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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 12  |  Issue : 2  |  Page : 119-124

Prevalence and risk factors for posttransplant diabetes mellitus: Data from government tertiary care center


Department of Nephrology, Government Stanley Medical College, Chennai, Tamil Nadu, India

Date of Web Publication29-Jun-2018

Correspondence Address:
Dr. M Archana Balakrishnan
7/3, Shenbagavalli Street, Ayanavaram, Chennai - 600 023, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_14_18

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  Abstract 


Background: Diabetes occurs in substantial number of patients following renal transplantation, contributing to mortality and morbidity in particular the cardiovascular disease and infection. The prevalence and risk factors in South Indian population is not precisely clear. Our study aimed at determining the prevalence, epidemiology, and risk factors in kidney transplant recipients with posttransplant diabetes mellitus (PTDM). Methodology: This is a single-center analytical, cross-sectional, and retrospective study of adult renal transplant recipients who underwent transplant between January 2014 and December 2016. Institutional ethics committee approval was obtained. Results: Of 149 patients transplanted, 115 were included for study. Twenty-six patients (22.6%) developed PTDM. The mean age of the PTDM group was 35.2 years and 76.92% were males. Univariate analysis revealed age (P < 0.001), sex (P < 0.04), smoking (P = 0.02), history of diabetes mellitus (P < 0.001), dialysis vintage (P < 0.04), and induction therapy (P < 0.01) to be significant risk factors. The dosage of tacrolimus and prednisolone at the time of discharge and at months 3 & 6 post-transplant was significantly higher in PTDM group. Multivariate logistic regression analysis indicated age (odds ratio [OR] = 3.77), male gender (OR = 2.35), family history (OR = 4.54), dialysis vintage of >1 year (OR = 1.75), and induction therapy (OR = 2.0) to be independent risk factors for PTDM. Conclusions: There is high risk of developing diabetes after transplant with one quarter of this south Indian cohort developing PTDM. Older age, male sex, family history of diabetes, dialysis vintage, and use of induction therapy were independent risk factors for PTDM.

Keywords: Posttransplant diabetes mellitus, prevalence, renal transplant recipients, risk factors


How to cite this article:
Jayam J, Balakrishnan M A, Srinivasaprasad N D, Sujit, Fernando M E. Prevalence and risk factors for posttransplant diabetes mellitus: Data from government tertiary care center. Indian J Transplant 2018;12:119-24

How to cite this URL:
Jayam J, Balakrishnan M A, Srinivasaprasad N D, Sujit, Fernando M E. Prevalence and risk factors for posttransplant diabetes mellitus: Data from government tertiary care center. Indian J Transplant [serial online] 2018 [cited 2019 Aug 17];12:119-24. Available from: http://www.ijtonline.in/text.asp?2018/12/2/119/235588




  Introduction Top


Since the first renal allograft transplantation was done in 1954, the number and the survival rates posttransplant had gradually increased. With rejections being controlled with effective immunosuppressive drugs, short-term quality of life had significantly improved and the long-term complications have received more attention recently.[1] Diabetes occurs in a substantial number of patients following renal transplantation. New-onset diabetes after transplant (NODAT) or posttransplant diabetes mellitus (PTDM) is associated with higher rates of cardiovascular disease and infection, which are the leading causes of death in renal transplant recipients and continues to be the Achilles heel in long-term survival of these patients.[2]

The reported incidence of PTDM is variable and must be interpreted in the context of definition used, time from transplant, study population, and immunosuppressive agents used for individual studies. International consensus guidelines regarding the definition of new-onset diabetes mellitus after transplantation were originally published in 2003, and updated recommendations from an international consensus meeting have come in 2014 which include use of the term PTDM over NODAT.[3],[4] Studies that were published before the development of the consensus definition described above reported rates ranging from 7% to 46%.[5] Indian literature reports rates between 16% and 30% with maximum cumulative incidence in 1st year posttransplant.[6],[7],[8],[9]

For improvement of the outcome of kidney transplant recipients, it is of great interest to know precisely the risk factors that contribute to PTDM development. Nonmodifiable risk factors for development of PTDM are age, race, genetic background, family history of diabetes, and previous glucose intolerance while the modifiable risk factors include obesity and overweight, hepatitis C virus and cytomegalovirus infections, and immunosuppressive drugs. Both steroids and calcineurin inhibitors appear to contribute to the development of PTDM, whereas the role of sirolimus is being increasingly recognized.

The prevalence of PTDM is unknown in South Indian population and it is important to study the epidemiology, risk factors, and the outcomes of PTDM. We aimed to determine the prevalence and risk factors for PTDM in South Indian population.

Aim of the study

  1. To study the prevalence and clinical profile of PTDM among the renal transplant recipients
  2. To assess the relevant risk factors contributing to the pathogenesis of PTDM.



  Methodology Top


With appropriate clearance from Institutional Ethics Committee, this single-center analytical, cross-sectional, retrospective study of adult renal transplant recipients who underwent transplant between January 2014 and December 2016 was done at our government tertiary care center.

PTDM was defined according to the criteria outlined in the 2003 international consensus guidelines and the 2014 updated recommendations. The guidelines go with the WHO and ADA definitions and includes the following: (1) symptoms of diabetes plus random plasma glucose ≥200 mg/dL. (2) fasting plasma glucose ≥126 mg/dL. (3) two-hour plasma glucose ≥200 mg/dL during an oral glucose tolerance test. The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.

The study population who did not develop PTDM till the period of observation acted as controls. Recipients who had diabetes before renal transplantation and those recipients who had transient hyperglycemia while on intravenous steroids were excluded from the study. So were the recipients who died in the early posttransplant period or lost follow-up before 1 year.

All patients received standard triple immunosuppression with tacrolimus, mycophenolate mofetil, and prednisolone. The dosage of tacrolimus was 0.1 mg/kg to start with followed by uptitration. Methyl prednisolone injections were given for all patients before clamp release. Thymoglobulin induction was given for all deceased donor, spousal, and high-risk cases. Living-related transplant recipients (low risk) were not given any induction therapy.

The data analyzed were age, gender, history of smoking, family history of diabetes, dialysis vintage, pre- and postoperative fasting blood sugar, graft type (live versus deceased), induction therapy, recovery of graft function, acute rejection, and immunosuppressive drug dosages.

Statistical analysis

The data are reported as a mean for continuous variables and as a number and proportion for categorical variables. Unadjusted univariate analysis was done using Chi-square or Fisher's exact test as appropriate. Multivariate analysis was done using logistic regression to determine the independent predictors of PTDM from the potential confounders. SPSS version 20 (SPSS, IBM Statistics, USA) was used for analysis of data.


  Results Top


A total of 149 patients underwent renal transplant in our center over the study period of 3 years, and 115 eligible patients were enrolled for the study. There were 92 (80%) male and 23 (20%) female patients. Of the total 115, 32 (27.8%) were deceased donor renal transplants and 83 (72.8%) were living renal transplants including spousal donors. Among 26 patients who developed PTDM, 20 were males and 6 were females [Table 1]. Seventy-seven percentage (n = 20) of the patients developed PTDM in the 1st year posttransplant. The mean age of the PTDM group was 35.23 years and that of non-PTDM group was 28.64 years at the time of transplant [Table 1].
Table 1: Demographics

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Native kidney disease could not be identified in 86 patients (74.78%). Hemodialysis (HD) was the most common modality of renal replacement therapy in our hospital with 103 out of 115 cases (89%) on standard thrice weekly HD and one patient was on continuous ambulatory peritoneal dialysis. Eleven patients underwent preemptive renal transplant, out of which only 2 patients developed PTDM [Table 1].

The type of the graft did not have a significant effect on PTDM occurrence with seven (26.92%) deceased donor recipients and nineteen (73.08%) living donor recipients developing PTDM (P > 0.9). Of the 115 patients, 72 had immediate graft recovery, 34 had slow graft function, and 9 of them had delayed graft function. The recovery of graft did not have significant association with PTDM (P = 0.07) [Table 1].

Only 6 patients were current smokers, and there was an association of smoking with PTDM (P = 0.02). Six patients with a positive family history in the 1st degree relatives developed PTDM. Twenty-three percent (n = 6) in PTDM group and 1.1% (n = 1) in the non-PTDM group had a family history of diabetes (P< 0.001). Dialysis vintage was <1 year in majority of the patients (80.9%), 1–2 years in 13.9%, and >2 years in 5.2%. The mean dialysis vintage in PTDM and non-PTDM group was 10.7 (±7.0) months and 7.7(±6.5) months, respectively (P = 0.04) [Table 2].
Table 2: Risk factors - univariate analysis

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The preoperative fasting blood glucose levels were relatively higher in the PTDM group (115 ± 24.18 mg/dl vs. 109 ± 32.69) but were not statistically significant (P = 0.38). At 6 months' posttransplant patient, the mean blood glucose level was 106.5 ± 43 in non-PTDM group with 77 patients having normal blood glucose level and 12 of them having impaired fasting glucose [Table 2].

Of the 39 patients who received induction therapy, 14 (35%) developed PTDM and 12 out of 76 patients who did not receive induction therapy developed PTDM (P = 0.01). Twenty-six (22.6%) patients in the study developed acute rejection of whom eight patients developed PTDM. Thirty percent in PTDM group and 19% in non-PTDM group had a history of rejection (P = 0.02) [Table 2].

Standard triple immunosuppression with tacrolimus, mycophenolate mofetil, and prednisolone was started for all the patients from day 0. The mean dosage of all these drugs was calculated at discharge (14 days), 3-month posttransplant, and 6-month posttransplant. The dosage of tacrolimus on Day 14, 3rd and 6th month as well as the dosage of prednisolone on Day 14 and 3rd month was significantly higher in the PTDM group. However, multivariate analysis did not prove them to be independent predictors of PTDM [Table 3] and [Table 4].
Table 3: Dosage of immunosuppressives - univariate analysis

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Table 4: Multivariate analysis by logistic regression

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On multivariate logistic regression analysis, age >40, male gender, family history of diabetes, dialysis vintage, and use of induction therapy were the significant independent risk factors associated with PTDM [Table 4]. The incidence of infections was significantly high with PTDM group (16 vs. 33 patients, P = 0.04). The results of our study are comparable with those studies published after the international consensus guidelines in 2003 in terms of prevalence and risk factors [Table 5].
Table 5: Prevalence of posttransplant diabetes mellitus - global trend - postinternational consensus guidelines

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  Discussion Top


Since the description of an entity called PTDM by Starlz in 1964 and the subsequent recognition of PTDM as a complication associated with renal transplantation in 1970s, the knowledge about this disease has evolved.[15] PTDM now is known to be a significant contributor to the patient and graft outcome both in short and long term. The incidence report across the literature had been highly variable ranging between 2% and 53%.[16] However, after the establishment of International consensus guidelines, there is a better universal agreement on the definition of PTDM.

Recent reports across the world postestablishment of international consensus guidelines ranges from 4% to 25% in United States,[10] 18% in European cohort,[11] 23% in African countries,[12] 20% in Chinese population,[13] and 27% in middle east countries.[14] USRDS registry-based annual data published in 2011 show a striking prevalence of 40%. Indian literature shows wide variation in prevalence ranging from 16.7% in a study by Sharma et al., 19.12% in an observation by Prakash et al. to as high as 54.5% in study by Bora et al.[6],[7],[8] Another recent study from Kolkata by Sanyal et al. showed the prevalence to be 33.3%.[9]

In our study, the prevalence of PTDM was 22.6%. Seventy-seven percentage (n = 20) developed PTDM in the 1st year of renal transplant with prevalence increasing over time. This was consistent with the early observations of studies from United states and middle east with an estimated cumulative incidence of 9%, 16%, and 24% at 3-month, 12-month, and 36-month posttransplant, respectively.[14],[17] This early onset of PTDM could be explained by the intense immune suppression earlier in posttransplant including higher dose of steroids and tacrolimus.

Increasing age has been found to be a risk factor for PTDM by several studies. A large series from United states showed the relative risk of developing PTDM was 2 times higher for patients of 45–59 years' group and 2.6 times higher for >60 years of age. The mean age of PTDM population was 45 years and 51 years, respectively, in studies from middle east and China, respectively.[13],[14] In our study, the mean age of the PTDM group was significantly higher compared with control group (P< 0.001). Multivariate logistic regression analysis showed age >40 years to be independent risk factor (odds ratio [OR] 3.77, confidence interval [CI] 1.06–6.33). This is in line with findings from North Indian cohorts with mean age being >40 in most series.[6],[7],[8],[9]

There was an overall male preponderance in our study population, and male gender was found to be independent risk factor (OR 2.35, CI 1.37–3.99). The native kidney disease could not be identified in majority 75% of the patients, and the modality of the dialysis did not have any bearing on the PTDM occurrence (P = 0.998). The type of graft did not seem to affect the occurrence of PTDM with prevalence not being different in living-related versus deceased donor recipients (P > 0.99) which is in line with literature reports. However, the recent Chinese cohort showed cadaveric grafts to be associated with 1.5-fold higher risk in comparison with living grafts citing intense immunosuppression as the possible reason.[11] The rate of recovery of graft was not significant as well with PTDM being similar in immediate, slow, and delayed graft functions group (P = 0.07).

In our study, smoking and family history of diabetes mellitus were found to be significant risk factors. On multivariate logistic regression analysis, family history of DM was found to be an independent risk factor for PTDM (OR: 1.75, CI: 1.04–2.93) as in line studies by Prakash et al. and Bora et al. Interestingly dialysis vintage of >1 year was found to be a significant risk factor by both univariate (P = 0.04) and multivariate analysis (OR 1.75, CI 1.04-2.93). Literature evidence for the same is divisive with majority not showing any significant causal relation. Recent study from middle east by Razeghi et al. shows significant association with dialysis vintage.[17] The plausible mechanism cited is the malnutrition and altered insulin metabolism in the dialysis population precipitating PTDM in phenotypically predisposed individuals at later stage.[18]

Preoperative fasting blood glucose had been established as risk factor for PTDM in several series. Cosio et al. showed 2-fold increased risk of PTDM in patients with high pretransplant fasting blood glucose and those with impaired fasting blood glucose levels.[19] Our series also had similar findings with preoperative fasting blood sugars being high in NODAT group but was not statistically significant (P = 0.38) and was differing from the findings by Prakash et al. and Sanyal et al.

Use of induction therapy with anti-thymocyte globulin and acute rejection episodes were found to be associated with higher prevalence of PTDM (P = 0.01 and P = 0.02 respectively). Induction therapy was also an independent risk factor for PTDM in our series, as determined by regression analysis. Evidence of rejection being risk factor has varied across studies. In the Chinese cohort described by Lv et al., there was no relation between acute rejection episode and PTDM.[13] On the contrary, two studies from middle east provide evidence for acute rejection being a risk factor for PTDM and PTDM predisposing to acute rejection.[14],[20]

Immunosuppressive drugs are believed to be the major inciting agents and modifiable risk factors for PTDM, especially in the early posttransplant period. Glucocorticoids are associated with the greatest risk and their diabetogenicity is dose dependent with a 0.01 mg/kg/day increase in prednisolone adding a 5% risk of developing PTDM.[21] The predominant pathomechanism is insulin resistance though high-dose steroids can impair insulin secretion.[22],[23] In our series, the mean dose of prednisolone at discharge (14 days) and 3 months' posttransplant was significantly higher in the PTDM group (P< 0.001 and P = 0.01 respectively). However, trials with early withdrawal of steroids have not impacted the occurrence of PTDM.[24]

The calcineurin inhibitors have been attributed to the reduced incidence of acute rejection in the early posttransplant period but a higher incidence of PTDM. A 2004 meta-analysis found that insulin-treated diabetes mellitus occurred in 10 percent of renal transplant recipients on tacrolimus versus 3 percent of those on cyclosporine based regimens.[5] The primary mechanism of tacrolimus induced PTDM is by altered pancreatic B cell signaling and survival. Just like steroids, the mean dosage of tacrolimus was high at discharge, 3-month, and 6-month posttransplant (P< 0.003, P < 0.04, and P < 0.03) in our series. In one study, levels higher than 15 ng/mL were significantly associated with the development of glucose intolerance and NODAT at 1 year. However, the 3- and 6-month tacrolimus level was not significantly different between our study and control groups (5.88 ng/ml versus 6.39 ng/ml, P = 0.5).[25]

The nonmodifiable risk factors including age >40 years, male gender, family history of DM, and modifiable risk factors including dialysis vintage and use of induction therapy were the independent predictors of PTDM. The incidence of infective complications was higher in the PTDM group in our study (P = 0.04) including 5 CMV infections in the study group.

Our study has few limitations. This is a retrospective analysis and only included patients from a single center. However, it is reassuring that the results of this study match with the other international studies of the different populations.


  Conclusions Top


Our study has shown that up to one quarter of the patient develop PTDM in the south Indian population. Age >40 years, male gender, family history of diabetes, dialysis vintage of >1 year, and use of induction therapy were identified as independent risk factors for PTDM. The infective complications were higher in the PTDM group compared with controls.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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