Epithelial Sodium Channel (ENaC) as a Novel Mechanism for Hypertension and Volume Expansion in Type 2 Diabetes

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2013 by University of New Mexico
Sponsor:
Collaborators:
Dialysis Clinic, Inc.
University of Pittsburgh
Information provided by (Responsible Party):
University of New Mexico
ClinicalTrials.gov Identifier:
NCT01804777
First received: March 1, 2013
Last updated: September 25, 2013
Last verified: February 2013
  Purpose

The purpose of this study is to determine with the administration of amiloride, observe an enhanced natriuresis, reduction in blood pressure and weight compared to the administration of hydrochlorothiazide in Type 2 Diabetics.


Condition Intervention Phase
Proteinuria
Hypertension
Type II Diabetes
Drug: Amiloride
Drug: HCTZ
Phase 0

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Health Services Research
Official Title: ENaC as a Novel Mechanism for Hypertension and Volume Expansion in Type 2 Diabetes

Resource links provided by NLM:


Further study details as provided by University of New Mexico:

Primary Outcome Measures:
  • Blood Pressure [ Time Frame: one month ] [ Designated as safety issue: No ]
    Change in clinic systolic BP. This BP measure will be the average of three serial BP measurements taken one minute apart after 5 minutes of sitting quietly.


Secondary Outcome Measures:
  • Hypertension [ Time Frame: one month ] [ Designated as safety issue: No ]
    To demonstrate effect size on relevant hypertension outcomes such as volume status and urinary sodium excretion. Also assess the fractional excretion of sodium (FENa) and chloride (FECI). Endpoint will be the 24 hour urine excretion.


Estimated Enrollment: 20
Study Start Date: March 2013
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Amiloride 10 mg, 20 mg, and diet
Amiloride 10 mg for 14 days and diet. Then dose titrated up at day 14 to 20 mg, and diet.
Drug: Amiloride

Amiloride 10 mg taken every day for two weeks, along with adherence to specified diet.

On day 14 titrate dose up to Amiloride 20 mg, take every day for two weeks after completion of two week intake of Amiloride 10 mg, along with adherence to specified diet.

Other Name: Midamor
Active Comparator: HCTZ 12.5 mg, 25 mg and diet
HCTZ 12.5 mg for 14 days and diet. Then dose titrated up at day 14 to 25 mg, and diet
Drug: HCTZ

HCTZ 12.5 mg taken every day for two weeks, along with adherence to specified diet.

On day 14 titrate dose up to HCTZ 25 mg taken every day for two weeks after completion of two week intake of HCTZ 12.5 mg, along with adherence to specified diet

Other Names:
  • Hydrochlorthiazide
  • Aquazide H
  • HydroDIURIL
  • Microzide

Detailed Description:

Renal sodium retention and extracellular fluid volume expansion are hallmarks of nephrotic syndrome. There is abundant evidence that this occurs even in the absence of activation of hormones that are known to activate renal Na transporters. Proteinuria not only reflects glomerular damage, but also functions as a risk factor for cardiovascular disease, stroke, end stage renal disease and is associated with extracellular volume expansion and high BP.

In the natural course of Type II diabetes, microalbuminuria and elevations in blood pressure are thought to occur at around the same time. Blood pressure in microalbuminuric diabetics is more sensitive to dietary salt intake than in normoalbuminuric patients despite both groups having similar aldosterone and plasma renin activity levels. Proteolytic processing of ENaC subunits might provide the primary defect in renal sodium handling in these microalbuminuric individuals. However, proteinuria is not consistently identified as a risk factor for incipient elevation in blood pressure and in some studies elevated blood pressure predicts the advent of microalbuminuria.

Analyses of normotensive normoalbuminuric subjects in previous studies have found that higher urinary albumin levels in the normal range predicted incident hypertension. A similar finding was seen in a non-diabetic cohort. These studies suggest that these disparate results may be related to the cut off that defined microalbuminuria. Another possible explanation is that an ENaC activator, like plasmin, contributes to the generation of incident hypertension in some individuals. Levels of albuminuria may not necessarily be reflective of ENaC activator levels and may vary from individual to individual. Perhaps urinary plasmin and plasminogen provides a more robust biomarker for those individuals who may develop hypertension.

Recent evidence suggests that in some individuals with glomerular damage, proteases not normally found in urine enter the urinary space and aberrantly cleave ENaC. In this setting, filtered plasminogen (inactive precursor) is converted to plasmin (active protease) by urokinase that is expressed in tubular epithelial lumen. The proteolytic activation of ENaC would generate a primary defect in renal sodium handling, a mechanism that may be a particularly important factor leading to increases in extracellular fluid volume and BP that accompany nephrotic syndrome.

While previous studies have examined the role of amiloride in low-renin hypertension, and as an additional agent the conventional treatment of hypertension, no human trials have tested whether ENaC inhibitors impact blood pressure and volume status in the setting of proteinuria. Over a ten year period, millions of diabetics, 5.3% of Type II diabetics and 28% of Type I diabetics develop macroscopic proteinuria.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • Inclusion Criteria:

    1. Age 18 to 80 yrs at randomization
    2. History of Type 2 Diabetes
    3. Presence of systolic hypertension or pre-hypertension (average systolic blood pressure (SBP) ≥120 mmHg and <180 mmHg.)
    4. Urinary protein/creatinine ratio >300 mg/g creatinine at screening
    5. Hemoglobin A1C<8%
    6. Willing and able to give informed consent
  • Exclusion Criteria:

    1. Average SBP of ≥180 mmHg or diastolic blood pressure (DBP) of ≥110 mmHg
    2. Current symptomatic heart failure, history of New York Heart Association Class III or IV congestive heart failure, or left ventricular (LV) ejection fraction (by any method) <25%; these patients may be harmed with withdrawal of diuretics
    3. Serum potassium level <3.5 or >5.0 at screening
    4. History of hyperkalemia in the last two years (serum K>5.5)
    5. Contraindication to use of hydrochlorothiazide or amiloride
    6. Unstable angina pectoris or acute myocardial infarction (MI) in last 3 months
    7. Known secondary causes of hypertension (HTN) (screening for these conditions will not be required)
    8. Estimated glomerular filtration rate (GFR) <60 mL/min/1.73m², as determined by validated estimating equations
    9. On or expected to be on immunosuppressive therapy
    10. Any history of solid organ transplantation
    11. Significant dementia
    12. Other factors likely to limit adherence during trial (eg. alcohol or substance abuse, plan to move in next year, history of non-adherence to medications, appointments and medical care, reluctance of close family members to participate in trial, lack of support from primary healthcare provider)
    13. Participation in another investigational trial within 4 weeks of the screening visit
    14. Arm Circumference too large or too small to allow accurate blood pressure measurement
    15. Pregnancy or currently trying to become pregnant (although this is unlikely because of age limit
    16. Incarceration
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01804777

Contacts
Contact: Mark L Unruh, MD MSc 505-272-4750 MLUnruh@salud.unm.edu

Locations
United States, New Mexico
University of New Mexico Hospital; Clinical & Translational Science Center Recruiting
Albuquerque, New Mexico, United States, 87131
Principal Investigator: Mark L Unruh, MD MSc         
Sponsors and Collaborators
University of New Mexico
Dialysis Clinic, Inc.
University of Pittsburgh
Investigators
Principal Investigator: Mark L Unruh, MD MSc University of New Mexico
  More Information

Publications:
Responsible Party: University of New Mexico
ClinicalTrials.gov Identifier: NCT01804777     History of Changes
Other Study ID Numbers: 13-017
Study First Received: March 1, 2013
Last Updated: September 25, 2013
Health Authority: United States: Data and Safety Monitoring Board
United States: Institutional Review Board

Keywords provided by University of New Mexico:
ENaC
Amiloride
Hydrochlorothiazide(HCTZ)
Hypertension
Type II Diabetes
Natriuresis
Proteinuria

Additional relevant MeSH terms:
Proteinuria
Diabetes Mellitus
Diabetes Mellitus, Type 2
Hypertension
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Vascular Diseases
Cardiovascular Diseases
Urination Disorders
Urologic Diseases
Urological Manifestations
Signs and Symptoms
Amiloride
Hydrochlorothiazide
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Acid Sensing Ion Channel Blockers
Sodium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Epithelial Sodium Channel Blockers
Diuretics, Potassium Sparing
Cardiovascular Agents
Therapeutic Uses
Antihypertensive Agents
Sodium Chloride Symporter Inhibitors

ClinicalTrials.gov processed this record on August 20, 2014