Fibrosis of Peritoneal Membrane as Target of New Therapies in Peritoneal Dialysis

Abstract

Peritoneal dialysis (PD) is an efficient renal replacement therapy for patients with end-stage renal disease. Even if it ensures an outcome equivalent to hemodialysis and a better quality of life, in the long-term, PD is associated with the development of peritoneal fibrosis and the consequents patient morbidity and PD technique failure. This unfavorable effect is mostly due to the bio-incompatibility of PD solution (mainly based on high glucose concentration). In the present review, we described the mechanisms and the signaling pathway that governs peritoneal fibrosis, epithelial to mesenchymal transition of mesothelial cells, and angiogenesis. Lastly, we summarize the present and future strategies for developing more biocompatible PD solutions.

Keywords: biocompatibility; fibrosis; peritoneal dialysis.

Figure 1

Graphical representation of metabolic control of fibrosis. Several metabolic processes such as glycolysis, glutaminolysis, and fatty acid oxidation contribute to the deposition and other ECM components. High glucose levels activate glycolysis directly by increasing HIF-1a expression, which in turn amplifies the production of TGF-b1. The latter would not only further sustain high glycolytic rates but also fibrogenesis. The increased production of lactate sustains macrophages polarization toward an inflammatory phenotype, which worsens the fibrosis. In addition, the increased glycolytic rate makes glycolytic intermediates available in larger quantities, contributing to the synthesis of amino acid substrates for collagen synthesis. Moreover, glutamine has a role in collagen synthesis, but it can also contribute to ATP production through oxidative phosphorylation. A key metabolic switch in maintaining a chronically activated fibrogenic state is the pyruvate dehydrogenase complex (PDH).

Figure 2

Metabolic strategies to control fibrosis could be based on inhibiting glycolysis, fatty acid, and pyruvate oxidation. Glycolysis can be modulated by inhibiting hexokinase 2 by 2-deoxyglucose, though the safety of this approach must be proved. The alternative strategy is coupling glycolysis with the Krebs cycle by inhibiting PDH Kinase using DCA or increasing PDH activity by reducing the intramitochondrial acetyl-CoA pool using L-carnitine.