Peritoneal Membrane Function Research Articles

Dyslipidemia in Peritoneal Dialysis: Implications for Peritoneal Membrane Function and Patient Outcomes.

Dyslipidemia is a common metabolic complication in patients undergoing peritoneal dialysis (PD) and has traditionally been viewed primarily in terms of cardiovascular risk. Current guidelines do not recommend initiating lipid-lowering therapy in dialysis patients due to insufficient evidence of its benefits on cardiovascular mortality. However, the impact of dyslipidemia in PD patients may extend beyond cardiovascular concerns, influencing PD-related outcomes such as the peritoneal ultrafiltration rate, residual kidney function, PD technique survival, and overall mortality. This review challenges the traditional perspective by discussing dyslipidemia's potential role in PD-related complications, which may account for the observed link between dyslipidemia and increased all-cause mortality in PD patients. It explores the pathophysiology of dyslipidemia in PD, the molecular mechanisms linking dyslipidemia to peritoneal membrane dysfunction, and summarizes clinical evidence supporting this hypothesis. In addition, this paper examines the potential for therapeutic strategies to manage dyslipidemia to improve peritoneal membrane function and patient outcomes. The review calls for future research to investigate dyslipidemia as a potential contributor to peritoneal membrane dysfunction and to develop targeted interventions for PD patients.

Selective activation of PPARα by pemafibrate mitigates peritoneal inflammation and fibrosis through suppression of NLRP3 inflammasome and modulation of inflammation

Peritoneal inflammation and fibrosis remain major challenges to the long-term maintenance of peritoneal dialysis. Pemafibrate, a selective peroxisome proliferator-activated receptor α (PPARα) modulator, has been implicated in the management of fibrosis-related disorders. We investigated whether pemafibrate ameliorates peritoneal inflammation and fibrosis and explored the underlying mechanisms in mice with methylglyoxal (MGO)-induced peritoneal fibrosis (MGO mice). MGO mice exhibited peritoneal fibrosis with increased expression of mesenchymal markers, transforming growth factor-β1 (TGF-β1), and substantial deposition of extracellular matrix (ECM) proteins. Additionally, MGO mice exhibited peritoneal inflammation as indicated by elevated tumor necrosis factor-α expression and macrophage infiltration in peritoneal tissue. These effects were mitigated by pemafibrate treatment, which also restored peritoneal membrane function. Furthermore, pemafibrate promoted anti-inflammatory macrophage polarization in both mice and THP-1 cells. In human peritoneal mesothelial cells (HPMCs), pemafibrate effectively inhibited interferon-γ-induced production of TGF-β1 and ECM while suppressing the proinflammatory cytokines nuclear factor-κB (NF-κB) and activator protein 1. The NF-κB inhibitory effect of pemafibrate involved stabilization of the NF-κB inhibitory protein IkBα. Notably, pemafibrate hindered activation of the NLR family pyrin domain containing 3/caspase-1 axis in interferon-γ-stimulated THP-1 cells. These findings suggest that pemafibrate ameliorates peritoneal inflammation and fibrosis, making it a promising candidate for peritoneal fibrosis therapy.

Pathophysiological Mechanisms of Peritoneal Fibrosis and Peritoneal Membrane Dysfunction in Peritoneal Dialysis.

The characteristic feature of chronic peritoneal damage in peritoneal dialysis (PD) is a decline in ultrafiltration capacity associated with pathological fibrosis and angiogenesis. The pathogenesis of peritoneal fibrosis is attributed to bioincompatible factors of PD fluid and peritonitis. Uremia is associated with peritoneal membrane inflammation that affects fibrosis, neoangiogenesis, and baseline peritoneal membrane function. Net ultrafiltration volume is affected by capillary surface area, vasculopathy, peritoneal fibrosis, and lymphangiogenesis. Many inflammatory cytokines induce fibrogenic growth factors, with crosstalk between macrophages and fibroblasts. Transforming growth factor (TGF)-β and vascular endothelial growth factor (VEGF)-A are the key mediators of fibrosis and angiogenesis, respectively. Bioincompatible factors of PD fluid upregulate TGF-β expression by mesothelial cells that contributes to the development of fibrosis. Angiogenesis and lymphangiogenesis can progress during fibrosis via TGF-β-VEGF-A/C pathways. Complement activation occurs in fungal peritonitis and progresses insidiously during PD. Analyses of the human peritoneal membrane have clarified the mechanisms by which encapsulating peritoneal sclerosis develops. Different effects of dialysates on the peritoneal membrane were also recognized, particularly in terms of vascular damage. Understanding the pathophysiologies of the peritoneal membrane will lead to preservation of peritoneal membrane function and improvements in technical survival, mortality, and quality of life for PD patients.

#2784 Deep learning algorithm predicts individual ultrafiltration trajectories for patients on automated peritoneal dialysis 12 weeks ahead

Abstract Background and Aims Adequate small solute clearance and ultrafiltration (UF) are the main requirements for fluid and salt homeostasis on peritoneal dialysis (PD). New automated peritoneal dialysis (APD) systems that allow remote patient monitoring in terms of PD treatment analysis have the potential to improve clinical outcomes. UF on APD although dependent on PD prescription, i.e. fill volumes and glucose concentration, exhibits substantial intra- and interindividual variation, even day-by-day. As conventional statistical methods are not able to assess these complex non-linear relationships adequately, we aimed to build a deep learning algorithm to predict ultrafiltration trajectories of individual patients 12 weeks ahead. Method Data on daily UF and PD prescriptions (i.e., glucose concentration, fill volumes) was extracted from the APD cycler management software (PD Link, Baxter, IL, USA) and patient charts at the Medical University of Vienna, for a secondary analysis of this cohort. The Keras high-level API for TensorFlow in R software (R Core Team 2023) was used to create a Long Short-Term Memory (LSTM) recurrent neural network based on historic prescription and gcUF data of 26 weeks (after the first 90 days of APD) to predict individual UF trajectories for the following 12 weeks. Results APD machine readouts from a total of 123 patients, with a mean time on PD of 117 (±73) days, were retrieved. The final recurrent neural network consisted of four LSTM layers with 64 cells each, sigmoid activation. The final model was fit using 30 epochs, 49 steps per epoch, and recurrent dropout to avoid overfitting. A 40-40-20% data split was used to train, validate, and test the model adequately. This deep learning algorithm was able to predict individual UF values, for each day of the upcoming 12 weeks, with an accuracy of at mean 201ml. Upon visual inspection, predicted individual UF trajectories smoothly resemble the overall day-by-day trajectory of the patient but fail to account for extreme spikes in either direction. Conclusion In conclusion, historic daily APD cycler and prescription data in coalescence with respective daily measurements of membrane function (i.e., gcUF) can be used to predict individual daily ultrafiltration values and trajectories of APD patients 12 weeks ahead using a deep learning algorithm. Therefore, continuous collection of PD prescription data and UF measurements may be used to monitor peritoneal membrane function of patients on APD and alert clinical teams upon detection of relevant changes of UF trajectories already 12 weeks ahead to facilitate early intervention. In contrast to current “screening” methods on PD, i.e., Peritoneal Equilibrium Test, these methods could reduce treatment burden.

Effects of sodium-glucose co-transporter 2 inhibitors on ultrafiltration in patients with peritoneal dialysis: a protocol for a randomized, double-blind, placebo-controlled, crossover trial (EMPOWERED)

BackgroundVolume overload is common and associated with high mortality in patients on peritoneal dialysis (PD). Traditional strategies including diuretics, water/salt restriction, and icodextrin-based solutions cannot always fully correct this condition, necessitating novel alternative strategies. Recent studies confirmed the expression of sodium–glucose cotransporter 2 (SGLT2) in the human peritoneum. Experimental data suggest that SGLT2 inhibitors decrease glucose absorption from the PD solution, thereby increasing the ultrafiltration volume. This trial aims to assess whether SGLT2 inhibitors increase the ultrafiltration volume in patients on PD.MethodsThe EMPOWERED trial (trial registration: jRCTs051230081) is a multicenter, randomized, double-blind, placebo-controlled, crossover trial. Patients with clinically diagnosed chronic heart failure are eligible regardless of the presence of diabetes if they use at least 3 L/day glucose-based PD solutions. Participants will be randomly assigned (1:1) to receive empagliflozin 10 mg once daily and then placebo or vice versa. Each treatment period will last 8 weeks with a 4-week washout period. This study will recruit at least 36 randomized participants. The primary endpoint is the change in the daily ultrafiltration volume from baseline to week 8 in each intervention period. The key secondary endpoints include changes in the biomarkers of drained PD solutions, renal residual function, and anemia-related parameters.ConclusionsThis trial aims to assess the benefit of SGLT2 inhibitors in fluid management with a novel mechanism of action in patients on PD. It will also provide insights into the effects of SGLT2 inhibitors on solute transport across the peritoneal membrane and residual renal function.

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.

#4793 DOES PRIOR ABDOMINAL SURGERY INFLUENCE TECHNIQUE SURVIVAL OF PERITONEAL DIALYSIS PATIENTS?

Abstract Background and Aims Prior abdominal surgery may result in peritoneal membrane adhesions and fibrosis, compromising the success of peritoneal dialysis (PD). The impact of this factor on peritoneal membrane function and PD technique survival has not been adequately investigated. The aim of our study was to disclosure the effect of prior abdominal surgical procedures on PD technique survival (main outcome), efficacy rates and also evaluate the risk of infectious complications (secondaries outcomes). Method We performed a retrospective, longitudinal study, that included 155 PD patients followed at our unit, since September 2018 to September 2022. Two groups were created: G1 (without previous abdominal surgery) and G2 (with previous abdominal surgery). Demographic and clinical characteristics, such as age, gender, chronic kidney disease (CKD) etiology, time on PD program, dialytic efficacy (Kt/V), peritoneal equilibration test results and episodes of peritonitis were registered from our unit database. Statistical analyses were performed using SPSS statistics version 23,0. The statistical hypothesis tests with p-value <0,05 were considered significant. Results One-hundred and fifty-five patients (female: 50,9%) with a mean age of 55,4 ± 7 years were selected. The main CKD cause was glomerular diseases (n = 43, 27,7%), followed by uncertain etiology (n = 32, 20,6%) and autosomal dominant polycystic kidney disease (n = 21, 13,5%). G1 (n = 87; 56,1%) and G2 (n = 68; 43,9%) had similar distributions of gender (female: 50,6% vs 47,1%, p = 0,061), age (50,4± 9 vs 55,4 ±10 years, p = 0,076) and dialysis vintage (27,9 vs 28,2 months, p = 0,081). In G1, 62,1% of patients were on continuous ambulatory peritoneal dialysis (vs 55,9% in G2). The majority of patients were high-average transporters in both groups (58,6% vs 54,4%, p = 0,066). Previous comorbidities were (G1 vs G2): arterial hypertension (95,4% vs. 98,5%, p = 0,87), diabetes (27,6% vs. 26,5%, p = 0,83), heart failure (25,3% vs. 26,5%, p = 0,64), peripheral arterial disease (28,7% vs 35,3%, p = 0,082), body mass index >30 kg/m2 (20,7% vs 29,4%, p = 0,072) and dyslipidemia (64,4% vs. 64,7%, p = 0,91). In G1, Kt/V was inferior a 1,7 in 36,8% of patients (vs 66,2% in G2, p<0,001). Seven patients (8,1%) have reported more than one peritonitis during time in PD in group 1 (vs 32,4% in G2, p<0,001). We found no differences in PD technique survival between both groups. Transition to hemodialysis happened in 26,4% of patients in G1 (vs 26,5% in G2, p = 0,092). Mortality rate was similar in both groups (6,9% vs 10,3%, p = 0,063). Conclusion According to our results, prior abdominal surgical procedures do not appear to compromise technique survival in patients on PD. Although, abdominal surgical events places PD patients in a higher risk of infectious complications and lower efficacy rates. Thus, this group of patients deserve a more detailed evaluation before starting PD, in order to understand if they are good candidates for the technique, as this may not be the most advantageous for them in the long term.

#6690 THE ASSOCIATION BETWEEN SERUM CHEMERIN AND PERITONEAL MEMBRANE TRANSPORT FUNCTION IN INCIDENT PERITONEAL DIALYSIS PATIENTS: A PROSPECTIVE COHORT STUDY

Abstract Background and Aims Some biomarkers in drained dialysate or peritoneal membrane have been found related to the dialysate/plasma ratio of creatinine at 4 h (D/P Cr) in patients undergoing peritoneal dialysis (PD). But so far, there is no report on serum markers. Some biomarkers are associated with cardiovascular diseases (CVDs). Chemerin is a multifunctional chemoattractant adipokine which plays roles in inflammation, adipogenesis and metabolism. In this study, we intended to investigate the role of chemerin in the peritoneal membrane transport function and CVDs in incident PD patients. Method This prospective cohort study was conducted in our PD center. The patients underwent initial standardized peritoneal equilibration test (PET) after PD for 4–6 weeks. Level of serum chemerin was determined via enzyme-linked immunosorbent assay (ELISA). The patients’ CVDs were recorded during the follow-up period. Results 151 eligible patients with a mean age of 46.59±13.52 years were enrolled. And the median duration of PD was 25.0 months. The median concentration of serum chemerin was 29.09 ng/mL. Baseline D/P Cr was found to be positively correlated with serum chemerin (r = 0.244, p = 0.003). The multivariate analyses revealed that serum chemerin (p = 0.002), age (p = 0.041), albumin (p = 0.000), and high-density lipoprotein (HDL) (p = 0.022) were independent factors of D/P Cr. The serum chemerin level was significantly higher in diabetes mellitus (DM) patients than that of patients without DM (36.45 vs 27.37 ng/mL, p = 0.000). And there was a significant statistical difference in CVDs between the high chemerin group (≥29.09 ng/mL) and low chemerin group (<29.09 ng/mL) (42% vs 21%, p = 0.009). Conclusion Serum chemerin has a positive correlation with baseline D/P Cr in incident PD patients. It may be a biomarker that can predict the baseline transport function of peritoneal membrane. And serum chemerin may be a risk factor of CVDs for incident PD patients. Multicenter studies with a larger sample size are warranted in the future.

#4387 LIQUID BIOPSY IN PATIENTS TREATED WITH BIOCOMPATIBLE PERITONEAL DIALYSIS FLUIDS – ITS RELATIONSHIP WITH CYTOLOGICAL AND HISTOLOGICAL FINDINGS

Abstract Background and Aims Peritoneal fibrosis can limit long term peritoneal membrane function in peritoneal dialysis (PD) patients. It has been related to bioincompatible PD fluids and peritoneal infections. There are no prospective studies regarding correlation between effluent biomarkers and peritoneal biopsy findings. Our aim was to study the possible relation of peritoneal effluent biomarkers and peritoneal morphology alterations. Method Multicenter prospective study in a cohort of stable PD patients treated with biocompatible PD fluids who received a kidney transplant. We collected in each patient peritoneal biopsy samples and peritoneal effluent fluid. We analyzed the relation between effluent biomarkers, phenotype of mesothelial cells (MC) cultured ex vivo, and peritoneal biopsy parameters (mesothelial integrity, fibrosis and hyalinizing vasculopathy). We compared them with patient characteristics, including peritoneal transport parameters. The biomarkers tested were Collagen-1 (COL-1), Fibronectin (FN), Collagen-13 (COL-13), Interleukin-6 (IL-6), Trombospondin-1, Cadherin 13 (CDH-13), CA-125, Gremlin-1 (GREM-1), Matrix metalloproteinase 2 (MMP-2), CC chemokine ligand 18 (CCL18), Plasminogen activator inhibitor 1 (PAI-1) and Vascular endothelial growth factor A (VEGF-A). Results Forty patients were included (mean age 54.5±15 years, 64% male, 24.1% diabetics). Mean time on PD was 25.5±27 months, 62.1% were on automated PD (APD) and 17.2% had prior peritonitis episodes. A normal MC culture phenotype was observed in 78% of patients. In peritoneal biopsies samples we found partial or total mesothelium preservation in 39%, submesothelial thickness in 42% and vasculopathy in 14% of cases. Effluent PAI-1 levels were significantly lower in patients with mesothelial cell loss than in those with mesothelial preservation (21.62 vs. 38.59 pg/ml respectively; p = 0.031). Patients with peritoneal fibrosis showed significantly higher effluent CDH-13 levels (3.51 vs. 2.32 pg/ml; p = 0.048) and supernatant PAI-1 levels (1183 vs. 72.73; p = 0.000) than those without fibrosis. No other statistical differences were found in other biomarkers analysed. Conclusion Most patients treated with biocompatible peritoneal dialysis fluids showed normal mesothelial cell phenotype in peritoneal effluent culture. Lower PAI-1 effluent levels were associated with mesothelial cell loss and higher effluent CDH-13 levels were related to peritoneal fibrosis.

Effects of sitagliptin on peritoneal membrane: The potential role of mesothelial cell tight junction proteins.

The roles of tight junction (TJ) proteins in peritoneal membrane transport and peritoneal dialysis (PD) require further characterisation. Dipeptidyl peptidase-4 is expressed in mesothelial cells, and its activity may affect peritoneal membrane function and morphology. Human peritoneal mesothelial cells (HPMCs) were isolated and cultured from omentum obtained during abdominal surgery, and paracellular transport functions were evaluated by measuring transmesothelial electrical resistance (TMER) and dextran flux. Sprague-Dawley rats were infused daily with 4.25% peritoneal dialysate with and without sitagliptin administration for 8 weeks. At the end of this period, rat peritoneal mesothelial cells (RPMCs) were isolated to evaluate TJ protein expression. In HPMCs, the protein expression of claudin-1, claudin-15, occludin and E-cadherin was decreased by TGF-β treatment but reversed by sitagliptin co-treatment. TMER was decreased by TGF-β treatment but improved by sitagliptin co-treatment. Consistent with this, dextran flux was increased by TGF-β treatment and reversed by sitagliptin co-treatment. In the animal experiment, sitagliptin-treated rats had a lower D2/D0 glucose ratio and a higher D2/P2 creatinine ratio than PD controls during the peritoneal equilibration test. Protein expression of claudin-1, claudin-15 and E-cadherin decreased in RPMCs from PD controls but was not affected in those from sitagliptin-treated rats. Peritoneal fibrosis was induced in PD controls but ameliorated in sitagliptin-treated rats. The expression of TJ proteins including claudin-1 and claudin-15 was associated with transport function both in HPMCs and in a rat model of PD. Sitagliptin prevents peritoneal fibrosis in PD and can potentially restore peritoneal mesothelial cell TJ proteins.

Prediction of Mortality in Patients on Peritoneal Dialysis Based on the Fibrinogen Mannosylation.

As we already reported, fibrinogen fucosylation emerged as a prognostic marker of peritoneal membrane function in end-stage renal disease (ESRD) patients on peritoneal dialysis. After a follow-up period of 18 months, we estimated the ability of employed lectins, as well as other biochemical parameters, to serve as mortality predictors in these patients. Following a univariate Cox regression analysis, ferritin, urea clearance, residual diuresis, hyperglycemia, and an increase in the signal intensity obtained with Galanthus nivalis lectin (GNL) emerged as potential mortality predictors, but additional multivariate Cox regression analysis pointed only to glucose concentration and GNL as mortality predictors. Higher signal intensity obtained with GNL in patients that died suggested the importance of paucimannosidic/highly mannosidic N-glycan structures on fibrinogen as factors that are related to unwanted cardiovascular events and all-cause mortality and can possibly be seen as a prediction tool. Altered glycan structures composed of mannose residues are expected to affect the reactivity of mannosylated glycoproteins with mannose-binding lectin and possibly the entire cascade of events linked to this lectin. Since patients with ESRD are prone to cardiovascular complications and the formation of atherosclerotic plaques, one can hypothesize that fibrinogen with increasingly exposed mannose residues may contribute to the unwanted events.

Inflammatory chemokine (C-C motif) ligand 8 inhibition ameliorates peritoneal fibrosis.

Peritoneal fibrosis (PF) is an irreversible complication of peritoneal dialysis (PD) that leads to loss of peritoneal membrane function. We investigated PD effluent and serum levels and the tissue expression of chemokine (C-C motif) ligand 8 (CCL8) in patients with PD. Additionally, we investigated their association with PF in a mouse model. Eighty-two end-stage renal disease (ESRD) patients with PD were examined. CCL8 levels were measured via enzyme-linked immunosorbent assays in PD effluents and serum and analyzed with peritoneal transport parameters. Human peritoneal mesothelial cells (hPMCs) were obtained from the PD effluents of 20 patients. Primary cultured hPMCs were treated with recombinant (r) transforming growth factor (TGF)-β, and CCL8 expression was assessed via western blotting. As the duration of PD increased, the concentration of CCL8 in PD effluents significantly increased. Correlations between peritoneal transport parameters and dialysate CCL8 levels were observed. Western blotting analysis showed that CCL8 was upregulated via rTGF-β treatment, accompanied by increases in markers of inflammation, fibrosis, senescence, and apoptosis in hPMCs after induction of fibrosis with rTGF-β. Anti-CCL8 monoclonal antibody (mAb) treatment suppressed the rTGF-β-induced increase in all analyzed markers. Immunohistochemical analysis revealed that CCL8 along with fibrosis- and inflammation-related markers were significantly increased in the PF mouse model. Functional blockade of CCL8 using a CCR8 inhibitor (R243) abrogated peritoneal inflammation and fibrosis in vivo. In conclusion, high CCL8 levels in PD effluents may be associated with an increased risk of PD failure, and the CCL8 pathway is associated with PF. CCL8 blockade can ameliorate peritoneal inflammation and fibrosis.

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.

Dual therapy with an angiotensin receptor blocker and a JAK1/2 inhibitor attenuates dialysate-induced angiogenesis and preserves peritoneal membrane structure and function in an experimental CKD rat model.

Peritoneal dialysis (PD) is limited by reduced efficacy over time. We previously showed that a Janus kinase 1/2 inhibitor (JAK1/2i) reduced inflammation, hypervascularity and fibrosis induced by 4.25% dextrose dialysate (4.25%D) intraperitoneally (IP) infused for 10 days in rats with normal kidney function. JAK/STAT signalling mediates inflammatory pathways, including angiotensin signalling. We now tested the effect of long-term JAK1/2i and/or an angiotensin receptor blocker (ARB) on peritoneal membrane (PM) in polycystic kidneys (PCK) rats infused with 4.25%D. Except for controls, all PCK rats had a tunnelled PD catheter: (1) no infusions; (2) 4.25%D; (3) 4.25%D + JAK1/2i (5 mg/kg); (4) 4.25%D +losartan (5 mg/kg); and (5) 4.25%D + losartan +JAK1/2i (5 mg/kg each) IP BID × 16 weeks (N = 5/group). PM VEGFR2 staining areas and submesothelial compact zone (SMCZ) width were morphometrically measured. Peritoneal equilibration testing measured peritoneal ultrafiltration (UF) by calculating dialysate glucose at time 0 and 90 min (D/D0 glucose). 4.25%D caused hypervascularity, SMCZ widening, fibrosis and UF functional decline in PCK rats. Angiogenesis was significantly attenuated by JAK1/2i ± ARB but not by ARB monotherapy. Both treatments reduced SMCZ area. UF was preserved consistently by dual therapy (p < 0.05) but with inconsistent responses by monotherapies. Long-term JAK1/2i ± ARB reduced angiogenesis and fibrosis, and the combination consistently maintained UF. In clinical practice, angiotensin inhibition has been advocated to maintain residual kidney function. Our study suggests that adding JAK1/2i to angiotensin inhibition may preserve PM structure and UF.

Enhanced Oxidative DNA-Damage in Peritoneal Dialysis Patients via the TXNIP/TRX Axis.

Peritoneal dialysis (PD) is an effective method of renal replacement therapy, providing a high level of patient autonomy. Nevertheless, the long-term use of PD is limited due to deleterious effects of PD fluids to the structure and function of the peritoneal membrane leading to loss of dialysis efficacy. PD patients show excessive oxidative stress compared to controls or chronic kidney disease (CKD) patients not on dialysis. Therefore, defense systems against detrimental events play a pivotal role in the integrity of the peritoneal membrane. The thioredoxin-interacting-protein (TXNIP)/thioredoxin (TRX) system also plays a major role in maintaining the redox homeostasis. We hypothesized that the upregulation of TXNIP negatively influences TRX activity, resulting in enhanced oxidative DNA-damage in PD patients. Therefore, we collected plasma samples and human peritoneal biopsies of healthy controls and PD patients as well. Using ELISA-analysis and immunohistochemistry, we showed that PD patients had elevated TXNIP levels compared to healthy controls. Furthermore, we demonstrated that PD patients had a reduced TRX activity, thereby leading to increased oxidative DNA-damage. Hence, targeting the TXNIP/TRX system as well as the use of oxidative stress scavengers could become promising therapeutic approaches potentially applicable in clinical practice in order to sustain and improve peritoneal membrane function.

International Icodextrin Use and Association with Peritoneal Membrane Function, Fluid Removal, Patient and Technique Survival.

Icodextrin has been shown in randomized controlled trials to benefit fluid management in peritoneal dialysis (PD). We describe international icodextrin prescription practices and their relationship to clinical outcomes. We analyzed data from the prospective, international PDOPPS, from Australia/New Zealand, Canada, Japan, the United Kingdom, and the United States. Membrane function and 24-hour ultrafiltration according to icodextrin and glucose prescription was determined at baseline. Using an instrumental variable approach, Cox regression, stratified by country, was used to determine any association of icodextrin use to death and permanent transfer to hemodialysis (HDT), adjusted for demographics, comorbidities, serum albumin, urine volume, transplant waitlist status, PD modality, center size, and study phase. Icodextrin was prescribed in 1986 (35%) of 5617 patients, >43% of patients in all countries, except in the United States, where it was only used in 17% and associated with a far greater use of hypertonic glucose. Patients on icodextrin had more coronary artery disease and diabetes, longer dialysis vintage, lower residual kidney function, faster peritoneal solute transfer rates, and lower ultrafiltration capacity. Prescriptions with or without icodextrin achieved equivalent ultrafiltration (median 750 ml/d [interquartile range 300-1345 ml/d] versus 765 ml/d [251-1345 ml/d]). Icodextrin use was not associated with mortality (HR=1.03; 95% CI, 0.72 to 1.48) or HDT (HR 1.2; 95% CI, 0.92 to 1.57). There are large national and center differences in icodextrin prescription, with the United States using significantly less. Icodextrin was associated with hypertonic glucose avoidance but equivalent ultrafiltration, which may affect any potential survival advantage or HDT.

MO710: Longitudinal Effects of Different Biocompatible Peritoneal Solutions on Membrane Function

Abstract BACKGROUND AND AIMS Peritoneal biocompatible dialysates (low GDPs, neutral pH) seem to sustain more steady peritoneal membrane characteristics compared to conventional ones. However, various brand biocompatible dialysates have different composition (e.g. in lactate concentration) and there is no published study comparing their effects on membrane characteristics in long peritoneal dialysis (PD). Our PD unit has been using solely two brands of biocompatible dialysates (Balance, Fresenius© and Physioneal, Baxter©) since 2000. The aim of our study was to compare longitudinal data on peritoneal membrane function between these two different brand solutions METHOD Membrane characteristics were assessed by uni-peritoneal equilibration test (uni-PET, a combination of modified and mini PET), which is performed at least annually on every patient. Patients with no less than two PETs were included. We estimated dialysate to plasma (D/P) creatinine, ultrafiltration (UF) at 4 h, sodium seiving expressed as Dip/DPNa = [(dialysate sodium time 0/plasma sodium)–(dialysate sodium time 1 h/plasma sodium)], sodium removal (in 1 h) and free water transport (FWT). We collected clinical and lab data of the patients too. RESULTS A total of 85 patients (age 61.1 ± 15.1 years) were included—38 patients on Balance and 47 on Physioneal. The main characteristics of the patients are shown in Τable 1. Baseline membrane characteristics presented no differences between the two groups (D/Pcre 0.75 ± 0.125 versus 0.745 ± 0.11, P = 0.71—UF 660 ± 285 mL versus 651 ± 252 mL, P = 0.86—DipDPNA 0.05 ± 0.03 versus 0.047 ± 0.046 P = 0.54—sodium removal 30 (15.7, 42.3) mEq versus 38 (17.3, 46)mEq, P = 0.31—FWT 149 ± 85 mL versus 140 ± 109 mL, P = 0.69). The patients were followed up for a median of 36 months (range 2.4–143). A total of 219 PETs were performed. Analysis for repeated PET tests was performed by using generalized linear regression models. The membrane characteristics (D/Pcre, Dip/DPNa, FWT and UF) of both groups remained stable longitudinally and overall no differences between the two different solutions were observed (Fig. 1). Only at the fourth year of follow-up, patients on Balance solutions had lower D/Pcre compared to Physioneal (0.62 versus 0.72, P = 0.003). CONCLUSION Different biocompatible solutions had no differences on peritoneal membrane characteristics longitudinally.

MO679: Peritonitis May Disrupt Cyclic Periodicity of Ultrafiltration in Peritoneal Dialysis

Abstract BACKGROUND AND AIMS Due to chronic damage of the peritoneal membrane on long-term treatment, peritoneal dialysis (PD) is a time-limited therapy. Effective PD is achieved by adequate peritoneal ultrafiltration (UF) and small solute clearance while maintaining an appropriate fluid and salt homeostasis. Availability of remote patient monitoring on automated PD (APD) allows clinicians to remotely retrieve data for treatment analysis, proposed to improve clinical outcomes. However, machine-derived data are vastly different from traditionally observed data (e.g. quantity, noise, missing normative values). Recently correlation of daily UF changes on APD with changing peritoneal membrane function in association with clinical risk factors and outcomes has been observed. High intra- and interpatient variability of UF remains not fully explained. We aim at a better understanding of UF variability by submitting APD machine readouts to spectral analysis in association with clinical risk factors of membrane dysfunction. METHOD This was a secondary analysis of the Medical University of Vienna APD cycler treatment data from patients using Homechoice Pro cyclers (Baxter, IL, USA), extracted from the cycler management software (PD link, Baxter). Analysis was conducted using R software (R Core Team 2020). Daily UF was processed using the Lomb-Scargle periodogram (LSP), a method commonly used in astrophysics and neurophysiology to detect rhythms in (unevenly sampled) time series. Peaks of power spectrum, frequencies, and periodicities were compared between patients with and without peritonitis episodes during their PD treatment utilizing a Mann–Whitney U-test and associated with the total number of peritonitis episodes using Kendall rank correlation. A P-value &amp;lt; 0.05 was considered significant; all tests were two-sided. RESULTS LSP analysis was performed on daily UF data from n = 129 APD patients with a mean observation time of 598 days (SD ± 517), male: female 61:39% (n = 79:50), incident: prevalent patients 77:23% (n = 99:30), and diabetic: non-diabetic patients 25:75% (n = 32:97). Observation time extended from the introduction of APD until kidney transplantation (43%, n = 55), transfer to hemodialysis (23%, n = 29), death (27%, n = 35), kidney function recovery (8%, n = 1), or loss to follow-up (7%, n = 9). After inspection of LSPs n = 9 patients were excluded from further analysis as their periodicity matched the time of their clinical endpoint. A total of 45 of the remaining 120 patients (38%) never experienced a peritonitis episode, and a total of 0.3 (SD ± 0.7) peritonitis episodes/patient-year were observed. LSP computation revealed cyclic periodicity in UF in all patients with an overall median peak period length of 329 days (IQR 62–882 days), median peak power of 21 (IQR 7–91), and median peak frequency of 0.42 (IQR 0.36–0.46). Differences between patients with and without peritonitis episodes during PD treatment are displayed in Table 1. Correlation analysis revealed significant association between the number of peritonitis episodes and peak periodicity of UF (tau=0.14, P = 0.04), and peak power (tau = 0.21, P = 0.003). Peak frequency of UF was not significantly correlated. CONCLUSION Patients on APD cycler treatment seem to display cyclic periodicity of UF, being significantly associated with the number of peritonitis episodes and significantly different between patients with and without peritonitis episodes. Smaller-scale periodicity (median 216 days) in patients without peritonitis seems to be disrupted by peritonitis resulting in significantly higher periodicity (median 670 days). The causes and implications of these results remain unclear and need further investigation. However, as peritonitis is a known risk factor for peritoneal membrane dysfunction, prolongation of UF periodicity might reflect disruption of peritoneal membrane function.

Assessing mechanical catheter dysfunction in automated tidal peritoneal dialysis using cycler software: a case control, proof-of-concept study

New recommendations on evaluation of peritoneal membrane function suggest ruling out catheter dysfunction when evaluating patients with low ultrafiltration capacity. We introduce the use of a combination of parameters obtained from the cycler software PD Link with HomeChoicePro (Baxter International Inc., Illinois, United States) cyclers for predicting catheter dysfunction in automated peritoneal dialysis patients (APD). Out of 117 patients treated at the Medical University of Vienna between 2015 and 2021, we retrospectively identified all patients with verified catheter dysfunction (n = 14) and compared them to controls without clinical evidence of mechanical catheter problems and a recent X-ray confirming PD catheter tip in the rectovesical/rectouterine space (n = 19). All patients had a coiled single-cuff PD catheter, performed tidal PD, and received neutral pH bicarbonate/lactate-buffered PD fluids with low-glucose degradation products on APD. Icodextrin-containing PD fluids were used for daytime dwells. We retrieved cycler data for seven days each and tested parameters' predictive capability of catheter dysfunction. Total number of alarms/week > 7 as single predictive parameter of catheter dislocation identified 85.7% (sensitivity) of patients with dislocated catheter, whereas 31.6% (1-specificity) of control patients were false positive. A combination of parameters (number of alarms/week > 7, total drain time > 22 min, ultrafiltration of last fill < 150 mL) where at least two of three parameters appeared identified the same proportion of patients with catheter dislocation, but was more accurate in identifying controls (21.1% false positive). In contrast to yearly PET measurements, an easily applicable combination of daily cycler readout parameters, also available in new APD systems connected to remote monitoring platforms shows potential for diagnosis of catheter dysfunction during routine follow-up.

Aquaporin-1 variants: a step further towards precise prescription in peritoneal dialysis?

With a concerted effort to increase home dialysis utilization, it is crucial to better understand patient characteristics that affect the quality of dialysis delivered, as well as the likelihood of technique failure. In peritoneal dialysis (PD), the quality of dialysis is dictated by the patient’s peritoneal membrane water and solute transport characteristics. Studies that shed light on determinants of peritoneal membrane function in an individual patient may assist providers in personalizing PD prescriptions.