New Onset Diabetes and Nephropathy after Renal Transplantation

Newo nset diabetes mellitus after transplantation (NODAT) is an important complication after kidney transplantation, responsible for increased mortality mainly related to cardiovascular events and infections. It has been also identified as an independent risk factor associated with graft loss. The varying definitions of diabetes used in the literature, and the prevalence and incidence of NODAT, are difficult to establish: it varies from 2 to 50% in the kidney transplant population. However, using the World Health Organization and the American Diabetes Association criteria, it occurs in ~15% of transplant recipients at 1 year in the USA, and ~5–1 0% in Europe. The main recipientr elated risk factors include old age, high body weight and high body mass index (BMI) before transplantation, Afro American or Hispanic ethnicity, hepatitis C virus (HCV) infection, and impaired fasting glucose level before transplantation. The other significant risk factors include male donor, acute rejection episodes, cytomegalovirus (CMV) infection and the immunosuppressive regimen, especially the use of tacrolimus (FK506), steroids, or mammalian target for rapamycin inhibitors. While some risk factors cannot be modified, others, such as recipient body weight, BMI, HCV or CMV infection, and immunosuppressive regimen can be controlled with an appropriate diet or treatment. Screening for impaired fasting glucose should be done before transplantation in dialysis or end stage renal disease patients to identify patients at risk for NODAT. In patients with increased BMI, weight loss before transplantation reduces the risk of NODAT. HCV infection should be treated before transplantation. Prolonged antiC MV prophylaxis may be used. Cyclosporine A is preferred to tacrolimus in patients at high risk of NODAT. A steroidf ree regimen or early steroid withdrawal is encouraged to reduce the risk of NODAT.

Prevention of Diabetic Nephropathy Lai KN, Tang SCW (eds): Diabetes and the Kidney Contrib Nephrol Basel, Karger, 2011, vol 170, pp 247–255 New-Onset Diabetes and Nephropathy after Renal Transplantation Joelle Guitarda и Lionel Rostainga,b и Nassim Kamara,b a Department of Nephrology, Dialysis, and Organ Transplantation, CHU Rangueil, and INSERM U563, IFR-BMT, CHU Purpan, Toulouse, France b Abstract New-onset diabetes mellitus after transplantation (NODAT) is an important complication after kidney transplantation, responsible for increased mortality mainly related to cardiovascular events and infections It has been also identified as an independent risk factor associated with graft loss The varying definitions of diabetes used in the literature, and the prevalence and incidence of NODAT, are difficult to establish: it varies from to 50% in the kidney transplant population However, using the World Health Organization and the American Diabetes Association criteria, it occurs in ~15% of transplant recipients at year in the USA, and ~5–10% in Europe The main recipient-related risk factors include old age, high body weight and high body mass index (BMI) before transplantation, Afro-American or Hispanic ethnicity, hepatitis C virus (HCV) infection, and impaired fasting glucose level before transplantation The other significant risk factors include male donor, acute rejection episodes, cytomegalovirus (CMV) infection and the immunosuppressive regimen, especially the use of tacrolimus (FK506), steroids, or mammalian target for rapamycin inhibitors While some risk factors cannot be modified, others, such as recipient body weight, BMI, HCV or CMV infection, and immunosuppressive regimen can be controlled with an appropriate diet or treatment Screening for impaired fasting glucose should be done before transplantation in dialysis or end-stage renal disease patients to identify patients at risk for NODAT In patients with increased BMI, weight loss before transplantation reduces the risk of NODAT HCV infection should be treated before transplantation Prolonged anti-CMV prophylaxis may be used Cyclosporine A is preferred to tacrolimus in patients at high risk of NODAT A steroid-free regimen or early steroid withdrawal is encouraged to reduce the risk of NODAT The introduction of novel immunosuppressive drugs has allowed a significant decrease in the incidence of allograft rejection after renal transplantation Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/31/2015 9:57:08 AM Copyright © 2011 S Karger AG, Basel Patient and graft survival rates, however, have not significantly improved [1], partly because of the increased burden of posttransplant complications, including new-onset diabetes mellitus after transplantation (NODAT) Harmful Effect of New-Onset Diabetes Mellitus after Renal Transplantation Increased mortality has been reported in patients with NODAT compared to patients without NODAT [2], mainly due to cardiovascular complications, but also because of an increased incidence of infections Compared to kidney transplant patients without NODAT, diabetic patients have a higher incidence and greater severity of infections, which results in increased posttransplant mortality [2] Cosio et al [3] have shown that the 5-year cumulative incidence of cardiovascular events was correlated with fasting glucose level at year after transplantation [3] The incidence of cardiovascular events was significantly higher in patients with diabetes or a moderately elevated fasting glucose level compared to those with a normal fasting glucose level at year after transplantation In addition, a multivariate analysis identified fasting glucose levels at 1, 4, and 12 months after transplantation, as independent predictive factors for a cardiovascular event occurring after kidney transplantation [3] In a prospective study, Ducloux et al [4] had shown that NODAT is an independent risk factor for the appearance of atheromatous disease in kidney transplant patients (RR = 1.34, 95% CI 1.04–2.18) Pretransplantation diabetes is also a predictive factor for all-cause and cardiovascular mortality after kidney transplantation [5] NODAT also accounts for lower graft survival [2] and is an independent risk factor associated with graft loss [6] At years, graft function, as defined by serum creatinine level, is significantly lower in NODAT patients compared to patients without NODAT [6] Authentic biopsy-proven diabetic nephropathy has been reported in patients who develop NODAT Moreover, classic complications of diabetes mellitus, such as ketoacidosis, hyperosmotic diabetic coma, or peripheral neuropathy, have been described in renal-allograft patients with NODAT [6] NODAT also has an impact on the quality of life of transplant patients and represents an important economic burden [7] The varying definitions of diabetes used in the literature and the prevalence and incidence of NODAT are difficult to establish 248 Guitard · Rostaing · Kamar Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/31/2015 9:57:08 AM Prevalence and Incidence of New-Onset Diabetes Mellitus after Renal Transplantation According to the World Health Organization (WHO) and the American Diabetes Association (ADA), diabetes is currently defined by the association of diabetes symptoms (polyuria, polydipsia, weight loss) and a fasting glucose level ≥7 mm (1.26 g/dl), or a nonfasting glucose level of ≥11.1 mm (2 g/dl), or the use of insulin and/or oral antidiabetic drugs Impaired glucose tolerance is defined by a fasting glucose level between 6.1 and mm Abnormal glucose levels must be assessed twice to confirm diagnosis The prevalence and incidence of diabetes is higher in transplant patients than in the general population, and is estimated to be between and 50% according to the literature [8] NODAT usually occurs in the first posttransplantation months [8] Using the USRDS registry, Kasiske et al [2] estimated the cumulative incidence of NODAT in patients who had received a first renal allograft between 1996 and 2000 Patients were considered diabetic if reported to the Medicare system The cumulative incidences were 9.1, 16, and 24% at 3, 12, and 36 months, respectively [2] Using the WHO/ADA criteria for diabetes, Cosio et al [3] reported a prevalence of impaired glucose tolerance and NODAT in 33 and 13% of patients, respectively, at year after transplantation [3] A French multicenter observational study that included 527 patients identified using WHO criteria reported a NODAT prevalence of 7%, with a median time until NODAT onset of 1.6 months [9] Impaired fasting glucose was found in 7.9% of patients [9] Diabetes is probably underestimated in the majority of studies For example, in 122 renal transplant patients in whom fasting glucose levels were between 5.6 and 6.1 mm, and who had undergone an oral glucose tolerance test (OGT), the occurrence of NODAT, impaired fasting glucose, or high fasting glucose levels were diagnosed in 10, 14, and 18% of patients, respectively [10] Similarly, with the help of an OGT, Porrini et al [11] reported a 33% incidence of impaired fasting glucose and a 20% incidence of NODAT in 154 nondiabetic renal transplant patients receiving a tacrolimus-based immunosuppressive regimen in the first year after kidney transplantation [11] Conversely, a normal fasting glucose level and a normal OGT at day after transplantation are independent protective factors against NODAT [12] Numerous studies have identified risk factors associated with NODAT (table 1) [13] The main recipient-related risk factors include old age, high body weight and high body mass index (BMI) before transplantation, Afro-American or Hispanic ethnicity, hepatitis C virus (HCV) infection, and an impaired fasting glucose level before transplantation Weight gain during the first posttransplantation year does not seem to be associated with NODAT The polymorphism New-Onset Diabetes and Nephropathy after Renal Transplantation 249 Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/31/2015 9:57:08 AM Risk Factors for New-Onset Diabetes Mellitus after Transplantation Table Main risk factors for new-onset diabetes mellitus after kidney transplantation Recipients’ factors – – – – – – – – – – – – older age male gender (controversial) family history of diabetes weight at transplantation high BMI before transplantation maximum BMI before transplantation Afro-American or Hispanic ethnicity low educational status HCV infection fasting glucose level before transplantation impaired fasting glucose level before transplantation metabolic syndrome: high triglyceride level low high-density lipoprotein level Transplantation factors – – – – – – male donor cadaveric donor (controversial) number of HLA mismatches (controversial) occurrence of at least one episode of acute rejection CMV infection immunosuppressive regimen: use of tacrolimus tacrolimus trough levels steroid pulses high steroid daily dosage high cumulative dose of steroids use of mTOR inhibitors of the promoter region of interleukin-6, in the position 174(G→C), has been associated not only with type diabetes and insulin resistance, but also with NODAT [14] The rs7903146 polymorphism of transcription factor-7-like was also significantly associated with NODAT in a population of 1,229 kidney transplant patients (OR 1.55, p = 0.02, for the CT genotype, and OR 1.79, p = 0.04, for the TT genotype) [15] The other significant risk factors associated with transplantation are gender (male donors), acute rejection episodes, cytomegalovirus (CMV) infection, and the immunosuppressive regimen, especially the use of tacrolimus (FK506), steroids, and mammalian target for rapamycin inhibitors An induction therapy with basiliximab has been recently identified as a risk factor for NODAT [16] Basiliximab, a monoclonal antibody directed against the receptor of interleukin-2 (CD25), inhibits CD4+ CD25+ lymphocytes that include 250 Guitard · Rostaing · Kamar Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/31/2015 9:57:08 AM HLA = Human leukocyte antigen; mTOR = mammalian target for rapamycin regulatory CD25+ CD4+ FOXP3+ T cells Apparently, these subpopulations play a role in the development of diabetes, in particular type diabetes [16] Although there is no clear pathophysiological explanation, it has been shown that albuminuria on day after transplantation [12], and albuminuria at months and after transplantation [17], are associated with NODAT Adiponectin, an anti-inflammatory protein synthesized by adipocytes, reduces insulin resistance and atheromatosis Elevated adiponectin levels appear to prevent NODAT [18] Although some risk factors cannot be modified, others, such as recipient body weight and BMI, HCV or CMV infection, and the immunosuppressive regimen, could be controlled with an appropriate diet or modified treatment Measures to Reduce New-Onset Diabetes Mellitus after Transplantation Risk Factors? Screening for Impaired Fasting Glucose before Transplantation Screening for impaired fasting glucose should be done before transplantation in dialysis or end-stage renal disease patients to identify patients at risk for NODAT, in order to ensure meticulous posttransplantation surveillance of glycemic levels and to adapt the immunosuppressive regimen Treatment of HCV Infection before Transplantation A meta-analysis has shown that the relative risk of NODAT is 3.97-fold greater (CI 95%: 1.83–8.61) in HCV-positive renal transplant patients compared to HCV-negative renal transplant patients [19] In HCV-positive patients, NODAT may occur more frequently in patients treated with tacrolimus compared to those receiving cyclosporine A (CsA; 57.8 vs 7.7%, p < 0.0001) [20] However, the mechanism by which HCV favors NODAT is not well established HCV may affect glucose metabolism by inducing hepatocyte necrosis Moreover, a link between HCV infection and insulin resistance has been established in vitro and in vivo Finally, HCV could induce dysregulation in the hepatocyte production of cytokines and insulin receptors As treatment of HCV infection is contraindicated after kidney transplantation because of the high risk of interferon therapy-induced acute rejection, it is recommended to treat all prospective HCV-positive, RNA-positive, renal transplantation candidates in order to achieve viral eradication before transplantation [21] New-Onset Diabetes and Nephropathy after Renal Transplantation 251 Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/31/2015 9:57:08 AM Reducing Excess Weight before Transplantation In patients with increased BMI, weight loss before transplantation reduces the risk of NODAT, cardiovascular events, and postoperative complications Selection of Immunosuppressive Regimen Calcineurin Inhibitors Tacrolimus seems more prone to induce NODAT than CsA In a meta-analysis that evaluated the effect of different calcineurin inhibitors (CNIs) on the incidence of NODAT, Heisel et al [22] found a higher incidence of NODAT in patients receiving FK506 than patients receiving CsA (9.8 vs 2.7%, RR = 3.7, CI 95%: 2.6–15.36, p < 0.0001) The DIRECT Study is an international multicenter randomized study that compared the incidence of NODAT in de novo renal transplant recipients who received either CsA or FK506 [23] Amongst the nondiabetic patients before transplantation, the incidence of NODAT at months after transplantation was 26% in the CsA arm and 33.6% in the FK506 arm (p = 0.0046) At months, 8.9% of patients receiving CsA and 16.8% of patients receiving FK506 had received treatment for diabetes (p = 0.005) [23] The economic impact of immunosuppressive regimen-induced diabetes was evaluated to be USD 2,025 and USD 3,308 per patient receiving tacrolimus at and years after transplantation, respectively, while similar figures for patients receiving CsA were only USD 1,137 and USD 1,611, respectively [7] Both CsA and FK506 induce diabetes by reducing insulin secretion and also, to a lesser extent, by inducing insulin resistance [24] Insulin resistance is increased by concomitant administration of steroids [24] Asberg et al [25] have shown that, at year after transplantation, insulin sensitivity was significantly improved in patients who had never received CNIs compared to patients treated with CNIs The different tissue localizations of the molecular targets of CsA and FK506 could account for the greater impact of FK506 on NODAT Indeed, FKBP12, the target of FK506, is highly expressed in β-cells in the islets of Langerhans, whereas CsAs, which target cyclophilin, is mostly expressed in the heart, liver, and kidney Conversion from tacrolimus to cyclosporine in patients with NODAT significantly improves fasting glucose levels and glycated hemoglobin compared to patients maintained on tacrolimus [26] At 1-year after conversion, remission of NODAT, as defined by fasting glucose levels