Apelin as a Potential Treatment for Chronic Kidney Disease (AlPaCKa)

Apelin as a Potential Treatment for Chronic Kidney Disease: The AlPaCKa Study

Chronic kidney disease (CKD) affects 8-16% of the world's population, and is independently associated with cardiovascular disease (CVD). As renal function declines, rates of major adverse cardiovascular events, cardiovascular and all-cause mortality increase. In addition to hypertension, increased arterial stiffness is characteristic of CKD, a marker of CVD risk, and an independent predictor of mortality in CKD patients. The endothelium is an important regulator of arterial stiffness, and endothelial dysfunction is a feature of CKD and a predictor of CVD. Current treatment of CKD is limited and aims to reduce blood pressure and proteinuria through the use of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB). However, many patients still progress to end-stage renal failure and often these patients die as a result of CVD.

A novel peptide, apelin, is proposed to be a potential treatment for CKD, with additional cardiovascular benefits. The AlPaCKa study investigators will carry out forearm blood flow and renal clearance studies in 25 patients with CKD and 25 matched healthy volunteers to determine the effects of apelin on cardiovascular and renal parameters. It is hoped apelin will be confirmed as a potential future treatment for CKD.

Study Overview

• Status: Completed
• Conditions: Cardiovascular Diseases; Chronic Kidney Diseases; Endothelial Dysfunction
• Intervention / Treatment: Other: [Pyr]apelin-13

Detailed Description

The apelins are a family of peptides whose most abundant isoform is [Pyr1]apelin-13. This binds to a single G protein coupled receptor known as 'APJ', which is widely expressed particularly in endothelium and cardiomyocytes. Apelin is the most powerful inotropic agent discovered to date, and apelin infusion into healthy humans leads to endothelium-dependent vasodilatation and BP lowering. Given its vasodilatory and inotropic effects, apelin is being investigated as a novel therapy for heart failure and pulmonary arterial hypertension, both of which are features of CKD. The apelin/APJ system is widely expressed in the human kidney (endothelium, smooth muscle cells, glomeruli) with a predominance in the renal medulla. It is recognised to have a role in fluid homeostasis, and apelin infusion in rodents leads to a dose-dependent diuresis but it is difficult to discriminate how much of this is due to renal vasodilatation as opposed to a direct tubular effect. However, it has been shown that apelin counteracts the antidiuretic effect of vasopressin at the tubular level. Evidence therefore suggests that apelin could have additional cardioprotective effects in CKD and could promote natriuresis and diuresis. To date there are no clinical studies of the actions of apelin in the kidney in health or CKD, or its effect on systemic haemodynamics in CKD.

Twenty-five patients with CKD and 25 matched healthy volunteers will undergo forearm blood flow studies with acetylcholine, sodium nitroprusside and apelin to determine the local haemodynamic effects of apelin in CKD, specifically the effects on endothelial function. The same subjects will then complete two renal clearance studies during systemic apelin / placebo infusion (randomised and double-blinded), by standard renal para-aminohippurate and inulin clearance techniques. Blood and urine samples will be collected every 30 minutes. This will allow the effects of apelin on renal function, renal blood flow, proteinuria, natriuresis and diuresis to be demonstrated. Cardiovascular effects will be determined by systemic bioimpedance measures and pulse wave velocity. This study aims to open a new area of clinical research with apelin.

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Edinburgh, United Kingdom, EH4 2XU
    • Clinical Research Centre, Western General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adults >18yrs
• Stable, non-diabetic chronic kidney disease stages 1 - 4 as defined by Kidney Disease: Improving Global Outcomes (KDIGO) 2012 classification (estimated Glomerular Filtration Rate (eGFR) >15ml/min/1.73m2)
• Clinically optimised on an angiotensin converting enzyme inhibitor / angiotensin receptor blocker, or intolerant to these agents.

Exclusion Criteria:

• Age <18 years
• Diabetes mellitus
• Overt cardiovascular disease
• Blood pressure >160/100mmHg
• Estimated GFR of <15ml/min/1.73m2
• Renal transplant recipients
• Haemodialysis / peritoneal dialysis patients
• Serum albumin <30g/L
• Patients receiving tolvaptan therapy for polycystic kidney disease
• Patients not medically fit to attend for study visits
• Patients without mental capacity or willingness to provide informed consent
• History of multiple and/or severe allergic reaction to drugs (including study drugs) or food
• Patients who are pregnant or breast feeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Chronic Kidney Disease patients; Forearm blood flow studies - acetylcholine (7.5, 15, 30microgram/min), sodium nitroprusside (1, 2, 4microgram/min) and [Pyr1]apelin-13 (0.3, 1, 3, 10, 30, 100nmol/min). Incremental doses of each lasting 8 minutes with saline washout between drugs. Renal clearance studies; Two standard para-aminohippurate (PAH) / iohexol clearance studies with infusion of either apelin or placebo on each day.; Dose of PAH / iohexol dependent on renal function. Continuous infusion lasting 6.5hours in total.; [[Pyr1]apelin-13 infusions: 1nmol/min and 30nmol/min for 30 minutes each.	Other: [Pyr]apelin-13; Peptide [Pyr]apelin-13 infusion
Active Comparator: Healthy volunteers; Forearm blood flow studies - acetylcholine (7.5, 15, 30microgram/min), sodium nitroprusside (1, 2, 4microgram/min) and [Pyr1]apelin-13 (0.3, 1, 3, 10, 30, 100nmol/min). Incremental doses of each lasting 8 minutes with saline washout between drugs. Renal clearance studies; Two standard para-aminohippurate (PAH) / iohexol clearance studies with infusion of either apelin or placebo on each day.; Dose of PAH / iohexol dependent on renal function. Continuous infusion lasting 6.5hours in total.; [Pyr1]apelin-13 infusions: 1nmol/min and 30nmol/min for 30 minutes each.	Other: [Pyr]apelin-13; Peptide [Pyr]apelin-13 infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in forearm blood flow	Venous occlusion plethysmography	1 hour
Change in renal blood flow	Para-aminohippurate clearance study	4 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in arterial stiffness	Pulse wave velocity measures	1 hour
Change in natriuresis	Urinary sodium excretion measures	4 hours
Change in diuresis	Free water clearance measurement	4 hours
Change in blood pressure	Blood pressure monitoring	4 hours
Change in proteinuria	Urinary protein excretion	4 hours
Change in chorioretinal metrics as assessed by optical coherence tomography (OCT	Optical coherence tomography measurements	4 hours

Collaborators and Investigators

• Sponsor: University of Edinburgh
• Collaborators: Kidney Cancer UK
• Investigators: Principal Investigator: Neeraj Dhaun, PhD, University of Edinburgh

Study record dates

Study Major Dates

• Study Start (Actual): February 4, 2020
• Primary Completion (Actual): December 14, 2022
• Study Completion (Actual): December 14, 2022

Study Registration Dates

• First Submitted: December 11, 2018
• First Submitted That Met QC Criteria: May 17, 2019
• First Posted (Actual): May 20, 2019

Study Record Updates

• Last Update Posted (Actual): January 27, 2023
• Last Update Submitted That Met QC Criteria: January 25, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency; Cardiovascular Diseases; Kidney Diseases; Renal Insufficiency, Chronic
• Other Study ID Numbers: AC18094

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: No data to be shared

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No