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Saudi Journal of Kidney Diseases and Transplantation
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RENAL DATA FROM THE ARAB WORLD  
Year : 2012  |  Volume : 23  |  Issue : 5  |  Page : 1104-1108
Post-transplantation diabetes mellitus


1 Nephrology-Dialysis-Renal Transplantation Unit, Ibn Sina Hospital, Rabat, Morocco
2 Biochemistry Unit, Ibn Sina Hospital, Rabat, Morocco

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Date of Web Publication13-Sep-2012
 

   Abstract 

To determine the prevalence of post-kidney transplantation diabetes (PTDM) and to assess its risk factors, we retrospectively studied 92 non-diabetic kidney transplant patients. The immunosuppressive drugs used to prevent rejection included prednisone, a calcineurin inhibitor (cyclosporine or tacrolimus) and an antimetabolite (azathioprine or mycofenolate mofetil). Diabetes was defined according to the WHO criteria and the American Diabetes Association. The mean age of our patients was 35.8 ± 10.5 years, and there was a clear male predominance (56 men and 36 women). The graft was from living related donor in 71/92 (76%) patients. The prevalence of dia­betes in post-kidney transplant was 15.2%. The factors increasing the occurrence of PTDM included advanced age, high doses of steroids and cyclosporine. Management of PTDM included diet modification, oral anti-diabetic and insulin. We conclude that the prevalence of PTDM is significant in our transplant population and risk factors for its development are multiple and require aggressive multifaceted management.

How to cite this article:
Zbiti N, Souly K, Errami Z, Guendouz L, Benamar L, Ezaitouni F, Ouzeddoun N, Bayahia R, Chabraoui A, Rhou H. Post-transplantation diabetes mellitus. Saudi J Kidney Dis Transpl 2012;23:1104-8

How to cite this URL:
Zbiti N, Souly K, Errami Z, Guendouz L, Benamar L, Ezaitouni F, Ouzeddoun N, Bayahia R, Chabraoui A, Rhou H. Post-transplantation diabetes mellitus. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2020 Jul 11];23:1104-8. Available from: http://www.sjkdt.org/text.asp?2012/23/5/1104/100971

   Introduction Top


Post-transplant diabetes mellitus (PTDM) is a complication that ensues after solid organ trans­plantation. The first cases were described in 1964 after a liver transplant by Thomas Starzl. [1] The incidence of PTDM is highly variable, ranging from 2-53%; 4-25% after kidney trans­plantation and 2.5-25% after liver transplantation. [1],[2],[3] PTDM is a major cardiovascular risk factor that compromises the renal grafts prog­nosis. It is an independent predictor of graft loss and death. [1]

The aim of our study was to determine the pre­valence of PTDM and to assess the risk factors in our population.


   Materials and Methods Top


We retrospectively studied 92 kidney trans­plant adult patients over a period of 22 years. We excluded all the known diabetic patients before transplantation. The immunosuppressive protocol used to prevent graft rejection included ethylprednisolone bolus of 500 mg on the day of transplantation, 2 h before surgery, followed by oral prednisone 1 mg/kg/day during ten days, then 0.5 mg/kg/day until the 30 th post­operative day and 0.4 mg/kg/day until the 60 th post-operative day. A progressive tapering was used to reach oral prednisolone of 10 mg daily at three months. A calcineurin inhibitor (cyclosporine A microemulsion) added to corticosteroids at a dose of 5 mg/kg/day was started 48 h before transplantation for the first three months with a target of cyclosporine trough concentration levels (C0) between 150 and 180 ng/mL and 2-h cyclosporine concentration levels (C2) between 800 and 1000 ng/mL during the first three months. Antimetobolites [Mycofenolate mofetil (MMF) or azathioprine] were added as well to the immunosuppressive agents; MMF as 2 g/ day started 48 h before transplantation divided into two or three times doses per day after meals, and the dose was reduced in case of hematological toxicity or digestive disorder.

We analyzed the demographic parameters (age, sex, dialysis time, original nephropathy, fami­lial diabetes, time between transplantation and the diabetes' appearance and donor type), clin­ical parameters [weight, size and body mass index (BMI) calculated according to its formula kg/m 2 ] and biological parameters (renal func­tion, glucose blood levels, glycated hemoglobin, serologic C virus profile, cyclosporine trough levels at the end of the first month, six months and one year after renal transplantation).

The criteria for diagnosing glucose intolerance and post-transplant diabetes followed the stan­dards established by the World Health Organi­zation (WHO), the American Diabetes Associa­tion (ADA) and the Brazilian Society of Diabetes Association (SBD) as follows:

  • Diabetes symptoms with randomized plasma blood glucose ≥2 g/L (11.1 mmol/L) or
  • Fasting plasma glucose (FPG) (at least 8 h fast) ≥1.26 g/L (7 mmol/L). [1],[2]


Glucose blood levels were determined with a specific electrode technique on a Synchrone clinical system CX7 deltaTM (Beckman). The determination of glycated hemoglobin was per­formed by the immunoturbidimetry technique on an Integra 400 plus TM robot (Cobas). The cyclosporine serum levels were measured with an immunofluorescence technique using the TDx® system cyclosporine kits (Abbott), and the interpretation was determined with a TDxFLx SystemTM spectrophotometer (Abbott).


   Statistical Analysis Top


Statistical analysis was performed using the SPSS 15.1 software. We used the mean ± stan­dard deviation and percentage for the quantita­tive and qualitative variable analysis, respectively. We used the "t" Student test for comparison of the means and the chi square for percentages. The difference was considered significant when P <0.05.


   Results Top


The mean age of our patients was 35.8 ± 10.5 years (range from 26 to 65 years) and there was a clear male predominance (56 men and 36 women), with a sex ratio of 1.55. The mean dia­lysis time (hemodialysis and peritoneal dialysis combined) before transplantation was 32.4 ± 21.4 months, ranging from three to 264 months. The original nephropathy was undetermined in 59.2% of the cases, glomerular in 15.5%, tu­bular-interstitial in 19.7% and hereditary in 5.6%. Familial diabetes mellitus was found in five cases [Table 1] and [Table 2]. The graft was from related living donor in 71 (76%) patients; among them, 67 grafts (94.3%) were performed in Morocco. All the 21 kidney transplantations from a cadaveric donor were accomplished abroad. After a mean transplantation time of three months, 14/92 (15.2%) transplanted patients de­veloped a PTDM. At the time of PTDM diag­nosis, the mean corticosteroid dose was 0.25 mg/kg/day, cyclosporine dose was 3 mg/kg/ day and fasting glucose level was 1.39 ± 0.3 g/L (from 1.26 g/L to 1.82 g/L). The risk factors for developing of PTDM included advanced age at the transplantation time (P = 0.026), high doses of steroids one month after the intervention (P = 0.043) and high doses of cyclosporine trough levels at the end of the first month post-trans­plantation (258.60 ± 200.16 ng/mL (P = 0.045) [Table 3].
Table 1: Demographic parameters of the study population.

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Table 2: Clinical and therapeutic characteristics of the post-transplant diabetic patients (n = 14).

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Table 3: Post-transplant diabetic patients risk factors.

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Diabetes treatment included dietetic measures as the first step, associated with progressive reduction of corticosteroid doses until reaching a daily dose of 5 mg in some cases or discon­tinuation in others. Insulin therapy was required in four patients and oral anti-diabetic (OAD) agents (such as Gliclazide, Metformine and Glimepiride) in five cases.

After a mean follow-up of 48 ± 12 months, we report in our 14 diabetic patients seven infec­tions (respiratory in four cases, urinary in three) controlled with antibiotic therapy. The diabetes control was satisfying with a glycated hemoglobin of 7 ± 0.6%. No episodes of acidosis or deterioration of renal function were encoun­tered. Five patients were weaned off and four continued on anti-diabetic medications; three on insulin and one on glimepiride.


   Discussion Top


In our study, the prevalence of PTDM was estimated at 15.2%, and the mean time for its appearance was three months. The factors affecting the development of a PTDM included advanced age, familial history of diabetes mellitus, carbohydrates intolerance before kidney transplantation, immunosuppressive agents (glucocorticoids, calcineurin inhibitors), overweight, cadaveric kidney transplant and hepatitis C vi­rus infection. [4],[5],[6],[7] In our study, the factors linked to the appearance of diabetes included advanced age when the renal transplantation was per­formed, high corticosteroid doses at three months after the intervention and high cyclosporine blood trough levels one month after transplan­tation. Moreover, we did not find a difference in the incidence of PTDM with hepatitis C virus infection (7/78 versus 3/14) or with the time spent on dialysis, which was longer (32.4 ± 30.1 months vs. 31.3 ± 20.1 months). Overweight was not found as a risk factor (21.3 ± 4.2 kg/m 2 vs. 23.3 ± 3.5 kg/m 2 ), which is probably related to the reduced number of patients in our study. Hjelmesaeth et al showed that the risk of deve­loping PTDM increases by 5% when the corticosteroid dose is raised by 0.01 mg/kg/day. [8] Tacrolimus is the most implicated drug in PTDM genesis; the diabetogenic risk is five-times higher than the cyclosporine one. [4],[9] The described abnormalities are linked to blood trough levels, especially when tacrolimus is added to corticosteroids, the effects being rever­sible when the medication is interrupted. [9] Tacrolimus has only been used in one patient who developed PTDM, which is similar to type 2 diabetes, and is characterized primarily by insulin resistance in addition to insulin deficiency. Corticosteroids can cause insulin resistance and an increase in hepatic glucose production in addition to reduction of insulin-induced vasodilation and glucose transporter translocation in the muscles and amplification of lipolysis in the adipose tissue. Calcineurin inhibitors reduce insulin production and secretion by a toxic mechanism on β-pancreatic cells and increase insulin resistance. The interactions between glucocorticosteroids and cyclosporine A in cytochrome P-450 also increase insulin resistance. [2],[10]

Because PTDM is comparable to type 2 dia­betes, the patients benefited from diet modi­fications. Oral anti-diabetic and insulin therapy were added in case diet was not sufficient for control of blood sugar.

Finally, PTDM can compromise the transplan­ted patients' follow-up as it increases health events and hospitalizations and affects the pa­tients' quality of life. [11],[12] Furthermore, diabetes that belongs to the metabolic syndrome is a major cardiovascular risk factor that affects the renal graft prognosis and reduces patients survival. [13]

We conclude that prevalence of PTDM is significant in our transplant population and risk factors for its development are multiple and require aggressive multifaceted management.

 
   References Top

1.Legendre C, Fary Ka E, Karras A, Flamant M, Martinez F, Thervet E. Diabètes secondaires aux traitements immunosuppresseurs en transplan­tation rénale. Encycl Méd Chir, Endocrinologie-Nutrition 2003, 10-366-D-30.  Back to cited text no. 1
    
2.Mourad G, Garrigue V, Bismuth J, Szwarc I, Delmas S, Iborra F. Suivi et complications non immunologiques de la transplantation rénale. Encycl Méd Chir, Néphrologie 2005, 18-065-D-10.  Back to cited text no. 2
    
3.Montori VM, Basu A, Erwin PJ, Velosa JA, Gabriel SE, Kudva YC. Post-transplantation diabetes: A systematic review of the literature. Diabetes Care 2002;25:583-92.  Back to cited text no. 3
    
4.Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ. Diabetes mellitus after kidney transplantation in the United States. Am J Transpl 2003;3:178-85.  Back to cited text no. 4
    
5.Nam JH, Mun JI, Kim SI, et al. Âeta-cell dys­function rather than insulin resistance is the main contributing factor for the development of postrenal transplantation diabetes mellitus. Transplantation 2001;71:1417-23.  Back to cited text no. 5
    
6.Gentil MA, Luna E, Rodriguez-Algarra G, et al. Incidence of diabetes mellitus requiring insulin treatment after renal transplantation in patients with hepatitis C. Nephrol Dial Transplant 2002;17:887-91.  Back to cited text no. 6
    
7.Mathew JT, Rao M, Job V, Ratnaswamy S, Jacob CK. Post-transplant hyperglycaemia: A study of risk factors. Nephrol Dial Transplant 2003;18:164-71  Back to cited text no. 7
    
8.Hjelmesaeth J, Hartmann A, Kofstad J, et al. Glucose intolerance after renal transplantation depends upon prednisolone dose and recipient age. Transplantation 1997;64:979-83.  Back to cited text no. 8
    
9.Backman LA. Post-transplant diabetes mellitus: the last 10 years with tacrolimus. Nephrol Dial Transplant 2004;19:13-6.  Back to cited text no. 9
    
10.Bloom RD, Crutchlow MF. Transplant-associated hyperglycemia. Transplantation Rev 2008;22: 39-51.  Back to cited text no. 10
    
11.Cosio FG, Alamir A, Yim S, et al. Patient sur­vival after renal transplantation: impact of post-transplant diabetes. Kidney Int 1998;53:767-72.  Back to cited text no. 11
    
12.Ramezani M, Ghoddousi K, Hashemi M, Khoddami-Vishte HR, Fatemi-Zadeh S, Saadat SH, et al. Diabetes as the cause of End-Stage renal disease affects the pattern of post kidney transplant rehospitalizations. Transplant Proc 2007;39:966-9.  Back to cited text no. 12
    
13.Faenza A, Fuga G, Nardo B, et al. Metabolic syndrome after kidney transplantation. Transplant Proc 2007;39:1843-6.  Back to cited text no. 13
    

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Correspondence Address:
N Zbiti
Nephrology-Dialysis-Renal Transplantation Unit, Ibn Sina Hospital, Rabat
Morocco
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DOI: 10.4103/1319-2442.100971

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