By Asher Mendelson MD, Critical Care and Medical Biophysics
ISPD 2018 Scientific Committee member, and chair, Basic Science Pre-course
The PD community has always had an interesting relationship with glucose.
As a trusted friend, this molecule underpins the essential physiology that makes PD possible – osmotic pressure gradient across the peritoneal membrane. Moreover, glucose is safe (in the classic toxicology sense of the word), abundant, and straightforward to manufacture which makes it easy to understand why glucose has been the osmotic workhorse of PD for over fifty years. Yet as a reviled scourge, this very same substance induces long-term inflammation and damage to the peritoneal membrane thereby rendering itself progressively less efficacious as an osmotic agent. What’s more, daily exposure to glucose exacerbates many of the metabolic comorbidities already burdening patients with ESRD.
None of this is new information to most people reading this editorial. PD clinicians and scientists have long acknowledged the deleterious effects of glucose-based PD therapy and the need to limit daily exposure. At the same time, we also recognize that no alternative osmotic agent has ever fulfilled the necessary criteria to enable removal of glucose from a PD prescription. Glucose is the devil we know, but is it forever here to stay?
In 2009, I was a rotating medical intern in Vancouver when I first learned about peritoneal dialysis and the glucose dilemma. I was fascinated by this dialysis modality and immediately captivated by the work of Professor Bengt Rippe and the physiology of the three pore model. With naive enthusiasm, I approached Dr. Jay Kizhakkedathu, polymer chemist and UBC professor, to outline the problem. “Let’s just replace glucose with something synthetic,” I said, “but it still needs to work. Also, it would be nice if it wasn’t toxic.” Serendipitously, Jay had a molecule in mind that might just do the trick.
Shortly thereafter, our Vancouver PD Research Group began designing hyperbranched polyglycerol (HPG) as a novel synthetic osmotic agent for use in PD. Most of the alternative osmotic agents under investigation (such as dextrose polymer, amino acids, and carnitine) have established metabolic pathways and safety profiles that allowed their rapid transition to human PD trials for efficacy and biocompatibility. By contrast, designing a synthetic osmotic agent necessitates deliberate consideration in order to meet the fundamental requirements of PD therapy.
In our first proof-of-concept experiments, we showed that HPG could achieve UF and solute clearance in an acute rodent model of PD without causing serious harm to the peritoneal membrane (1). Next, we looked to expand our understanding of how HPG functions as an osmotic agent by evaluating the UF profile of varying sizes of HPG over both shorter and longer dwell times (2). Similar to the peritoneal kinetics described theoretically by Professor Rippe with the three pore model (3), we found that HPGs with molecular weight 1 kDa and 3 kDa struck a good balance which maximized their osmotic capacity. These molecules were small enough to create a hyperosmolar PD solution without a prohibitive %wt in solution, but also large enough to possess a reflection coefficient that keeps them in the peritoneal cavity. In our animal model of PD, these characteristics allow HPG to produce both early and sustained UF for up to 8 hours (similar to the kinetics of a bimodal solution). Importantly, because most UF was likely occurring across small pores in the peritoneal membrane, HPG also achieved more sodium removal for each dwell when compared to conventional glucose-based PD solutions that rely substantially on UF from aquaporins.
We then turned to address the question of long-term impact on the peritoneal membrane with a 12-week rodent model of daily IP exposure (4). We demonstrated that when compared to neutral pH, low-GDP PD solution, HPG solution induced less inflammation, less neoangiogenesis, and better preservation of peritoneal structure and function. These findings were consistent across the multiple modalities we used to evaluate the peritoneal membrane, including histology, immunohistochemistry, UF capacity, and transcriptome analysis.
Most recently, in partnership with The Centre for Drug Research and Development, we have begun answering some of the key questions related to absorption, metabolism, and excretion of HPG that will enable us to bring this technology to the PD clinic. Interestingly, the modest increase in molecular weight of HPG from 1 kDa to 3 kDa significantly decreases the absorption of HPG across the rodent peritoneal membrane (unpublished data). Moreover, our group is developing new animal models of ESRD which are essential to delineate the excretion pathways of HPG when renal function is non-existent.
In summary, this project has taught me much about the incremental nature of scientific development and the need to stay focused on a long-term goal. I believe the PD community should find the ongoing use of glucose-based PD therapy strongly undesirable, and work collectively to develop a replacement. As with all forms of drug discovery, I feel we should be exploring various candidate compounds in parallel; only then can we ensure a novel solution will come along that can change the lives of PD patients around the world. I look forward to sharing our work with you at ISPD 2018 in Vancouver.
COI: Asher Mendelson is co-inventor of a patent application relating to HPG PD solution
1. Mendelson AA, Q Guan, et al. Hyperbranched polyglycerol is an efficacious and biocompatible novel osmotic agent in a rodent model of peritoneal dialysis. Perit Dial Int. 2013 Jan;33(1):15-27.
2. Du C, Mendelson AA, et al. The size-dependent efficacy and biocompatibility of hyperbranched polyglycerol in peritoneal dialysis. Biomaterials 2014 Feb;35(5):1378-89.
3. Rippe B, Zakaria el R, Carlsson O. Theoretical analysis of osmotic agents in peritoneal dialysis. What size is an ideal osmotic agent? Perit Dial Int 1996;16(Suppl. 1):S97-103.
4. Du C, Mendelson AA, et al. Hyperbranched polyglycerol is superior to glucose for long-term preservation of peritoneal membrane in a rat model of chronic peritoneal dialysis. J Transl Med. 2016 Dec 13;14(1):338