Peritoneal Dialysis Fluid Research Articles

Effects of neutral pH and low-glucose degradation product-containing peritoneal dialysis fluid on systemic markers of inflammation and endothelial dysfunction: a randomized controlled 1-year follow-up study

The local peritoneal effects of low-glucose degradation product (GDP)-containing peritoneal dialysis fluid (PDF) have been extensively described. However, the systemic effects of prolonged prescription of these solutions are unknown. This study aimed to evaluate the effects of neutral pH and low-GDP PDF on systemic inflammation and endothelial dysfunction markers in peritoneal dialysis (PD) patients. This is a multicenter, open labeled, randomized controlled trial including one hundred fifty-two patients initiating continuous ambulatory peritoneal dialysis for end-stage renal disease from seven centers in Korea. Participants were randomly allocated to conventional PDF (Stay safe®; Fresenius Medical Care, Bad Homburg, Germany) or low-GDP PDF (Balance®; Fresenius Medical Care) and were followed for 1 year. Primary outcome variable was the inflammation and endothelial dysfunction index (IEDI), a composite score derived from serum levels of soluble intercellular adhesion molecule (sICAM)-1, soluble vascular cellular adhesion molecule (sVCAM)-1 and high-sensitivity C-reactive protein (hs-CRP). sICAM-1, sVCAM-1, residual renal function (RRF), peritoneal membrane transport characteristics, ultrafiltration volume and nutritional parameters were measured as secondary outcome variables. Of 152 patients randomized, 146 (low-GDP: conventional PDF, 79:67) patients entered the trial (46% male, 53% with diabetes mellitus). At 12-month follow-up, the low-GDP group had significantly lower levels of IEDI, sICAM-1 and sVCAM-1 compared to the conventional group; hs-CRP was not different between groups. Peritoneal transport characteristics, RRF, nutritional parameters, incidence of peritonitis and death-censored technique survival were not different between groups. Neutral pH and low-GDP PDF likely produce fewer changes in markers of endothelial dysfunction compared to conventional PDF in incident PD patients.

Alanyl–glutamine dipeptide restores the cytoprotective stress proteome of mesothelial cells exposed to peritoneal dialysis fluids

Exposure of mesothelial cells to peritoneal dialysis fluids (PDF) results in cytoprotective cellular stress responses (CSR) that counteract PDF-induced damage. In this study, we tested the hypothesis that the CSR may be inadequate in relevant models of peritoneal dialysis (PD) due to insufficient levels of glutamine, resulting in increased vulnerability against PDF cytotoxicity. We particularly investigated the role of alanyl-glutamine (Ala-Gln) dipeptide on the cytoprotective PDF stress proteome. Adequacy of CSR was investigated in two human in vitro models (immortalized cell line MeT-5A and mesothelial cells derived from peritoneal effluent of uraemic patients) following exposure to heat-sterilized glucose-based PDF (PD4-Dianeal, Baxter) diluted with medium and, in a comparative proteomics approach, at different levels of glutamine ranging from depletion (0 mM) via physiological (0.7 mM) to pharmacological levels (8 mM administered as Ala-Gln). Despite severe cellular injury, expression of cytoprotective proteins was dampened upon PDF exposure at physiological glutamine levels, indicating an inadequate CSR. Depletion of glutamine aggravated cell injury and further reduced the CSR, whereas addition of Ala-Gln at pharmacological level restored an adequate CSR, decreasing cellular damage in both PDF exposure systems. Ala-Gln specifically stimulated chaperoning activity, and cytoprotective processes were markedly enhanced in the PDF stress proteome. Taken together, this study demonstrates an inadequate CSR of mesothelial cells following PDF exposure associated with low and physiological levels of glutamine, indicating a new and potentially relevant pathomechanism. Supplementation of PDF with pharmacological doses of Ala-Gln restored the cytoprotective stress proteome, resulting in improved resistance of mesothelial cells to exposure to PDF. Future work will study the clinical relevance of CSR-mediated cytoprotection.

Encapsulating peritoneal sclerosis: the state of affairs

Encapsulating peritoneal sclerosis (EPS) is a severe complication of long-term peritoneal dialysis (PD) with a 50% mortality rate. EPS is characterized by progressive and excessive fibrotic thickening of the peritoneum, leading to encapsulation of the bowels and intestinal obstruction. At present, EPS cannot be detected with certainty during its early stages; however, a progressive loss of ultrafiltration capacity often precedes its development. Studies that attempted to elucidate the pathogenesis of EPS have shown that the duration of exposure to PD fluids is the most important risk factor for EPS, and that young age and possibly the effects of peritonitis are additional contributory factors. The pathophysiology of EPS is probably best described as a multiple-hit process with a central role for transforming growth factor β. A form of EPS that develops shortly after kidney transplantation has also been recognized as a distinct clinical entity, and may be a common form of EPS in countries with a high transplantation rate. Criteria have been developed to identify EPS by abdominal CT scan at the symptomatic stage, but further clinical research is needed to identify early EPS in asymptomatic patients, to clarify additional risk factors for EPS and to define optimal treatment strategies.

Nephrology literature watch

Nephrology literature watch

PD solutions: New and old

AbstractPeritoneal dialysis (PD) solutions have evolved since Boen described the appropriate composition of a suitable fluid comprising an osmotic agent, electrolytes, and buffer substance in 1969. New solutions introducing alternative osmotic agents and bicarbonate as an alternative to lactate‐buffered solutions have been developed. These so‐called biocompatible solutions belong to a very heterogeneous group of PD fluids that share some features but are distinct in other aspects. All biocompatible solutions have a substantially reduced level of toxic glucose degradation products (GDPs). However, the new solutions differ in their absolute GDP content, osmotic agent, buffer substance, and pH. The differences from the conventional solutions and the characteristics of the distinct new solutions are presented in this review together with a discussion of their potential clinical benefits and implications. Dial. Transplant. © 2011 Wiley Periodicals, Inc.

RESIDUAL RENAL FUNCTION IN PERITONEAL DIALYSIS PATIENTS

Background: Peritoneal dialysis is used regularlly in treatment of ESRDs. Residual renal function (RRF) in these patients helps the adequacy of PD therapy very much. Objectives: 1. Study RRF of PD patients at Department of Nephro – Rheumatology, Hue Central Hospital. 2. Search the correlation between RRF and Kt/V. Patients and methods: 35 PD patients at Department of Nephro – Rheumatology, Hue Central Hospital. Measure RRF and Kt/V by formulars that depend on blood, urine and PD fluid samples. Results: Mean RRF of PD patients is 4.36 ± 13.8 ml/minute. There is a close correlation between RRF and Kt/V (r=0.79, p<0.01). Conclusion: RRF in PD patients correlates with Kt/V.

Effects of recombinant human endostatin on peritoneal angiogenesis in peritoneal dialysis rats

To investigate the effects of recombinant human endostatin (Endostar) on peritoneum angiogenesis in a model of dialysate exposure in rats. Forty male Sprague-Dawley rats were randomized to five groups: normal (group 1); uraemia (group 2); 4.25% peritoneal dialysate (PD) uraemic (group 3); uraemia + PD + recombinant human endostatin 10 mg/kg PD (group 4); and uraemia + PD + recombinant human endostatin 40 mg/kg PD (group 5). The uraemic rats model was established by 5/6 nephrectomy. Endostatin was administrated by s.c. injection every other day, over 28 days. After 28 days of PD fluid exposure, immunohistochemistry and reverse transcript polymerase chain reaction were used to detect protein and mRNA expressions of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in each group. Microvessel density (MVD) was measured by immunohistochemistry. Compared with group 1, the mRNA and protein expressions of VEGF and bFGF were significantly upregulated in groups 2 and 3 (P < 0.05). Compared with group 3, the mRNA and protein expressions of VEGF and bFGF were significantly downregulated in groups 4 and 5 (P < 0.05). Compared with group 4, the mRNA and protein expressions of VEGF and bFGF were significantly downregulated in group 5 (P < 0.05). Compared with group 1, MVD was significantly upregulated in groups 2 and 3 (P < 0.05). Compared with group 3, MVD was significantly downregulated in groups 4 and 5 (P < 0.05). Endostar can effectively inhibit rat peritoneum neoangiogenesis and the effect was dose-dependent.

Non-physiological osmolarity and pH in peritoneal dialysis fluid impair complement regulation in rat peritoneal mesothelial cells

Non-physiological osmolarity and pH in peritoneal dialysis fluid impair complement regulation in rat peritoneal mesothelial cells

Oral supplementation with sulodexide inhibits neo-angiogenesis in a rat model of peritoneal perfusion

Peritoneal dialysis (PD) is associated with functional and morphological alterations of the peritoneal membrane (PM). It is hypothesized that vascular endothelial growth factor (VEGF) plays a role in this process. Sulodexide is a glycosaminoglycan with effects on vascular biology. Therefore, the impact of oral sulodexide on PM function and morphology in a rat model of peritoneal perfusion was evaluated. Rats received 10 mL peritoneal dialysate fluid (PDF) twice daily via a tunnelled PD catheter. The test-PD group (Sul) received 15 mg/kg/day oral sulodexide versus none in the control-PD group (Con). A third group received no PDF (Sham). After 12 weeks, a peritoneal equilibration test was performed and the PM was sampled. Neo-angiogenesis was evaluated using immunostaining with von Willebrand, and epithelial-to-mesenchymal transition (EMT) using co-localization of cytokeratin and α-smooth muscle actin. VEGF was determined in the dialysate by enzyme-linked immunosorbent assay. PD induced loss of ultrafiltration, also in the sulodexide group. Creatinine and glucose transport were better preserved, and sodium dip was more pronounced in the sulodexide group versus control. Submesothelial thickness, neo-angiogenesis and EMT were more pronounced in the Con versus Sul versus Sham group. VEGF in the dialysate, corrected for diffusion was higher in Con and Sul versus Sham. Oral sulodexide administration diminishes neo-vascularization, submesothelial thickening and EMT induced by exposure to PDF in a rat model. As there was no difference in VEGF at the protein level in the dialysate, we hypothesize that oral sulodexide inhibits VEGF locally by binding.

The impact of dialysis solution biocompatibility on ultrafiltration and on free water transport in rats

This study compares different peritoneal dialysis fluids (PDF) in rats over a short contact time. For greater accuracy, net ultrafiltration (UF) and peritoneal transport indices, mass transfer area coefficient (MTAC) were scaled for the in vivo peritoneal surface area recruited (ivPSA) measured by microcomputerized tomography. Wistar rats underwent nephrectomy (5/6ths), were randomized into two groups and given 1.5% glucose PDF, either conventional acidic lactate (n = 14) or pH neutral bicarbonate (BicaVera) (n = 13); MTAC and UF were measured using a 90-min peritoneal equilibrium test (PET), fill volume (IPV) of 10 ml/100 g; small pore fluid transport was determined from sodium balance and used to calculate free water transport (FWT). Each ivPSA value was significantly correlated with the actual IPV, which varied from one rat to another. At 90 min of contact, there was no difference in recruited ivPSA in relation to PDFs. There was a difference (p < 0.01) in net UF/ivPSA 0.45 vs. 1.41 cm(2)/ml for bicarbonate versus lactate, as there was in the proportion of FWT with bicarbonate (42 ± 5% of net UF) compared to lactate (29 ± 4% of net UF). Net UF for individual values of ivPSA differs between conventional PDF and more biocompatible solutions, such as bicarbonate PDF. This observed change in UF cannot be fully explained by differences in glucose transport. The changes in FWT may be explained by the impact of the PDF biocompatibility on aquaporin function.

Blocking TGF-β1 Protects the Peritoneal Membrane from Dialysate-Induced Damage

During peritoneal dialysis (PD), mesothelial cells undergo mesothelial-to-mesenchymal transition (MMT), a process associated with peritoneal-membrane dysfunction. Because TGF-β1 can induce MMT, we evaluated the efficacy of TGF-β1-blocking peptides in modulating MMT and ameliorating peritoneal damage in a mouse model of PD. Exposure of the peritoneum to PD fluid induced fibrosis, angiogenesis, functional impairment, and the accumulation of fibroblasts. In addition to expressing fibroblast-specific protein-1 (FSP-1), some fibroblasts co-expressed cytokeratin, indicating their mesothelial origin. These intermediate-phenotype (Cyto(+)/FSP-1(+)) fibroblasts had features of myofibroblasts with fibrogenic capacity. PD fluid treatment triggered the appearance of CD31(+)/FSP-1(+) and CD45(+)/FSP-1(+) cells, suggesting that fibroblasts also originate from endothelial cells and from cells recruited from bone marrow. Administration of blocking peptides significantly ameliorated fibrosis and angiogenesis, improved peritoneal function, and reduced the number of FSP-1(+) cells, especially in the Cyto(+)/FSP-1(+) subpopulation. Conversely, overexpression of TGF-β1 in the peritoneum by adenovirus-mediated gene transfer led to a marked accumulation of fibroblasts, most of which derived from the mesothelium. Taken together, these results demonstrate that TGF-β1 drives the peritoneal deterioration induced by dialysis fluid and highlights a role of TGF-β1-mediated MMT in the pathophysiology of peritoneal-membrane dysfunction.

Quantification of the six major α-dicarbonyl contaminants in peritoneal dialysis fluids by UHPLC/DAD/MSMS

During heat sterilization of peritoneal dialysis solutions, glucose is partially transformed into glucose degradation products (GDPs), which significantly reduce the biocompatibility of these medicinal products. Targeted α-dicarbonyl screening identified glyoxal, methylglyoxal, 3-deoxyglucosone, 3,4-dideooxyglucosone-3-ene, glucosone, and 3-deoxygalactosone as the major six GDPs with α-dicarbonyl structure. In the present study, an ultra-high-performance liquid chromatography method was developed which allows the separation of all relevant α-dicarbonyl GDPs within a run time of 15 min after derivatization with o-phenylenediamine. Hyphenated diode array detection/tandem mass spectrometry detection provides very robust quantification and, at the same time, unequivocal peak confirmation. Systematic evaluation of the derivatization process resulted in an optimal derivatization period that provided maximal derivatization yield, minimal de novo formation (uncertainty range ±5%), and maximal sample throughput. The limit of detection of the method ranged from 0.13 to 0.19 μM and the limit of quantification from 0.40 to 0.57 μM. Relative standard deviations were below 5%, and recovery rates ranged between 91% and 154%, dependent on the type and concentration of the analyte (in 87 out of 90 samples, recovery rates were 100 ± 15%). The method was then applied for the analysis of commercial peritoneal dialysis fluids (nine different product types, samples from three lots of each).

Solutions for peritoneal dialysis in children: recommendations by the European Pediatric Dialysis Working Group

The purpose of this article is to provide recommendations on the choice of peritoneal dialysis (PD) fluids in children by the European Pediatric Dialysis Working Group. The literature on experimental and clinical studies with PD solutions in children and adults was analyzed together with consensus discussions within the group. A grading was performed based on the international KDIGO nomenclature and methods. The lowest glucose concentration possible should be used. Icodextrin may be applied once daily during the long dwell, in particular in children with insufficient ultrafiltration. Infants on PD are at risk of ultrafiltration-associated sodium depletion, while anuric adolescents may have water and salt overload. Hence, the sodium chloride balance needs to be closely monitored. In growing children, the calcium balance should be positive and dialysate calcium adapted according to individual needs. Limited clinical experience with amino acid-based PD fluids in children suggests good tolerability. The anabolic effect, however, is small; adequate enteral nutrition is preferred. CPD fluids with reduced glucose degradation products (GDP) content reduce local and systemic toxicity and should be preferred whenever possible. Correction of metabolic acidosis is superior with pH neutral bicarbonate-based fluids compared with single-chamber, acidic, lactate-based solutions. Prospective comparisons of low GDP solutions with different buffer compositions are still few, and firm recommendations cannot yet be given, except when hepatic lactate metabolism is severely compromised.

Influence of Intraperitoneal Volume on QT Dispersion in Patients with Continuous Ambulatory Peritoneal Dialysis: Acute Cardiac Impact of Peritoneal Dialysis

Aim: The leading cause of mortality in dialysis patients is cardiovascular complications, including ventricular arrhythmias and sudden cardiac death. QT dispersion (QTd), a simple noninvasive arrhythmogenic marker, is used to assess homogeneity of cardiac repolarization. It was also significantly prolonged in continuous ambulatory peritoneal dialysis (CAPD) patients. The acute cardiac effect of increased abdominal pressure due to infused dialysate during CAPD is not clear yet. In this study we aimed to evaluate corrected QTd (cQTd) and cardiac injury markers such as plasma pro-brain natriuretic peptide (proBNP) and troponin I (TnI) in CAPD patients before and after an infusion of peritoneal dialysate fluid. Methods: Thirty subjects (16 women, 14 men; mean age, 40.21 ± 12.34 years) enrolled in our study. QTd, cQTd, maximum QT (QTmax), maximum corrected QT (cQTmax), minimum QT (QTmin), and minimum corrected QT (cQTmin) intervals were measured from standard 12-lead electrocardiography. Results: We found that cQTmax, cQTmin, and cQTd were not changed from baseline measurement after infusion of dialysate in CAPD patients (460 ± 49 vs. 460 ± 38, p = 0.9; 410 ± 36 vs. 410 ± 41, p = 0.8; 470 ± 30 vs. 460 ± 25, p = 0.7, respectively). There were no statistically significant differences between before and after peritoneal dialysate according to the levels of proBNP and TnI (155.64 ± 76.41 vs. 208.30 ± 118.46, p = 0.2; 0.008 ± 0.007 vs. 0.01 ± 0.011; p = 0.4, respectively). Conclusion: In conclusion, we did not find any significant effect of peritoneal dialysate fluid infusion volume on QTd and cardiac injury markers in patients with chronic renal failure receiving CAPD therapy, which is thought to be a safer modality of dialysis.

An infant with alternating metabolic acidosis and alkalosis: question

A 40-day-old infant was referred to our center from a local hospital with abnormal renal function tests, oliguria, and dehydration. The infant was the third child of consanguineous parents; none of the other siblings were reported to have any relevant medical condition. His birth was uneventful except for caesarian section delivery due to preeclampsia of the mother at 37 weeks gestation (birth weight 2800 g). A lowgrade fever and upper respiratory infection was documented on the tenth day of life, which was followed by diarrhea. Upon treatment with intravenous ampicillin, fever subsided but diarrhea persisted with watery green soft stools five times per day. The infant was reported not to have gained weight favorably, but was above the tenth percentile. He was vaccinated according to the national schedule up to this point and his medication history was not significant. The infant had received one dose of gentamicin in the local hospital, but this treatment was discontinued immediately after the admission test results became available, which revealed a blood urea nitrogen level of 116 mg/dl and a serum creatinine level of 4.2 mg/dl. He was then transferred to our center. At presentation, the infant appeared to be ill, lethargic, and dehydrated on physical examination. Vital signs on admission were reported as systolic blood pressure of 55 mmHg, pulse rate of 140 bpm, respiratory rate of 35 per minute, and axillary temperature of 36.8°C. Laboratory results on admission showed a partly compensated metabolic acidosis, renal failure, hyperkalemia, hyponatremia, and hyperphosphatemia (see Table 1). All attempts to drain a urine sample by Foley catheter were unsuccessful. Renal ultrasonography demonstrated renal parenchymal changes but no signs of obstruction or hydronephrosis. Initial treatment consisted of intravenous fluid administration, emergency peritoneal dialysis, and kayexalate enema. Calcium gluconate, furosemide, and ceftizoxime were administered parenterally. The infant showed significant improvement after 3 days of peritoneal dialysis and strict fluid and electrolyte management. Breastfeeding restarted on the second day of admission and upon resolution of all symptoms the infant was discharged. The infant was hospitalized for a second time in our center on his 80th day of life, shortly after discharge from a local hospital where he had been diagnosed with a respiratory infection after a productive cough for 10 days and low-grade fever; treatment had been intravenous ampicillin. Following the initial discharge the infant exhibited poor feeding and worsening of the lethargy and was re-admitted to our center. On physical examination, the infant had tachypnea and moderate dehydration, but not hypotension or fever (pulse rate 120 bpm, respiratory rate 50 per minute, blood pressure 85/55 mmHg, axillary temperature 36.8°C). Heart and lung auscultation was normal. He had not gained weight since the last hospitalAn answer to this question is available at http://dx.doi.org/10.1007/ s00467-011-1901-2

HSP Induction in Mesothelial Cells by Peritoneal Dialysis Fluid Depends on Biocompatibility Test System

We have previously shown that exposure of mesothelial cells (MC) to peritoneal dialysis fluids (PDF) not only caused toxic injury, but also induced cytoprotective heat shock proteins (HSP). This study was performed in order to compare HSP expression in MC upon PDF exposure in three currently used biocompatibility test systems. Omentum-derived human peritoneal MC underwent 3 modalities of exposure to heat- or filter-sterilized PDF: (A) pure PDF for 60 minutes followed by a recovery-period in pure culture medium for 24 hours; (B) 1:1 mixture of PDF and culture medium for 24 hours or (C) pure PDF for 60 minutes followed by a recovery-period in a 1:1 mixture of PDF and culture medium for 24 hours. Biocompatibility was assessed by LDH-release into the supernatant and HSP-72 expression in MC lysates. Short-term exposure of MC to pure PDF (Modality A) resulted in concordant LDH release and upregulation of HSP-72, regardless of heat or filter sterilization. In contrast, both test systems that exposed MC to heat-sterilized PDF during the recovery period (Modalities B and C) resulted in severe cellular lethality but low HSP-72 expression. This study clearly shows that HSP expression in MC upon PDF exposure depends on the biocompatibility test system. The presence of heat-sterilized PDF during recovery resulted in significant downregulation of Hsp-72 despite severe cell injury. Therefore, Hsp-72 expression reflects adequate cellular stress responses rather than PDF cytotoxicity.

Peritoneal Dialysis Fluid Induces P38-Dependent Inflammation in Human Mesothelial Cells

Noninfectious upregulation of proinflammatory pathways in mesothelial cells may represent an integral part of their stress response upon exposure to peritoneal dialysis fluids (PDF). The aim of this study was to evaluate the role of the stress-inducible mitogen-activated protein kinase (MAPK) p38 in regulation of inflammatory and stress responses in mesothelial cells following in vitro exposure to PDF. Human peritoneal mesothelial cells were exposed to Dianeal PD4 or Physioneal (Baxter AG, Vienna, Austria) containing 1.36% glucose and then allowed to recover. Phosphorylation of p38, induction of heat shock protein-70 (HSP70), release of lactate dehydrogenase (LDH), secretion of interleukin (IL)-8, gene transcription, and mRNA stability were assessed with and without the MAPK p38 inhibitor SB203580. Exposure to Dianeal resulted in phosphorylation of p38 within 30 minutes (309% of control, p < 0.05) and increased IL-8 release (370% of control, p < 0.05), HSP70 expression (151% of control, p < 0.05), and LDH release (180% of control, p < 0.05). Exposure to Physioneal resulted in attenuated changes in IL-8, HSP70, and LDH. Addition of the p38 inhibitor SB203580 to Dianeal resulted in dampened IL-8 release (-55%; p < 0.05) and basal HSP70 expression, and unchanged LDH release. Effects of p38 on IL-8 were at transcriptional, posttranscriptional, and translational levels. These data confirm concordant p38-dependent upregulation of IL-8 and HSP70 following exposure to bioincompatible PDF. The MAPK p38 pathway therefore links proinflammatory processes and the cellular stress response in human peritoneal mesothelial cells.

A Peritoneal Dialysis Regimen Low in Glucose and Glucose Degradation Products Results in Increased Cancer Antigen 125 and Peritoneal Activation

Glucose and glucose degradation products (GDPs) in peritoneal dialysis fluids (PDFs) are both thought to mediate progressive peritoneal worsening. In a multicenter, prospective, randomized crossover study, incident continuous ambulatory peritoneal dialysis patients were treated either with conventional lactate-buffered PDF (sPD regimen) or with a regimen low in glucose and GDPs: Nutrineal×1, Extraneal×1, and Physioneal×2 (NEPP regimen; all solutions: Baxter Healthcare, Utrecht, The Netherlands). After 6 months, patients were switched to the alternative regimen for another 6 months. After 6 weeks of run-in, before the switch, and at the end of the study, 4-hour peritoneal equilibration tests were performed, and overnight effluents were analyzed for cells and biomarkers. Differences between the regimens were assessed by multivariate analysis corrected for time and regimen sequence. The 45 patients who completed the study were equally distributed over both groups. During NEPP treatment, D(4)/D(0) glucose was lower (p < 0.01) and D/P creatinine was higher (p = 0.04). In NEPP overnight effluent, mesothelial cells (p < 0.0001), cancer antigen 125 (p < 0.0001), hyaluronan (p < 0.0001), leukocytes (p < 0.001), interleukins 6 (p = 0.001) and 8 (p = 0.0001), and vascular endothelial growth factor (VEGF, p < 0.0001) were increased by a factor of 2-3 compared with levels in sPD effluent. The NEPP regimen was associated with higher transport parameters, but that association disappeared after the addition of VEGF to the model. The association between NEPP and higher effluent levels of VEGF could not be attributed to glucose and GDP loads. Study results indicate preservation of the mesothelium and increased peritoneal activation during NEPP treatment. Whether the increase in VEGF reflects an increase in mesothelial cell mass or whether it points to another, undesirable mechanism cannot be determined from the present study. Longitudinal studies are needed to finally evaluate the usefulness of the NEPP regimen for further clinical use.

Clearance of p-Cresol Sulfate and β-2-Microglobulin from Dialysate by Commercially Available Sorbent Technology

Dialysate regeneration by sorbents is an alternative to conventional single-pass dialysis. Little is known about the capacity of sorbents to clear dialysate of “middle molecules” and protein-bound uremic toxins. We studied p-cresol sulfate (PCS) and β-2-microglobulin (β2M) removal from dialysate by a sorbent: 1. PCS (40 mg PCS dissolved in 4 L of fresh dialysate) was recirculated through a sorbent cartridge (SORB Technology, Inc.) for analysis of PCS removal. 2. Spent peritoneal dialysate was recirculated on the “blood” side of a high-flux dialyzer. On the “dialysate” side of the membrane, bicarbonate dialysate was recirculated through a sorbent cartridge. β2M was measured in both streams. Two results are of particular importance for the use of regenerated fluid in chronic dialysis: 1. PCS was virtually completely removed from the dialysate. On average, PCS concentration was reduced to 1.4% of the starting concentration after 60 minutes. PCS extraction across the sorbent was nearly complete at any time. 2. β2M was on average reduced to 14.3% of the starting concentration after 60 minutes. Postsorbent concentrations were consistently below the validated range of the test method. We conclude that PCS and β2M are efficiently removed from the dialysate by commercially available sorbent technology. Spent peritoneal dialysis fluid can be cleared of β2M when circulated against sorbent-regenerated dialysate using a high-flux membrane.

Interleukin-1 Receptor-Mediated Inflammation Impairs the Heat Shock Response of Human Mesothelial Cells

Bioincompatibility of peritoneal dialysis fluids (PDF) limits their use in renal replacement therapy. PDF exposure harms mesothelial cells but induces heat shock proteins (HSP), which are essential for repair and cytoprotection. We searched for cellular pathways that impair the heat shock response in mesothelial cells after PDF-exposure. In a dose-response experiment, increasing PDF-exposure times resulted in rapidly increasing mesothelial cell damage but decreasing HSP expression, confirming impaired heat shock response. Using proteomics and bioinformatics, simultaneously activated apoptosis-related and inflammation-related pathways were identified as candidate mechanisms. Testing the role of sterile inflammation, addition of necrotic cell material to mesothelial cells increased, whereas addition of the interleukin-1 receptor (IL-1R) antagonist anakinra to PDF decreased release of inflammatory cytokines. Addition of anakinra during PDF exposure resulted in cytoprotection and increased chaperone expression. Thus, activation of the IL-1R plays a pivotal role in impairment of the heat shock response of mesothelial cells to PDF. Danger signals from injured cells lead to an elevated level of cytokine release associated with sterile inflammation, which reduces expression of HSP and other cytoprotective chaperones and exacerbates PDF damage. Blocking the IL-1R pathway might be useful in limiting damage during peritoneal dialysis.