The systemic and renal haemodynamic effects of apelin in health and chronic kidney disease

Abstract Background and Aims Chronic kidney disease (CKD) is a leading cause of global morbidity and mortality and is independently associated with cardiovascular disease. Indeed, patients with CKD are more likely to die of cardiovascular disease than they are to progress to kidney failure. Despite current standard of care, outcomes remain poor and newer therapies are needed. Apelin, an endothelium-dependent vasodilator and potent inotrope, is a potential novel treatment for CKD. There are no clinical studies of the renal actions of apelin, but pre-clinical data show that it regulates glomerular haemodynamics and promotes aquaresis. We investigated the cardiovascular and renal actions of apelin in healthy volunteers and in patients with CKD. Method Patients with stable, non-diabetic CKD and age- and sex-matched healthy volunteers were recruited to a prospective, randomised, double-blind and placebo-controlled study. Subjects received either pyroglutamated apelin-13 ([Pyr1]apelin-13, 1 nmol/min and 30 nmol/min) or placebo on two separate visits. Cardiovascular assessments included blood pressure, impedance cardiography and pulse wave velocity; iohexol and para-aminohippurate clearance were used to assess glomerular filtration rate (GFR) and renal blood flow, respectively. Tubular function was examined via urinary sodium, potassium and free water excretion. Results Twelve patients with CKD and 12 healthy volunteers were recruited and completed both phases of the study protocol. Baseline characteristics are shown in Table 1. Whilst infusion of 1 nmol/min [Pyr1]apelin-13 did not affect systemic haemodynamics, 30 nmol/min [Pyr1]apelin-13 led to significant changes. Compared to placebo, mean arterial pressure fell by 3 mmHg and 4 mmHg in health and CKD, respectively (p<0.05 for both groups), and systemic vascular resistance index fell by 309 dynes*s*cm−5 m2 and 407 dynes*s*cm−5 m2, respectively (p<0.01 for both groups). Cardiac index increased by 0.3 L/min/m2 and 0.2 L/min/m2, respectively (p<0.05 for both groups compared to placebo). In contrast, both 1 nmol/min and 30 nmol/min [Pyr1]apelin-13 had similar effects on renal haemodynamics. Effective renal blood flow increased by ∼15% in health and CKD (p<0.01 compared to placebo for both groups). GFR fell by ∼4 mL/min compared to placebo in patients with CKD (p<0.01) but we observed no change in healthy volunteers. As a result of these changes in effective renal blood flow and GFR, filtration fraction fell by ∼3% in CKD, reflected by a fall in proteinuria of ∼25% (p<0.001 compared to placebo for both). Both low and high doses of [Pyr1]apelin-13 promoted natriuresis and free water clearance in health and CKD. In comparison to placebo, sodium excretion increased by ∼30% and free water clearance by ∼15% in both groups (p<0.05 for all comparisons). Overall, the effects of apelin were prolonged in CKD. Conclusion Apelin offers systemic and renal haemodynamic benefits to patients with CKD. If these effects were maintained longer-term they would translate to improved cardiovascular and renal outcomes in this at-risk patient group. Clinical trials of long-acting, oral apelin analogues are now justified in CKD and other conditions with impaired salt and water balance.