Endothelin Receptor Antagonism in Proteinuric Nephropathy
Condition: Chronic Kidney Disease; Proteinuria
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Proteinuria
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): BQ-123 (selective endothelin A receptor antagonist); 0.9 % saline; Nifedipine
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Single dose of BQ-123 given at a dose of 1000 nmol/min for 15 min intravenously.; Single 15ml 0.9% saline infused for 15 mins as placebo control; Single dose of nifedipine 10 mg given orally as active control
Other intervention name(s): Adalat
Intervention MeSH terms: Nifedipine; Endothelin A Receptor Antagonists
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Endothelin antagonist; Chronic kidney disease; Proteinuria; Cardiovascular disease; Blood pressure; Arterial stiffness; Endothelial function