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

• ClinicalTrials.gov Identifier: NCT03956576
• Recruitment Status: Recruiting
• First Posted: May 20, 2019
• Last Update Posted: March 18, 2021
• Sponsor: University of Edinburgh
• Collaborator: Kidney Cancer UK
• Information provided by (Responsible Party): University of Edinburgh

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Chronic Kidney Diseases; Cardiovascular Diseases; Endothelial Dysfunction	Other: [Pyr]apelin-13	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Apelin as a Potential Treatment for Chronic Kidney Disease: The AlPaCKa Study
• Actual Study Start Date: February 4, 2020
• Estimated Primary Completion Date: February 1, 2023
• Estimated Study Completion Date: February 1, 2023

Arms and Interventions

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 infusion initial rate 30nmol/min for 1 hour; subsequently 300nmol/min for 2 hours.; Crossover design, so patients will receive both apelin and placebo infusion.	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 infusion initial rate 30nmol/min for 1 hour; subsequently 300nmol/min for 2 hours.; Crossover design, so patients will receive both apelin and placebo infusion.	Other: [Pyr]apelin-13; Peptide [Pyr]apelin-13 infusion

Outcome Measures

Primary Outcome Measures :

1. Change in forearm blood flow [ Time Frame: 1 hour ]
   Venous occlusion plethysmography
2. Change in renal blood flow [ Time Frame: 4 hours ]
   Para-aminohippurate clearance study

Secondary Outcome Measures :

1. Change in arterial stiffness [ Time Frame: 1 hour ]
   Pulse wave velocity measures
2. Change in natriuresis [ Time Frame: 4 hours ]
   Urinary sodium excretion measures
3. Change in diuresis [ Time Frame: 4 hours ]
   Free water clearance measurement
4. Change in blood pressure [ Time Frame: 4 hours ]
   Blood pressure monitoring
5. Change in proteinuria [ Time Frame: 4 hours ]
   Urinary protein excretion
6. Change in chorioretinal metrics as assessed by optical coherence tomography (OCT [ Time Frame: 4 hours ]
   Optical coherence tomography measurements

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Contacts

Contact: Fiona Chapman, MBChB; 0131 242 3326; fchapman@ed.ac.uk

Contact: Neeraj Dhaun, PhD; 0131 242 3326; bean.dhaun@ed.ac.uk

Locations

United Kingdom

Clinical Research Centre, Western General Hospital; Recruiting

Edinburgh, United Kingdom, EH4 2XU

Contact: Neeraj Dhaun, PhD bean.dhaun@ed.ac.uk

Sponsors and Collaborators

University of Edinburgh

Kidney Cancer UK

Investigators

• Principal Investigator: Neeraj Dhaun, PhD; University of Edinburgh

More Information

• Responsible Party: University of Edinburgh
• ClinicalTrials.gov Identifier: NCT03956576
• Other Study ID Numbers: AC18094
• First Posted: May 20, 2019
• Last Update Posted: March 18, 2021
• Last Verified: March 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: No data to be shared

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Kidney Diseases; Renal Insufficiency, Chronic; Cardiovascular Diseases; Urologic Diseases; Renal Insufficiency