Hyperbranched Polyglycerol Is an Efficacious and Biocompatible Novel Osmotic Agent in a Rodent Model of Peritoneal Dialysis

♦ Objectives: To enhance the effectiveness of peritoneal dialysis (PD), new biocompatible PD solutions may be needed. The present study was designed to test the efficacy and biocompatibility of hyperbranched polyglycerol (HPG)—a nontoxic, nonimmunogenic water-soluble polyether polymer—in PD.♦ Methods: Adult Sprague-Dawley rats were instilled with 30 mL HPG solution (molecular weight 3 kDa; 2.5% - 15%) or control glucose PD solution (2.5% Dianeal: Baxter Healthcare Corporation, Deerfield, IL, USA), and intraperitoneal fluid was recovered after 4 hours. Peritoneal injury and cellular infiltration were determined by histologic and flow cytometric analysis. Human peritoneal mesothelial cells were assessed for viability in vitro after 3 hours of PD fluid exposure.♦ Results: The 15% HPG solution achieved a 4-hour dose-related ultrafiltration up to 43.33 ± 5.24 mL and a dose-related urea clearance up to 39.17 ± 5.21 mL, results that were superior to those with control PD solution (p < 0.05). The dialysate-to-plasma (D/P) ratios of urea with 7.5% and 15% HPG solution were not statistically different from those with control PD solution. Compared with fluid recovered from the control group, fluid recovered from the HPG group contained proportionally fewer neutrophils (3.63% ± 0.87% vs 9.31% ± 2.89%, p < 0.0001). Detachment of mesothelial cells positive for human bone marrow endothelial protein 1 did not increase in the HPG group compared with the stain control (p = 0.1832), but it was elevated in the control PD solution group (1.62% ± 0.68% vs 0.41% ± 0.31%, p = 0.0031). Peritoneal biopsies from animals in the HPG PD group, compared with those from control PD animals, demonstrated less neutrophilic infiltration and reduced thickness. Human peritoneal mesothelial cell survival after HPG exposure was superior in vitro (p < 0.0001, 7.5% HPG vs control; p < 0.01, 15% HPG vs control). Exposure to glucose PD solution induced cytoplasmic vacuolation and caspase 3-independent necrotic cell death that was not seen with HPG solution.♦ Conclusions: Our novel HPG PD solution demonstrated effective ultrafiltration and waste removal with reduced peritoneal injury in a rodent model of PD.Key words: Peritoneal dialysis solution, biocompatibility, hyperbranched polyglycerol, preclinical studyPeritoneal dialysis (PD) is a simple and safe renal replacement therapy (1-4) that currently constitutes 0% - 70% of national dialysis programs worldwide (5). To date, glucose remains the most common osmotic agent in commercial PD solutions, although other osmotic agents such as amino acids and glucose polymer (icodextrin) are available. A high level of glucose in PD solution has been documented to be associated with many systemic and locoregional health complications for PD patients. Daily exposure to glucose can cause hyperglycemia, hyperinsulinemia, obesity, and exacerbation of diabetes mellitus (6). Moreover, long-term exposure to glucose and glucose degradation products has been shown to directly damage the peritoneal membrane, leading to abnormal mesothelial transformation, maladaptive angiogenesis, and ultrafiltration (UF) failure (7-9). Thus, PD may become less effective over time or lead to metabolic complications that are not favorable over the long term, thereby adversely affecting both PD duration and mortality. New biocompatible PD solutions that address some of these unwanted complications are needed.Hyperbranched polyglycerol (HPG) is a compact, branched, and highly water-soluble polyether polymer (Figure 1) synthesized by single-step, multi-branching, ring-opening polymerization of glycidol under slow monomer addition (10). Hyperbranched polyglycerol can be precisely synthesized over a wide range of molecular weights and is chemically stable as a narrow distributed polymer in aqueous solution (11-13). It is highly hydrophilic and water-soluble (>400 mg/mL), with a very low intrinsic viscosity (4 - 7 mL g^-1), and therefore large amounts of the polymer can easily be dissolved in water (13,14). It also has multiple hydroxyl groups per molecule of polymer and exists at physiologic pH in aqueous solution (14). In experimental studies, we demonstrated that HPG and its derivative molecules are highly blood-compatible, nonimmunogenic, and nontoxic (14-17). Unlike other polymers, HPG has been shown to have very limited organ accumulation after intravenous injection (14,18). It does not activate the platelet, coagulation, or complement systems (14). Taken together, these properties make HPG a promising candidate for use as an osmotic agent in PD.Open in a separate windowFigure 1— Chemical structure of hyperbranched polyglycerol.