Search

Background: Post-transplant diabetes mellitus is one of the most important cardiovascular risk factors after solid organ transplantation. Factors other than hyperglycaemia found in patients post-transplant, affect the level of haemoglobin A1c (HbA1c), and new markers of hyperglycaemia are needed. Our aim was to establish a 95% reference interval for glycated albumin in kidney transplant recipients, and to compare glycated albumin concentrations to the diagnostic criteria for diabetes mellitus post-transplant using oral glucose tolerance test and HbA1c. Methods: A total of 341 non-diabetic kidney transplant recipients aged ≥18 years who underwent an oral glucose tolerance test at 8 weeks and 1 year after transplantation were included. Glycated albumin was determined by liquid chromatography coupled with tandem mass spectrometry. Results: The 95% reference interval for glycated albumin was 8.2 (90% CI: 7.2–8.5) to 12.8% (90% CI: 12.2–13.5) which is not significantly different from our laboratory's 95% reference interval for persons without diabetes. At both 8 weeks and 1 year after transplantation, 35 patients (10.3%) fulfilled one, two or all three diagnostic criteria for diabetes mellitus. One year after transplantation, eight additional patients had glycated albumin concentration >12.8%. Conclusion: Our findings are in accordance with the notion that kidney transplant recipients form glycation end products like normal controls as estimated by glycated albumin and HbA1c. Further studies should address glycated albumin as a supplemental tool for the diagnosis of post-transplant diabetes mellitus in kidney transplant recipients. [ABSTRACT FROM AUTHOR]

Background: Patients with diabetes mellitus treated with successful pancreas transplantation (PTX) normalize hyperglycemia, but are exposed to immunosuppressive drugs that may impair endothelial function. This study aimed to evaluate endothelial function in single PTX recipients. Methods: Flow‐mediated dilatation (FMD) in the brachial artery was measured by ultrasound 8 weeks after transplantation in single PTX (n = 27) and compared with healthy controls (n = 58), simultaneous pancreas and kidney recipients (n = 9), and kidney transplant recipients with (n = 41) and without (n = 95) diabetes mellitus. Adjustments for age, gender, blood pressure, and body mass index were included in a linear regression model. Changes in FMD from before to 1 year after transplantation were assessed in a subgroup of PTX recipients (n = 9). Results: Flow‐mediated dilatation% in PTX recipients was not inferior to healthy controls (8.7 ± 3.6 vs 7.7 ± 3.3, P =.06) and simultaneous pancreas and kidney recipients (6.7 ± 4.5, P =.24) in an adjusted model, and superior to kidney recipients with and without diabetes (3.0 ± 3.0 and 4.8 ± 3.3, respectively, both P <.005). FMD% improved significantly from eight weeks to one year after PTX, mean 7.9 ± 4.2% vs 11.8 ± 4.8% (N = 9; P =.03). Conclusion: Flow‐mediated dilatation is well preserved in patients undergoing pancreas transplantation and is not impaired when immunosuppressive drugs are introduced. [ABSTRACT FROM AUTHOR]

Objective: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have lately become the recommended treatment in patients with type 2 diabetes and high cardiovascular risk. Patients with posttransplant diabetes mellitus (PTDM) also have high cardiovascular risk. The aim of this study was to investigate the safety and efficacy of empagliflozin in renal transplant recipients with PTDM.Research Design and Methods: Forty-nine renal transplant recipients were included in an investigator-initiated, single-center, prospective, double-blind study and randomized to receive either 10 mg empagliflozin or placebo once daily for 24 weeks. Patients transplanted >1 year ago, diagnosed with PTDM, with stable renal function (estimated glomerular filtration rate [eGFR] >30 mL/min/1.73 m2), and with stable immunosuppressive therapy were studied.Results: Forty-four renal transplant recipients (22 empagliflozin/22 placebo, 34 males) completed the study. Median (interquartile range) change in glycated hemoglobin (HbA1c) was significantly reduced with empagliflozin compared with placebo: -0.2% (-0.6, -0.1) (-2.0 mmol/mol [-6.5, -1.0]) vs. 0.1% (-0.1, 0.4) (1.0 mmol/mol [-0.75, 3.8]) (P = 0.025). The magnitude of glucose reduction was dependent on GFR and baseline HbA1c. The treatment also resulted in a significant reduction in body weight of -2.5 kg (-4.0, -0.05) compared with an increase of 1.0 kg (0.0, 2.0) in the placebo group (P = 0.014). There were no significant differences between the groups in adverse events, immunosuppressive drug levels, or eGFR.Conclusions: Empagliflozin appeared safe and improved glycemic control in renal transplant recipients with PTDM compared with placebo. A concomitant reduction in body weight was seen. [ABSTRACT FROM AUTHOR]

Summary: In this study, we investigate the association between selected inflammatory‐related biomarkers and post‐transplant hyperglycemia in kidney transplant recipients. This retrospective analysis comprises 852 patients receiving a kidney transplant at the Norwegian national transplant center between 2007 and 2012, all having a normal oral glucose tolerance test (OGTT) before transplantation. A diagnostic OGTT was performed 10 weeks post‐transplant to examine the association between inflammation‐related biomarkers and two‐hour plasma glucose (2HPG) by multivariable linear regression models adjusting for BMI, age, graft function, fasting insulin levels, dosage of prednisolone, and concentration of calcineurin inhibitors. Six of 20 biomarkers were significantly associated with 2HPG in multivariate analyses showing strong associations with soluble tumor necrosis factor type 1 (P = 0.027), Pentraxin 3 (P = 0.019), macrophage migration inhibitory factor (P = 0.024), and endothelial protein C receptor (P = 0.001). These associated markers reflect several distinct but also overlapping pathways including activation of tumor necrosis factor, macrophages, and endothelial cells. The multinomial logistic regression model showed a clear association between the inflammatory biomarkers and post‐transplant diabetes mellitus (PTDM). The association between a range of inflammation markers and PTDM suggests that these markers may be target for future studies on pathogenesis and perhaps also treatment of PTDM. [ABSTRACT FROM AUTHOR]

Body composition after kidney transplantation is linked to glucose metabolism, and impaired glucose metabolism is associated with increased risk of cardiovascular events and death. One year after transplantation, we examined 150 patients for post-transplant diabetes performing oral glucose tolerance tests and body composition measurements including visceral adipose tissue ( VAT) content from dual-energy X-ray absorptiometry scans. We found that glucose metabolism was generally improved over the first year post-transplant, and that the levels of VAT and percentage VAT of total body fat mass ( VAT%tot) were lowest in those with normal glucose tolerance and highest in those with post-transplant diabetes mellitus. In a multivariable linear regression analysis, 87.4% of the variability in fasting glucose concentration was explained by insulin resistance ( P<.001, HOMA- IR index), beta cell function ( P<.001, HOMA-beta), VATBFM) were lowest in those with normal glucose tolerance and highest in those with post-transplant diabetes mellitus. In a multivariable linear regression analysis, 87.4% of the variability in fasting glucose concentration was explained by insulin resistance ( P<.001, HOMA- IR index), beta cell function ( P<.001, HOMA-beta), VAT%tot BFM ( P=.007), and body mass index ( BMI; P=.015; total model P<.001), while insulin resistance ( P<.001) and beta cell function ( P<.001) explained 31.9% of the variability in 2-hour glucose concentration in a multivariable model (total model P<.001). VAT was associated with glucose metabolism to a larger degree than BMI. In conclusion, VAT is associated with hyperglycemia one year after kidney transplantation, and insulin resistance and beta cell function estimates are the most robust markers of glucose metabolism. [ABSTRACT FROM AUTHOR]

Current diagnostic criteria for post-transplantation diabetes mellitus ( PTDM) are either fasting plasma glucose ≥7.0 mmol/l (≥126 mg/dl) or postchallenge plasma glucose ≥11.1 mmol/l (≥200 mg/dl) 2 h after glucose administration [oral glucose tolerance test ( OGTT) criterion]. In this retrospective cohort study of 1632 renal transplant recipients ( RTRs) without known diabetes mellitus at the time of transplantation, we estimated mortality hazard ratios for patients diagnosed with PTDM by either conventional glucose criteria or the proposed glycated haemoglobin (HbA1c) criterion [HbA1c ≥6.5% (≥48 mmol/mol)]. During a median follow-up of 7.0 years, 311 patients died. Compared with nondiabetic patients and after adjustment for confounders, patients diagnosed with PTDM based on chronic hyperglycaemia early after transplantation (manifest PTDM) or by the OGTT criterion at 10 weeks post-transplant suffered a higher mortality risk ( HR 1.59, 95% CI 1.06-2.38, P = 0.02 and HR 1.56, 95% CI 1.04-2.38, P = 0.03, respectively). In contrast, patients diagnosed with PTDM by the HbA1c criterion at 10 weeks or between 10 weeks and 1 year post-transplant were not associated with mortality ( HR 0.96, 95% CI 0.61-1.51, P = 0.86 and 1.58, 95% CI 0.74-3.36, P = 0.24 respectively). After adjustment for confounders and competing risks, only patients with manifest PTDM had a significantly higher cardiovascular mortality risk (subdistributional HR 2.31, 95% CI 1.19-4.47, P < 0.001). Since many cases with PTDM were only identified by the OGTT, we recommend monitoring fasting plasma glucose early after renal transplantation followed by an OGTT at 2-3 months post-transplant in patients without overt diabetes mellitus. [ABSTRACT FROM AUTHOR]

Objective: Development of posttransplantation diabetes (PTDM) is characterized by reduced insulin secretion and sensitivity. We aimed to investigate whether hyperglucagonemia could play a role in PTDM and to examine the insulinotropic and glucagonostatic effects of the incretin hormone glucagon-like peptide 1 (GLP-1) during fasting and hyperglycemic conditions, respectively.Research Design and Methods: Renal transplant recipients with (n = 12) and without (n = 12) PTDM underwent two separate experimental days with 3-h intravenous infusions of GLP-1 (0.8 pmol/kg/min) and saline, respectively. After 1 h of infusion, a 2-h hyperglycemic clamp (fasting plasma glucose + 5 mmol/L) was established. Five grams of arginine was given as an intravenous bolus 10 min before termination of the clamp.Results: Fasting concentrations of glucagon (P = 0.92) and insulin (P = 0.23) were similar between the groups. In PTDM patients, glucose-induced glucagon suppression was significantly less pronounced (maximal suppression from baseline: 43 ± 12 vs. 65 ± 12%, P < 0.001), while first- and second-phase insulin secretion were significantly lower. The PTDM group also exhibited a significantly lower insulin response to arginine (P = 0.01) but similar glucagon and proinsulin responses compared with control subjects. In the preclamp phase, GLP-1 lowered fasting plasma glucose to the same extent in both groups but reduced glucagon only in PTDM patients. During hyperglycemic clamp, GLP-1 reduced glucagon concentrations and increased first- and second-phase insulin secretion in both groups.Conclusions: PTDM is characterized by reduced glucose-induced insulin secretion and attenuated glucagon suppression during a hyperglycemic clamp. Similar to the case in type 2 diabetes, GLP-1 infusion seems to improve (insulin) or even normalize (glucagon) these pathophysiological defects. [ABSTRACT FROM AUTHOR]

Background New-onset diabetes after transplantation (NODAT) is a common complication after renal transplantation. There are limited available oral drugs to treat hyperglycaemia in this population owing to reduced renal function, potential interactions with immunosuppressive drugs and adverse effects such as hypoglycaemic events that may increase the cardiovascular risk. This study was initiated to investigate efficacy and safety of sitagliptin treatment that may represent a novel alternative in renal transplant recipients. Methods Nineteen long-term stable renal transplant recipients with NODAT were included in a controlled, cross-over study and randomized to first receive either sitagliptin 50–100 mg/day or a sitagliptin-free period of 4 weeks. Median age (interquartile range, IQR) was 67 (62–72) years (12 males/7 females), all studied 1 (1–3) year after transplantation. The immunosuppressive regimen was a triple calcineurin inhibitor-based therapy. Oral glucose tolerance test (OGTT) with insulin and C-peptide responses and laser Doppler (LD) flowmetry assessment of endothelial function were performed at baseline and after each treatment period. Home measurements of plasma glucose were performed daily during the study. Results The median (IQR) first- and second-phase insulin secretion responses increased significantly by 56.3% (45.2–112.6%, P = 0.005) and 39.3% (26.5–81.0%, P = 0.006), respectively, following sitagliptin treatment as compared with no sitagliptin treatment. Fasting and 2-h plasma glucose concentrations fell significantly {0.9 mmol/L [0.5–1.7 mmol/L (16.2 mg/dL), P = 0.003] and 2.9 mmol/L [0.5–6.4 mmol/L (52.3 mg/dL), P = 0.004], respectively}, as did also home measurements of plasma glucose. Endothelial function and plasma markers of cardiovascular risk were unaffected. No serious adverse events were observed. Two mild and asymptomatic hypoglycaemic episodes were observed in combination with glipizide. Conclusions Sitagliptin increases insulin secretion and reduces fasting and postprandial plasma glucose in renal transplant recipients with NODAT. The short-term treatment was well tolerated, and sitagliptin seems safe in this population. [ABSTRACT FROM AUTHOR]

Calcineurin inhibitors (CNI) are involved in the development of post-transplant diabetes mellitus (PTDM). Changes in insulin secretion and sensitivity contribute to the development of PTDM and are associated with endothelial function. Methods: In a pre-defined substudy of a previously published randomized trial in renal transplant recipients we compared the effect of CNI treatment (n = 23) with complete CNI-avoidance (n = 21) on insulin secretion and sensitivity (oral glucose tolerance test) as well as endothelial function (laser Doppler flowmetry), 10 wk and 12 months following transplantation. Results: Insulin sensitivity differed 10 wk post-transplant and was significantly better after 12 months in patients never treated with CNI drugs [0.091 (0.050) vs. 0.083 (0.036) μmol/kg/min/pmol/L, p = 0.043]. Insulin secretion tended to be higher in CNI treated patients at both time points (p = 0.068). Endothelial function was not significantly different at week 10 [540 (205) vs. 227 (565) arbitary units × minutes, p = 0.35] or month 12 [510 (620) vs. 243 (242), p = 0.33]. Conclusions: Findings in the present study indicate that long-term CNI treatment negatively affects glucose metabolism and this may contribute to the increased risk for premature cardiovascular disease in CNI treated renal transplant recipients. Further studies to elucidate this hypothesis are, however, needed. [ABSTRACT FROM AUTHOR]

Background: The use of HbA1c ≥6.5% for diagnosis of diabetes has been challenged for post-transplantation diabetes mellitus (PTDM) also known as new onset diabetes after transplantation (NODAT) due to a low sensitivity early after renal transplantation. PTDM diagnosed with an oral glucose tolerance test (OGTT) is highly predictable for long-term patient mortality. HbA1c was introduced for diagnosis based on the risk of developing diabetic retinopathy. The utility of HbA1c measures versus glucose criteria has not been widely assessed in stable transplant patients but still HbA1c is widely used in this population. The aim of the present analyses was to validate the utility of fasting plasma glucose (FPG) together with HbA1c in diagnosing PTDM in stable renal transplant recipients (RTRs).Methods: OGTT's were performed one year after transplantation in 494 consecutive RTRs without diabetes. FPG and HbA1c were obtained the same day, before starting the OGTT. Validation was performed using C-statistics and logistic regression analyses.Results: PTDM was diagnosed in 51 patients (10.3%) by glucose criteria, 38 (74%) patients were diagnosed by FPG ≥7.0 mmol/L [126.1 mg/dl], and 13 (26%) only by 2-h plasma glucose. Six of the latter had HbA1c ≥6.5%. Only seven patients out of the 51 (13.7%) PTDM patients remained undiagnosed when HbA1c ≥6.5% was used together with FPG, and five of these regressed to normal after a median follow-up of 14 months. ROC curves including FPG and HbA1c versus OGTT derived criteria revealed an AUC of 0.858.Conclusions: Combining standard diagnostic FPG and HbA1c criteria captured almost all patients with persistent PTDM in stable RTRs. The combined use of the criteria appears to be an applicable diagnostic strategy for PTDM without the need of an OGTT one year post-transplant.Trial Registration: Retrospectively registered. [ABSTRACT FROM AUTHOR]