|Year : 2018 | Volume
| Issue : 2 | Page : 103-109
Incidence and associated risk factors of new-onset diabetes mellitus after transplantation in renal transplant recipients: A retrospective single-center study in Nepal
Rajendra Kumar Agrawal1, Rohit Agrawal2, Priyanka Agrawal3, Anil Baral1, Rajani Hada1
1 Department of Nephrology, National Academy of Medical Sciences, Bir Hospital, Kathmandu, Nepal
2 Department of Internal Medicine, John H. Stroger, Jr. Hospital of Cook County, Chicago, Illinois, USA
3 Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
|Date of Web Publication||29-Jun-2018|
Dr. Rajendra Kumar Agrawal
National Academy of Medical Sciences, Bir Hospital, Kathmandu
Source of Support: None, Conflict of Interest: None
Introduction: New-onset diabetes mellitus after transplantation (NODAT) is a major complication of renal transplantation, with a prevalence rate ranging from 2% to 53% across the globe. There is no information about the prevalence of NODAT in the Nepalese population. This paper describes the demographics, clinical characteristics, and risk factors associated with the development of NODAT in renal transplant patients from Bir Hospital, Nepal. Materials and Methods: Data were retrospectively collected for 110 patients that underwent renal transplantation at Bir Hospital from December 2008 to 2015. Patients who had diabetes before undergoing the transplant and those who did not have a 6-month follow-up posttransplant were dropped from the analysis, thus leaving 97 patients for analysis. Results: The incidence rate of NODAT among all patients analyzed was 22.68/100 people. Increasing age and body weight were not found to be associated with the increased incidence of NODAT. Mother-to-offspring transplants had a higher risk of NODAT presentation in the recipient. The study did not show any association between trough levels of tacrolimus and the risk of NODAT. Conclusion: New-onset Diabetes mellitus after transplantation is a major complication in patients with renal transplants and can also increase risk for cardiovascular complications. Longitudinal studies with larger sample and longer follow-up durations are required to understand the prevalence and risk factors as well as management of NODAL in the Nepalese population Discussion: Longitudinal studies with longer follow-up and rigorous data collection are required to better quantify the burden of NODAT on renal transplant patients and address these complications wisely.
Keywords: Nepal, new-onset diabetes mellitus after transplantation, renal transplantation, risk factor, tacrolimus
|How to cite this article:|
Agrawal RK, Agrawal R, Agrawal P, Baral A, Hada R. Incidence and associated risk factors of new-onset diabetes mellitus after transplantation in renal transplant recipients: A retrospective single-center study in Nepal. Indian J Transplant 2018;12:103-9
|How to cite this URL:|
Agrawal RK, Agrawal R, Agrawal P, Baral A, Hada R. Incidence and associated risk factors of new-onset diabetes mellitus after transplantation in renal transplant recipients: A retrospective single-center study in Nepal. Indian J Transplant [serial online] 2018 [cited 2021 Apr 10];12:103-9. Available from: https://www.ijtonline.in/text.asp?2018/12/2/103/235591
| Introduction|| |
Renal transplantation is considered the best line of treatment for patients suffering from end-stage renal disease (ESRD). In 2008, 68% of all solid organ transplants that occurred worldwide comprised on renal transplants. In the United States, >3000 patients are added to the wait list for a kidney every month. The demand for renal transplantations has led to major advances in the treatment modality. However, posttransplant complications such as new-onset diabetes mellitus after transplantation (NODAT) have shown to increase the risk of morbidity and mortality among patients by putting them at a higher risk for cardiovascular diseases, infectious complications, and graft loss among others.,,
NODAT is considered a major complication of transplantation as per the International Consensus Guidelines 2003. NODAT has a prevalence of two to 53% among renal transplant recipients, the wide variation in reporting mainly attributed to ill-defined diagnostic criteria for NODAT, lack of confirmatory tests, variable follow-up durations at different facilities, and presence of risk factors. Due to short follow-ups, these rates are potentially undermined as research has shown a linear progression in the incidence of NODAT among patients over time, with around 9% at 3 months after transplant, 16% at 12 months, and 24% at 2 years posttransplant.,
Past research has established obesity, old age, and family history of diabetes, hepatitis C virus infection, and some immunosuppressant drugs as some of the risk factors associated with increased incidence of NODAT among patients who undergo renal transplantation.,,, Recently, nucleotide polymorphisms in TCF7 L2 and R325W genes have also shown association with the development of NODAT.,,, Polycystic kidney disease has also been highly associated with an increased risk of developing NODAT after transplantation.,,, In addition, multiple clinical trials on corticosteroids such as prednisolone, and immunosuppressant drugs such as calcineurin inhibitors (tacrolimus and cyclosporine) have shown an increase in diabetogenic effects at various doses, which thereby increased the rate of incidence of NODAT.,
Renal transplantations have been in practice for more than half a century. However, in Nepal, transplants were introduced as a treatment option for patients with ESRD only in 2008. With a mortality rate of 21/100,000 populations due to kidney diseases in Nepal, renal transplants are a more sought after treatment modality compared to dialysis. Renal transplants are shown to be more effective than dialysis, both in long-term quality of life and overall treatment costs., Due to its recent introduction in the medical fraternity, there is a lack of epidemiological as well as clinical data on the complications with renal transplantation in the Nepalese population, and NODAT is no exception. Subsequently, evidence-based guidelines, suitable in the Nepal context, are not available for clinicians to refer to for the management of patients who develop NODAT posttransplantation. The aim of the study was to generate information on the demographics of renal transplant patients in Bir Hospital and readdress the risk factors associated with the presentation of NODAT in patients who received a renal transplant.
This paper describes  demographic and clinical characteristics of nondiabetic patients who received a transplant and  risk factors associated with the development of NODAT in those patients.
| Materials and Methods|| |
This retrospective study was conducted at National Academy of Medical Sciences, Bir Hospital, Kathmandu, Nepal. A total of 110 patients who underwent renal transplantation at the Department of Nephrology between 2008 and 2015 were included in the study. The patients were both males and females from all age groups. Inclusion criteria for the study were patients had to be  nondiabetic before receiving the transplant, received a renal transplant, had at least 6 months of posttransplant follow-up, and  a functional graft. All patients were of Asian origin.
Definition of new-onset diabetes mellitus after transplantation
Patients were considered to have NODAT only if they were nondiabetic pretransplantation. The diagnostic criteria for NODAT followed recommendations proposed by the American Diabetes Association in 2007: Symptoms of diabetes with fasting plasma glucose (FPG) of >7.0 mmol/l, random plasma glucose >11.1 mmol/l, and a 2-h plasma glucose of >11.1 mmol/l on an oral glucose tolerance test. An FPG level of 5.6–6.9 mmol/l is considered as impaired fasting glucose, and a 2-h blood glucose level of 7.8–11.0 mmol/l is considered impaired glucose tolerance.
Data were collected retrospectively from outpatient and hospital records from patients who underwent renal transplantation at Bir Hospital. General data (age, sex, blood group, BMI, present and past medical history, other relevant history, and physical examination), primary renal diagnosis, ongoing treatment record including duration of hemodialysis, and preoperative biochemical records (hemoglobin and blood sugar) were recorded. Donor information (age, relation to recipient, and blood group), human leukocyte antigen (HLA) typing and cross-matching results, intraoperative immune induction, and initial immunosuppressant regime data were also extracted from the records. Postoperative data included tacrolimus trough level, blood sugar levels, and renal function tests (creatinine). Apart from this, information of total hospitalized days and day of NODAT diagnosis was also recorded.
During the transplant surgery, each transplant recipient was given induction therapy comprising of daclizumab (2 doses), basiliximab (2 doses), or antithymocyte globulin (total 3.5 mg/kg body weight in three divided doses per day) depending on the availability. IV methyl prednisolone (500 mg) was administered at the release of clamp of the anastomosis to all recipients. Posttransplantation, tacrolimus was given to the patients at a dose of 0.1 mg/kg of body weight in two adjusted doses per day. The daily tacrolimus dose was then adjusted according to the trough level of serum tacrolimus on demand. For the purpose of analysis, mean of all readings per week was considered for the first 4 weeks, followed by mean of all readings per month for the next 6 months. Mycophenolate mofetil (500 mg twice daily for patients below 50 kg weight and 750 mg twice daily for patients above 50 kg weight) and prednisolone (started from 20 mg once daily and tapered every 2 weeks by 2.5 mg after 1-month posttransplantation, up until the minimum dose of 5 mg/day) were also given to all recipients.
Data was retrieved from medical case files and manually entered into Microsoft Excel 2010 by the primary research and crosschecked for accuracy by other researchers on the study. The data were analyzed using STATA/SE 14.1 quantitative data analysis software. Six patients had a history of diabetes, four patients had graft rejection immediately after the transplant, and two patients died within 3 months of receiving a kidney and thus were excluded from the analysis. One additional observation was excluded due to incomplete follow-up. In the analysis, 97 observations were included. Age, duration of hemodialysis, and posttransplant tacrolimus levels were considered as linear variables. Gender, blood group, body mass index, primary renal disease, donor-recipient relationship, and induction therapy were categorical or nominal.
Descriptive analyses were run to get counts, frequencies, means, and standard deviations for patient characteristics. Chi-square tests and t-tests were applied to compare variables. Tacrolimus levels were considered as longitudinal variables since dosage was dependent on the prior dose and trough level of serum tacrolimus. Univariate and multivariate logistic regression models were conducted to analyze potential risk factors for NODAT. 95% confidence intervals (CIs) for the odds ratios (ORs) were reported by applying cluster correlates.
Ethical approval was obtained from the Institutional Review Board of the National Academy of Medical Sciences, Bir Hospital (IRB Protocol Number: 96512073174).
| Results|| |
Around 97 nondiabetic patients received a renal transplant in the 8-year period. Almost 86% were men. The mean age of the patients at the time of transplant was 32.1 ± 9.5 years. The mean body mass index was 20.2 ± 2.16 kg/m 2. One-third of the patients were O + ve blood group. All transplants were ABO compatible [Table 1].
The most common renal disease for which transplant was required was chronic glomerulonephritis (n = 71, 74%). Other diseases were obstructive uropathy and hypertensive nephropathy, while some cases (n = 13) were undetermined. All patients except two were treated with hemodialysis before kidney replacement therapy. The two patients underwent continuous ambulatory peritoneal dialysis. The mean duration of hemodialysis was 7.8 ± 8.3 months. The mean pretransplant plasma glucose level was 90.84 ± 14.67 mmol/l. The mean panel reactive antibody titer was 17.01 ± 14.40%. Eight patients underwent preemptive transplantation [Table 2].
|Table 2: General preoperative characteristics of renal transplant recipients and donors|
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Mean duration of stay in the hospital was 18.01 ± 10.61 days. Within a 6-month follow-up period, NODAT developed in 22 of the 97 patients who had received a transplant, thus an incidence rate of 22.68 (95% CI 15–32)/100 people. The average duration of development of NODAT among the patients was 62.7 ± 43.4 days (median – 55 days). Patients were discharged from the hospital on an average of 18-day posttransplantation and recalled for follow-ups every week [Table 3].
The mean age for donors was 43.2 ± 11.04 years. Almost 38% were mothers of the patient and around 8% were fathers. Thirty-three percent of the donors were related to the patient by marriage, i.e., were spouses or mothers-in-laws. More than one-third (n = 35) of the recipient–donor duo had a total HLA mismatch of 3. Only 8.25% of the patients had a total HLA mismatch of zero [Table 2].
In the adjusted analysis, with a unit increase in age, the odds of developing NODAT increased by 15% (95% CI 9–19). Women were seen to have a 79% (95% CI 58–90) lower risk of developing NODAT than men, when adjusting for all other factors. On considering blood group, transplant recipients who had either O +ve or AB +ve blood group were, respectively, 89% (95% CI 72–96) and 75% (95% CI 41–90) less likely to develop NODAT compared to those who had A +ve blood group. The odd of developing NODAT among individuals with a normal BMI was 0.39 (95% CI 0.22–0.67) as compared to underweight individuals [Table 4].
|Table 4: Unadjusted and adjusted analysis of development of posttransplant new-onset diabetes mellitus after transplantation by potential risk factors|
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Patients who had to receive a transplant due to obstructed uropathy had 0.08 (95% CI 0.02–0.37) odds of developing NODAT posttransplantation compared to those patients who had to receive a transplant due to chronic glomerulonephritis. It was seen that patients who received an organ from their mother had a 76% (95% CI 41–90) lower risk of developing NODAT compared to those who received an organ from their father. Transplant recipients who had a total HLA mismatch of one or more (total mismatch 1 –OR 9.13, 95% CI 3.70–22.52; total mismatch 2 – OR 30.23, 95% CI 11.92–76.69; total mismatch 3 – OR 2.53, 95% CI 1.21–5.28; and total mismatch 4 – OR 9.20, 95% CI 3.64–23.28) had a significantly higher risk of developing NODAT compared to those who had a 0 HLA mismatch with their donors. Similarly, a month increase in the total duration of hemodialysis increased the risk of developing NODAT posttransplantation by 9% (95% CI– 7–12). Patients who received antithymocyte globulin induction therapy after transplantation also showed an 88% lower chance of developing NODAT compared to those who received daclizumab. The serum tacrolimus trough levels did not have any association with the development of NODAT among transplant recipients in the sample studied.
| Discussion|| |
The incidence rate of NODAT in patients who underwent renal transplantation was seen to be around 22.68% from this retrospective study. This rate is in compliance with the range of incidence rates of 2%–53% mentioned in other studies., However, the rate is significantly higher than the estimated prevalence rate of 3.3% for diabetes in Nepal., A study conducted in China reported a 20.32% incidence rate of NODAT, which is very close to the result from our study. On the contrary, in India, various studies have reported incidence rates of NODAT, ranging between 29% and 38%, which are much higher than the results from our study., Another retrospective study conducted in India in a smaller population showed incidence rate of NODAT to be only 19.12%. These variations are probably due to the use of different definitions and diagnostic criteria for NODAT, follow-up durations, and sample sizes.
Increasing age was not found significantly associated with an increased risk of developing NODAT in our study. However, many studies have repeatedly shown that patients about 45 years of age were more than twice as likely to develop NODAT after a transplant as compared to younger transplant recipients.,, The need for higher doses of immunosuppressant drugs in older populations is cited as the main reason for the increased risk. Females had a lower risk of development of NODAT after transplantation, as has been reported in other studies., Pretransplant weight was found to be a significant predictor for the development of NODAT posttransplant. In this study, all renal transplant patients were underweight or had a normal BMI, which can explain the lack of association between body weight and NODAT.
Renal transplants are being done more using ABO incompatible donor and recipient duos due to shortage of compatible donors.,, However, this study had 100% ABO-compatible transplants and thus does not provide the opportunity for comparison with ABO-incompatible donors on the risk for development of NODAT. The risk of NODAT was low for mother-to-child transplants as seen in this study; however, risk of graft rejection is higher for this combination according to earlier reports. The study also showed low risk of development of NODAT with spousal donor–recipient duos. Past studies have shown successful renal transplants when the spouse was a highly motivated and healthy donor.
Prior studies have shown a negative inverse association between the trough levels of tacrolimus and risk of development of NODAT posttransplantation, i.e., higher the trough levels, more the risk of developing NODAT. However, due to small sample size and use of trough levels as longitudinal data, this study was not able to show any link between tacrolimus trough levels and increased risk of NODAT.
This study is a first attempt at quantifying the burden of new-onset diabetes after renal transplantation in the Nepal context, as well as evaluating the risk factors associated with the development of NODAT. However, the study has its own limitations. Since data were analyzed retrospectively, there are some gaps in data collection. There were no preset diagnostic criteria for NODAT. Furthermore, preexisting impaired glucose tolerance was not accessed by pretransplant oral glucose tolerance test. There is a possibility that few patients who developed NODAT had pretransplant impaired glucose tolerance. Similarly, inclusion criteria could not be established for patient selection. The sample comprises of transplants that occurred only in one hospital setting in the past 8 years. Many covariates that have already been established as risk factors for the development of NODAT, such as family history of diabetes and hepatitis C infection, are missing for analysis in the study.
More detailed and rigorous data collection is required as well as patients need to be followed prospectively for longer durations in the future studies to capture the accurate incidence of NODAT and its associated risk factors so that pretransplant preparations, posttransplant treatment, and lifestyle modifications can be suggested for improved outcomes in the Nepalese population. In addition, all hospital settings with transplant facilities should pool their data to have a nationally representative database for research and evaluation.
NODAT is a major complication in patients with renal transplants and has the potential of putting these patients at undue risk of cardiovascular diseases. Further studies need to be done to establish better understanding of the prevalence of NODAT in the Nepalese population and its associated risk factors to provide clinicians with proper guidelines in treating these complications to provide better quality of care and life.
We would like to thank all the clinicians and hospital staff who were part of the renal transplant team at Bir Hospital between 2008 and 2015, without whose assistance the transplants would not have been successful. We would like to give our special thanks to all the patients and their family members who got treated at the hospital and trusted us with their treatment and care.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]