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Characterisation of Peritoneal Calcification in Encapsulating Peritoneal Sclerosis

Mohamed Moinuddin, Mohammed Mohsin Zia

[Thesis]. Manchester, UK: The University of Manchester; 2017.

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Abstract

Encapsulating peritoneal sclerosis (EPS) is a rare complication of long-term peritoneal dialysis (PD). EPS is associated with extensive thickening and fibrosis of the peritoneum resulting in the formation of a fibrous cocoon encapsulating the bowel leading to intestinal obstruction. The presence of peritoneal thickening, peritoneal calcification and bowel obstruction is considered to be diagnostic of EPS. The current understanding of the pathogenesis of EPS is through the â€˜two-hitâ€™ fibrosis model. This model, however, does not explain the development of peritoneal calcification in patients with EPS. This thesis addresses the hypothesis that altered bone mineral metabolism in ESRF patients together with the mechanical stress of PD influences mesothelial cells to differentiate into osteoblasts promoting calcification in peritoneal tissue. Peritoneal calcification leads to increased tissue stiffness causing progressive fibrosis and the development of EPS. We compared the temporal evolution of the levels of bone mineral markers during PD between patients who developed EPS and control patients on PD. We found that raised serum levels of calcium, phosphate and alkaline phosphatase during PD increased the risk of development of EPS. We compared peritoneum from patients with EPS with that of PD patients without EPS using histological techniques. We found that calcification, organised fibrillary collagen and elastic fibres were significantly more abundant in the EPS peritoneum. Peritoneal calcification was also generalised and distributed not only on the peritoneal surface but also in the sub-mesothelial zone of fibrosis. EPS peritoneum also exhibited osteocalcin, an osteogenic protein, suggesting a cellular mechanism of calcification. Atomic force microscopy of EPS peritoneum showed increased stiffness when compared to control PD peritoneum with the areas of calcification possibly contributing to the increase in tissue stiffness. Human omental cells (HOMCs) were isolated by protease digestion and characterised using a panel of mesothelial markers. HOMCs were cultured in phosphate rich media and phosphate and calcium rich media. HOMCs when cultured with high extracellular levels of calcium showed accelerated mineralisation with upregulation of osteogenic transcription factor runx-2 suggesting osteoblastic transformation. In summary, this thesis indicates that poorly controlled secondary hyperparathyroidism is a risk factor for the development of EPS. On a background of PD related simple sclerosis, uncontrolled secondary hyperparathyroidism can lead to the transformation of mesothelial cells to osteoblasts. This leads to increased matrix deposition and matrix mineralisation causing increased matrix stiffness. Increase in matrix stiffness leads to progressive fibrosis culminating in EPS. Peritoneal calcification can act as the second hit leading to progressive fibrosis and development of EPS.