Circulating Advanced Glycation Endproducts and Long-Term Risk of Cardiovascular Mortality in Kidney Transplant Recipients

Abstract

Background and objectives: In kidney transplant recipients, elevated circulating advanced glycation endproducts (AGEs) are the result of increased formation and decreased kidney clearance. AGEs trigger several intracellular mechanisms that ultimately yield excess cardiovascular disease. We hypothesized that, in stable kidney transplant recipients, circulating AGEs are associated with long-term risk of cardiovascular mortality, and that such a relationship is mediated by inflammatory, oxidative stress, and endothelial dysfunction biomarkers.

Design, setting, participants, & measurements: Prospective cohort study of stable kidney transplant recipients recruited between 2001 and 2003 in a university setting. We performed multivariable-adjusted Cox regression analyses to assess the association of AGEs (i.e., N^ε-[Carboxymethyl]lysine (CML) and N^ε-[Carboxyethyl]lysine (CEL), measured by tandem mass spectrometry) with cardiovascular mortality. Mediation analyses were performed according to Preacher and Hayes's procedure.

Results: We included 555 kidney transplant recipients (age 51±12 years, 56% men). During a median follow-up of 6.9 years, 122 kidney transplant recipients died (52% deaths were due to cardiovascular causes). CML and CEL concentrations were directly associated with cardiovascular mortality (respectively, hazard ratio, 1.55; 95% confidence interval, 1.24 to 1.95; P<0.001; and hazard ratio, 1.53; 95% confidence interval 1.18 to 1.98; P=0.002), independent of age, diabetes, smoking status, body mass index, eGFR and proteinuria. Further adjustments, including cardiovascular history, did not materially change these findings. In mediation analyses, free thiol groups and soluble vascular cell adhesion molecule-1 consistently explained approximately 35% of the association of CML and CEL with cardiovascular mortality.

Conclusions: In stable kidney transplant recipients, circulating levels of AGEs are independently associated with long-term risk of cardiovascular mortality.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_09_17_CJN00540119.mp3.

Trial registration: ClinicalTrials.gov NCT03272854.

Keywords: Glycation End Products, Advanced; ROC curve; Transplantation, Homologous; advanced glycation end-product; allografts; area under curve; biopsy; cardiovascular disease; cardiovascular mortality; cohort studies; confidence interval; endothelial dysfunction; fibrosis; glomerulonephritis; humans; hypoxia; kidney biopsy; kidney disease; kidney diseases; kidney transplantation; magnetic resonance imaging; oxidative stress; oxygen; renal transplantation.