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Date of Award

10-2002

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Sciences

Supervisor

Jack Gauldie

Abstract

Background: peritoneal dialysis (PD) is a valuable therapy for end-stage renal disease. Changes in the peritoneal transport properties, including increased solute transport and ultrafiltration (UF) dysfinction are main clinical limitations of PD. The capillary wall of peritoneal blood vessels plays a key role as a barrier to solute transport. Therefore, neovascularization of the peritoneal tissues is a main determinant in the functional changes in the peritoneal membrane. I hypothesize that ultrafiltration of dysfunction is caused by increased peritoneal vascularization with a concomitant increase in glucose transport from peritoneal cavity and rapid loss of the ultrafiltration gradient. Further, I hypothesize that this increased vascular surface area is induced by profibrotic and inflammatory cytokines such as transforming growth factor (TGF) β, interleukin (IL) 1β, and tumour necrosis factor (TNF) α through upregulation of angiogenic cytokines such as vascular endothelial growth factor (VEGF). Methods: I used adenovirus mediated gene transfer of cytokines such as TGFβ1, il-1β, and TNFα to the peritoneal of rats and studied the effects of histology, angiogenesis, gene regulation, solute transport, and UF. I also used an animal model of daily peritoneal exposure to dialysate solution. The angiogenic and fibrogenic response of the peritoneum to this model was detailed, along with the effect of overexpression of angiostatin and decorin by adenovirus mediated gene transfer Results: Adenovirus mediated gene transfer of TGFβ1 led to increased peritoneal fibrosis and angiogenesis which persisted to 28 days. These histologic changes were associated with increased solute transport of glucose and decreased UF. In vitro and in vivo, TGFβ1 appeared to up regulate expression of VEGF. Inflammatory cytokines such as TNFα and IL-1β both induced fibrosis, angiogenesis, and peritoneal membrane dysfunction. The kinetics of the response was quite different. TNFα induced a very transient response with a complete resolution of changes by 21 days after adenovirus infection. The response induced by IL-1β was more sustained. I hypothesize that the strong expression of tissue inhibitor of metalloproteinase after IL-1β treatment may explain the prolonged fibrogenic response after IL-1β. Daily exposure to dialysate also induced a strong fibrogenic and angiogenic response in the peritoneum. The anti-angiogenic agent angiostatin, when overexpressed using adenovirus mediated gene transfer, reduced the vascularization and improved the ultrafiltration dysfunction. Decorin, a proteoglycan that binds and inactivates TGFβ, reduced peritoneal fibrosis, but did not alter the angiogenic response, nor did it improve peritoneal membrane function. Discussion: These experiments have clarified the role of angiogenesis in UF dysfunction. The correlation between blood vessel density and ultrafiltration, along with the improvement in UF after treatment with angiostatin, is compelling evidence that vascularization of the peritoneal membrane causes UF dysfunction. There is a close associate between fibrosis and angiogenesis in the perotineum. Fibrosis appears to be necessary for a prolonged angiogenic response. Further work is required to identify the factors leading to the interaction between fibrosis and angiogenesis. The role of the interstitium and lymphatics in solute transport and UF dysfunction needs to be better defined. Finally, anti-angiogenic therapies need to be studied in these models of peritoneal membrane dysfunction and eventually applied to patients on PD to improve the quality and duration of this therapy.

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