Endothelin Receptor Antagonism in Proteinuric Nephropathy

Study Description

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Brief Summary:

The number of people with kidney problems is increasing rapidly, related in part to the increasing prevalence of diabetes. Patients with kidney problems tend to have protein leaking into the urine (proteinuria). Both proteinuria and the kidney disease itself are associated with an increased risk of heart disease. Reducing proteinuria is an important treatment goal in people with kidney problems. Endothelin is a chemical produced both by blood vessels and the kidney. Higher than normal levels of endothelin are thought to contribute to progression of kidney disease and proteinuria. By using drugs that block the effects of endothelin ('endothelin receptor antagonists') we can hopefully reduce both of these. The purpose of the study is to ascertain whether endothelin receptor antagonists improve kidney function and reduce proteinuria more so than other commonly used drugs.

Condition or disease	Intervention/treatment	Phase
Chronic Kidney Disease; Proteinuria	Drug: BQ-123 (selective endothelin A receptor antagonist); Drug: 0.9 % saline; Drug: Nifedipine	Phase 1

Detailed Description:

Response to ETA Receptor Antagonism/Nifedipine/Placebo Prior to the study visit subjects will be asked to refrain from alcohol for 24 hours. Tea and coffee will not be permitted for at least 12 hours before each visit. Studies will be conducted in a quiet, temperature-controlled room.

On arrival at the Clinical Research Centre on the study day, a brief medical enquiry and examination will confirm the ongoing suitability of the subject for the study. An intravenous cannula will be inserted into the antecubital fossa of each arm. We have developed a basic protocol described fully in our previous studies that allows us to measure systemic haemodynamics by the well validated technique of bioimpedance and renal function by standard para-aminohippurate (PAH; renal blood flow) and inulin (glomerular filtration rate) clearance studies.

Urinary protein excretion will be measured by collecting urine over 30 minute time periods. To ascertain the contribution of renal haemodynamics to any change in protein excretion renal blood flow and glomerular filtration rate will be measured. In addition, blood and urine will also be assayed for sodium, creatinine and osmolality to allow calculation of fractional excretion of sodium and free water clearance.

Systemic haemodynamic monitoring will be performed at 15 minute intervals during drug/placebo administration and at 30 minute intervals outwith these periods.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	22 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose:	Basic Science
Official Title:	The Systemic & Renal Effects of Endothelin Receptor Antagonism in Proteinuric Nephropathy
Study Start Date :	May 2006
Actual Primary Completion Date :	November 2007
Actual Study Completion Date :	December 2007

Arms and Interventions

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Arm	Intervention/treatment
Placebo Comparator: 1; Placebo control arm of study	Drug: 0.9 % saline; Single 15ml 0.9% saline infused for 15 mins as placebo control
Experimental: 2; BQ-123 arm of study	Drug: BQ-123 (selective endothelin A receptor antagonist); Single dose of BQ-123 given at a dose of 1000 nmol/min for 15 min intravenously.
Active Comparator: 3; Nifedipine arm of study	Drug: Nifedipine; Single dose of nifedipine 10 mg given orally as active control; Other Name: Adalat

Outcome Measures

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Primary Outcome Measures :

1. Proteinuria [ Time Frame: Acute change in proteinuria over 4 hour period following BQ-123 dosing ]
2. Blood pressure [ Time Frame: Acute change in blood pressure over 4 hour period following BQ-123 dosing ]

Secondary Outcome Measures :

1. Arterial stiffness (as measured by pulse wave velocity) [ Time Frame: Acute change in arterial stiffness over 4 hour period following BQ-123 dosing ]
2. Endothelial function (as measured by flow-mediated dilatation) [ Time Frame: Acute change in endothelial function over 4 hour period following BQ-123 dosing ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 70 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Male or female
• Age 18-70
• Body mass index <35
• Blood pressure <160/110 mmHg
• CKD stage 2-5 as per the K/DOQI classification
• Proteinuria in one of the following categories: 0.3-1.5, >1.5-3.0, and >3.0-6.0 g/24hrs
• Normal serum albumin

Exclusion Criteria:

• Subject is below the age of legal consent, or is mentally or legally incapacitated
• History of multiple and/or severe allergic reactions to drugs (including study drugs), or food
• The subject has donated blood (450 ml) within the last 4 weeks
• Past or present drug or alcohol abuse including intravenous drug abuse at any time
• Participation in another clinical trial within 1 month
• Considered to be at high risk of HIV or hepatitis B
• Pregnant

Contacts and Locations

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Locations

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

Sponsors and Collaborators

University of Edinburgh

British Heart Foundation

Investigators

Principal Investigator:	Neeraj Dhaun, MBChB	The University of Edinburgh
Study Director:	David J Webb, MD	The University of Edinburgh

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Dr Neeraj Dhaun, The University of Edinburgh
ClinicalTrials.gov Identifier:	NCT00722215 History of Changes
Other Study ID Numbers:	2006/WCRC/02; PG/05/91; 06/MRE00/12
First Posted:	July 25, 2008
Last Update Posted:	July 25, 2008
Last Verified:	August 2006

Keywords provided by University of Edinburgh:

Endothelin antagonist; Chronic kidney disease; Proteinuria; Cardiovascular disease	Blood pressure; Arterial stiffness; Endothelial function

Additional relevant MeSH terms:

Kidney Diseases; Renal Insufficiency, Chronic; Proteinuria; Urologic Diseases; Renal Insufficiency; Urination Disorders; Urological Manifestations; Signs and Symptoms; Nifedipine; cyclo(Trp-Asp-Pro-Val-Leu)	Endothelin A Receptor Antagonists; Calcium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Tocolytic Agents; Reproductive Control Agents; Physiological Effects of Drugs; Antihypertensive Agents; Endothelin Receptor Antagonists