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      Dyslipidemia and Intraperitoneal Inflammation Axis in Peritoneal Dialysis Patients: A Cross-Sectional Pilot Study

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          Abstract

          Background: We have hypothesized that the problem of dyslipidemia in peritoneal dialysis (PD) patients lies beyond certain levels of plasma lipoprotein and involves cardiovascular risk, but can also influence the development of chronic intraperitoneal inflammation. Objectives: The aim of our work was to define whether the association of dyslipidemia with intraperitoneal inflammation really exists and if it could it be used in a prospective cohort of PD patients. Patients and Methods: We performed a cross-sectional, single-center, pilot study involving 40 nondiabetic PD patients (27 men and 13 women with an average age of 49.3 ± 12.2 years). The median time on PD was 29 (18.5–37) months. The parameters dialysis adequacy, blood lipid profile, and the concentrations of tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, and interleukin (IL)-10 in peritoneal dialysate effluent (PDE) were determined. Cohen’s d effect size was computed post hoc to determine the differences between groups in the concentrations of pro- and anti-inflammatory mediators. Results: PD patients with atherogenic dyslipidemia had significantly high levels of MCP-1 compared with dyslipidemia-free patients (Cohen’s d = 1.32). A reduced high-density lipoprotein cholesterol level was associated with a high intraperitoneal production of the proinflammatory mediator TNF-α ( p < 0.0001) and anti-inflammatory IL-10 ( p < 0.0001). Atherogenic index of plasma was directly correlated with MCP-1 ( p < 0.0001) and TNF-α ( p < 0.0001). In multiple regression analysis, MCP-1 appeared to predict PD inadequacy ( R<sup>2</sup> = 0.58; F ratio = 9.4; p = 0.006) independently of age and blood C-reactive protein level. Effect size was 1.38 with α = 0.05, n = 40, and 3 predictors. Conclusions: Our cross-sectional pilot study first demonstrated a close interaction between the atherogenic lipid profile and a high concentration of MCP-1 in PDE; this might be a prognostic marker for PD inadequacy. The potential significance of our finding is that it provides useful preliminary information necessary for further research into this area.

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          Most cited references38

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          Dyslipidemia in patients with chronic kidney disease: etiology and management

          Patients with chronic kidney disease (CKD), including those with end-stage renal disease, treated with dialysis, or renal transplant recipients have an increased risk for cardiovascular disease (CVD) morbidity and mortality. Dyslipidemia, often present in this patient population, is an important risk factor for CVD development. Specific quantitative and qualitative changes are seen at different stages of renal impairment and are associated with the degree of glomerular filtration rate declining. Patients with non-dialysis-dependent CKD have low high-density lipoproteins (HDL), normal or low total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol, increased triglycerides as well as increased apolipoprotein B (apoB), lipoprotein(a) (Lp (a)), intermediate- and very-low-density lipoprotein (IDL, VLDL; “remnant particles”), and small dense LDL particles. In patients with nephrotic syndrome lipid profile is more atherogenic with increased TC, LDL, and triglycerides. Lipid profile in hemodialysis (HD) patients is usually similar to that in non-dialysis-dependent CKD patients. Patients on peritoneal dialysis (PD) have more altered dyslipidemia compared to HD patients, which is more atherogenic in nature. These differences may be attributed to PD per se but may also be associated with the selection of dialytic modality. In renal transplant recipients, TC, LDL, VLDL, and triglycerides are elevated, whereas HDL is significantly reduced. Many factors can influence post-transplant dyslipidemia including immunosuppressive agents. This patient population is obviously at high risk; hence, prompt diagnosis and management are required to improve their clinical outcomes. Various studies have shown statins to be effective in the cardiovascular risk reduction in patients with mild-to-moderate CKD as well as in renal transplant recipients. However, according to recent clinical randomized controlled trials (4D, A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Dialysis: an Assessment of Survival and Cardiovascular Events, and Study of Heart and Renal protection), these beneficial effects are uncertain in dialyzed patients. Therefore, further research for the most suitable treatment options is needed.
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            Molecular Mechanisms Underlying Peritoneal EMT and Fibrosis

            Peritoneal dialysis is a form of renal replacement alternative to the hemodialysis. During this treatment, the peritoneal membrane acts as a permeable barrier for exchange of solutes and water. Continual exposure to dialysis solutions, as well as episodes of peritonitis and hemoperitoneum, can cause acute/chronic inflammation and injury to the peritoneal membrane, which undergoes progressive fibrosis, angiogenesis, and vasculopathy, eventually leading to discontinuation of the peritoneal dialysis. Among the different events controlling this pathological process, epithelial to mesenchymal transition of mesothelial cells plays a main role in the induction of fibrosis and in subsequent functional deterioration of the peritoneal membrane. Here, the main extracellular inducers and cellular players are described. Moreover, signaling pathways acting during this process are elucidated, with emphasis on signals delivered by TGF-β family members and by Toll-like/IL-1β receptors. The understanding of molecular mechanisms underlying fibrosis of the peritoneal membrane has both a basic and a translational relevance, since it may be useful for setup of therapies aimed at counteracting the deterioration as well as restoring the homeostasis of the peritoneal membrane.
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              Independent effects of systemic and peritoneal inflammation on peritoneal dialysis survival.

              Systemic inflammation, as evidenced by elevated inflammatory cytokines, is a feature of advanced renal failure and predicts worse survival. Dialysate IL-6 concentrations associate with variability in peritoneal small solute transport rate (PSTR), which has also been linked to patient survival. Here, we determined the link between systemic and intraperitoneal inflammation with regards to peritoneal membrane function and patient survival as part of the Global Fluid Study, a multinational, multicenter, prospective, combined incident and prevalent cohort study (n=959 patients) with up to 8 years of follow-up. Data collected included patient demographic characteristics, comorbidity, modality, dialysis prescription, and peritoneal membrane function. Dialysate and plasma cytokines were measured by electrochemiluminescence. A total of 426 survival endpoints occurred in 559 incident and 358 prevalent patients from 10 centers in Korea, Canada, and the United Kingdom. On patient entry to the study, systemic and intraperitoneal cytokine networks were dissociated, with evidence of local cytokine production within the peritoneum. After adjustment for multiple covariates, systemic inflammation was associated with age and comorbidity and independently predicted patient survival in both incident and prevalent cohorts. In contrast, intraperitoneal inflammation was the most important determinant of PSTR but did not affect survival. In prevalent patients, the relationship between local inflammation and membrane function persisted but did not account for an increased mortality associated with faster PSTR. These data suggest that systemic and local intraperitoneal inflammation reflect distinct processes and consequences in patients treated with peritoneal dialysis, so their prevention may require different therapeutic approaches; the significance of intraperitoneal inflammation requires further elucidation.
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                Author and article information

                Journal
                KDD
                KDD
                10.1159/issn.2296-9357
                Kidney Diseases
                S. Karger AG
                2296-9381
                2296-9357
                2020
                January 2020
                06 November 2019
                : 6
                : 1
                : 35-42
                Affiliations
                [_a] aDepartment of Nephrology and Dialysis, State Institution, Institute of Nephrology of the National Academy of Medical Sciences, Kyiv, Ukraine
                [_b] bImmunology Laboratory, State Institution, Institute of Nephrology of the National Academy of Medical Sciences, Kyiv, Ukraine
                Author notes
                *Natalia Stepanova, MD, PhD, Dr.Sc, Head of Department of Nephrology and Dialysis, State Institution, Institute of Nephrology of the National Academy of Medical Sciences, Degtyarivska 17 V, Kyiv 04050 (Ukraine), E-Mail nmstep88@gmail.com
                Author information
                https://orcid.org/0000-0002-1070-3602
                Article
                503632 PMC6995979 Kidney Dis 2020;6:35–42
                10.1159/000503632
                PMC6995979
                32021872
                3e6c2b8b-41af-4b2a-ad8d-0770e6437432
                © 2019 The Author(s) Published by S. Karger AG, Basel

                This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 25 February 2019
                : 30 August 2019
                Page count
                Figures: 1, Tables: 4, Pages: 8
                Categories
                Research Article

                Cardiovascular Medicine,Nephrology
                Dyslipidemia,Intraperitoneal inflammation,Peritoneal dialysis

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