|Year : 2016 | Volume
| Issue : 6 | Page : 1155-1161
|New-onset diabetes after kidney transplantation: Incidence, risk factors, and outcomes
Hassan Aleid1, Ahmad Alhuraiji2, Abdullah Alqaraawi2, Ammar Abdulbaki1, Mai Altalhi1, Mohamed Shoukri3, Eldali Abdelmoneim3, Tariq Ali1
1 Department of Kidney and Pancreas Transplantation, King Faisal Specialist Hospital, Riyadh, Saudi Arabia
2 Department of Medicine, King Faisal Specialist Hospital, Riyadh, Saudi Arabia
3 Department of Biostatistics and Epidemiology, King Faisal Specialist Hospital, Riyadh, Saudi Arabia
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|Date of Web Publication||28-Nov-2016|
| Abstract|| |
Many patients develop new-onset diabetes after kidney transplantation (NODAT). Its incidence and epidemiology are unknown in the Saudi population. We aimed to study the incidence, epidemiology, and outcomes of kidney transplant recipients who developed NODAT. This is a retrospective study of all adults who received kidney transplant between January 2003 and December 2009. NODAT was defined according to the criteria outlined in the 2003 International Consensus guidelines. A total of 500 patients were included in this study, 54% were male patients. One hundred thirty-six patients (27%) developed diabetes (NODAT group). In the univariate analysis, patients were older in the NODAT group (P <0.001), were of higher weight (P = 0.006), and had positive family history of diabetes (P = 0.002). Similarly, more patients in this group had impaired glucose tolerance before transplant (P = 0.01) and history of hepatitis C infection (P = 0.005). In the multivariate analysis, older age [odds ratio (OR) 1.06], family history of diabetes (OR 1.09), hepatitis C infection (OR 1.92), and impaired fasting glucose (OR 1.79) were significant risk factors for the development of NODAT. Mortality was 6% in the NODAT group and 0.5% in the non-diabetic group had died (P <0.001). Graft survival was not different between the groups (P = 0.35). In conclusion, there is a significant risk of developing diabetes after renal transplantation. Patients are at higher risk if they are older, have a family history of diabetes, pre-transplant impaired fasting/random glucose, and hepatitis C virus infection.
|How to cite this article:|
Aleid H, Alhuraiji A, Alqaraawi A, Abdulbaki A, Altalhi M, Shoukri M, Abdelmoneim E, Ali T. New-onset diabetes after kidney transplantation: Incidence, risk factors, and outcomes. Saudi J Kidney Dis Transpl 2016;27:1155-61
|How to cite this URL:|
Aleid H, Alhuraiji A, Alqaraawi A, Abdulbaki A, Altalhi M, Shoukri M, Abdelmoneim E, Ali T. New-onset diabetes after kidney transplantation: Incidence, risk factors, and outcomes. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2020 Jan 19];27:1155-61. Available from: http://www.sjkdt.org/text.asp?2016/27/6/1155/194603
| Introduction|| |
Kidney transplantation is considered the best form of renal replacement therapy for patients with the end-stage renal disease. Kidney transplantation has shown to improve quality of life, morbidity, and mortality. ,, However, improvement in the short-term outcomes  has not fully translated into the improvement of the longterm outcomes. The important long-term complications in these patients include development of cardiovascular disease, diabetes, and malignancy. 
Unfortunately, many patients develop diabetes after kidney transplantation termed as new onset diabetes after transplantation (NODAT). NODAT has been reported to be associated with poor outcomes. ,, The incidence of NODAT is variable in the literature ranging from 7-40%. ,, In 2003, new guidelines were developed to define NODAT.  With these guidelines, it is relatively easy to compare the incidence of NODAT across different populations.
A study using data from the United States Renal Data System estimated a cumulative incidence of 9%, 16%, and 24% at 3, 12, and 36 months post-transplant, respectively.  Older age, male donors, increasing human leukocyte antigens mismatches, hepatitis C infection, body mass index ≥30 kg/m 2 , and the use of tacrolimus were associated with the development of NODAT. A Canadian study reported an incidence of 9.8% and also found that older age, deceased donor, hepatitis C, rejection, and use of tacrolimus were the risk factors for developing NODAT. 
The incidence of NODAT is unknown in the Saudi population. It is important to determine its incidence, to study epidemiology and outcomes of NODAT in the local population. We aimed to determine the incidence and outcomes of NODAT and to identify risk factors for its development in the Saudi population.
| Study Design and Methods|| |
This is a single-center retrospective study of all adult kidney transplant recipients who received a kidney transplant between January 2003 to December 2009 at King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. About 150 adult renal transplant procedures are performed in this center every year.
All kidney transplant recipients aged 18 years and above were included in this study. The following patients were excluded from the study: (1) those patients who fulfilled the criteria of diabetes before transplantation, (2) multi-organ transplant recipients, and (3) patients who had a graft failure or died within one month of transplantation.
NODAT was defined according to the criteria outlined in the 2003 international consensus guidelines,  namely (1) fasting plasma glucose level of ≥7 mmol/L (≥126 mg/dL) taken on two separate occasions, and/or (2) random plasma glucose level of ≥11.1 mmol/L (≥200 mg/dL) taken on two separate occasions, and/or (1) positive oral glucose tolerance test and (2) new use of insulin or oral hypoglycemic agents to lower blood sugar in previously non-diabetic patients.
Impaired fasting glucose (IFG) was defined as fasting plasma glucose between 5.6 and 6.9 mmol/L (100-126 mg/dL) and/or random plasma glucose between 7.9 and 11 mmol/L (142-199 mg/dL).
All patients were followed up in the clinic according to the following schedule: twice weekly for the first three months, once weekly from month four to month six, once monthly from month six to month 12, and every 3-6 month thereafter.
During all these visits, blood samples were drawn for biochemical analysis including plasma glucose appropriately labeled as fasting or random.
Thymoglobulin or Simulect was used as the induction agents along with methylprednisolone according to the local protocol. Patients received two doses of methylprednisolone and on day 2 started on prednisone 80 mg with daily tapering such that by day 7, they were on 20 mg of prednisone, which was gradually tapered to 5 mg by 6-8 weeks. The most commonly used long-term immunosuppressive medications consisted of prednisone, mycophenolate mofetil (CellCept) and tacrolimus. Some patients received cyclosporine or rapamycin. The types of immunosuppressive agents were noted at each clinic visit along with the trough blood levels of cyclosporine and tacrolimus.
Patients also received prophylaxis against cytomegalovirus infection (mostly valganciclovir), pneumocystis (Septra), and tuberculosis (isoniazid) according to the local protocol. Data were collected by four investigators from both the case records (patients' files) and electronic database.
This study proposal was reviewed and approved by the Local Research Ethics Committee.
| Statistical Analysis|| |
The data are reported as a mean for continuous variables and as a number and proportion for categorical variables. P <0.05 and 95% confidence interval (CI) was considered statistically significant.
Unadjusted univariate analysis was done using Chi-square or Fisher's exact test as appropriate. Unadjusted odds ratio (OR) with 95 CI was calculated using Mantel-Haenszel methods. When comparing two groups, Fisher's exact test was done for categorical variables and independent t-test for continuous variables.
Multivariate analysis was done using logistic regression to determine the independent predictors of NODAT from the potential confounders. All the statistical analyses of data were done using the software packages SPSS version 20 (SPSS, IBM Statistics, USA) and SAS version 9.3 (Statistical Analysis System, SAS Institute Inc., Cary, NC, USA).
| Results|| |
A total of 500 patients were included in this study, 382 patients (77%) received living-related transplant and 118 (13%) received kidneys from deceased donors. There were 268 (54%) male and 232 female patients [Table 1]. Among the 136 patients (27%) who developed diabetes (NODAT group), 78 were males and 58 were females. The mean age at the time of transplant was 35 years in the nondiabetic group (range 18-72 years) and 45 years in the NODAT group (range 20-76) [Table 2].
Only 63 patients were current smokers, and there was no association of smoking with posttransplant diabetes (P = 0.74). Delayed graft function (DGF) was observed in 41 patients (8.2%), DGF was not associated with posttransplant diabetes (P = 0.49).
Increasing age was associated with a higher incidence of NODAT. About 60% of the renal transplant recipients who were aged >60 years developed NODAT [Table 2] and [Table 3].
The mean weight at the time of transplant was 66 kg in the NODAT and 62 kg in patients who did not develop diabetes (P = 0.006). Similarly, pre-transplant BMI was 26 and 24, respectively (P <0.001). The risk of NODAT increased across the BMI categories [Table 3].
One hundred and eighty-six patients with a positive family history of diabetes in the first-degree relatives developed NODAT. Fortythree percent of patients in the NODAT group and 35% in the non-diabetic group had a family history of diabetes (P = 0.001).
A total of 464 patients (93%) had normal fasting glucose before transplantation, 119 such patients (26%) developed diabetes. Of the 36 patients who had impaired glucose tolerance, 17 patients developed NODAT (P = 0.01). In the non-diabetic group, at 12-month post-transplantation, 259 patients had normal fasting glucose level and 89 (25%) had IFG [Table 2].
Before transplantation, 102 patients were positive for the hepatitis C antibody, of whom 39 developed diabetes: 29% of the patients in the NODAT group and 17% in the nondiabetic group had a positive history of HVC infection (P = 0.005).
At the time of transplantation, 50% patients were taking B-blockers, of whom 15% developed diabetes. Among those patients who were not taking a B-blocker, 13% developed NODAT (P = 0.37).
Cyclosporine A (CsA) was initiated in 73 patients, a comparison with the tacrolimus was not made as a significant number of patients were converted from CsA to tacrolimus or rapamycin at different time points (>50% in the NODAT group). By six months, only eight patients who remained on CsA developed diabetes. However, 25% of those who were started on tacrolimus became diabetic.
At day 5, post-transplantation the mean tacrolimus level was 10.2 in the NODAT group versus 9.2 in the non-diabetic group (P = 0.04). FK levels were 9.9 and 10.6, respectively, at three months (P = 0.05). After this time point, there was no statistically significant association between FK level and development of diabetes.
Ninety-seven patients (19%) developed early rejection of whom, 36 became diabetic. Twenty-six percent in the NODAT group and 17% in the non-diabetic group had a history of rejection (P = 0.01).
Of 136 patients who developed NODAT, 101 did so in the first six months. Another 15 patients developed NODAT in the next six months, and only 20 patients developed NODAT after one-year post-transplantation. The incidence of NODAT gradually decreased over time with the vast majority developing diabetes in the first six months.
At the end of the study period, nine patients (6%) in the NODAT group and two patients (0.5%) in the non-diabetic group had died (P <0.001). As the mortality was very low in both groups, statistical significance could not be confirmed in multivariate analysis. Five patients in the NODAT group and eight patients in the non-diabetic group had lost their graft by the end of the study period (P = 0.35) [Table 1].
On multivariate logistic regression analysis, older age, family history of diabetes, impaired glucose intolerance, and hepatitis C infection were found to be statistically significant risk factors for the development of NODAT [Table 4].
| Discussion|| |
This study has shown that around quarter of patients develop NODAT in the Saudi population. Older age, family history of diabetes, impaired fasting glucose, and hepatitis C infection were identified as risk factors for the development of NODAT. The mortality was high among those patients who developed NODAT.
A Canadian study reported an incidence of 9.8% in their population,  whereas an American study found that incidence of NODAT was 5% for insulin requirement and 6% for patients requiring oral hypoglycemic agents.  In this study, the majority of patients (65%) were Caucasians. A larger US study of kidney transplant recipients reported an incidence of 16% in the US population at three months post-transplantation.  Our study of Saudi population has found a much higher incidence of NODAT. The prevalence of diabetes in the general population in Saudi Arabia has been estimated at 24% in 2004  and 30% in 2011.  A single center study in Bahrain reported a prevalence of NODAT at 33%.  Our high incidence of diabetes in the transplant population is in keeping with the demographic trends in the area.
In the present study, the prevalence of NODAT continued to rise with time, but the majority of patients (101 of 136) developed diabetes within six months of transplantation. A study using data from the United Renal Data System estimated a cumulative incidence of 9%, 16%, and 24% at 3, 12, and 36 months post-transplant, respectively.  This study also confirms the high incidence during the first post-transplant year. The median time to develop NODAT was found to be 44 days in a Canadian study.  Our study along with other reports confirms that incidence is higher in the initial post-transplant period. This is in keeping with the initial use of immunosuppressive medication, especially higher doses of steroids and the treatment of early rejection episodes.
Increasing age has been found as an independent risk factor for NODAT.  This database study has shown a relative risk of 1.90 for patients aged between 45 and 60 years and a relative risk of 2.6 for patients aged 60+.  A study from the Middle East has shown that people who developed NODAT were significantly older than those who did not develop diabetes (51 years vs. 41 years) (16). Our study has also shown that older age is a significant risk factor for the development of diabetes (OR 1.061, CI: 1.044-1.079).
Our study found a significant association of hepatitis C virus (HCV) infection and NODAT. A previous study reported that 39% of HCV positive patients developed NODAT, whereas only 10% patients who were HCV negative developed diabetes.  A Canadian study found a borderline association (P = 0.05),  whereas the American study has shown a very significant association of HCV infection to the development of diabetes (P <0.0001).  An increased prevalence of diabetes mellitus has also been observed in individuals infected with HCV, both in the general population, as well as in patients with advanced liver disease before and after transplantation.  In renal transplant patients, HCV infection has been reported to occur with a frequency ranging from 10-40% and is associated with an increased risk of both allograft failure and mortality. ,
In the present study, the mortality rate was high in the NODAT group (P <0.001), but this finding was not confirmed in multivariate analysis due to very small number of patients in both groups. However, there was no significant difference in the graft survival between the two groups. A previous study has shown an increased risk of graft failure in the NODAT group, but a higher rate of graft failure was thought to be associated with higher risk for death in the NODAT group.  A longterm follow-up study has shown a significant mortality of 31% in the NODAT group compared to 16% mortality in patients who did not develop post-transplant diabetes. 
There are few limitations of this study; this is a retrospective analysis and only included patients from a single center. The population studied was mainly Saudi population and results may not be applicable to other populations. However, it is reassuring that the results of this study match with the other international studies of the different populations. Further, prospective studies are required in this area.
| Conclusion|| |
There is a significant risk of developing diabetes after renal transplantation. Patients are at higher risk, if they are older, have a family history of diabetes, pre-transplant impaired fasting/random glucose, and HCV infection.
Conflict of interest: None declared.
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Department of Kidney and Pancreas Transplantation, King Faisal Specialist Hospital, Riyadh
[Table 1], [Table 2], [Table 3], [Table 4]
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