The osmo-metabolic approach: a novel and tantalizing glucose-sparing strategy in peritoneal dialysis

Abstract

Peritoneal dialysis (PD) is a viable but under-prescribed treatment for uremic patients. Concerns about its use include the bio-incompatibility of PD fluids, due to their potential for altering the functional and anatomical integrity of the peritoneal membrane. Many of these effects are thought to be due to the high glucose content of these solutions, with attendant issues of products generated during heat treatment of glucose-containing solutions. Moreover, excessive intraperitoneal absorption of glucose from the dialysate has many potential systemic metabolic effects. This article reviews the efforts to develop alternative PD solutions that obviate some of these side effects, through the replacement of part of their glucose content with other osmolytes which are at least as efficient in removing fluids as glucose, but less impactful on patient metabolism. In particular, we will summarize clinical studies on the use of alternative osmotic ingredients that are commercially available (icodextrin and amino acids) and preclinical studies on alternative solutions under development (taurine, polyglycerol, carnitine and xylitol). In addition to the expected benefit of a glucose-sparing approach, we describe an 'osmo-metabolic' approach in formulating novel PD solutions, in which there is the possibility of exploiting the pharmaco-metabolic properties of some of the osmolytes to attenuate the systemic side effects due to glucose. This approach has the potential to ameliorate pre-existing co-morbidities, including insulin resistance and type-2 diabetes, which have a high prevalence in the dialysis population, including in PD patients.

A Novel Formulation of Glucose-Sparing Peritoneal Dialysis Solutions with l-Carnitine Improves Biocompatibility on Human Mesothelial Cells

“…Reduced exposure of the PM to glucose is one of the key objectives of the current research in PD. A novel and tantalizing strategy is represented by the use of osmo-metabolic agents in the PD solutions [20,21]. This novel composition of PD solutions would ensure not only a reduction in the intraperitoneal glucose load without compromising UF, but also the independent mitigation of underlying metabolic disorders.…”

Biological Effects of XyloCore, a Glucose Sparing PD Solution, on Mesothelial Cells: Focus on Mesothelial-Mesenchymal Transition, Inflammation and Angiogenesis

“…Another novel strategy to improve the biocompatibility of PD solution is the osmo-metabolic approach, which is based on the use of compounds (osmo-metabolites) exhibiting both osmotically and metabolically favorable properties, like L-carnitine and xylitol [ 31 ]. The formulation of the novel PD solution (XyloCore) includes a low glucose amount (27.7 mmol/L), that did not seem to have the deleterious effects the higher concentration did [ 35 ], in order to take advantage of its UF ability.…”

“…Potential benefits of glucose-sparing by above formulations have been reported [ 30 ]. The use of such dialysates, however, is limited to as a single daily peritoneal exchange and replace no more than 30–50% of the glucose absorbed every day [ 31 ]. Moreover, direct knowledge of their impact on the peritoneal membrane is lacking, since no biopsies of peritoneal tissues have been obtained so far from PD patients on icodextrin or amino acid solutions [ 25 ].…”

“…In this scenario, new PD solutions in the developing phase are very promising, in particular those containing Xylitol and L-Carnitine [ 31 , 32 ].…”

“…Xylitol is a five-carbon sugar alcohol derived by the reduction of D-xylulose. Once inside the cell, D-Xylitol is oxidized to D-xylulose and then phosphorylated to D-xylulose-5-phosphate, an intermediate of the pentose monophosphate shunt [ 31 ]. Xylitol can act as an osmotic agent [ 37 ], improves insulin sensitivity and glycemic control in diabetic patients [ 31 , 37 ], and has a good biocompatibility and toxicity profile [ 32 , 38 ].…”