Development Of New-onset Diabetes Mellitus After Transplantation Research Articles

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.

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.

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.

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.

Effect of Smoking on Development of New Onset Diabetes Mellitus after Transplantation (NODAT) of Kidney

Abstract Purpose: Cigarette smoking has adverse effects on kidney transplant recipients, causing cardiovascular disease, kidney function impairment, and cancer. New onset diabetes mellitus after transplantation (NODAT) represents serious complication of transplantation of solid organs. Methods: In the group of 252 patients after kidney transplantation, we identified smokers and current non-smokers (the patient who has not been smoking or who is ex smoker) for the period of minimum 24 months. In the monitored period of 12 months after transplantation, we detected presence of NODAT in both groups. The group contained only those patients who did not have diabetes mellitus (of type 1 and 2) at the time of kidney transplantation. Results: The group of smokers was composed of 88 patients (34.9 %) and non-smokers 164 patients (65.1 %). The average age of smokers was 52 years ± 12.4, and of current non-smokers it was 44.8 years ± 12.8 (P < 0.0001). The smokers had significantly lower body mass index (BMI) at the time of kidney transplantation (P = 0.0059) and also 12 months after transplantation (P = 0.0069), lower weight gain 12 months after transplantation (P = 0.0220) and larger waist circumference 12 months after transplantation (P < 0.0001). Conclusion: In our group, smoking had no effect on development of NODAT, the smokers had lower values of BMI and waist circumference, however, the guideline development group feels that, as for the general population, success of smoking cessation can be enhanced by offering structured smoking cessation programs.

Risk factors for new-onset diabetes mellitus after living donor kidney transplantation in Korea - a retrospective single center study.

BackgroundNew-onset diabetes mellitus after transplantation (NODAT) is a serious complication following renal transplantation. The aim of this study was to identify the risk factors for the development of NODAT in Korean transplant patients.MethodsRecipients who underwent living donor kidney transplantation between January 2009 and April 2012 at Asan Medical Center were reviewed. Diagnosis of NODAT was defined according to the American Diabetes Association criteria.ResultsA total of 418 patients were enrolled. NODAT was diagnosed in 85 (20.4 %) patients within 1 year. By multivariate analysis, old age (odds ratio [OR], 1.05; 95 % Confidence interval [CI]: 1.01–1.08), family history of diabetes mellitus (OR, 2.48; 95 % CI: 1.04–5.94), pre-transplant high serum glucose level (OR, 1.04; 95 % CI: 1.01–1.08), and obesity (OR, 3.46; 95 % CI: 1.55–7.73) were independent risk factors for NODAT.ConclusionOld age, family history of diabetes, pre-transplant high plasma glucose level, and obesity are independent factors associated with the development of diabetes after renal transplantation. In contrast, serum magnesium levels and the use of tacrolimus are not associated with the development of NODAT.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-016-0321-8) contains supplementary material, which is available to authorized users.

Correlation between CMV Infection and NODAT

Purpose: New-onset diabetes mellitus after transplantation (NODAT) is a well-known complication of transplantation. Materials and methods: Retrospectively, we detected CMV replication (PCR) in every month after transplantation of kidney in the first 12 months after transplantation in patients in a homogenous group from the aspect of immunosuppresion. Results: In the group of 167 patients (control group: n = 103, NODAT group: n = 64), the average value of CMV viremia was without any significant difference between the NODAT group and the control group (P = 0.9285). In the 10th month after kidney transplantation, we recorded significantly higher CMV viremia in the NODAT group (p < 0.0001), however, in the multi variant analysis, that difference was not confirmed. Thus, in our group, CMV is of no relevance with the development of NODAT in the monitored period. The survival of patients and graft was 12 months after kidney transplantation without any statistically significant difference between the monitored groups (P = 0.6113 - survival of the patient; P = 0.5381 – survival of the graft). Conclusion: Our analysis shows that in regular monitoring of CMV viremia and applying chemoprophylaxison the risk recipeints, CMV is not the risk factor for NODAT.

The impact of cytomegalovirus infection on new-onset diabetes mellitus after kidney transplantation: a review on current findings.

Context: New onset diabetes mellitus after transplantation (NODAT) increases the risk of cardiovascular disease, rate of infections, graft rejection and graft loss as well as decreases patient and graft survival rates. There is a controversy surrounding the impact of cytomegalovirus (CMV) infection in the development of NODAT. This meta-analysis aims to identify the role of CMV infection leading to the development of NODAT in kidney recipient patients. Evidence Acquisitions: We searched several electronic databases, including PubMed, Embase, Medline, Scopus, Trip Database and Google Scholar for studies that completely fulfill our criteria between January 1990 and January 2014 Results: Seven studies with 1389 kidney transplant patients were included in this metaanalysis.The mean age of patients ranged from 42.8 to 48.8 years and males made up 53% to 75% of patients in the cohort studies. The incidence of NODAT varies from 14.3% to 27.1% in these studies. Overall adj OR was 1.94 [exp (0.66)] with a 95% CI of 1.26-2.98 [exp (0.23) and (1.09)]. There was no significant publication bias based on the Begg’s and Egger’s test (p value = 0.17 and 0.54, respectively). Conclusions: Our study showed that CMV infection is a risk factor for increasing incidence of NODAT. Thus, prophylaxis against CMV infection after kidney transplantation is strongly suggested. However, further clinical trials and cohorts are needed to confirm this association.

Can New-Onset Diabetes After Kidney Transplant Be Prevented?

Because the negative consequences of new-onset diabetes mellitus after transplantation (NODAT) diminish the significant gains of kidney transplantation, it is imperative to develop clinical interventions to reduce the incidence of NODAT. In this review, we discuss whether intensive lifestyle interventions that delay or prevent type 2 diabetes mellitus may decrease the incidence of NODAT. We examine the literature pertaining to incidence and timing of onset of NODAT, as well as the risk factors and pathophysiology that NODAT shares with type 2 diabetes mellitus, namely pathways related to increased insulin resistance and decreased insulin secretion. Our central hypothesis is that NODAT results from the same metabolic risk factors that underlie type 2 diabetes mellitus. These risk factors are altered and enhanced by transplantation, “tipping” some transplant recipients with seemingly normal glucose homeostasis before transplant toward the development of NODAT. We describe the diabetogenic properties of transplant immunosuppressive drugs. We describe novel methods of prevention that are being explored, including resting the pancreatic β-cells by administration of basal insulin during the period immediately after transplant. On the basis of the current evidence, we propose that intensive lifestyle modification, adapted for individuals with chronic kidney disease or end-stage renal disease, as well as resting pancreatic β-cells during the immediate postoperative period, may lower the incidence of NODAT.

Calcineurin inhibitors acutely improve insulin sensitivity without affecting insulin secretion in healthy human volunteers

New onset diabetes after transplantation is related to treatment with immunosuppressive medications. Clinical studies have shown that risk of new onset diabetes is greater with tacrolimus compared with ciclosporin. The diabetogenicity of ciclosporin and tacrolimus has been attributed to both beta cell dysfunction and impaired insulin sensitivity. This is the first trial to investigate beta cell function and insulin sensitivity using gold standard methodology in healthy human volunteers treated with clinically relevant doses of ciclosporin and tacrolimus. We document that both drugs acutely increase insulin sensitivity, while first phase and pulsatile insulin secretion remain unaffected. This study demonstrates that ciclosporin and tacrolimus have similar acute effects on glucose metabolism in healthy humans. AIM The introduction of calcineurin inhibitors (CNIs) ciclosporin (CsA) and tacrolimus (Tac) has improved the outcome of organ transplants, but complications such as new onset diabetes mellitus after transplantation (NODAT) cause impairment of survival rates. The relative contribution of each CNI to the pathogenesis and development of NODAT remains unclear. We sought to compare the impact of CsA and Tac on glucose metabolism in human subjects. Ten healthy men underwent 5 h infusions of CsA, Tac and saline in a randomized, double-blind, crossover study. During infusion glucose metabolism was investigated using following methods: a hyperinsulinaemic-euglycemic clamp, an intravenous glucose tolerance test (i.v.GTT), glucose-stimulated insulin concentration-time series and indirect calorimetry. Clamp derived insulin sensitivity was increased by 25% during CsA (P < 0.0001) and 13% during Tac administration (P = 0.047), whereas first phase and pulsatile insulin secretion were unaffected. Coinciding with the CNI induced improved insulin sensitivity, glucose oxidation rates increased, while insulin clearance rates decreased, only non-significantly. Tac singularly lowered hsCRP concentrations, otherwise no changes were observed in circulating glucagon, FFA or adiponectin concentrations. Mean blood concentrations of CNIs were 486.9 ± 23.5 µg l(-1) for CsA and 12.8 ± 0.5 µg l(-1) for Tac. Acute effects of i.v. CsA, and to a lesser degree Tac infusions, in healthy volunteers include increased insulin sensitivity, without any effect on first phase or pulsatile insulin secretion.

Elevated Serum Gamma-Glutamyltransferase and Hypomagnesemia Are Not Related With New-Onset Diabetes After Transplantation

Background New-onset diabetes mellitus after transplantation (NODAT) contributes to the risk of cardiovascular disease (CVD) and infection, reducing graft and patient survival in kidney transplant recipients. To reduce CVD and improve outcomes of kidney transplant recipients, it is of great interest to more precisely elucidate the risk factors that contribute to the development of NODAT. A previous study reported that hypomagnesemia is an independent predictor of NODAT. Elevated gamma-glutamyltransferase (GGT) activity increases the risk of incident type 2 diabetes in the general population. The objective of this study was to determine whether magnesium (Mg) and GGT were risk factors for NODAT among our population of kidney transplant recipients. Methods We retrospectively analyzed 205 non-previously diabetic kidney transplant recipients. GGT was measured before transplantation as well as at months 1, 2, and 12. Mg was measured at months 1, 2, and 12. NODAT was defined at month 12 and at the end of follow-up according to the “2003 international consensus guidelines.” Results Although 36 patients (17.5%) developed NODAT at month 12, 55 patients (26.8%) displayed it at the end of follow-up. We did not observe any significant difference, either in mean Mg (month 1, 1.73 ± 0.24 vs 1.75 ± 0.30 [ P = .824]; month 2, 1.71 ± 0.22 vs 1.68 ± 0.26 [ P = .565]; month 12, 1.77 ± 0.27 vs 1.80 ± 0.24 [ P = .596]) or GGT values (pretransplantation, 32 ± 27 vs 33 ± 85 [ P = .866]; month 1:39 ± 24 vs 48 ± 70 [ P = .452]; month 2, 53 ± 96 vs 48 ± 83 [ P = .739]; month 12, 40 ± 37 vs 38 ± 53 [ P = .830]) between NODAT and non-NODAT patients at month 12 or at the end of follow-up. Conclusion Hypomagnesemia and high GGT activity were not risk factors for NODAT development in kidney transplant recipients.

Endothelial nitric oxide synthase gene intron 4 polymorphism predicts new onset diabetes mellitus after transplantation in kidney allograft recipients treated with cyclosporin A

Nitric oxide (NO), synthesized from LS: -arginine by the enzyme endothelial nitric oxide synthase (eNOS), is a potent vasodilator and has been implicated in mediating insulin-induced uptake and metabolism of glucose in skeletal muscle. Polymorphisms of the eNOS gene have been associated with altered eNOS activity and NO levels. Although several factors have been demonstrated for new onset diabetes mellitus after transplantation (NODAT), determining a genetic susceptibility for all patients requires further study. In our study, we evaluated the relationship between eNOS gene intron 4 polymorphism and NODAT in kidney allograft recipients. A total of 82 consecutive patients who received their first kidney transplantation and maintained graft function for at least a 12-month post-transplant period and who used triple therapy including cyclosporin A (CsA) for maintenance immunosuppression were included. PCR-RFLP was used for genetic analyses. Nine of 82 patients (11%) developed NODAT. Concerning the prevalence of eNOS intron 4 gene polymorphism, a significantly higher percentage of 4a allele carriers developed NODAT than non-carriers [6/26 (23.1%) versus 3/56 (5.4%), P = 0.02]. Compared with non-diabetics, NODAT patients were older (P = 0.04), had higher rate of hepatitis C (P < 0.05) and higher body mass index at the time of transplantation (P = 0.03). In regression analyses, having a 4a allele of the eNOS gene intron 4 polymorphism (P = 0.02) and HCV seropositivity (P = 0.03) were found to be independent risk factors for the development of NODAT. These findings suggest that carrying a 4a allele of the eNOS gene intron 4 polymorphism is associated with NODAT. This may help us to further understand the individual risk for development of NODAT in kidney allograft recipients under CsA treatment.

Mammalian Target of Rapamycin and Diabetes: What Does the Current Evidence Tell Us?

New-onset diabetes mellitus after transplantation (NODAT) is a serious complication in organ transplantation; not only does it enhance the risk of graft dysfunction, it also increases cardiovascular morbidity and mortality. The mammalian target of rapamycin (mTOR) is regulated independently by insulin, amino acids, and energy sufficiency. It integrates signal from growth factors, hormones, nutrients, and cellular energy levels to regulate protein translation and cell growth, proliferation, and survival. In addition, mTOR generates an inhibitory feedback loop on insulin receptor substrate (IRS) proteins. Therefore, it was suggested that mTOR might link nutrient excess with both obesity and insulin resistance. In this review, we summarize the role of mTOR and its inhibitor sirolimus (SRL) on chronic hyperglycemia and insulin resistance in β cells, adipose tissue, liver, and muscle. We further hypothesize, based on data from the literature and generated in our laboratory, that SRL could counteract the development of NODAT in stable glucose homeostasis due to its positive effects on insulin-stimulated glucose uptake, whereas in conditions that require an adaptive β cell proliferation (such as pregnancy and weight increase), the administration of SRL might have effects that would promote the development of NODAT. Therefore, it seems crucial for patient outcome to consider these potentially contrasting effects of SRL.

Obesity, Adiponectin and Inflammation as Predictors of New-Onset Diabetes Mellitus After Kidney Transplantation

The high incidence of new-onset diabetes mellitus after transplantation (NODAT) suggests the need to find new factors to explain the pathogenesis. Our objectives were (1) to confirm that low levels of pre-transplant adiponectin are an independent risk factor for the development of NODAT in a larger transplanted population; (2) to analyze whether adiponectin is a better predictor of NODAT than other inflammatory markers (C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and pregnancy-associated plasma protein A (PAPP-A)) and (3) to assess the relationship between obesity, inflammatory markers and NODAT. One hundred ninety-nine non-diabetic patients (128 men; age: 53 +/- 11 years; body mass index (BMI) 24.98 +/- 3.76 kg/m2) were included. Pre-transplant plasma glucose, insulin, adiponectin, CRP, TNF-alpha, IL-6 and PAPP-A were measured. Forty-five patients developed NODAT. Patients with NODAT had a greater BMI (p = 0.005). Adiponectin was lower (p < 0.001) and CRP higher (p = 0.032) in patients with NODAT. Multivariate logistic regression and Cox analysis showed that the calcineurin inhibitor used, pre-transplant BMI and adiponectin were predictors of NODAT. ROC analysis showed that an adiponectin concentration of 11.4 microg/mL had a significant negative prediction for NODAT risk (sensitivity: 81% and specificity: 70%). Of the inflammatory markers studied, adiponectin proved to be an independent predictor of NODAT.