Background. Autosomal dominant polycystic kidney disease (ADPKD) is linked with risk for posttransplantation diabetes mellitus (PTDM), but this association has methodologic limitations like diagnostic criteria. The aim of this study was to use contemporary diagnostic criteria for PTDM and explore any risk association for kidney transplant recipients with ADPKD. Methods. We undertook a retrospective analysis of 1560 nondiabetic kidney transplant recipients between 2007 and 2018 at a single center, of whom 248 (15.9%) had ADPKD. Local/national data were linked for every patient, with manual data capture of PTDM diagnosis by International Consensus Recommendations. We then pooled our data with eligible studies after an updated systematic review and performed a meta-analysis to estimate the pooled effect. Results. Comparing ADPKD versus non-ADPKD kidney transplant recipients, PTDM risk was not significantly different at our center (19.4% versus 14.9%, respectively; P = 0.085). ADPKD patients who developed PTDM were older, borderline heavier, and less likely to be recipients of living kidney donor compared with ADPKD patients who remained free of PTDM. Systematic review of the literature identified 14 eligible studies, of which 8 had a PTDM diagnosis consistent with Consensus recommendations. In the meta-analysis, we observed an increased odds ratio (OR) of kidney transplant recipients with ADPKD developing PTDM regardless of all study inclusion (OR, 1.98; 95% confidence interval, 1.43-2.75) or restricted study inclusion based on robust PTDM diagnostic criteria (OR, 1.81; 95% confidence interval, 1.16-2.83). Conclusions. ADPKD kidney transplant candidates should be counseled of their increased risk for PTDM, with further work warranted to investigate any underlying metabolic pathophysiology.
Introduction:The aim of this study was to compare the management strategy and clinical outcomes for kidney transplant recipients with pre-transplant versus post-transplantation diabetes (PTDM) in a contemporary cohort.Methods: This is a single-centre, retrospective. observational study of kidney transplant recipients between 2007 and 2018 with follow-up to 31 December 2020. Data were extracted from hospital electronic patient records, with clinical outcomes linked to national data sets. PTDM was diagnosed by international consensus guidelines. Unadjusted and adjusted survival outcomes were assessed with Kaplan-Meier curves and Cox regression models, respectively, with PTDM handled as a time-varying covariate.Results: Data were analysed for 1,757 kidney transplant recipients, of whom 11.8% (n = 207) had pre-transplant diabetes, and 13.8% (n = 243) developed PTDM with median time to onset 108 days (IQR 46-549 days). Median followup was 1,839 days (IQR 928-2985 days). Disparate management strategies were observed, although insulin was the commonest glucose-lowering therapy for all patients with diabetes. In adjusted models, PTDM was associated with lower mortality (HR 0.663, 95% CI 0.543-0.810) and pre-diabetes with higher mortality (HR 1.675, 95% CI 1.396-2.011). However, if analyses are restricted to those with at least 5-year follow-up, then PTDM has no association with mortality (HR 0.771, 95% CI 0.419-1.096), but pre-transplant diabetes remains associated with higher mortality (HR 2.029, 95% CI 1.367-3.012).Conclusions: Pre-transplant diabetes remains associated with increased mortality risk after kidney transplantation, but PTDM effects are time dependent.Development of PTDM should be encouraged as a mandated registry return to study the long-term impact on survival outcomes.
Background. The association between specific HLA alleles and risk for posttransplantation diabetes (PTDM) in a contemporary and multiethnic kidney transplant recipient cohort is not clear. Methods. In this single-center analysis, data were retrospectively analyzed for 1560 nondiabetic kidney transplant recipients at a single center between 2007 and 2018, with median follow-up of 33 mo (interquartile range 8-73). HLA typing methodology was by DNA analysis and reported at the resolution required for the national allocation scheme. Diagnosis of PTDM was aligned with International Consensus recommendations. Results. PTDM developed in 231 kidney transplant recipients. Exploring 99 HLA alleles, the presence of Cw12, B52, B38, B58, DQ4, A80, and DR13 and the absence of DQ3 and DR04 were associated with significant increases in PTDM risk. In a multivariable Cox regression model, adjusting for other clinical risk factors for PTDM, the presence of Cw12 (hazard ratio [HR], 1.57; 95% CI, 1.08-2.27; P = 0.017) and DQ4 (HR, 1.78; 95% CI, 1.07-2.96; P = 0.026) were found to be independent risk factors for PTDM. There was also evidence that the presence of B58 increases PTDM risk within the subgroup of recipients of White ethnicity (HR, 5.01; 95% CI,; P < 0.001). Conclusion. Our data suggest that specific HLA alleles can be associated with PTDM risk, which can be used pretransplantation for PTDM risk stratification. However, association is not causality, and this work requires replication and further investigation to understand underlying biological mechanisms.
Background and Aims BK infection remains a risk factor for kidney transplant dysfunction and allograft loss. While many risk factors are reported in the literature, many are from historical cohorts and have never been validated in the contemporary era. The aim of this study was to explore risk factors for BK virus infection in the contemporary era of kidney transplantation and immunosuppression using a well-phenotyped clinical cohort. Method In this single-centre observational study, data was extracted from hospital informatics systems for all kidney allograft recipients transplanted between January 1st 2007 and June 30th 2018. BK virus was checked in the context of any transplant dysfunction (indication-based) aligned with UK guidance. Positive BK virus results were defined as >200 copies/ml. Clinical outcomes extracted from electronic hospital records were linked with national datasets. Univariate analysis was undertaken to investigate the association between donor-, recipient- and transplant-related variables and risk for BK virus reactivation. Any variable with a p-value <0.15 in univariate Results Data was analysed for 1,770 kidney transplant recipients with median follow up 5.3 years (IQR 2.7 to 8.7 years). BK virus was associated with (versus without); male sex (8.3% versus 5.3% respectively, p=0.010), ABO-incompatible transplantation (12.7% versus 5.9% respectively, p=0.021) and delayed graft function (9.0% versus 6.3% respectively, p=0.032). In a multivariate analysis, including all variables in univariate analysis with p-value <0.15, the only independent variables associated with BK infection were recipient male sex (OR 2.051 [95% CI 1.196-3.519], p=0.009 and ABO-incompatible transplantation (OR 4.087 {95% CI 1.847-9.042], p=0.001). From an outcome perspective, recipients with BK viraemia had worse graft function at 1-, 3- and 5-year post kidney transplantation but no increased risk for death-censored graft loss. Conclusion In the contemporary era, only recipient male sex and ABO-incompatible kidney transplantation are independently associated with risk for BK infection. Study limitations include lack of data regarding novel risk factors (e.g. BK virus serostatus). Association does not imply causality and we suggest further work is warranted to validate contemporary risk factors for BK infection in different kidney transplant population cohorts.
Background and Aims The latest consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommends metformin and lifestyle intervention as first-line therapy for type 2 diabetes. Second-line therapy recommendation is the use sodium-glucose cotransporter 2 (SGLT 2) inhibitors (if estimated glomerular filtration rate [eGFR] is adequate) or GLP-1 receptor agonists if eGFR is inadequate (or SGLT-2 inhibitors not tolerated). No recommendation is made for dipeptidyl peptidase-4 (DPP-4) inhibitors. Therapy choices are limited for patients with both type 2 diabetes and moderate-to-severe chronic kidney disease (CKD) and it is unclear from published data if observed cardiovascular benefits of new anti-diabetic agents extend to the CKD cohort. The aim of this study was to undertake a systematic review of all published CVOT trials using new anti-diabetic agents (GLP-1 receptor agonist, DPP-4 inhibitor, SGLT 2 inhibitor). Method We searched MEDLINE (via PubMed and the Cochrane Central Register of Controlled Trials) up to 1st December 2019. Data was stratified by trial entry eGFR into normal (eGFR ≥60 ml/min) and CKD (eGFR <60 ml/min), with data extracted for primary major cardiovascular event (MACE) rates such as cardiovascular death, stroke and/or myocardial infarct. A meta-analysis with random effects model was performed to estimate overall hazard ratios (HRs) for MACE with new anti-diabetic agents stratified by eGFR. Inter-study heterogeneity was assessed with the I2 index and Cochran’s Q test. Results We analysed 13 studies from 16 that were eligible after our search strategy, with 2 excluded due lack of data stratified by eGFR and 1 excluded due to combined MACE/renal outcomes. The studies (GLP-1 agonists, n=6; DPP-4 inhibitors, n=4; SGLT 2 inhibitors, n=3) had a combined total of 128,266 participants (22.1% with eGFR <60 ml/min). HR for MACE with GLP-1 agonists for participants with eGFR ≥60 ml/min was 0.87 (95% CI 0.77-0.98; p=0.02) and for participants with eGFR <60 ml/min was 0.90 (95% CI 0.78-1.04; p=0.14). HR for MACE with DPP-4 inhibitors for participants with eGFR ≥60 ml/min was 0.99 (95% CI 0.92-1.07; p=0.86) and for participants with eGFR <60 ml/min was 0.99 (95% CI 0.91-1.08; p=0.86). HR for MACE with SGLT 2 inhibitors for participants with eGFR ≥60 ml/min was 0.98 (95% CI 0.88-1.10; p=0.78) and for participants with eGFR <60 ml/min was 0.82 (95% CI 0.70-0.96; p=0.01). Significant heterogeneity was observed in the meta-analyses for each new anti-diabetic therapy drug class stratified by eGFR. Conclusion Among the new anti-diabetic agents, our study suggests efficacy for prevention of MACE in the setting of CKD exists only for SGLT 2 inhibitors and not with GLP-1 receptor agonists or DPP-4 inhibitors. Targeted CVOT studies incorporating participants with diabetes and CKD are critical to guide glycaemic management in these high-risk patients. Until then, we suggest recommendations for second-line therapy in patients with type 2 diabetes and renal impairment should be amended to reflect the current evidence base supporting prevention of MACE with SGLT 2 inhibitors versus other new anti-diabetic agents.
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