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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2018  |  Volume : 29  |  Issue : 4  |  Page : 863-871
New-onset diabetes after transplantation among renal transplant recipients at a new transplant center; King Fahad Specialist Hospital-Dammam, Saudi Arabia


1 Multi-Organ Transplant Center, King Fahad Specialist Hospital-Dammam, Dammam, Saudi Arabia
2 Department of Medicine, Endocrine Section, King Fahad Specialist Hospital-Dammam, Dammam, Saudi Arabia
3 Department of Medicine, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia

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Date of Submission07-Jul-2017
Date of Decision13-Sep-2017
Date of Acceptance17-Sep-2017
Date of Web Publication28-Aug-2018
 

   Abstract 

New-onset diabetes after transplant (NODAT) has been reported to occur in 4%-25% of renal transplant recipients. Its development has also been shown to be associated with an adverse impact on patient survival and an increased risk of graft rejection and graft loss, as well as an increased incidence of infectious complications. The study aims to describe the incidence of NODAT and its important risk factors in a single center. We conducted a retrospective analysis of data from all kidney transplant recipients in our center, transplanted between September 2008 and May 2013. Out of 311 patients, 77 had diabetes mellitus (DM) before transplantation and were excluded, leaving 234 patients as the study population. NODAT was diagnosed based on the WHO definition for DM: any two readings of fasting blood sugar >7 mmol/L or random blood sugar >11 or the use of hypoglycemic medications after 1st posttransplant month. The mean age of the study patients was 36 years ± 14 years; 55.5% were male, 69% had living-related transplant, 31% had deceased donor transplant, 98% were on tacrolimus-based immunosuppression regimen, 2% on cyclosporine and all patients were on the steroid-based regimen. The 1 and 5-year cumulative incidence of NODAT was 14.1% and 27.5%, respectively. The median duration to onset of NODAT was 2.5 months. The body mass index of >30 kg/m2 and age >60 years at the time of transplant were significantly associated with the occurrence of NODAT. Our finding of incidence was not different from what has been reported in the literature. Larger prospective and multicenter studies are needed.

How to cite this article:
Abdulrahman MM, Idris MA, Elhakimi WF, Akhtar M, Hammam M, Aldajani AA, Aljamaan YM, Alshahri HM, Housawi A. New-onset diabetes after transplantation among renal transplant recipients at a new transplant center; King Fahad Specialist Hospital-Dammam, Saudi Arabia. Saudi J Kidney Dis Transpl 2018;29:863-71

How to cite this URL:
Abdulrahman MM, Idris MA, Elhakimi WF, Akhtar M, Hammam M, Aldajani AA, Aljamaan YM, Alshahri HM, Housawi A. New-onset diabetes after transplantation among renal transplant recipients at a new transplant center; King Fahad Specialist Hospital-Dammam, Saudi Arabia. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2019 Nov 18];29:863-71. Available from: http://www.sjkdt.org/text.asp?2018/29/4/863/239641

   Introduction Top


New-onset diabetes after transplantation (NODAT) is a common complication faced by organ transplant recipients associated with significant reduction of the overall patient and graft survival.[1] Depending on the definition used, the incidence of NODAT has been found to be between 4% and 25% among kidney allograft recipients.[2] The risk factors of NODAT, which have been found in the literature, can be categorized into three groups. First, nonmodifiable risk factors such as patient age >45 years are 2.2 times more vulnerable to develop NODAT. Furthermore, recipients who received kidneys from male donors have a higher risk of having NODAT. Having human leukocyte antigens (HLAs) such as HLA B42, HLA B27, HLA B13, and HLA B15 was found to be associated with higher occurrence of NODAT.[3],[4],[5] In addition, being African-Americans or Hispanics increases the risk of having this complication.[5],[6] Second, modifiable risk factors such as obesity with a risk of 1.73;[5] use of immunosuppressive drugs such as cortico-steroids, sirolimus, or tacrolimus increases the risk of NODAT by up to 74%.[5],[7],[8] Several studies had proposed a possible decrease in the incidence of NODAT when patients were treated with steroid-free immunosuppression.[3] Thus, the ability to predict the risk for developing NODAT would be very helpful in choosing the suitable immunosuppressant for an individual.[6] Third, potentially modifiable risk factors such as hepatitis C virus (HCV) infection and cytomegalovirus (CMV) infection were also found to be associated with NODAT.[3]

However, the incidence and risk factors of NODAT are probably different among different ethnic groups similar to the incidence of type-2 diabetes mellitus (DM).[4] In our region, this is not very well studied. Previous studies suggest that NODAT may be more common among Saudi patients (41%).[9]

At the King Fahad Specialist Hospital-Dammam (KFSH-D), by the end of September 2013 around 360 renal trans-plants have been performed in adults. Studying the incidence and risk factors of this population can give a picture of the magnitude of the problem in our region and how we can tackle it in the future.


   Objectives Top


Our primary objective is to determine the the incidence of NODAT among kidney transplant recipients at KFSH-D.

The secondary objectives are to identify the risk factors for NODAT in this population and to measure the extent of the impact of NODAT on patient and graft survival.


   Methods Top


Inclusion criteria

All adult kidney transplant recipients and transplant recipients followed-up between October 2008 and September 2013.

Exclusion criteria

Patients <18 years and those who were transplanted outside KFSH-D, as well as patients with history of DM before transplantation, patients who did not complete one month after transplantation (this is done to exclude patients with hyperglycemia due to stress of surgery, high dose of steroids and hospital admission; some studies exclude up to three months posttransplant). Others found that hyperglycemia meeting the criteria for diabetes is identified in more than 90% of kidney allograft recipients if checked in the initial weeks after transplantation.[10],[11],[12]


   Statistical Analysis Top


P <0.05 was considered as statistically significant. All analyses were performed by the IBM Statistical Package for the Social Sciences version 20.0 and Microsoft Excel 2010. We used the following statistical measures for this study.

Parametric variables were summarized using the mean and compared using the t-test. Non-parametric variables were summarized using the median and compared using Mann–Whitney U-test. Categorical variables were summarized using proportions and compared using the Chi-square test. Univariate analysis was used to determine the risk factors associated with the development of NODAT. Multivariate analysis was then used to determine which of these factors was significantly associated with the development of NODAT.

Kaplan-Meier method was used to determine graft and patient survival. The log-rank test was used to study the effect of NODAT on graft and patient survival. Regarding sample size, we used “G-Power 3” software to calculate a preferred number of patients providing the appropriate power of the study. For Chi-square test, the preferred sample size would be 220 patients based on the alpha value of 0.05, the power of 0.95, medium effect size (d) of 0.3 and degree of freedom of 5.


   Results Top


Study population

The study included 234 adult nondiabetic patients who received a kidney transplant in KFSH-D over a 5-year period, from September 2008 to September 2013. One patient (0.4%) received a simultaneous kidney/liver transplant while the remainder received only a kidney transplant.

There were 165 living donor kidney transplants and 69 deceased donor kidney transplants. The mean age of living donors was 31.5 ± 8.2 years (range 18–57 years) and 80% of them were male. Among living donors, 30.9% were offsprings, 49.7% were siblings, 9.1% were parents, 4.8% were spouses, 3% were other relatives and 2.4% were unrelated. The mean age of deceased donors was 37.1 ± 11.5 years (range 2–54 years) and 89.7% of them were males [Table 1].
Table 1: Baseline characteristics of studied kidney transplant recipients (n=234).

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The mean age of the recipients was 36.8 ± 14.1 years (range 15–76 years). Recipient baseline characteristics are outlined in [Table 1]. The cause of renal impairment could not be identified in 58.1% of cases, while the most frequently identified causes are shown in [Table 2].
Table 2: Most probable cause of renal failure in studied kidney transplant recipients (n=234).

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Induction agents used included anti-thymo-cyte globulin (ATG) in 65.4% and basiliximab in 34.2% while one patient received no induction (0.4%). Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil (MMF) and prednisolone in 98.7% of patients, while three patients were maintained on cyclosporine, MMF and prednisolone (1.3%).

The vast majority of patients (97.9%) were CMV positive. All patients received CMV prophylaxis.

Transplant outcome

Immediate, slow, and delayed graft function was observed in 92.1%, 5.5%, and 2.4% of living-donor transplants compared to 46.4%, 30.4%, and 23.2% of deceased-donor transplants, respectively. Patient and graft survival rates are outlined in [Table 3].
Table 3: Patient and graft survival postkidney transplantation in the study cohort (n=234).

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New onset diabetes after transplant

Of the total of 234 patients who were not diabetic at baseline, 66 patients developed NODAT (28.2%). The cumulative incidence of NODAT was 25% at one year and 27% at two years. The median time to diagnosis was 76 days posttransplant (range: 10 days to 1110 days). More than half of the cases (54.5%) were diagnosed within the first three months and 71% of cases were diagnosed within the first six months [Figure 1]. On univariate analysis, male gender, age, obesity, HCV infection, and family history of DM were all associated with NODAT. On multivariate analysis, the only independent risk factors for NODAT were obesity and age at the time of transplantation [Table 4]. Among patients diagnosed with NODAT, the hyperglycemic state was transient in 59.1% and persistent in 40.9% of patients. Transient NODAT was diagnosed after a median duration of 76 days post-transplant (range 17 days to 1110 days) while persistent NODAT was diagnosed after a median duration of 180 days posttransplant (range 10 days to 840 days) the difference was not statistically significant.
Table 4: Risk factors for new-onset diabetes after transplantation among study cohort using multivariate analysis (n=234).

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Figure 1: Cumulative incidence of NODAT among studied kidney transplant recipients (n = 234).
NODAT: New-onset diabetes after transplantation.


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Overall, 51.4% of patients diagnosed with NODAT required pharmacological treatment for diabetes [Figure 2]. Pharmacological treatment was required for 90% of patients with persistent NODAT compared to 30% of patients with transient NODAT (P = 0.00) [Figure 3]. In patients with transient NODAT, the median duration of pharmacological treatment was five months (range 10 days to 1479 days). In patients with persistent NODAT, the median duration of pharmacological treatment was 31 months until the last follow-up (range 11 -55 months). NODAT had no significant effect on patient or graft survival in our study [Figure 4], [Figure 5], [Figure 6].
Figure 2: Management of NODAT in the studied patients (n = 66).
NODAT: New-onset diabetes after transplantation.


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Figure 3: Proportion of patients requiring pharmacological treatment for NODAT (n = 66).
NODAT: New-onset diabetes after transplantation.


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Figure 4: Patient survival in relation to NODAT (n = 234).
NODAT: New-onset diabetes after transplantation.


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Figure 5: Graft survival (censored for patient death) in relation to NODAT (n = 234).
NODAT: New-onset diabetes after transplantation.


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Figure 6: Graft survival (uncensored for patient death) in relation to NODAT (n = 234).
NODAT: New-onset diabetes after transplantation.


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   Discussion Top


In our study, from a total of 234 patients who were not diabetic at baseline, 66 patients developed NODAT (28.2%) by the end of the study period. The cumulative incidence of NODAT was 25% at one year and 27% at two years. In comparison, older studies published in 2002 reported an incidence ranging from to 2% to 50%.[13] In newer publications, the incidence varied between 9% and 39% in the 1st year after transplantation.[14]

The median time to diagnosis was 76 days posttransplant (range: 10 days to 1110 days). More than half of the cases (54.5%) were diagnosed within the first three months and 71% of cases were diagnosed within the first six months. Some studies have found that hyperglycemia meeting the criteria for diabetes is identified in more than 90% of kidney allograft recipients if checked in the initial weeks after transplantation (coinciding with peri-operative stress, high drug exposure, and corticosteroid induction).[10],[11] Another study in the region showed that 12 patients (18.2%) developed NODAT in the 1st month post-transplant, 24 patients (36.4%) developed it in from 2nd to 12th month, 8 patients (12.1%) in 2nd year and 22 patients (33.3%) after two years.[15]

The high incidence of NODAT in our region could be related to the high incidence of type-2 DM in our region. Furthermore, it is worth mentioning that many of those labeled as having NODAT as per the definition used above have sporadic readings of high blood sugar and not persistent hyperglycemia, and did not receive treatment

We identified several risk factors for NODAT on univariate analysis; male gender, age, obesity, HCV infection, and family history of DM were all associated with NODAT. On multivariate analysis, the only independent risk factors for NODAT were obesity and age at the time of transplantation. Older age has long been observed to be an important risk factor for the development of NODAT, and these findings were well correlated in one study performed by Cosio et al[16] who demonstrated that transplant recipients older than 45 years of age were 2.2 times more likely to develop NODAT than those younger at the time of transplantation (P <0.0001). Obesity has been found to be a risk factor for NODAT with relative risk of 1.73 in previous studies,[5] this is consistent with our finding with relative risk of 2.6. Other nonmodifiable risk factors like male recipient was not found to be associated with NODAT on multivariate analysis in our study unlike other studies.[5] HCV as a risk factor was not statistically significant on multivariate analysis in our study; this could be due to the small number of patients who were HCV positive (5% of all transplanted patients), and the short duration of the study.

Some relatively new studies have found that basiliximab induction could be a risk factor with relative risk of NODAT of 2.3 (95% CI 1.4-3.9) compared to that of patients without basiliximab.[1] Another study from Norway found that use of basiliximab as induction therapy may be associated with impaired glucose homeostasis after kidney transplantation.[18] However this was not addressed in our study.

NODAT had no significant effect on patient or graft survival in the study and this might be due to the small number of patients and short duration of the study. One patient died due to nonrenal cause. However, Bee et al[19] studied 388 renal transplants and found a significant difference in long-term survival between patients with NODAT and nondiabetics. Five-and 10 year-survival was 85.7% and 72%, respectively, for patients with NODAT, compared with 96.1% and 89.3% for those without diabetes (P <0.001). Furthermore, there was a significant difference in graft survival: 5-and 10-year graft survival was 89.4% and 81%, respectively, for patients with NODAT compared to 94% and 85.2% for those without diabetes (P = 0.045). The study of Kasiske et al[20] showed that NODAT was associated with an increased risk of graft failure (relative risk 1.63, P <0.0001) and death-censored graft failure (relative risk 1.87, P <0.0001). Another study of Valderhaug et al,[21] showed that, each 1 mmol/L increase in fasting plasma glucose or 2 h plasma glucose was associated with 11% (95% confidence interval -1%, 24%) and 5% (1%, 9%) increments in all-cause mortality risk and 19% (1%, 39%) and 6% (1%, 12%) increments in cardiovascular mortality risk, respectively.

Although studies in the general population show that intensive modification of diet and physical activity can prevent or delay progression of pre-diabetes to overt type-2 DM, the question of whether NODAT can be prevented using a similar strategy has not, to our knowledge, been tested.[22]


   Conclusion Top


The study revealed relatively high incidence of NODAT (28.1%), and the only statistically significant risk factors were obesity and age at the time of transplantation. Most cases of NODAT were transient and diagnosed in the first six months posttransplant.

The limitation in our study was that it was a single-center retrospective study and the follow-up was of short duration.

We recommend multi-center prospective studies to come up with exact incidence of NODAT and to properly study the risk factors.

Conflict of interest: None declared.

 
   References Top

1.
Hjelmesaeth J, Hartmann A, Leivestad T, et al. The impact of early-diagnosed new-onset posttransplantation diabetes mellitus on survival and major cardiac events. Kidney Int 2006;69: 588-95.  Back to cited text no. 1
    
2.
Pham PT, Pham PM, Pham SV, Pham PA, Pham PC. New onset diabetes after transplantation (NODAT) : An overview. Diabetes Metab Syndr Obes 2011;4:175-86.  Back to cited text no. 2
    
3.
Luan FL, Steffick DE, Ojo AO. New-onset diabetes mellitus in kidney transplant recipients discharged on steroid-free immunosup-pression. Transplantation 2011;91:334-41.  Back to cited text no. 3
    
4.
Numakura K, Satoh S, Tsuchiya N, et al. Clinical and genetic risk factors for post-transplant diabetes mellitus in adult renal transplant recipients treated with tacrolimus. Transplantation 2005;80:1419-24.  Back to cited text no. 4
    
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Sarno G, Muscogiuri G, De Rosa P. New-onset diabetes after kidney transplantation: Prevalence, risk factors, and management. Transplantation 2012;93:1189-95.  Back to cited text no. 5
    
6.
Yang J, Hutchinson II, Shah T, Min DI. Genetic and clinical risk factors of new-onset diabetes after transplantation in Hispanic kidney transplant recipients. Transplantation 2011;91:1114-9.  Back to cited text no. 6
    
7.
Matas AJ, Gillingham KJ, Humar A, et al. Posttransplant diabetes mellitus and acute rejection: Impact on kidney transplant outcome. Transplantation 2008;85:338-43.  Back to cited text no. 7
    
8.
Bodziak KA, Hricik DE. New-onset diabetes mellitus after solid organ transplantation. Transpl Int 2009;22:519-30.  Back to cited text no. 8
    
9.
Onwubalili JK, Obineche EN. High incidence of post-transplant diabetes mellitus in a single-centre study. Nephrol Dial Transplant 1992;7: 346-9.  Back to cited text no. 9
    
10.
Chakkera HA, Weil EJ, Castro J, et al. Hyperglycemia during the immediate period after kidney transplantation. Clin J Am Soc Nephrol 2009;4:853-9.  Back to cited text no. 10
    
11.
Hecking M, Haidinger M, Döller D, et al. Early basal insulin therapy decreases new-onset diabetes after renal transplantation. J Am Soc Nephrol 2012;23:739-49.  Back to cited text no. 11
    
12.
Weng LC, Chiang YJ, Lin MH, et al. Association between use of FK506 and prevalence of post-transplantation diabetes mellitus in kidney transplant patients. Transplant Proc 2014;46:529-31.  Back to cited text no. 12
    
13.
Montori VM, Basu A, Erwin PJ, et al. Posttransplantation diabetes: A systematic review of the literature. Diabetes Care 2002;25:583-92.  Back to cited text no. 13
    
14.
Yates CJ, Fourlanos S, Hjelmesaeth J, Colman PG, Cohney SJ. New-onset diabetes after kidney transplantation-changes and challenges. Am J Transplant 2012;12:820-8.  Back to cited text no. 14
    
15.
Ghafari A, PourAli R, Sepehrvand N, Hatami S, Modarres V. Post-transplantation diabetes mellitus; frequency and related risk factors: A single center study. Saudi J Kidney Dis Transpl 2010;21:842-5.  Back to cited text no. 15
[PUBMED]  [Full text]  
16.
Cosio FG, Pesavento TE, Osei K, Henry ML, Ferguson RM. Post-transplant diabetes mellitus: Increasing incidence in renal allograft recipients transplanted in recent years. Kidney Int 2001;59:732-7.  Back to cited text no. 16
    
17.
Prasad N, Gurjer D, Bhadauria D, et al. Is basi-liximab induction, a novel risk factor for new onset diabetes after transplantation for living donor renal allograft recipients? Nephrology (Carlton) 2014;19:244-50.  Back to cited text no. 17
    
18.
Aasebø W, Midtvedt K, Valderhaug TG, et al. Impaired glucose homeostasis in renal transplant recipients receiving basiliximab. Nephrol Dial Transplant 2010;25:1289-93.  Back to cited text no. 18
    
19.
Bee YM, Tan HC, Tay TL, et al. Incidence and risk factors for development of new-onset diabetes after kidney transplantation. Ann Acad Med Singapore 2011;40:160-7.  Back to cited text no. 19
    
20.
Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 2003; 3:178-85.  Back to cited text no. 20
    
21.
Valderhaug TG, Hjelmesæth J, Hartmann A, et al. The association of early post-transplant glucose levels with long-term mortality. Diabetologia 2011;54:1341-9.  Back to cited text no. 21
    
22.
Saito T, Watanabe M, Nishida J, et al. Lifestyle modification and prevention of type 2 diabetes in overweight Japanese with impaired fasting glucose levels: A randomized controlled trial. Arch Intern Med 2011;171:1352-60.  Back to cited text no. 22
    

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Correspondence Address:
Dr. Abdulrahman Housawi
Multi-Organ Transplant Center, King Fahad Specialist Hospital, Dammam
Saudi Arabia
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DOI: 10.4103/1319-2442.239641

PMID: 30152423

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    Figures

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