Development Of Post-transplant Diabetes Mellitus Research Articles

#1888 Association between intrapatient variability of serum tacrolimus levels with the development of diabetes in post-kidney transplantation patients

Abstract Background and Aims Kidney transplantation is the most cost-effective renal replacement therapy compared to dialysis. Diabetes is main cause of increased cardiovascular risk and death. Post-transplant Diabetes Mellitus (PTDM) it refers to presence of diabetes in an environment after kidney transplantation; According to the ADA (American Diabetes Association) criteria, the diagnosis must be made with a tolerance test with 75 grams of oral glucose (Oral glucose tolerance test-OGTT) or the determination of glycosylated hemoglobin 1Ac (Hb1Ac) in a post-transplant period of stability of the immunosuppression dose and without infections. There are various risk factors for the development of PTDM: hypomagnesemia, glucocorticoids, calcineurin inhibitors (tacrolimus and cyclosporine); hepatitis C virus and cytomegalovirus infections. In a Mexican kidney transplant recipients in Guadalajara, Andrade SG demonstrated that the incidence of PTDM was 10.1% at 1 year post-transplant. In the Spanish population, Porrini E demonstrated that tacrolimus represents a risk factor for the development of PTDM, increasing the incidence of prediabetes by 33% at 12 months post-transplant. Several mechanisms have been implicated in the association of calcineurin inhibitor and PTDM: decreased insulin secretion, glucose intolerance, reduced pancreatic beta cell mass, increased islet apoptosis and decreased insulin gene expression. Studies mention that tacrolimus (FK) is more diabetogenic than cyclosporine (CsA) especially at levels above 20 ng/mL. The DIRECT study (Diabetes Incidence after Renal Transplantation) showed the incidence in 73 kidney transplant patients with CsA (26%) and 96 FK patients (33.6%, p = 0.046). By the other side, Malik RF mentions that FK levels aren´t a risk factor for the development of PTDM. To demonstrate that the high intrapatient variability of tacrolimus/cyclosporine serum levels correlates with the development of diabetes (PTDM) in kidney transplant recipients at the central military hospital in Mexico City. Method Observational, analytical, longitudinal and retrospective study. All kidney transplant recipients from living donors and cadaveric donors from January 2002 to December 2020 were included. FK and CsA were used as maintenance immunosuppression. Serum levels of FK/CsA, Hb1Ac and glucose were measured at months 0, 3, 6, 9 and 12 and intra-patient variability (IPV) of FK/CsA levels was calculated for each patient. The patients were separated into 2 groups, IPV low and IPV high according to the mean the coefficient of variability (CV). The IPV of the calcineurin inhibitor was estimated by calculating the CV in each patient according to the following equation: CV(%)= (SD/mean trough concentration of FK/ CsA)×100. The diagnosis of PTDM followed the criteria of the American Diabetes Association. The Mann Whitney U test was used. Results 638 kidney transplant recipients were included. The mean age of the recipients was 36.78 (±12.81) years. At the time of kidney transplant, the BMI was 22.67 (±3.90) and 25.76 (±3.99) kg/m² BS at 1 year post-transplant for whole cohort. At 1 year post-transplant, 72.3% patients were on FK and 27.7% on CsA. Hb1Ac for whole cohort was 4.81 (±0.71)% and 4.84 (±0.77)% at month 0 and 12 post-kidney transplant, respectively. FK and CsA levels were 12.41 (±5.31) and 234.34 (±87.80) ng/mL and 9.13 (±5.3) and 194.38 (±92.44) ng/mL in the PTDM and non-PTDM groups, respectively (p = 0.029). 17.96% of patients developed PTDM. Mean CV of the entire cohort was 33.84 (±20.41)%. When performing the analysis of the IPV coefficient by subgroups of maintenance immunosuppression used at 1 year post-transplant: the IPV of FK was 43.39 (±18.49)% and 29.99 (±17.56)% in the PTDM and non-PTDM groups respectively, p = 0.000, which shows that patients with a high IPV coefficient of tacrolimus developed more PTDM than those with low variability, student's t-test to compare IPV was 0.03. The IPV of CsA was 38.61 (±18.76)% and 37.51 (±25.67)% in the PTDM and non-PTDM groups respectively, p = 0.819. Conclusion High intrapatient variability of tacrolimus was correlated with the development of PTDM in Mexican kidney transplant recipients.

#715 Adiponectin / leptin ratio as an index to determine the risk of metabolic and rejection complications in patients after kidney transplantation

Abstract Background and Aims Adipose tissue, as an endocrine and paracrine organ, produces several hormones that are involved in the regulation of metabolic and inflammatory processes or immune system activity. While leptin is the main pro-inflammatory marker of adipose tissue, adiponectin is characterized by its anti-inflammatory effects. The adiponectin / leptin (A/L) ratio had been shown to correlate better with the occurrence of cardiometabolic risk factors than hormone concentrations alone. Results in the general population suggest that an A/L ratio > 1 can be considered normal, an A/L ratio of 0.5-1 indicates a moderate increase, and an A/L ration < 0.5 a high increase in cardiometabolic risk. The first aim of our study was to determine the risk of developing post-transplant diabetes mellitus (PTDM), prediabetes and other metabolic risk factors in relation to the A/L ratio in patients after kidney transplantation (KT). The second aim was to determine the risk of developing acute graft rejection in relation to the A/L ratio in patients after KT. Method A total of 104 patients were included in our prospective analysis after applying inclusion and exclusion criteria. Pre-transplantation and subsequently at 3, 6 and 12 months after KT, we recorded baseline characteristics of donors and recipients, including parameters characterizing graft function, metabolic (lipid profile, indices of glucose metabolism) and anthropometric parameters. At the same time, we examined serum adipocytokine concentrations (adiponectin, leptin) and calculated the A/L ratio. In the third month after KT, all patients underwent protocol graft biopsy and donor specific antibody (DSA) testing by Luminex method. Results We found that during the follow-up period, there was a significant increase in the A/L ratio in the control group (p = 0.0013) and, on the other hand, a significant decrease in the group who developed PTDM (p = 0.0003). Comparing the different subgroups divided on the A/L ratio one year after KT, we found that patients with an A/L < 0.5 were significantly longer in the dialysis program, had higher body mass index (BMI), waist circumference, worse graft function, and a higher prevalence of prediabetes and PTDM compared with those whose A/L ratio was > 1. Using logistic regression in multivariate analysis, we identified age at the time of KT [OR 1.0709, (p = 0.0337)], triglycerides level at 1 year after KT [OR 2.7735, (p = 0.446)] and A/L ratio < 0.5 [OR 3.1724, (p = 0.014)] as independent risk factors for the development of prediabetes and PTDM 1 year after KT. At the same time, after adjusting for differences in baseline donor and recipient characteristics, we identified the subgroup with an A/L ratio < 0.5 pre-transplant [HR 1.6126, (p = 0.0133)] and 3 months after KT [HR 1.3150, (p = 0.0172)] as an independent risk factor for the development of acute graft rejection. In the subsequent specification of the rejection episode, we found that A/L ratio < 0.5 pre-transplant [HR 2.2353, (p = 0.0357)] and 3 months after KT [HR 3.0954, (p = 0.0237)] is and independent risk factor for the occurrence of acute humoral rejection with DSA positivity. Conclusion In our study, we found that an A/L ratio < 0.5 is an independent risk factor for the development of prediabetes, PTDM 1 year after KT and acute humoral graft rejection with de novo DSA production in the third month after KT. This is the first study to investigate the correlation of the A/L ratio with the risk of developing metabolic and immunological complications in patients after KT.

#97 Study of association between post transplant diabetes mellitus (PTDM) and hypomagnesemia

Abstract Background and Aims New onset diabetes after transplantation (NODAT) or PTDM (Post-transplant Diabetes Mellitus) is associated with increased morbidity, renal graft loss, cardiovascular complications, mortality and increased health care costs. It has been shown that incidence of NODAT is rising in recent years. It is suggested that there is more prominent role of beta cell dysfunction rather than insulin resistance in patients with PTDM. Hypomagnesemia which is commonly seen in post-transplant patients is suggested to have a role in promoting beta cell dysfunction. Emerging modifiable risk factors for PTDM like hypomagnesemia need to be studied which may help to improve its prevalence and outcomes. Method This study was single centre study to assess association of PTDM or NODAT with hypomagnesemia. Other risk factors like body mass index (BMI) >25 kg/m2, higher age and sex of the recipient were also studied. This study was a prospective, non-randomised, comparative, observational study. Duration of the study was from 1st October 2016 to 28th February 2018. Recipients with age > 18 years with at least 2 fasting blood sugar readings of >126 mg/dl or 2 post prandial readings of >200 mg/dl or need for antidiabetic medications beyond 1-month post-transplant were studied as PTDM or NODAT. Patients with deceased donor transplant, second kidney transplant, simultaneous other organ transplant, active Hepatitis C infection, active cytomegalovirus infection, patients with acute rejection, patients with polycystic kidney disease and patients with basiliximab induction were excluded. Results After applying exclusion and exclusion criteria, 98 patients were studied in total. Among 98 patients around 40 patients developed PTDM. When assessed independently higher age of the patient (age more than 50 years) was associated with PTDM (p = .030) while sex of the recipient was not associated with PTDM (P = .188). BMI >25 kg/m2 was significantly associated with PTDM at 1 month (p = .0001), 2 month (p < .0001), 3 month (p < .0001), 6 month (p < .0001), 9 month (p = .0001) and 12 month (p = .003) post-transplant. No statistical difference between doses of steroids were seen in patients with or without PTDM. All 98 patients received tacrolimus as part of their immunosuppressant regime. Time varying serum tacrolimus trough levels were not associated with PTDM and was removed as confounder by using univariate cox proportional hazard model (p = 0.691). After univariate and subsequently multivariate logistic regression analysis only hypomagnesemia was significantly associated with PTDM (p = .0001). After using univariate and subsequently multivariate cox proportional hazard model to study time varying risk factors, both hypomagnesemia (HR, 0.099; 95% CI, 0.016-0.624, p = .014) and BMI >25 kg/m2 (HR, 3.435; 95% CI, 1.657-7.119, p = .001) were associated with PTDM. Significantly a greater number of patients with lower magnesium levels developed PTDM early as compared to patients with normal magnesium levels (Spearman's coefficient of rank correlation (rho) = 0.53; 95% CI, 0.261-0.722, p = .0004). Conclusion Hypomagnesemia and overweight are modifiable risk factors significantly associated with PTDM even after removing confounding factors. Early development of PTDM in patient with hypomagnesemia further corroborates its role. Active interventions should be sought to control hypomagnesemia and overweight which may improve the morbidity and mortality of kidney transplant patients in long run.

Donor and recipient genetics: Implications for the development of posttransplant diabetes mellitus

Posttransplant diabetes mellitus (PTDM) is a prevalent complication of liver transplantation and is associated with cardiometabolic complications. We studied the consequences of genetic effects of liver donors and recipients on PTDM outcomes, focusing on the diverse genetic pathways related to insulin that play a role in the development of PTDM. One thousand one hundred fifteen liver transplant recipients without a pretransplant diagnosis of type 2 diabetes mellitus (T2D) and their paired donors recruited from 2 transplant centers had polygenic risk scores (PRS) for T2D, insulin secretion, and insulin sensitivity calculated. Among recipients in the highest T2D-PRS quintile, donor T2D-PRS did not contribute significantly to PTDM. However, in recipients with the lowest T2D genetic risk, donor livers with the highest T2D-PRS contributed to the development of PTDM (OR [95% CI] = 3.79 [1.10-13.1], P = .035). Recipient risk was linked to factors associated with insulin secretion (OR [95% CI] = 0.85 [0.74-0.98], P = .02), while donor livers contributed to PTDM via gene pathways involved in insulin sensitivity (OR [95% CI] = 0.86 [0.75-0.99], P = .03). Recipient and donor PRS independently and collectively serve as predictors of PTDM onset. The genetically influenced biological pathways in recipients primarily pertain to insulin secretion, whereas the genetic makeup of donors exerts an influence on insulin sensitivity.

Impact of varied immunosuppressive agents and post-transplant diabetes mellitus on prognosis among diverse transplant recipients (experimental studies).

The success of solid organ transplantation (SOT) and the use of immunosuppressive agents offer hope to patients with end-stage diseases. However, the impact of post-transplant diabetes mellitus (PTDM) on SOT patients has become increasingly evident. In our study, we utilized the Scientific Registry of Transplant Recipients (SRTR) database to investigate the association between PTDM and patient survival in various types of organ transplantations, including liver, kidney, intestinal, heart, lung, and combined heart-lung transplantations (all P <0.001). Our findings revealed a negative effect of PTDM on the survival of these patients. Furthermore, we examined the effects of both generic and innovator immunosuppressive agents on the development of PTDM and the overall survival of different SOT populations. Interestingly, the results were inconsistent, indicating that the impact of these agents may vary depending on the specific type of transplantation and patient population. Overall, our study provides a comprehensive and systematic assessment of the effects of different immunosuppressive agents on prognosis, as well as the impact of PTDM on the survival of patients undergoing various types of SOT. These findings emphasize the need for further research and highlight the importance of optimizing immunosuppressive regimens and managing PTDM in SOT patients to improve their long-term outcomes.

Does Antibiotic Use Increase the Risk of Post-Transplantation Diabetes Mellitus? A Retrospective Study of Renal Transplant Patients.

BACKGROUND This study aimed to investigate the incidence of post-transplant diabetes mellitus (PTDM) in renal transplant (RT) patients at our center and to explore new risk factors for PTDM. MATERIAL AND METHODS This retrospective study included RT patients from 2010 to 2022. Clinic data on RT patients were obtained from hospital electronic medical records. CYP3A5*3, POR*28, ABCB1 (3435 C>T), and ABCB1 (1236 C>T) were genotyped in RT patients. The associations between age, BMI, concentration of tacrolimus (TAC), polymorphism of genes, antibiotics (eg, penicillins, cephalosporins, oxazolidinones, quinolones), numbers and days of antibiotic use, and PTDM were analyzed. RESULTS In this study, 409 patients with RT were included. The cumulative incidence of PTDM in the first year after RT was 9.05%. The numbers and days of antibiotic use in PTDM patients were significantly higher than those in non-PTDM patients. Multivariate logistic regression analysis identified age (OR=1.047, P=0.014), body mass index (BMI) (OR=1.178, P=0.007), dose-adjusted trough concentration of TAC (TAC C₀/D) at 7 days after RT (OR=1.159, P=0.042), trough concentration of TAC (TAC C₀) at 28 days after RT (OR=1.094, P=0.042), and levofloxacin (OR=5.975, P=0.003) as independent risk factors for PTDM. CONCLUSIONS In addition to age, BMI, and TAC concentration after RT, antibiotic use may be a novel factor affecting PTDM. The use of antibiotics may influence the development of PTDM.

Effect of post-transplant diabetes mellitus on cardiovascular events and mortality: a single-center retrospective cohort study.

This study aims to investigate the impact of post-transplant diabetes mellitus (PTDM) on cardiovascular events, graft survival, and mortality and to determine the risk factors involved in developing PTDM. A total of 703 patients who underwent kidney transplantation were included in the study. The total sample was subdivided into three groups: (i) patients with PTDM; (ii) patients who had diabetes before the transplantation (DM); and (iii) patients without diabetes (NoDM). The data on graft failure, cardiovascular events, all-cause mortality, and the potential risk factors that play a role in developing PTDM were recorded and analyzed. The patients were followed for a median of 80 (6-300) months after transplantation. Out of all patients, 41 (5.8%) had DM before transplantation, and 101 (14.4%) developed PTDM. Recipient BMI, post-transplant fasting plasma glucose, and hepatitis C seropositivity were independent risk factors for PTDM development. The incidence of cardiovascular events was 6.1% in the NoDM group, 14.9% in the PTDM group, and 29.3% in the DM group (p < 0.001). In PTDM patients, hepatitis C seropositivity and the recipient's age at transplant were independent predictors of a cardiovascular event. There were no significant differences between the groups regarding the risk of graft loss. PTDM had no significant effect on all-cause mortality. However, the survival rates of DM patients were significantly reduced compared to those with NoDM or PTDM. PTDM had no impact on patient survival. Hepatitis C seropositivity and recipient age at transplant predicted cardiovascular events in PTDM patients.

Time-updated Fibroblast Growth Factor 23 Is Predictive for Posttransplant Diabetes Mellitus in Kidney Transplant Recipients.

This work aimed to study whether fibroblast growth factor 23 (FGF23) is predictive for incident posttransplant diabetes mellitus (PTDM) in kidney transplant recipients (KTRs). We repeatedly analyzed plasma C-terminal FGF23 concentrations in 170 KTRs enrolled in the TransplantLines Biobank and Cohort Study. Associations of time-updated plasma FGF23 with incident PTDM were studied by Cox regression. A total of 170 KTRs (46% female, aged 54.4 ± 12.4 years) with 540 FGF23 measurements were included. Plasma FGF23 concentrations at transplantation were 31.1 (0.76-2576) pmol/L. During a follow-up of 24 (12-24) months, 38 patients developed PTDM. The highest FGF23 tertile (compared to the lowest) was associated with an increased risk for PTDM (fully adjusted hazard ratio 20.9; 95% CI, 3.4-130.0; P < .001). In KTRs without diabetes at baseline, the highest tertile of FGF23, compared to the lowest, is predictive for development of PTDM.

Association of Muscle Mass Loss with Diabetes Development in Liver Transplantation Recipients.

Post-transplant diabetes mellitus (PTDM) is one of the most significant complications after transplantation. Patients with end-stage liver diseases requiring transplantation are prone to sarcopenia, but the association between sarcopenia and PTDM remains to be elucidated. We aimed to investigate the effect of postoperative muscle mass loss on PTDM development. A total of 500 patients who underwent liver transplantation at a tertiary care hospital between 2005 and 2020 were included. Skeletal muscle area at the level of the L3-L5 vertebrae was measured using computed tomography scans performed before and 1 year after the transplantation. The associations between the change in the muscle area after the transplantation and the incidence of PTDM was investigated using a Cox proportional hazard model. During the follow-up period (median, 4.9 years), PTDM occurred in 165 patients (33%). The muscle mass loss was greater in patients who developed PTDM than in those without PTDM. Muscle depletion significantly increased risk of developing PTDM after adjustment for other confounding factors (hazard ratio, 1.50; 95% confidence interval, 1.23 to 1.84; P=0.001). Of the 357 subjects who had muscle mass loss, 124 (34.7%) developed PTDM, whereas of the 143 patients in the muscle mass maintenance group, 41 (28.7%) developed PTDM. The cumulative incidence of PTDM was significantly higher in patients with muscle loss than in patients without muscle loss (P=0.034). Muscle depletion after liver transplantation is associated with increased risk of PTDM development.

Abstract 12489: Sex Differences in Incidence and Outcomes of Patients With New-Onset Post-Transplant Diabetes Mellitus After Heart Transplantation

Introduction: Post-transplant diabetes mellitus (PTDM) is a common complication following heart transplantation (HT), mostly commonly occurring in the first year after transplant. A few risk factors for the development of PTDM have been identified, including immunosuppressive medications such as calcineurin inhibitors and glucocorticoids. Some studies have suggested that among HT recipients, women have higher rates of acute rejection which may necessitate higher doses of steroids and further hyperglycemia. However, differences between sexes in the incidence of PTDM after HT have not been established. Methods: A retrospective review of patients who underwent HT at a large-volume center between January 1, 2010 and December 31, 2019 was performed. Patients undergoing re-transplantation or dual-organ transplantation were excluded. PTDM was defined as hemoglobin A1C≥6.5% or a random glucose &gt;200 after HT among patients with no prior history of DM. Predictors of PTDM by sex were analyzed with logistic regression, and post-transplant outcomes were analyzed with Chi-Square analysis. Results: Among 317 transplant patients without pre-transplant DM, 71 (22.4%) patients were identified who had PTDM: 24 females (33.7%), 47 males (66.2%). There were no statistically significant differences in baseline characteristics between males and females who developed PTDM including age, race, pre-transplant HTN, calcineurin or steroid dosing at 1 month and 1 year post-transplant. Baseline HTN (OR 2.9, [1.3, 6.7], p=0.009) and mean steroid dose over the first 2 years post-transplant (OR 1.2, [1.0, 1.3], p=0.006) were predictors of PTDM in females but not in males, and mean tacrolimus dose was a predictor in males (OR 1.1, [1.0, 1.2], p=0.001) but not in females. Time to PTDM diagnosis did not differ by sex (log-rank p=0.56). Additionally, post-transplant outcomes in patients with PTDM including acute cellular rejection, antibody-mediated rejection, coronary allograft vasculopathy and death did not differ by sex. Conclusion: PTDM is a common complication of HT. Our study suggests that risk factors for PTDM among HT recipients differ by sex. Future studies should investigate the mechanisms underlying these differences to further guide sex-specific post-HT care.

Tacrolimus and Diabetes in Kidney Transplantation: The Impact of Cyp3a5 Gene Polymorphism

To explore the correlation between single nucleotide polymorphisms (SNPs) of CYP3A4 rs2740574 and CYP3A5 rs776746 and post-transplant diabetes mellitus (PTDM) in Chinese renal allograft recipients treated with tacrolimus. A total of 244 patients treated with tacrolimus were included in this study, wherein DNA sequencing was detected through fluorescence in situ hybridization, and SNP genotyping was performed. Among the 244 patients, 44 (18%) developed PTDM. The PTDM group exhibited higher preoperative body mass index and fasting plasma glucose levels, with higher creatinine values one year after surgery. The CYP3A4 rs2740574 genotype was found to be unique in its homozygous AA form. For CYP3A5 rs776746, the genotypes were distributed as follows: 28 (11.5%) cases with AA, 101 (41.4%) cases with AG, and 115 (47.1%) cases with GG, respectively (P=.042). The AA genotype showed a statistically significant difference from both AG and GG genotypes. Furthermore, the A allele of CYP3A5 rs776746 was found to be associated with an increased risk for PTDM development. The occurrence of tacrolimus-related PTDM is associated with body mass index, fasting plasma glucose levels, and CYP3A5 genotype before renal transplantation. Post-transplant diabetes mellitus is correlated with unfavorable long-term renal graft function, whereas the expression of the CYP3A5 rs776746 gene is linked to an elevated risk of PTDM.

Leptin receptor gene polymorphisms in kidney transplant patients with post-transplant diabetes mellitus treated with tacrolimus

Post-transplant diabetes mellitus (PTDM) is a metabolic complication that often occurs after kidney transplantation. Factors that increase the risk of this complication are currently being researched, including polymorphisms in genes affecting carbohydrate-lipid metabolism. Leptin is a hormone that affects appetite and adipose tissue and plays an important role in regulating insulin secretion as well as glucose and lipid metabolism. The aim of this study was to examine the association between leptin receptor gene polymorphisms and the development of post-transplant diabetes mellitus in patients treated with tacrolimus. The study was carried out in a group of 201 patients who underwent kidney transplantation. The follow-up period was 12 months. PTDM was diagnosed in 35 patients. Analysing the LEPR gene rs1137101 polymorphism, we observed in patients with PTDM an increased frequency of GG genotype carriers (GG vs AA, OR 3.36; 95 % CI 0.99–11.46; p = 0.04). There were no statistically significant differences in the distribution of the LEPR rs1137100 and LEPR rs1805094 polymorphisms between patients with and without PTDM. Multivariate regression analysis confirmed that female sex, advanced age, increased BMI and a higher number of LEPR rs1137101 G alleles were independent risk factors for PTDM development. The risk of PTDM development was almost 3.5 times greater in LEPR rs1137101 G allele carriers than in AA homozygotes (GG + AG vs AA; OR 3.48; 95 %CI (1.09–11.18), p = 0.035). The results suggest that patients after kidney transplantation with the LEPR gene rs1137101 G allele may have an increased risk of post-transplant diabetes development.

The Association between CDKAL1 Gene rs10946398 Polymorphism and Post-Transplant Diabetes in Kidney Allograft Recipients Treated with Tacrolimus.

Post-transplant diabetes mellitus (PTDM) is a common complication that occurs in kidney transplant patients, increasing the risk of infection, cardiovascular disease and loss of graft function. Currently, factors that increase the risk of this complication are being sought, among them polymorphisms in genes that regulate carbohydrate metabolism and influence pancreatic β-cell function. The aim of this study was to evaluate the association of selected polymorphisms of genes affecting carbohydrate metabolism, such as CDKAL1 rs10946398, GCK rs1799884, GCKR rs780094 and DGKB/TMEM195 rs2191349, with the development of post-transplant diabetes in kidney transplant patients. This study included 201 Caucasian patients after kidney transplantation treated with tacrolimus. An association was observed between the CDKAL1 rs10946398 gene polymorphism and PTDM. Among patients with PTDM, there was an increased prevalence of the CC genotype in the PTDM group compared to the group without PTDM. The chance of PTDM in those with the CC genotype was 2.60 times higher compared to those with the AC + AA genotypes (CC vs. AC + AA OR (95% CI): 2.60 (1.02-6.61), p = 0.040). Multivariate logistic regression analysis showed that advanced age and the CC genotype (rare homozygote) of CDKAL1 rs10946398 were risk factors for the development of PTDM at 1 year after transplantation. There was no statistically significant association between GCK rs1799884, GCKR rs780094 or DGKB/TMEM195 rs2191349 polymorphisms and the development of post-transplant diabetes mellitus in kidney transplant patients. The results of this study suggest that the CDKAL1 rs10946398 CC genotype is associated with the increased risk of PTDM development in patients after kidney graft transplantation treated with tacrolimus.

#2937 INDIRECT INSULIN RESISTANCE INDICES AND THEIR CUT-OFF VALUES FOR POST-TRANSPLANTATION DIABETES MELLITUS IN KIDNEY TRANSPLANT RECIPIENTS

Abstract Background and Aims Insulin resistance determination in kidney transplant recipients (KTRs) plays an important role to identify KTRs at risk of posttransplantation diabetes mellitus (PTDM) development. Current methods to measure insulin resistance include the hyperinsulinemic-euglycemic (HIEG) clamp technique, and minimal model approximation of the metabolism of glucose (MMAMG). These methods, however, require considerable time and are expense, complex, and invasive. As a result, indirect insulin resistance indices such as homeostasis model assessment-insulin resistance (HOMA-IR), visceral adiposity index (VAI), lipid accumulation product (LAP), or triglycerides-glucose (TyG) index, are used in epidemiological and clinical studies in the general population due to their simplicity and ease of use. However, it is unknown to what extent those indices may contribute to determine insulin resistance and PTDM development in KTRs. Therefore, this study aimed to investigate the role of indirect insulin resistance indices to determine insulin resistance and PTDM development in KTRs. Method We included 472 stable outpatient KTRs (with a functioning graft ≥1 year) without diabetes from a prospective cohort study. Crude and multivariable Cox proportional hazards regression analysis were performed to determine whether indirect insulin resistance indices (HOMA-IR, VAI, LAP, and TyG index) were prospectively associated with incident PTDM. We analyzed each measure using receiver operating characteristic (ROC) curve for the development of PTDM. The cut-off value was determined as the value with the highest Youden index score in the specificity dominant area. Results During a median 9.6 years [interquartile range (IQR) 6.6–10.2] of follow up, 68 (14%) KTRs developed PTDM. In Cox regression analyses, all indirect insulin resistance indices associated with incident PTDM, independent of potential confounders. ROC curve was 0.764 (95% CI,0.703-0.826) for HOMA-IR, 0.685 (95% CI,0.615-0.757) for VAI, 0.743 (95% CI,0.678-0.808) for LAP, and 0.698 (95% CI,0.629-0.766) for TyG index, with no significant difference between them (p = 0.05). The cut-off values with their corresponding sensitivity and specificity for each indices are presented in Table 1. To test this cut-off value, the association between the indices and incident PTDM was examined by using each index as a categorical variable (HOMA-IR&amp;lt;2.47 vs ≥2.47; VAI&amp;lt;4.01 vs ≥4.01; LAP&amp;lt;87.04 vs ≥87.04; TyG index&amp;lt;4.94 vs ≥4.94). Indirect insulin resistance indices as a categorical variable predicted incident PTDM independent of age, sex, smoking, time to transplantation, systolic blood pressure, eGFR, and medication. Conclusion Indirect insulin resistance indices could be used to predict incident PTDM in KTRs. In addition to HOMA-IR, insulin-free surrogates of insulin resistance might serve as useful methods to identify KTRs at risk for PTDM development.

Microbial and metabolic features in renal transplant recipients with post-transplantation diabetes mellitus.

Post-transplantation diabetes mellitus (PTDM) is a common complication in renal transplant recipients (RTRs). Gut microbiome plays important roles in a variety of chronic metabolic diseases, but its association with the occurrence and development of PTDM is still unknown. The present study integrates the analysis of gut microbiome and metabolites to further identify the characteristics of PTDM. A total of 100 RTRs fecal samples were collected in our study. Among them, 55 samples were submitted to Hiseq sequencing, and 100 samples were used for non-targeted metabolomics analysis. The gut microbiome and metabolomics of RTRs were comprehensively characterized. The species Dialister invisus was significantly associated with fasting plasma glucose (FPG). The functions of tryptophan and phenylalanine biosynthesis were enhanced in RTRs with PTDM, while the functions of fructose and butyric acid metabolism were reduced. Fecal metabolome analysis indicated that RTRs with PTDM had unique metabolite distribution characteristics, and two differentially expressed specific metabolites were significantly correlated with FPG. The correlation analysis of gut microbiome and metabolites showed that gut microbiome had an obvious effect on the metabolic characteristics of RTRs with PTDM. Moreover, the relative abundance of microbial function is associated with the expression of several specific gut microbiome and metabolites. Our study identified the characteristics of gut microbiome and fecal metabolites in RTRs with PTDM, and we also found two important metabolites and a bacterium were significantly associated with PTDM, which might be used as novel targets in the research field of PTDM.

Risk Factors for Development of Early Onset Post-Transplant Diabetes Mellitus (PTDM) – A Prospective Study from a Tertiary Care Centre in India

ABSTRACT Introduction: Kidney transplantation is the best form of kidney replacement therapy. Posttransplant diabetes mellitus (PTDM) is an important complication seen in transplant recipients. The present study was done to identify the incidence and risk factors for the development of early-onset PTDM at a tertiary care center in India. Materials and Methods: This was a prospective study carried out from May 1, 2016, to April 30, 2017, at a tertiary care center and included all the adult first transplant recipients. The patients were followed up for six months after transplantation and the incidence of early PTDM was noted. The patients were divided into two groups, namely, PTDM and non-PTDM groups to identify risk factors for PTDM and to compare the outcome between the two groups. Results: This study included 66 patients. Patients developing PTDM had higher age (44.07 ± 9.69 years vs. 35.98 ± 11.17 years; P = 0.013), significantly higher prevalence of family history of diabetes (57.14% vs. 15.38%; P = 0.001), higher pretransplant fasting plasma blood glucose (93.86 ± 8.59 mg/dL vs. 86.21 ± 7.53 mg/dL; P = 0.007), and higher pretransplant glycated hemoglobin (HbA1c) level (5.2% ± 0.39% vs. 4.9% ± 0.52%; P = 0.006). We did not find any association of PTDM with obesity, gender, type of induction therapy, hepatitis C infection, cytomegalovirus infection, and mean trough tacrolimus levels. Conclusions: In our study, patients who developed PTDM were of higher age, with increased levels of fasting blood sugar and HbA1c pretransplant, had a family history of diabetes, and were likely to have received antirejection therapy.

Post-Transplant Diabetes Mellitus in Renal Transplant Recipients, Single-Centre Data: Incidence, Risk Factors, and Effect on Graft Function and Mortality

Background: De novo post-transplant diabetes mellitus (PTDM) is a frequent complication among renal transplant recipients; it confers a high risk for graft failure and patient mortality. This single-centre study aimed to determine the incidence and risk factors of PTDM and its effects on graft outcome and mortality. Methods: In a single-centre longitudinal cohort analysis of 383 non-diabetic renal transplant follow-up recipients, outcomes were analysed through a detailed chart review. We hypothesized that different donor and recipient characters such as age, gender, and HLA mismatch would affect PTDM development in renal transplant recipients. PTDM is defined on basis of fasting plasma sugar (≥7 mmol/L or ≥126 mg/dL), random plasma sugar (≥11.1 mmol/L or ≥200 mg/dL), and glycated haemoglobin (HBA1C: >6.5% or 48 mmol/mol). We assessed PTDM incidence, risk factors, and its effect on patient mortality and graft outcome using Cox regression. Results: The mean age at the time of transplantation was 35.70 (±14.27) years, and 50.91% were male. PTDM incidence in the study period was 23.30%. Independent risk factors include older age at the time of transplantation, cyclosporine immunosuppression, cytomegalovirus, and hepatitis C virus infection. PTDM is not associated with graft dysfunction, whereas it significantly carries high mortality. Conclusion: PTDM is common among renal transplant recipients. Older age at the time of transplantation, cyclosporine immunosuppression, cytomegalovirus, and hepatitis C virus are risk factors. PTDM carries high mortality but is not associated with graft failure.

New-Onset Diabetes Mellitus in Post-renal Transplant Patients on Tacrolimus and Mycophenolate: A Systematic Review.

A frequent complication in kidney transplantation is post-transplant diabetes mellitus (PTDM). The primary goal of this study is to review the risk factors and preventive methods and compare the different available anti-diabetic medications for the management of PTDM. We searched databases like Pubmed and Google Scholar for related articles using specific terms and phrases. Following a thorough investigation, we applied the inclusion and exclusion criteria and completed a quality assessment. Modifiable risk factors have a significant role in the development of PTDM.The combinations of immunosuppressive treatment tacrolimus (TAC), cyclosporine A (CYC), and everolimus (EVL), steroids increase the incidence of PTDM significantly. Insulin is the most effective treatment for PTDM in the early transplant period; however, oral anti-diabetic medications look promising. Further clinical trials are required to determine the optimum treatment method for reducing the occurrence of PTDM and treating the existing condition with novel anti-hyperglycemic medications.

426.5: Regular Physical Activity in the Prevention of Post-transplant Diabetes Mellitus and Associated Metabolic Conditions in Kidney Transplant Recipients

Introduction: Post-transplant diabetes mellitus (PTDM) is significant risk factor for the survival of graft recipients and occurs in 10-30% of patients after kidney transplant (KT). PTDM is associated with premature cardiovascular morbidity and mortality. Insulin resistance (IR) at the time of KT is the most significant risk factor for the development of PTDM in patients after KT, as demonstrated by several analyzes. It is possible to reduce the high incidence of PTDM and affect the long-term survival of patients and grafts by influencing just modifiable risk factors, including obesity and the associated IR. The aim of this work is to determine the effect of regular physical activity on the development of PTDM and its risk factors in patients after KT. Methods: This was a prospective controlled analysis, which included 44 patients after primary KT in the Martin Transplant Center. Half consisted of a study group (n = 22) whose patients were assigned to perform regular physical activity. The primary goal was to complete at least 150 minutes of moderate intensity physical exertion per week. They performed an aerobic or combined (aerobic + strength) type of sports activity. Monitoring was provided by a sports tracker (Xiaomi Mi Band 4 compatible with Mi Fit mobile application). The other half was made up of a control group. The exclusion criterion at that time was already diagnosed with diabetes mellitus or a pre-diabetic condition. IR was assessed using the HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) index from fasting blood glucose and insulinemia values. Each patient underwent an oral glucose tolerance test (oGTT) at the end of follow-up. Patients in both groups have the same immunosuppressive protocol. The duration of follow-up was 6 months. Results: We confirmed a statistically significantly higher IR at 6 months (P = 0.0202) and fasting blood glucose at 3 and 6 months (P = 0.0279) by multivariate analysis in the control group (figure 1, 2). After the end of the follow-up, there were significantly fewer patients with normal oGTT in the control group compared to the study group at 6 months (P < 0.0001), significantly more patients with pre-diabetic condition (impaired plasma glucose, impaired glucose tolerance) (P = 0.0078) and diagnosed with PTDM (P = 0.0212) (figure 3). Significantly lower waist circumference at 3 and 6 months (P = 0.0437, P = 0.0372) and low-density lipoprotein at 6 months (P = 0.0444) were found in the study group compared to the control group. In the study group, the subgroup performing intensive training achieved a significant additional effect on the reduction of waist circumference (P = 0.0173). Patients practicing only aerobic activity achieved significant decrease in triglycerides compared to those practicing combined activity (P = 0.046). Conclusion: In our study, we confirmed a significant effect of regular physical activity in preventing the development of PTDM and associated pre-diabetic conditions.

P15.05: Safety of Once-Weekly Dulaglutide on Post-transplant Diabetes Mellitus: A Preliminary Single-Centre Experience

Introduction: Almost all immunosuppressive drugs (IS), including glucocorticoids, calcineurin and mTOR inhibitors, play a central role in the development of Post-Transplant Diabetes Mellitus (PTDM). IS potentially cause the development of a dysglycemic state, both for the direct cytotoxic action on pancreatic beta cells and for the induction of insulin resistance. PTDM is also associated with increased risk for cardiovascular disease and with worse graft and patients’ survival. Currently there are no clear recommendations on the choice of the most safe and effective anti-diabetic drug for PTDM. IS are linked with several pharmacokinetic interactions and burdened with vary degree of nephrotoxicity. Glucagon like peptide- 1 receptor agonists (GLP1RA) are largely used for the treatment of type 2 diabetes. They act stimulating endogenous insulin secretion in a glucose-dependent manner. GLP1RAs reduce blood sugar by stimulating insulin release, suppressing high glucagon levels, delaying gastric emptying, and reducing food intake. Furthermore, GLP1 has been shown to promote proliferation of beta cells in animal models. GLP1RA has proven to be safe and effective in reducing HbA1c without directly causing hypoglycemia and has shown a clear association with cardiovascular risk reduction and renal protection. Despite GLP1RA seems to act with a mechanism that perfectly contrasts the pathogenetic aspects of PTDM, in the literature clinical experience is entirely limited to case series and retrospective studies. Method: In order to assess primarily safety of GLP1RA therapy in patients with PTDM we have prospectively enrolled a sample of N = 20 patients referred to liver (N = 10), renal (N = 5), as well as heart (N = 4) and lung (N = 1) transplant at ISMETT. All patients were placed on once-weekly dulaglutide therapy. Weight, HbA1c Level, as well as complete lipid profile and liver function tests were performed at 3 months and again at 6 months. One-way Repeated measurements ANOVA was used to test significant change in collected variables over time. Results: The study was closed at 6 months follow-up visit. Mild gastrointestinal symptoms were experienced by patients at the treatment start and resolved in 2 weeks. There were no persistent side effects due to dulaglutide in our study population and all recruited patients were on dulaglutide at 6 months evaluation. Body weight, Total cholesterol, Fibrosis-4 Index, alanine aminotransferase and aspartate aminotransferase levels were all reduced at the end of the follow-up, while blood glucose as well as HbA1c were stable over time (Table 1, Figure 1). Conclusion: Dulaglutide has proven to be safe in a population of transplanted patients with PTDM. In addition, a significative reduction of metabolic parameters was found. GLP1RA could be a preferred treatment for patients with PTDM considering also the extraglycemic effects of cardiovascular and renal protection.