Chronic kidney disease and peritoneal dialysis induced inflammation: set the controls for the heart and the vasculature?

Cardiovascular diseases are the main cause of mortality and morbidity in people with CKD receiving peritoneal dialysis. This increased risk is likely brought about by the high inflammatory burden associated to CKD and to PD therapy. How systemic and local inflammation influences the development and progression of cardiovascular disease in this context is discussed in Chapter 1 and the current gaps in knowledge are explored. The main aim of this thesis was to understand how and to what extent inflammation secondary to CKD and peritoneal dialysis is driving the development of cardiovascular disease. In Chapter 2 we developed and characterised a new model. We combined a 5/6ths nephrectomy, peritoneal dialysis fluid exposure and a high-cholesterol diet into a new model of atherosclerosis. We found PD-fluid specifically accelerated and aggravated the plaque phenotype and progression. These changes were accompanied by rampant vascular and systemic T-cell inflammation, most notably increases in T-cells bearing the vascular homing marker CX3CR1. These data suggest an essential role for T-cell inflammation, in particular vascular homing T-cells. In Chapter 3 we demonstrated that anti-inflammatory therapy, in the form of anti-galectin-2 nanobodies, was able to ameliorate the progression of existing atherosclerosis in ApoE-/- mice by polarising macrophages towards a classically anti-inflammatory “M2” like phenotype. Importantly these nanobodies were also previously described to promote arteriogenesis, meaning this dual use treatment was a novel discovery. Existing plaques were reduced in their size, and the plaques were less severe, with less fibrous cap atheromas. Remarkably, nanobody treatment reduced serum cholesterol levels. These data hold promise for macrophage modulating therapies able to promote arteriogenesis whilst reducing atherosclerosis. In Chapter 4 we describe the effects of induced kidney failure and PD-fluid exposure on cardiac function, and discuss the impact of empagliflozin on these processes. This model of uraemic cardiomyopathy was created via a 5/6 nephrectomy, peritoneal dialysis fluid exposure and a high-fat “Western” style diet. The physical inductions utilised resulted in a transient cardiac echo phenotype and the common heart failure findings such as BNP and ANP and lung congestion were absent. However, there was significant cardiac inflammation- there was fibrosis of the left ventricle and extensive T-cell infiltration, the latter of which was ameliorated by empagliflozin to expose a novel therapeutic mechanism. In Chapter 5 we demonstrate for the first time the role of hyaluronan in the development and progression of vascular calcification. We show that hyaluronic acid directly regulates vascular smooth muscle cell osteogenic differentiation, a key process in calcification. This new process can be therapeutically targeted in the future to specifically reduce medial calcification. Finally, Chapter 6 discusses the main findings of this thesis and evaluates them within the context of the wider field and offers future perspectives for where these data can now be taken.