| Abstract|| |
This cross-sectional study conducted at Sindh Institute of Urology and Transplantation, Karachi, Pakistan aimed to determine the frequency and risk factors of posttransplant diabetes mellitus (PTDM) among live-related kidney transplant recipients and their short-term prognosis and included renal transplant recipients (nondiabetic before transplant) of either gender, aged 18–60 years with transplant duration two to six months. Patients with two reading of fasting plasma glucose ≥126 mg/dL were labeled as diabetic. A total of 191 patients (154 males and 37 females) with the age between 18 to 60 years (31.5 ± 9.33 years) were included and 30 patients (15.8%) including 23 males and seven females had PTDM. Age of the patients between 26 and 35 years, previous hepatitis C virus (HCV) infection/antiviral therapy, and Tacrolimus as maintenance immunosuppression were found to be more frequent among those with PTDM. After six months of follow-up, the serum creatinine of patients with PTDM was significantly higher than that of those without PTDM (1.15 ± 0.28 vs. 1.01 ± 0.16, P ≤0.0121); however at one year follow up, there was no significant difference between the serum creatinine of both groups (1.28 ± 0.38 vs. 1.37 ± 0.59, P = 0.332). PTDM is an important metabolic derangement affecting a number of kidney transplant recipients. Its risk factors are previous HCV infection, tacrolimus as immunosuppression and young age. It can have an adverse effect on graft function and survival. Therefore, long-term follow-up is warranted to optimize the graft function and patient survival.
|How to cite this article:|
Mohammad KG, Idrees MK, Ali T, Akhtar F. Posttransplant diabetes mellitus among live-related kidney transplant recipients: Sindh Institute of Urology and Transplantation experience. Saudi J Kidney Dis Transpl 2018;29:1320-5
|How to cite this URL:|
Mohammad KG, Idrees MK, Ali T, Akhtar F. Posttransplant diabetes mellitus among live-related kidney transplant recipients: Sindh Institute of Urology and Transplantation experience. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2019 Jun 18];29:1320-5. Available from: http://www.sjkdt.org/text.asp?2018/29/6/1320/248294
| Introduction|| |
Kidney transplantation is regarded as the best available management for selected patients withend-stage renal disease (ESRD); but at the cost of increased risk of side effects of immunosuppression including but not limited to posttransplant diabetes mellitus (PTDM) [also known as new-onset diabetes after transplantation (NODAT)]. Initially, there was confusion about the terminology, but International Consensus Meeting on posttransplantation diabetes mellitus has recommended using the term PTDM (instead of NODAT) for clinically stable patients who develop persistent post-transplantation hyperglycemia.
PTDM is reported in 2%–50% of kidney transplant recipients. Data from the US renal data system indicate that 17.4% of adult kidney transplant recipients had developed PTDM at one year posttransplantation.
PTDM has adverse impact on both graft and patient survival, and it has been linked to higher rate of cardiovascular events and infections than general population. A single-center study consisting of more than 700 kidney transplant recipients demonstrated worse 10-year actuarial patient survival among patients with PTDM compared with those without PTDM; however, there was no difference in graft survival. Another study showed that compared with recipients with normal glucose tolerance, recipients with post-transplantation diabetes mellitus had a tendency toward increased overall graft failure.
The highest risk of developing PTDM is during the first six months of transplantation. Hyperglycemia after transplantation has been likened with diabetes mellitus type 2; however, it appears rapidly and the transition to full-blown diabetes is clearly much faster than DM type 2 in general population.,
Many of the riskfactors that predispose the nontransplant patients/general population to diabetes mellitus has been identified as a contributing factor for new-onset diabetes including age above 40 years, male gender, obesity, family history of DM, chronic hepatitis C virus (HCV) infection, and cytomegalovirus (CMV) infection. Specific transplant-related factors may also enhance the risk of new-onset diabetes such as increasing HLA mismatches, acute rejection episodes, immunosuppressive medications (steroids and tacrolimus), delayed graft function, recipient of deceased donor kidney, impaired glucose tolerance in pre transplant period, and underlying primary renal disease (e.g., autosomal dominant poly-cystic kidney disease).
There has been controversy in the best diagnostic test and diagnostic criteria for PTDM. KDIGO guidelines recommend screening all nondiabetic kidney transplant recipients with fasting plasma glucose (FPG), oral glucose tolerance test (OGTT), and/or HbA1C assay at least weekly for four weeks, every three months for one year, and annually thereafter. The 2014 International Consensus Expert Panel recommended incorporating postprandial glucose and HbA1C levels in the screening and diagnostic framework for PTDM. It further suggested that the 2003 American Diabetes Association criteria be used to define impaired fasting glucose (FPG ≥100 mg/dL and <126 mg/dL), and PTDM should not be diagnosed before 45 days after transplantation.
International studies have revealed high frequency of NODAT in renal transplant recipients but no such data available in Pakistan. We could find only one study from Pakistan done 16 years ago to study the prevalence of PTDM in early posttransplant period. Hence, this study is conducted to find the frequency of PTDM and associated risk factors among patients who received renal transplant at our institute. This study may be an initiative for further larger studies.
| Materials and Methods|| |
This cross-sectional study was conducted at transplant follow-up clinic, Sindh Institute of Urology and Transplantation (SIUT), Karachi Pakistan, started in April 2014 and included all the postrenal transplant recipients of either gender, aged 18 to 60 years who had received live-related renal transplant at SIUT with transplant duration two to six months. These patients were selected by consecutive sampling technique. Those with a history of diabetes mellitus/impaired glucose tolerance before renal transplant were excluded from the study. At our institution, all the ESRD patients who are candidate for renal transplantation have their fasting, and random blood glucose level and HbA1c level checked. OGTT is performed if blood glucose levels are higher than normal range.
Data were collected after informed consent. All the patients had at least twice monthly follow-up visits in posttransplant clinic up to three months then monthly thereafter up to one year. In each visit, a brief history of any presenting complaint was obtained and routine clinical examination done. All the patients underwent blood investigations related to graft functions (including serum creatinine), fasting, and casual plasma glucose was checked and results documented in patients hospital record/ file. Patient having FPG ≥126 mg/dL had a confirmatory test with the measurement of FPG on another day. Patients with two reading of FPG ≥126 mg/dL were labeled as diabetic.
Data were analyzed on Statistical Package for the Social Science version 15 (SPSS Inc., Chicago, IL, USA). Patients were divided into two groups; those with (i) PTDM and (ii) no PTDM. Qualitative variables, such as gender and positive family history of DM, were presented by their frequencies. Quantitative variables such as age and duration of transplant were calculated by mean ± standard deviation. Stratification with respect to age and gender was done to see the effect on these outcome variables. Poststratification chi-square test was applied. Risk factors of PTDM were compared among both groups to find the difference between the two groups. The result was considered significant at P<0.05.
| Results|| |
A total of 191 patients (154 males and 37 females) with the age between 18 to 60 years who received live-related renal transplant at SIUT with the transplant duration of <6 months were included in this study. The average age of the patient was 31.5 ± 9.33 years. Sixty-two (32.6%) patients were between age group of 18–25 years, 69 (36.8%) were between 26–35 years, 46 patients (24.2%) were 36–45 years, and 14 (7.4%) were above 45 years of age.
Out of 191 transplant recipients, 30 (15.8%) including 23 males and seven females had PTDM [Table 1]. The incidence of PTDM was significantly higher in those patients with the age between 26–35 years (P = 0.03); however, there was no significant difference between the mean ages of patients with PTDM and those without PTDM. Most of the patients developed PTDM after 3.28 ± 1.08 months of transplant.
|Table 1: Demographics and risk factors of posttransplant diabetes mellitus.|
Click here to view
The family history for DM was positive in 81 patients (42.4%). There was no statistically significant difference between patients with PTDM and without PTDM regarding age, gender distribution, family history of diabetes mellitus, body mass index (BMI), CMV infection, and rejection/pulse steroid.
All the patients had an induction with IV methylprednisolone [except six patients with zero match who had induction with Anti-Thymocyte Globulin (ATG)], and maintenance immunosuppression consisted of prednisolone, calcineurin inhibitor (cyclosporine/tacrolimus) and azathioprine/mycophenolate. There was no difference in induction immunosuppression between the two groups. Among patients with PTDM, nine were receiving tacrolimus as compared to 13 patients in the group of patients without PTDM, and this difference was statistically significant (P ≤0.0038). However, there was no significant difference in trough level of tacrolimus between the two groups at the time of diagnosis of PTDM. As regards previous HCV infection/antiviral therapy for HCV infection, there was numerical difference (two patients in both groups) ; however, it did not reach statistical significance (P = 0.0668).
After six months of follow-up, the serum creatinine of patients with PTDM was significantly higher than that of those without PTDM (1.15 ± 0.28 vs. 1.01 ± 0.16, P ≤0.0121). There was no significant difference in calcineurin inhibitors (cyclosporine/tacro-limus) levels between the two groups. At one year follow-up, there was no significant difference between the serum creatinine of both groups (1.28 ± 0.38 vs. 1.37 ± 0.59, P = 0.332).
| Discussion|| |
The frequency of diabetes in patients with kidney transplant is significantly higher compared with the normal population, and this high number is distressing because PTDM is a risk factor for cardiovascular disease, mortality, associated with adverse impact on graft survival, high rate of infections, and increased healthcare costs.,
Thirty (15.8%) out of 191 renal transplant recipients developed PTDM. There is wide variation in incidence/prevalence/frequency of PTDM in the literature. The variation in the reported PTDM incidence may be explained by the differences in the study plan, transplant populations, the duration of follow-up and also the lack of standard definition of the condition. Our figure is close to the reported from the other countries in the south Asian region. Montori et al reviewed 19 studies (3611 patients) in 2002 and noted that over three decades the incidence of PTDM had decreased to below 10%. The average age of the patient was 31.5 ± 9.33 years. The incidence of PTDM was high in patients up to 45 years and comprised nearly 79% of our patients having PTDM. Patel et al found that the incidence of PTDM was significantly high among transplant recipients older than 45 years of age. The higher incidence of PTDM in younger age group in our study is contrary to other studies. It may be due to fact that most of our transplant recipients are younger than other parts of the world. There was no male predominance (17.5% males vs. 18% females) in our patients having PTDM in contrast to the studies conducted internationally showing male domi-nance. Most of the patients in our study developed NODAT after 3.28 ± 1.08 months of transplantation. Vincenti et al reported that 20.8% kidney transplant recipients developed PTDM in first six months of transplant. Obesity and high BMI is a risk factor for PTDM, but we did not find this association in our study population. A study from our institution had reported statistically significant higher incidence of PTDM among kidney transplant recipients having higher BMI and metabolic syndrome.
Family history is a strong risk for the development of NODAT but did not find this association among our patients. In a Spanish multicenter cross-sectional study consisting of 2178 solid organ transplant recipients (including 1410 recipients of kidney transplant), a positive family history of diabetes was associated with increase in the risk of developing PTDM.
HCV infection is also a well-known risk factor for the development of diabetes mellitus, both in general population and after trans-plant., Although there were only few patients with history of HCV infection in our study, the frequency was higher in those with PTDM than those without PTDM; however, this did not reach statistical significance (P = 0.0668).
Patients receiving tacrolimus had statistically significant higher frequency of PTDM than those taking receiving cyclosporine in our study; however, there was no statistically significant difference in trough levels of tacrolimus between the two groups. Higher frequency of PTDM among those receiving tacrolimus has been confirmed in numerous studies and could be due to impaired insulin release and/or increased insulin resistance, islet cell damage in the form of cytoplasmic swelling, and vacuolization as a result of CNI therapy.,
Allograft rejection and pulse steroid therapy are known risk factors for PTDM; however, there was no statistically significant difference between the two groups with and without PTDM among our patients. This is similar to the observation of Patel et al and could be due to short period of study.
CMV infection has been considered a risk factor for PTDM among kidney transplant recipients; however, we did not find this association among our patients. Our observation concurs with that of Dedinská. It was reported from our institute that out of 1000 initial live-related renal transplants, 100% of donors and recipients were CMV IgG positive and nearly 30% transplant recipients developed CMV infection on longer follow-up.
After six months of follow-up, serum crea-tinine of patients with PTDM was significantly higher than those without PTDM (1.15 ± 0.28 vs 1.01 ± 0.16, P ≤0.0121). This is in concurrence with results from larger studies. However, at one year, there was no significant difference in serum creatinine of the two groups (P = 0.332). This may be due to better glycemic control, change in immunosuppres-sion, dietary counseling, or more probably to other factors affecting graft function. Good control of blood glucose levels can decrease the negative influence of PTDM on patient and graft survival.
The main limitation of this study is that this was a single-center cross-sectional study with short follow-up period.
| Conclusion|| |
PTDM is an important metabolic derangement affecting a number of kidney transplant recipients. Its risk factors are previous HCV infection, tacrolimus as immunosuppression and young age. It can have adverse effect on graft function and survival. Therefore, long-term follow-up is warranted to optimize the graft function and patient survival.
Conflict of interest: None declared.
| References|| |
Abecassis M, Bartlett ST, Collins AJ, et al. Kidney transplantation as primary therapy for end-stage renal disease: A National Kidney Foundation/Kidney Disease Outcomes Quality Initiative (NKF/KDOQITM) Conference. Clin J Am Soc Nephrol 2008;3:471-80.
Sharif A, Hecking M, de Vries AP, et al. Proceedings from an international consensus meeting on posttransplantation diabetes mellitus: Recommendations and future directions. Am J Transplant 2014;14:1992-2000.
Juan Khong M, Ping Chong CH. Prevention and management of new-onset diabetes mellitus in kidney transplantation. Neth J Med 2014;72:127-34.
Shin JI, Palta M, Djamali A, Astor BC. Higher pretransplantation Hemoglobin A1c is associated with greater risk of posttransplant diabetes mellitus. Kidney Int Rep 2017;2(6): 1076-1087.
. Joss N, Staatz CE, Thomson AH, Jardine AG. Predictors of new onset diabetes after renal transplantation. Clin Transplant 2007;21: 136-43.
Valderhaug TG, Hjelmesæth J, Jenssen T, Roislien J, Leivestad T, Hartmann A. Early posttransplantation hyperglycemia in kidney transplant recipients is associated with overall long-term graft losses. Transplantation 2012; 94:714-20.
Vincenti F, Friman S, Scheuermann E, Rostaing L, Jenssen T, Campistol JM et al. Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus. Am J Transplant 2007;7:1506-14.
Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 2003;3:178-85.
Langsford D, Dwyer K. Dysglycemia after renal transplantation: Definition, pathogenesis, outcomes and implications for management. World J Diabetes 2015;6:1132-51.
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009;9 Suppl 3:S1-155.
Jawad F, Rizvi SA. Posttransplant diabetes mellitus in live-related renal transplantation. Transplant Proc 2000;32:1888.
Patel DD, Modi KP, Patel AK, Chaudhary V. New onset of diabetes mellitus in Indian renal transplant recipient: A retrospective study. Int J Pharm Pharm Sci 2015;7:228-32.
Prakash J, Rathore SR, Singh TB, Choudhury TA, Prabhakar, Usha. New onset diabetes after transplantation (NODAT): Analysis of pre-transplant risk factors in renal allograft recipients. Indian J Transplant 2012;6:77-82. [Full text]
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.
Rizvi SA, Naqvi SA, Zafar MN, Akhtar SF. A kidney transplantation model in a low-resource country: An experience from Pakistan. Kidney Int Suppl (2011) 2013;3:236-40.
Elahi T, Akhtar F, Ahmed E, Naqvi R. Prevalence of Metabolic syndrome in renal transplant recipients – A single centre experience. J Pak Med Assoc 2009;59:533-6.
Martínez-Castelao A, Hernández MD, Pascual J, et al. Detection and treatment of post kidney transplant hyperglycemia: A Spanish multicenter cross-sectional study. Transplant Proc 2005;37:3813-6.
Hammerstad SS, Grock SF, Lee HJ, Hasham A, Sundaram N, Tomer Y. Diabetes and hepatitis C: A two-way association. Front Endocrinol (Lausanne) 2015;6:134.
Webster AC, Woodroffe RC, Taylor RS, Chapman JR, Craig JC. Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: Meta-analysis and meta-regression of randomised trial data. BMJ 2005;331:810.
Palepu S, Prasad GV. New-onset diabetes mellitus after kidney transplantation: Current status and future directions. World J Diabetes 2015;6:445-55.
Dedinská I, Laca Ľ, Miklušica J, Kantárová D, Galajda P, Mokáň M. Correlation between CMV infection and post-transplantation new-onset diabetes mellitus. Int J Organ Transplant Med 2016;7:173-82.
Rizvi SA, Naqvi SA, Hussain Z, et al. Renal transplantation in developing countries. Kidney Int Suppl 2003;83:S96-100.
Choi JY, Kwon OJ. Post-transplant diabetes mellitus: Is it associated with poor allograft outcomes in renal transplants? Transplant Proc 2013;45:2892-8.
Sezer S, Akgul A, Altunoglu A, Arat Z, Ozdemir FN, Haberal M. Post-transplant diabetes mellitus: Impact of good blood glucose regulation on renal transplant recipient outcome. Transplant Proc 2006;38:533-6.
Dr. Muhammad Khalid Idrees
Department of Nephrology and Transplantation, Sindh Institute of Urology and Transplantation, Karachi