Evaluation of Renal Sodium Excretion After Salt Loading in Heart Failure With Preserved Ejection Fraction (ERES-HFpEF)

April 14, 2021 updated by: Adhish Agarwal
Heart failure (HF) affects 2-3% of the population, and is characterized by impaired sodium balance which results in fluid overload. Ejection fraction, a measure of systolic function, is reduced in only about half of all HF patients. Incidence of heart failure with preserved ejection fraction (HFpEF) has increased in the last 20 years making it a growing public health problem. Currently, most patients admitted to the hospital with heart failure have preserved rather than reduced ejection fractions. However, to date it remains unknown why patients with HFpEF retain salt and water. The hypothesis is that patients with clinical HFpEF have an impaired renal response to salt loading, intravascular expansion and diuretics. Characterization of the salt and water excretory renal response to intravascular salt, fluid and diuretic load in patients with HFpEF will provide insight into the pathophysiology of HFpEF, and may help in the development of novel strategies to target renal sodium handling in patients with HFpEF. This characterization is the primary objective of this pilot project.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

In patients with heart failure with reduced ejection fraction (HFrEF), poor renal perfusion and neuro-hormonal activation cause renal salt and water retention. In contrast to HFrEF, patients with HFpEF have blunted neuro-hormonal activation, and other mechanisms likely cause fluid overload. Investigators have proposed several mechanisms including inflammatory state, endothelial dysfunction, decreased vascular compliance, pulmonary hypertension, and reduced nitric oxide (NO) bioavailability. However, the etiology and pathophysiology of fluid overload in HFpEF patients remains controversial.

Renal dysfunction is common in patients with HFpEF, and is associated with cardiac remodeling. HFpEF is associated with coronary microvascular endothelial activation and oxidative stress, which through reduction of NO dependent signaling contributes to the high cardiomyocyte stiffness and hypertrophy. Plasma sodium stiffens vascular endothelium and reduces NO release. Thus, renal sodium retention may play a pivotal role in the pathophysiology of HFpEF. Patients with HFrEF indeed have abnormal renal sodium excretion in response to salt load; however, it remains unclear if patients with HFpEF also have an impaired renal sodium excretion in response to a salt load, volume expansion or diuretics.

Since (as noted above) renal sodium retention may play an important role in the pathophysiology of HFpEF, it may be critically important to characterize renal sodium handling in patients with clinical HFpEF in response to salt loading, intravascular expansion and diuretic challenge. Impaired sodium excretion has been previously demonstrated in response to volume expansion in pre-clinical systolic and diastolic dysfunction, but not in patients with clinical HFpEF. Further, it is of note that this impairment in renal sodium excretion is rescued by exogenous B-type natriuretic peptide (BNP), which is a natriuretic peptide that is increased in most patients with HFpEF. It is possible, although not reported, that baseline BNP [which is commonly assessed by N-terminal prohormone of BNP (NT-proBNP)] levels affect renal sodium handling in HFpEF patients in response to salt and volume load, or diuretic challenge. It is also unknown if baseline kidney function, measured by estimated glomerular filtration rate (eGFR), affects natriuresis in patients with HFpEF after salt loading or diuretic challenge. Renal tubular function may also have important effects on salt retention in HF patients.

Characterization of the natriuretic response to intravascular salt and volume load and diuretic challenge, and of tubular function, in patients with HFpEF will provide insight into the pathophysiology of HFpEF, and may help in the development of novel strategies to target renal sodium handling in patients with HFpEF.

Study Type

Interventional

Enrollment (Actual)

14

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Utah
      • Salt Lake City, Utah, United States, 84132
        • University of Utah

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • History of chronic (> 6 months) heart failure with current New York Heart Association II-III symptoms
  • Left ventricular ejection fraction > 50% on a clinically indicated echocardiogram obtained within last 12 months
  • Clinical compensated heart failure
  • On constant medical therapy for heart failure; without changes in heart failure medication regimen (including diuretics) for previous 14 days and not expected to change in the next 2 days

Exclusion Criteria:

  • Unable to comply with protocol or procedures
  • Uncontrolled severe hypertension: systolic blood pressure > 160 mmHg
  • Significant renal impairment as defined by estimated glomerular filtration rate < 30ml/min/1.73m^2 determined by Chronic Kidney Disease - Epidemiology Collaboration equation
  • Significant proteinuria (> 0.5 g protein/daily protein or equivalent)
  • Body Mass Index > 40 kg/m^2
  • Acute coronary syndrome within last 4 weeks
  • Coronary revascularization procedures (percutaneous coronary intervention or cardiac artery bypass graft) or valve surgery within 30 days of screening
  • Cardiac resynchronization therapy, with or without implantable cardioverter defibrillator within 90 days of screening
  • Clinically relevant cardiac valvular disease
  • Hypertrophic or restrictive cardiomyopathy, constrictive pericarditis, active myocarditis, active endocarditis, or complex congenital heart disease
  • Cirrhosis of the liver
  • History of known hydronephrosis
  • History of adrenal insufficiency

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Saline Loading and Diuretic Challenge
Subjects receive intravenous infusion of 0.9% Sodium Chloride, followed by diuretic challenge with bolus injection of Furosemide 40 mg
Drug: 0.9% Sodium Chloride
Intravenous infusion of 0.25ml/kg/min of 0.9% sodium chloride intravenously for a total of 60 minutes
Other Names:
  • normal saline
Drug: Furosemide 40 mg
Bolus intravenous injection of 40 mg furosemide

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Urinary Sodium Excretion
Time Frame: 5 Hours
Amount of sodium excretion following saline loading and diuretic challenge will be compared between HFpEF patients and controls
5 Hours
Urine Volume
Time Frame: 5 Hours
Volume of urine collected following saline loading and diuretic challenge will be compared between HFpEF patients and controls
5 Hours

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in NT-proBNP
Time Frame: 5 Hours
Average change in NT-proBNP values before and after saline loading and diuretic challenge will be compared between HFpEF patients and controls
5 Hours
Serum Aldosterone
Time Frame: 5 Hours
Serum Aldosterone levels at baseline, after saline loading and after furosemide administration compared between HFpEF patients and controls
5 Hours
Plasma Renin Activity
Time Frame: 5 Hours
Plasma renin activity levels at baseline, after saline loading and after furosemide administration compared between HFpEF patients and controls
5 Hours
Plasma Nor-epinephrine
Time Frame: 5 Hours
Plasma nor-epinephrine levels at baseline, after saline loading and after furosemide administration compared between HFpEF patients and controls
5 Hours

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Urinary Exosomes
Time Frame: 5 Hours
Sodium transporters in Urinary exosomes will be characterized and compared between HFpEF patients and controls
5 Hours

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Adhish Agarwal

Collaborators

University of Utah Center for Clinical and Translational Science

Investigators

  • Principal Investigator: Adhish Agarwal, MD, University of Utah

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 6, 2019

Primary Completion (Actual)

February 20, 2020

Study Completion (Actual)

February 20, 2020

Study Registration Dates

First Submitted

February 8, 2019

First Submitted That Met QC Criteria

February 8, 2019

First Posted (Actual)

February 12, 2019

Study Record Updates

Last Update Posted (Actual)

April 19, 2021

Last Update Submitted That Met QC Criteria

April 14, 2021

Last Verified

April 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB_00112270

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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