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Sustained low peritoneal effluent CCL18 levels are associated with preservation of peritoneal membrane function in peritoneal dialysis.

ABSTRACT: Peritoneal membrane failure (PMF) and, ultimately, encapsulating peritoneal sclerosis (EPS) are the most serious peritoneal dialysis (PD) complications. Combining clinical and peritoneal transport data with the measurement of molecular biomarkers, such as the chemokine CCL18, would improve the complex diagnosis and management of PMF. We measured CCL18 levels in 43 patients' effluent and serum at baseline and after 1, 2, and 3 years of PD treatment by retrospective longitudinal study, and evaluated their association with PMF/EPS development and peritoneal risk factors. To confirm the trends observed in the longitudinal study, a cross-sectional study was performed on 61 isolated samples from long-term (more than 3 years) patients treated with PD. We observed that the patients with no membrane dysfunction showed sustained low CCL18 levels in peritoneal effluent over time. An increase in CCL18 levels at any time was predictive of PMF development (final CCL18 increase over baseline, p = .014; and maximum CCL18 increase, p = .039). At year 3 of PD, CCL18 values in effluent under 3.15 ng/ml showed an 89.5% negative predictive value, and higher levels were associated with later PMF (odds ratio 4.3; 95% CI 0.90-20.89; p = .067). Moreover, CCL18 levels in effluent at year 3 of PD were independently associated with a risk of PMF development, adjusted for the classical (water and creatinine) peritoneal transport parameters. These trends were confirmed in a cross-sectional study of 61 long-term patients treated with PD. In conclusion, our study shows the diagnostic capacity of chemokine CCL18 levels in peritoneal effluent to predict PMF and suggests CCL18 as a new marker and mediator of this serious condition as well as a new potential therapeutic target.

SUBMITTER: Ossorio M

PROVIDER: S-EPMC5393879 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Sustained low peritoneal effluent CCL18 levels are associated with preservation of peritoneal membrane function in peritoneal dialysis.

Ossorio Marta M Bajo María Auxiliadora MA Del Peso Gloria G Martínez Virginia V Fernández María M Castro María José MJ Rodríguez-Sanz Aranzazu A Madero Rosario R Bellón Teresa T Selgas Rafael R

PloS one 20170417 4

Peritoneal membrane failure (PMF) and, ultimately, encapsulating peritoneal sclerosis (EPS) are the most serious peritoneal dialysis (PD) complications. Combining clinical and peritoneal transport data with the measurement of molecular biomarkers, such as the chemokine CCL18, would improve the complex diagnosis and management of PMF. We measured CCL18 levels in 43 patients' effluent and serum at baseline and after 1, 2, and 3 years of PD treatment by retrospective longitudinal study, and evaluat ...[more]

PMID: 28414753

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Project description:Peritoneal dialysis (PD) fluids are cytotoxic to the peritoneum. Recent studies have shown that alanyl-glutamine (AlaGln) modulates the cellular stress response, improves mesothelial cell survival, reduces submesothelial thickening in experimental models of PD, and in clinical studies improves PD effluent cell stress and immune responses. However, the mechanisms of AlaGln-mediated membrane protection are not yet fully understood. Here, we explore those mechanisms through application of a novel proteomics approach in a clinically relevant in vivo model in rats. Experimental PD was performed for 5 weeks using conventional single-chamber bag (SCB) or neutral dual-chamber bag (DCB), PD fluid (PDF), with or without AlaGln supplementation, via a surgically implanted catheter. Rats subjected to a single dwell without catheter implantation served as controls. The peritoneal surface proteome was directly harvested by detergent extraction and subjected to proteomic analysis by two-dimensional difference gel electrophoresis (2D-DiGE) with protein identification by mass spectrometry. An integrated bioinformatic approach was applied to identify proteins significantly affected by the treatments despite biological variation and interfering high abundance proteins. From 505 of 744 common spots on 59 gels, 222 unique proteins were identified. Using UniProt database information, proteins were assigned either as high abundance plasma proteins, or as cellular proteins. Statistical analysis employed an adapted workflow from RNA-sequencing, the trimmed mean of M-values (TMM) for normalization, and a mixed model for computational identification of significantly differentially abundant proteins. The most prominently enriched pathways after 5 weeks chronic treatment with SCB or DCB, PDFs belonged to clusters reflecting tissue damage and cell differentiation by cytoskeletal reorganization, immune responses, altered metabolism, and oxidative stress and redox homeostasis. Although the AlaGln effect was not as prominent, associated enriched pathways showed mostly regression to control or patterns opposite that of the PDF effect. Our study describes the novel peritoneal surface proteome through combined proteomic and bioinformatic analyses, and assesses changes elicited by chronic experimental PD. The biological processes so identified promise to link molecular mechanisms of membrane damage and protection in the in vivo rat model to pathomechanisms and cytoprotective effects observed in vitro and in clinical PD.

Project description:Introduction: Preservation of peritoneal function is essential in long-term peritoneal dialysis. Biocompatible dialysis solutions might prevent or postpone the membrane alteration resulting in ultrafiltration failure and consecutive morbidity and mortality.Methods: We conducted an observational cohort study in which we made a longitudinal comparison between the course of peritoneal solute and fluid transport during treatment with conventional and biocompatible solutions. Therefore, prospectively collected peritoneal transport data from the yearly standard peritoneal permeability analysis were analyzed in 251 incident patients treated between 1994 and censoring in 2016. Fluid transport included small pore and free water transport. Solute transport was assessed by creatinine mass transfer area coefficient and glucose absorption. Linear mixed models including change point analyses were performed. Interaction with peritonitis was examined.Results: One hundred thirty-five patients received conventional and 116 biocompatible solutions. Sixty-seven percent (conventional) and 64% (biocompatible) of these underwent minimally three transport measurements. Initially, biocompatible fluids showed higher small solute transport and lower ultrafiltration than conventional fluids up to 3 years. Thereafter, conventional fluids showed an increase in small solute transport (+2.7 ml/min per year; 95% confidence interval [CI]: 0.9 to 4.5) and a decrease of free water transport (-28.0 ml/min per year; 95% CI: -60.4 to 4.4). These were minor or absent in biocompatible treatment. Peritonitis induced a decrease of transcapillary ultrafiltration after 2 years on dialysis with conventional solutions (-291 ml/min per year; 95% CI: -550 to -32) while this was absent in biocompatible treatment.Conclusion: Despite a higher initial solute transport with biocompatible solutions, these have less influence on functional long-term peritoneal alterations than conventional solutions.

Dataset Information

Sustained low peritoneal effluent CCL18 levels are associated with preservation of peritoneal membrane function in peritoneal dialysis.

Publications

Sustained low peritoneal effluent CCL18 levels are associated with preservation of peritoneal membrane function in peritoneal dialysis.

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