Local membrane versus systemic consequences of peritoneal dialysis treatment

Abstract

The primary intent of this thesis is to delineate the relative roles of local membrane and systemic consequences of peritoneal dialysis therapy, with particular reference to the role of inflammation and a severe, uncommon complication, encapsulating peritoneal sclerosis (EPS). Data sources comprised observational cohort studies as well as registry data: the Stoke PD study, a single centre study with clinical data, the Global Fluid Study (GFS), a multinational study with clinical data and repeated dialysate and plasma samples, and Scottish Renal Registry (SRR) and AnzData registry data.
Through a cross sectional analysis of dialysate and plasma samples from GFS for inflammatory cytokines, we demonstrated that peritoneal and systemic inflammation are mostly separate processes although there is an association for IL-6 along with a steep concentration gradient from dialysate to plasma. Peritoneal inflammation, though IL-6, is the strongest determinant of peritoneal solute transport, and systemic inflammation, though IL-6, is a strong predictor of patient survival although peritoneal may contribute to systemic inflammation.
Through a nested case control study of GFS we showed that inflammatory cytokines are upregulated within the peritoneum prior to developing EPS. With a nested case control design from the Stoke PD study, we showed that a decrease in ultrafiltration, likely due to increased fibrosis causing a reduction in osmotic conductance to glucose, also predisposes to EPS. A competing risks analysis of SRR and AnzData showed that patients at a high risk of death, have a low risk of EPS. These findings provide supporting evidence for the theory that the risk of EPS develops through the accumulation of inflammation-driven fibrosis due to dialysate exposure over a long period of time. Dialysate contains high concentrations of glucose and absorption of this drives impairment of systemic glucose metabolism, demonstrated through a cross sectional analysis of GFS.