Targeting metabolism to improve the host response to peritoneal dialysis

Chronic Kidney Disease (CKD) is a major health problem which affects up to 12% of the population and is on the rise globally. The primary treatment, haemodialysis puts constant pressure on healthcare systems, the speed of transplants cannot keep up with demand and not every patient is eligible for a transplant. Therefore, at-home peritoneal dialysis (PD) is increasingly used as a better option, both financially and for quality of life, as it limits time in hospital and gives patients more freedom. Unfortunately, PD is not currently a permanent treatment option; complications can arise, such as peritoneal infections (peritonitis) and immune cell-driven fibrosis (scarring of peritoneal membranes). Therefore, research that addresses the function of immune cells in PD is likely to improve the longevity of treatment, decrease the burden on health systems and improve the quality of life of patients. PD functions by using a peritoneal catheter to fill and drain the peritoneal cavity with approximately 2 litres of dialysis fluid - a basic mixture of sugar and stabilisers designed only to draw waste metabolites from the blood. My previous research has shown that vital immune cells in peritoneum require a broader range of metabolites to perform their anti-microbial function, including amino acids such as glutamate. Currently, the health and function of immune cells are currently not considered in PD. This project will investigate the benefits of metabolite alteration of PD fluid (e.g. addition of glutamate) to promote cell health and immune defence, which will prevent the poor outcomes of PD. The goals of this project to define the best additives for peritoneal dialysis fluid that improves the longevity of this treatment option for patients, and to determine whether altering the metabolism of immune cells can treat peritonitis.

Chronic Kidney Disease (CKD) is a major health problem which affects up to 12% of the population and is on the rise globally. Haemodialysis puts constant pressure on healthcare systems, the speed of transplants cannot keep up with demand and not every patient is eligible for a transplant. Therefore, at-home peritoneal dialysis (PD) is increasingly used as a better option, both financially and for quality of life, as it limits time in hospital and gives patients more freedom. Unfortunately, PD is not currently a permanent treatment option; complications can arise, such as peritonitis and fibrosis. Immune cells, including macrophages, neutrophils and T-cells are key defenders against peritonitis but also promote inflammation that results in fibrosis. Therefore, research that defines and restores the normal function of immune cells in PD is likely to improve the longevity of treatment, decrease the burden on health systems and improve the quality of life of patients. PD functions by using a peritoneal catheter to fill and drain the peritoneal cavity with approximately 2 litres of dialysis fluid - a basic mixture of glucose and buffers designed only to draw waste metabolites from the blood. My previous research has shown that peritoneal macrophages require peritoneal-enriched glutamate or glutamine to perform anti-microbial functions. In addition, it is well reported that T-cells require glutamine for proliferation/maintenance of adaptive immune defence. However, the health and function of immune cells are not considered in PD. This project will investigate the benefits of metabolite alteration of PD fluid (e.g. glutamate) to promote cell health and immune defence, which will prevent the poor outcomes of PD. The goals of this project are to i) define the peritoneal metabolome changes in PD, ii) determine additives for peritoneal dialysis fluid that improves longevity of PD, and iii) determine whether altering the metabolism of immune cells can treat peritonitis.