Hyperkalaemia is the term used to describe raised potassium level in the blood and, if severe, can constitute a medical emergency. Prevalence estimates have historically varied greatly depending on the population investigated with reports ranging from 1-10% in patients admitted to hospital. Management of severe hyperkalaemia (serum potassium >6.5 mmol/L) is typically undertaken in hospital with the use of intravenous insulin and dextrose as first line treatment, which requires regular monitoring, often requires repeat dosing and can expose patients to additional risk, morbidity and a prolonged length of hospital stay. Thus, there is an unmet need to develop a treatment regimen that both acts quickly and specifically enough to be of use in the acute setting but also which is safe and well-tolerated by patients. This thesis investigates the epidemiology and management of hyperkalaemia and explores clinical outcomes associated with hyperkalaemia with a view to enhancing the design of hyperkalaemia management trials by identifying clinically meaningful endpoints. This thesis was undertaken during the COVID-19 pandemic, which caused wide-spread disruption to non-COVID related research, and as a result also includes my work on the design and execution of the COVID-19 prophylaxis trial PROTECT-V.

To improve understanding of the prevalence of hyperkalaemia we conducted the first systematic review (chapter two) of all reported observational studies describing the prevalence and/or incidence of hyperkalaemia. This work has provided a comprehensive published review on the prevalence and incidence of hyperkalaemia across a large number of relevant sub-groups and clarifies our understanding of risk-factors for developing hyperkalaemia. Pooled mean hyperkalaemia prevalence was 1.3% amongst the general population, 8.7% amongst adult inpatients and up to 20.7% in patients requiring renal replacement therapy. Another sub-group at risk of hyperkalaemia are users of medications that inhibit the renin-angiotensin-aldosterone system (RAASi) which are commonly prescribed as a cornerstone therapy to patients with chronic kidney disease or heart failure who already have an increased risk of hyperkalaemia. The prevalence of hyperkalaemia in RAASi users was 5.8% which rises to 12.2% amongst hospital inpatients taking RAASi. Hyperkalaemia can cause stoppages in RAASi therapy and the work described in chapter 3 which resulted in a publication, explores the adverse clinical impact of these stoppages in a large UK primary care dataset that was linked to secondary care records. The risk of hospitalisation, cardiac arrhythmia, heart failure hospitalisation and cardiac arrest were all higher amongst patients who suffered interruptions or cessation of their RAASi therapy. The fourth chapter reports the largest, published UK observational study to date of the emergency management of hyperkalaemia. Our work highlights that insulin dextrose treatment failed in over one third of patients and hypoglycaemia occurred in one in five patients. This work was used to provide clinically meaningful trial endpoints and guide the design of the HELP-K trial that is described in chapter 5. This trial aimed to provide contemporary evidence for the use of novel potassium-binding medications in the emergency setting to try and reduce the risk of treatment failure with insulin dextrose and to limit the associated morbidity of hypoglycaemia and prolonged length of hospital stay reported in chapter 4. Whilst there remains much work to be done to improve the evidence base for emergency hyperkalaemia management the work contained within this thesis helps improve the epidemiological understanding of hyperkalaemia in the real-world setting with contemporary knowledge that, I hope, will be useful to health-care providers, health policy makers and patients.