Ultrafiltration Failure Research Articles

Deletion of p38 MAPK in macrophages ameliorates peritoneal fibrosis and inflammation in peritoneal dialysis

One of the most common causes of peritoneal dialysis withdrawal is ultrafiltration failure which is characterized by peritoneal membrane thickening and fibrosis. Although previous studies have demonstrated the inhibitory effect of p38 MAPK inhibitors on peritoneal fibrosis in mice, it was unclear which specific cells contribute to peritoneal fibrosis. To investigate the role of p38 MAPK in peritoneal fibrosis more precisely, we examined the expression of p38 MAPK in human peritoneum and generated systemic inducible p38 MAPK knockout mice and macrophage-specific p38 MAPK knockout mice. Furthermore, the response to lipopolysaccharide (LPS) was assessed in p38 MAPK-knocked down RAW 264.7 cells to further explore the role of p38 MAPK in macrophages. We found that phosphorylated p38 MAPK levels were increased in the thickened peritoneum of both human and mice. Both chlorhexidine gluconate (CG)-treated systemic inducible and macrophage-specific p38 MAPK knockout mice ameliorated peritoneal thickening, mRNA expression related to inflammation and fibrosis, and the number of αSMA- and MAC-2-positive cells in the peritoneum compared to CG control mice. Reduction of p38 MAPK in RAW 264.7 cells suppressed inflammatory mRNA expression induced by LPS. These findings suggest that p38 MAPK in macrophages plays a critical role in peritoneal inflammation and thickening.

Transitioning to peritoneal dialysis: it does not matter where you come from.

Patients with end-stage renal disease (ESRD) frequently change renal replacement (RRT) therapy modality due to medical or social reasons. We aimed to evaluate the outcomes of patients under peritoneal dialysis (PD) according to the preceding RRT modality. We conducted a retrospective observational single-center study in prevalent PD patients from January 1, 2010, to December 31, 2017, who were followed for 60 months or until they dropped out of PD. Patients were divided into three groups according to the preceding RRT: prior hemodialysis (HD), failed kidney transplant (KT), and PD-first. Among 152 patients, 115 were PD-first, 22 transitioned from HD, and 15 from a failing KT. There was a tendency for ultrafiltration failure to occur more in patients transitioning from HD (27.3% vs. 9.6% vs. 6.7%, p = 0.07). Residual renal function was better preserved in the group with no prior RRT (p < 0.001). A tendency towards a higher annual rate of peritonitis was observed in the prior KT group (0.70 peritonitis/year per patient vs. 0.10 vs. 0.21, p = 0.065). Thirteen patients (8.6%) had a major cardiovascular event, 5 of those had been transferred from a failing KT (p = 0.004). There were no differences between PD-first, prior KT, and prior HD in terms of death and technique survival (p = 0.195 and p = 0.917, respectively) and PD efficacy was adequate in all groups. PD is a suitable option for ESRD patients regardless of the previous RRT and should be offered to patients according to their clinical and social status and preferences.

Rationale and design of ELIXIR, a randomized, controlled trial to evaluate efficacy and safety of XyloCore, a glucose-sparing solution for peritoneal dialysis.

Peritoneal dialysis adoption and technique survival is affected by limitations related to peritoneal membrane longevity and metabolic alterations. Indeed, almost all peritoneal dialysis fluids exploit glucose as an osmotic agent that rapidly diffuses across the peritoneal membrane, potentially resulting in metabolic abnormalities such as hyperglycemia, hyperinsulinemia, obesity, and hyperlipidemia. Moreover, glucose-degradation products generated during heat sterilization, other than glucose itself, induce significant morphological and functional changes in the peritoneum leading to ultrafiltration failure. The partial substitution of glucose with osmotic agents characterized by a better local and systemic biocompatibility has been suggested as a potential strategy to innovate peritoneal dialysis fluids. The approach aims to minimize glucose-associated toxicity, preserving the peritoneal membrane welfare and counteracting common comorbidities. In this work, we report the clinical trial design of ELIXIR, a phase III randomized, controlled, blinded outcome assessment study comparing Xylocore®, an innovative formulation based on Xylitol and l-carnitine, to standard glucose-based regimens, in end-stage kidney disease patients treated with continuous ambulatory peritoneal dialysis; 170 patients will be randomized (1:1) to receive XyloCore® or to continue their pre-randomization peritoneal dialysis (PD) therapy with glucose-only PD solutions, for 6 months. The primary study's objective is to demonstrate the noninferiority of XyloCore® in terms of Kt/V urea, for which a clinically acceptable noninferiority margin of -0.25 has been determined, assuming that all patients will be treated aiming to a minimum target of 1.7 and an optimal target of 2.0.

Short-term peritoneal rest reduces peritoneal solute transport rate and increases ultrafiltration in high/high average transport peritoneal dialysis patients: a crossover randomized controlled trial

ABSTRACT Background The peritoneal solute transport rate (PSTR) tends to increase over time in some patients undergoing peritoneal dialysis (PD), potentially leading to ultrafiltration (UF) failure. Previous case reports have shown a significant decrease in PSTR and subsequent recovery of UF after discontinuing PD for a while. Therefore, we conducted a randomized controlled crossover study to evaluate the impact of short-term peritoneal rest on PSTR. Methods The study involved 14 continuous ambulatory peritoneal dialysis (CAPD) patients with high/high-average transport rate. Two groups were randomly assigned different treatment sequences: one group underwent daily intermittent peritoneal dialysis (IPD) for 4 weeks followed by CAPD, while the other group initially received CAPD treatment for 4 weeks and then switched to IPD. Peritoneal equilibration tests were performed before and after each treatment to evaluate PSTR and paired t-tests were used to compare the changes. Volume load, serum potassium and other clinical indicators were monitored at the same time. Results Short-term peritoneal rest (daily IPD) significantly reduced PSTR, with a decrease in the dialysate:plasma creatinine ratio from 0.71 ± 0.05 to 0.65 ± 0.07 (P &amp;lt; .001). Additionally, ultrafiltration significantly increased from 210 ± 165 ml to 407 ± 209 ml (P = .001). But there were no significant changes in interleukin-6 and vascular endothelial growth factor of PD effluent. No serious adverse events such as hypotension or hyperkalaemia occurred. Conclusions In PD patients with high and high-average transport, a 4-week period of short-term peritoneal rest by switching from CAPD to IPD (without long dwell) can lead to reductions in PSTR and increases in UF volumes, while maintaining clinical safety.

Pressure induces peritoneal fibrosis and inflammation through CD44 signaling

Peritoneal dialysis (PD) is a widely used sustainable kidney replacement therapy. Prolonged use of PD fluids is associated with mesothelial-mesenchymal transition, peritoneal fibrosis, and eventual ultrafiltration (UF) failure. However, the impact of pressure on the peritoneum remains unclear. In the present study, we hypothesized increased pressure is a potential contributing factor to peritoneal fibrosis and investigated the possible mechanisms. In vitro experiments found that pressurization led to a mesenchymal phenotype, the expression of fibrotic markers and inflammatory factors in human mesothelial MeT-5A cells. Pressure also increased cell proliferation and augmented cell migration potential in MeT-5A cells. The mouse PD model and human peritoneum equilibrium test (PET) data both showed a positive association between higher pressure and increased small solute transport, along with decreased net UF. Mechanistically, we found that significant upregulation of CD44 in mesothelial cells upon pressurization. Notably, the treatment of CD44 neutralizing antibodies prevented pressure-induced phenotypic changes in mesothelial cells, while a CD44 inhibitor oligo-fucoidan ameliorated pressure-induced peritoneal thickening, fibrosis, and inflammation in PD mice. To conclude, intraperitoneal pressure results in peritoneal fibrosis in PD via CD44-mediated mesothelial changes and inflammation. CD44 blockage can be utilized as a novel preventive approach for PD-related peritoneal fibrosis and UF failure.

Detections of Chemicals and Migratory Plastics in Peritoneal Dialysis Fluids

Background: Peritoneal dialysis (PD) is an important modality of renal replacement therapy (RRT). Peritonitis and ultrafiltration failure are complications that have a long-term impact on PD patients. Besides touch contamination, procedural errors and clinical reasons of peritonitis, contaminants, and constituents of peritoneal dialysis fluids (PDFs) have been implicated in causing peritonitis and ultrafiltration failure. This study was aimed to test the PDFs in India for the presence of migratory plastics. Materials and Methods: PDFs from the two manufacturers in India were tested using liquid chromatography mass spectrometry (LCMS) and gas chromatography mass spectrometry (GCMS) with headspace analysis (volatile compounds) and pyrolysis of plastics (polymer compounds). The storage conditions and handling were uniform. Results: The results revealed impurities of acetate compounds and aldehyde derivatives of glucose degradation products (GDPs) with contaminants and leachable plastics. There were high levels of GDP derivative in the form of 5-hydroxymethylfurfural compounds (5-HMF). The analysis revealed the presence of plastic softeners in very high concentrations. Conclusion: The study unmasks the presence of chemicals and GDPs that can be implicated in pathogenesis of sterile peritonitis and ultrafiltration failure. The study demonstrated the presence of leachable plastics. In conclusion, LCMS and GCMS studies can be used to test PDFs for unwanted chemicals prior to human use.

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.

#2055 Variations in free water transport condition ultrafiltration capacity since basal times

Abstract Background and Aims There is great variability in free water carrying capacity (FFWC) in incident patients, but the extent to which this variability impacts inherent ultrafiltration failure (UF) is unknown. The peritoneal equilibration test (PET) with 3.86% glucose allows measurement of permeability (D/Pcr), standard UF (UFs) and sodium screening (CriNa) as an indirect measure of TAL. Our objectives were to determine to what extent variations in free water transport condition a related ultrafiltration failure. To assess, according to the variables studied, whether or not the patient`s comorbidities or anthropometric data influenced our study. Method We conducted a study in 58 incident patients in our hospital between 2009-2023 in which we evaluated D/Pcr, UFs and CriNa in PET -3.86. We recorded the dialysis pattern and daily UF. Results The PET -3.86% results were evaluated (Table 1), showing the clinical and peritoneal transport characteristics of the total patients and the comparison between patients with CriNa lower or higher than the median. The patients with lower CriNa were older and had lower UFs and UFd. We found a correlation between CriNa and UFs (0.39, p = 0.002) and daily UF (0.318, p = 0.05). In the multiple regression analysis, CriNa and D/Pcr maintain the correlation with UFs independently. While only CriNa maintains the correlation with daily UF, despite there being no differences in the use of DPA or icodextrin. Conclusion On analyzing the results, we found that the intrinsic variations of the membrane, in the free water transport capacity, justify part of the ultrafiltration capacity measured both in kinetics and daily ultrafiltration. As for age, we found that the older the patient is, the lower the sodium sieving, at least initially. With this study we emphasize the importance of assessing variations in free water transport capacity using the peritoneal equilibrium test as a tool.

#494 Analysis of technique failure and reasons for the end of follow-up in a peritoneal dialysis unit

Abstract Background and Aims Currently, there are various definitions for peritoneal dialysis technique failure, and several related factors are described. There is controversy regarding whether mortality should be considered a form of technique failure or not, as it involves an event of a different nature. Besides, the exit form peritoneal dialysis (PD) technique can occur due to the transition to hemodialysis (HD), kidney transplantation or the patient's death in general. The aim of this study was to investigate which factors are associated with survival in peritoneal dialysis technique. Method A retrospective study was conducted with 111 incident PD patients in the dialysis unit of Hospital Universitario Virgen de las Nieves, in Granada, Spain, between 2015 and 2020. A survival curve was obtained, evaluating the association of different variables with technique failure and the end of follow-up. By identifying mortality as a competitive risk for technique failure, a Fine and Gray competitive risks model was applied. Results A total of 111 patients were analyzed, with an annual technique survival of 90%, being it 83% at two years, and 74% at three years. Table 1 reflects the demographic and clinical characteristics of the patients. The main causes of technique failure were psychosocial causes (19%), peritoneal catheter mechanical issues (12%), ultrafiltration failure (9.52%), and peritonitis (9.52%). The main reasons for the end of follow-up were kidney transplantation (55%), transfer to HD (26%), and death (12.6%). Among the deceased, 64% were of cardiovascular origin, and 21% were infectious. Technique failure was more observed in patients over 65 years old, in those with a Charlson index higher than 4 points, with diabetes, a history of cardiovascular disease (CVD) and heart failure (HF), in former smokers, and in diabetic kidney disease. Conclusion Technique survival in our center was 90% at one year and 83% at two years, similar to previous Spanish records. The reasons for technique exit were: 55% due to kidney transplantation, 26% due to transfer to hemodialysis, and 19% due to for psychosocial causes. Risk factors related to technique failure were advanced age, Charlson index, diabetes, and a history of cardiovascular disease (CVD) and heart failure (HF).

BMSC-derived Exosomes Ameliorate Peritoneal Dialysis-associated Peritoneal Fibrosis via the Mir-27a-3p/TP53 Pathway.

Peritoneal fibrosis (PF) is the main cause of declining efficiency and ultrafiltration failure of the peritoneum, which restricts the long-term application of peritoneal dialysis (PD). This study aimed to investigate the therapeutic effects and mechanisms of bone marrow mesenchymal stem cells-derived exosomes (BMSC-Exos) on PF in response to PD. Small RNA sequencing analysis of BMSC-Exos was performed by second-generation sequencing. C57BL/6J mice were infused with 4.25% glucose-based peritoneal dialysis fluid (PDF) for 6 consecutive weeks to establish a PF model. A total of 36 mice were randomly divided into 6 groups: control group, 1.5% PDF group, 2.5% PDF group, 4.25% PDF group, BMSC-Exos treatment group, and BMSC-Exos+TP53 treatment group. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed to measure the expression level of miR-27a-3p in BMSC-Exos and peritoneum of mice treated with different concentrations of PDF. HE and Masson staining were performed to evaluate the extent of PF. The therapeutic potential of BMSC-Exos for PF was examined through pathological examination, RT-qPCR, Western blotting, and peritoneal function analyses. Epithelial-mesenchymal transition (EMT) of HMrSV5 was induced with 4.25% PDF. Cells were divided into control group, 4.25% PDF group, BMSC-Exos treatment group, and BMSC-Exos+TP53 treatment group. Cell Counting Kit-8 assay was used to measure cell viability, and transwell migration assay was used to verify the capacity of BMSC-Exos to inhibit EMT in HMrSV5 cells. Small RNA sequencing analysis showed that miR-27a-3p was highly expressed in BMSC-derived exosomes compared to BMSCs. The RT-qPCR results showed that the expression of miR-27a-3p was upregulated in BMSC-Exos, but decreased in PD mice. We found that PF was glucose concentration-dependently enhanced in the peritoneum of the PD mice. Compared with the control mice, the PD mice showed high solute transport and decreased ultrafiltration volume as well as an obvious fibroproliferative response, with markedly increased peritoneal thickness and higher expression of α-SMA, collagen-I, fibronectin, and ECM1. The mice with PD showed decreased miR-27a-3p. Peritoneal structural and functional damage was significantly attenuated after BMSC-Exos treatment, while PF and mesothelial damage were significantly ameliorated. Additionally, markers of fibrosis (α-SMA, collagen-I, fibronectin, ECM1) and profibrotic cytokines (TGF-β1, PDGF) were downregulated at the mRNA and protein levels after BMSC-Exos treatment. In HMrSV5 cells, BMSC-Exos reversed the decrease in cell viability and the increase in cell migratory capacity caused by high-glucose PDF. Western blotting and RT-qPCR analysis revealed that BMSC-Exos treatment resulted in increased expression of E-cadherin (epithelial marker) and decreased expression of α-SMA, Snail, and vimentin (mesenchymal markers) compared to those of the 4.25% PDF-treated cells. Importantly, a dual-luciferase reporter assay showed that TP53 was a target gene of miR-27a-3p. TP53 overexpression significantly reversed the decreases in PF and EMT progression induced by BMSC-Exos. The present results demonstrate that BMSC-Exos showed an obvious protective effect on PD-related PF and suggest that BMSC-derived exosomal miR-27a-3p may exert its inhibitory effect on PF and EMT progression by targeting TP53.

Coupling Osmotic Efficacy with Biocompatibility in Peritoneal Dialysis: A Stiff Challenge.

Peritoneal dialysis (PD) is a home-based efficacious modality for the replacement of renal function in end-stage kidney failure patients, but it is still under-prescribed. A major limitation is the durability of the dialytic technique. Continuous exposure of the peritoneum to bioincompatible conventional glucose-based solutions is thought to be the main cause of the long-term morpho-functional peritoneal changes that eventually result in ultrafiltration failure. Poor PD solution biocompatibility is primarily related to the high glucose content, which is not only detrimental to the peritoneal membrane but has many potential metabolic side effects. To improve the clinical outcome and prolong the survival of the treatment, PD-related bioincompatibility urgently needs to be overcome. However, combining dialytic and osmotic efficacy with a satisfactory biocompatible profile is proving to be quite difficult. New approaches targeting the composition of the PD solution include the replacement of glucose with other osmotic agents, and the addition of cytoprotective or osmo-metabolic compounds. Other strategies include the infusion of mesenchymal cells or the administration of orally active agents. In the present article, we review the current evidence on efforts to improve the biocompatible and functional performance of PD, focusing on studies performed in vivo (animal models of PD, human subjects on PD).

Determination of Extra- and Intraperitoneal Fluid during Peritoneal Dialysis using Bioimpedance.

In peritoneal dialysis (PD), ultrafiltration (UF) failure is commonly attributed to dysfunction of the peritoneal membrane, resulting in decreased ultrafiltration volume (UFV). Our objective was to evaluate whether fluid absorption and UF can be assessed by monitoring intraperitoneal fluid using segmental bioimpedance analysis (sBIA). Twenty PD patients were studied during either a peritoneal equilibration test (PET; n = 7) or automated PD (APD; n = 13). Eight electrodes were positioned on the lower abdomen and connected to a bioimpedance device (Hydra 4200). A physical model of abdominal extracellular volume (VABD) was introduced, consisting of the fluid in extraperitoneal (VEPF) and the intraperitoneal cavity (VIPF). The change in the fluid surrounding the peritoneal cavity (ΔVEPF) was determined by assessing the difference in VEPF before and after PD. ΔVDwell was calculated as the difference between VABD at the end and the start of the dialysate dwell. The rate of ΔVDwell change due to UF or absorption can be estimated from VABD profiles. Total fluid (VIPF, D) in the peritoneal cavity was calculated which was used to compare actual drain volume (VDrain). VDrain and VIPF, D exhibited a strong correlation (PET: R2 = 0.98, p<0.0001; APD: R2 = 0.94, p<0.0001). Stable ΔVEPF (ΔVEPF = 0) was linked to rapid glucose transport, as measured by standard PET. This study presents a new model utilizing a bioimpedance method to monitor fluid volume across the peritoneal membrane. While the limitation of peritoneal residual volume remains unknown, this approach holds promise for providing a direct measurement of fluid transport during PD.

Physiology of peritoneal dialysis; pathophysiology in long-term patients.

The microvascular wall of peritoneal tissues is the main barrier in solute and water transport in the initial phase of peritoneal dialysis (PD). Small solute transport is mainly by diffusion through inter-endothelial pores, as is hydrostatic fluid transport with dissolved solutes. Water is also transported through the intra-endothelial water channel aquaporin-1(AQP-1) by a glucose-induced crystalloid osmotic gradient (free water transport). In the current review the physiology of peritoneal transport will be discussed both during the first years of PD and after long-term treatment with emphasis on the peritoneal interstitial tissue and its role in free water transport. Attention will be paid to the role of glucose-induced pseudohypoxia causing both increased expression of fibrogenetic factors and of the glucose transporter GLUT-1. The former leads to peritoneal fibrosis, the latter to a reduced crystalloid osmotic gradient, explaining the decrease in free water transport as a cause of ultrafiltration failure. These phenomena strongly suggest that the extremely high dialysate glucose concentrations are the driving force of both morphologic and functional peritoneal alterations that may develop during long-term PD.

A protective role of nintedanib in peritoneal fibrosis through H19-EZH2-KLF2 axis via impeding mesothelial-to-mesenchymal transition.

Peritoneal fibrosis (PF), a common complication of long-term peritoneal dialysis, accounts for peritoneal ultrafiltration failure to develop into increased mortality. Nintedanib has previously been shown to protect against multi-organ fibrosis, including PF. Unfortunately, the precise molecular mechanism underlying nintedanib in the pathogenesis of PF remains elusive. The mouse model of PF was generated by chlorhexidine gluconate (CG) injection with or without nintedanib administration, either with the simulation for the cell model of PF by constructing high-glucose (HG)-treated human peritoneal mesothelial cells (HPMCs). HE and Masson staining were applied to assess the histopathological changes of peritoneum and collagen deposition. FISH, RT-qPCR, western blot and immunofluorescence were employed to examine distribution or expression of targeted genes. Cell viability was detected using CCK-8 assay. Cell morphology was observed under a microscope. RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) assays were applied to validate the H19-EZH2-KLF2 regulatory axis. Aberrantly overexpressed H19 was observed in both the mouse and cell model of PF, of which knockdown significantly blocked HG-induced mesothelial-to-mesenchymal transition (MMT) of HPMCs. Moreover, loss of H19 further strengthened nintedanib-mediated suppressive effects against MMT process in a mouse model of PF. Mechanistically, H19 could epigenetically repressed KLF2 via recruiting EZH2. Furthermore, TGF-β/Smad pathway was inactivated by nintedanib through mediating H19/KLF2 axis. In summary, nintedanib disrupts MMT process through regulating H19/EZH2/KLF2 axis and TGF-β/Smad pathway, which laid the experimental foundation for nintedanib in the treatment of PF.

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.

Melatonin decreases GSDME mediated mesothelial cell pyroptosis and prevents peritoneal fibrosis and ultrafiltration failure.

Peritoneal fibrosis together with increased capillaries is the primary cause of peritoneal dialysis failure. Mesothelial cell loss is an initiating event for peritoneal fibrosis. We find that the elevated glucose concentrations in peritoneal dialysate drive mesothelial cell pyroptosis in a manner dependent on caspase-3 and Gasdermin E, driving downstream inflammatory responses, including the activation of macrophages. Moreover, pyroptosis is associated with elevated vascular endothelial growth factor A and C, two key factors in vascular angiogenesis and lymphatic vessel formation. GSDME deficiency mice are protected from high glucose induced peritoneal fibrosis and ultrafiltration failure. Application of melatonin abrogates mesothelial cell pyroptosis through a MT1R-mediated action, and successfully reduces peritoneal fibrosis and angiogenesis in an animal model while preserving dialysis efficacy. Mechanistically, melatonin treatment maintains mitochondrial integrity in mesothelial cells, meanwhile activating mTOR signaling through an increase in the glycolysis product dihydroxyacetone phosphate. These effects together with quenching free radicals by melatonin help mesothelial cells maintain a relatively stable internal environment in the face of high-glucose stress. Thus, Melatonin treatment holds some promise in preserving mesothelium integrity and in decreasing angiogenesis to protect peritoneum function in patients undergoing peritoneal dialysis.

A review of research progress on mechanisms of peritoneal fibrosis related to peritoneal dialysis.

Peritoneal dialysis (PD) is an effective alternative treatment for patients with end-stage renal disease (ESRD) and is increasingly being adopted and promoted worldwide. However, as the duration of peritoneal dialysis extends, it can expose problems with dialysis inadequacy and ultrafiltration failure. The exact mechanism and aetiology of ultrafiltration failure have been of great concern, with triggers such as biological incompatibility of peritoneal dialysis solutions, uraemia toxins, and recurrent intraperitoneal inflammation initiating multiple pathways that regulate the release of various cytokines, promote the transcription of fibrosis-related genes, and deposit extracellular matrix. As a result, peritoneal fibrosis occurs. Exploring the pathogenic factors and molecular mechanisms can help us prevent peritoneal fibrosis and prolong the duration of Peritoneal dialysis.

Glucose-induced pseudohypoxia and advanced glycosylation end products explain peritoneal damage in long-term peritoneal dialysis.

Long-term peritoneal dialysis is associated with the development of peritoneal membrane alterations, both in morphology and function. Impaired ultrafiltration (UF) is the most important functional change, and peritoneal fibrosis is the major morphological alteration. Both are caused by the continuous exposure to dialysis solutions that are different from plasma water with regard to the buffer substance and the extremely high-glucose concentrations. Glucose has been incriminated as the major cause of long-term peritoneal membrane changes, but the precise mechanism has not been identified. We argue that glucose causes the membrane alterations by peritoneal pseudohypoxia and by the formation of advanced glycosylation end products (AGEs). After a summary of UF kinetics including the role of glucose transporters (GLUT), and a discussion on morphologic alterations, relationships between function and morphology and a survey of the pathogenesis of UF failure (UFF), it will be argued that impaired UF is partly caused by a reduction in small pore fluid transport as a consequence of AGE-related vasculopathy and - more importantly - in diminished free water transport due to pseudohypoxia, caused by increased peritoneal cellular expression of GLUT-1. The metabolism of intracellular glucose will be reviewed. This occurs in the glycolysis and in the polyol/sorbitol pathway, the latter is activated in case of a large supply. In both pathways the ratio between the reduced and oxidised form of nicotinamide dinucleotide (NADH/NAD+ ratio) will increase, especially because normal compensatory mechanisms may be impaired, and activate expression of hypoxia-inducible factor-1 (HIF-1). The latter gene activates various profibrotic factors and GLUT-1. Besides replacement of glucose as an osmotic agent, medical treatment/prevention is currently limited to tamoxifen and possibly Renin/angiotensis/aldosteron (RAA) inhibitors.

Oxidative stress as the bridge between dyslipidemia and peritoneal ultrafiltration failure: A bi-center cross-sectional cohort study

stress and dyslipidemia are common concerns in patients undergoing peritoneal dialysis (PD) and are associated with adverse clinical outcomes. However, the interplay between these factors and their impact on peritoneal ultrafiltration (UF) remains poorly understood.&#x0D; Methods: In this bi-center cross-sectional cohort study, we examined the relationships between dyslipidemia, oxidative stress, and peritoneal UF in patients undergoing PD. A comprehensive set of oxidative stress markers, lipid profiles, and clinical variables were assessed.&#x0D; Results. Among the 114 patients, aged 55 (48-65) years, with a dialysis vintage of 31 (14-50) months, 76 (66.7%) were diagnosed with dyslipidemia. Patients with dyslipidemia experienced significantly higher proportions of patients with peritoneal UF below 400 mL per day, suggesting ultrafiltration failure (UFF) (χ2 = 4.9, p = 0.02). An elevated D/P creatinine ratio was associated with higher levels of total cholesterol (r = 0.39, p = 0.0005), low-density lipoprotein cholesterol (r = 0.26, p = 0.02), triglycerides (r = 0.33, p = 0.005), and the atherogenic index of plasma (AIP) (r = 0.27, p = 0.01). UF rate displayed a positive correlation with high-density lipoprotein cholesterol (r = 0.31, p = 0.003) and a negative correlation with AIP (r = -0.33, p = 0.004). The ROC analysis revealed that an AIP value exceeding 4.3 could effectively predict UFF, with a sensitivity of 83.3% and a specificity of 73.4%&#x0D; Dyslipidemia was significantly associated with increased intensity of oxidative stress, with elevated malondialdehyde (MDA) (p = 0.0002), oxidative stress index (OSI) (p &lt; 0.0001), and reduced antioxidant markers. UFF was also associated with higher oxidative stress, as indicated by increased MDA (p = 0.005) and OSI (p = 0.0009). Patients with both dyslipidemia and UFF exhibited the highest levels of oxidative stress (p &lt; 0.0001). Taking potential confounders into account in the ANCOVA analysis, a significant interaction effect of dyslipidemia (F = 7.6, p = 0.007) and UF rate (F = 8.6, p = 0.004) on oxidative stress was observed.&#x0D; Conclusion. Dyslipidemia and UFF are independently associated with elevated oxidative stress in PD patients, and their coexistence exacerbates this oxidative burden. Understanding these relationships is crucial for developing interventions to improve clinical outcomes in this population. Targeted therapies addressing oxidative stress and dyslipidemia warrant further investigation.

Influence of peritoneal residual volume on the results of the peritoneal equilibration test. Prospective study

BackgroundCategorization of the capacity of ultrafiltration during a peritoneal equilibration test (PET) is a usual step during the monitoring of peritoneal transport characteristics of Peritoneal Dialysis (PD) patients. Quantifying the peritoneal residual volume (Vr) after the dwell preceding the PET (Vrpre) and at the end of the test (Vrpost) could help to improve the accuracy of the estimation of this variable. MethodFollowing a prospective design, we calculated Vrpre and Vrpost in 116 patients, incident or prevalent on DP, who underwent one or two (n = 27) PET with 3,86/4,25% glucose-based PD solutions and complete drainage at 60 min. We evaluated the consistency of Vr by comparing Vrpre and Vrpost, as also these two parameters in repeated tests. We scrutinized potential associations between demographic and clinical factors, on one side, and the amount of Vr on the other, as also the impact of correcting ultrafiltration during PET for Vr on the categorization of the capacity of ultrafiltration. ResultsAs a mean, Vrpost was larger than Vrpre. Consequently, correction of ultrafiltration for Vr resulted in significantly higher values than those obtained according to the standard procedure (494 vs. 449 mL, p < 0,0005). We disclosed marked inconsistencies for different estimations of Vr in the same patients (Vrpre vs Vrpost and repeated PET studies). Moreover, no demographic or clinical variable was able to predict the amount of Vr. We observed a significant deviation (>200 mL) between both methods of estimation of the capacity of utrafiltration in only 12,9% of the patients. However, 21,1% of the patients categorized as cases of ultrafiltration failure according to the standard procedure did not maintain this condition after correction for Vr. ConclusionsCorrection for Vr of the capacity of ultrafiltration during a PET carries, as a mean, a minor impact on the categorization of this parameter. However, the results of the test can be significantly affected in 12,9% of the cases. We have been unable to detect demographic or clinical predictors of Vr, which suggests a random component for the mechanics of single peritoneal exchanges. We suggest that Vr should be estimated at the time of categorizing the capacity of ultrafiltration, whenever inconsistencies during serial PET studies are detected.