Long-term Peritoneal Dialysis Patients Research Articles

Selective therapeutic efficacy of tyrosine kinase inhibitor sorafenib on the restoration of methylglyoxal-induced peritoneal fibrosis

Peritoneal fibrosis, a common complication observed in long-term peritoneal dialysis patients, can gradually lead to ultrafiltration failure and the development of encapsulating peritoneal sclerosis. Although mechanisms of peritoneal fibrosis have been proposed, effective therapeutic options are unsatisfactory. Recently, several tyrosine kinase inhibitors have proven to be anti-fibrosis in rodent models. To assess the potential therapeutic effects of tyrosine kinase inhibitors on peritoneal fibrosis in the larger animal model, a novel porcine model of peritoneal fibrosis induced by 40 mM methylglyoxal in 2.5 % dialysate was established, and two different doses (20 mg/kg and 30 mg/kg) of sorafenib were given orally to evaluate their therapeutic efficacy in this study. Our results showed that sorafenib effectively reduced adhesions between peritoneal organs and significantly diminished the thickening of both the parietal and visceral peritoneum. Angiogenesis, vascular endothelial growth factor A production, myofibroblast infiltration, and decreased endothelial glycocalyx resulting from dialysate and methylglyoxal stimulations were also alleviated with sorafenib. However, therapeutic efficacy in ameliorating loss of mesothelial cells, restoring decreased ultrafiltration volume, and improving elevated small solutes transport rates was limited. In conclusion, this study demonstrated that sorafenib could potentially be used for peritoneal fibrosis treatment, but applying sorafenib alone might not be sufficient to fully rescue methylglyoxal-induced peritoneal defects.

The relationship between changes in peritoneal membrane solute transfer characteristics and cardiac remodeling in patients with peritoneal dialysis.

We aimed to determine the relationship between the dilatation of the heart chambers and the change in peritoneal membrane solute transfer characteristics (PMTC) in long-term peritoneal dialysis (PD) patients. This is a retrospective, single-center study including the follow-up of maintenance PD patients. According to the changes in PMTC from baseline to the last visit, patients were divided into three groups; stable (n = 11), increased (n = 41), and decreased transporters (n = 35). Left atrium (LA) and Right ventricle (RV) dilatation were more prominent in the PMTC-decreased group compared to PMTC-increased and stable groups (p < 0.001 and p = 0.07, respectively). The Cox regression analysis showed that only decreased PMTC was associated with LA dilatation (HR 2.89 [CI 95%1.54, 5.45] p < 0.01) and RV dilatation (HR 3.01 [CI 95%1.40, 6.21] p < 0.01). PD can be associated with unfavorable dynamic changes in cardiac structure and functions even at the subclinical level.

Prognosis and factors related to severe secondary hyperparathyroidism in long-term peritoneal dialysis patients

Secondary hyperparathyroidism (SHPT) can progress to severe SHPT (sSHPT), which affects the survival rate and quality of life of patients. This retrospective cohort study investigated risk factors for sSHPT and the association between SHPT and mortality (all-cause and infection-related) among 771 clinically stable patients (421 male patients; mean age, 51.2 years; median dialysis vintage, 28.3 months) who underwent >3 months of regular peritoneal dialysis (PD) between January 2013 and March 2021. The sSHPT and non-sSHPT groups comprised 75 (9.7%) (median progression, 35 months) and 696 patients, respectively. sSHPT was defined as a serum intact parathyroid hormone (PTH) level >800 pg/mL observed three times after active vitamin D pulse therapy. The influence of sSHPT on the prognosis of and risk factors for sSHPT progression were evaluated using logistic and Cox regression analyses. After adjusting for confounding factors, higher (each 100-pg/mL increase) baseline PTH levels (95% confidence interval (CI) 1.206–1.649, p < .001), longer (each 1-year increase) dialysis vintages (95% CI 1.013–1.060, p = .002), higher concomitant diabetes rates (95% CI 1.375–10.374, p = .010), and lower (each 1-absolute unit decrease) Kt/V values (95% CI 0.859–0.984, p = .015) were independent risk factors for progression to sSHPT in patients on PD. During follow-up, 211 deaths occurred (sSHPT group, n = 35; non-sSHPT group, n = 176). The sSHPT group had significantly higher infection-related mortality rates than the non-sSHPT group (12.0% vs. 4.3%; p < .05), and sSHPT was associated with increased infection-related mortality. In conclusion, patients with sSHPT are at higher risk for death and infection-related mortality than patients without sSHPT.

A time-averaged serum bicarbonate-based nomogram to predict the probability of residual kidney function preservation for patients undergoing peritoneal dialysis.

Residual kidney function (RKF) is an important prognostic indicator in peritoneal dialysis (PD) patients. So far, there are no prediction tools available for RKF, and the association between serum bicarbonate and RKF has received little attention in patients with PD. We aimed to develop a nomogram for the preservation of RKF based on the time-averaged serum bicarbonate (TA-Bic) levels. A prediction model was established by conducting a retrospective cohort study of 151 PD patients who had been treated at the First Affiliated Hospital of Anhui Medical University. The nomogram was developed using a multivariate Cox regression model. The discrimination, calibration, and clinical utility of the model were evaluated by the C-index, receiver operating curve (ROC) curve, calibration curve, and decision curve analysis. In the elderly PD onset, higher baseline values of residual glomerular filtration rate, total Kt/V and higher TA-Bic levels were identified as protective predictors of RKF loss. The nomogram was conducted on the basis of the minimum value of the Akaike Information Criterion and Bayesian Information Criterion with a reasonable C-index of 0.766, showing great discrimination, proper calibration, and high potential for clinical practice. Through the total score of the nomogram, the patients were classified into the high-risk group and low-risk group, and a higher cumulative incidence of complete RRF loss was found in the high-risk group compared with the patients in the low-risk group. The novel predictive nomogram model can predict the probability of RKF preservation in long-term PD patients with high accuracy. Future studies are needed to externally validate the current nomogram before clinical application.

Unravelling the role of Sildenafil and SB204741 in suppressing fibrotic potential of peritoneal fibroblasts obtained from PD patients.

Introduction: Peritoneal fibrosis (PF) results in technique failure in peritoneal dialysis (PD) patients. Peritoneal fibroblasts are characterized by increase in the ACTA2 gene, responsible for alpha smooth muscle actin (α-SΜΑ), extracellular matrix (ECM) production, and inflammatory cytokines production, which are the are key mediators in the pathogenesis of PF. 5-hydroxytryptamine (5-HT; serotonin) induces ECM synthesis in fibroblasts in a transforming growth factor-beta 1 (TGF-β1) dependent manner. The purpose of our study was to identify the potential mechanism and role of sildenafil and 5HT2B receptor inhibitor (SB204741) combination in attenuating PD-associated peritoneal fibrosis. Methods: Studies were performed to determine the effect of TGF-β1, sildenafil, and SB204741 on human peritoneal fibroblasts (HPFBs) isolated from the parietal peritoneum of patients in long-term PD patients (n = 6) and controls (n = 6). HPFBs were incubated with TGF-β1 (10ng/mL) for 1h and later with TGF-β1 (10ng/mL)/[sildenafil (10µM) or SB204741 (1µM)] and their combination for 24h (post-treatment strategy). In the pre-treatment strategy, HPFBs were pre-treated with sildenafil (10µM) or SB204741 (1µM) and a combination of the two for 1h and later with only TGF-β1 (10ng/mL) for 24h. Results: The anti-fibrotic effects of the combination of sildenafil and SB204741 were greater than that of each drug alone. In TGF-β1-stimulated HPFBs, pro-fibrotic genes (COL1A1, COL1A2, ACTA2, CTGF, FN1, and TGFB1) exhibited higher expression than in controls, which are crucial targets of sildenafil and SB204741 against peritoneal fibrosis. The synergistic approach played an anti-fibrotic role by regulating the pro- and anti-fibrotic gene responses as well as inflammatory cytokine responses. The combination treatment significantly attenuated peritoneal fibrosis, as evident by the almost complete amelioration of ACTA2 expression, restoration of anti-fibrotic genes (MMP2/TIMP1), and, at least, by reducing the expression of pro-inflammatory cytokines (IFN-γ, IL-4, IL-17, IL-1β, IL-6, TNF-α, and TGF-β1) along with an increase in IL-10 levels. Discussion: Taken together, the above research evidences that the combination of sildenafil and SB204741 may have therapeutic potential in suppressing peritoneal fibrosis due to peritoneal dialysis.

Identification of Genes Associated with Decreasing Abundance of Monocytes in Long-Term Peritoneal Dialysis Patients.

Chronic kidney disease (CKD) will become an end-stage renal disease (ESRD) at stage 5. Peritoneal dialysis (PD) is required for renal replacement therapy. This study aims to identify monocytes-related genes in peritoneal cells from long-term PD (LPD) patients and short-term PD (SPD) patients. Bulk RNA-seq data (GSE125498 dataset) and ScRNA-seq data (GSE130888) were downloaded to identify differentially expressed genes, monocytes-related genes, and monocytes marker genes in LPD patients. Immune infiltration was analyzed in the GSE125498 dataset. Core genes associated with monocytes changes were screened out, followed by functional analysis and expression validation using RT-PCR. Monocytes are the most abundant immune cell in PD. The number of monocytes was remarkably decreased in LPD compared with SPD. A total of 16 up-regulated core genes negatively correlated with the abundance of monocytes were obtained in LPD. The expression of 16 core genes was lower in monocyte clusters than that in other cell clusters. In addition, LCK, CD3G, CD3E, CD3D, and LAT were involved in the signaling pathways of Th1 and Th2 cell differentiation, T cell receptor signaling pathway, and Th17 cell differentiation. CD2 was involved in hematopoietic cell lineage signaling pathway. Identification of monocytes related-genes and related signaling pathways could be helpful in understanding the molecular mechanism of monocytes changes during PD.

Clinical risk factors for peritoneal dialysis withdrawal at different dialysis duration

Background The duration of patients maintained on peritoneal dialysis (PD) varied. This study investigated the clinical risk factors for PD withdrawal at different dialysis duration. Methods Patients who initiated PD from 1994 to 2011 were recruited and followed for at least 10 years until 2021. Patients were grouped into four groups according to dialysis duration or time on treatment (TOT) when withdrew PD. Results A cohort of 586 patients were enrolled (mean age of 54.9 years, median dialysis duration or TOT of 47.9 months). Patients who maintained PD for longer than 10 years were younger, with lower prevalence of diabetes, lower serum C-reactive protein (CRP) level and white blood cell (WBC) count, higher serum albumin and pre-albumin level, higher normalized protein catabolic rate (nPCR) and residual kidney function, and more common use of renin–angiotensin system inhibitors (RASi) at baseline (p < 0.05 for all). Peritonitis related death and ultrafiltration failure related HD transferring increased along with time on PD (p < 0.001). Old age, diabetes, low serum albumin, high WBC count, hypertensive nephropathy, and nonuse of RASi were associated with increased risk of non-transplantation related PD withdrawal (p < 0.05 for all). Low baseline CRP and use of RASi were independent predictors for long-term PD maintenance (p < 0.05 for all). Conclusions Long-term PD patients demonstrated young age, low prevalence of diabetes, better nutrition status, absence of inflammation, better residual kidney function, and higher proportion of RASi usage at baseline. Absence of inflammation and use of RASi were independently associated with long-term PD maintenance.

Inhibition of EZH2 suppresses peritoneal angiogenesis by targeting a VEGFR2/ERK1/2/HIF-1α-dependent signaling pathway.

The catalytic subunit of polycomb repressive complex 2 (PRC2), enhancer of zeste homolog 2 (EZH2), has been reported to be involved in angiogenesis in some tumors and autoimmune diseases. However, the mechanisms by which EZH2 regulates peritoneal angiogenesis remain unclear. We detected the expression of EZH2 in clinical samples and the peritoneal tissue of a mouse peritoneal fibrosis model induced by chlorhexidine gluconate (CG). In addition, we further investigated the mechanisms by which inhibition of EZH2 by 3-deazaneplanocin A (3-DZNeP) alleviated the CG-induced peritoneal fibrosis mouse model in vivo and 3-DZNeP or EZH2 siRNA treatment in cultured human peritoneal mesothelial cells (HPMCs) and human umbilical vein endothelial cells (HUVECs). The expression of EZH2 in the peritoneum of long-term peritoneal dialysis (PD) patients and the CG-induced peritoneal fibrosis mouse model was remarkably increased and this was positively associated with higher expression of vascular markers (CD31, CD34, VEGF, p-VEGFR2). Peritoneal injection of 3-DZNeP attenuated angiogenesis in the peritoneum of CG-injured mice; improved peritoneal membrane function; and decreased phosphorylation of STAT3, ERK1/2, and activation of Wnt1/β-catenin. In in vitro experiments, we demonstrated that inhibition of EZH2 by 3-DZNeP or EZH2 siRNA decreased tube formation and the migratory ability of HUVECs via two pathways: the Wnt1/β-catenin pathway and the IL-6/STAT3 pathway. Suppression of the Wnt1/β-catenin pathway and the IL-6/STAT3 pathway subsequently reduced VEGF production in HPMCs. Using specific inhibitors of VEGFR2, ERK1/2, and HIF-1α, we found that a VEGFR2/ERK1/2/HIF-1α axis existed and contributed to angiogenesis in vitro. Moreover, phosphorylation of VEGFR2 and activation of the ERK1/2 pathway and HIF-1α in HUVECs could be suppressed by inhibition of EZH2. Taken together, the results of this study suggest that EZH2 may be a novel target for preventing peritoneal angiogenesis in PD patients. © 2022 The Pathological Society of Great Britain and Ireland.

Relative Contributions of Pseudohypoxia and Inflammation to Peritoneal Alterations with Long-Term Peritoneal Dialysis Patients.

Long-term peritoneal dialysis is associated with alterations in peritoneal function, like the development of high small solute transfer rates and impaired ultrafiltration. Also, morphologic changes can develop, the most prominent being loss of mesothelium, vasculopathy, and interstitial fibrosis. Current research suggests peritoneal inflammation as the driving force for these alterations. In this review, the available evidence for inflammation is examined and a new hypothesis is put forward consisting of high glucose-induced pseudohypoxia. Hypoxia of cells is characterized by a high (oxidized-reduced nicotinamide dinucleotide ratio) NADH-NAD+ ratio in their cytosol. Pseudohypoxia is similar but occurs when excessive amounts of glucose are metabolized, as is the case for peritoneal interstitial cells in peritoneal dialysis. The glucose-induced high NADH-NAD+ ratio upregulates the hypoxia-inducible factor-1 gene, which stimulates not only the glucose transporter-1 gene but also many profibrotic genes like TGFβ, vascular endothelial growth factor, plasminogen activator inhibitor-1, and connective tissue growth factor, all known to be involved in the development of peritoneal fibrosis. This review discusses the causes and consequences of pseudohypoxia in peritoneal dialysis and the available options for treatment and prevention. Reducing peritoneal exposure to the excessively high dialysate glucose load is the cornerstone to avoid the pseudohypoxia-induced alterations. This can partly be done by the use of icodextrin or by combinations of low molecular mass osmotic agents, all in a low dose. The addition of alanyl-glutamine to the dialysis solution needs further clinical investigation.

Oxidative Stress-Induced Alterations of Cellular Localization and Expression of Aquaporin 1 Lead to Defected Water Transport upon Peritoneal Fibrosis.

Being one of the renal replacement therapies, peritoneal dialysis (PD) maintains around 15% of end-stage kidney disease patients’ lives; however, complications such as peritoneal fibrosis and ultrafiltration failure during long-term PD compromise its application. Previously, we established a sodium hypochlorite (NaClO)-induced peritoneal fibrosis porcine model, which helped to bridge the rodent model toward pre-clinical human peritoneal fibrosis research. In this study, the peritoneal equilibration test (PET) was established to evaluate instant functional changes in the peritoneum in the pig model. Similar to observations from long-term PD patients, increasing small solutes transport and loss of sodium sieving were observed. Mechanistic investigation from both in vivo and in vitro data suggested that disruption of cytoskeleton induced by excessive reactive oxygen species defected intracellular transport of aquaporin 1, this likely resulted in the disappearance of sodium sieving upon PET. Functional interference of aquaporin 1 on free water transport would result in PD failure in patients.

Blockade of Autophagy Prevents the Development and Progression of Peritoneal Fibrosis.

Peritoneal fibrosis (PF) is a major cause of ultrafiltration failure in long-term peritoneal dialysis (PD) patients. Nevertheless, limited measures have been shown to be effective for the prevention and treatment of PF. Some views reveal that activation of autophagy ameliorates PF but others demonstrate that autophagy promotes PF. It is obvious that the role of autophagy in PF is controversial and further studies are needed. Here, we investigated the role of autophagy in rat models of PF and damaged cultured human peritoneal mesothelial cells (HPMCs). Autophagy was highly activated in fibrotic peritoneum from two PF rat models induced by 4.25% peritoneal dialysate fluid (PDF) and 0.1% chlorhexidine gluconate (CG). Blockade of autophagy with 3-MA effectively prevented PF in both models and reversed epithelial to mesenchymal transition (EMT) by down-regulating TGF-β/Smad3 signaling pathway and downstream nuclear transcription factors Slug and Snail. Treatment with 3-MA also inhibited activation of EGFR/ERK1/2 signaling pathway during PF. Moreover, 3-MA prominently decreased STAT3/NF-κB-mediated inflammatory response and macrophage infiltration, and prevented peritoneal angiogenesis through downregulation of β-catenin signal. In addition, TGF-β1 stimulation up-regulated autophagic activity as evidenced by the increased autophagosome in vitro. Exposure of HPMCs to TGF-β1 resulted in the induction of EMT and activation of TGF-β/Smad3, EGFR/ERK1/2 signaling pathways. Treatment with 3-MA blocked all these responses. In addition, delayed administration of 3-MA was effective in reducing EMT induced by TGF-β1. Taken together, our study indicated that autophagy might promote PF and 3-MA had anti-fibrosis effect in vivo and in vitro. These results suggest that autophagy could be a potential target on PF therapy for clinical patients with long-term PD.

Ongoing Exposure to Peritoneal Dialysis Fluid Alters Resident Peritoneal Macrophage Phenotype and Activation Propensity.

Peritoneal dialysis (PD) is a more continuous alternative to haemodialysis, for patients with chronic kidney disease, with considerable initial benefits for survival, patient independence and healthcare costs. However, long-term PD is associated with significant pathology, negating the positive effects over haemodialysis. Importantly, peritonitis and activation of macrophages is closely associated with disease progression and treatment failure. However, recent advances in macrophage biology suggest opposite functions for macrophages of different cellular origins. While monocyte-derived macrophages promote disease progression in some models of fibrosis, tissue resident macrophages have rather been associated with protective roles. Thus, we aimed to identify the relative contribution of tissue resident macrophages to PD induced inflammation in mice. Unexpectedly, we found an incremental loss of homeostatic characteristics, anti-inflammatory and efferocytic functionality in peritoneal resident macrophages, accompanied by enhanced inflammatory responses to external stimuli. Moreover, presence of glucose degradation products within the dialysis fluid led to markedly enhanced inflammation and almost complete disappearance of tissue resident cells. Thus, alterations in tissue resident macrophages may render long-term PD patients sensitive to developing peritonitis and consequently fibrosis/sclerosis.

STAT3/HIF-1\u03b1 signaling activation mediates peritoneal fibrosis induced by high glucose

BackgroundEpithelial-mesenchymal transition (EMT) of mesothelial cells is a key step in the peritoneal fibrosis (PF). Recent evidence indicates that signal transducer and activator of transcription 3 (STAT3) might mediate the process of renal fibrosis, which could induce the expression of hypoxia-inducible factor-1α (HIF-1α). Here, we investigated the effect of STAT3 activation on HIF-1α expression and the EMT of mesothelial cells, furthermore the role of pharmacological blockade of STAT3 in the process of PF during peritoneal dialysis (PD) treatment.MethodsFirstly, we investigated the STAT3 signaling in human peritoneal mesothelial cells (HPMCs) from drained PD effluent. Secondly, we explored the effect of STAT3 signaling activation on the EMT and the expression of HIF-1α in human mesothelial cells (Met-5A) induced by high glucose. Finally, peritoneal fibrosis was induced by daily intraperitoneal injection with peritoneal dialysis fluid (PDF) so as to explore the role of pharmacological blockade of STAT3 in this process.ResultsCompared with the new PD patient, the level of phosphorylated STAT3 was up-regulated in peritoneal mesothelial cells from long-term PD patients. High glucose (60 mmol/L) induced over-expression of Collagen I, Fibronectin, α-SMA and reduced the expression of E-cadherin in Met-5A cells, which could be abrogated by STAT3 inhibitor S3I-201 pretreatment as well as by siRNA for STAT3. Furthermore, high glucose-mediated STAT3 activation in mesothelial cells induced the expression of HIF-1α and the profibrotic effect of STAT3 signaling was alleviated by siRNA for HIF-1α. Daily intraperitoneal injection of high-glucose based dialysis fluid (HG-PDF) induced peritoneal fibrosis in the mice, accompanied by the phosphorylation of STAT3. Immunostaining showed that phosphorylated STAT3 was expressed mostly in α-SMA positive cells in the peritoneal membrane induced by HG-PDF. Administration of S3I-201 prevented the progression of peritoneal fibrosis, angiogenesis, macrophage infiltration as well as the expression of HIF-1α in the peritoneal membrane induced by high glucose.ConclusionsTaken together, these findings identified a novel mechanism linking STAT3/HIF-1α signaling to peritoneal fibrosis during long-term PD treatment. It provided the first evidence that pharmacological inhibition of STAT3 signaling attenuated high glucose-mediated mesothelial cells EMT as well as peritoneal fibrosis.

MO695THE ASSOCIATION OF CIRCULATING CD14++CD16+ MONOCYTES, NATURAL KILLER CELLS AND REGULATORY T CELLS SUBPOPULATIONS WITH CARDIOVASCULAR DISEASE IN A COHORT OF PERITONEAL DIALYSIS PATIENTS

Abstract Background and Aims Advanced chronic kidney disease (CKD) is characterized by elevated expression of the proinflammatory and pro-atherogenic CD14++CD16+ monocytes subset. The role of lymphocyte subpopulations including natural killer (NK) cells and CD4+CD25+ regulatory T cells (Tregs) in the modulation of inflammation and immunity and subsequent cardiovascular implications have received increasing attention. The role of immune cell subpopulations remains to be determined in peritoneal dialysis (PD) patients. The aim of this pilot study was to investigate potential correlations between blood levels of CD14++CD16+ monocytes, NK cells and Tregs with phenotypes of established cardiovascular disease (CVD), including coronary artery disease (CAD) and heart failure (HF) in a cohort of PD patients. Method 29 stable PD patients (mean age 66.96 years ±14.5, 62% males) were enrolled. Exclusion criteria were a history of malignancy, autoimmune disease, active or chronic infections and a recent (&amp;lt; 3 months) cardiovascular event. Demographic, laboratory and bioimpedance measurements data (overhydration, extracellular and total body water and their ratios) were collected. The analysis of peripheral blood immune cell subsets was performed using flow cytometry (FC). Additionally, in 7 PD patients the distribution of the immune cells was evaluated by FC at two time points: T0 (before initiation of PD - CKD stage G5) and T1 (after PD start). Results The median dialysis vintage was 34.5 (range 3.2-141) months. Overall, PD patients had 527 ± 199 monocytes and 1731 ± 489 lymphocytes while mean percentage of CD14++CD16+ monocytes was 9.3 ±6.36% (normal range 2-8%), NK cells 16.6±10.3% (normal range 5-15%) and Tregs 2.1±1.76% (normal range 1-3%). There was no correlation of either of these cell subpopulations with age, PD vintage, inflammation markers (CRP, fibrinogen, albumin, hsTroponin-I), overhydration markers or comorbidities. Only increased NK cells were associated with the presence of HF in PD (24.87 vs 14.92%, p 0.047). In multiple regression analysis, NK cells levels were strongly associated with the presence of edema (beta coef=13.7, p&amp;lt;0.001) and CAD (beta coef=7.1, p=0.046). At T0 mean percentage of CD14++CD16+ monocytes, NK cells and Tregs were 9.7 ±4.5%, 17.1 ±3.84% and 2.38± 1.26% respectively whereas at T1 mean percentage of CD14++CD16+ monocytes was 13.3% ±8.4, NK cells 19.8±6.47% and Tregs 1.5±0.6%. Paired t-test of cell subpopulations (T0 vs T1) showed that only the Tregs were significantly decreased (p =0.018), while the other subpopulations did not differ and remained increased. Conclusion Our study is the first to evaluate the potential association between specific immune cell subsets and cardiovascular disease in long-term PD patients. Increased NK cells levels directly correlate both with the presence of HF and CAD in PD patients. Longitudinal results suggest that CD14++CD16+ and NK cells remain increased after PD start, while Tregs decrease further. The state of pro-inflammation and immune deregulation appear to persist after initiating PD. Future research is required to evaluate the role of immune cells subsets as potential tools to identify patients who are at the highest risk for complications and to guide interventions that may improve clinical outcomes.

Vascular endothelial growth factor-mediated peritoneal neoangiogenesis in peritoneal dialysis.

Peritoneal dialysis (PD) is an important renal replacement therapy for patients with end-stage renal diseases, which is limited by peritoneal neoangiogenesis leading to ultrafiltration failure (UFF). Vascular endothelial growth factor (VEGF) and its receptors are key angiogenic factors involved in almost every step of peritoneal neoangiogenesis. Impaired mesothelial cells are the major sources of VEGF in the peritoneum. The expression of VEGF will be up-regulated in specific pathological conditions in PD patients, such as with non-biocompatible peritoneal dialysate, uremia and inflammation, and so on. Other working cells (i.e. vascular endothelial cells, macrophages and adipocytes) can also stimulate the secretion of VEGF. Meanwhile, hypoxia and activation of complement system further aggravate peritoneal injury and contribute to neoangiogenesis. There are several signalling pathways participating in VEGF-mediated peritoneal neoangiogenesis including tumour growth factor-β, Wnt/β-catenin, Notch and interleukin-6/signal transducer and activator of transcription 3. Moreover, VEGF is highly expressed in dialysate effluent of long-term PD patients and is associated with peritoneal transport function, which supports its role in the alteration of peritoneal structure and function. In this review, we systematically summarize the angiogenic effect of VEGF and evaluate it as a potential target for the prevention of peritoneal neoangiogenesis and UFF. Preservation of the peritoneal membrane using targeted therapy of VEGF-mediated peritoneal neoangiogenesis may increase the longevity of the PD modality for those who require life-long dialysis.

IL-17A as a Potential Therapeutic Target for Patients on Peritoneal Dialysis.

Chronic kidney disease (CKD) is a health problem reaching epidemic proportions. There is no cure for CKD, and patients may progress to end-stage renal disease (ESRD). Peritoneal dialysis (PD) is a current replacement therapy option for ESRD patients until renal transplantation can be achieved. One important problem in long-term PD patients is peritoneal membrane failure. The mechanisms involved in peritoneal damage include activation of the inflammatory and immune responses, associated with submesothelial immune infiltrates, angiogenesis, loss of the mesothelial layer due to cell death and mesothelial to mesenchymal transition, and collagen accumulation in the submesothelial compact zone. These processes lead to fibrosis and loss of peritoneal membrane function. Peritoneal inflammation and membrane failure are strongly associated with additional problems in PD patients, mainly with a very high risk of cardiovascular disease. Among the inflammatory mediators involved in peritoneal damage, cytokine IL-17A has recently been proposed as a potential therapeutic target for chronic inflammatory diseases, including CKD. Although IL-17A is the hallmark cytokine of Th17 immune cells, many other cells can also produce or secrete IL-17A. In the peritoneum of PD patients, IL-17A-secreting cells comprise Th17 cells, γδ T cells, mast cells, and neutrophils. Experimental studies demonstrated that IL-17A blockade ameliorated peritoneal damage caused by exposure to PD fluids. This article provides a comprehensive review of recent advances on the role of IL-17A in peritoneal membrane injury during PD and other PD-associated complications.

Increased miR-7641 Levels in Peritoneal Hyalinizing Vasculopathy in Long-Term Peritoneal Dialysis Patients.

Peritoneal hyalinizing vasculopathy (PHV) represents the cornerstone of long-term peritoneal dialysis (PD), and especially characterizes patients associated with encapsulating peritoneal sclerosis. However, the mechanisms of PHV development remain unknown. A cross sectional study was performed in 100 non-selected peritoneal biopsies of PD patients. Clinical data were collected and lesions were evaluated by immunohistochemistry. In selected biopsies a microRNA (miRNA)-sequencing analysis was performed. Only fifteen patients (15%) showed PHV at different degrees. PHV prevalence was significantly lower among patients using PD fluids containing low glucose degradation products (GDP) (5.9% vs. 24.5%), angiotensin converting enzyme inhibitors (ACEIs) (7.5% vs. 23.4%), statins (6.5% vs. 22.6%) or presenting residual renal function, suggesting the existence of several PHV protective factors. Peritoneal biopsies from PHV samples showed loss of endothelial markers and induction of mesenchymal proteins, associated with collagen IV accumulation and wide reduplication of the basement membrane. Moreover, co-expression of endothelial and mesenchymal markers, as well as TGF-β1/Smad3 signaling activation were found in PHV biopsies. These findings suggest that an endothelial-to-mesenchymal transition (EndMT) process was taking place. Additionally, significantly higher levels of miR-7641 were observed in severe PHV compared to non-PHV peritoneal biopsies. Peritoneal damage by GDPs induce miRNA deregulation and an EndMT process in submesothelial vessels, which could contribute to collagen IV accumulation and PHV.

P1209ROLE OF NTPROBNP IN LONG-TERM PERITONEAL DIALYSIS PATIENTS

Abstract Background and Aims Plasma N-terminal fragment of pro brain natriuretic peptide (NTproBNP) concentration is elevated in cardiovascular diseases such as congestive heart failure, where increased levels of NTproBNP indicate cardiac dysfunction, hypervolemia, and higher risk of hospitalization and death. These associations have also been studied in patients with chronic kidney disease (CKD), where NTproBNP value remains controversial, especially in long-term peritoneal dialysis (PD) patients with respect to its pathophysiologic implications. This study aim was to determine whether NTproBNP was a predictor of hospital admissions and cardiovascular events among patients on automated (APD) and continuous (CAPD) ambulatory peritoneal dialysis. Methods This was a cross-sectional study which included stable patients from two Peritoneal Dialysis Units. Plasma NTproBNP concentration was measured in stable adult peritoneal dialysis patients attending for routine assessments on PD outpatient clinic. In all patients, demographic variables, clinical and other laboratory parameters were recorded and analyzed. Descriptive statistics was performed. Groups were compared using independent t-test for comparison of continuous variables and Chi square test for categorical variables. In order to evaluate relationship between NTproBNP and the other variables multivariate logistic regression and Pearson bivariate analysis were used. Results The study enrolled 70 patients (male/female 44/26; mean age 55.3±14.6 years; APD/CAPD 25/45; PD duration 28±24.2months). One third (31.4%) of the patients was diabetic, 12.9% presented cardiac insufficiency and 20% had cardiovascular disease. Pearson bivariate correlation analysis revealed that patients with higher weekly kt/v (p=0.039), total fluid removal (diuresis and ultrafiltration) (p=0.027) and total weekly creatinine clearance (p=0.007) had lower NTproBNP values. These patients had also significant lower plasmatic creatinine and phosphorus levels. We found no significant association with residual kidney function, peritoneal transport (D/P creatinine), serum albumin levels and c-reactive protein. We also found that patients with higher NTproBNP levels had significantly more cardiovascular events (p=0.010) and a trend for more common hospital admissions (p=0.066). There were no significant differences regarding NTproBNP between the two modalities of peritoneal dialysis (APD and CAPD patients) or in patients who were PD first. As expected, patients with cardiac dysfunction had significant higher NTproBNP values (p=0.004). Diabetic patients had higher NTproBNP levels, althought this difference was not significant. Conclusion Despite the inconsistency in the NTproBNP value among long-term PD patients, results from most studies concur that NTproBNP levels are closely associated with left ventricular dysfunction, morbidity and mortality in these patients. In our study, patients with higher NTproBNP levels had more cardiovascular events and a trend for more common hospital admissions. Regular monitoring of NTproBNP levels among PD patients may be useful for providing care for these patients. Plus, NTproBNP was associated with better PD efficacy, greater fluid removal and higher creatinine clearance, reinforcing clinical relevance of PD optimization. These results require confirmation in a prospective study.

Relationship between plasminogen activator inhibitor-1 gene alterations and fibrosis in peritoneal dialysis patients.

Peritoneal fibrosis (PF) is a pathological change that occurs mostly long-term peritoneal dialysis (PD) patients, as a result of triggering the inflammatory response. Plasminogen activator inhibitor-1 (PAI-1) is an important molecule featured in the development of fibrosis. It has been shown in literature that PAI-1 gene alterations are associated with fibrosis in many tissues and organs. However, PAI-1 gene alterations in long-term PD patients have not yet been investigated. In this study, PAI-1 4G/5G polymorphism was examined by reverse hybridization, and all coding exons of the PAI-1 gene were examined by sequence analysis to provide treatment modification in patients with predisposition before fibrosis develops. The patients were divided into two groups according to ultrafiltration failure test and duration of PD treatment: those with suspected PF or a high probability of developing PF (36%) and those with a low probability of developing PF (64%). There was no significant difference between the two groups in findings such as peritoneal equilibration test (PET), Kt/V, the content of the PD solution used, peritonitis, and PAI-1 4G/5G polymorphism (P > .05). A total of eight gene alterations (rs2227660, rs2227668, rs2854233, rs41281004, rs61553169, rs368413856, rs2227684) were detected by sequence analysis, one of which was exonic (rs6092). When the genotype distributions of these variants were examined, no significant difference was found between the two groups. PAI-1 gene changes were not detected in patients with the probability of developing PF. There is a need for further studies involving other molecules responsible for predisposing to PF with larger patient populations in patients undergoing long-term PD treatment.

Effect of Long-term Peritoneal Dialysis on Change in Visceral Fat Area: A Single-Center Experience.

Introduction:Visceral fat area (VFA) is known to increase after initiation of peritoneal dialysis (PD). However, the factors contributing to the increase in VFA in long-term PD patients have not been sufficiently elucidated. The present study investigated factors that affect VFA in patients who continue PD for ≥3 years.Methods:Twenty patients (63.1 ± 10.3 years, 9 men, 11 diabetic patients) between January 2008 and January 2015 were included. VFA, subcutaneous fat area (SFA) and waist circumference at initiation and follow-up were measured at the level of the umbilicus by computed tomography using an image analysis system. Change in VFA was defined as the value obtained by dividing VFA at the final follow-up by that at the initiation. The correlations between clinical parameters at initiation and changes in VFA were analyzed.Results:There was no significant change in body weight (57.6 ± 10.4 vs 58.3 ± 7.8 kg, P = 0.296) during the mean final follow-up period of 55 ± 13 months, although VFA increased significantly (103.6 ± 39.2 vs 122.6 ± 38.3 cm2, P = 0.030). Although subcutaneous fat area (SFA) did not change (124.7 ± 52.3 vs 124.5 ± 49.2 cm2, P = 0.989), waist circumference increased significantly (79.4 ± 8.4 vs 83.7 ± 6.9 cm, P = 0.010). SFA (r = −0.735, P < 0.001), waist circumference (r = − 0.644, P = 0.002), high-density lipoprotein cholesterol (HDL-C) (r = 0.487, P = 0.029), and age (r = 0.507, P = 0.023) correlated significantly with changes in VFA.Conclusions:VFA might increase with long-term PD in patients with end-stage kidney disease who have high HDL-C, small SFA, and small waist circumference at initiation.