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Apelin as a Potential Treatment for Chronic Kidney Disease (AlPaCKa)
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 |
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 (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 |
| 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
|
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
|
Other: [Pyr]apelin-13
Peptide [Pyr]apelin-13 infusion
|
- Change in forearm blood flow [ Time Frame: 1 hour ]Venous occlusion plethysmography
- Change in renal blood flow [ Time Frame: 4 hours ]Para-aminohippurate clearance study
- Change in arterial stiffness [ Time Frame: 1 hour ]Pulse wave velocity measures
- Change in natriuresis [ Time Frame: 4 hours ]Urinary sodium excretion measures
- Change in diuresis [ Time Frame: 4 hours ]Free water clearance measurement
- Change in blood pressure [ Time Frame: 4 hours ]Blood pressure monitoring
- Change in proteinuria [ Time Frame: 4 hours ]Urinary protein excretion
- Change in chorioretinal metrics as assessed by optical coherence tomography (OCT [ Time Frame: 4 hours ]Optical coherence tomography measurements
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | Yes |
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
| Contact: Fiona Chapman, MBChB | 0131 242 3326 | fchapman@ed.ac.uk | |
| Contact: Neeraj Dhaun, PhD | 0131 242 3326 | bean.dhaun@ed.ac.uk |
| United Kingdom | |
| Clinical Research Centre, Western General Hospital | Recruiting |
| Edinburgh, United Kingdom, EH4 2XU | |
| Contact: Neeraj Dhaun, PhD bean.dhaun@ed.ac.uk | |
| Principal Investigator: | Neeraj Dhaun, PhD | University of Edinburgh |
| Tracking Information | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| First Submitted Date ICMJE | December 11, 2018 | ||||||||
| First Posted Date ICMJE | May 20, 2019 | ||||||||
| Last Update Posted Date | March 18, 2021 | ||||||||
| Actual Study Start Date ICMJE | February 4, 2020 | ||||||||
| Estimated Primary Completion Date | February 1, 2023 (Final data collection date for primary outcome measure) | ||||||||
| Current Primary Outcome Measures ICMJE |
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| Original Primary Outcome Measures ICMJE | Same as current | ||||||||
| Change History | |||||||||
| Current Secondary Outcome Measures ICMJE |
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| Original Secondary Outcome Measures ICMJE | Same as current | ||||||||
| Current Other Pre-specified Outcome Measures | Not Provided | ||||||||
| Original Other Pre-specified Outcome Measures | Not Provided | ||||||||
| Descriptive Information | |||||||||
| Brief Title ICMJE | Apelin as a Potential Treatment for Chronic Kidney Disease | ||||||||
| Official Title ICMJE | Apelin as a Potential Treatment for Chronic Kidney Disease: The AlPaCKa Study | ||||||||
| 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. |
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| 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. |
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| Study Type ICMJE | Interventional | ||||||||
| Study Phase ICMJE | Not Applicable | ||||||||
| Study Design ICMJE | Allocation: Randomized Intervention Model: Crossover Assignment Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) Primary Purpose: Basic Science |
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| Condition ICMJE |
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| Intervention ICMJE | Other: [Pyr]apelin-13
Peptide [Pyr]apelin-13 infusion
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| Study Arms ICMJE |
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| Publications * | Not Provided | ||||||||
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* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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| Recruitment Information | |||||||||
| Recruitment Status ICMJE | Recruiting | ||||||||
| Estimated Enrollment ICMJE |
50 | ||||||||
| Original Estimated Enrollment ICMJE | Same as current | ||||||||
| Estimated Study Completion Date ICMJE | February 1, 2023 | ||||||||
| Estimated Primary Completion Date | February 1, 2023 (Final data collection date for primary outcome measure) | ||||||||
| Eligibility Criteria ICMJE |
Inclusion Criteria:
Exclusion Criteria:
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| Sex/Gender ICMJE |
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| Ages ICMJE | 18 Years and older (Adult, Older Adult) | ||||||||
| Accepts Healthy Volunteers ICMJE | Yes | ||||||||
| Contacts ICMJE |
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| Listed Location Countries ICMJE | United Kingdom | ||||||||
| Removed Location Countries | |||||||||
| Administrative Information | |||||||||
| NCT Number ICMJE | NCT03956576 | ||||||||
| Other Study ID Numbers ICMJE | AC18094 | ||||||||
| Has Data Monitoring Committee | No | ||||||||
| U.S. FDA-regulated Product |
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| IPD Sharing Statement ICMJE |
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| Responsible Party | University of Edinburgh | ||||||||
| Study Sponsor ICMJE | University of Edinburgh | ||||||||
| Collaborators ICMJE | Kidney Cancer UK | ||||||||
| Investigators ICMJE |
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| PRS Account | University of Edinburgh | ||||||||
| Verification Date | March 2021 | ||||||||
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ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |
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