Conventional Peritoneal Dialysis Research Articles

Pathogenesis and treatment of peritoneal membrane failure

Peritoneal dialysis (PD) is a viable treatment option for end stage renal disease (ESRD) patients worldwide. PD may provide a survival advantages over hemodialysis (HD) in the early years of treatment. However, the benefits of PD are short-lived, as peritoneal membrane failure ensues in many patients, owing mainly to structural and functional changes in the peritoneal membrane from the use of conventional bio-incompatible PD solutions, which are hyperosmolar, acidic, have lactate buffer and contain high concentrations of glucose and glucose degradation products (GDPs). Current data suggest that chronic exposure of the peritoneum to contemporary PD fluids provokes activation of various inflammatory, fibrogenic and angiogenic cytokines, interplay of which leads to progressive peritoneal fibrosis, vasculopathy and neoangiogenesis. There is emerging evidence that peritoneal vascular changes are mainly responsible for increased solute transport and ultrafiltration failure in long-term PD. However, the precise pathophysiologic mechanisms initiating and propagating peritoneal fibrosis and angiogenesis remain elusive. The protection of the peritoneal membrane from long-term toxic and metabolic effects of high GDP-containing, conventional, glucose-based solutions is a prime objective to improve PD outcome. Recent development of new, more biocompatible, PD solutions should help to preserve peritoneal membrane function, promote ultrafiltration, improve nutritional status and, hopefully, preserve peritoneal membrane and improve overall PD outcomes. Elucidation of molecular mechanisms involved in the cellular responses leading to peritoneal fibrosis and angiogenesis spurs new therapeutic strategies that might protect the peritoneal membrane against the consequences of longstanding PD.

3,4-DGE in Peritoneal Dialysis Fluids Cannot be Found in Plasma after Infusion into the Peritoneal Cavity

Glucose degradation products (GDPs) are important in the outcome of peritoneal dialysis (PD) treatment. 3,4-dideoxyglucosone-3-ene (3,4-DGE) is the most cytotoxic GDP found in conventionally manufactured fluids and may, in addition, be recruited from 3-deoxyglucosone (3-DG). It is not known what happens with those GDPs in patients during PD. The aim of this study was to investigate if the 3,4-DGE and 3-DG in PD fluids can be found in plasma during treatment. PD patients were dialyzed with a conventional PD fluid containing 43 micromol/L 3,4-DGE and 281 micromol/L 3-DG. Parallel experiments were performed in rats as well as in vitro with human plasma. The rats were dialyzed with a PD fluid containing 100 micromol/L 3,4-DGE and 200 micromol/L 3-DG. The concentration of 3,4-DGE in the peritoneum decreased at a much higher rate than 3-DG during the dwell. 3,4-DGE was not, however, detected in the plasma of patients or rats during dialysis. The concentration of 3-DG in plasma peaked shortly after infusion of the fluid to the peritoneal cavity. The concentration of 3,4-DGE during experimental incubation in plasma decreased rapidly, while the concentration of 3-DG decreased only 10% as rapidly or less. 3,4-DGE could not be detected in plasma from either PD patients or rats during dialysis. This is presumably due to its high reactivity. 3-DG may, on the other hand, pass through the membrane and be detected in the blood.

Effects of peritoneal dialysis fluid biocompatibility on baroreflex sensitivity

Conventional low biocompatibility peritoneal dialysis (PD) fluid composition has been driven by manufacturing expediency and cost limitations. PD is associated with significant acute changes in cardiovascular functional parameters, at least in part influenced by fluid composition. Short-term control of blood pressure (BP) is under control of the baroreflex arc. The aim of this study was to investigate the effects of PD fluid biocompatibility on baroreflex sensitivity (BRS). We studied 10 non-diabetic established continuous ambulatory PD patients, in a randomized crossover trial comparing conventional and biocompatible PD fluids. Systemic hemodynamics were continuously monitored using digital pulse-wave analysis. Plasma glucose and insulin were assessed during treatment with both 1.36% and 3.86% glucose-containing fluids. BRS was calculated offline from continuous BP and interbeat interval data. BRS was significantly higher with conventional PD fluid during both 1.36% (P<0.001) and 3.86% (P<0.001) dwells. Systolic BP was higher; heart rate, stroke volume, and cardiac output were lower; and total peripheral resistance increased during exposure to either fluid. There were significant differences between fluids with respect to the magnitude of these responses. Plasma glucose and insulin concentrations, and ultrafiltration volumes were significantly higher during the 3.86% dwell than the 1.36% dwell, but there were no differences between standard and biocompatible fluids. We have demonstrated for the first time that PD fluid biocompatibility rapidly affects BRS. These changes occur against a background of cardiovascular variability, hyperinsulinemia, and hyperglycemia. Further research is needed to explore the mechanism and, more importantly, the consequences of these findings.

Use of new peritoneal dialysis solutions in children

Standard peritoneal dialysis (PD) solutions with low pH and containing high concentrations of lactate and glucose have been demonstrated to negatively affect the peritoneal membrane, mesothelial cell viability, residential peritoneal cells, and also to inhibit phagocytic functions. An increasing body of experimental evidence supports the idea that the peritoneal hypervascularization and fibrosis observed in long-term PD are causally related to the acute and chronic toxicity of conventional PD solutions. A Physioneal (lactate/bicarbonate mixed buffer pH 7-7.4), Physioneal, Extraneal (7.5% icodextrin), Nutrineal (1.1% amino-acid-containing solution) regimen, for example, offers a significant reduction in carbohydrate load (approximately 40-50%), lower exposure to and absorption of glucose degradation products, reduced oxidative stress, and improved volume control when compared with a first-generation DDDD (4 x Dianeal) regimen. The positive aspects of each solution that we have observed in our patients allow a recommendation on the potential benefit of using these solutions in children treated with PD. In fact, data from the literature as well as the results of the studies reported in this paper show that in children the application of neutral pH bicarbonate/lactate-buffered solution for the standard nighttime APD prescription, icodextrin solution for a long daytime dwell, and AA-based solution in malnourished patients is safe and effective. Extended clinical trials should be encouraged to better define the PD schedules for the combined use of these solutions that may be associated with the best clinical efficacy and the highest level of biocompatibility.

The Clinical Usefulness of Peritoneal Dialysis Fluids with Neutral pH and Low Glucose Degradation Product Concentration: An Open Randomized Prospective Trial

Long-term peritoneal dialysis (PD) is associated with the development of various structural and functional changes to the peritoneal membrane when bioincompatible conventional peritoneal dialysis fluids (PDFs) are used. In this study, we looked at patients that were treated with conventional PDFs and then changed to novel biocompatible PDFs with a neutral pH and a low concentration of glucose degradation products (GDPs) to investigate whether this change could result in the arrest or reversal of peritoneal membrane deterioration. In an open label, randomized prospective trial, the clinical effects of conventional PDFs and biocompatible PDFs with neutral pH and very low concentration of GDPs were compared in 104 patients equally divided between both study PDFs. Blood and effluent dialysate samples, peritoneal equilibration tests, and adequacy evaluation were undertaken at baseline, 4, 8, and 12 months. The target variables were the ratio of dialysate-to-plasma (D/P) creatinine, peritoneal ultrafiltration, residual renal function, dialysis adequacy indices, and effluent cancer antigen 125 (CA125). D/P creatinine values were not different in the two groups. Peritoneal ultrafiltration was significantly higher in the low-GDP PDF group than in the conventional PDF group at all follow-up times (4 months: 9.1 +/- 4.3 vs 6.0 +/- 3.0; 8 months: 8.3 +/- 3.4 vs 6.0 +/- 3.0; 12 months: 8.9 +/- 3.3 vs 6.1 +/- 3.3 mL/g dextrose/day; p < 0.05). Peritoneal Kt/V urea values and total weekly Kt/V urea values at 4 months were significantly higher in the low-GDP PDF group than in the conventional PDF group. Residual renal function was not statistically significant. Effluent CA125 levels were significantly higher in the low-GDP PDF group at all follow-up visits (4 months: 37.8 +/- 20.8 vs 22.0 +/- 9.5; 8 months: 41.2 +/- 20.3 vs 25.9 +/- 11.3; 12 months: 40.4 +/- 21.4 vs 28.6 +/- 13.0 U/mL; p < 0.05). Among anuric patients, peritoneal ultrafiltration at 4, 8, and 12 months, total weekly Kt/V at 4 and 8 months, and CA125 levels at all follow-up visits were significantly higher in patients treated with low-GDP PDF than those treated with conventional PDF. However, among anuric patients, D/P creatinine showed no significant differences between the low-GDP PDF group and the conventional PDF group. The use of biocompatible PDFs with neutral pH and low GDP concentration can contribute to improvement of peritoneal ultrafiltration and peritoneal effluent CA125 level, an indicator of peritoneal membrane integrity in PD patients.

Short-Term Effects of a New Bicarbonate/Lactate-Buffered and Conventional Peritoneal Dialysis Fluid on Peritoneal and Systemic Inflammation in CAPD Patients: A Randomized Controlled Study

This study was designed to compare the local peritoneal and systemic inflammatory effects of a conventional lactate-based (Lac) peritoneal dialysis (PD) solution and a new biocompatible bicarbonate/lactate-based (Bic/Lac) solution having low concentration of glucose degradation products. 26 stable, prevalent PD patients were enrolled in this prospective study. They sequentially underwent 3 months of therapy with the Lac solution and 3 months with the Bic/Lac solution in a randomized order. Flow cytometry was used to measure the expression of inflammatory molecules on peritoneal cells in overnight effluent collected at the end of each study period. 21 patients successfully completed the study. Mean fluorescence intensity of human leukocyte antigen (HLA)-DR and CD14 expression by macrophages were not different between Lac and Bic/Lac. The peritoneal appearance rate of cancer antigen 125 (kU/minute) was 68 +/- 37 with Lac and 133 +/- 66 with Bic/Lac (p < 0.001), and of interleukin (IL)-6 (ng/minute), 0.28 +/- 0.2 with Lac and 0.18 +/- 0.16 with Bic/Lac (p = 0.014). HLA-DR macrophage expression and IL-6 peritoneal appearance rates did not correlate. Serum concentrations with Lac and Bic/Lac were, for IL-6, 3.49 +/- 2.28 and 3.72 +/- 2.46 ng/L (p = 0.17), and for high-sensitivity C-reactive protein, 2.31 +/- 2.98 and 2.71 +/- 3.31 mg/L (p = 0.32) respectively. The concentration of effluent macrophages (x10(6)/L) with Lac was 1.6 +/- 1.6 and with Bic/Lac 2.6 +/- 3.3 (p = 0.07). We conclude that, although there was a significant reduction in peritoneal IL-6 in patients using Bic/Lac solution, systemic levels of inflammatory markers did not differ between the two solutions and no changes were present in macrophage surface activation markers, suggesting perhaps a less important role of peritoneal macrophages in the intraperitoneal chronic inflammatory process. The number of effluent macrophages tended to be higher in patients using the Bic/Lac solution, possibly contributing to improved intraperitoneal defense.

The Alteration of Dialysate Cancer Antigen 125 Concentration Under a Biocompatible Bicarbonate Peritoneal Dialysis Solution and the Preservation of the Mesothelial Cell Viability

Background. The importance to maintain the peritoneal membrane integrity for peritoneal dialysis (PD) patients by using biocompatible solutions (with low or no glucose as osmotic factor and low in glucose degradation products-GDPs, without lactate as a buffer and with normal pH) becomes progressively more evident. The aim of the present study was to investigate the clinical effects of a novel bicarbonate-based biocompatible PD fluid, evaluating the alteration in the concentrations of dialysate marker CA125, a glucoprotein indicator of mesothelial cell mass. Patients and Methods. This is a single-center, prospective cohort study of 12 stable CAPD patients (4 women, 8 men), mean age 71.3 ± of 6.01 years, mean PD duration 31.9 ± 21.33 months, treated with the usual conventional PD solutions (with increased GDPs, low pH, and lactate as a buffer system). After a six-month period, the patients changed for the next six-month period into bicarbonate PD solutions (BicaVera, Fresenius®), after which they returned into their previous schema of conventional solutions for another six months. The dialysate marker of CA125 was repeatedly estimated at the beginning of the study (T0), after six months phase with the bicarbonate solutions (T6), and at the end of study (T12), after the second six-month use of the conventional PD solutions. All the samples were taken at the end of a four-hour dwell of an exchange with PD solution 2.5% glucose. Results. The dialysate mean value of CA125 at the beginning of the study (Td0-with conventional PD solutions) was 15.07 ± 5.72U/mL. After six months with bicarbonate PD solutions, the mean CA125 value increased to 111.97 ± 66.21U/mL, while the mean values dropped again to 22.72 ± 16.06 U/mL at the end of the study, after the patients' return for another six months to the conventional solutions use. There was a statistically significant difference between the mean CA125 levels at the beginning (Td0) and the middle of the study (Td6; p = 0.00079) as well as between the mean levels of CA125 in the middle (Td6) and at the end of the study (Td12; p = 0.0014). In contrast, comparing the mean dialysate values of CA125 at the beginning (Td0) and at the end of the study (Td12), no statistically significant difference was revealed (p = 0.13). Conclusions. For the use of the bicarbonate-based PD, more biocompatible solutions for six months produced a statistically significant increase in the dialysate concentration of the mesothelial cell mass indicator CA125. The decrease at the end of the study of CA125 mean value at a level similar with that observed at the beginning, after the six-month period of the conventional PD solutions, indicates that the clinical use of the new bicarbonate-based PD solutions may have an advantageous role in the preservation of peritoneal cell mass, maintaining also the integrity and longevity of the peritoneal membrane.

The cellular contribution to effluent potassium and its relation to free water transport during peritoneal dialysis

Aquaporin-1 (AQP-1) dysfunction is one of the valid theories for decreased free water transport (FWT) in long-term peritoneal dialysis (PD) ultrafiltration failure (UFF). We questioned whether apoptosis of peritoneal cells could be reflected in an increased release of cellular (CR) K(+) and explain AQP-1 dysfunction. If so, negative relationships between CR-K(+) and FWT would be expected. Therefore, we analysed CR-K(+) to total peritoneal K(+) removal, for possible relationships with FWT, the duration of PD, the presence of late UFF and effluent cancer antigen (CA) 125. Standard peritoneal permeability analyses done with 3.86% glucose were investigated cross-sectionally in three extreme groups: group I: 19 patients <1 year on PD; group II: 20 patients >4 years on PD without UFF; group III: 19 patients >4 years on PD with UFF. Group III had the lowest values of FWT and CR-K(+) (P < 0.01). CR-K(+) had a positive correlation with FWT in groups I and II, but not in group III. These correlations were also present using much simpler methodologies: replacement of CR-K(+) by mass transfer area coefficient (MTAC)-K(+)/MTAC-creatinine ratio or dialysate over plasma (D/P)-K(+)/D/P-creatinine ratio and replacement of FWT by Na(+)-sieving. No relationship with CA125 was present. This study shows that other than diffusive and convectional, K(+) transport is not excluded in patients treated with conventional glucose-based PD solutions. We found evidence for release of K(+) from cells. In general, CR-K(+) was related to parameters of FWT, except for long-term patients with UFF. This suggests glucose-induced hypertonic cell shrinkage as a basic physiological phenomenon during PD. The absence of this relationship in long-term PD patients with UFF either suggests a reduction or inhibition of K(+)-channels and may be due to another mechanism than AQP-1 dysfunction. Most likely, CR-K(+) in UFF does not reflect apoptosis. However, the D/P-K(+)/D/P-creatinine ratio may be useful in detecting peritoneal changes.

Antiglycation and Antioxidant Effect of Carnosine against Glucose Degradation Products in Peritoneal Mesothelial Cells

Background/Aim:Toxicity with advanced glycation end products (AGEs) is a major problem in uremic patients. Treatment with peritoneal dialysis (PD) exacerbates AGE formation as a result of bioincompatibility of the conventional peritoneal dialysis fluid (PDF). The presence of glucose degradation products (GDPs) in PDF is the main cause of its bioincompatibility. Carnosine is an endogenous dipeptide with a powerful antiglycation/antioxidant activity. In an attempt to improve PDF biocompatibility, we evaluated the effect of carnosine in human peritoneal mesothelial cells (HPMC) incubated with PDF or GDPs in vitro. Methods: HPMC were incubated for short or prolonged time with PDF in the presence or absence of carnosine. Similarly, HPMC were incubated in the same condition but with a combination of GDPs. Following the incubation, cells were tested for their viability, protein carbonyl content and reactive oxygen species (ROS) production. Results: Results demonstrated a significant protective effect of carnosine to HPMC in both acute and chronic conditions with PDF or GDPs as judged by the enhancement of cell viability, preserved protein from modification and decreased ROS production. Conclusion: Carnosine enhanced HPMC viability against the toxic effect of GDPs probably through protection of cellular protein from modification and from ROS-mediated oxidative damage. The salutary effect of carnosine may render it a desirable candidate for improving PDF biocompatibility and reducing AGE complications in PD patients.

Glycosaminoglycans and Proteoglycans: Overlooked Entities?

By virtue of their high net negative charge, glycosaminoglycans and proteoglycans play pivotal roles in biologic processes such as cell-cell and cell-matrix interactions, sequestration of growth factors, activation of chemokines and cytokines, and permselectivity of basement membranes. The present article reviews the putative roles of glycosaminoglycans and proteoglycans in the peritoneal cavity during normal peritoneal homeostasis and chronic inflammation, the latter induced by constant exposure of the peritoneum to non-physiologic peritoneal dialysis (PD) solutions. Glycosaminoglycans have been identified in the mesothelial glycocalyx, a slippery, non-adhesive layer that protects the peritoneal membrane from abrasion and infection. Dermatan sulfate proteoglycans can neutralize the activity of transforming growth factor beta1 and can thus play an essential role in modulating peritoneal fibrosis. Heparan sulfate proteoglycans play a crucial role in the sequestration of growth factors; they also modulate selective permeability of proteins across the peritoneal cavity. Reduced expression of perlecan, a heparan sulfate proteoglycan of the basement membrane, is observed in peritoneal biopsies obtained from established PD patients, consequent to prolonged exposure to the elevated glucose concentrations in conventional PD solutions. Supplementation of PD fluids with glycosaminoglycans has been shown to be beneficial to both the structural and functional integrity of the peritoneum. Recent advances in the field of glycobiology have revealed a multitude of biologic processes that are controlled or influenced by glycosaminoglycans and proteoglycans. Altered synthesis of these macromolecules during PD has serious implications for the peritoneal transport of proteins, host defense, wound healing, inflammation, and fibrosis.

Effects of Glucose-Free Dialysis Solutions on Human Peritoneal Mesothelial Cells

Background: Glucose-free dialysis solutions may be more biocompatible owing to the physiological pH and the lack of glucose degradation products, and the effects can be reflected by the changes in some markers of peritoneal mesothelial cells (PMC). Method: Peritoneal effluents were collected in 17 CAPD patients after one daily exchange of glucose-containing dialysate to Nutrineal (1.1% amino acid-based PDF), and human PMC were cultured from peritoneal effluent and treated with various peritoneal dialysis (PD) solutions. Results: The level of cancer antigen 125 (CA125) in peritoneal effluent increased significantly after using Nutrineal® for 3 months (p = 0.045), whereas that of procollagen I peptide (PICP) remained unaltered. Production of CA125 by human PMC showed a time-responsive increase after stimulation with Nutrineal and Extraneal (icodextran-based PDF). An increased expression of CA125 was observed in cultured human PMC treated with various PD solutions, and the increase induced by Nutrineal was lower than that induced by 4.25% Dianeal® and Extraneal®. A lower increase was also observed for lactate dehydrogenase (LDH). The levels of heat shock protein 70 (HSP70), however, were not altered. Conclusion: Nutrineal is more biocompatible to the peritoneal membrane than the conventional PD solutions tested herein, reflected by both the in vivo and in vitro response of CA125.

Update on peritoneal dialysis solutions

Since the widespread introduction of peritoneal dialysis (PD) into the standard care of patients with chronic kidney disease there has been a shift from the initial focus on technique survival to refinement of the therapy to enhance biocompatibility and improve both the local peritoneal and systemic consequences of PD. One of the most significant contributions to these advances has been the development of novel PD solutions. The use of new manufacturing techniques, buffer presentation, and new osmotic alternatives to glucose have allowed potentially improved peritoneal survival (in terms of structure and function) and improved subjective patient experience. Additional benefits have also included, enhanced management of salt and water removal, supported nutritional status and improvement in the systemic metabolic derangements associated with conventional PD treatment, based on glucose-containing lactate-buffered solutions. The selection of suitable targets for modulation of therapy continues to be hampered by our continued relative ignorance of the local and particularly systemic effects of PD compounded by the dearth of quality, outcome-based studies. The aim of this review is to summarize the characteristics of the next generation of PD fluids currently available, and then to evaluate their possible place in treatment by considering the difference in their effects in a series of structural and functional areas potentially relevant to improving patient outcomes.

Improved In Vitro Biocompatibility of Bicarbonate-Buffered Peritoneal Dialysis Fluid

Conventional peritoneal dialysis fluids (PDFs) have been shown to damage the mesothelial layer and are associated with the development of peritoneal fibrosis and neoangiogenesis. New-generation PDFs have therefore been developed with physiological pH and reduced levels of glucose degradation products (GDPs), precursors of advanced glycation end products (AGEs). In this work, we evaluated and compared the improved biocompatibility of two new-generation PDFs (Balance and bicaVera) using mesothelial cell biology; we also compared them to a standard PDF (stay.safe) (all PDFs by Fresenius Medical Care, Fresnes, France). stay.safe, Balance, and bicaVera were tested for their effect on human peritoneal mesothelial cell (HPMC) viability by measuring cell proliferation and apoptosis, and oncosis induction. The formation of AGEs was evaluated by immunoassay. Transforming growth factor beta-1 and vascular endothelial growth factor (VEGF) were immunoassayed in HPMC supernatants exposed to the above PDFs. At 15 g/L glucose concentration, HPMC exposure to bicaVera resulted in higher cell proliferation compared to Balance (p < 0.001) and stay.safe (p < 0.001). Compared to the lactate-buffered PDFs (Balance and stay.safe), oncosis was significantly lower in cells exposed to bicaVera (p < 0.05). bicaVera, containing lower amounts of GDPs, generated less AGE formation (p < 0.05) and VEGF production (p < 0.05) than either Balance or stay.safe. New-generation PDFs with physiological pH and lower GDP levels, especially if bicarbonate-buffered (bicaVera), have fewer in vitro toxic effects on mesothelial cells and may contribute to peritoneal preservation, thus improving long-term treatment of PD patients.

Novel Role for Mast Cells in Omental Tissue Remodeling and Cell Recruitment in Experimental Peritoneal Dialysis

Because of its dynamic structure, the omentum plays a key role in the immunity of the peritoneal cavity by orchestrating peritoneal cell recruitment. Because mast cells accumulate in the omentum upon experimental peritoneal dialysis (PD) and may produce angiogenic/profibrotic factors, it was hypothesized that mast cells mediate omental tissue remodeling during PD. Daily treatment with conventional PD fluid (PDF) for 5 wk resulted in a strong omental remodeling response, characterized by an approximately 10-fold increase in mast cell density (P < 0.01), an approximately 20-fold increase in vessel density (P < 0.02), an approximately 20-fold increase in the number of milky spots (P < 0.01), and a four-fold increase in submesothelial matrix thickness (P < 0.0003) in wild-type rats. In contrast, all PDF-induced omental changes were significantly reduced in mast cell-deficient Ws/Ws rats or in wild-type rats that were treated orally with a mast cell stabilizer cromoglycate. A time-course experiment showed mast cell accumulation immediately before the formation of blood vessels and milky spots. Functionally, PDF evoked a peritoneal cell influx, which was significantly reduced in Ws/Ws rats (P < 0.04) and in wild-type rats that were treated with cromoglycate (P < 0.03). Cromoglycate treatment also completely prevented PDF-induced omental adhesions to the catheter tip (P = 0.0002). Mesothelial damage, angiogenesis, and fibrosis of mesentery and parietal peritoneum as well as glucose absorption rate and ultrafiltration capacity proved to be mast cell independent. Data strongly support the hypothesis that mast cells mediate PDF-induced omental tissue remodeling and, subsequently, peritoneal cell influx and adhesion formation, providing therapeutic possibilities of modulating omental function.

Clinical biocompatibility of a neutral peritoneal dialysis solution with minimal glucose-degradation products--A 1-year randomized control trial

Chronic utilization of a bio-incompatible peritoneal dialysis (PD) solution with acidic pH and a high content of glucose degradation product (GDP) has been implicated as a contributing cause of peritoneal failure. We compared a newly formulated solution of neutral pH and low levels of GDP to a standard PD solution. Fifty new PD patients were randomized to a conventional lactate-buffered fluid (control) and a pH neutral, lactate-buffered, low GDP solution (balance). Patients were followed for 12 months. Serum samples were assayed for C-reactive protein (CRP). PD effluent was collected and assayed for cancer antigen-125 (CA125) and hyaluronan (HA). Clinical end points were the residual renal function and dialysis adequacy indices. After 52 weeks of treatment, PD fluid CA125 rose from 2.45 +/- 0.96 to 14.30 +/- 2.17 U/ml (P < 0.001), and HA declined from 2.26 +/- 0.60 to 1.45 +/- 0.32 mug/ml (P = 0.07) in the balance group. The balance group had a higher PD fluid CA-125 (14.30 +/- 2.17 vs 7.36 +/- 2.23 U/ml, P = 0.007), lower HA (1.45 +/- 0.32 vs 2.55 +/- 0.32 mug/ml, P = 0.007), and lower serum CRP level (1.77 +/- 0.42 vs 7.73 +/- 2.42 mg/l, P = 0.026) than the control group at 52 weeks. There was no difference in dialysis adequacy indices, ultrafiltration volume, urine output, residual renal function, peritonitis rate or need of hospitalization in 1 year. As compared to conventional PD solution, the use of balance, a neutral pH, low GDP solution resulted in a superior profile of PDE mesothelial cell marker and a lower degree of systemic inflammation, and the difference was maintained for 1 year. It remains to be determined whether these effects could result in better long-term clinical outcome.

Biocompatibility of Peritoneal Dialysis Fluid and Influence of Compositions on Peritoneal Fibrosis

Conventional peritoneal dialysis fluid (PDF) is a bioincompatible solution because of several components. These unphysiological compositions might contribute to the development of peritoneal fibrosis. In the present overview we summarize the influence of each composition of PDF (acidic pH, high concentration of glucose and glucose degradation products; advanced glycation end-products and lactate) on the peritoneal fibrotic changes in long peritoneal dialysis (PD) patients. We also summarized the report of new approaches to the prevention of peritoneal fibrosis in Japan.

Oxidative stress during peritoneal dialysis: Implications in functional and structural changes in the membrane

Progressive peritoneal fibrosis, membrane hyperpermeability, and ultrafiltration failure have been observed in patients on long-term peritoneal dialysis (PD). The present study tested the hypothesis that reactive oxygen species (ROS) generated by conventional PD solution (PDS) mediate functional and structural alterations of peritoneal membrane in vivo. Sprague-Dawley rats were randomized to control, PDS, PDS with an antioxidant, and PDS with an angiotensin II (Ang II) receptor blocker. Commercial PDS containing 3.86% glucose (20-30 ml) with or without N-acetylcystein (NAC) 10 mM or losartan 5 mg/kg was administered intraperitoneally twice a day for 12 weeks. Control rats received sham injection. Rats treated with PDS had significantly lower drain volume and D(4)/D(0) glucose, but higher D(4)/P(4) creatinine and increased membrane thickness and endothelial NOS (eNOS) expression compared to control rats. Omental transforming growth factor (TGF)-beta1, vascular endothelial growth factor (VEGF), collagen I, and heat-shock protein (hsp) 47 expression and lipid peroxide levels and dialysate VEGF and Ang II concentrations were significantly increased in rats treated with PDS compared to control. All of these changes were prevented by both NAC and losartan. In conclusion, the present study demonstrates that ROS generated by conventional PDS are, in large part, responsible for peritoneal fibrosis and membrane hyperpermeability. We suggest that antioxidants or Ang II receptor blockers may allow better preservation of the structural and functional integrity of the peritoneal membrane during long-term PD.

Peritoneal Injury by Methylglyoxal in Peritoneal Dialysis

Peritonealdialysis (PD) is a common treatment for patients with reduced or absent renal function. Long-term PD leads to peritoneal injury with structural changes and functional decline, such as ultrafiltration loss. At worst, peritoneal injury leads to encapsulating peritoneal sclerosis, a serious complication of PD. Glucose degradation products contained in PD fluids contribute to the bioincompatibility of conventional PD fluids. Methylglyoxal (MGO) is an extremely toxic glucose degradation product. The present study examined the injurious effect of MGO on peritoneum in vivo. Male Sprague-Dawley rats (n = 6) were administered PD fluids (pH 5.0) containing 0, 0.66, 2, 6.6, or 20 mmol/L MGO every day for 21 days. On day 22, peritoneal function was estimated by the peritoneal equilibration test. Drained dialysate was analyzed for type IV collagen-7S, matrix metalloproteinase (MMP), and vascular endothelial growth factor (VEGF). Histological analysis was also performed. In rats receiving PD fluids containing more than 0.66 mmol/L MGO, peritoneal function decreased significantly and levels of type IV collagen-7S and MMP-2 in drained dialysate increased significantly. In the 20-mmol/L MGO-treated rats, loss of body weight, expression of VEGF, thickening of the peritoneum, and formation of abdominal cocoon were induced. MMP-2 and VEGF were produced by infiltrating cells in the peritoneum. Type IV collagen was detected in basement membrane of microvessels. MGO induced not only peritoneal injury but also abdominal cocoon formation in vivo. The decline of peritoneal function may result from reconstitution of microvessel basement membrane or neovascularization.

The Role of the Glyoxalase Pathway in Reducing Mesothelial Toxicity of Glucose Degradation Products

The glucose degradation products (GDP) presentin conventional peritoneal dialysis fluids (PDF) may exert adverse effects toward human peritoneal mesothelial cells (HPMC). Some GDP can be detoxified by the glyoxalase/ glutathione pathway. It has been shown that the addition of glyoxalase I (GLO-I) and reduced glutathione (GSH) to PDF effectively eliminates GDP. We have therefore examined the GLO-I/GSH system in HPMC and assessed the impact of GLO-I/ GSH-treated PDF on the viability and function of HPMC. Heat-sterilized PDF (H-PDF) was incubated in the presence or absence of GLO-I and GSH for 1 hour at 37 degrees C, and then mixed with an equal volume of serum-free M199 medium and applied to HPMCin culture. After 24 hours, HPMC were assessed for viability, the release of interleukin-6, GLO-I activity, and cellular glutathione. The effects were compared to those exerted by filter-sterilized PDF (F-PDF), which was devoid of GDP. Exposure of HPMC to H-PDF resulted in reduced GLO-I activity, GSH depletion, and a decrease in cell viability. Pretreatment of H-PDF with either a combination of GLO-I and GSH or GSH alone markedly reduced inhibitory effects of H-PDF toward HPMC, as measured by cell viability and inter-Leukin-6 generation. Exposure of HPMC to the GSH precursor L-2-oxothiazolidine-carboxylic acid increased cellular GSH and prevented the loss of GLO-I activity in response to H-PDF. Exposure to conventional GDP-rich PDF impairs the activity of the glyoxalase/glutathione system in HPMC. Pretreatment of PDF with GSH or replenishment of cellular GSH protects HPMC against GDP-mediated toxicity.

Improved biocompatibility of bicarbonate/lactate-buffered PDF is not related to pH

Chronic exposure to conventional peritoneal dialysis fluid (PDF) is associated with functional and structural alterations of the peritoneal membrane. The bioincompatibility of conventional PDF can be due to hypertonicity, high glucose concentration, lactate buffering system, presence of glucose degradation products (GDPs) and/or acidic pH. Although various investigators have studied the sole effects of hyperosmolarity, high glucose, GDPs and lactate buffer in experimental PD, less attention has been paid to the chronic impact of low pH in vivo. Rats received daily 10 ml of either conventional lactate-buffered PDF (pH 5.2; n=7), a standard bicarbonate/lactate-buffered PDF with physiological pH (n=8), bicarbonate/lactate-buffered PDF with acidic pH (adjusted to pH 5.2 with 1 N hydrochloride, n=5), or bicarbonate/lactate buffer, without glucose, pH 7.4 (n=7). Fluids were instilled via peritoneal catheters connected to implanted subcutaneous mini vascular access ports for 8 weeks. Control animals with or without peritoneal catheters served as control groups (n=8/group). Various functional (2 h PET) and morphological/cellular parameters were analyzed. Compared with control groups and the buffer group, conventional lactate-buffered PDF induced a number of morphological/cellular changes, including angiogenesis and fibrosis in various peritoneal tissues (all parameters P<0.05), accompanied by increased glucose absorption and reduced ultrafiltration capacity. Daily exposure to standard or acidified bicarbonate/lactate-buffered PDF improved the performance of the peritoneal membrane, evidenced by reduced new vessel formation in omentum (P<0.02) and parietal peritoneum (P<0.008), reduced fibrosis (P<0.02) and improved ultrafiltration capacity. No significant differences were found between standard and acidified bicarbonate/lactate-buffered PDF. During PET, acidic PDF was neutralized within 15 to 20 min. The bicarbonate/lactate-buffered PDF, acidity per se did not contribute substantially to peritoneal worsening in our in vivo model for PD, which might be explained by the buffering capacity of the peritoneum.