Glucose Derivative Induced Vasculopathy in Children on Chronic Peritoneal Dialysis

Abstract

Rationale: Patients with chronic kidney disease (CKD) have an exceedingly high cardiovascular risk; which further increases in patients on peritoneal dialysis (PD). The pathophysiological role of reactive metabolites accumulating in CKD such as glucose degradation products (GDP) is uncertain. Objective: Delineating the impact of GDP present in PD fluids in accelerated vasculopathy development in patients with CKD. Methods and Results: Omental and parietal peritoneal tissues were obtained from 107 children with CKD before dialysis and 90 children on chronic PD with PD fluids containing very low or high concentrations of GDP. Omental arterioles, protected from local PD fluid exposure by surrounding fat, were microdissected for multiomics analyses. High-GDP exposed omental arterioles exhibited 3-fold higher advanced glycation endproduct concentrations and upregulated genes involved in cell death/apoptosis and suppressed genes related to cell viability/survival, cytoskeleton organization, and immune response biofunctions. Vasculopathy-associated canonical pathways concordantly regulated on gene and protein level with high-GDP exposure included cell death/proliferation, apoptosis, cytoskeleton organization, metabolism and detoxification, cell junction signaling, and immune response. Parietal peritoneal arterioles of patients exposed to high-GDP fluids exhibited lumen narrowing compared to patients with CKD stage 5 (end-stage kidney disease) and patients on low-GDP PD, intima thickness was increased. Protein quantification verified increased proapoptotic activity and cytoskeleton disintegration, single-molecule-localization microscopy demonstrated arteriolar endothelial ZO-1 (zonula occludens-1) disruption. Absolute and per endoluminal surface length, arteriolar endothelial cell counts inversely correlated with GDP exposure, caspase-3, TGF (transforming growth factor)-β–induced pSMAD2/3 (phosphorylated SMAD2/3), interleukin-6, ZO-1 abundance, and lumen narrowing. In vitro, 3,4-dideoxyglucosone-3-ene reduced lamin-A/C and membrane ZO-1 assembly, increased pSMAD2/3, and ionic and 4 and 10 kDa permeability of arterial endothelial cells. Conclusions: Our findings indicate a fundamental role of GDP in PD-associated vasculopathy, exerted by endothelial cell junction and cytoskeleton disruption, and induction of apoptosis. They should redirect the focus of research and intervention on targeting reactive metabolite overload in CKD and PD. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01893710.