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Improved Glucose Tolerance in a Kidney Transplant Recipient With Type 2 Diabetes Mellitus After Switching From Tacrolimus To Belatacept: A Case Report and Review of Potential Mechanisms.

ABSTRACT: The introduction of immunosuppressant belatacept, an inhibitor of the CD28-80/86 pathway, has improved 1-year outcomes in kidney transplant recipients with preexistent diabetes mellitus and has also reduced the risk of posttransplant diabetes mellitus. So far, no studies have compared a tacrolimus-based with a belatacept-based immunosuppressive regimen with regard to improving glucose tolerance after kidney transplantation. Here, we present the case of a 54-year-old man with type 2 diabetes mellitus who was converted from belatacept to tacrolimus 1 year after a successful kidney transplantation. Thereafter, he quickly developed severe hyperglycemia, and administration of insulin was needed to improve metabolic control. Six months after this episode, he was converted back to belatacept because of nausea, diarrhea, and hyperglycemia. After switching back to belatacept and within 4 days after stopping tacrolimus glucose tolerance improved and insulin therapy could be discontinued. Although belatacept is considered less diabetogenic than tacrolimus, the rapid improvement of glucose tolerance after switching to belatacept is remarkable. In this article, the potential mechanisms of this observation are discussed.

SUBMITTER: de Graav GN

PROVIDER: S-EPMC5912016 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Improved Glucose Tolerance in a Kidney Transplant Recipient With Type 2 Diabetes Mellitus After Switching From Tacrolimus To Belatacept: A Case Report and Review of Potential Mechanisms.

de Graav Gretchen N GN van der Zwan Marieke M Baan Carla C CC Janssen Joop A M J L JAMJL Hesselink Dennis A DA

Transplantation direct 20180220 3

The introduction of immunosuppressant belatacept, an inhibitor of the CD28-80/86 pathway, has improved 1-year outcomes in kidney transplant recipients with preexistent diabetes mellitus and has also reduced the risk of posttransplant diabetes mellitus. So far, no studies have compared a tacrolimus-based with a belatacept-based immunosuppressive regimen with regard to improving glucose tolerance after kidney transplantation. Here, we present the case of a 54-year-old man with type 2 diabetes mell ...[more]

PMID: 29707621

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Project description:BACKGROUND:Calcineurin-inhibitors and hepatitis C virus (HCV) infection increase the risk of post-transplant diabetes mellitus. Chronic HCV infection promotes insulin resistance rather than beta-cell dysfunction. The objective was to elucidate whether a conversion from tacrolimus to cyclosporine A affects fasting and/or dynamic insulin sensitivity, insulin secretion or all in HCV-positive renal transplant recipients. METHODS:In this prospective, single-center study 10 HCV-positive renal transplant recipients underwent 2h-75g-oral glucose tolerance tests before and three months after the conversion of immunosuppression from tacrolimus to cyclosporine A. Established oral glucose tolerance test-based parameters of fasting and dynamic insulin sensitivity and insulin secretion were calculated. Data are expressed as median (IQR). RESULTS:After conversion, both fasting and challenged glucose levels decreased significantly. This was mainly attributable to a significant amelioration of post-prandial dynamic glucose sensitivity as measured by the oral glucose sensitivity-index OGIS [422.17 (370.82-441.92) vs. 468.80 (414.27-488.57) mL/min/m2, p = 0.005), which also resulted in significant improvements of the disposition index (p = 0.017) and adaptation index (p = 0.017) as markers of overall glucose tolerance and beta-cell function. Fasting insulin sensitivity (p = 0.721), insulinogenic index as marker of first-phase insulin secretion [0.064 (0.032-0.106) vs. 0.083 (0.054-0.144) nmol/mmol, p = 0.093) and hepatic insulin extraction (p = 0.646) remained unaltered. No changes of plasma HCV-RNA levels (p = 0.285) or liver stiffness (hepatic fibrosis and necroinflammation, p = 0.463) were observed after the conversion of immunosuppression. CONCLUSIONS:HCV-positive renal transplant recipients show significantly improved glucose-stimulated insulin sensitivity and overall glucose tolerance after conversion from tacrolimus to cyclosporine A. Considering the HCV-induced insulin resistance, HCV-positive renal transplant recipients may benefit from a cyclosporine A-based immunosuppressive regimen. TRIAL REGISTRATION:ClinicalTrials.gov NCT02108301.

Project description:BACKGROUND:Tacrolimus (FK506)-induced diabetes mellitus is one of the most important factors of post-transplant diabetes mellitus (PTDM). However, the detailed mechanisms underlying PTDM are still unclear. Farnesoid X receptor (FXR) regulates glycolipid metabolism. The objective of this study was to explore whether FXR is involved in the development of tacrolimus-induced diabetes mellitus. METHODS:After C57BL/6J mice were treated with tacrolimus (FK506) for 3 months, the fasting blood glucose levels, body weights, renal morphological alterations, and mRNA expression levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose transporter 2 (GLUT2) among the control group, the FK506 group and the FK506 + GW4064 (a FXR agonist) group (n = 7) were measured. The intracellular location of peroxisome proliferator activated receptor γ coactivator-1α (PGC1α) and forkhead box O1 (FOXO1) was detected by immunofluorescence. Human renal cortex proximal tubule epithelial cells (HK-2) were treated with 15 μM FK506 or 4 μM FXR agonist (GW4064) for 24, 48 and 72 h, and the expression levels of FXR, gluconeogenesis and glucose uptake, representing the enzymes PEPCK and GLUT2, were detected with real-time PCR and western blot analyses. Finally, the mRNA levels of PEPCK and GLUT2 in HK-2 cells were measured after FXR was upregulated. RESULTS:FK506 significantly inhibited the mRNA and protein levels of FXR at 48 h and 72 h in HK-2 cells (P < 0.05). Meanwhile, FK506 promoted gluconeogenesis and inhibited glucose uptake in HK-2 cells (P < 0.05). However, overexpression of FXR in transfected HK-2 cell lines significantly inhibited gluconeogenesis and promoted glucose uptake (P < 0.05). The FXR agonist GW4064 significantly decreased the fasting blood glucose in mice challenged with FK506 for 3 months (P < 0.05), inhibited gluconeogenesis (P < 0.05) and significantly promoted glucose uptake (P < 0.05). Immunofluorescence staining and western blot analyses further revealed that FXR activation may affect the translocation of PGC1α and FOXO1 from the nucleus to the cytoplasm. CONCLUSIONS:FXR activation may mitigate tacrolimus-induced diabetes mellitus by regulating gluconeogenesis as well as glucose uptake of renal cortex proximal tubule epithelial cells in a PGC1α/FOXO1-dependent manner, which may be a potential therapeutic strategy for the prevention and treatment of PTDM.

Project description:Rationale & objectiveKidney function can be adversely affected by significant tricuspid regurgitation (TR) owing to effects on cardiac output and systemic venous congestion. However, the impact of significant TR on short- and long-term kidney function following a kidney transplant remains uncertain.Study designRetrospective observational cohort.Setting & participantsKidney transplant recipients from a single center between 2016 and 2019.ExposureSignificant TR, defined by at least moderate regurgitation, on echocardiogram before kidney transplantation.OutcomesPrimary end points included the estimated glomerular filtration rate (eGFR) at the following 3 time points: 2 weeks, 3 months, and 1 year after transplantation. Secondary end points included major adverse cardiac events including nonfatal myocardial infarction, all-cause mortality, and hospitalization owing to cardiovascular disease.Analytical approachPropensity score matching was performed in 1:3 ratio between patients treated with significant TR and controls, within a caliper 0.05 standard deviation of the propensity score, to analyze for the primary end point.ResultsAmong 557 kidney transplant recipients, 26 (5%) exhibited significant TR pretransplantation. According to propensity score matching analysis, with 1:3 ratio between 24 patients with significant TR and 72 controls, the presence of significant TR was associated with a lower eGFR posttransplantation. Specifically, the mean eGFR was 41.2 mL/min/1.73 m2 compared to 53.3 mL/min/1.73 m2 at 2 weeks (P < 0.01), 50.0 mL/min/1.73 m2 versus 60.3 mL/min/1.73 m2 at 3 months (P < 0.01), and 49.4 mL/min/1.73 m2 versus 61.2 mL/min/1.73 m2 at 1 year (P < 0.01). Delayed graft function was observed in 41.7% of the patients with significant TR compared to 12.5% of those without significant TR (P < 0.01). No patients with significant TR required dialysis after 1 year. 1-year major adverse cardiac events were nonsignificantly higher among patients with significant TR (20.8% vs 8.1%; P = 0.16).LimitationsRetrospective design and relatively small TR population.ConclusionsThe presence of significant TR among kidney transplant recipients was associated with a lower eGFR at 2 weeks, 3 months, and 1 year following transplant, although all remained dialysis independent at 1 year.

Dataset Information

Improved Glucose Tolerance in a Kidney Transplant Recipient With Type 2 Diabetes Mellitus After Switching From Tacrolimus To Belatacept: A Case Report and Review of Potential Mechanisms.

Publications

Improved Glucose Tolerance in a Kidney Transplant Recipient With Type 2 Diabetes Mellitus After Switching From Tacrolimus To Belatacept: A Case Report and Review of Potential Mechanisms.

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