A Novel Formulation of Glucose-Sparing Peritoneal Dialysis Solutions with  l -Carnitine Improves Biocompatibility on Human Mesothelial Cells

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Abstract

The main reason why peritoneal dialysis (PD) still has limited use in the management of patients with end-stage renal disease (ESRD) lies in the fact that the currently used glucose-based PD solutions are not completely biocompatible and determine, over time, the degeneration of the peritoneal membrane (PM) and consequent loss of ultrafiltration (UF). Here we evaluated the biocompatibility of a novel formulation of dialytic solutions, in which a substantial amount of glucose is replaced by two osmometabolic agents, xylitol and l-carnitine. The effect of this novel formulation on cell viability, the integrity of the mesothelial barrier and secretion of pro-inflammatory cytokines was evaluated on human mesothelial cells grown on cell culture inserts and exposed to the PD solution only at the apical side, mimicking the condition of a PD dwell. The results were compared to those obtained after exposure to a panel of dialytic solutions commonly used in clinical practice. We report here compelling evidence that this novel formulation shows better performance in terms of higher cell viability, better preservation of the integrity of the mesothelial layer and reduced release of pro-inflammatory cytokines. This new formulation could represent a step forward towards obtaining PD solutions with high biocompatibility.

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Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells.

María Yañez-Mó, Enrique Lara-Pezzi, Rafael Selgas … (2003)

During continuous ambulatory peritoneal dialysis, the peritoneum is exposed to bioincompatible dialysis fluids that cause denudation of mesothelial cells and, ultimately, tissue fibrosis and failure of ultrafiltration. However, the mechanism of this process has yet to be elucidated. Mesothelial cells isolated from effluents in dialysis fluid from patients undergoing continuous ambulatory peritoneal dialysis were phenotypically characterized by flow cytometry, confocal immunofluorescence, Western blotting, and reverse-transcriptase polymerase chain reaction. These cells were compared with mesothelial cells from omentum and treated with various stimuli in vitro to mimic the transdifferentiation observed during continuous ambulatory peritoneal dialysis. Results were confirmed in vivo by immunohistochemical analysis performed on peritoneal-biopsy specimens. Soon after dialysis is initiated, peritoneal mesothelial cells undergo a transition from an epithelial phenotype to a mesenchymal phenotype with a progressive loss of epithelial morphology and a decrease in the expression of cytokeratins and E-cadherin through an induction of the transcriptional repressor snail. Mesothelial cells also acquire a migratory phenotype with the up-regulation of expression of alpha2 integrin. In vitro analyses point to wound repair and profibrotic and inflammatory cytokines as factors that initiate mesothelial transdifferentiation. Immunohistochemical studies of peritoneal-biopsy specimens from patients undergoing continuous ambulatory peritoneal dialysis demonstrate the expression of the mesothelial markers intercellular adhesion molecule 1 and cytokeratins in fibroblast-like cells entrapped in the stroma, suggesting that these cells stemmed from local conversion of mesothelial cells. Our results suggest that mesothelial cells have an active role in the structural and functional alteration of the peritoneum during peritoneal dialysis. The findings suggest potential targets for the design of new dialysis solutions and markers for the monitoring of patients. Copyright 2003 Massachusetts Medical Society

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The Current State of Peritoneal Dialysis.

Rajnish Mehrotra, Olivier Devuyst, Simon J. Davies … (2016)

Technical innovations in peritoneal dialysis (PD), now used widely for the long-term treatment of ESRD, have significantly reduced therapy-related complications, allowing patients to be maintained on PD for longer periods. Indeed, the survival rate for patients treated with PD is now equivalent to that with in-center hemodialysis. In parallel, changes in public policy have spurred an unprecedented expansion in the use of PD in many parts of the world. Meanwhile, our improved understanding of the molecular mechanisms involved in solute and water transport across the peritoneum and of the pathobiology of structural and functional changes in the peritoneum with long-term PD has provided new targets for improving efficiency and for intervention. As with hemodialysis, almost half of all deaths on PD occur because of cardiovascular events, and there is great interest in identifying modality-specific factors contributing to these events. Notably, tremendous progress has been made in developing interventions that substantially reduce the risk of PD-related peritonitis. Yet the gains have been unequal among individual centers, primarily because of unequal clinical application of knowledge gained from research. The work to date has further highlighted the areas in need of innovation as we continue to strive to improve the health and outcomes of patients treated with PD.

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Morphologic changes in the peritoneal membrane of patients with renal disease.

Andrew Mackenzie, Christopher T Ruhland, … (2002)

This study examined the morphologic features of the parietal peritoneal membranes of 130 patients undergoing peritoneal dialysis (PD) and compared them with the features of the peritoneal membranes of normal individuals, uremic predialysis patients, and patients undergoing hemodialysis. The median thickness of the submesothelial compact collagenous zone was 50 microm for normal subjects, 140 microm for uremic patients, 150 microm for patients undergoing hemodialysis, and 270 microm for patients undergoing PD (P 97 mo, 700 microm (n = 19)]. Vascular changes included progressive subendothelial hyalinization, with luminal narrowing or obliteration. These changes were absent in samples from normal subjects but were present in 28% of samples from uremic patients and 56% of biopsies from patients undergoing PD. In the PD group, the prevalence of vasculopathy increased significantly with therapy duration (P = 0.0001). The density of blood vessels per unit length of peritoneum was significantly higher for patients with membrane failure and was correlated with the degree of fibrosis (P = 0.01). For the first time, a comprehensive cross-sectional analysis of the morphologic changes in the peritoneal membranes of patients undergoing PD is provided. The infrequency of fibrosis in the absence of vasculopathy suggests that vasculopathy may predispose patients to the development of fibrosis. This study provides a sufficiently large cohort of samples to allow structure-function relationships to be established, as well as providing a repository of tissue for further studies.

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Author and article information

Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 24 December 2020

Publication date Collection: January 2021

Volume: 22

Issue: 1

Electronic Location Identifier: 123

Affiliations

[1 ]Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy; francesca.piccapane@ 123456uniba.it (F.P.); andrea.gerbino@ 123456uniba.it (A.G.); maria.svelto@ 123456uniba.it (M.S.)

[2 ]Department of Medicine, G. d’Annunzio University of Chieti-Pescara, 66013 Chieti, Italy; mario.bonomini@ 123456unich.it

[3 ]Department of Emergency and Organ Transplantation, University of Bari, 70125 Bari, Italy; giuseppe.castellano@ 123456uniba.it

[4 ]Department of Sciences, University of Basilicata, 85100 Potenza, Italy; monica.carmosino@ 123456unibas.it

[5 ]Department of Research and Development, CoreQuest Sagl, Technopole, 6928 Manno, Switzerland; a.arduini@ 123456corequest.ch

Author notes

[* ]Correspondence: giuseppe.procino@ 123456uniba.it

Author information

Mario Bonomini https://orcid.org/0000-0002-8466-6314

Giuseppe Castellano https://orcid.org/0000-0002-0153-3795

Andrea Gerbino https://orcid.org/0000-0002-2839-0130

Giuseppe Procino https://orcid.org/0000-0002-0043-7523

Article

Publisher ID: ijms-22-00123

DOI: 10.3390/ijms22010123

PMC ID: 7795315

PubMed ID: 33374405

SO-VID: 7a9d9398-5b06-4efb-8181-3014303dec7c

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

A Novel Formulation of Glucose-Sparing Peritoneal Dialysis Solutions with l-Carnitine Improves Biocompatibility on Human Mesothelial Cells

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Abstract

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Most cited references 65

Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells.

The Current State of Peritoneal Dialysis.

Morphologic changes in the peritoneal membrane of patients with renal disease.

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