Ultrafiltration Failure In Patients Research Articles

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.

Differentially Expressed microRNAs in Peritoneal Dialysis Effluent-Derived Exosomes from the Patients with Ultrafiltration Failure.

Background Ultrafiltration failure remains one of the most severe complications of long-term peritoneal dialysis (PD), which results in death. This study aimed to characterize the circulating exosomal microRNA (miRNA) profiles associated with ultrafiltration failure and explore its underlying mechanisms. Methods Exosomes were isolated from the peritoneal dialysis effluent (PDE) of patients with ultrafiltration failure or success using the ultracentrifugation method, and then transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blot were used for exosome characterization. After that, the isolated exosomes were sent for small RNA sequencing, and eight differentially expressed miRNAs (DE-miRNAs) were chosen for RT-qPCR validation. Results TEM, NTA, and western blot revealed that exosomes were successfully isolated. After sequencing, 70 DE-miRNAs involved in ultrafiltration were identified, including 41 upregulated ones and 29 downregulated ones. Functional analyses revealed that these DE-miRNAs were significantly enriched in pathways of cancer, ubiquitin-mediated proteolysis, axon orientation, and the Rap1 and Ras signaling pathways. In addition, the consistency rate of RT-qPCR and sequencing results was 75%, which indicated the relatively high reliability of the sequencing data. Conclusions Our findings implied that these DE-miRNAs may be potential biomarkers of ultrafiltration failure, which would help us to discover novel therapeutic targets/pathways for ultrafiltration failure in patients with end-stage renal disease.

MO683: Peritoneal Transport Characteristics, Sodium Sieving and Dialysate Electrolyte Clearance in Peritoneal Dialysis Patients: 4.25% Peritoneal Equilibration Test Analysis

Abstract BACKGROUND AND AIMS Peritoneal dialysis (PD) is a well-established renal replacement therapy for patients with end-stage renal disease. The peritoneal equilibration test (PET) is widely used for assessing peritoneal solute transport. Recently, the International Society for PD committee recommended performing PET with 4.25% dextrose solution instead of traditional 2.5% dextrose solution to provide better information on ultrafiltration capacity. This study aims to explore the peritoneal transport characteristics, sodium sieving and electrolyte clearance with PET-4.25%. METHOD We conducted a cross-sectional study in PD patients treated in West China Hospital between June 2021 and December 2021. All patients underwent PET-4.25%. Peritoneal transport characteristics, sodium sieving and dialysate electrolyte clearance were analysed. RESULTS A total of 108 patients (61 males, 56%; mean age 48 ± 4 years old, median PD duration 17 months) were included. Dialysate to plasma (D/P) creatinine values at 4 h were distributed similarly in PET-2.5% and PET-4.25% (Fig. 1). The dialysate sodium decreased at the beginning of PET-4.25% and gradually increased, while other dialysate electrolyte levels continued to increase or decrease during the 4 h (Fig. 2). Most patients had their maximal sodium dip at 2 h (N = 80, 74%). The mean sodium dip at 1 h was 7.28 ± 2.93 mmol/L (sodium sieving ratio 0.057 ± 0.023), and the mean maximal sodium dip was 8.81 ± 4.18 mmol/L. In both univariate and multivariate analyses, sodium sieving was negatively correlated with 4-h D/P creatinine and glomerular filtration rate (GFR) and positively correlated with PET-4.25% ultrafiltration volume (Fig. 3). The total clearances of sodium, potassium, chloride, calcium, magnesium and phosphate with 2 L of 4.25% dextrose were 66.9 ± 22.4 mmol, 6.64 ± 1.25 mmol, 62.7 ± 27.7 mmol, 0.07 ± 0.27 mmol, 0.63 ± 0.19 mmol and 1.98 ± 0.63 mmol, respectively. The amount of electrolyte clearance was not related to peritoneal transport characteristics. Nine patients were diagnosed with ultrafiltration failure (UFF). Patients with UFF had significantly lower sodium and chloride clearance than non-UFF patients. CONCLUSION PET-4.25% could assess peritoneal transport characteristics with similar results to PET-2.5%, while it could provide more information on ultrafiltration capacity. Four-hour D/P creatinine, GFR and ultrafiltration volume are independent predictors for sodium sieving. Dialysate electrolyte clearance is not related to peritoneal transport characteristics, while sodium clearance is decreased in UFF patients.

Dimethylaminomicheliolide ameliorates peritoneal fibrosis through the activation of autophagy.

Peritoneal fibrosis (PF) is a major cause of ultrafiltration failure in patients receiving long-term peritoneal dialysis (PD), and effective prevention and treatment strategies are urgently needed. The dimethylamino Michael adduct of a natural product-derived micheliolide (MCL), dimethylaminomicheliolide (DMAMCL), is a new lead compound with the advantages of high stability, low toxicity, and sustainable release of MCL. This study aimed to investigate the protective effect of DMAMCL against PD-related PF and the mechanisms involved. In this study, we found that DMAMCL significantly decreased PD-induced extracellular matrix (ECM) deposition in a mouse model of PD, and that delayed DMAMCL administration halted the progression of PF in an established PD model. In addition, rapamycin administration induced autophagy and significantly ameliorated PF. The protective effect of DMAMCL against PF was weakened when co-administered with DMAMCL and 3-methyladenine. Inducing autophagy by rapamycin decreased transforming growth factor-β1-induced ECM accumulation in vitro. MCL promoted autophagy and inhibited ECM deposition. The anti-fibrotic effect of MCL was eliminated when knocking down ATG7 by siRNA. Taken together, DMAMCL might prevent against PF through activating autophagy. The anti-fibrotic effect of DMAMCL may be a new candidate for the treatment in patients with PD-related PF. KEY MESSAGES: Dimethylaminomicheliolide, the pro-drug of micheliolide, protects against peritoneal fibrosis in a mouse peritoneal dialysis model. Micheliolide inhibits TGF-β1-induced extracellular matrix accumulation in vitro. Autophagy plays a protective role against peritoneal fibrosis. The antifibrogenic effect of dimethylaminomicheliolide may be due to the activation of autophagy.

Alterations of peritoneal transport characteristics in dialysis patients with ultrafiltration failure: tissue and capillary components.

Ultrafiltration failure (UFF) in peritoneal dialysis (PD) patients is due to altered peritoneal transport properties leading to reduced capacity to remove excess water. Here, with the aim to establish the role of local alterations of the two major transport barriers, peritoneal tissue and capillary wall, we investigate changes in overall peritoneal transport characteristics in UFF patients in relation to corresponding local alterations of peritoneal tissue and capillary wall transport properties. Six-hour dwell studies using 3.86% glucose solutions and radioisotopically labelled serum albumin added to dialysate as a volume marker were analysed in 31 continuous ambulatory PD patients, 20 with normal ultrafiltration (NUF) and 11 with UFF. For each patient, the physiologically based parameters were evaluated for both transport barriers using the spatially distributed approach based on the individual intraperitoneal profiles of volume and concentrations of glucose, sodium, urea and creatinine. UFF patients as compared with NUF patients had increased solute diffusivity in both barriers, peritoneal tissue and capillary wall, decreased tissue hydraulic conductivity and increased local lymphatic absorption and functional decrease in the fraction of the ultra-small pores. This resulted in altered distribution of fluid and solutes in the peritoneal tissue, and decreased penetration depths of fluid and solutes into the tissue in UFF patients. Mathematical modelling using a spatially distributed approach for the description of clinical data suggests that alterations both in the capillary wall and in the tissue barrier contribute to UFF through their effect on transport and distribution of solutes and fluid within the tissue.

MiR-15a-5p suppresses inflammation and fibrosis of peritoneal mesothelial cells induced by peritoneal dialysis via targeting VEGFA.

Long-term peritoneal dialysis (PD) often ends up with ultrafiltration failure (UFF) which is partially caused by persistent inflammation and fibrosis of peritoneal tissues. However, the mechanism is still unclear. In the current study, the peritoneum from UFF patients demonstrated inflammation and fibrosis which were positively related to theexpression of vascular endothelial growth factor A (VEGFA). The in vitro model using human peritoneal mesothelial cells (HPMCs) stimulated by high glucose or advanced glycation end (AGE) product showed consistent changes of inflammation, fibrosis, and VEGFA. What's more, we showed that VEGFA was an instigator of inflammation and fibrosis. Several microRNAs (miRNAs) have been reported to regulate expression of VEGFA elsewhere. Five of them were selected to test the expression in the peritoneum ofpatients with PD. Results suggested that miR-15a-5p was the most significantly downregulated one. Also, in high glucose or AGE product-stimulated HPMCs, miR-15a-5p decreased. When miRNA mimic was used to restore the expression of miR-15a-5p, high glucose-induced VEGFA was repressed. The predicted binding site between these two molecules was confirmed by the dual-luciferase assay. Restoration of miR-15a-5p restrained inflammation and fibrosis of HPMCs. TGF-β1/Smad2 was shown to be the downstream signaling pathway and their activity was regulated by miR-15a-5p/VEGFA. In conclusion, our current study demonstrates that miR-15a-5p acts as a regulator of VEGFA mRNA and the following inflammation and fibrosis in peritoneal mesothelial cells. The miR-15a-5p/VEGFA pathway may be a potential target for preventing ultrafiltration failure in patients with PD.

Estimation of Residual Peritoneal Volume Using Technetium-99m Sulfur Colloid Scintigraphy.

Residual peritoneal volume (RPV) may contribute in the development of ultrafiltration failure in patients with normal transcapillary ultrafiltration. The aim of this study was to estimate the RPV using intraperitoneal technetium-99m Sulfur Colloid (Tc). Twenty patients on peritoneal dialysis were studied. RPV was estimated by: 1) intraperitoneal instillation of Tc (RPV-Tc) and 2) classic Twardowski calculations using endogenous solutes, such as urea (RPV-u), creatinine (RPV-cr), and albumin (RPV-alb). Each method's reproducibility was assessed in a subgroup of patients in two consecutive measurements 48 h apart. Both methods displayed reproducibility (r = 0.93, p = 0.001 for RPVTc and r = 0.90, p = 0.001 for RPV-alb) between days 1 and 2, respectively. We found a statistically significant difference between RPV-Tc and RPV-cr measurements (347.3 ± 116.7 vs. 450.0 ± 67.8 ml; p =0.001) and RPV-u (515.5 ± 49.4 ml; p < 0.001), but not with RPV-alb (400.1 ± 88.2 ml; p = 0.308). A good correlation was observed only between RPV-Tc and RPV-alb (p < 0.001). The Tc method can estimate the RPV as efficiently as the high molecular weight endogenous solute measurement method. It can also provide an imaging estimate of the intraperitoneal distribution of RPV.

Opposing Roles for Smad2 and Smad3 in Peritoneal Fibrosis in Vivo and in Vitro

Peritoneal fibrosis is a major cause of ultrafiltration failure in patients receiving continuous ambulatory peritoneal dialysis. Transforming growth factor (TGF)-β1 is an important mediator in this process; however, its signaling mechanisms had not been explored. Thus, we examined TGF-β1/Smad signaling in human peritoneal biopsy specimens associated with continuous ambulatory peritoneal dialysis. We found that TGF-β/Smad2/3 signaling was highly activated in patients with increased collagen deposition and thickening of the peritoneal membrane who were receiving continuous ambulatory peritoneal dialysis. Long-term exposure of wild-type mice to 4.25% peritoneal dialysis solution for 30 days induced significant peritoneal fibrosis with impaired peritoneal equilibrium, which was prevented in Smad3 knockout mice. In contrast, conditional Smad2 gene deletion in the peritoneum exacerbated peritoneal fibrosis and dysfunction. The contrasting roles of Smad2 and Smad3 in peritoneal fibrosis were also examined invitro. Cultured mesothelial cells from Smad3 knockout mice were resistant to TGF-β1-induced collagen I production and the transition toward a myofibroblast phenotype as seen in wild-type cells, whereas Smad2 deficiency in mesothelial cells failed to modulate the profibrotic response to TGF-β1. Inconclusion, this study found activation of TGF-β/Smad signaling in peritoneal fibrosis in patients receiving continuous ambulatory peritoneal dialysis and identifies opposing roles for Smad2 and Smad3in peritoneal dialysis-associated peritoneal fibrosis. These findings provide a mechanistic basis for future therapies targeting TGF-β/Smad signaling in peritoneal fibrosis.

Two-in-One Protocol: Simultaneous Small-Pore and Ultrasmall-Pore Peritoneal Transport Quantification

Reduced free water transport (FWT) through ultrasmall pores contributes to net ultrafiltration failure (UFF) and should be seen as a sign of more severe functional deterioration of the peritoneal membrane. The modified peritoneal equilibration test (PET), measuring the dip in dialysate Na concentration, estimates only FWT. Our aim was to simultaneously quantify small-solute transport, FWT, and small-pore ultrafiltration (SPUF) during a single PET procedure. We performed a 4-hour, 3.86% glucose PET, with additional measurement of ultrafiltration (UF) at 60 minutes, in 70 peritoneal dialysis patients (mean age: 50 ± 16 years; 61% women; PD vintage: 26 ± 23 months). We calculated the dialysate-to-plasma ratios (D/P) of creatinine and Na at 0 and 60 minutes, and the Na dip (Dip(D/PNa60')), the delta dialysate Na 0-60 (ΔDNa(0-60)), FWT, and SPUF. Sodium sieving (as measured by ΔDNa(0-60)) correlated strongly with the corrected Dip(D/PNa60') (r = 0.85, p < 0.0001) and the corrected FWT (r = 0.41, p = 0.005). Total UF showed better correlation with FWT than with indirect measurements of Na sieving (r = 0.46, p < 0.0001 for FWT; r = 0.360, p < 0.0001 for Dip(D/PNa60')). Corrected FWT fraction was 0.45 ± 0.16. A negative correlation was found between time on PD and both total UF and FWT (r = -0.253, p = 0.035 and r = -0.272, p = 0.023 respectively). The 11 patients (15.7%) diagnosed with UFF had lower FWT (89 mL vs 164 mL, p < 0.05) and higher D/P creatinine (0.75 vs 0.70, p < 0.05) than did the group with normal UF. The SPUF correlated positively with FWT in the normal UF group, but negatively in UFF patients (r = -0.709, p = 0.015). Among UFF patients on PD for a longer period, 44.4% had a FWT percentage below 45%. Measurement of FWT and SPUF is feasible by simultaneous quantification during a modified 3.86% glucose PET, and FWT is a decisive parameter for detecting causes of UFF in addition to increased effective capillary surface.

The time course of peritoneal transport parameters in peritoneal dialysis patients who develop encapsulating peritoneal sclerosis

Encapsulating peritoneal sclerosis (EPS) is a severe complication of peritoneal dialysis (PD). The first aim was to analyse the risk of EPS in patients who had developed ultrafiltration failure (UFF). The second aim was to identify specific peritoneal transport alterations that distinguish patients with UFF from patients who will develop EPS. All patients of this study were treated with PD between July 1995 and December 2008 in the Academic Medical Center, Amsterdam, the Netherlands. Risk analysis: all PD patients who developed UFF after at least 2 years of PD. Peritoneal transport analysis: all patients who had PD for at least 55 months were included: 12 EPS patients, 21 patients with UFF and 26 patients with normal ultrafiltration (UF). The peritoneal function was measured yearly with a standard peritoneal permeability analysis. UFF was defined as net UF < 400 mL after a 4-h dwell with a 3.86% dialysis solution. Risk analysis: Of the 48 UFF patients, 10 eventually developed EPS. Fifty percent of the patients who continued PD for more than 3 years after the establishment of UFF developed EPS. Peritoneal function analysis: No differences were present for the time courses of solute transport and fluid transport between the EPS and the UFF groups. Overall, the EPS and normal UF groups had lower values for the effective lymphatic absorption rate (ELAR) than the UFF group. The risk of EPS increases with continuation of PD while UFF is present. Transport characteristics are similar between EPS patients and UFF patients without this complication. A constantly low ELAR may distinguish the EPS patients from those with UFF only.

Treatment of severe ultrafiltration failure with nonglucose dialysis solutions in patients with and without peritoneal sclerosis

Introduction. Ultrafiltration failure (UFF) in peritoneal dialysis (PD) patients is a reflection of changes in the peritoneal membrane, which can include mesothelial damage, neoangiogenesis, and occasionally, peritoneal fibrosis. These structural changes are probably induced by the use of bioincompatible dialysis solutions. Therefore, we investigated the effects of the treatment with a combination of nonglucose dialysis solutions in patients with severe UFF.Methods. Ten patients with UFF (net ultrafiltration <400 mL/4 h on 3.86% glucose) were treated with a combination of glycerol and icodextrin with or without amino acid-based dialysis solutions for 3 months. Four of them were diagnosed with encapsulating peritoneal sclerosis (PS), proven by peritoneal biopsies. Standard peritoneal permeability analyses (SPA), using 3.86% glucose, were performed, and dialysate CA125 appearance rate (AR-CA125) was analysed at the start, after 6 weeks and after 12 weeks. PS and non-PS patients were compared.Results. One patient underwent transplant after 6 weeks, one was withdrawn from PD because of clinical signs of encapsulating PS before the 3-month period ended. PS patients had been treated with PD for a longer duration than the non-PS patients (102 versus 52 months, P = 0.05), but no differences in baseline transport parameters or AR-CA125 were present. During the study, no differences were observed for transport characteristics when the results of the whole group at 6 and 12 weeks were compared to baseline. For the non-PS patients, however, a significant increase in the transcapillary ultrafiltration rate (from 2.2 mL/min to 2.6 mL/min, P < 0.05) and a decrease in the MTAC creatinine (from 14.3 mL/min to 12.6 mL/min, P < 0.05) were found after 6 weeks of glucose-free treatment. Free-water transport, measured as the maximum dip in the dialysate-to-plasma ratio of sodium and as the transport through the ultrasmall pores in the first minute, tended to improve, but this difference did not reach significance. In addition, the AR-CA125 increased significantly (from 2.8 U/min to 16.1 U/min, P < 0.05). Continued treatment did not reach statistical difference even after 3 months. No changes were observed in the PS patients.Conclusions. In the present study, an improvement of UFF in the non-PS patients was obtained by withdrawal of glucose-based dialysis solutions. The abnormalities in PS patients are probably irreversible. Early withdrawal of glucose-based dialysis solutions or at least a marked reduction in glucose exposure should be considered in UFF patients, but the identification of the patients who would benefit most needs further studies.

Relationship between dialysate oxidized protein and peritoneal membrane transport properties in patients on peritoneal dialysis

Increased levels of oxidized proteins have been reported in the serum of patients with end-stage renal disease, though little is known regarding the oxidized protein content of the dialysate in patients on peritoneal dialysis (PD) and no information is available as to how this may correlate with important clinical and laboratory variables, including abnormal peritoneal membrane function. In this study we attempted to identify oxidized proteins in the dialysate of patients on PD using western blot analysis, and examined the relationship between these proteins and the function of the peritoneal membrane and other clinical and laboratory variables. Peritoneal dialysate and serum samples were obtained from 18 patients on PD, and western blot analysis using an antibody to oxidized protein was carried out with reprobing for albumin. Oxidized protein/albumin ratios were determined and compared with various clinical and laboratory variables including peritoneal equilibration test results. Oxidized protein/albumin ratios were higher in the dialysate of patients who were high/high average transporters compared to low/low average transporters. Oxidized protein ratios were also found to be higher in the dialysate of patients who had diminished urine output as a reflection of loss of residual renal function. Negative correlations were noted between oxidized protein ratios in the dialysate and serum albumin levels and creatinine clearance. Higher levels of oxidized protein in the dialysate appear to be correlated with high/high average peritoneal membrane transport characteristics and may be related to loss of residual renal function. These preliminary findings suggest that it is plausible that oxidized proteins in the dialysate might play a contributory role in complications including membrane damage and ultrafiltration failure in patients on PD.

Overnight Mesothelial Cell Exfoliation: A Magic Tool for Predicting Future Ultrafiltration Failure in Patients on Continuous Ambulatory Peritoneal Dialysis

Continuous exposure of the peritoneal membrane to dialysis solutions during long-term dialysis results in mesothelial cell loss, peritoneal membrane damage, and thereby, ultrafiltration (UF) failure, a major determinant of mortality in patients on continuous ambulatory peritoneal dialysis (CAPD). Unfortunately, none of tests available today can predict long-term UF decline. Here, we propose a new tool to predict such a change. Mesothelial cells from 8-hour overnight effluents (1.36% glucose dialysis solution) were harvested, co-stained with cytokeratin (a mesothelial marker) and TUNEL (an apoptotic marker), and were counted using flow cytometry in 48 patients recently started on CAPD. Adequacy of dialysis, UF, nutrition status, dialysate cancer antigen 125 (CA125), and a peritoneal equilibration test (3.86% glucose peritoneal dialysis solution) were simultaneously assessed and were re-evaluated 1 year later. The numbers of total and apoptotic mesothelial cells were 0.19 +/- 0.19 million and 0.08 +/- 0.12 million cells per bag, respectively. Both numbers correlated well with the levels of end dialysate-to-initial dialysate (D/D(0)) glucose, dialysate-to-plasma (D/P) creatinine, and sodium dipping. Notably, the counts of cells of both types in patients with diabetes or with high or high-average transport were significantly greater than the equivalent counts in nondiabetic patients or those with low or low-average transport. A cut-off of 0.06 million total mesothelial cells per bag had sensitivity of 1 and a specificity of 0.75 in predicting a further decline in D/D(0) glucose and a sensitivity of 0.86 and a specificity of 0.63 to predict a further decline in UF over a 1-year period. In contrast, dialysate CA125 and other measured parameters had low predictive values. The greater the loss of exfoliated cells, the worse the expected decline in UF. The ability of a count of mesothelial cells to predict a future decline in UF warrants further investigation in clinical practice.

Analysis of fluid transport pathways and their determinants in peritoneal dialysis patients with ultrafiltration failure

Ultrafiltration failure (UFF) is a serious complication of peritoneal dialysis (PD). The aim of the study was to analyze changes in water transport and their determinants in UFF patients over the time on PD. Standard peritoneal permeability analyses of 50 stable PD patients with UFF were analyzed. Fluid transport through small pores (SPT), free water transport (FWT) at 60 min, their contributions on total ultrafiltration (SPTC and FWTC), and their determinants were assessed. Patients were divided in Group I (UFF) treated for less than 24 months, Group II treated 24-60 months, and Group III treated for more than 60 months. Group I (UFF) was compared with Group I (non-UFF) matched for the duration of PD treatment and age. Transcapillary ultrafiltration (TCUF), SPT, FWT, and FWTC were significantly lower in Group III when compared to the other UFF groups. In this group also, negative relationship was present between FWT, the ultrafiltration coefficient LpA, and osmotic conductance to glucose on one hand and PD duration on the other. FWT was positively related to osmotic conductance to glucose in all groups. Group I (UFF) showed significantly higher solute transport, effective lymphatic absorption rate, lower TCUF, and lower FWT than Group I (non-UFF). The patterns of UFF in PD patients are dependent on the duration of treatment.

Inherent high peritoneal transport and ultrafiltration deficiency: their mid-term clinical relevance

High peritoneal transport has been associated with poorer outcome in peritoneal dialysis (PD) patients, but not necessarily because of PD-dependent conditions. Our primary objective was to analyse the influences of baseline peritoneal small solute transport and ultrafiltration (UF) capacity on patient and technique survival, after adjusting for comorbid conditions. A secondary objective was to determine whether high transport was associated with basal comorbidity. In this prospective observational patient/technique survival study, we followed 410 patients who started PD. At the baseline, we collected data to define comorbidities, tally the Charlson index, determine the baseline mass transfer area coefficients (MTAC) of urea and creatinine, net UF, plasma albumin and residual renal function (RRF). No data other than the information on patient and technique survival were recorded after baseline. The mean follow-up was 33 +/- 28 months. Dropouts during the study were due to renal transplantation in 140 cases, death in 142 cases and transfer to haemodialysis (HD) in 77 cases. Patients with inherent UF deficiency, high transport rate or both were not significantly different in the survival analysis from the rest. In the Cox hazards analysis, only age, Charlson index and a lower RRF were the significant mortality risk factors. None of the baseline parameters studied was a predictor of technique failure. High transporter patients had lower plasma albumin and UF capacity, comorbidity and more frequent liver diseases than the rest. Moderate to severe liver disease (n = 14) was significantly associated with the inherent high transport status, but was never accompanied by UF failure (UFF). UFF patients showed higher RRF, creatinine-MTAC and age. Neither the high transport nor the inherent UFF status has any influence on patient and technique survival. The inherent high small solute transport status is associated with hypoalbuminaemia and a greater comorbidity index. The Charlson index, age and lower RRF are the only independent predictors of mortality. Technique dropout is not predicted by any of the variables studied at the baseline.

Analysis of the Prevalence and Causes of Ultrafiltration Failure during Long-Term Peritoneal Dialysis: A Cross-Sectional Study

Ultrafiltration failure (UFF) is a major complication of peritoneal dialysis (PD). It can occur at any stage of PD, but develops in time and is, therefore, especially important in long-term treatment. To investigate its prevalence and to identify possible causes, we performed a multicenter study in The Netherlands, where patients treated with PD for more than 4 years were studied using a peritoneal function test (standard peritoneal permeability analysis) with 3.86% glucose. UFF was defined as net UF < 400 mL after a 4-hour dwell. 55 patients unselected for the presence or absence of UFF were analyzed. Mean age was 48 years (range 18 - 74 years); duration of PD ranged from 48 to 144 months (median 61 months); UFF was present in 20 patients (36%). Patients with and without UFF did not differ in age or duration of PD. Median values for patients with normal UF compared to patients with UFF were, for net UF 659 mL versus 120 mL (p < 0.01), transcapillary UF rate 3.8 versus 2.1 mL/ minute (p < 0.01), effective lymphatic absorption 1.0 versus 1.6 mL/min (p < 0.05), mass transfer area coefficient (MTAC) for creatinine 9.0 versus 12.9 mL/min (p< 0.01), dialysate-to-plasma ratio (D/P) for creatinine 0.71 versus 0.86 (p < 0.01), glucose absorption 60% versus 73% (p < 0.01), maximum dip in D/P sodium (as a measure of free water transport) 0.109 versus 0.032 (p < 0.01), and osmotic conductance to glucose 3.0 versus 2.1 microL/min/mmHg (p < 0.05). As causes for UFF, high MTAC creatinine, defined as > 12.5 mL/min, or a glucose absorption > 72%, both reflecting a large vascular surface, a lymphatic absorption rate (LAR) of > 2.14 mL/min, and a decreased dip in D/P sodium of < 0.046 were identified. Most patients had a combination of causes (12 patients), whereas there was only a decreased dip in D/P sodium in 3 patients, only high MTAC creatinine in 1 patient, and only high LAR in 2 patients. We could not identify a cause in 2 patients. Both groups had similar clearances of serum proteins and peritoneal restriction coefficients. However, dialysate cancer antigen 125 concentrations, reflecting mesothelial cell mass, were lower in the UFF patients (2.79 vs 5.38 U/L). The prevalence of UFF is high in long-term PD. It is caused mainly by a large vascular surface area and by impaired channel-mediated water transport. In addition, these patients also had signs of a reduced mesothelial cell mass, indicating damage of the peritoneum on both vascular and mesothelial sites.

Risk Factors Responsible for Ultrafiltration Failure in Early Stages of Peritoneal Dialysis

To define risk factors for ultrafiltration failure (UFF) during early stages of peritoneal dialysis (PD). Retrospective analysis of a group of patients whose peritoneal function was prospectively followed. A tertiary-care public university hospital. Nineteen of 90 long-term PD patients required a peritoneal resting period to recover UF capacity: 8 had this requirement before the third year on PD (early, EUFF group) and 11 had a late requirement (LUFF group). The remaining 71 patients, those with stable peritoneal function over time, constituted the control group. Peritoneal UF capacity under standard conditions (monthly) and small solute peritoneal transport (yearly). None of the conditions appearing at the start of PD or during the observation period could be definitely identified as the cause of UFF. There were no differences in characteristics between the EUFF group and the other two groups, except for the higher prevalence of diabetes in the EUFF group. Residual renal function (RRF) declined in all three groups during the first 2 years, with rapid loss during the third year in the EUFF group. This rapid loss in RRF was coincident with UFF. Peritoneal solute and water transport at baseline was similar in the three groups. After 2 years on PD, individuals in the EUFF group showed a significantly lower UF and higher creatinine mass transfer coefficient values than those in the LUFF group. Diabetic patients in the control group showed remarkable stability in UF capacity over time. During the second year on PD, requirement for increases in dialysate glucose concentration was 3.4 +/- 0.5% in the LUFF group, but as high as 25.5 +/- 24.2% in the EUFF group. The accumulated days of active peritonitis (APID, days with cloudy effluent) were similar for the three groups after 1, 2, and 3 years on PD. Interestingly, diabetic patients in the control group showed an APID index significantly lower than the overall EUFF group. Diabetics in the control group also had significantly lower APID versus nondiabetics in the control group (p = 0.016). Our findings suggest that certain patients develop early UFF type I. Diabetic state and a higher glucose requirement to obtain adequate UF suggest that glucose on both sides of the peritoneal membrane could be responsible. The mechanisms for this higher requirement remain to be elucidated. The identification of a larger cohort of these early UFF patients should lead to a better exploration of the primary pathogenic mechanisms.

Analysis of Non Enzymatic Glycosylation In Vivo: Impact of Different Dialysis Solutions

Glucose-containing dialysis solutions in peritoneal dialysis (PD) patients induce non enzymatic glycosylation (NEG) within the peritoneal cavity. The subsequent formation of advanced glycosylation end-products (AGEs) may be implicated in the functional deterioration of the peritoneal membrane in long-term PD patients. AIM OF THE STUDY AND PARAMETERS: Measurement of NEG by the determination of percent glycation of albumin and IgG (GP), and of AGEs by measuring pentosidine content of protein in 4-hour effluents (Peff) and serum. In 5 patients each, a comparison was made between 3.86% glucose and 1.36% glucose (GP and Peff), and between 3.86% glucose and 7.5% icodextrin (Peff). Nine patients with clinically severe ultrafiltration failure (UFF) were compared to nine patients treated with PD for 1 month. Six of the patients with UFF were treated with non glucose dialysis solutions and Peff was studied again after 6 weeks. No difference was found between Peff comparing 3.86% glucose to either 1.36% glucose or icodextrin. GP were higher in 3.86% glucose than in 1.36%. Glycated/non glycated (G/NG) protein clearance ratios were 1.29 for albumin and 1.12 for IgG (p = 0.003). In contrast to GP, both Peff and serum pentosidine were higher in the UFF patients than in the recently started patients. Peff, but not GP, correlated with duration of PD (r = 0.67, p = 0.04). In 5 of 6 patients treated with non glucose dialysate, Peff decreased while serum pentosidine was stable. These data show that 4-hour Peff contents are not influenced by glucose concentration or osmolality, in contrast to GP. The relation between Peff and duration of PD, and the effect of non glucose dialysate on Peff, suggest that long-term glucose exposure is an important determinant of membrane glycosylation. Thus Peff probably reflects the long-term effects of intraperitoneal glycosylation of peritoneal membrane proteins. Treatment with non glucose dialysis solutions may result in "washout" of glycosylated proteins from the peritoneal membrane.

Beta-Blockers May Cause Ultrafiltration Failure in Peritoneal Dialysis Patients

To elucidate mechanisms of ultrafiltration failure (UFF) in patients on continuous ambulatory peritoneal dialysis (CAPD). Retrospective analysis of patients with UFF during CAPD compared with cross-sectionally selected controls. University peritoneal dialysis center. Thirteen patients with UFF during CAPD necessitating change to hemodialysis (n = 6) or continuous cycling peritoneal dialysis (n = 1), or causing greatly increased need for high glucose-containing solutes, were compared with 18 CAPD patients without such problems. Fisher's exact test, Student's independent t-test, univariate and multivariate correlation analyses. Data were collected prior to analyses. Systolic blood pressure and total cholesterol and triglyceride levels were higher in the UFF patients than in the controls (p = 0.006, p = 0.028, p = 0.013). Beta-blockers were used by 12 of the UFF patients, but only 2/ 18 controls (p < 0.0001). There was no intergroup difference in number of women, patient age or weight, incidence of diabetes or previous peritonitis, duration of PD, serum levels of albumin, creatinine, iron, or ferritin, or dosage of erythropoietin. Correlation was found between the daily amount of glucose instilled into the abdomen and serum triglycerides (r = +0.72, p < 0.001), total cholesterol (r = +0.56, p = 0.008), and HbA1C (r =-0.41, p = 0.039). Many patients were high absorbers of dialysis glucose. The study indicates that beta-blockers may cause UFF, and that glucose and lipid metabolism differed between these patients and controls without UFF.

Quantitation of Lymphatic Drainage of the Peritoneal Cavity in Sheep: Comparison of Direct Cannulation Techniques with Indirect Methods to Estimate L Ymph Flow

It has been suggested that lymphatics may contribute to ultrafiltration failure in patients on continuous ambulatory peritoneal dialysis (CAPD) by absorbing dialysate and ultrafiltrate from the peritoneal cavity. In most studies lymphatic drainage has been estimated from the disappearance of an instilled tracer from the peritoneal cavity or estimated from the appearance of an intraperitoneally administered tracer in the bloodstream. However, in sheep it is possible to cannulate several of the relevant lymphatics that drain the peritoneal cavity and assess lymph drainage parameters directly. The purpose of this study was to estimate lymph drainage from the peritoneal cavity in sheep using the disappearance of tracer from the cavity and the appearance of intraperitoneally instilled tracer in the bloodstream and to compare these results with those obtained from our previous studies using cannulation techniques. Experiments were performed in anesthetized and nonanesthetized animals. Volumes of 50 mL/kg of Dianeal 4.25% containing 25 microCi of 125I-albumin were infused into the peritoneal cavity. In anesthetized sheep the calculated peritoneal lymph drainage from monitoring the disappearance of tracer from the peritoneal cavity over 6 hours was 1.873 +/- 0.364 mL/kg/hour. Monitoring the appearance of tracer in the blood gave significantly lower peritoneal lymph flow rates of 1.094 +/- 0.241 mL/kg/hour. Directly measured lymph flow rates from our earlier publication were lower still and ranged from 0.156 +/- 0.028-0.265 +/- 0.049 mL/hour/kg, depending on how we estimated the right lymph duct contribution to peritoneal drainage, since we could not cannulate this vessel. We repeated these experiments in conscious sheep. The value for lymph flow estimated from the disappearance of tracer from the peritoneal cavity was 2.398 +/- 0.617 mL/hour/kg and from the appearance of tracer in the blood, 1.424 +/- 0.113 mL/hour/kg. The lymph flow rates monitored from indwelling lymphatic catheters ranged from 1.021 +/- 0.186-1.523 +/- 0.213 mL/hour/kg (again, depending on our estimates for the right lymph duct). Lymph flow rates measured from indwelling lymphatic catheters provided the most conservative values for lymphatic drainage of the peritoneal cavity under dialysis conditions. Estimates of lymphatic drainage based on the appearance of tracer in the blood gave values that were on average higher. The method using the disappearance of tracer from the cavity to estimate lymph flows overestimated peritoneal lymph drainage. Fluid was lost from the peritoneal cavity, and the estimated proportion of liquid lost through lymphatic drainage depended on the technique used to measure lymph flow rates.