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, as well as 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.

Aging of the Peritoneal Dialysis Membrane

“…It can be hypothesized that expression of GLUT-1 by peritoneal interstitial myofibroblasts, the density of which increases in long-term PD, explains the high tissue apparent diffusivity of glucose causing its enhanced disappearance from the peritoneal cavity. Both will lead to a reduction of the crystalloid osmotic gradient for AQP-1 ( Krediet, 2021 ). This is illustrated in Figure 1 .…”

“…Note that 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 (upper panel), but decreases in long-term PD patients due to uptake of glucose by interstitial myofibroblasts, leading to a lower crystalloid osmotic pressure gradient (lower panel). Taken from Krediet (2021) with permission of the American Society of Nephrology.…”

“…Increased expression of GLUT-1 on peritoneal interstitial myofibrobasts may cause a vicious circle, in which the cellular uptake of dialysate glucose is stimulated leading to more pseudohypoxia and thereby more stimulation of GLUT-1 expression, This induces a further augmentation of cellular glucose uptake and a reduction of the interstitial glucose gradient. A progressive decline in peritoneal ultrafiltration is the clinically relevant result ( Krediet, 2021 ).…”

Angiogenic Role of Mesothelium-Derived Chemokine CXCL1 During Unfavorable Peritoneal Tissue Remodeling in Patients Receiving Peritoneal Dialysis as Renal Replacement Therapy

“…While it is recognized that the gradual decline in peritoneal membrane function during PD is partly due to adverse tissue remodeling and angiogenesis (21), the molecular mechanisms underlying these processes are still poorly understood to date (59). So far, vascular changes in the dialyzed peritoneum have been analysed almost solely in relation to VEGF expression (17).…”

High intraperitoneal interleukin-6 levels predict ultrafiltration (UF) insufficiency in peritoneal dialysis patients: A prospective cohort study

“…The prevalence of late UF insufficiency (>2 years) has been reported to be 21 and 36% in long-term PD patients (4,5). Increasing evidence show that acquired UF insufficiency is not only associated with fast PSTR, but also related to decreased osmotic conductance to glucose (OCG) due to scarring of the vessels and interstitium (6,7). The pathologic mechanism underlying such alterations remain unknown, but appears to be related to chronic inflammation induced by continuous exposure to bioincompatible PD fluids (PDF) and uremia, possibly exacerbated by episodes of peritonitis (8)(9)(10).…”