#4063 APELIN INCREASES FOREARM BLOOD FLOW IN CHRONIC KIDNEY DISEASE
Authors: Chapman Fiona , Melville Vanessa , Bruce Lorraine , Maguire Janet , Davenport Anthony , Newby David , Dhaun Neeraj 
Published: June 2023

Abstract

Background and Aims
Chronic kidney disease (CKD) affects 1 in 10 people and cardiovascular disease is its commonest complication. Despite current standard of care, many patients continue to progress to kidney failure and/or die of cardiovascular disease. Thus, there is an urgent unmet need for new treatments that slow kidney function decline and offer broad cardiovascular protection. The apelin system, comprising the apelin receptor and its two endogenous ligands apelin and elabela, is an attractive therapeutic target for CKD. Apelin is an endothelium-dependent vasodilator and a potent inotrope. Clinical studies show that apelin improves endothelial function in health and heart failure, and pre-clinical studies in models of kidney disease find apelin offers renoprotection. At present, apelin has not been studied in patients with CKD. The aims of this study were to examine the local vascular actions of apelin in CKD.

Method
Participants with stable, non-diabetic CKD and age- and sex-matched healthy volunteers were recruited to a prospective, randomised, placebo-controlled study. Blood pressure and arterial stiffness (measured using pulse wave velocity) were assessed at baseline. Endothelial function was examined using gold-standard venous occlusion plethysmography. Forearm vasodilatation was measured in response to incremental intra-arterial doses of acetylcholine (7.5, 15 and 30 μg/min, used to assess endothelium-dependent vasodilatation), sodium nitroprusside (1, 2 and 4 μg/min, used to assess endothelium-independent vasodilatation), and pyroglutamated apelin-13 ([Pyr1]apelin-13; 0.3, 1, 3, 10, 30 and 100 nmol/min). Circulating tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) were assessed as measures of endogenous fibrinolysis.

Results
Fifteen patients with CKD (mean age 55±4 years; 53% male) and 15 healthy volunteers (mean age 51±3 years; 67% male) completed the study. In comparison to healthy volunteers, patients with CKD had a higher blood pressure (mean arterial pressure: 102 mmHg versus 93 mmHg, p&lt;0.05) and increased pulse wave velocity (7.5±2.2 m/s versus 6.0±0.9 m/s, p&lt;0.01). Similar dose-dependent vasodilatation to acetylcholine and sodium nitroprusside was seen in both groups. [Pyr1]apelin-13 increased forearm blood flow by a maximum of ∼30% in both health and CKD (p&lt;0.01 compared to baseline for both) (Figure 1). This response appeared to be dose-dependent. Net tPA antigen release increased 20-70 fold in response to [Pyr1]apelin-13 in both health and CKD, with a trend to a greater release in CKD. There was no change in PAI-1. No relationship was seen between the response to [Pyr1]apelin-13 and kidney function.

Conclusion
Apelin promotes vasodilatation in optimally managed patients with CKD and may regulate endogenous fibrinolysis. If this effect were maintained in the long-term with systemic apelin treatment, it would be expected to reduce cardiovascular risk. Systemic studies are now justified to investigate the haemodynamic and renal effects of apelin in these patients.