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Table of Contents
COMMENTARY
Year : 2018  |  Volume : 12  |  Issue : 2  |  Page : 75-77

Posttransplantation diabetes mellitus in renal allograft recipients – Indian perspective


Department of Nephrology and Renal Transplantation, Asian Institute of Nephrology and Urology, Hyderabad, Telangana, India

Date of Web Publication29-Jun-2018

Correspondence Address:
Dr. Praveen Kumar Etta
Department of Nephrology and Renal Transplantation, Asian Institute of Nephrology and Urology, Hyderabad, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_20_18

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How to cite this article:
Etta PK. Posttransplantation diabetes mellitus in renal allograft recipients – Indian perspective. Indian J Transplant 2018;12:75-7

How to cite this URL:
Etta PK. Posttransplantation diabetes mellitus in renal allograft recipients – Indian perspective. Indian J Transplant [serial online] 2018 [cited 2018 Sep 25];12:75-7. Available from: http://www.ijtonline.in/text.asp?2018/12/2/75/235592



Posttransplantation diabetes mellitus (PTDM) or new-onset diabetes mellitus after transplantation (NODAT) occurs in a significant number of renal allograft recipients and is associated with higher rates of cardiovascular disease and infection, contributing to increased morbidity and mortality. It is characterized by both β-cell dysfunction and reduced insulin sensitivity. International consensus guidelines regarding PTDM were published in 2003 and updated in 2014, which prefers to use the term PTDM over NODAT since some of these cases might represent unknown diabetes that was present before transplantation.[1] These guidelines use the standard World Health Organization and American Diabetes Association criteria for the diagnosis. The glycated hemoglobin (HbA1c) cannot be accurately interpreted within the first 3 months after transplantation and is not recommended for the diagnosis in the early posttransplant period.

Transient hyperglycemia is much more common in the immediate posttransplant period and may itself is a risk factor for the future development of PTDM. One Indian study showed that posttransplant hyperglycemia was associated with a fourfold increased risk of PTDM.[2] In the same study, PTDM was developed in 46.7% of patients with posttransplant hyperglycemia. Some researchers have defined PTDM as a long-term (>3 months) requirement for glycemic control therapy to prevent overdiagnosis. Postprandial hyperglycemia is the typical presentation of PTDM as opposed to elevated fasting blood glucose levels.

The incidence rates are higher in the first 1 year after transplantation. The reported incidence is variable due to differences in the definitions used, time since transplantation, duration of follow-up, study population, immunosuppressive drugs, and other modifiable and nonmodifiable risk factors. From Indian literature, the reported prevalences of PTDM were 19.12% by Prakash et al., 16.75% by Sharma et al., 33.33% by Sanyal et al., and 54.5% by Bora et al.[3],[4],[5],[6] In a study in this issue by Edwin et al., the authors have observed that 22.6% prevalence of PTDM.[7]

The risk factors include increased age, obesity or other component of metabolic syndrome, African American race, Hispanic ethnicity, family history of diabetes, gestational diabetes, pretransplant impaired fasting glucose or impaired glucose tolerance, polycystic kidney disease, increased HLA mismatches, deceased donor allografts, history of acute rejection, hepatitis-C (HCV) and cytomegalovirus (CMV) infections, and use of immunosuppressive drugs such as glucocorticoids, calcineurin inhibitors (CNIs), and mammalian target of rapamycin inhibitors. In the study by Edwin et al., the authors have observed that age >40 years, male gender, family history of diabetes, dialysis vintage of >1 year, and anti-thymocyte globulin (ATG) induction as independent risk factors for PTDM.[7] Basiliximab was not used in any patient in their study. Induction with ATG was not a contributory factor in another Indian study.[5] One study from North India concluded that relative risk of PTDM with basiliximab induction was 2.3 (95% confidence interval 1.4–3.9) compared to that of patients without induction.[8]

Although glucocorticoid induced dysglycemia is dose-dependent, the complete steroid withdrawal has not been clearly shown to reduce the incidence of PTDM.[9],[10] Corticosteroids induce diabetes predominantly by promoting insulin resistance, and CNI causes islet-cell toxicity and may directly affect transcriptional regulation of insulin expression. Hypomagnesemia induced by CNI may also precipitate glucose intolerance. Among CNIs, tacrolimus is more diabetogenic than cyclosporine, as concluded in Diabetes Incidence after Renal Transplantation: Neoral C Monitoring Versus Tacrolimus (DIRECT) study.[11] Few meta-analyses also showed that higher incidence of PTDM in patients receiving tacrolimus compared to cyclosporine.[12],[13] Azathioprine and mycophenolate mofetil (MMF) do not induce PTDM. The use of few drugs such as statins, angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and cotrimoxazole may be associated with a reduced risk of PTDM.[14],[15]

In a meta-analysis, HCV-infected renal transplant recipients were at almost four times greater risk of developing PTDM compared with uninfected individuals.[16] Proposed mechanisms include HCV-induced islet-cell dysfunction, insulin resistance, and abnormalities in glucose metabolism. HCV therapy before transplantation may reduce the incidence of PTDM. One larger retrospective study from North India which looked at long-term outcomes of HCV-infected renal allograft recipients showed significantly high prevalence of PTDM in HCV positive group (39.6%) as compared to HCV negative group (18.9%).[17] In this study, all the HCV-infected patients received therapy before transplantation. The role of CMV infection is controversial. In one study, asymptomatic CMV infection was associated with a fourfold increased risk of PTDM.[18]

The development of PTDM has adverse effect on both patient and graft survival, mainly by increased risk of cardiovascular disease and infections. de novo diabetic nephropathy in the allograft due to PTDM can also result in graft loss.[19]

Management includes pretransplant evaluation, posttransplant monitoring, lifestyle modification, and antidiabetic therapy. Oral hypoglycemic agents either as monotherapy or combination therapy, or insulin are required in most patients at least in the first few months after transplantation. Control of other cardiovascular risk factors such as hypertension and dyslipidemia is also important. The potential benefit of modification of immunosuppressive therapy must be weighed against the risk of rejection. An open-label, randomized prospective pilot study from North India demonstrated a significant improvement in HbA1c in the cyclosporine conversion arm compared with tacrolimus continuation group among renal allograft recipients.[20]

Insulin is preferred during first few weeks after transplantation and one study suggested intensified early treatment with regimens that include basal insulin significantly reduce the risk of PTDM after 1 year, presumably through insulin-mediated protection of β cells.[21] The oral hypoglycemic agents such as sulfonylureas, metformin (biguanide), meglitinides, dipeptidyl peptidase-4 (DPP-4) inhibitors or gliptins, and thiazolidinediones are the approved therapies for use in PTDM.

Gliptins do not cause hypoglycemia (due to glucose-dependent action), do not induce weight gain, and do not seem to interact with immunosuppressive drugs. Therefore, it seems prudent to consider them as potential first-line oral drugs to treat PTDM. Sitagliptin, vildagliptin, repaglinide, and nateglinide have been used among transplant recipients in short-term studies with documented safety and efficacy. Till date, only one double-blind, placebo-controlled randomized trial has been performed in PTDM which concluded that vildagliptin is efficacious in renal transplant recipients.[22] Sitagliptin may prolong the QT interval especially if used with cyclosporine. Linagliptin is cleared by extra-renal pathway and one Indian study evaluated its efficacy and safety in PTDM.[23]

Thiazolidinediones may worsen bone loss, lead to weight gain, edema formation, anemia, congestive heart failure, and predispose to CNI toxicity. They are generally used as a last resort of oral therapy. Metformin can be initiated in patients with an estimated GFR as low as 45 ml/min and most cases of metformin-induced lactic acidosis have been reported in combination with ACEI or ARB in patients with reduced GFR. Alpha-glucosidase inhibitors may worsen the gastrointestinal side effects of MMF. Incretin mimetics-exenatide, liraglutide, and lixisenatide and sodium-glucose cotransporter 2 inhibitors-canagliflozin, dapagliflozin, empagliflozin have not yet been validated for use in PTDM.



 
  References Top

1.
Sharif A, Hecking M, de Vries AP, Porrini E, Hornum M, Rasoul-Rockenschaub S, et al. Proceedings from an international consensus meeting on posttransplantation diabetes mellitus: Recommendations and future directions. Am J Transplant 2014;14:1992-2000.  Back to cited text no. 1
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2.
Memon SS, Tandon N, Mahajan S, Bansal VK, Krishna A, Subbiah A, et al. The prevalence of new onset diabetes mellitus after renal transplantation in patients with immediate posttransplant hyperglycemia in a tertiary care centre. Indian J Endocrinol Metab 2017;21:871-5.  Back to cited text no. 2
    
3.
Prakash J, Rathore SS, Singh TB, Choudhury TA, Prabhakar U. New onset diabetes after transplantation (NODAT): Analysis of pre-transplant risk factors in renal allograft recipients. Indian J Transplant 2012;6:77-82.  Back to cited text no. 3
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4.
Sharma A, Minz M, Singh S. Incidence of glucose metabolic abnormalities in Indian living renal allograft recipients on tacrolimus-based triple drug immunosuppression. Transplant Proc 2008;40:2414-5.  Back to cited text no. 4
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Sanyal D, Das P, Gupta S, Bhattacharjee K. Evaluation of pre-transplant risk factors as independent predictors on the new onset of diabetes after renal transplants (NODAT). J Endocrinol Thyroid Res 2017;2:555-76.  Back to cited text no. 5
    
6.
Bora GS, Guleria S, Reddy VS, Tandon N, Gupta N, Gupta S, et al. Risk factors for the development of new-onset diabetes mellitus in a living related renal transplant program. Transplant Proc 2010;42:4072-3.  Back to cited text no. 6
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7.
Jayam J, Balakrishnan MA, Srinivasaprasad ND, S S, Fernando ME. Prevalence and risk factors for posttransplant diabetes mellitus data from government tertiary care centre. Indian J Transplant 2018;12:119-24.  Back to cited text no. 7
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8.
Prasad N, Gurjer D, Bhadauria D, Gupta A, Srivastava A, Kaul A, et al. Is basiliximab 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. 8
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9.
Pirsch JD, Henning AK, First MR, Fitzsimmons W, Gaber AO, Reisfield R, et al. New-onset diabetes after transplantation: Results from a double-blind early corticosteroid withdrawal trial. Am J Transplant 2015;15:1982-90.  Back to cited text no. 9
    
10.
Woodle ES, First MR, Pirsch J, Shihab F, Gaber AO, Van Veldhuisen P, et al. Aprospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy. Ann Surg 2008;248:564-77.  Back to cited text no. 10
    
11.
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.  Back to cited text no. 11
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12.
Heisel O, Heisel R, Balshaw R, Keown P. New onset diabetes mellitus in patients receiving calcineurin inhibitors: A systematic review and meta-analysis. Am J Transplant 2004;4:583-95.  Back to cited text no. 12
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13.
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.  Back to cited text no. 13
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14.
Prasad GV, Kim SJ, Huang M, Nash MM, Zaltzman JS, Fenton SS, et al. Reduced incidence of new-onset diabetes mellitus after renal transplantation with 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors (statins). Am J Transplant 2004;4:1897-903.  Back to cited text no. 14
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15.
Strevel EL, Kuper A, Gold WL. Severe and protracted hypoglycaemia associated with co-trimoxazole use. Lancet Infect Dis 2006;6:178-82.  Back to cited text no. 15
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Fabrizi F, Martin P, Dixit V, Bunnapradist S, Kanwal F, Dulai G, et al. Post-transplant diabetes mellitus and HCV seropositive status after renal transplantation: Meta-analysis of clinical studies. Am J Transplant 2005;5:2433-40.  Back to cited text no. 16
    
17.
Prasad N, Etta PK, Jaiswal A, Sharma RK, Bhadauria D, Saraswat V, et al. Long-term outcomes of hepatitis C virus infected renal allograft recipients. Indian J Transplant 2017;11:35-41.  Back to cited text no. 17
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18.
Hjelmesaeth J, Sagedal S, Hartmann A, Rollag H, Egeland T, Hagen M, et al. Asymptomatic cytomegalovirus infection is associated with increased risk of new-onset diabetes mellitus and impaired insulin release after renal transplantation. Diabetologia 2004;47:1550-6.  Back to cited text no. 18
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19.
Owda AK, Abdallah AH, Haleem A, Hawas FA, Mousa D, Fedail H, et al. De novo diabetes mellitus in kidney allografts: Nodular sclerosis and diffuse glomerulosclerosis leading to graft failure. Nephrol Dial Transplant 1999;14:2004-7.  Back to cited text no. 19
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20.
Rathi M, Rajkumar V, Rao N, Sharma A, Kumar S, Ramachandran R, et al. Conversion from tacrolimus to cyclosporine in patients with new-onset diabetes after renal transplant: An open-label randomized prospective pilot study. Transplant Proc 2015;47:1158-61.  Back to cited text no. 20
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21.
Hecking M, Haidinger M, Döller D, Werzowa J, Tura A, Zhang J, 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. 21
    
22.
Haidinger M, Werzowa J, Hecking M, Antlanger M, Stemer G, Pleiner J, et al. Efficacy and safety of vildagliptin in new-onset diabetes after kidney transplantation – A randomized, double-blind, placebo-controlled trial. Am J Transplant 2014;14:115-23.  Back to cited text no. 22
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23.
Sanyal D, Gupta S, Das P. A retrospective study evaluating efficacy and safety of linagliptin in treatment of NODAT (in renal transplant recipients) in a real world setting. Indian J Endocrinol Metab 2013;17:S203-5.  Back to cited text no. 23
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