Clinical trial NCT00722215: Endothelin Receptor Antagonism in Proteinuric Nephropathy
Official title: The Systemic & Renal Effects of Endothelin Receptor Antagonism in Proteinuric Nephropathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Chronic Kidney Disease
Proteinuria
Keywords: Endothelin antagonist
Chronic kidney disease
Proteinuria
Cardiovascular disease
Blood pressure
Arterial stiffness
Endothelial function
Lead sponsor: University of Edinburgh
Sponsor class: OTHER
Collaborators: name: British Heart Foundation
First posted: 2008-07-25
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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.

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.

Eligibility 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

Primary outcomes:
measure: Proteinuria
timeFrame: Acute change in proteinuria over 4 hour period following BQ-123 dosing
measure: Blood pressure
timeFrame: Acute change in blood pressure over 4 hour period following BQ-123 dosing
Secondary outcomes:
measure: Arterial stiffness (as measured by pulse wave velocity)
timeFrame: Acute change in arterial stiffness over 4 hour period following BQ-123 dosing
measure: Endothelial function (as measured by flow-mediated dilatation)
timeFrame: Acute change in endothelial function over 4 hour period following BQ-123 dosing
Other outcomes:
Locations:
city: Edinburgh
country: United Kingdom
facility: Clinical Research Centre, Western General Hospital
state: Scotland
Study officials:
affiliation: University of Edinburgh
name: Neeraj Dhaun, MBChB
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Edinburgh
name: David J Webb, MD
role: STUDY_DIRECTOR
References: