A randomized clinical trial with a 0.6% amino acid/ 1.4% glycerol peritoneal dialysis solution.

BACKGROUND: Glucose is an accepted osmotic agent for peritoneal dialysis (PD) although it has several drawbacks. Some of these drawbacks have been addressed by the introduction of solutions with low glucose degradation products and physiological pH in dual-chambered bags. Despite this achievement, there is a need for alternative osmotic agents.This randomized clinical trial analyzes 3-month's clinical experience with a mixture of 0.6% amino acids and 1.4% glycerol. METHODS: The study was performed at the renal units of the University Hospitals Ghent, Belgium, and Utrecht, The Netherlands. Stable PD patients were randomized for either protocol A (test solution, n = 5) or protocol B (control regimen, n = 5). In both protocols, there was a run-in phase of 1 month with a dialysis regimen of 2 x 2 L 2.27% glucose solution (Dianeal; Baxter, Nivelles, Belgium), 1 x 2 L Extraneal (Baxter), and 1 x 2 L glucose solution (Dianeal). After this month-long run-in period, patients in group A received during 3 months 2 x 2 L amino acid/glycerol solution, 1 x 2 L Extraneal, and at least 1 x 2 L of a classic glucose solution. RESULTS: Glucose absorption decreased in the test group during the test phase (from 84.2 +/- 8.7 to 11.7 +/- 11.6 g/24 hours, p = 0.001). Dialysate levels of cancer antigen 125 (CA125) increased in the test group, from 17.5 +/- 11.0 to 32.4 +/- 4.6 units/L (p = 0.04), whereas, in the control group, the levels remained stable (15.5 +/- 8.7 and 14.9 +/- 9.8 units/L respectively, p = 0.4). There were no differences in serum urea, serum bicarbonate, serum osmolarity, serum albumin, or parameters related to skin-fold thickness or serum glycerol levels between control and test solutions. No differences were observed in obtained ultrafiltration after a 4-hour dwell with 2.27% glucose or the test solution, both measured at week 4 of the run-in period and week 12 of the test period. CONCLUSION: This study demonstrated that the use of a new 0.6% amino acid/1.4% glycerol-containing dialysis solution is safe and well tolerated. Glucose load was reduced significantly and dialysate CA125 levels improved significantly. Ultrafiltration was comparable with that of a 2.27% glucose solution. All these factors, in combination with the potential nutritional benefits, can contribute to a beneficial impact on the success of the PD technique. Further long-term studies in larger patient groups are warranted to explore the potential of this promising new solution.

Peritoneal dialysis solutions inhibit the differentiation and maturation of human monocyte-derived dendritic cells: effect of lactate and glucose-degradation products.

Peritoneal dialysis (PD) is a well-established therapy for end-stage renal failure, but its efficiency is limited by recurrent peritonitis. As PD solutions impair local inflammatory responses within the peritoneal cavity, we have analyzed their influence on the in vitro maturation of human monocyte-derived dendritic cells (MDDC). Evaluation of MDDC maturation parameters [expression of adhesion and costimulatory molecules, receptor-mediated endocytosis, allogeneic T cell activation, production of tumor necrosis factor alpha, interleukin (IL)-6 and IL-12 p70, and nuclear factor (NF)-kappaB activation] revealed that currently used PD solutions differentially inhibit the lipopolysaccharide (LPS)-induced maturation of MDDC, an inhibition that correlated with their ability to impair the LPS-stimulated NF-kappaB activation. Evaluation of PD components revealed that sodium lactate and glucose-degradation products impaired the acquisition of maturation parameters and NF-kappaB activation in a dose-dependent manner. Moreover, PD solutions impaired monocyte-MDDC differentiation, inhibiting the acquisition of DC markers such as CD1a and DC-specific intercellular adhesion molecule-3 grabbing nonintegrin (CD209). These findings have important implications for the initiation of immune responses under high lactate conditions, such as those occurring within tumor tissues or after macrophage activation.

The in vitro biocompatibility performance of a 25 mmol/L bicarbonate/10 mmol/L lactate-buffered peritoneal dialysis fluid.

UNLABELLED: The in vitro biocompatibility performance of a 25 mmol/L bicarbonate/10 mmol/L lactate-buffered peritoneal dialysis fluid. BACKGROUND: The biocompatibility profile of a new peritoneal dialysis (PD) solution (Physioneal 35) was determined using a selection of in vitro assay systems. Physioneal 35 is buffered by a combination of 25 mmol/L bicarbonate and 10 mmol/L lactate, thereby providing a solution with a total of 35 mmol/L of alkali to complement the currently available 25 mmol/L bicarbonate and 15 mmol/L lactate combination solution, Physioneal 40. In addition, the new solution contains a calcium concentration of 1.75 mmol/L rather than 1.25 mmol/L present in Physioneal 40. Physioneal 35 and 40 are manufactured in double chamber bag systems that permit separation of glucose from the buffer during sterilization. When the two chambers are mixed just before patient use, the resulting solution has a neutral pH and reduced glucose degradation content. Physioneal 35 was evaluated for its cytotoxicity potential using a murine fibroblast assay, its acute effect on human neutrophil and human peritoneal mesothelial cell function, and its in vitro potential to form advanced glycation end products (AGE). The biocompatibility characteristics of this new formulation were compared with that of a conventional, lactate-based solution and to that of its parent formulation, Physioneal 40. METHODS: Proliferation of murine fibroblasts was determined after exposure to dialysis fluids for 72 hours. Cell viability was assayed by the ability to take up neutral red dye. Human neutrophils were exposed for 15 minutes to dialysis fluids, and their ATP content and phorbol 12-myristate 13-acetate (PMA) stimulated chemiluminescence response was determined as a measure of viability and respiratory burst activity, respectively. Cellular interleukin (IL)-1beta-driven IL-8 synthesis by human mesothelial cells following acute exposure to dialysis fluids was also assessed. Advanced glycation end product formation in the dialysis fluids was measured after 5 and 20 days of incubation with human serum albumin (HSA) as the model protein. RESULTS: In all assays employed, the biocompatibility profile of Physioneal 35 was similar to that of the Physioneal 40 parent formulation. Physioneal 35 showed a significant improvement in biocompatibility performance compared to a pH neutralized conventional lactate-buffered peritoneal dialysis solution in the murine fibroblast assay. In the acute exposure assays, human neutrophil viability and respiratory burst were significantly improved compared with the acidic, conventional solution; however, no statistically significant improvement were seen in mesothelial cells. AGE formation, which is thought to be an important mechanism by which glucose and glucose degradation products cause structural and functional changes of the peritoneal membrane, was significantly lower in Physioneal 35 compared with the conventional dialysis solution. CONCLUSION: The biocompatibility profile of Physioneal 35 was similar to that of the original Physioneal 40 bicarbonate/ lactate-buffered dialysis solution, confirming that differences in both buffer content and calcium concentration do not affect biocompatibility performance. Both bicarbonate/lactate formulations (Physioneal 35 and Physioneal 40) were more biocompatible than a conventional lactate-buffered dialysis solution in this in vitro biocompatibility assessment.

Continuous dialysis with bicarbonate/lactate-buffered peritoneal dialysis fluids results in a long-term improvement in ex vivo peritoneal macrophage function.

To circumvent the potentially negative consequences of long-term exposure to unphysiologic acidic lactate-buffered peritoneal dialysis fluids (PDF), neutral pH solutions buffered with bicarbonate/lactate have recently been introduced in phase 2 and 3 clinical trials. This study examines the longitudinal changes in peritoneal macrophage (PMØ) function in patients dialyzed continuously with either lactate (LPD; 40 mM lactate, pH 5.2)-buffered or bicarbonate/lactate (TBL; 25 mM/15 mM bicarbonate/lactate, pH 7.3)-buffered PDF. Before the study, during the run in period of a phase 3 clinical trial, all patients had been taking LPD for at least the previous 18 wk. At the beginning of the study (day 0), both constitutive and serum-treated zymosan (STZ) stimulated tumor necrosis factor alpha (TNF-alpha) synthesis were assessed in PMØ isolated from 12-h dwell effluent (with 1.36% glucose) in all patients. The patients were subsequently randomized to either continuous TBL or LPD therapy and PMØ function was assessed after further 3- and 6-mo periods in all patients. At all time points measured STZ induced a dose-dependent increase in PMØ TNF-alpha secretion (P = 0.043 versus control for doses greater than 100 microg/ml). In patients continuously dialyzed with LPD, constitutive PMØ TNF-alpha synthesis levels (mean +/- SEM, pg/10(6) PMØ per18 h, n = 5 patients) were 154 +/- 65, 261 +/- 60, and 101 +/- 99 at 0, 3, and 6 mo, respectively. Stimulated STZ (1000 microg/ml) levels were 1340 +/- 519, 1046 +/- 586, and 758 +/- 250 at 0, 3, and 6 mo, respectively. In patients dialyzed with TBL, constitutive PMØ TNF-alpha synthesis levels (pg/10(6) PMØ per 18 h, n = 5 patients) were 300 +/- 136, 106 +/- 35, and 213 +/- 62 at 0, 3, and 6 mo, respectively. Stimulated STZ (1000 microg/ml) levels were 1969 +/- 751, 1541 +/- 330, and 2670 +/- 671 at 0, 3, and 6 mo, respectively. At 6 mo, STZ-stimulated PMØ TNF-alpha synthesis was significantly higher in patients treated with TBL compared with those treated with LPD (P = 0.0035). These data suggest that in patients continuously dialyzed with a neutral pH solution, there is a long-term improvement in PMØ function compared with patients on conventional therapy. Better PMØ function suggests improved host defense status and may affect the peritoneum's susceptibility to infection and potentially reduce the negative consequences of repeated intraperitoneal inflammation on long-term membrane function.

Better preservation of peritoneal morphologic features and defense in rats after long-term exposure to a bicarbonate/lactate-buffered solution.

The long-term effects of a standard lactate-buffered dialysis fluid and a new, two-chamber, bicarbonate/lactate-buffered dialysis fluid (with fewer glucose degradation products and a neutral pH) were compared in an in vivo peritoneal exposure model. Rats were given daily injections, via an access port, of 10 ml of standard solution or bicarbonate/lactate-buffered solution for 9 to 10 wk. The omentum, peritoneum, and mesothelial cell layer were screened for morphologic changes. In addition, the bacterial clearing capacity of the peritoneal cells was studied. Significantly more milky spots and blood vessels were observed in the omenta of animals treated with standard solution (P < 0.03 for both parameters). Electron-microscopic analysis demonstrated dramatic changes in the appearance of the vascular endothelial cells of the milky spots and a severely damaged or even absent mesothelium on the peritoneal membrane of the standard solution-treated animals. In contrast, the mesothelium was still present in the bicarbonate/lactate-buffered solution group, although the cells lost microvilli. Both peritoneal dialysis fluids significantly increased the density of mesothelial cells (per square millimeter) on the surface of the liver and the thickness of the submesothelial extracellular matrix of the peritoneum (both P < 0.04 for both fluids versus control). A significantly better ex vivo bacterial clearing capacity was observed with peritoneal cells from the bicarbonate/lactate-buffered solution group, compared with the standard solution group (P < 0.05 in both experiments). These results demonstrate that instillation of bicarbonate/lactate-buffered solution into rats for 9 to 10 wk preserves both morphologic and immune parameters much more effectively, compared with standard solution. These findings may be of considerable clinical importance.