Peritoneal Dialysis Fluid Supplementation with Alanyl-Glutamine Attenuates Conventional Dialysis Fluid-Mediated Endothelial Cell Injury by Restoring Perturbed Cytoprotective Responses

Abstract

Long-term clinical outcome of peritoneal dialysis (PD) depends on adequate removal of small solutes and water. The peritoneal endothelium represents the key barrier and peritoneal transport dysfunction is associated with vascular changes. Alanyl-glutamine (AlaGln) has been shown to counteract PD-induced deteriorations but the effect on vascular changes has not yet been elucidated. Using multiplexed proteomic and bioinformatic analyses we investigated the molecular mechanisms of vascular pathology in-vitro (primary human umbilical vein endothelial cells, HUVEC) and ex-vivo (arterioles of patients undergoing PD) following exposure to PD-fluid. An overlap of 1813 proteins (40%) of over 3100 proteins was identified in both sample types. PD-fluid treatment significantly altered 378 in endothelial cells and 192 in arterioles. The HUVEC proteome resembles the arteriolar proteome with expected sample specific differences of mainly immune system processes only present in arterioles and extracellular region proteins primarily found in HUVEC. AlaGln-addition to PD-fluid revealed 359 differentially abundant proteins and restored the molecular process landscape altered by PD fluid. This study provides evidence on validity and inherent limitations of studying endothelial pathomechanisms in-vitro compared to vascular ex-vivo findings. AlaGln could reduce PD-associated vasculopathy by reducing endothelial cellular damage, restoring perturbed abundances of pathologically important proteins and enriching protective processes.

A Novel UPLC-MS/MS Method Identifies Organ-Specific Dipeptide Profiles

“…To increase endogenous Gln concentrations, stable glutamine releasing dipeptides such as Ala-Gln and Gly-Gln are used [ 17 , 18 , 19 , 20 ] instead of free Gln. Parenteral supplementation with Gln dipeptides significantly reduced hospital mortality and infectious complication rates in critically ill patients [ 18 , 19 , 21 ] and short-term supplementation of peritoneal dialysis fluids resulted in restored stress responses and improved immune competence of peritoneal cells [ 20 ]. Besides the liver, skeletal muscle also generates a major portion of the total pool of free amino acids and is a major store for glutamine.…”

Biological Effects of XyloCore, a Glucose Sparing PD Solution, on Mesothelial Cells: Focus on Mesothelial-Mesenchymal Transition, Inflammation and Angiogenesis

“…The addition of the dipeptide alanyl-glutamine (Ala-Gln) to the PD dialysate has been shown in experimental models to protect from peritoneal membrane deterioration [ 63 ], to restore cytoprotective cell response [ 64 ], and to reduce PD-associated vasculopathy enabling protective processes [ 65 ]. Early clinical trials in man confirmed that the addition of Ala-Gln to glucose-based PD solutions restored the stress response and improved cellular host-defences in PD cells [ 66 ].…”

How to Improve the Biocompatibility of Peritoneal Dialysis Solutions (without Jeopardizing the Patient’s Health)

“…The results of two different dipeptide-based PD solution rat/mice studies, within 15 years of each other, have provided evidence that the use of PD solutions containing dipeptides may have a local protective effect (peritoneal membrane/cavity), as well as positive systemic effects (sustained UF, smaller changes in plasma amino acid levels), resulting in better biocompatibility [ 122 ]. More recently, PD fluid supplemented with Ala-Gln dipeptide (8 mM) could reduce PD-associated vasculopathy by reducing endothelial cellular damage, restoring the perturbed abundances of pathologically high levels of key proteins, and enabling protective processes [ 123 ].…”