Apelin as a potential treatment for chronic kidney disease

Abstract

Chronic kidney disease (CKD) is a global health emergency. It affects ~10% of the global population, and cardiovascular disease is its commonest endpoint. Current standard of care treatment involves using blockers of the renin-angiotensin0aldosterone system (RAAS) and sodium-glucose co-transporter 2 inhibitors which reduce blood pressure and proteinuria and slow CKD progression. However, despite these agents many patients with CKD still progress to kidney failure and the requirement for dialysis or a kidney transplant. Newer treatments are urgently needed, and something that could also offer both cardiovascular and renal protection would be particularly attractive.

The apelin system, comprising the apelin receptor and its two endogenous ligands, apelin and elabela, is a very appealing therapeutic target for CKD. Apelin is a vasodilator and the most potent inotrope discovered to date. Clinical studies demonstrate that it lowers blood pressure and increases cardiac output in healthy humans and in those with heart failure. In pre-clinical studies, apelin regulates kidney blood flow and promotes aquaresis. The aims of this thesis were to define the actions of the apelin system in human kidneys and explore its potential therapeutic benefit in clinical CKD.

Firstly, I have shown that the apelin system is expressed throughout the nephron in healthy human kidneys. Additionally, as estimated glomerular filtration rate (eGFR) declines, plasma apelin concentration increases. Apelin concentration is associated with arterial stiffness and endothelial function, both validated surrogate measures of cardiovascular risk. Moreover, plasma apelin independently associates with eGFR decline. These data highlight the important relationship between the apelin system and the kidney and justify studies of apelin receptor agonism in CKD.

This thesis presents data from the first human studies examining the cardiovascular and renal responses to pyroglutamated apelin-13 ([Pyr1]apelin-13, the most abundant apelin isoform in human plasma) in health and CKD. Endothelial dysfunction is a feature of CKD and a measure of increased cardiovascular risk. I have demonstrated that apelin enhances endothelial function in CKD. Intra-arterial infusion of [Pyr1]apelin-13 led to a ~30% increase in forearm blood flow and was associated with an increase in tissue plasminogen activator (an endogenous fibrinolytic released by the endothelium). Using renal clearance studies, I measured systemic and renal haemodynamic and tubular responses to apelin and placebo in healthy humans and in patients with CKD receiving standard of care treatment. Acute infusion of [Pyr1]apelin-13 led to a fall in blood pressure and systemic vascular resistance and an increase in cardiac output in both health and CKD. In both health and CKD, [Pyr1]apelin increased renal blood flow; GFR fell in patients with CKD only. In those with CKD, I also observed a fall in filtration fraction and proteinuria. Finally, [Pyr1]apelin-13 promoted natriuresis and free water clearance in health and CKD.

In summary, the work presented here shows that the apelin system offers exciting therapeutic potential in CKD. Acute apelin infusion has beneficial cardiovascular and renal effects which, if maintained longer-term would be expected to translate to cardiorenal protection. The development of oral apelin analogues, and subsequent clinical trials, is now justified for patients with kidney disease.