Higher initial tacrolimus blood levels and concentration-dose ratios in kidney transplant recipients who develop diabetes mellitus

Posttransplantation diabetes mellitus (PTDM) is a common complication of kidney transplantation, associated with poorer graft and patient outcomes. Tacrolimus is a strong immunosuppressive drug associated with low acute rejection rates, but a higher risk for PTDM. High trough levels of tacrolimus during the first month after transplantation have been found to be a significant risk factor for the development of PTDM. The aim of this single-center study was to identify the risk factors for the development of PTDM among kidney transplant recipients under tacrolimus therapy. We examined 73 cadaveric kidney transplant recipients receiving tacrolimus between 1994 and 2003. Age, donor and recipient gender, dialysis method, body mass index (BMI), first year weight gain, mismatches, incidence of acute rejection and delayed graft function, hepatitis C serology, first year cumulative steroid dose, first tacrolimus blood level, first tacrolimus blood level <15 ng/mL, and corresponding tacrolimus daily doses and concentration/dose ratios (CDR) were also collected. PTDM was defined as at least 2 fasting blood glucose values > or =126 mg/dL, according to the World Health Organization criteria. Incidence of first year PTDM was 27.4%. Patients with PTDM showed significantly higher age, BMI, first tacrolimus blood level, first tacrolimus CDR, and CDR with tacrolimus blood level <15 ng/mL as well as less 1-year weight gain. After logistic regression, age (relative risk [RR] 1.060, confidence interval [CI] 95%, 1.001-1.122; P = .043) and first tacrolimus blood level (RR 1.154; CI 95%, 1.038-1.283; P = .008) remain significant risk factors for developing PTDM. Older age and initial tacrolimus blood levels were the main risk factors for PTDM among our group of patients. Kidney transplant recipients who develop PTDM maintain a high CDR of tacrolimus.     

New onset diabetes mellitus incidence and risk factors in kidney transplantation: results of the observational cross-sectional study diapason

BACKGROUND: New-onset diabetes mellitus (NODM) is a frequent complication of kidney transplantation. Data on NODM are mainly available in the United States. A study was implemented in a French population of kidney transplants. The incidence and risk factors of NODM were analysed. Diabetes was defined according to American Diabetes/World Health Organization guidelines. METHODS: Diapason is an observational cross-sectional study of 527 kidney transplant patients from 17 units based on data collected at a single routine visit 6 to 24 months after kidney transplantation. RESULTS: The mean age of the patients was 47.2 years, and 61.1% were men; 49.5% were receiving cyclosporine microemulsion and 50.5% tacrolimus. NODM developed in 7.0% after a median interval of 1.6 months. Univariate analysis identified six pretransplantation risk factors: advanced age, impaired fasting glucose, at least two cardiovascular risk factors, hepatitis C status, maximums lifetime body mass index above 25, and tacrolimus or cyclosporine therapy. Four independent factors were identified by multivariate analysis: body mass index above 25 (OR = 5.1), pretransplantation impaired fasting glucose (OR = 4.7), hepatitis C status (OR = 4.7), and tacrolimus versus cyclosporine treatment (OR = 3.0). CONCLUSIONS: NODM is associated with risk factors present prior to kidney transplantation and with treatment with tacrolimus as opposed to cyclosporine. Therefore, the choice of calcineurin inhibitor should be based on the patient's overall risk profile.     

Risk Factors for Development of New-Onset Diabetes Mellitus and Progressive Impairment of Glucose Metabolism After Living-Donor Liver Transplantation

Background

New-onset diabetes mellitus (NODM) has a negative impact on graft and patient survivals. Hepatitis C virus (HCV) infection, high body mass index, increased donor and recipient ages, and calcineurin inhibitor (CNI) type have been identified as risk factors for the development of NODM. We aimed to elucidate the risk factors for the development of NODM and those for progressive glucose intolerance in adult living-donor liver transplant (LDLT) recipients.

Methods

We collected data from 188 primary liver transplant recipients (age > 16 years) who underwent LDLT from June 1991 to December 2011 at Hiroshima University Hospital. Risk factors for NODM and progressive impairment of glucose metabolism in pre-transplantation diabetes mellitus (DM) recipients were examined.

Results

Pre-transplantation DM was diagnosed in 32 recipients (19.3%). The overall incidence of NODM was 6.0% (8/134 recipients). Multivariate analysis revealed that old recipient age (≥55 years) is a unique predictive risk factor for developing NODM. The incident of pre-transplantation DM was significantly higher in recipients with HCV infection than in those without HCV. A high pre-transplantation triglyceride level was an independent risk factor for progressive impairment of glucose tolerance among 32 LDLT recipients with pre-transplantation DM. All of the NODM patients were being treated with tacrolimus at the time of diagnosis. Switching the CNI from tacrolimus to cyclosporine allowed one-half of the patients (4/8) to withdraw from insulin-dependent therapy. NODM and post-transplantation glucose intolerance had no negative impact on patient and graft outcomes.

Conclusions

Older age of the recipient (≥55 years) was a significant risk factor for NODM. Hypertriglyceridemia in the recipients with DM is an independent risk factor for post-transplantation progressive impairment of glucose metabolism. NODM had no negative impact on outcomes in the LDLT recipients.     

Rescue therapy with tacrolimus in simultaneous pancreas/kidney transplantation

Abstract Tacrolimus has been effective both in primary and rescue therapy following steroid and OKT3-resistant acute rejection in liver and kidney transplantation. Due to the effects of tacrolimus on glucose metabolism, there has been concern about its use in simultaneous pancreas/kidney transplantation. We report on the results of six patients (three female, three male, age 35.2 ± 7.3 years) converted from cyclosporin A to tacrolimus following simultaneous pancreas/kidney transplantation in steroid-resistant acute rejection. Tacrolimus was induced 2.8 ± 1.7 months (range 1–4.8 months) after transplantation; follow-up was 3–18 months. Following conversion, creatinine levels declined in all patients [3.5 ± 1.2 mg/dl before conversion, 3.0 ± 1.9 mg/dl ( n = 6) at three months, 1.4 ± 0.1 mg/dl at 1 year (n = 3)]. Before conversion, fasting blood glucose levels averaged 154 ± 33 mg/dl, with three patients receiving insulin. Three months later no patient required insulin, the mean glucose level being 107 ± 23 mg/dl ( n = 6); at 1 year it was 92 ± 9 mg/dl ( n - 3). One patient lost his pancreatic graft after 4 months due to a mycotic aneurysm. We conclude that conversion to tacrolimus is a safe and effective treatment in cases of steroid-resistant rejections following pancreas/kidney transplantation.     

Factors influencing the onset of diabetes mellitus after kidney transplantation: a single French center experience

Posttransplantation diabetes mellitus (PTDM) is a complication arising mostly during the first 6 months after kidney transplantation. Considering the serious outcomes of chronic hyperglycemia in kidney transplant patients, the recognition of factors that contribute to the onset of PTDM is of particular relevance. A retrospective analysis was performed to document the incidence of and the risk factors for diabetes mellitus occurring in the first year after kidney transplantation among 177 adult patients, without previously known diabetes transplanted between January 1998 and December 2000. PTDM, defined as fasting plasma glucose > or = 126 mg/dL confirmed by repeat testing on a different day, occurred in 48 (27.12%) patients of whom 36 showed transient changes during the first year after transplantation. Univariate analysis identified variables to be associated with the onset of PTDM: older recipient age (P = .05), male gender (P = .03), family history of diabetes (P = .04), advanced donor age (P = .008), absence of induction immunosuppression (P = .04), use of tacrolimus (vs cyclosporine; P = .01), one or more than one (steroid-treated) acute rejection episode(s) (P = .000001), cytomegalovirus infection (P = .02), and use of beta-blockers or diuretics (P = .05). By multivariate analysis, five factors were independently associated with the onset of PTDM: two episodes of rejection (odds ratio = 42.69, P = .000025), one episode of rejection (5.01, P = .007), older recipient age (1.06, P = .017), family history of diabetes (7.24, P = .011), and weight at transplantation (1.03, P = .048). Tacrolimus treatment remained of borderline significance (2.77, P = .05). In addition to traditional risk factors predisposing to the development of type 2 diabetes in the general population, episodes of acute rejection significantly influence the incidence of PTDM.     

Risk factors for development of new-onset diabetes mellitus after kidney transplantation

BACKGROUND: New-onset diabetes mellitus after kidney transplantation (NODM) is an important co morbid condition that is associated with inferior graft and patient survival. The objective of this study was to identify donor, recipient and transplant factors, and choices of immunosuppression associated with development of NODM using Organ Procurement Transplant Network/United Network of Organ Sharing database (OPTN/UNOS). METHODS: From January 2004 to December 2005, 15,309 adult kidney transplants alone with at least one follow-up report as of March 2006 were identified in the OPTN/UNOS database. Among these, 1,581 patients developed NODM during the follow-up period. We examined the risk factors of NODM using multivariate Cox regression analysis using the time to diagnosis of NODM as a time-varying end point. Other events such as graft loss, patient death, and lost to follow-up were censored. RESULTS: NODM was reported in 10% in our study population with mean follow-up time of 306 days. After adjusting for other known factors, independent factors associated with the development of NODM included recipient age (29% increase of relative risk [RR] for every 10-year age increment), obesity (RR = 1.39 for body mass index [BMI] 25-30 and RR = 1.85 for BMI > 30 vs. BMI < 25), tacrolimus use (RR = 1.50), hepatitis C virus (HCV) positivity (RR = 1.42), and African-American recipients (RR = 1.32). Alemtuzumab was associated with a lower risk of NODM (RR = 0.52). DISCUSSION: Using OPTN/UNOS database, we identified risk factors for development of NODM. Some of these factors are potentially modifiable, including obesity, HCV infection, and the use of tacrolimus. Clinical trials are needed to assess whether modifying these "modifiable risk factors" will indeed prevent NODM.     

Rescue therapy with tacrolimus in simultaneous pancreas/kidney transplantation

Tacrolimus has been effective both in primary and rescue therapy following steroid and OKT3-resistant acute rejection in liver and kidney transplantation. Due to the effects of tacrolimus on glucose metabolism, there has been concern about its use in simultaneous pancreas/kidney transplantation. We report on the results of six patients (three female, three male, age 35.2 ± 7.3 years) converted from cyclosporin A to tacrolimus following simultaneous pancreas/kidney transplantation in steroid-resistant acute rejection. Tacrolimus was induced 2.8 ± 1.7 months (range 1–4.8 months) after transplantation; follow-up was 3–18 months. Following conversion, creatinine levels declined in all patients [3.5 ± 1.2 mg/dl before conversion, 3.0 ± 1.9 mg/dl (n = 6) at three months, 1.4 ± 0.1 mg/dl at 1 year (n = 3)]. Before conversion, fasting blood glucose levels averaged 154 ± 33 mg/dl, with three patients receiving insulin. Three months later no patient required insulin, the mean glucose level being 107 ± 23 mg/dl (n = 6); at 1 year it was 92 ± 9 mg/dl (n = 3). One patient lost his pancreatic graft after 4 months due to a mycotic aneurysm. We conclude that conversion to tacrolimus is a safe and effective treatment in cases of steroid-resistant rejections following pancreas/kidney transplantation.     

Posttransplant diabetes mellitus: incidence and risk factors

Posttransplant diabetes mellitus (PTDM) is common post transplantation and is associated with tacrolimus (TAC) and steroid therapy. The aim of the present study was to analyze the incidences of PTDM and associated risk factors. METHODS: We selected renal transplant recipients treated with TAC, mycophenolate mofetil (MM), and steroids. Exclusion criteria were recipients <18 years old, history of diabetes, recipients of kidney/pancreas, and/or those receiving cyclosporine or sirolimus. PTDM was defined as glucose >126 mg/dL, with or without drug therapy. RESULTS: Among 67 patients who fulfilled the inclusion criteria, 18 (26.8%) developed PTDM within 2 months of transplantation. Compared with normal glucose patients, the PTDM group was older, male, received a kidney from deceased donors, and showed higher pretransplant glucose levels. No differences were noticed in renal function or daily dose of TAC or steroids. However, TAC trough levels in the first month were higher among the PTDM group, despite the lower dose per kilogram. After 1 year of follow-up, weight gain as well as daily TAC per kilogram dose was less among PTDM patients. Analysis of potential risk factors showed a higher incidence of hepatitis C virus infection in the PTDM group, as well as a higher frequency of HLA DR13. CONCLUSION: The incidence of PTDM diagnosed in the early posttransplant period in the present series was 26.8%. Risk factors included older age, male gender, recipients of kidneys from deceased donors, hepatitis C virus infection, higher pretransplant glucose levels, and higher TAC trough levels during the first month posttransplant.     

New-onset diabetes after liver transplantation: from pathogenesis to management.

New-onset diabetes mellitus (NODM) develops in approximately 15% of liver transplant recipients, and a similar proportion of patients have diabetes prior to transplantation. Preexisting diabetes and probably NODM are associated with increased mortality and risk of infection. NODM occurs more frequently among patients with hepatitis C infection; additional risk factors include family history, male gender, increasing weight, and alcoholic cirrhosis. Corticosteroid therapy, particularly bolus injections, increases likelihood of NODM, and randomized clinical trials and retrospective studies have shown NODM to occur more frequently with tacrolimus compared with cyclosporine. Patients undergoing liver transplantation should be screened for diabetes risk factors, and fasting plasma glucose should be monitored regularly in all transplant recipients. Management of NODM is essentially similar to that of diabetes in the nontransplant population, and includes dietary and lifestyle modifications. In choosing oral agents and/or insulin, the individual medical profile of the patient must be considered carefully. Corticosteroid exposure should be limited as much as possible, and reduction of calcineurin inhibitor dose is prudent. Switching from tacrolimus to cyclosporine may be required in some cases to achieve improvement or resolution. In conclusion, prospective trials are necessary to properly define antidiabetic therapy and immunosuppressive strategies in this population.     

Diabetes mellitus after kidney transplantation: a French multicentre observational study.

BACKGROUND: New-onset diabetes mellitus (NODM)-a common complication of kidney transplantation-is associated with increases in graft loss, morbidity and mortality. METHODS: This is a purely observational study of 527 patients taking a calcineurin inhibitor (CNI), based on data collected at a single routine visit 6-24 months after kidney transplantation. Diabetes was defined according to ADA/WHO guidelines. RESULTS: The mean age of the patients was 47.2 years and 61.1% were men; 49.5% were receiving cyclosporine microemulsion (CsA-ME) and 50.5% tacrolimus (Tac). NODM developed in 7.0% after a median interval of 1.6 months. In CsA-ME-treated patients, the unadjusted cumulative risks of NODM were 5.5% and 8.4% at 1- and 2-year post-transplantation, while in Tac-treated patients, the risks were respectively 17.4% and 21%. Four independent risk factors (RFs) were identified by multivariate analysis: maximum lifetime body mass index>25 [odds ratio (OR)=5.1], pre-transplantation impaired fasting glucose (OR=4.7), hepatitis C status (OR=4.7) and Tac vs CsA-ME treatment (OR=3.0). CONCLUSIONS: NODM is associated with certain RFs present prior to kidney transplantation, and with treatment with Tac as opposed to CsA-ME.     

肾移植术后糖尿病的临床特性及高危因素

目的 研究肾移植术后糖尿病（ＰＴＤＭ）的临床特性及高危因素。方法 将５１２例肾移植患者分为２组,其中４８例ＰＴＤＭ患者为糖尿病组。其余４６４例患者为非糖尿病组。定期监测患者体重、用药情况、生化指标、病毒抗体,并用血清学方法及聚合酶链反应（ＰＣＲ）方法检测主要组织相容性抗原（ＨＬＡ）。结果 糖尿病组的平均年龄及术后６个月内激素的用量明显高于非糖尿病组。肾移植术后半年内易出现ＰＴＤＭ,且全部ＰＴＤＭ     

Early Steroid Withdrawal Regimen Prevents New-Onset Diabetes Mellitus in Old-Age Recipients After Living Donor Liver Transplantation

Background

Steroid use after liver transplantation is known to increase the risk of new-onset diabetes mellitus (NODM). In this study, we tried to identify a patient subgroup who would benefit with regard to NODM by an early steroid withdrawal regimen (ESWR) after living donor liver transplantation (LDLT)

Methods

Among 100 adult LDLT patients, 65 were on a conventional immunosuppressive regimen (CIR), and 35 were on an ESWR. With the ESWR, the steroid was tapered off mostly within 7?days with induction of basiliximab in combination with tacrolimus and mycophenolate mofetil (MMF). The CIR was a combination of tacrolimus and steroid. MMF was added in selected patients. Steroid was tapered off 2–6?months after LT. The presence of NODM was investigated cross-sectionally 6?months after LT.

Results

There was no significant difference in terms of acute cellular rejection, sepsis, or death during follow-up. NODM had developed in 13 patients (13?%). Old recipient age (≥55) and pretransplant history of hypertension were significant risk factors for NODM. The type of immunosuppression was the single risk factor for NODM in subgroup of old-age recipients (≥55?years) on the CIR (hazard ratio 13.34, p?=?0.04).

Conclusions

ESWR can safely reduce the incidence of NODM after LDLT in old-age recipients. Therefore, ESWR should be considered first in old-age recipients undergoing LDLT.     

Prospective, multicenter, randomized trial to compare incidence of new-onset diabetes mellitus and glucose metabolism in patients receiving cyclosporine microemulsion versus tacrolimus after de novo kidney transplantation

New-onset diabetes mellitus (NODM) is associated with increased risk of graft failure and death in renal transplant recipients. Some clinical studies have indicated that NODM risk is higher with tacrolimus than cyclosporine, but no comparative trial has used American Diabetic Association (ADA)/World Health Organization (WHO) criteria for diagnosis of diabetes mellitus. The Diabetes Incidence After Renal Transplantation, Neoral C2 Monitoring Versus Tacrolimus (DIRECT) study is a 6-month open-label, multicenter trial comparing the impact of tacrolimus and Neoral (cyclosporine microemulsion) on glucose metabolism in 700 de novo kidney transplant recipients, based on ADA/WHO criteria. Patients are randomized to tacrolimus (C0 monitoring) or Neoral (C2 monitoring), stratified by baseline diabetic status and ethnicity. All patients receive basiliximab, corticosteroids, and mycophenolate mofetil or enteric-coated mycophenolate acid (myfortic). Pooled interim 3-month results from a subset of 115 patients receiving either tacrolimus or Neoral showed that the primary efficacy end-point (biopsy-proven acute rejection [BPAR], graft loss or death) occurred in 11 patients (10%). There were four graft losses and only one death, which occurred after graft loss. Eight patients experienced BPAR (7.3%). Among 99 patients who were nondiabetic at baseline, 14 developed NODM by month 3, 17 developed impaired fasting glucose or impaired glucose tolerance, and another 5 patients received hypoglycemic treatment for at least 14 consecutive days or at the month 3 visit, resulting in a 36% incidence of impaired glucose metabolism. At 3 months, median GFR (Nankivell) was 63.7 mL/min; median serum creatinine was 137 micromol/L. Full complete results are expected in December 2005.     

Relative risk of new-onset diabetes during the first year after renal transplantation in patients receiving tacrolimus or cyclosporine immunosuppression

Clinical trials have consistently shown a higher incidence of new-onset diabetes mellitus with tacrolimus than cyclosporine. However, in protocol-driven studies steroid doses are comparable in both treatment arms, while in clinical practice steroid dose used in conjunction with tacrolimus or cyclosporine may differ. This retrospective study analysed renal transplant recipients without pre-existing diabetes receiving tacrolimus (n = 100) or cyclosporine (n = 100) for whom one-year follow-up data were available. Diabetes was defined as use of insulin or oral hypoglycemic agents; fasting glucose >6.9 mmol/L; or non-fasting glucose >11 mmol/L on three consecutive occasions. Tacrolimus-treated patients were significantly older than cyclosporine-treated patients (49 +/- 14 vs. 44 +/- 13 yr, p < 0.05) and received a significantly lower cumulative dose of corticosteroids over the first three months post-transplant (1284 +/- 379 vs. 1714 +/- 486 mg, p < 0.0001). At 3, 6, 9 and 12 months significantly more tacrolimus-treated patients had new-onset diabetes than cyclosporine- treated patients. At 12 months, 18 patients receiving tacrolimus and two receiving cyclosporine had diabetes (p < 0.0001). There was a clear relationship between age and incidence of new-onset diabetes at three months in the tacrolimus cohort. After stratifying patients by age group, the frequency of diabetes was significantly higher with tacrolimus than with cyclosporine in patients aged 40-60 yr [8/46 (17.4%) vs. 2/48 (4.2%), p < 0.05] and >60 yr [9/28 (32.1%) vs. 0/14 (0%), p < 0.05]. The mean tacrolimus trough level during the first three months was similar in patients with diabetes (13.1 +/- 2.3 ng/mL) or without diabetes (13.0 +/- 2.8 ng/mL, n.s.). These results indicate that new-onset diabetes is strongly and significantly associated with tacrolimus vs. cyclosporine in renal transplant recipients, even when steroid dosing is lower with tacrolimus.     

Prevalence of new-onset diabetes mellitus in Brazilian liver transplant recipients: association with HCV infection

New-onset diabetes melittus (NODM) is a serious complication following transplantation. Recent studies suggest an association between hepatitis C virus (HCV) infection and DM both in nontransplant settings as well as after liver transplantation (LT). The aim of this study was to assess the prevalence of NODM among Brazilian LT recipients, analyzing possible risk factors including HCV infection. We conducted a cross-sectional study to evaluate the prevalence of NODM in 82 LT recipients with a posttransplant follow-up > or =1 year including 29 HCV-positive patients and 53 with other causes for liver disease. Patients were considered to meet the criteria for DM if they had two consecutive fasting glucose values > or =126 mg/dL or if they were taking insulin or oral hypoglycemic agents at the time of the study. The overall prevalence of NODM was 18.29% with a median interval of 20 months between LT and diagnosis of DM. The age, sex, and race distribution, immunosuppressive regimen, number of rejection episodes treated with pulse therapy, and family history of DM were similar in both groups. However, the frequency of BMI > or = 30 in the pre- and posttransplant periods was higher among patients who developed NODM (P = .02). Upon multivariate analysis of the entire cohort, HCV infection was the only significant predictor of NODM (OR = 4.31, CI = 1.17 to 15.84, P = .02). In conclusion, our study confirmed an association between HCV infection and NODM among Brazilian liver transplant recipients, suggesting that HCV infection may have a potential role in the pathogenesis of posttransplantation DM.     

Maturation of dose-corrected tacrolimus predose trough levels in pediatric kidney allograft recipients

BACKGROUND: In contrast to adult kidney recipients, in whom the long-term evolution and clinical determinants of tacrolimus pharmacokinetics are well studied, less is known about the long-term evolution of tacrolimus pharmacokinetics in pediatric kidney transplant recipients. METHODS: One-hundred and five pediatric recipients of a kidney allograft, all treated with a corticosteroid-free immunosuppressive protocol, were included. The evolution of tacrolimus doses and predose trough (C0) levels was recorded at 3, 6, 9, 12, 18, and 24 months after transplantation, as well as all C0 levels obtained in the first 2 years after transplantation. The evolution and clinical determinants of tacrolimus exposure parameters were analyzed. RESULTS: Dose-corrected tacrolimus C0 levels (C0/dose/kg) increased in the first 2 years after kidney transplantation in pediatric recipients (P=0.001). This decrease in dose requirement by time was only significant in children older than 5 years at the time of transplantation (P=0.38, 0.03, and 0.001 for age groups <5, 5-12, and >12 years, respectively). In addition, the younger patients had significantly higher dose requirements (dose/kg) compared with older recipients (P=0.0002). CONCLUSION: Pediatric kidney transplant recipients exhibit maturation of dose-corrected tacrolimus predose trough levels with time after transplantation. This cannot be explained by differences in corticosteroid use, because all patients were treated with a corticosteroid-free protocol. The higher dose requirements for younger recipients and the absence of tacrolimus maturation in the youngest recipients suggest that age-dependent changes in tacrolimus intestinal first-pass effect, metabolism, or distribution play a role. Whether age-specific tacrolimus dosing algorithms will improve outcome needs further study.     

New-onset diabetes mellitus in cyclosporine-treated organ transplant patients in Taiwan: interim analysis (6 months) of postmarketing surveillance

Posttransplant new-onset diabetes mellitus (NODM) is an important complication among patients receiving immunosuppressants. It has a considerable impact on chronic allograft dysfunction. Calcineurin inhibitors have been implicated in the development of posttransplant NODM. Since high-risk candidates also undergo transplantation, prevention and control of posttransplant NODM is important. A 3-year postmarketing surveillance study is currently underway in Taiwan to evaluate the incidence and risk factors leading to development of NODM among de novo and maintenance solid-organ transplant patients receiving cyclosporine (CsA)-based immunosuppressive therapy. Concomitant therapy consisted of basiliximab, mycophenolate mofetil or enteric-coated mycophenolate sodium, and corticosteroids. Diabetes was diagnosed according to the American Diabetes Association criteria. This 6-month protocol-defined interim analysis included 101 patients (84 de novo, 17 maintenance) who received renal (n = 77), liver (n = 13), or heart (n = 11) transplantation. At the end of 6 months, 8/101 (7.92%) patients experienced NODM. The mean time to NODM was 3.05 months. No significant difference was observed between NODM and non-NODM patients for risk factors: age, body mass index, blood pressure, gender, high-density lipoproteins/triglycerides hdl/tg, and anti-hepatitis C virus. The composite endpoint of biopsy-proven acute rejection, graft loss, or death was reached in four patients, with a mean time to event of 3.81 months. Infections were noted in 34 subjects but, no malignancies. Among 389 adverse events reported in 91 patients (90.1%), the majority were of mild to moderate severity. Two deaths were reported: heart transplant recipients with acute rejection and cytomegalovirus meningitis with respiratory failure. Long-term enrollment with follow-up evaluation of these NODM patients up to 3 years will help evaluate the NODM incidence rates and exact graft survival and overall survival rates of CsA-treated transplant patients in Taiwan.     

Incidence and risk factors for the metabolic syndrome and posttransplant diabetes in renal transplant recipients taking tacrolimus

Objectives

We investigated the incidence and risk factors for the metabolic syndrome (MS) and posttransplant diabetes mellitus (PTDM) among renal transplant recipients on tacrolimus-based immunosuppressive regimens during the first year posttransplant. In addition, we studied the relationship between MS and PTDM with transplant renal function at 1 year.

Methods

We included the 100 patients who received a renal transplant in our unit between January 2007 and June 2008, collecting demographic, clinical and biochemical characteristics at 1, 6, and 12 months posttransplantation. We excluded 15% of patients with pretransplantation diabetes. MS was defined according to the National Cholesterol Education Program criteria and PTDM according to World Health Organization criteria. Insulin resistance at one year posttransplant was measured using the homeostasis model assessment (HOMA) index.

Results

Insulin therapy was required in 46% of patients during the first hospitalization and hyperglycemia was present in 65% of the cases. The incidence of PTDM decreased throughout the first year posttransplant, namely, 44%, 24%, and 13% at 1, 6, and 12 months, respectively. The incidence of MS increased to 33%, 48% and 50% at 1, 6, and 12 months, respectively. Age, body mass index, plasma fasting glucose levels at 1 month posttransplant, and pretransplant fasting triglyceridemia predicted PTDM. Rejection and in-patient hyperglycemia predicted MS. PTDM and MS were closely correlated (P = .004). The HOMA index was higher among patients with MS than other subjects at 1 year posttransplant: 3.2 (1.2) versus 2.3 (0.9; P = .035). Neither PTDM nor MS was associated with impaired plasma creatinine levels at 1 year after kidney transplantation.

Conclusion

There was an high incidence of PTDM and MS among kidney transplant recipients treated with tacrolimus as the main immunosuppressive agent. The HOMA index was a good test of insulin resistance in this population. Screening and treatment of risk factors may avoid the development of these entities, which are related to poor cardiovascular outcomes.     

New onset hyperglycemia and diabetes are associated with increased cardiovascular risk after kidney transplantation

BACKGROUND: Post-transplant diabetes (PTDM) is a common and serious complication of kidney transplantation. The implications of developing hyperglycemia of lesser severity are not well understood. METHODS: In this study we used American Diabetes Association (ADA) criteria to assess the incidence of abnormal glycemia post-transplant, the variables that relate to this complication, and the relationship between hyperglycemia and cardiovascular (CV) disease. Included in the study were 490 kidney recipients, transplanted from 1998 to 2003, without a history of diabetes, and with a pretransplant fasting glucose <126 mg/dL. RESULTS: Within one week post-transplant, 45% of recipients had impaired fasting glycemia (IFG, glucose 100-125 mg/dL), and 21% PTDM (glucose > or =126). One year post-transplant, 33% of patients had IFG, and 13% PTDM. Risk factors for hyperglycemia at one year included: older recipient, male gender, higher BMI, higher pretransplant glucose, and higher glucose one week post-transplant (all P < 0.002 by multivariable analyses). During a follow-up period of 40 +/- 14 months, 12% of recipients had CV events (cardiac, CVA, and/or peripheral). Increasing fasting glucose levels at one, four, and/or 12 months post-transplant were significantly related to CV events. Furthermore, these relationships were independent of other CV risk factors, including: older age, CV events pretransplant, male gender, dyslipidemia, and transplant year. Fasting glucose levels >100 mg/dL were associated with higher incidence of post-transplant cardiac (P= 0.001) and peripheral vascular disease events (P= 0.003). CONCLUSION: The incidence of post-transplant hyperglycemia and its CV impact have been underestimated. Pretransplant characteristics and, particularly, the glycemia during the first month post-transplant identified patients at risk of PTDM. Increasing glucose levels greater than 100 mg/dL, any time after the first month post-transplant, are associated with increasing CV risk. We postulate that aggressive detection and treatment of post-transplant hyperglycemia may significantly reduce CV morbidity and mortality after kidney transplantation.     

New Onset Diabetes Mellitus in Patients Receiving Calcineurin Inhibitors: A Systematic Review and Meta-Analysis

New onset diabetes mellitus (NODM) is a serious complication of transplantation. This meta-analysis evaluates the reported incidence of NODM after solid organ transplantation in patients receiving CNI treatment. Databases from January 1992 to April 2002 were searched. Fifty-six publications providing NODM incidence data were reviewed. Sixteen prospective, randomized comparative studies providing information on incidence of insulin-dependent diabetes mellitus (IDDM) were subjected to meta-analysis. New onset diabetes mellitus was reported in 13.4% of patients after solid organ transplantation, with a higher incidence in patients receiving tacrolimus than cyclosporine (16.6% vs. 9.8%). This trend was observed across renal, liver, heart and lung transplant groups. Meta-analysis of 16 studies included patients receiving either tacrolimus (n=1636) or cyclosporine (n=1407). The incidence of IDDM was significantly higher among tacrolimus-treated patients (10.4% vs. 4.5%, p<0.00001), an effect observed in renal (9.8% vs. 2.7% p<0.00001) and nonrenal (11.1% vs. 6.2%; p<0.003) groups, and among patients receiving equal doses of concomitant medication in both treatment arms (12.0% vs. 3.0%; p<0.00001). The reported incidence of NODM during the past decade was significantly higher among patients receiving tacrolimus than cyclosporine. These data provide a quantitative foundation for studies designed to reduce the rates of NODM following solid organ transplantation.