Dynamic Frailty Before Kidney Transplantation: Time of Measurement Matters.

BACKGROUND: Frail kidney transplant (KT) recipients have higher risk of adverse post-KT outcomes. Yet, there is interest in measuring frailty at KT evaluation and then using this information for post-KT risk stratification. Given long wait times for KT, frailty may improve or worsen between evaluation and KT. Patterns, predictors, and post-KT adverse outcomes associated with these changes are unclear. METHODS: Five hundred sixty-nine adult KT candidates were enrolled in a cohort study of frailty (November 2009-September 2017) at evaluation and followed up at KT. Patterns of frailty transitions were categorized as follows: (1) binary state change (frail/nonfrail), (2) 3-category state change (frail/intermediate/nonfrail), and (3) raw score change (-5 to 5). Adjusted Cox proportional hazard and logistic regression models were used to test whether patterns of frailty transitions were associated with adverse post-KT outcomes. RESULTS: Between evaluation and KT, 22.0% became more frail, while 24.4% became less frail. Black race (relative risk ratio, 1.98; 95% confidence interval [CI], 1.07-3.67) was associated with frail-to-nonfrail transition, and diabetes (relative risk ratio, 2.56; 95% CI, 1.22-5.39) was associated with remaining stably frail. Candidates who became more frail between 3-category states (hazard ratio, 2.27; 95% CI, 1.11-4.65) and frailty scores (hazard ratio, 2.36; 95% CI, 1.12-4.99) had increased risk of post-KT mortality and had higher odds of length of stay ≥2 weeks (3-category states: odds ratio, 2.02; 95% CI, 1.20-3.40; frailty scores: odds ratio, 1.92; 95% CI, 1.13-3.25). CONCLUSIONS: Almost half of KT candidates experienced change in frailty between evaluation and KT, and those transitions were associated with mortality and longer length of stay. Monitoring changes in frailty from evaluation to admission may improve post-KT risk stratification.

Glycosphingolipids promote pro-atherogenic pathways in the pathogenesis of hyperglycemia-induced accelerated atherosclerosis.

INTRODUCTION: Three out of four people with diabetes will die of cardiovascular disease. However, the molecular mechanisms by which hyperglycemia promotes atherosclerosis, the major underlying cause of cardiovascular disease, are not clear. OBJECTIVES: Three distinct models of hyperglycemia-associated accelerated atherosclerosis were used to identify commonly altered metabolites and pathways associated with the disease. METHODS: Normoglycemic apolipoprotein-E-deficient mice served as atherosclerotic control. Hyperglycemia was induced by multiple low-dose streptozotocin injections, or by introducing a point-mutation in one copy of insulin-2 gene. Glucosamine-supplemented mice, which experience accelerated atherosclerosis to a similar extent as hyperglycemia-induced models without alterations in glucose or insulin levels, were also included in the analysis. Untargeted plasma metabolomics were used to investigate hyperglycemia-associated accelerated atherosclerosis in three disease models. The effect of specific significantly altered metabolites on pro-atherogenic processes was investigated in cultured human vascular cells. RESULTS: Hyperglycemic and glucosamine-supplemented mice showed distinct metabolomic profiles compared to controls. Meta-analysis of three disease models revealed 62 similarly altered metabolite features (FDR-adjusted p < 0.05). Identification of shared metabolites revealed alterations in glycerophospholipid and sphingolipid metabolism, and pro-atherogenic processes including inflammation and oxidative stress. Post-multivariate and pathway analyses indicated that the glycosphingolipid pathway is strongly associated with hyperglycemia-induced accelerated atherosclerosis in these atherogenic mouse models. Glycosphingolipids induced oxidative stress and inflammation in cultured human vascular cells. CONCLUSION: Glycosphingolipids are strongly associated with hyperglycemia-induced accelerated atherosclerosis in three distinct models. They also promote pro-atherogenic processes in cultured human cells. These results suggest glycosphingolipid pathway may be a potential therapeutic target to block or slow atherogenesis in diabetic patients.