Acquired Decline in Ultrafiltration in Peritoneal Dialysis: The Role of Glucose

Abstract

Ultrafiltration is essential in peritoneal dialysis (PD) for maintenance of euvolemia, making ultrafiltration insufficiency-preferably called ultrafiltration failure-an important complication. The mechanisms of ultrafiltration and ultrafiltration failure are more complex than generally assumed, especially after long-term treatment. Initially, ultrafiltration failure is mainly explained by a large number of perfused peritoneal microvessels, leading to a rapid decline of the crystalloid osmotic gradient, thereby decreasing aquaporin-mediated free water transport. The contribution of peritoneal interstitial tissue to ultrafiltration failure is limited during the first few years of PD, but becomes more important in long-term PD due to the development of interstitial fibrosis, which mainly consists of myofibroblasts. A dual hypothesis has been developed to explain why the continuous exposure of peritoneal tissues to the extremely high dialysate glucose concentrations causes progressive ultrafiltration decline. First, glucose absorption causes an increase of the intracellular NADH/NAD⁺ ratio, also called pseudohypoxia. Intracellular hypoxia stimulates myofibroblasts to produce profibrotic and angiogenetic factors, and the glucose transporter GLUT-1. Second, the increased GLUT-1 expression by myofibroblasts increases glucose uptake in these cells, leading to a reduction of the osmotic gradient for ultrafiltration. Reduction of peritoneal glucose exposure to prevent this vicious circle is essential for high-quality, long-term PD.

Keywords: free water transport; glucose transporters; hypoxia; myofibroblasts; osmolality; peritoneal dialysis; pseudohypoxia; small pore fluid transport; ultrafiltration insufficiency.

Figure 1.

The crystalloid osmotic gradient beteen the peritoneal cavity and the microcirculation. Schematic representation of the crystalloid osmotic gradient across the peritoneal interstitium in the first few years of PD, when only a small amount of fibroblasts is present (top panel), and the situation in long-term PD, where the gradient decreases in the interstitium due to cellular uptake of glucose (bottom panel). The peritoneal cavity lumen is covered with the mesothelial cell layer, the vascular lumen with endothelial cells, separated by small pores and resting on a basement membrane. AQP-1 is present in some endothelial cells. The lines show the estimated time course of the crystalloid osmotic pressure gradient between the dialysate-filled peritoneal cavity and the blood. Note the pressure gradient remains almost stable during the passage of fluid through the interstitium in patients at the start of PD, resulting in a high gradient for AQP-1 (top panel), but decreases in patients on long-term PD due to uptake of glucose by interstitial myofibroblasts, leading to a lower crystalloid osmotic pressure gradient (bottom panel). ECM, extracellular matrix.

Figure 2.

The vicious circle between glucose-induced pseudohypoxia, increased GLUT-1 expression, and the consequent augmented glucose uptake by interstitial cells. The black ovals represent GLUT-1; the vertical oval symbolizes constitutive GLUT-1, the GLUT-1 induced by intracellular pseudohypoxia. The broken line symbolizes the vicious circle that can develop between glucose uptake, metabolism, pseudohypoxia, and increased GLUT-1 expression in the continuous presence of extremely high extracellular glucose concentrations.