Biocompatible Peritoneal Dialysis: The Target Is Still Way Off

Abstract

Peritoneal dialysis (PD) is a cost-effective, home-based therapy for patients with end-stage renal disease achieving similar outcome as compared to hemodialysis. Still, a minority of patients only receive PD. To a significant extend, this discrepancy is explained by major limitations regarding PD efficiency and sustainability. Due to highly unphysiological composition of PD fluids, the peritoneal membrane undergoes rapid morphological and long-term functional alterations, which limit the treatment and contribute to adverse patient outcome. This review is focused on the peritoneal membrane ultrastructure and its transformation in patients with kidney disease and chronic PD, underlying molecular mechanisms, and potential systemic sequelae. Current knowledge on the impact of conventional and second-generation PD fluids is described; novel strategies and innovative PD fluid types are discussed.

Keywords: biocompatibility; glucose; glucose degradation products; junctions; peritoneal dialysis; peritoneum; transformation; transport.

Figure 1

Scheme of peritoneal dialysis application, peritoneal dialysis (PD) fluid composition, and local as well as systemic effects. Three vessel layer structure of the healthy peritoneal membrane as published previously (Schaefer et al., 2016a).

Figure 2

Transformation of the peritoneum with time on PD treatment with neutral pH, low GDP PD fluids. Blood microvessel density substantially increases within few months of PD. It is closely correlated with endothelial surface area, which presents the primary barrier for transport across the peritoneal dialysis membrane. Percentage of patients with substantial inflammatory cell infiltration and EMT increases with time on PD. VEGF signaling is particularly induced within the first year of PD, the TGF-β signaling cascade (pSMAD) activation is delayed but remains high during long-term treatment (Schaefer et al., 2018).

Figure 3

Overview on currently applied and potential novel PD fluid types. For about 50 years, conventional PD fluids have been based on glucose as the osmotically active agent and are heat sterilized in single-chamber bags at acidic pH together with selected electrolytes (Na, Ca, Mg, and Cl) and a buffer (lactate), which results in major glucose degradation product (GDP) formation (A). In the 1990s, second-generation PD fluids were developed. These multi-chamber bag systems substantially reduce GDP generation and allow for a physiologic buffer compound (bicarbonate) and a neutral pH of the ready-to-use PD fluid. At the same time, alternative osmotic compounds were introduced, an amino acid mixture and the oncotically active glucose polymer icodextrin (B). At present, protective agents counteracting local and systemic PD fluid toxicity are being developed, with alanyl-glutamine supplemented PD fluids have shown promising effects in first clinical trials (C). The fourth generation PD fluid type depicted reflects the vision of the ultimate future PD fluid (D).

Figure 4

Barriers for solute and water transport in PD. The endothelial and mesothelial cell monolayers form leaky membranes. Intercellular junctions define the selective permeability properties and thus paracellular bulk flow of small and large solutes together with water. An in-depth understanding of these key elements of PD should provide promising therapeutic targets to improve PD efficacy, biocompatibility, and sustainability.