New-onset Diabetes Mellitus After Transplantation Research Articles

Risk Factors of Chronic Kidney Diseases: A Retrospective, Record based Study from a Tertiary Care Hospital in India

Abstract Background: There is a alarming rise of chronic kidney diseases (CKDs) prevalence globally, which is associated with significant morbidity and mortality. The burden of Chronic Kidney Diseases is rapidly rising in developing countries. The study aimed to assess the major risk factors of CKD in patients of a tertiary hospital. Materials and Methods: Hospital-based, retrospective study was conducted at a hospital, in Mumbai, among CKD patients. Medical records of 500 CKD patients were analysed. Results: The mean age of participants was 53.87 years. Majority of the patients had risk factors for CKD such as hypertension and diabetes. The mean serum creatinine was 4.04 mg/dL. Majority of the cases were in G4 and G5 stages of CKD and 201 patients had undergone kidney transplant. Association between age and transplant was significant. Furthermore, association between developing New Onset Diabetes Mellitus After Transplantation (NODAT) was statistically significant. Conclusion: Major risk factors for CKD were hypertension, diabetes and advancing age. Most of the cases of CKD were diagnosed late. There should be increased awareness about CKD among the population with special emphasis on cases of hypertension and diabetes.

New-Onset Diabetes Mellitus after Kidney Transplantation.

New-Onset Diabetes Mellitus after Transplantation (NODAT) emerges as a prevalent complication post-kidney transplantation, with its incidence influenced by variations in NODAT definitions and follow-up periods. The condition's pathophysiology is marked by impaired insulin sensitivity and β-cell dysfunction. Significant risk factors encompass age, gender, obesity, and genetics, among others, with the use of post-transplant immunosuppressants intensifying the condition. NODAT's significant impact on patient survival and graft durability underscores the need for its prevention, early detection, and treatment. This review addresses the complexities of managing NODAT, including the challenges posed by various immunosuppressive regimens crucial for transplant success yet harmful to glucose metabolism. It discusses management strategies involving adjustments in immunosuppressive protocols, lifestyle modifications, and pharmacological interventions to minimize diabetes risk while maintaining transplant longevity. The importance of early detection and proactive, personalized intervention strategies to modify NODAT's trajectory is also emphasized, advocating for a shift towards more anticipatory post-transplant care.

PD31-11 MYOSTEATOSIS AS A NOVEL PREDICTOR OF NEW-ONSET DIABETES MELLITUS AFTER KIDNEY TRANSPLANTATION

You have accessJournal of UrologyCME1 Apr 2023PD31-11 MYOSTEATOSIS AS A NOVEL PREDICTOR OF NEW-ONSET DIABETES MELLITUS AFTER KIDNEY TRANSPLANTATION Takahito Wakamiya, Shimpei Yamashita, Kazuro Kikkawa, Yasuo Kohjimoto, and Isao Hara Takahito WakamiyaTakahito Wakamiya More articles by this author , Shimpei YamashitaShimpei Yamashita More articles by this author , Kazuro KikkawaKazuro Kikkawa More articles by this author , Yasuo KohjimotoYasuo Kohjimoto More articles by this author , and Isao HaraIsao Hara More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003324.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: No reports have shown an association between myosteatosis, the decline in the quality of skeletal muscle due to increased fat infiltration, and new-onset diabetes mellitus after transplantation (NODAT). We examine whether myosteatosis is a predictor of NODAT. METHODS: The study included 334 patients who underwent renal transplantation between January 2006 and March 2021. We excluded 27 patients younger than 18 years, 85 patients with diabetic nephropathy, history of diabetes, or diabetic type diagnosed by preoperative oral glucose tolerance test, 3 patients with early renal function loss, and finally, 219 patients were examined. Presurgical non-contrast CT images were used to evaluate sarcopenia and myosteatosis. To evaluate sarcopenia, the psoas muscle index (PMI) in cm2/m2 was calculated by normalizing the total area of the psoas muscle at level L3 by the square of the patient’s height. To evaluate myosteatosis, the average total psoas density (ATPD) in HU was also calculated as an average of the entire left and right psoas muscle density. We investigated whether preoperative skeletal muscle depletion including sarcopenia and myosteatosis is a new risk factor in addition to the previously reported risk factors for NODAT. RESULTS: Median recipient age and BMI were 45 years and 21.1 kg/m2, respectively, and 123 patients (56%) were male. The most common primary disease was chronic glomerulonephritis in 96 patients (43.8%), followed by IgA nephropathy in 40 patients (18.3%) and polycystic kidney disease in 16 patients (7.3%). Preoperative impaired glucose tolerance (IGT) was present in 58 patients (27%) and NODAT in 30 patients (14%), with median PMI and ATPD of 6 cm2/m2 and 41 HU, respectively. In univariate analysis of factors predicting NODAT, recipient age≥45 years (p<0.01), BMI≥25 kg/m2 (p<0.01), with IGT (p<0.01), ATPD<41.9HU (p=0.01); in multivariate analysis, BMI≥25 kg/m2 (p<0.01), with IGT (p<0.01) and ATPD<41.9 HU (p=0.03) were significant risk factors, respectively (Table 1). The incidence rates of NODAT were 3.7% with no risk factor, 10% with one risk factor, 33% with two risk factors, and 60% with three risk factors, respectively. The model effectively stratified patients with NODAT according to the number of risk factors (p<0.01). CONCLUSIONS: Myosteatosis is a new risk factor predicting NODAT. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e905 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Takahito Wakamiya More articles by this author Shimpei Yamashita More articles by this author Kazuro Kikkawa More articles by this author Yasuo Kohjimoto More articles by this author Isao Hara More articles by this author Expand All Advertisement PDF downloadLoading ...

Incidence and Risk Factors for the Development of New-Onset Diabetes after Kidney Transplantation

Abstract Objective New-onset diabetes mellitus after transplantation (NODAT), also known as posttransplant diabetes mellitus, is a common complication after kidney transplantation. It is associated with an increased risk of graft failure and death. Therefore, minimizing the risk of NODAT is a priority after kidney transplantation. This study aimed to determine the incidence of NODAT, the risk factors for its development, and the therapeutic drugs used for its management. Patients and Methods This is an observational, retrospective study on kidney recipients who were followed up in our center in 2021. After excluding known diabetic patients, second transplant patients, and those with follow-up periods less than 6 months, 308 recipients were included in the study. Demographic, clinical, and laboratory data were collected from the patient records. The patients were categorized as diabetic or nondiabetic. Results All patients' mean age was 35.9±11.6 years (standard deviation). The male-to-female ratio was 2.13:1. The overall incidence of NODAT was 38.3%. The median time to NODAT diagnosis was 6 months. Patients older than 40 were more likely to develop NODAT (61.1%; p = 0.000). The prevalence of pretransplant body mass index (BMI) more than 25 was significantly higher (67.6%) in diabetic than among nondiabetic patients (p = 0.000). NODAT patients were more likely to have had a rejection episode (65 vs. 35% in nondiabetic patients; p = 0.011). A high trough level of calcineurin inhibitors carried a significant risk of NODAT development. Tacrolimus trough level more than or equal to 10 ng/mL had an odds ratio of 57.9 (95% confidence interval [CI] 7.689–1262.2; p = 0.0007) for the development of NODAT. Likewise, a cyclosporine-A trough level more than or equal to 150 ng/mL had an odds ratio of 100.7 (95% CI: 7.31–4293.5; p = 0.0028). Conclusion NODAT incidence was high in this study. Older age, high BMI, prior rejection episode, steroid dose, and high calcineurin inhibitors trough levels were significant risk factors for developing NODAT.

Genetic polymorphisms of glucocorticoid receptor and their association with new-onset diabetes mellitus in kidney transplant recipients

IntroductionThe variability in developing New-onset Diabetes Mellitus After Transplantation (NODAT), together with previously well-established interindividual variation in glucocorticoid sensitivity, led us to hypothesize that polymorphisms in the NR3C1 gene encoding glucocorticoid receptor may alter glucose balance in kidney transplant recipients. This study aimed to evaluate the association of three functional polymorphisms, BclI, N363S, and ER22/23EK, on the NR3C1 gene with NODAT in kidney allograft recipients. MethodsFrom Jun 2020 to July 2022 in Shiraz, 52 patients with NODAT (case group) and 52 non-diabetic kidney transplant recipients (control group) were randomly screened and recruited in this case-control study. The PCR-RFLP technique determined the genotypes of BclI, N363S, and ER22/23EK polymorphisms. ResultsThe allelic frequencies of the mutant alleles of BclI, N363S, and ER22/23EK polymorphisms in all patients were 0.36, 0.03, and 0.009, respectively. BclI mutant genotypes (CG and GG) were significantly associated with an increased risk of NODAT (P = 0.016), while the two other polymorphisms disclosed no significant association with NODAT development. In the case group, no significant association was detected between the onset time of NODAT and studied polymorphisms, including BclI (P = 0.43), N363S (P = 0.30), and ER22/23EK. P value was not reported for the last polymorphism because all patients with NODAT had the wild-type genotype (GG/GG) and performing statistical analysis was not feasible. Among studied demographic/clinical/paraclinical variables, factors such as higher mean trough level of tacrolimus during the first month after transplantation and higher mean daily dose of prednisolone significantly linked with NODAT development. ConclusionOur data suggested that BclI polymorphism significantly affects NODAT development among Iranian kidney allograft recipients.

P8.125: Anti-thymocyte Globulin Versus Basiliximab Induction For Kidney Transplantation in Elderly Patients: Matched Analysis With Korean Multicentric Registry

Introduction: Basiliximab (BSX) and anti-thymocyte globulins (ATG), are two major immunosuppressive agents commonly used as induction therapy for kidney transplant (KT) recipients. The superiority of ATG over BSX has not been well established especially in elderly KT recipients with low immunological risk. Method: A total of 847 elderly (≥60 years) low-risk KT patients in the Korean Organ Transplantation Registry were matched with 2:1 propensity scores and compared according to the ATG and BSX induction therapy. The primary outcome was patient and graft survival. The secondary outcome was biopsy-proven rejection, graft function, BK virus nephropathy, infection, cancer, new-onset diabetes mellitus after transplantation (NODAT), and delayed graft function. Results: 165 patients in the ATG group were matched to 298 patients in the BSX group with an average age of 64.3 and 64.2 years, respectively. During 28.5 ± 10.4 months of mean follow up the cumulative probability of death censored graft failure at 3-year posttransplantation were 1.3% and 1.4% in ATG and BSX group without significant difference (p = 0.720). Cumulative probability of NODAT at 3-year posttransplantation was significantly higher in BSX group (35.6% versus 21.6%, p = 0.021). Median Tacrolimus trough level was significantly lower in 6 months after kidney transplantation in the ATG group (5.7 ng/mL versus 6.4 ng/mL, p = 0.001). There was no difference in other evaluated outcomes. Conclusion: Compared to BSX, in elderly low-risk KT, ATG reduced Tacrolimus and steroid requirements without all-cause mortality, rejection, infection difference. Resulting in reduced NODAT incidence.

Antithymocyte globulin versus basiliximab induction for kidney transplantation in elderly patients: matched analysis within the Korean multicentric registry.

BackgroundBasiliximab (BSX) and antithymocyte globulins (ATGs), are two major immunosuppressive agents commonly used as induction therapy for kidney transplant (KT) recipients. The superiority of ATG over BSX has not been well established, especially in elderly KT recipients with low immunological risk.MethodsA total of 847 elderly (≥60 years old), low-risk KT patients in the Korean Organ Transplantation Registry were propensity score-matched at a 1:2 ratio and compared according to ATG or BSX induction therapy. The primary outcome was patient and graft survival and biopsy-proven acute cellular rejection. The secondary outcome was graft function, BK virus nephropathy, infection, cancer, new-onset diabetes mellitus after transplantation (NODAT), and delayed graft function.ResultsIn total, 165 patients in the ATG group were matched with 298 patients in the BSX group with average ages of 64.3 and 64.2 years, respectively. During a follow-up of 28.5 ± 10.4 months, the cumulative probabilities of death-censored graft failure at 3 years posttransplantation were 1.3% and 1.4% in ATG and BSX groups, respectively, without a significant difference (p = 0.72). The cumulative probability of NODAT at 3 years posttransplantation was significantly higher in the BSX group (35.6% vs. 21.6%, p = 0.02). The median tacrolimus trough level was significantly lower at 6 months after KT in the ATG group (5.7 ng/mL vs. 6.4 ng/mL, p = 0.001). There were no differences in the other evaluated outcomes.ConclusionCompared with BSX, in elderly, low-risk KT patients, ATG reduced tacrolimus and steroid requirements without differences in all-cause mortality, rejection, or infection, resulting in a reduced NODAT incidence.

Post-transplant Diabetes Mellitus: What Physicians Need to Know.

Post-transplant diabetes mellitus (PTDM) is a common problem among solid organ transplant recipients contributing to morbidity and affecting patient as well as graft survival adversely. It can occur at any period following transplantation, but maximum incidence is observed in the first few months, with a second peak after a few years after transplantation. The pathogenesis is complex and poorly understood, however, it is associated with both dysfunctional beta-cells and insulin resistance. Both nonpharmacologic and antidiabetic therapies are important for adequate glycemic control. This point of view article provides a short review on PTDM in solid organ transplantation (SOT) recipients from a general physician's perspective.

IL-17 gene polymorphism (rs763780) in kidney recipients with post-transplant diabetes

Introduction: New-onset diabetes mellitus after transplantation (NODAT) is a common complication of organ transplantation, leading to allograft dysfunction. Genetic alterations of inflammatory cytokines have been reported to be associated with glucose homeostasis and diabetes. Objectives: This study evaluated the rs763780 polymorphism of IL-17F gene in transplant recipients with and without NODAT. Patients and Methods: The present retrospective study was conducted on ninety-one patients who have had a kidney transplant for at least three months. Patients were divided into two subgroups; recipients with NODAT (n=32) and kidney recipients without NODAT (n=59). After DNA extraction from patients’ blood samples, amplification and evaluation of specific polymorphism of the gene were performed using amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Clinical and demographic data of patients were collected. Results: The NODAT was detected in 81.3% (n=26) of TT genotype carriers, 12.5% of TC genotype carriers and 6.3% of CC genotype carriers. No statistically significant differences between the studied groups in the frequency of C and T alleles and the distribution of the abovementioned genotypes were detected (P≥0.721). In the NODAT group, graft rejection and age of patients were higher significantly (P≤0.017). Conclusion: No significant correlation between the incidence of diabetes and rs763780 polymorphism of IL-17F gene was observed.

Risk Factors for New-Onset Diabetes Mellitus After Heart Transplantation: A Nomogram Approach

New-onset diabetes mellitus after transplantation (NODAT) is a leading cause of morbidity and mortality after heart transplantation (HT), which still remains a clinical challenge. In this study, 522,708 follow-up records of HT were reviewed. After screening, 14,452 patients were analyzed when combined with immunosuppression records. We divided all patients into no-NODAT group, NODAT group, and preexisting diabetes group based on whether the patient had diabetes and the time when it occurred. Cox regression models were used to examine independent risk factors. A nomogram was established to predict the incidence of NODAT after HT. The machine learning method were used to confirm the prediction accuracy and reliability of the nomogram. Patients who experienced NODAT after HT had poor survival compared with those without NODAT. Tacrolimus, cyclosporine A (CsA), rapamycin, donor age, and recipient age at the time of transplant were significant predictors of NODAT. Tacrolimus had a more significant association with NODAT, followed by rapamycin and CsA. The nomogram method we adopted in this study had an accuracy of 63% in predicting the incidence of NODAT. The survival probability of HT recipients with NODAT showed a significant decreasing tendency. However, there was no difference in survival probability between patients with preexisting diabetes and patients with NODAT. Tacrolimus had a more significant association with NODAT than CsA and rapamycin.

Efficacy and Safety of Tacrolimus-Based Maintenance Regimens in De Novo Kidney Transplant Recipients: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

BackgroundTacrolimus is an established component of immunosuppressive regimens for kidney transplant recipients (KTRs); however, data comparing long-term outcomes between formulations are lacking. We conducted a systematic literature review and network meta-analysis assessing tacrolimus (primarily Advagraf [once-daily] and Prograf [twice-daily])-based maintenance regimens.Material/MethodsEmbase, MEDLINE, and Cochrane databases and congress proceedings were searched to identify studies of adult de novo KTRs who received tacrolimus-based therapy in phase II/III randomized controlled trials. Outcomes were acute rejection, graft/patient survival, and incidence of new-onset diabetes mellitus after transplantation (NODAT) and cytomegalovirus (CMV) infection. Bayesian network meta-analysis was used to analyze treatment effects on graft/patient survival.ResultsSixty-eight publications (61 primary) were included. Of 21 publications reporting graft rejection following Advagraf or Prograf treatment in ≥1 study arm, 12-month biopsy-proven acute rejection (BPAR) ranged from 3.3% with Prograf to 55.0% with mycophenolic acid (MPA)+corticosteroids (CS); >24 month BPAR ranged from 0% to 58.7% (the latter with bleselumab-based therapy). Fourteen publications reported graft loss following Advagraf (0–9.6%) or Prograf (0–7.5%). Patient mortality ≤24 months after transplantation (14 publications) ranged from 0% to 8.1% with Advagraf or Prograf. Advagraf+MPA+CS and reference treatment, Prograf+MPA+CS, were associated with a similar risk of graft loss (odds ratio 1.19; 95% credible-interval 0.51, 3.06) and mortality (odds ratio 1.21; 95% credible-interval 0.1557, 9.03). Incidence of NODAT and CMV varied by treatment arm.ConclusionsGraft loss and patient mortality rates were generally comparable between Advagraf- and Prograf-based regimens. Further prospective studies are needed to evaluate longer-term outcomes.

Pharmacogenetics Based Dose Prediction Model for Initial Tacrolimus Dosing in Renal Transplant Recipients.

Tacrolimus, an immunosuppressant used in solid organ transplantation, has a narrow therapeutic index and exhibits inter-individual pharmacokinetic variability. Achieving and maintaining a therapeutic level of the drug by giving appropriate doses is crucial for successful immunosuppression, especially during the initial post-transplant period. We studied the effect of CYP3A5, CYP3A4, and ABCB1 gene polymorphisms on tacrolimus trough concentrations in South Indian renal transplant recipients from Kerala to formulate a genotype-based dosing equation to calculate the required starting daily dose of tacrolimus to be given to each patient to attain optimal initial post-transplant period drug level. We also investigated the effect of these genes on drug-induced adverse effects and rejection episodes and looked into the global distribution of allele frequencies of these polymorphisms. One hundred forty-five renal transplant recipients on a triple immunosuppressive regimen of tacrolimus, mycophenolate mofetil, and steroid were included in this study. Clinical data including tacrolimus daily doses, trough levels (C0) and dose-adjusted tacrolimus trough concentration (C0/D) in blood at three time points (day 6, 6 months, and 1-year post-transplantation), adverse drug effects, rejection episodes, serum creatinine levels, etc., were recorded. The patients were genotyped for CYP3A5*3, CYP3A4*1B, CYP3A4*1G, ABCB1 G2677T, and ABCB1 C3435T polymorphisms by the PCR-RFLP method. We found that CYP3A5*3 polymorphism was the single most strongly associated factor determining the tacrolimus C0/D in blood at all three time points (p < 0.001). Using multiple linear regression, we formulated a simple and easy to compute equation that will help the clinician calculate the starting tacrolimus dose per kg body weight to be administered to a patient to attain optimal initial post-transplant period tacrolimus level. CYP3A5 expressors had an increased chance of rejection than non-expressors (p = 0.028), while non-expressors had an increased risk for new-onset diabetes mellitus after transplantation (NODAT) than expressors (p = 0.018). Genotype-guided initial tacrolimus dosing would help transplant recipients achieve optimal initial post-transplant period tacrolimus levels and thus prevent the adverse effects due to overdose and rejection due to inadequate dose. We observed inter-population differences in allele frequencies of drug metabolizer and transporter genes, emphasizing the importance of formulating population-specific dose prediction models to draw results of clinical relevance.

New-Onset Diabetes after Kidney Transplantation.

New-onset diabetes mellitus after transplantation (NODAT) is a frequent complication in kidney allograft recipients. It may be caused by modifiable and non-modifiable factors. The non-modifiable factors are the same that may lead to the development of type 2 diabetes in the general population, whilst the modifiable factors include peri-operative stress, hepatitis C or cytomegalovirus infection, vitamin D deficiency, hypomagnesemia, and immunosuppressive medications such as glucocorticoids, calcineurin inhibitors (tacrolimus more than cyclosporine), and mTOR inhibitors. The most worrying complication of NODAT are major adverse cardiovascular events which represent a leading cause of morbidity and mortality in transplanted patients. However, NODAT may also result in progressive diabetic kidney disease and is frequently associated with microvascular complications, eventually determining blindness or amputation. Preventive measures for NODAT include a careful assessment of glucose tolerance before transplantation, loss of over-weight, lifestyle modification, reduced caloric intake, and physical exercise. Concomitant measures include aggressive control of systemic blood pressure and lipids levels to reduce the risk of cardiovascular events. Hypomagnesemia and low levels of vitamin D should be corrected. Immunosuppressive strategies limiting the use of diabetogenic drugs are encouraged. Many hypoglycemic drugs are available and may be used in combination with metformin in difficult cases. In patients requiring insulin treatment, the dose and type of insulin should be decided on an individual basis as insulin requirements depend on the patient’s diet, amount of exercise, and renal function.

Clinical and genetic risk factors for new-onset diabetes mellitus after transplantation (NODAT) in major transplant centres in Malaysia

BackgroundNew-onset diabetes after transplantation (NODAT) is associated with reduced patient and graft survival. This study examined the clinical and selected genetic factors associated with NODAT among renal-transplanted Malaysian patients.MethodsThis study included 168 non-diabetic patients (58% males, 69% of Chinese ethnicity) who received renal transplantation between 1st January 1994 to 31st December 2014, and were followed up in two major renal transplant centres in Malaysia. Fasting blood glucose levels were used to diagnose NODAT in patients who received renal transplantation within 1 year. Two single nucleotide polymorphisms (SNPs), namely; rs1494558 (interleukin-7 receptor, IL-7R) and rs2232365 (mannose-binding leptin-2, MBL2) were selected and genotyped using Sequenom MassArray platform. Cox proportional hazard regression analyses were used to examine the risk of developing NODAT according to the different demographics and clinical covariates, utilizing four time-points (one-month, three-months, six-months, one-year) post-transplant.ResultsSeventeen per cent of patients (n = 29, 55% males, 69% Chinese) were found to have developed NODAT within one-year of renal transplantation based on their fasting blood glucose levels. NODAT patients had renal transplantation at an older age compared to non-NODAT (39.3 ± 13.4 vs 33.9 ± 11.8 years, p = 0.03). In multivariate analysis, renal-transplanted patients who received a higher daily dose of cyclosporine (mg) were associated with increased risk of NODAT (Hazard ratio (HR) =1.01 per mg increase in dose, 95% confidence interval (CI) 1.00–1.01, p = 0.002). Other demographic (gender, ethnicities, age at transplant) and clinical factors (primary kidney disease, type of donor, place of transplant, type of calcineurin inhibitors, duration of dialysis pre-transplant, BMI, creatinine levels, and daily doses of tacrolimus and prednisolone) were not found to be significantly associated with risk of NODAT. GA genotype of rs1494558 (HR = 3.15 95% CI 1.26, 7.86) and AG genotype of rs2232365 (HR = 2.57 95% CI 1.07, 6.18) were associated with increased risk of NODAT as compared to AA genotypes.ConclusionThe daily dose of cyclosporine and SNPs of IL-7R (rs1494558) and MBL2 (rs2232365) genes are significantly associated with the development of NODAT in the Malaysian renal transplant population.

SUN-312 INSIGHTS INTO THE ASSOCIATION OF CYP3A AND ABCB1 POLYMORPHISMS WITH TACROLIMUS-RELATED ADVERSE EFFECTS – VENTURING BEYOND THE CONVENTIONAL SNP-TAC LEVEL RELATIONSHIP

Tacrolimus (Tac), an immunosuppressant used in organ transplant recipients, exhibits an interindividual pharmacokinetic variability that affects the dose required to reach the target concentration in blood. Tac requires therapeutic monitoring of blood concentrations to prevent graft rejection owing to inadequate immunosuppression with low drug levels or toxicity due to high drug levels. Tac is metabolized by two enzymes of the cytochrome P450 family, CYP3A5 and CYP3A4, in the gut and liver, and transported in the gut by P-glycoprotein (P-gp), encoded by the MDR1/ABCB1 gene. The objective of the study is to investigate the association of CYP3A5, CYP3A4 and ABCB1 gene polymorphisms and their interactions with dose-adjusted Tac trough concentration in blood and drug-induced adverse effects in South Indian renal transplant recipients. Renal transplant recipients receiving Tac as an immunosuppressant were recruited from Government Medical College, Thiruvananthapuram, Kerala, India. Tac trough concentrations(C0), dose-adjusted Tac trough concentration(C0/D), doses, concomitant medications, drug adverse effects, etc. were recorded. DNA was isolated from blood collected from patients. SNP genotyping was performed using the PCR-RFLP method. Allele, genotype frequencies and linkage disequilibrium were calculated using UNPHASED software, v3.1.7. Comparison of C0/D to genotypes by one-way Anova and linear regression, box-plot analysis and multiple regression analysis to assess the effect of gene-gene interactions were performed using SPSS v20.0. The global variation in distribution of the polymorphisms was analyzed by comparing their allelic frequencies with existing world population data. CYP3A5*3 G (*3/*3) and CYP3A4*1G GG (wt/wt) genotypes were found to be strongly associated with higher Tac C0/D on post-operative day 6. CYP3A4*1B AA also showed a significant association with higher Tac C0/D. A combination of CYP3A5*3 GG and ABCB1 3435 CC genotypes could effectively predict a higher Tac C0/D in blood. We found that CYP3A5 AND CYP3A4 non-expressers had an increased chance of developing new-onset diabetes mellitus after transplantation (NODAT) compared to expressers. Carriers of at least one copy of ABCB1 G2677T Allele G were found to be at a higher risk of developing Tac toxicity. Allele frequencies of these gene polymorphisms in our population were found to be considerably different compared to other world populations. This is the first in-depth study including various functional polymorphisms and epistatic interactions between different genes to develop a robust prognostic and predictive pharmacogenomic biomarker with clinical applicability, which can predict individuals’ response to Tac. Our data will help identify patients who might have higher/lower Tac levels based on their genotype, and those at high risk of developing Tac-related complications can be identified before their organ transplant which can help the clinician decide the initial dosage of Tac. This tailor-made therapy could minimize adverse effects due to over-dosage and graft rejection due to low drug levels. Our findings on inter-ethnic differences in allele frequencies of drug metabolizer and transporter genes underscore the need to consider population-specific genetic backgrounds when conducting pharmacogenetic analyses and clinical trials.

Organized Management of Diabetes Mellitus in Lung Transplantation: Study of Glycemic Control and Patient Survival in a Single Center

ObjectiveTo study patient survival and glycemic control before and after lung transplantation (LTx) according to the diabetes status in patients submitted to an organized management of diabetes mellitus (DM) at the Strasbourg University Hospital, France. Material and MethodsTwo hundred and sixty-seven LTx recipients were included retrospectively and analyzed according to diabetes status: pretransplant diabetes, new-onset diabetes mellitus after transplant (NODAT) or no diabetes. Organized DM management was coordinated by a diabetologist trained in DM management before and after transplantation and included pretransplant screening, a close monitoring of glycemia after transplant and optimized treatment before and after LTx. ResultsDM was well-controlled after transplantation: mean glycosylated hemoglobin and fasting blood glucose levels after LTx were 5.8 ± 0.2% and 5.4 ± 0.1 mmol/L respectively, in pretransplant DM patients and 5.7 ± 0.1% and 5.6 ± 0.2 mmol/L respectively, in NODAT patients. The overall median survival time was 8.3 ± 1.9 years. Pretransplant DM increased the risk of mortality (1.82-fold increase; 95% confidence interval, 1.08-3.06; P = .02) in LTx recipients. ConclusionsOrganized management of diabetes achieved very satisfactory glycemic control in both pretransplant DM and NODAT patients. However, no specific protocols have been created for managing DM following LTx. As DM continues to become an increasing comorbidity in LTx, there exist a significant need of studies in this area.

Comparison of Glucose Tolerance between Kidney Transplant Recipients and Healthy Controls.

Post-transplant hyperglycemia and new-onset diabetes mellitus after transplantation (NODAT) are common and important metabolic complications. Decreased insulin secretion and increased insulin resistance are important to the pathophysiologic mechanism behind NODAT. However, the progression of glucose intolerance diagnosed late after kidney transplantation remains clearly unknown. Enrolled in this study were 94 kidney transplant recipients and 134 kidney transplant donors, as the healthy controls, who were treated at our institution. The 75 g-oral glucose tolerance test (OGTT) was performed in the recipients, and the healthy controls received an OGTT before donor nephrectomy. We assessed the prevalence of glucose intolerance including impaired fasting glucose and/or impaired glucose tolerance, as well as insulin secretion and insulin resistance using the homeostasis model assessment, and compared the results between the two groups. Multivariate analysis after adjustment for age, gender, body mass index, estimated glomerular filtration rate, and systolic blood pressure showed that the prevalence of glucose intolerance, insulin resistance, insulin secretion, and 2 h plasma glucose levels were significantly higher in the kidney transplant recipients compared to the healthy controls. Elevation of insulin secretion in kidney transplant recipients may be compensatory for increase of insulin resistance. Impaired compensatory pancreas β cell function may lead to glucose intolerance and NODAT in the future.

Genetic immune and inflammatory markers associated with diabetes in solid organ transplant recipients.

New-onset diabetes mellitus after transplantation (NODAT) is a complication following solid organ transplantation (SOT) and may be related to immune or inflammatory responses. We investigated whether single nucleotide polymorphisms (SNPs) within 158 immune- or inflammation-related genes contribute to NODAT in SOT recipients. The association between 263 SNPs and NODAT was investigated in a discovery sample of SOT recipients from the Swiss Transplant Cohort Study (STCS, n1 =696). Positive results were tested in a first STCS replication sample (n2 =489) and SNPs remaining significant after multiple test corrections were tested in a second SOT replication sample (n3 =156). Associations with diabetic traits were further tested in several large general population-based samples (n>480000). Only SP110 rs2114592C>T remained associated with NODAT in the STCS replication sample. Carriers of rs2114592-TT had 9.9 times (95% confidence interval [CI]: 3.22-30.5, P=.00006) higher risk for NODAT in the combined STCS samples (n=1184). rs2114592C>T was further associated with NODAT in the second SOT sample (odds ratio: 4.8, 95% CI: 1.55-14.6, P=.006). On the other hand, SP110 rs2114592C>T was not associated with diabetic traits in population-based samples, suggesting a specific gene-environment interaction, possibly due to the use of specific medications (ie, immunosuppressants) in transplant patients and/or to the illness that may unmask the gene effect.

New Onset Diabetes Mellitus after Transplantation (NODAT)-An Analysis of Incidence, Risk Factors and its Effects on Renal Allograft

Aim: New Onset Diabetes after Transplantation (NODAT) is one of the medical complications after kidney transplantation which affects adversely the allograft kidney and patient outcomes. The aim of this study was to know the incidence of development of NODAT, investigate risk factors and its effects on allograft kidney in our centre.Material and methods: This is a retrospective observational study of the patients who underwent the kidney transplant at the Narayana Medical College & Hospital from June 2009 to May 2016. Patients were divided into NODAT and non NODAT groups.Results: 21 out of 84 patients (25%) developed NODAT during the follow up period of 1st year post transplantation. We found age >30 years (OR: 3.8; P=0.012), family history of diabetes (OR: 8.6; P=0.0004), impaired fasting glucose (OR: 7.27; P=0.0003), postoperative hyperglycaemia (OR: 2.83; P=0.04), fasting triglycerides >150 mg/dl. (OR: 8.0 P=0.0001) and VLDL levels (42.52 ± 30.81 mg/dl. vs. 24.24 ± 5.51 mg/dl; P= 0.01) were risk factors for NODAT. Mean serum creatinine values were 1.23 ± 0.25 mg/dl vs.1.16 ± 0.35mg/dl (P= 0.42) and 1.61 ± 0.53 mg/dl vs. 1.44 ± 0.54 mg/dl (P= 0.24) at the end of 1st month and 1st year post-transplantation in NODAT and non NODAT groups respectively.Conclusion: The cumulative incidence of NODAT was 25% by the end of the1st post-transplantation year. Increasing age, family history of diabetes, dyslipidemia, pre-transplantation impaired fasting glucose and postoperative hyperglycaemia were considered as risk factors, some of which can be quite modifiable.

Incidence and associated risk factors of new-onset diabetes mellitus after transplantation in renal transplant recipients: A retrospective single-center study in Nepal

Introduction: New-onset diabetes mellitus after transplantation (NODAT) is a major complication of renal transplantation, with a prevalence rate ranging from 2% to 53% across the globe. There is no information about the prevalence of NODAT in the Nepalese population. This paper describes the demographics, clinical characteristics, and risk factors associated with the development of NODAT in renal transplant patients from Bir Hospital, Nepal. Materials and Methods: Data were retrospectively collected for 110 patients that underwent renal transplantation at Bir Hospital from December 2008 to 2015. Patients who had diabetes before undergoing the transplant and those who did not have a 6-month follow-up posttransplant were dropped from the analysis, thus leaving 97 patients for analysis. Results: The incidence rate of NODAT among all patients analyzed was 22.68/100 people. Increasing age and body weight were not found to be associated with the increased incidence of NODAT. Mother-to-offspring transplants had a higher risk of NODAT presentation in the recipient. The study did not show any association between trough levels of tacrolimus and the risk of NODAT. Conclusion: New-onset Diabetes mellitus after transplantation is a major complication in patients with renal transplants and can also increase risk for cardiovascular complications. Longitudinal studies with larger sample and longer follow-up durations are required to understand the prevalence and risk factors as well as management of NODAL in the Nepalese population Discussion: Longitudinal studies with longer follow-up and rigorous data collection are required to better quantify the burden of NODAT on renal transplant patients and address these complications wisely.