reported a decreasing incidence of PTDM in recent years, probably due to changes in immunosuppressive therapy, fewer rejections, and lower steroid doses. Concerning the impact of the initial nephropathy, many
Fig 1. Cumulative frequency of diabetes after renal transplantation.
HADJ ALI, ADBERRAHIM, BEN ABDELGHANI ET AL
studies have not found evidence for an association between the initial nephropathy and the risk of PTDM development.19 However, some analysis have observed a high incidence of PTDM among patients with chronic interstitial nephropathy or polycystic kidney disease.20,21 The current study confirmed the association of traditional risk factors prior to transplantation, including age, elevated BMI, family history of type 2 diabetes, hepatitis C infection, and vascular nephropathy. In fact, the annual rate of PTDM among patients with vascular nephropathy was 5.08% versus 2.24% for patients with a nonvascular nephropathy (P ⬍ .004). It is worth noting that 21.1% of patients with vascular disease had a family history of type 2 diabetes. Multivariate analysis uncovered the role of age, BMI, vascular nephropathy, and hepatitis C infection to be independent factors predisposing to PTDM. In conclusion, knowledge of these pretransplant risk factors may provide the basis for prophylactic modalities, Table 1. Risk Factors for Posttransplant Diabetes Mellitus: Univariate Analysis Factor
Age (y) ⬍35 ⱖ35 Gender Women Men Body mass index (kg/m2) Family history of diabetes Yes No HLA A30 B8 B27 B42 Yes No Initial nephropathy Vascular Chronic glomerular Unknown Chronic interstitial Others RRT PD HD Duration of RRT (/yr) C hepatitis Positive Negative Pretransplant hypertension Yes No Pretransplant hyperlipidemia Yes No
Table 2. Risk Factors for Posttransplant Diabetes Mellitus: Multivariate Analysis Factor
Age at transplantation moment (/yr) Pretransplant BMI (kg/m2) Initial vascular nephropathy (/others) Pretransplant positive hepatitis C (/negative hepatitis C)
1.046 1.003–1.092 1.107 1.004–1.220 7.056 2.14–23.201 2.72 1.124–6.574
⬍.04 ⬍.05 ⬍.02 ⬍.03
BMI; body mass index; CI, confidence interval.
including lifestyle and immunosuppression modifications, to delay or prevent the development of PTDM among patients who may be more susceptible to develop PTDM. Several studies have demonstrated diet and lifestyle modifications reduced the incidence of type 2 diabetes among patients at high risk to develop type 2 diabetes. We suggest the use of oral glucose tolerance tests to screen patients to identify those predisposed to develop this complication.
2.42 2.51 —
1* 1.10 1.34
— 0.58–2.08 1.042–1.23
5.08 2.77 2.01 1.96 1.20
7.07 2.6 1.57 1.98 1*
1.33–37.66 ⬍.03 0.57–11.91 NS 0.32–7.72 NS 0.39–9.93 NS — —
1.86 2.57 —
1* 1.96 1.092
— 0.73–5.22 0.98–1.21
— NS NS
NS — ⬍.004
HLA, human leukocyte antigen; PR, peritoneal dialysis; HD, hemodialysis; RRT, renal replacement therapy; CI, confidence interval. *Reference group.
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POST–RENAL TRANSPLANT DIABETES MELLITUS diabetes mellitus following kidney transplantation. Transplant Proc 41:4172, 2009 15. Florez JC, Jablonski KA, Bayley N, et al: TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med 355:241, 2006 16. Florez JC, Hirschhorn J, Altshuler D: The inherited basis of diabetes mellitus: implications for the genetic analysis of complex traits. Annu Rev Genomics Hum Genet 4:257, 2003 17. Fabrizi F, Martin P, Dixit V, et al: Post-transplant diabetes mellitus and HCV seropositive status after renal transplantation: meta-analysis of clinical studies. Am J Transplant 5:2433, 2005
571 18. Valderhaug TG, Hjelmesaeth J, Rollag H, et al: Reduced incidence of new-onset post-transplantation diabetes mellitus during the last decade. Transplantation 84:1125, 2007 19. Silva F, Queiros J, Vargas G, et al: Risk factors for posttransplant diabetes mellitus and impact of this complication after renal transplantation. Transplant Proc 32:2609, 2000 20. Vesco L, Busson M, Bedrossian J, et al: Diabetes mellitus after renal transplantation: characteristics, outcome and risk factors. Transplantation 61:1475, 1996 21. Hamer RA, Chow CL, Ong AC, et al: Polycystic kidney disease is a risk factor for new-onset diabetes after transplantation. Transplantation 83:36, 2007