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 prior to 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 multi-omics analyses. High-GDP exposed omental arterioles exhibited three-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 CKD5 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 zonula occludens-1 (ZO-1) disruption. Absolute and per endoluminal surface length, arteriolar endothelial cell counts inversely correlated with GDP exposure, caspase-3, TGF-ß induced pSMAD2/3, 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 10kDa 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.

Angiogenic Role of Mesothelium-Derived Chemokine CXCL1 During Unfavorable Peritoneal Tissue Remodeling in Patients Receiving Peritoneal Dialysis as Renal Replacement Therapy

“…While the in vitro induction and blocking experiments using the peritonitis effluent clearly demonstrate the pro-angiogenic potential of the IL-17/CXCL1 axis, the histological material from a rather small group of PD patients showed no apparent association between peritoneal IL-17 expression and vascularity. However, in a previous study on a larger cohort of PD patients treated with both low-and high-GDP fluids, the abundance of peritoneal IL-17 indeed correlated with microvessel density (72), thus supporting our current results. As PD-associated peritoneal remodeling develops gradually over the years, we are now conducting additional studies in a larger group of patients to characterize the time course of CXCL1-and VEGF-induced peritoneal angiogenesis, relative to inflammatory pathways.…”

“…In contrast, in children dialyzed with fluids with a high GDP content, angiogenesis and inflammatory cell infiltration is less pronounced, but associated with a diminished immune response, activation of cell death pathways and fibrosis, and accelerated arteriolopathy with significant lumen narrowing (72). Likewise, rapidly progressing peritoneal hyalinizing vasculopathy with no consistent increase in the number of CD31-positive vessels has been reported in adult patients treated with high GDPcontaining fluids (73,74).…”

Proteome-Wide Differential Effects of Peritoneal Dialysis Fluid Properties in an In Vitro Human Endothelial Cell Model

“…Patients chronically treated with PD exhibit pathohistological changes within the vasculature of their peritoneal membrane. The observed vascular alterations and involved pathomechanisms have been described to resemble those seen in diabetes mellitus patients, and may ultimately lead to ultrafiltration failure [ 17 , 27 , 28 , 29 , 30 ]. The endothelial pathomechanisms induced by properties of clinically used PD fluids, which potentially lead to these clinically relevant alterations, have not yet been elucidated.…”

Proteomics and Extracellular Vesicles as Novel Biomarker Sources in Peritoneal Dialysis in Children

“…Omics analysis also evidenced an inverse correlation between arteriolar endothelial cell counts and pSMAD2-3 induced TGF-β and IL-6. These findings question the use of high-GDP PD fluids, considering the significant cardiovascular risk of CKD patients and the suspected impact of GDP in accelerating vasculopathy development, and suggest focusing research on improvement of GDP clearance or safeguarding vascular endothelial integrity in PD patients [ 37 ].…”