What Did We Learn From Animal Models in Peritoneal Dialysis?

Abstract

The development of animal models in peritoneal dialysis has led to some breakthroughs in the application of this dialysis modality in clinical practice. These breakthroughs are (1) a better understanding of the physiology and pathophysiology of solute transport and ultrafiltration mechanisms, (2) the observation and integration of the long-term structural and functional alterations of the membrane, (3) a better understanding of the biocompatibility issues involved in PD, leading to the clinical introduction of more biocompatible dialysis solutions and finally, (4) the development of colloid osmotic solutions containing polyglucose polymers for application in the long dwells. Intravital miscroscopy provides information in live animals about diverse functional parameters, such as blood flow rate, vessel diameter, permeability to macromolecules, leukocyte-endothelium interaction, capillary recruitment, and lymph vessel kinetics. Also evaluation of different parameters in a living experimental animal, allowing integration of function and structure is possible. A variety of chronic PD models have been developed, mainly to study effects of long-term peritoneal dialysate exposure on peritoneal membrane function and structure. The implementation of different blocking agents of biochemical substances in these models has elucidated many molecular biological mechanisms involved in these processes. The important roles of aquaporins, vascular endothelial growth factor, nitric oxide, advanced glycation end product formation and their receptor (RAGE) upregulation and the integrated roles of all these factors in the fibrotic alterations of the membrane as observed in patients on long-term PD have been investigated. More recently, genetically modified mice have been used as an important tool to investigate the molecular basis of peritoneal changes during dialysis and during acute peritonitis.

The Pathophysiology of the Peritoneal Membrane

“…[7][8][9][10] Although these studies provide significant insight into peritoneal pathophysiology, it is widely acknowledged that they are limited in some cases by a lack of pathway specificity, adverse effects, and transient efficacy, so many questions remain to be addressed. [11][12][13] Until recently, the body size of a species was considered a major limiting factor in performing in vivo studies relevant to PD; however, the development of new approaches for in vivo phenotyping 14 coupled with molecular biology techniques provides the potential of using genetically modified mice for clinically relevant mechanistic studies addressing various key aspects of PD pathophysiology. 15,16 The purpose of this brief review is to illustrate how these studies (primarily in rodent models) provide a more complete understanding of basic mechanisms and pave the way for the development of novel, specifically targeted diagnostic and therapeutic strategies aimed at reducing infection and improv-ing membrane survival and long-term outcomes in patients who are on PD.…”

Transgenic Mouse Models

“…Studies in rat and rabbit models have demonstrated that the capillary endothelium constitutes the major barrier for solute and water transport during PD, and that transport across the membrane depends on the intrinsic permeability to each solute and the effective peritoneal surface area, reflecting the number of perfused capillaries within the peritoneum (2)(3)(4). In parallel, acute and chronic rodent models have been used to investigate the pathophysiology of peritonitis, peritoneal fibrosis, and angiogenesis in relation to biocompatibility and host defense mechanisms (3)(4)(5). However, the mechanistic investigations in rat and rabbit PD models have been based mostly on intervention studies using pharmacological agents, blocking antibodies, or transient expression systems including adenoviral vectors (6)(7)(8)(9).…”