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Evaluation of hyperbranched polyglycerol as a novel osmotic agent for use in peritoneal dialysis.

University of British Columbia

Peritoneal Dialysis (PD) is an effective method of renal replacement therapy for patients with end-stage renal disease. PD solution is instilled into the peritoneal cavity and water, solutes, and waste products are removed across the peritoneal membrane, which serves as a natural filter between the peritoneal cavity and the bloodstream. The current conventional PD solution uses hypertonic glucose as an osmotic agent to remove water – a process termed ultrafiltration (UF). Although effective, chronic daily exposure to glucose causes systemic metabolic complications for PD patients; it also directly damages the peritoneal membrane and eventually causes the filter to fail. Hyperbranched Polyglycerol (HPG) is a non-toxic, non-immunogenic synthetic polymer that contains no starch or glucose. HPG has shown very limited organ accumulation after intravenous injection. HPG offers many theoretical advantages over glucose-based PD including the ability to synthesize HPG over a range of molecular weights. This current thesis tests HPG as a glucose-sparing osmotic agent in PD solution. We used a rodent model of PD to evaluate solute and waste removal, ultrafiltration, and peritoneal biocompatibility over 0-8 hours of peritoneal exposure. We compared HPG solutions of molecular weights 0.5, 1, and 3 kDa with conventional glucose-based solution (Dianeal™ 2.5%) and buffered glucose-based solution (Physioneal™ 2.27%). We demonstrated that HPG solutions can induce superior and sustained UF for 8 hours, in contrast to glucose-based solutions that lose UF capacity after 4 hours. Sodium and urea removal was superior for HPG solutions, in part because HPG polymer acts as a colloid - as opposed to crystalloid - osmotic agent. We used neutrophil infiltration and peritoneal mesothelial cell detachment as markers of biocompatibility. We found that HPG solutions, particularly lower molecular weight polymers, demonstrate superior biocompatibility profiles when compared to glucose-based PD solutions. Taken together, these experiments support the proof-of concept of HPG as a promising novel osmotic agent in PD. Future studies are required to investigate the chronic effects of HPG exposure on the peritoneal membrane, as well as the metabolic and pharmacokinetic profiles of HPG PD solutions.

Text

2013-09-17

CC0 1.0 Universal

http://hdl.handle.net/2429/45077

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/publicdomain/zero/1.0/