Efficacy and Safety of Expanded Hemodialysis with the Theranova 400 Dialyzer: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Expanded hemodialysis therapy enabled by medium cut-off membranes may promote greater clearance of larger middle molecules that comprise putative uremic solutes than conventional high-flux dialysis. This randomized trial evaluated the efficacy and safety of hemodialysis treatment with a medium cut-off dialyzer. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Clinically stable patients on maintenance hemodialysis were randomized to receive dialysis with either a medium cut-off dialyzer (Theranova 400) or a high-flux dialyzer (Elisio-17H) over 24 weeks of treatment. The primary safety end point was the predialysis serum albumin level after 24 weeks of treatment. The primary efficacy end point was the reduction ratio of free λ light chains at 24 weeks of treatment. RESULTS: Among 172 patients on maintenance hemodialysis, mean age was 59±13 years, 61% were men, 40% were Black, and mean dialysis vintage was 5±4 years. Of the 86 patients randomized to each dialyzer, 65 completed the trial in each group. The reduction ratio for the removal of free λ light chains was significantly higher in the Theranova 400 group compared with the Elisio-17H group after 4 weeks (39% versus 20%) and 24 weeks (33% versus 17%; both P<0.001). Among secondary end points, the Theranova 400 group demonstrated significantly larger reduction ratios at 4 and 24 weeks for complement factor D, free κ light chains, TNFα, and ß2-microglobulin (P<0.001 for all), but not for IL-6. Predialysis serum albumin levels were similar between groups after 24 weeks (4 g/dl with the Theranova 400 and 4.1 g/dl with the Elisio-17H), consistent with noninferiority of the Theranova 400 dialyzer in maintaining predialysis serum albumin levels after 24 weeks of treatment. CONCLUSIONS: Hemodialysis therapy with the Theranova 400 dialyzer provides superior removal of larger middle molecules, as exemplified by free λ light chains, compared with a similar size high-flux dialyzer, while maintaining serum albumin level. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: A Multi-Center, Prospective, Randomized, Controlled, Open-Label, Parallel Study to Evaluate the Safety and Efficacy of the Theranova 400 Dialyzer in End Stage Renal Disease (ESRD) Patients, NCT03257410.

Effects of intraperitoneal hyaluronan on peritoneal fluid and solute transport in peritoneal dialysis patients.

BACKGROUND: Hyaluronan (HA) is a glycosaminoglycan found in connective tissues and tissue spaces, including the peritoneal cavity. In vivo studies in a rat model of peritoneal dialysis (PD) have shown that addition of HA to PD solution during an intraperitoneal dwell can alter peritoneal fluid transport and protect the peritoneal membrane from the effects of inflammation and repeated infusions of dialysis solution. The current study sought to evaluate the safety of intraperitoneal HA and its effect on peritoneal fluid and solute transport when administered during a dialysis dwell in humans. METHODS: 13 PD patients were enrolled in a prospective, randomized crossover study involving three dialysis treatments using the following PD solutions: (1) a commercially available PD solution (Dianeal PD-4, 1.36% glucose; Baxter Healthcare Corporation, Alliston, Ontario, Canada); (2) Dianeal PD-4 containing 0.1 g/L HA, and (3) Dianeal PD-4 containing 0.5 g/L HA. Each 6-hour dialysis exchange was separated from the other exchanges by a 2-week washout period. Radioiodinated human serum albumin (RISA) was administered with the dialysis solution to evaluate intraperitoneal volume, net ultrafiltration (UF), and fluid reabsorption. Peritoneal clearances, dialysate/plasma ratios (D/P), and mass transfer area coefficients (MTACs) were determined for sodium, urea, creatinine, albumin, and glucose. Safety was evaluated by monitoring adverse events and changes in serum chemistries. Ten patients completed all three dialysis exchanges and two additional patients completed at least one treatment exchange. RESULTS: There were no reported adverse events related to HA administration and no significant changes in serum chemistries. There were no significant differences in net UF or peritoneal volume profiles among the three treatments. Mean net UF calculated using residual volumes, estimated by RISA dilution, tended to be slightly higher during treatment with solution containing 0.1 g/L HA and 0.5 g/L HA [74 +/- 86 (SE) and 41 +/- 99 mL, respectively] compared to control treatment (-58 +/- 129 mL). Although not statistically significant, there was a trend toward decreased fluid reabsorption during treatment with HA. Solute clearances, D/P ratios, and MTACs were similar for the three treatments. Serum levels of HA were also unaffected by the two treatment solutions. CONCLUSIONS: These data support the acute safety of HA when administered intraperitoneally with the dialysis solution to PD patients. Due to the small sample size and variability in net UF and fluid reabsorption, statistically significant differences were not demonstrated for these parameters. However, a trend toward decreased fluid reabsorption was observed, suggesting that HA may act by a mechanism similar to that observed in animal studies. Further studies are necessary to evaluate whether the beneficial effects of HA observed in animal studies can be shown in humans.

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.