Peritoneal Ultrafiltration Failure Research Articles

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.

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.
 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.
 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%
 Dyslipidemia was significantly associated with increased intensity of oxidative stress, with elevated malondialdehyde (MDA) (p = 0.0002), oxidative stress index (OSI) (p < 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 < 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.
 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.

N-methylpiperazine-diepoxyovatodiolide ameliorates peritoneal fibrosis via suppressing TGF-β/Smad and JAK/STAT signaling pathway

Peritoneal fibrosis (PF) is the main cause of peritoneal ultrafiltration failure in patients undergoing long-term peritoneal dialysis (PD). Epithelial–mesenchymal transition (EMT) is the key pathogenesis of PF. However, currently, no specific treatments are available to suppress PF. N-methylpiperazine-diepoxyovatodiolide (NMPDOva) is a newly synthesized compound that involves a chemical modification of ovatodiolide. In this study, we aimed to explore the antifibrotic effects of NMPDOva in PD-related PF and underlying mechanisms. A mouse model of PD-related PF was established via daily intraperitoneal injection of 4.25% glucose PD fluid. In vitro studies were performed using the transforming growth factor-beta1 (TGF-β1)-stimulated HMrSV5 cell line. Pathological changes were observed, and fibrotic markers were significantly elevated in the peritoneal membrane in mice model of PD-related PF. However, NMPDOva treatment significantly alleviated PD-related PF by decreasing the extracellular matrix accumulation. NMPDOva treatment decreased the expression of fibronectin, collagen Ⅰ, and alpha-smooth muscle actin (α-SMA) in mice with PD-related PF. Moreover, NMPDOva could alleviate TGF-β1-induced EMT in HMrSV5 cells, inhibited phosphorylation and nuclear translocation of Smad2/3, and increased the expression of Smad7. Meanwhile, NMPDOva inhibited phosphorylation of JAK2 and STAT3. Collectively, these results indicated that NMPDOva prevents PD-related PF by inhibiting the TGF-β1/Smad and JAK/STAT signaling pathway. Therefore, because of these antifibrotic effects, NMPDOva may be a promising therapeutic agent for PD-related PF.

Autophagy in peritoneal fibrosis.

Peritoneal dialysis (PD) is a widely accepted renal replacement therapy for patients with end-stage renal disease (ESRD). Morphological and functional changes occur in the peritoneal membranes (PMs) of patients undergoing long-term PD. Peritoneal fibrosis (PF) is a common PD-related complication that ultimately leads to PM injury and peritoneal ultrafiltration failure. Autophagy is a cellular process of "self-eating" wherein damaged organelles, protein aggregates, and pathogenic microbes are degraded to maintain intracellular environment homeostasis and cell survival. Growing evidence shows that autophagy is involved in fibrosis progression, including renal fibrosis and hepatic fibrosis, in various organs. Multiple risk factors, including high-glucose peritoneal dialysis solution (HGPDS), stimulate the activation of autophagy, which participates in PF progression, in human peritoneal mesothelial cells (HPMCs). Nevertheless, the underlying roles and mechanisms of autophagy in PF progression remain unclear. In this review, we discuss the key roles and potential mechanisms of autophagy in PF to offer novel perspectives on future therapy strategies for PF and their limitations.

Loss of JNK-Associated Leucine Zipper Protein Promotes Peritoneal Dialysis-Related Peritoneal Fibrosis

Background: Peritoneal dialysis-related peritoneal fibrosis is the leading cause of peritoneal ultrafiltration failure. Multitude factors and pathological processes have been implicated in peritoneal fibrosis development and progression, whereas the intrinsic anti-fibrotic mechanism has rarely been explored. JNK-associated leucine zipper protein (JLP) has been recently found possessing powerful anti-fibrotic merits of overall antagonizing TGF-β-induced profibrotic effects. Objectives: We wondered whether JLP is expressed in the peritoneum, and if so, whether it exerts the anti-fibrotic effects similar to those in the kidney. Method: Here, we examined and confirmed JLP expression in peritoneum tissue of mice. Then, we established a peritoneal fibrosis model in Jlp wild-type and Jlp global deficient mice and observed the different effects of Jlp on peritoneal fibrosis progression. In vitro studies were performed on peritoneal mesothelial HMrSV5 cells with or without Jlp knockdown to investigate the underlying mechanism by which Jlp exerts anti-fibrotic effects. Results: We found that the expression of JLP decreased in a high-glucose peritoneal dialysis solution (HGPDS)-induced peritoneal fibrosis mouse model and in HGPDS-treated peritoneal mesothelial cell HMrSV5. JLP deletion exacerbated HGPDS-induced peritoneal fibrosis in peritoneal fibrosis mice, and knockdown of JLP resulted in an increased profibrotic response to HGPDS stimulation in HMrSV5 cells, which was associated with epithelial-to-mesenchymal transition, elevated autophagy, and apoptosis, as well as enhanced TGF-β1/Smad signaling activation. Conclusions: Our findings revealed a new anti-fibrotic factor of Jlp involved in peritoneal fibrosis induction and shed light on novel therapeutic targets in peritoneal ultrafiltration failure.

Adverse factors on nonenhanced abdominal CT for long-term continuous ambulatory peritoneal dialysis: a comparative study between patients who withdraw from and maintain long-term peritoneal dialysis.

PurposeTo investigate the imaging features of patients with long-term continuous ambulatory peritoneal dialysis (CAPD) on nonenhanced abdominal CT and to identify adverse factors for long-term CAPD.MethodsA total of 109 patients with less than 5 years of CAPD for peritoneal ultrafiltration failure who switched to hemodialysis (withdrawal group) and 23 patients with more than 10 years of CAPD (long-term group) were retrospectively enrolled. Nonenhanced CT manifestations in both groups were compared, including thickening and calcification of the parietal peritoneum, calcification of the mesangial margin and free margin of the small intestine wall, and calcification of the mesentery and abdominal aorta. A risk stratification model was proposed based on CT manifestations with statistically significant differences.ResultsThe presence of the following CT findings was significantly different between two groups: extensive thickening of the parietal peritoneum (78.9% vs. 21.7%, P < 0.01); severe calcification of the parietal peritoneum (60.6% vs. 8.7%, P < 0.01); calcification of the mesentery (32.1% vs. 4.3%, P < 0.05); and calcification of the free margin of the small intestine wall (49.5% vs. 13.0%, P < 0.05). However, there was no significant difference in calcification of the mesangial margin of the small intestine wall (40.3% vs. 30.4%) or in abdominal aortic calcification (56.9% vs. 61.1%) (P > 0.05). The area under the receiver operating characteristic curve (AUC) was 0.906 (sensitivity 87.6% and specificity 82.6%).ConclusionExtensive thickening of the parietal peritoneum, severe calcification of the parietal peritoneum, and calcification of the mesentery and the free margin of the small intestine wall are adverse factors for long-term CAPD.

Experimental models in peritoneal dialysis (Review).

Peritoneal dialysis (PD) is one of the most commonly used dialysis methods and plays an important role in maintaining the quality of life of patients with end-stage renal disease. However, long-term PD treatment is associated with adverse effects on the structure and function of peritoneal tissue, which may lead to peritoneal ultrafiltration failure, resulting in dialysis failure and eventually PD withdrawal. In order to prevent the occurrence of these effects, the important issues that need to be tackled are improvement of ultrafiltration, protection of peritoneal function and extension of dialysis time. In basic PD research, a reasonable experimental model is key to the smooth progress of experiments. A good PD model should not only simulate the process of human PD as accurately as possible, but also help researchers to understand the evolution process and pathogenesis of various complications related to PD treatment. To better promote the clinical application of PD technology, the present review will summarize and evaluate the in vivo PD experimental models available, thus providing a reference for relevant PD research.

P1149PERITONEAL MEMBRANE CHARACTERISTICS OVER TIME: A LONGITUDINAL STUDY

Abstract Background and Aims Modified PET (use of 3.86% glucose dialysate instead of 2.27%) and temporal drainage at one hour allows a more complete study of peritoneal membrane transport, as it provides information about sodium sieving, free water transport (FWT) and ultrafiltration failure (UFF). Longitudinal data using this PET are sporadic. Aims of our study were a) longitudinal follow-up of the membrane function using modified PET b) evaluation of UFF and association with clinical and membrane characteristics. Method We analyzed all modified PET tests performed in our unit during the last 9 years. Patients who underwent the first test during the first year of treatment and then once a year were included. We estimated classic peritoneal transport parameters like D/P creatinine, D/D0 glucose and ultrafiltration (UF) at 4 hours. Moreover we calculated sodium seiving expressed as Dip/DPNa= (Dialysate sodium time 0/plasma sodium)-(Dialysate sodium time 1 hour/plasma sodium)], sodium removal (in one hour) and FWT. We collected clinical and lab data of the patients too. Results A total of 219 PETs were performed in 85 PD patients, (median age 64 years (range 18-45). The baseline membrane characteristics of the patients were: DP creatinine=0.74±0.11, D/D0glucose=0.28±0.08, DipDPNa=0.05±0.04, sodium removal=29,804 ±26,894 (mmol/L), FWT=214.9±194.7 ml and UF =655.1±265.5 ml. On multivariate regression analysis D/P creatinine, FWT and sodium removal were significant independent covariates accounting for 50% of the variability of ultrafiltration . The patients were followed-up for a median of 36 months (range 2.4-143).For the repeated measurements, the analysis showed that the observed values of D/Pcre,D/D0, Dip/DPNa, FWT and UF remained rather stable across the different time measurements. During the study, 23 out of 85 pts developed peritoneal UF failure (UFF). Analysis was performed using univariate random effects logistic time-series models and only D/D0 (OR=0.84, P=0.001), D/P Cre (OR=1.15, p&amp;lt;0.001), urine volume (OR=1.26, p=0.027) and sodium removal (OR=0.99, p=0.003) were significantly associated with relative risk of UFF development. Conclusion Surprisingly, our patients present a stable membrane function over time. Possible explanations could be the low peritonitis rate and strict use of hypertonic glucose dialysates. Ultrafiltration failure was correlated with higher D/P creatinine and lower D/D0 glucose values, higher baseline urine volume and lower sodium sieving.

HIF1A and VEGF regulate each other by competing endogenous RNA mechanism and involve in the pathogenesis of peritoneal fibrosis

BackgroundPeritoneal fibrosis is a major intractable complication of long-term peritoneal dialysis, and would eventually lead to peritoneal ultrafiltration failure and the termination of peritoneal dialysis. Hypoxia-inducible factor 1-alpha (HIF1A) has been reported to regulate vascular endothelial growth factor (VEGF) and involves in peritoneal fibrosis, but the exact molecular regulation mechanism remains unknown. MethodsHIF1A and VEGF protein levels were measured in 42 peritoneal patients using enzyme linked immunosorbent assay. Bioinformatics, reverse transcription-polymerase chain reaction, correlation analysis, RNA interference, gene over-expression and luciferase assays were performed to clarify the competing endogenous RNA (ceRNA) regulation between HIF1A and VEGF. ResultsBoth HIF1A and VEGF levels were elevated in the peritoneal effluent of peritoneal dialysis patients with ultrafiltration problems, and were positively correlated with each other at protein level and mRNA level. Bioinformatics analysis identified 8 common targeted miRNAs for HIF1A and VEGF, including miR-17-5p, 20a, 20b, 93, 106a, 106b, 199a-5p and 203. MiR-17-5p was proved to be present in patients’ peritoneal effluent and selected for further studies. HIF1A mRNA and VEGF mRNA could regulate each other, and miR-17-5p was required in the regulations. Down/up regulation of HIF1A mRNA and VEGF mRNA resulted in up/down regulation of miR-17-5p. Furthermore, down/up regulation of miR-17-5p was associated with up/down regulation of HIF1A mRNA and VEGF mRNA. Luciferase assay indicated that HIF1A and VEGF regulated each other through 3′UTR. ConclusionHIF1A and VEGF could regulate each other in peritoneal mesothelial cell in the mediation of miR-17-5p and 3′UTR, indicating HIF1A and VEGF might regulate each other through competing endogenous RNA mechanism in the development of peritoneal fibrosis.

Hemodiafiltration in Infants With Complications During Peritoneal Dialysis

End-stage renal disease (ESRD) in neonates still has a high mortality, particularly in the first year of life. We present the combination of peritoneal dialysis (PD) with intermittent hemodiafiltration (iHDF) in neonates with ESRD. Four infants younger than 28 days were treated with PD and iHDF. Renal diagnoses leading to ESRD were cortical necrosis, prune belly syndrome, neonatal hemolytic uremic syndrome, and autosomal recessive polycystic kidney disease. Initially, three patients were on iHDF until PD was started. At the time when complications occurred during PD, patients were switched back to iHDF. iHDF was used five times as a bridge to PD in case of abdominal surgery. Two of the four patients were switched to iHDF because of peritoneal ultrafiltration failure due to recurrent peritoneal leaks. Once, iHDF became necessary due to refractory peritonitis. All four patients survived the first year of life. Two patients were transplanted successfully at an age of 35 and 22 months, respectively. The others are on renal replacement therapy, one on PD at the age of 28 months and one on iHDF at the age of 25 months, respectively. In case of PD complications, iHDF may be an appropriate bridge to achieve long-term survival until kidney transplantation.

MicroRNAs in peritoneal dialysis effluent are promising biomarkers for peritoneal fibrosis in peritoneal dialysis patients

Peritoneal fibrosis is a common complication of long-term peritoneal dialysis, and contributes to encapsulating peritoneal sclerosis and eventually peritoneal ultrafiltration failure, which restricts the wide application of peritoneal dialysis. Therefore, the prevention and treatment of peritoneal fibrosis is important to maintain peritoneal membrane integrity and prolong peritoneal dialysis treatment. Unfortunately, neither specific biomarkers nor effective therapies are available for peritoneal fibrosis in the clinic up to now. Emerging evidence suggests that extracellular microRNAs in body fluids are promising biomarkers for the diagnosis of diseases. microRNAs were reported to be involved in multiple fibrotic diseases and the serum levels of specific microRNAs were correlated with the degree of fibrosis. Moreover, extracellular microRNAs were found in peritoneal fluids and ascites. Based on these findings, here we present our hypothesis that extracellular microRNAs associated with peritoneal epithelial-to-mesenchymal transition and fibrosis could potentially be detected in peritoneal dialysis effluent, and serve as novel biomarkers for early assessment and diagnosis of peritoneal fibrosis.

Importance of Blood Pressure and Volume Control in Peritoneal Dialysis Patients

To review the factors that impact control of blood pressure and euvolemia in peritoneal dialysis patients. Review of the most recent publications on this subject; inclusion of some personal data on the relation between plasma volume and evolution of blood pressure in short-term and long-term peritoneal dialysis patients. Peritoneal dialysis program in a university hospital. The literature on circadian blood pressure and the role of the decreased compliance of the great vessels in uremia is reviewed. Analysis of the long-term evolution of plasma volume in peritoneal dialysis patients in correlation with the evolution of blood pressure indicates a positive correlation in 36 of 46 simultaneous determinations. The treatment of volume overload and hypertension in peritoneal dialysis includes the prescription of loop diuretics, preservation of residual renal function, reduction of dietary salt intake, and prevention and treatment of peritoneal ultrafiltration failure. A reduction in the great cardiovascular mortality in peritoneal dialysis patients as nowadays observed can only be expected when more attention is paid to better control of hypervolemia and hypertension in these patients.

Sclerosing Peritonitis Complicating Prolonged Use of Chlorhexidine in Alcohol in the Connection Procedure for Continuous Ambulatory Peritoneal Dialysis

Sclerosing peritonitis (SP) is an uncommon but serious complication of CAPD with various suggested etiologies. We have documented 14 cases of SP in 18 patients who had used chlorhexidine in alcohol (ChA) in the connection procedure for CAPD. Thirteen died. Nine of the 14 patients had been transferred to hemodialysis or renal transplantation, yet all still developed symptoms of SP within a few months after transfer - even the 5 who were originally asymptomatic. The main symptoms of SP were peritoneal ultrafiltration failure, exudative bloody ascites and intestinal obstruction. They presented at around 5 years (30-80 months) after commencement of CAPD. Most deaths were related to intestinal obstruction. Four other patients with a comparable duration of ChA exposure were continued on CAPD with the Travenol Spike System (TSS), without further exposure to ChA. They were all asymptomatic of SP after 9-12 months. Comparing the 2 groups of asymptomatic patients, those transferred to TSS had a much better outcome after 9 months than those transferred to HD or renal transplantation (P = 0.0476). We suggest that ChA is the main cause of SP in our patients and that continuing CAPD without further exposure to ChA is a better alternative than stopping CAPD to prevent the progression of SP.