Incidence Of Posttransplant 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.

Oral Glucose Tolerance Test as a Risk Marker for Developing Post-Transplant Diabetes Mellitus

IntroductionThe incidence of post-transplant diabetes mellitus (PTDM) can reach 30% during the first 6 months after kidney transplantation (KT), increasing the risk of graft failure and mortality. There is no well-established biomarker for predicting PTDM occurrence. This study evaluated the association between the abnormal 2-hour oral glucose tolerance test (OGTT) and the PTDM incidence. MethodsA retrospective single-center study, including adult kidney transplant recipients from deceased donors, was performed between March 2021 and June 2022. Exclusion criteria: age <18 years; pretransplant diabetes mellitus (DM); death with a functioning graft; loss of follow-up and/or graft failure before 6 months post-transplant. The results of pretransplant OGTT, fasting (FPG), and afternoon plasma glucose levels at hospitalization and FPG in the first, second, and third months post-transplant were evaluated. For analysis, patients were grouped according to the PTDM diagnosis: PTDM and non-PTDM. ResultsFrom 164 KT performed in the period, 50 (30%) were included, most male (n = 34, 68%), with a mean age of 48.3 ± 12.5 years. Nine patients (18%) developed PTDM, 44% between 3 and 6 months. General characteristics and immunosuppressive therapy were similar between the groups. The mean FPG in the pretransplant OGTT was significantly higher in the PTDM group compared with the non-PTDM group (85.7 ± 7.9 vs 79.1 ± 8.2, P = .03). The number of patients classified as impaired glucose tolerance (IGT) on the pre-transplant OGTT was significantly higher in the PTDM group. ConclusionIGT in the pretransplant OGTT was associated with PTDM cases in kidney transplant recipients without a previous diagnosis of DM.

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.

Micro-vascular complications of post-transplant diabetes mellitus in renal transplant recipients- an observational study

IntroductionThe incidence of post-transplant diabetes mellitus (PTDM) ranges from 2.5% to 20% in kidney transplant recipients. Diabetic retinopathy (DR), diabetic kidney disease (DKD), and distal symmetric polyneuropathy (DSPN) are the microvascular complications frequently seen in both type 1 and 2 diabetes mellitus (DM). However, the data regarding these complications in patients with PTDM is lacking. MethodA retrospective and prospective observational study of PTDM conducted at a tertiary care hospital from November 2018 to December 2020. 115 kidney transplant recipients who had PTDM of ≥5 years duration were included and analysed. ResultsThe mean duration of PTDM was 8.8 ± 3.0 years, and the mean of all available HbA1c values was 7.0 ± 0.9%. while none of the patients had evidence of diabetic retinopathy on direct ophthalmoscopy, 37.4% of patients (n = 43) had DSPN and this was associated with the duration of PTDM and age. The mean estimated glomerular filtration rate (eGFR) was 59.24 ± 21.82 ml/min/1.73m2, and patients had a median proteinuria of 620 mg/day (IQR 1290). Out of 115 patients, 20% of them (n = 23) underwent graft kidney biopsy, and 10 biopsies were diagnosed as de-novo DKD. Patients with biopsy proven DKD had a mean PTDM duration of 143.3 ± 52.4 months; a mean HbA1c level of 7.9 ± 1.3%; a mean eGFR of 44.8 ± 21.8 ml/min; and a median proteinuria of 2653 mg (IQR 2758). An additional analysis of all 23 biopsied patients showed that HbA1c level and degree of proteinuria were significantly associated with de-novo DKD. ConclusionPTDM in transplant patients had milder microvascular complications than usually expected in Type 1/2 diabetes in non-transplant patients. DR was not strongly associated with DKD in PTDM patients. Furthermore, de-novo DKD development was associated with poor glycaemic control and increased proteinuria.

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.

Influencing factors of post-transplantation diabetes mellitus in kidney transplant recipients and establishment of a risk prediction model.

The aim was to explore the influencing factors of post-trans-plantation diabetes mellitus (PTDM) in kidney transplant recipients and to es-tablish a risk prediction model. A retrospective analysis was performed on the clinical data of 408 patients subjected to kidney transplantation from May 2015 to March 2022. With the simple random sampling method, they were divided into a training set (n=306) and a test set (n=102) at a ratio of 3:1. According to the occurrence of PTDM, the training set was further classified into PTDM and non-PTDM groups. The influencing factors of PTDM were identified by least absolute shrinkage and selection operator and multivariate logistic regression analysis. A nomogram prediction model was constructed and validated. Non-PT-DM and PTDM groups had significantly different preoperative body mass index (BMI), family history of diabetes mellitus, 2-h preoperative and postprandial blood glucose, 2-hpreoperative and postprandial peptide index, postoperative hypomagnesemia, whole blood concentration of tacrolimus, triacylglycerol, glycated albumin and fasting blood glucose (P&lt;0.05). BMI, family history of diabetes mellitus, 2-h preoperative and postprandial blood glucose, and post-operative whole blood tacrolimus concentration were independent risk factors for PTDM. In contrast, the 2-h preoperative and postprandial peptide index was an independent protective factor (P&lt;0.05). The incidence of PTDM in patients receiving kidney transplantation correlates with the family history of diabetes mellitus, preoperative BMI, 2-h postprandial blood glucose, 2-h postprandial peptide index, and postoperative whole blood tacrolimus concentration.

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.

Excellent efficacy and beneficial safety during observational 5-year follow-up of rapid steroid withdrawal after renal transplantation (Harmony FU study).

We previously reported excellent efficacy and improved safety aspects of rapid steroid withdrawal (RSWD) in the randomized controlled 1-year "Harmony" trial with 587 predominantly deceased-donor kidney transplant recipients randomized either to basiliximab or rabbit antithymocyte globulin induction therapy and compared with standard immunosuppressive therapy consisting of basiliximab, low tacrolimus once daily, mycophenolate mofetil and corticosteroids. The 5-year post-trial follow-up (FU) data were obtained in an observational manner at a 3- and a 5-year visit only for those Harmony patients who consented to participate and covered clinical events that occurred from the second year onwards. Biopsy-proven acute rejection and death-censored graft loss rates remained low and independent of RSWD. Rapid steroid withdrawal was an independent positive factor for patient survival (adjusted hazard ratio 0.554, 95% confidence interval 0.314-0.976; P=.041).The reduced incidence of post-transplantation diabetes mellitus in RSWD patients during the original 1-year study period was not compensated by later incidences during FU. Incidences of other important outcome parameters such as opportunistic infections, malignancies, cardiovascular morbidity/risk factors, donor-specific antibody formation or kidney function did not differ during FU period. With all the limitations of a post-trial FU study, the Harmony FU data confirm excellent efficacy and beneficial safety aspects of RSWD under modern immunosuppressive therapy over the course of 5 years after kidney transplantation in an immunologically low-risk, elderly population of Caucasian kidney transplant recipients. Trial registration: Clinical trial registration number: Investigator Initiated Trial (NCT00724022, FU study DRKS00005786).

#3973 EXCELLENT EFFICACY AND BENEFICIAL SAFETY DURING FIVE YEAR FOLLOW-UP OF RAPID STEROID WITHDRAWAL AFTER RENAL TRANSPLANTATION (HARMONY STUDY)

Abstract Background and Aims We previously reported excellent efficacy and improved safety aspects of rapid steroid withdrawal in the randomized controlled one year “Harmony” trial with 587 predominantly deceased-donor kidney transplant recipients randomized either to basiliximab or rabbit antithymocyte globulin induction therapy and compared to standard immunosuppressive therapy consisting of basiliximab, low tacrolimus once daily, mycophenolate mofetil, and corticosteroids. The five-year post-trial follow-up (FU) data reported here were obtained in an observational manner to evaluate, how these excellent short-term surrogate parameters will translate into hard long-term outcome parameters like patient death/graft loss. Method The five-year post-trial follow-up data were obtained in an observational manner at a three and a five-year visit for patients who consented to participate and covered clinical events that occurred from the second year onwards. Results Biopsy-proven acute rejection and death-censored graft loss rates remained low and independent of rapid steroid withdrawal (see Figure 1). Rapid steroid withdrawal was an independent positive factor for patient survival (adjusted hazard ratio 0.554, 95 % confidence interval 0.314 to 0.976; p = 0.041, see Table 1). The reduced incidence of post-transplantation diabetes mellitus in rapid steroid withdrawal patients during the original one-year study period was not compensated by later incidences during follow-up. Incidences of other important outcome parameters such as opportunistic infections, malignancies, cardiovascular morbidity/risk factors, donor specific antibody formation, or kidney function did not differ during follow-up period. Conclusion The Harmony follow-up trial confirms excellent efficacy and beneficial safety aspects of rapid steroid withdrawal under modern immunosuppressive therapy demonstrating for the first time increased patient survival in an immunologically low-risk, elderly population of Caucasian kidney transplant recipients.

Metabolic-Related Index to Predict Post-Transplantation Diabetes Mellitus After Kidney Transplantation.

Metabolic-related markers are novel tools for assessing insulin resistance. Early identification of post-transplantation diabetes mellitus (PTDM) before hyperglycemia can be helpful to attenuate the rapid development of diabetic complications. This article aims to explore the convenient and inexpensive values of metabolic-related markers, including TyG, TyG-BMI, TG/HDL-C, and non-HDL-C/HDL-C for predicting PTDM. The data of 191 kidney transplant recipients in our center were collected retrospectively. The association between TyG, TyG-BMI, TG/HDL-C, non-HDL-C/HDL-C and the risk of PTDM was examined by the area under the curve and logistic regression analyses. During 6 months follow-up, 12.04% of KT recipients developed PTDM, and significantly higher values of TyG-BMI, TyG, and non-HDL-C/HDL-C was found in patients with PTDM than in nondiabetic patients, especially among the recipients taking tacrolimus, regardless of gender. The incidence of PTDM increased along with the values of TyG or TyG-BMI. After adjusting for multiple potential factors, recipients with the highest trisector of TyG or TyG-BMI still had a higher risk of PTDM morbidity. In conclusion, TyG, TyG-BMI, TG/HDL-C and non-HDL-C/HDL-C can be used as cost-effective and promising monitors to identify individuals at high risk of PTDM, and TyG-BMI was the best alternative marker among the four markers.

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.

Pretransplant BMI Should Be

The aim of this study was to determine the appropriate body mass index (BMI) in Japanese kidney transplant (KTx) recipients. We analyzed the effects of pre- and post-transplant (Tx) obesity on graft and patient survival, perioperative complications, post-transplant diabetes mellitus (PTDM), and cardiovascular disease (CVD) in Japanese KTx recipients. This retrospective study included 269 recipients who underwent KTx from 2008 through 2020 at Niigata University Hospital. Obesity was defined as a body mass index (BMI) ≥25 kg/m2. We examined the association between pre- and post-Tx obesity and graft survival, patient survival, the incidence of PTDM and CVD, and perioperative surgical complications. The graft survival rate was lower in the pre-Tx BMI ≥25 kg/m2 group, although there was no significant difference in patient survival. There was no difference in graft and patient survival between the post-Tx BMI ≥25 kg/m2 group and the <25 kg/m2 group. A pre-Tx BMI ≥25 kg/m2 was an independent risk factor for biopsy-proven allograft rejection. New-onset DM after transplantation was significantly more common in the BMI ≥25 kg/m2 group than in the BMI <25 kg/m2 group (36% vs 13%; P=.002). The incidence of CVD was significantly higher in the post-Tx BMI ≥30 kg/m2 group than in the BMI <30 kg/m2 group (50% vs 11%; P=.023). There were no differences in surgical operating time, intraoperative blood loss, or perioperative complications between the obese and non-obese groups. Pre-Tx BMI ≥25 kg/m2 may be a risk factor for allograft rejection and graft loss. Post-Tx BMI should be <25 kg/m2 to reduce the risk for PTDM.

Comparative study of once daily tacrolimus (extended-release capsule) versus conventional twice daily tacrolimus in renal transplant recipients

Background: One of the common causes of chronic allograft nephropathy is nonadherence to medications, contributing to 30% of graft loss in the developed world. The non-adherence is attributed predominantly to pill burden. Once-daily dosing of tacrolimus instead of conventional twice-daily dosing may enhance adherence to medication and improve long-term outcomes. The present study is a retrospective analysis comparing the safety and effectiveness of De Novo (use from day 1) once daily (OD) Tacrolimus (extended-release capsules) to conventional twice-a-day (BD) tacrolimus, in renal transplant recipients operated at Suguna Hospital Bangalore India. Material and Methods: Records of 24 Transplant patients on De novo OD Tacrolimus were analyzed and compared retrospectively to 24 transplant patients treated De Novo with conventional BD tacrolimus on a regular follow-up for at least 2 yrs. post-transplant at our center. Results: Various parameters recorded till the last follow-up were analyzed and compared. The average weight of the cohort (64.6 kg vs. 66.6 kg), average tacrolimus dose (2.7 mg vs. 2.15 mg), average Tac dose/kg body weight (0.04 mg vs. 0.03 mg), average Sr.Creatinine, at Last, Follow up (1.2 mg/dl vs. 1.32 mg/dl) were comparable in both groups and were statistically insignificant (p &gt; 0.05). However, there was a higher incidence of Post-Transplant Diabetes Mellitus (PTDM) noted in the Conventional BD Tacrolimus group (20.83%) compared to the OD Tacrolimus group (4.1%) and it was statistically significant (p = 0.17). The Infection rate of 41.67% in the conventional BD Tacrolimus group was much higher compared to the OD Tacrolimus group (4.17%) which was statistically significant (p = 0.01). There was 100% patient and graft survival at the end of two years in both groups. Tacrolimus Dose for OD and Conventional BD dosing were similar, unlike earlier studies recommending a 10% increase in dose for OD tacrolimus compared to BD dosing. Conclusion: OD Tacrolimus dose is comparable to conventional BD dose Tacrolimus in its safety and Efficacy; however, it scores over conventional BD dose Tacrolimus in terms of post-transplant infections and post-transplant diabetes mellitus (PTDM) and a more stable serum trough level.

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.

Fast Tacrolimus Metabolism Does Not Promote Post-Transplant Diabetes Mellitus after Kidney Transplantation.

Post-transplant diabetes mellitus (PTDM) after kidney transplantation induced by tacrolimus is an important issue. Fast tacrolimus metabolism, which can be estimated by concentration-to-dose (C/D) ratio, is associated with increased nephrotoxicity and unfavorable outcomes after kidney transplantation. Herein, we elucidate whether fast tacrolimus metabolism also increases the risk for PTDM. Data from 596 non-diabetic patients treated with tacrolimus-based immunosuppression at the time of kidney transplantation between 2007 and 2015 were retrospectively analyzed. The median follow-up time after kidney transplantation was 4.7 years (IQR 4.2 years). Our analysis was complemented by experimental modeling of fast and slow tacrolimus metabolism kinetics in cultured insulin-producing pancreatic cells (INS-1 cells). During the follow-up period, 117 (19.6%) patients developed PTDM. Of all patients, 210 (35.2%) were classified as fast metabolizers (C/D ratio < 1.05 ng/mL × 1/mg). Fast tacrolimus metabolizers did not have a higher incidence of PTDM than slow tacrolimus metabolizers (p = 0.496). Consistent with this, insulin secretion and the viability of tacrolimus-treated INS-1 cells exposed to 12 h of tacrolimus concentrations analogous to the serum profiles of fast or slow tacrolimus metabolizers or to continuous exposure did not differ (p = 0.286). In conclusion, fast tacrolimus metabolism is not associated with increased incidence of PTDM after kidney transplantation, either in vitro or in vivo. A short period of incubation of INS-1 cells with tacrolimus using different concentration profiles led to comparable effects on cell viability and insulin secretion in vitro. Consistent with this, in our patient, collective fast Tac metabolizers did not show a higher PTDM incidence compared to slow metabolizers.

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.

Posttransplantation Diabetes Mellitus Among Solid Organ Recipients in a Danish Cohort.

Post-transplant diabetes mellitus (PTDM) is associated with a higher risk of adverse outcomes. We aimed to describe the proportion of patients with diabetes prior to solid organ transplantation (SOT) and post-transplant diabetes mellitus (PTDM) in three time periods (early-likely PTDM: 0–45 days; 46–365 days and >365 days) post-transplant and to estimate possible risk factors associated with PTDM in each time-period. Additionally, we compared the risk of death and causes of death in patients with diabetes prior to transplant, PTDM, and non-diabetes patients. A total of 959 SOT recipients (heart, lung, liver, and kidney) transplanted at University Hospital of Copenhagen between 2010 and 2015 were included. The highest PTDM incidence was observed at 46–365 days after transplant in all SOT recipients. Age and the Charlson Comorbidity Index (CCI Score) in all time periods were the two most important risk factors for PTDM. Compared to non-diabetes patients, SOT recipients with pre-transplant diabetes and PTDM patients had a higher risk of all-cause mortality death (aHR: 1.77, 95% CI: 1.16–2.69 and aHR: 1.89, 95% CI: 1.17–3.06 respectively). Pre-transplant diabetes and PTDM patients had a higher risk of death due to cardiovascular diseases and cancer, respectively, when compared to non-diabetes patients.

A Randomized Controlled Trial on Safety of Steroid Avoidance in Immunologically Low-Risk Kidney Transplant Recipients

IntroductionSteroid-based immunosuppression after transplantation increases the risk of post-transplant diabetes mellitus (PTDM), with adverse effects on patient and graft survival. In the SAILOR study, we investigated the safety and efficacy of complete steroid avoidance in immunologically low-risk kidney recipients without diabetes on the current standard-of-care maintenance regimen with tacrolimus/mycophenolate mofetil (MMF).MethodsIn this 2-year, multicenter, open-label trial, a total of 222 patients were randomized to receive either steroid avoidance protocol (tacrolimus/MMF/antithymocyte globulin [ATG] induction [n = 113]) or steroid maintenance protocol (tacrolimus/MMF/prednisolone/basiliximab-induction [n = 109]).ResultsAt 1 year, no significant differences were found between steroid avoidance and steroid maintenance arms in the incidence of PTDM, the primary end point (12.4% vs. 18.3%, respectively, P = 0.30, CI: 16.3–4.4), or in overall biopsy-proven rejections (15% vs. 13.8%, respectively, P = 0.85). At 2 years, the composite end point of freedom from acute rejection, graft loss, and death (81% vs. 85%, respectively, P = 0.4), kidney function, or adverse events was comparable between the 2 arms. Moreover, 63.9% of the patients in the steroid avoidance arm remained free from steroids at 2 years.ConclusionThe SAILOR study provides further evidence for the feasibility, safety, and efficacy of early steroid-free treatment at 2 years in immunologically low-risk kidney recipients with tacrolimus/MMF maintenance regimen.

Posttransplant Diabetes Mellitus and Immunosuppression Selection in Older and Obese Kidney Recipients

Rationale & ObjectivePosttransplant diabetes mellitus (DM) after kidney transplantation increases morbidity and mortality, particularly in older and obese recipients. We aimed to examine the impact of immunosuppression selection on the risk of posttransplant DM among both older and obese kidney transplant recipients.Study DesignRetrospective database study.Setting & ParticipantsKidney-only transplant recipients aged ≥18 years from 2005 to 2016 in the United States from US Renal Data System records, which integrate Organ Procurement and Transplantation Network/United Network for Organ Sharing records with Medicare billing claims.ExposuresVarious immunosuppression regimens in the first 3 months after transplant.OutcomesDevelopment of DM >3 months-to-1 year posttransplant.Analytical ApproachWe used multivariable Cox regression to compare the incidence of posttransplant DM by immunosuppression regimen with the reference regimen of thymoglobulin (TMG) or alemtuzumab (ALEM) with tacrolimus + mycophenolic acid + prednisone using inverse propensity weighting.Results12.7% of kidney transplant recipients developed posttransplant DM with higher incidences in older (≥55 years vs <55 years: 16.7% vs 10.1%) and obese (body mass index [BMI] ≥ 30 kg/m2 vs BMI < 30 kg/m2: 17.1% vs 10.9%) patients. The incidence of posttransplant DM was lower with steroid avoidance [TMG/ALEM + no prednisone (8.4%) and IL2rAb + no prednisone (9.7%)] than TMG/ALEM with triple therapy (13.1%). After adjustment for donor and recipient characteristics, TMG/ALEM with steroid avoidance was beneficial for all groups [age < 55 years: adjusted HR (aHR), 0.63 (95% confidence interval [CI], 0.54-0.72); age ≥ 55 years: aHR, 0.69 (95% CI, 0.60-0.79); BMI < 30 kg/m2: aHR, 0.69 (95% CI, 0.60-0.78); BMI ≥ 30 kg/m2: aHR, 0.67 (95% CI, 0.57-0.79)]. However, IL2rAb with steroid avoidance was beneficial only for older patients (aHR, 0.76; 95% CI, 0.58-0.99) and for those with BMI < 30 kg/m2 (aHR, 0.63; 95% CI, 0.46-0.87).LimitationsRetrospective study and lacked data on immunosuppression levels.ConclusionsThe beneficial impact of steroid avoidance using tacrolimus on posttransplant DM appears to differ by patient age and induction regimen.