Vascular Effects of Mineralocorticoid Receptor Antagonism in Kidney Disease
Condition: Chronic Kidney Disease; Albuminuria
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Albuminuria
Study type: Interventional
Phase: Phase 2

Summary: 
      Vascular endothelial dysfunction increases cardiovascular (CV) risk and contributes to the
      progression of chronic kidney disease (CKD). Mineralocorticoid receptor (MR) antagonists have
      been shown to improve endothelial function, as well as decrease CV mortality and proteinuria.
      The specific biochemical pathways that produce these pharmacological effects for MR
      antagonists, however, are poorly understood. This study investigates the effect of MR
      antagonism on endothelial function in patients with moderate (stage III) CKD using a
      randomized, controlled trial. Three specific aims are proposed: Aim 1: To determine if
      spironolactone improves endothelial function as compared to amiloride in patients with stage
      III CKD; Aim 2: To determine if oxidative stress is associated with changes in endothelial
      function by spironolactone compared to amiloride in patients with stage III CKD; and Aim 3:
      To determine if endothelial dysfunction contributes to albuminuria in patients with stage III
      CKD. The clinical relevance is to improve understanding of the mechanisms of kidney function
      decline in CKD in order to develop interventions to delay or prevent dialysis, which would
      translate into alleviating patient suffering, caregiver burden, and health care costs.
    

Detailed description: 
      Study participants with proteinuric, stage III CKD will be randomly assigned in a
      double-masked fashion to spironolactone 25mg daily or amiloride 5 mg daily for 6 weeks and
      then crossed over to the alternate study medication after a 1 month wash-out period. Vascular
      function will be assessed at baseline and the end of each 6 week treatment period by: 1)
      ultrasound guided flow-mediated dilation (FMD) of the brachial artery, 2) impedence
      cardiography, 3) pulse-wave velocity, 4) 24 hour ambulatory blood pressure monitoring, and 5)
      serum and urine biomarkers. Participants will undergo a total of 7 visits over 16-18 weeks; 3
      of the 7 visits will involve vascular function testing.

      A study visit where vascular function testing is to be performed will begin at 0800 in the
      morning and start with a vital sign assessment including height, weight, body fat percent,
      and left arm automated BP measurement followed by confirmation of fasting status and a brief
      past medical history. Each participant will then lie supine for 10 minutes in preparation for
      vascular function testing. Following the pulse wave velocity, impedence cardiography, and FMD
      measurements, the participant will have his/her blood and urine collected for laboratory
      testing. Laboratory testing will include ~20 mL of blood for plasma and serum testing.
      Participants will return 24 hour urine samples and have a 24 hour ambulatory monitor placed.
      This entire visit is expected to take 2 hours.

      Study visits where vascular function testing will not be performed (e.g., screening visit,
      visit 2, visit 4, and visit 5; should last 30 minutes and involve a medication assessment,
      vital sign check, and blood collection for serum potassium (~4 mL of blood).

      All study medication will be prepared by the the University of Alabama (UAB) Research
      Pharmacy in matching capsules and placed in pill bottles labeled "A" and "B". The order of
      medication dispensing will follow simple randomization using an a priori randomization list
      prepared by the research pharmacy. All study personnel with participant interaction are
      masked to the order of study medication.
    

Intervention name(s): Spironolactone; Amiloride
Intervention type(s): Drug; Drug
Intervention MeSH terms: Amiloride; Spironolactone
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Mineralocorticoid Receptor Antagonists; Mineralocorticoid Effects