Heart Failure, Kidney Dysfunction
Conditions
Keywords
heart failure, heart failure with and without kidney dysfunction
Brief summary
The investigators' objective is to define the effects of decreasing the furosemide dose on heart, kidney and humoral function in people with compensated heart failure and kidney dysfunction and also in people with compensated heart failure without kidney dysfunction. Secondly, to define the humoral activation in both groups.
Detailed description
The broad objective of this protocol is to advance our understanding of the pathophysiological mechanisms of human Cardiorenal Syndrome (CRS) with a specific emphasis upon the biological interaction between diuretic therapy, the renin-angiotensin-aldosterone-system (RAAS) and cyclic 3'-5'-guanosine monophosphate (cGMP) pathway.
Interventions
DRUGFurosemide
Subjects received their clinically prescribed dose of furosemide for a 3 week stabilization period, then were assessed for cardiorenal and humoral function. Subjects then had a 50% reduction of the furosemide dose for a 3 week stabilization period, and were assessed for cardiorenal and humoral function again.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Mayo Clinic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
for Subjects with Compensated CHF without Renal Dysfunction: * Left ventricular ejection fraction of equal or less than 40% assessed by echocardiography, nuclear scan, MRI, or left ventriculogram within the past 36 months. * Stable New York Heart Association (NYHA) class II and III symptoms as defined by: a) no change in NYHA symptoms over the past 3 months; b) on stable doses of ACE inhibitor or beta blocker or digoxin or furosemide or angiotensin II receptor, type 1 (AT1) blocker over the past 3 months; c) no episode of decompensated CHF over the past 6 months. * Calculated creatinine clearance of equal or less than 80 ml/min, using the Cockcroft-Gault formula assessed within the past 36 months and a confirmatory calculated creatinine clearance equal or less than 80 ml/min at the time of enrollment. Inclusion Criteria for Subjects with Compensated CHF with Renal Dysfunction: * Left ventricular ejection fraction of equal or less than 40% assessed by echocardiography, nuclear scan or left ventriculogram within the past 36 months. * Stable New York Heart Association (NYHA) class II and III symptoms as defined by: a) no change in NYHA symptoms over the past 3 months; b) on stable doses of ACE inhibitor or beta blocker or digoxin or furosemide or AT1 blocker over the past 3 months; c) no episode of decompensated CHF over the past 6 months. * Calculated creatinine clearance of equal or less than 60 ml/min and greater than 20 ml/min, using the Cockcroft-Gault formula assessed within the past 36 months and a confirmatory calculated creatinine clearance equal or less than 60 ml/min and greater than 20 ml/min at the time of enrollment.
Exclusion criteria
for both groups: * Prior diagnosis of intrinsic renal diseases including renal artery stenosis of \> 50% * Peritoneal or hemodialysis within 90 days or anticipation that dialysis or ultrafiltration of any form will be required during the study period * Patients who are taking aldosterone antagonist * Hospitalization for decompensated CHF during the past 6 months * Subjects on other diuretics besides furosemide * Myocardial infarction within 6 months of screening * Unstable angina within 6 months of screening or any evidence of myocardial ischemia * Significant valvular stenosis, hypertrophic, restrictive or obstructive cardiomyopathy, constrictive pericarditis, primary pulmonary hypertension, or biopsy proven active myocarditis * Severe congenital heart diseases * Sustained ventricular tachycardia or ventricular fibrillation within 14 days of screening * Second or third degree heart block without a permanent cardiac pacemaker * Stroke within 3 months of screening or other evidence of significantly compromised central nervous system (CNS) perfusion * Alanine Aminotransferase (ALT) result \>1.5 times the upper limit of normal * Serum sodium of \< 125 milliequivalent (mEq)/dL or \> 150 mEq/dL * Serum potassium of \< 3.5 mEq/dL or \> 5.5 mEq/dL * Serum digoxin level of \> 2.0 ng/ml * Hemoglobin \< 10 gm/dl * Other acute or chronic medical conditions or laboratory abnormality which may increase the risks associated with study participation or may interfere with interpretation of the data * Received an investigational drug within 1 month prior to dosing * Patients with an allergy to iodine. * Female subject who is pregnant or breastfeeding * In the opinion of the investigator is unlikely to comply with the study protocol or is unsuitable for any reason.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Renal Function as Measured by Glomerular Filtration Rate (GFR) at Baseline and in Response to Decreasing Furosemide Dose | 3 weeks, approximately 6 weeks | Kidney function was measured by GFR determined by iothalamate clearance. GFR describes the flow rate of filtered fluid through the kidney measured in milliliters per minute per 1.73 m\^2 of body surface area. A lower GFR means the kidney is not filtering normally. An estimated GFR of less than 60 mg/min/1.73 m\^2 of body surface area is considered to be impaired kidney function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Renal Plasma Flow at Baseline and in Response to Decreasing Furosemide Dose | 3 weeks, approximately 6 weeks | Effective renal plasma flow (eRPF) is a measure used to calculate renal plasma flow (RPF) and hence estimate renal function. Renal plasma flow is the volume of blood plasma that flows through the kidneys per unit time, measured as ml/min. |
| Aldosterone at Baseline and in Response to Decreasing Furosemide Dose | 3 weeks, approximately 6 weeks | Aldosterone is part of the renin-angiotensin-aldosterone system (RAAS). Drugs that interfere with the secretion or action of aldosterone are in use as antihypertensives, like lisinopril, which lowers blood pressure by blocking the angiotensin-converting enzyme (ACE), leading to lower aldosterone secretion. The net effect of these drugs is to reduce sodium and water retention but increase retention of potassium. |
| Plasma Renin Activity at Baseline and in Response to Decreasing Furosemide Dose | 3 weeks, approximately 6 weeks | Plasma renin activity is a measure of the activity of the plasma enzyme renin, which plays a major role in the body's regulation of blood pressure, thirst, and urine output. Renin is an enzyme that hydrolyses angiotensinogen secreted from the liver into the peptide angiotensin I. Renin's primary function is to cause an increase in blood pressure, leading to restoration of perfusion pressure in the kidneys. |
| Angiotensin II at Baseline and in Response to Decreasing Furosemide Dose | 3 weeks, approximately 6 weeks | Renin activates the renin-angiotensin system by cleaving angiotensinogen, produced by the liver, to yield angiotensin I, which is further converted into angiotensin II by the angiotensin-converting enzyme (ACE) primarily within the capillaries of the lungs. Angiotensin II then constricts blood vessels, increases the secretion of antidiuretic hormone (ADH) and aldosterone, and stimulates the hypothalamus to activate the thirst reflex, each leading to an increase in blood pressure. |
| Plasma Cyclic Guanosine Monophosphate (cGMP) at Baseline and in Response to Decreasing Furosemide Dose | 3 weeks, approximately 6 weeks | Any change in atrial filling pressures leads to the release of atrial natriuretic peptides (ANP) from the heart. Once released, atrial peptides exert potent direct vasodilator and natriuretic actions by virtue of the ability to increase their intracellular second messenger, cGMP. Plasma cGMP correlates closely with the severity of congestive heart failure. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from outpatients being treated at the Mayo Clinic in Rochester, Minnesota.
Pre-assignment details
There was 1 screen failure and 8 subjects withdrew prior to group assignment: 1 due to chest pain, 1 due to surgical procedure scheduled to take place during treatment phase, 1 due to fluid overload, 2 due to time constraints of work and family issues, and 3 due to primary physician-initiated medication titration.
Participants by arm
| Arm | Count |
|---|---|
| Compensated CHF Without Renal Dysfunction Preserved renal function was defined as GFR greater than or equal to 60 mg/min/1.73m\^2. | 13 |
| Compensated CHF With Renal Dysfunction Renal Dysfunction was defined as GFR less than 60 mg/min/1.73m\^2. | 19 |
| Total | 32 |
Baseline characteristics
| Characteristic | Compensated CHF Without Renal Dysfunction | Compensated CHF With Renal Dysfunction | Total |
|---|---|---|---|
| Age, Continuous | 68 years STANDARD_DEVIATION 3 | 76 years STANDARD_DEVIATION 2 | 72.7 years STANDARD_DEVIATION 9.6 |
| Region of Enrollment United States | 13 participants | 19 participants | 32 participants |
| Sex: Female, Male Female | 4 Participants | 6 Participants | 10 Participants |
| Sex: Female, Male Male | 9 Participants | 13 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 13 | 1 / 19 |
| serious Total, serious adverse events | 0 / 13 | 2 / 19 |
Outcome results
Primary
Renal Function as Measured by Glomerular Filtration Rate (GFR) at Baseline and in Response to Decreasing Furosemide Dose
Kidney function was measured by GFR determined by iothalamate clearance. GFR describes the flow rate of filtered fluid through the kidney measured in milliliters per minute per 1.73 m\^2 of body surface area. A lower GFR means the kidney is not filtering normally. An estimated GFR of less than 60 mg/min/1.73 m\^2 of body surface area is considered to be impaired kidney function.
Time frame: 3 weeks, approximately 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Compensated CHF Without Renal Dysfunction | Renal Function as Measured by Glomerular Filtration Rate (GFR) at Baseline and in Response to Decreasing Furosemide Dose | Approximately 6 weeks | 73 ml/min | Standard Deviation 5 |
| Compensated CHF Without Renal Dysfunction | Renal Function as Measured by Glomerular Filtration Rate (GFR) at Baseline and in Response to Decreasing Furosemide Dose | Baseline (3 weeks) | 77 ml/min | Standard Deviation 3 |
| Compensated CHF With Renal Dysfunction | Renal Function as Measured by Glomerular Filtration Rate (GFR) at Baseline and in Response to Decreasing Furosemide Dose | Baseline (3 weeks) | 42 ml/min | Standard Deviation 3 |
| Compensated CHF With Renal Dysfunction | Renal Function as Measured by Glomerular Filtration Rate (GFR) at Baseline and in Response to Decreasing Furosemide Dose | Approximately 6 weeks | 50 ml/min | Standard Deviation 4 |
Comparison: Comparison between baseline dose of furosemide (3 weeks) versus reduced dose of furosemide (approximately 6 weeks).p-value: <0.05t-test, 2 sided
Comparison: Comparison between GFR taken at baseline dose Furosemide (3 weeks) versus normal GFRp-value: <0.05t-test, 1 sided
Secondary
Aldosterone at Baseline and in Response to Decreasing Furosemide Dose
Aldosterone is part of the renin-angiotensin-aldosterone system (RAAS). Drugs that interfere with the secretion or action of aldosterone are in use as antihypertensives, like lisinopril, which lowers blood pressure by blocking the angiotensin-converting enzyme (ACE), leading to lower aldosterone secretion. The net effect of these drugs is to reduce sodium and water retention but increase retention of potassium.
Time frame: 3 weeks, approximately 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Compensated CHF Without Renal Dysfunction | Aldosterone at Baseline and in Response to Decreasing Furosemide Dose | Baseline (3 weeks) | 7.9 ng/dL | Standard Deviation 1.8 |
| Compensated CHF Without Renal Dysfunction | Aldosterone at Baseline and in Response to Decreasing Furosemide Dose | Approximately 6 weeks | 7.6 ng/dL | Standard Deviation 1.3 |
| Compensated CHF With Renal Dysfunction | Aldosterone at Baseline and in Response to Decreasing Furosemide Dose | Baseline (3 weeks) | 4.9 ng/dL | Standard Deviation 0.6 |
| Compensated CHF With Renal Dysfunction | Aldosterone at Baseline and in Response to Decreasing Furosemide Dose | Approximately 6 weeks | 4.9 ng/dL | Standard Deviation 0.6 |
Secondary
Angiotensin II at Baseline and in Response to Decreasing Furosemide Dose
Renin activates the renin-angiotensin system by cleaving angiotensinogen, produced by the liver, to yield angiotensin I, which is further converted into angiotensin II by the angiotensin-converting enzyme (ACE) primarily within the capillaries of the lungs. Angiotensin II then constricts blood vessels, increases the secretion of antidiuretic hormone (ADH) and aldosterone, and stimulates the hypothalamus to activate the thirst reflex, each leading to an increase in blood pressure.
Time frame: 3 weeks, approximately 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Compensated CHF Without Renal Dysfunction | Angiotensin II at Baseline and in Response to Decreasing Furosemide Dose | Baseline (3 weeks) | 3.3 pg/mL | Standard Deviation 0.6 |
| Compensated CHF Without Renal Dysfunction | Angiotensin II at Baseline and in Response to Decreasing Furosemide Dose | Approximately 6 weeks | 3.4 pg/mL | Standard Deviation 1 |
| Compensated CHF With Renal Dysfunction | Angiotensin II at Baseline and in Response to Decreasing Furosemide Dose | Baseline (3 weeks) | 3.1 pg/mL | Standard Deviation 0.7 |
| Compensated CHF With Renal Dysfunction | Angiotensin II at Baseline and in Response to Decreasing Furosemide Dose | Approximately 6 weeks | 3.2 pg/mL | Standard Deviation 0.9 |
Secondary
Plasma Cyclic Guanosine Monophosphate (cGMP) at Baseline and in Response to Decreasing Furosemide Dose
Any change in atrial filling pressures leads to the release of atrial natriuretic peptides (ANP) from the heart. Once released, atrial peptides exert potent direct vasodilator and natriuretic actions by virtue of the ability to increase their intracellular second messenger, cGMP. Plasma cGMP correlates closely with the severity of congestive heart failure.
Time frame: 3 weeks, approximately 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Compensated CHF Without Renal Dysfunction | Plasma Cyclic Guanosine Monophosphate (cGMP) at Baseline and in Response to Decreasing Furosemide Dose | Baseline (3 weeks) | 5.0 pg/mL | Standard Deviation 0.9 |
| Compensated CHF Without Renal Dysfunction | Plasma Cyclic Guanosine Monophosphate (cGMP) at Baseline and in Response to Decreasing Furosemide Dose | Approximately 6 weeks | 4.6 pg/mL | Standard Deviation 0.7 |
| Compensated CHF With Renal Dysfunction | Plasma Cyclic Guanosine Monophosphate (cGMP) at Baseline and in Response to Decreasing Furosemide Dose | Baseline (3 weeks) | 5.7 pg/mL | Standard Deviation 0.8 |
| Compensated CHF With Renal Dysfunction | Plasma Cyclic Guanosine Monophosphate (cGMP) at Baseline and in Response to Decreasing Furosemide Dose | Approximately 6 weeks | 7.0 pg/mL | Standard Deviation 1 |
Comparison: Comparison between reduced dose Furosemide and baseline dose Furosemidep-value: 0.075t-test, 2 sided
Secondary
Plasma Renin Activity at Baseline and in Response to Decreasing Furosemide Dose
Plasma renin activity is a measure of the activity of the plasma enzyme renin, which plays a major role in the body's regulation of blood pressure, thirst, and urine output. Renin is an enzyme that hydrolyses angiotensinogen secreted from the liver into the peptide angiotensin I. Renin's primary function is to cause an increase in blood pressure, leading to restoration of perfusion pressure in the kidneys.
Time frame: 3 weeks, approximately 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Compensated CHF Without Renal Dysfunction | Plasma Renin Activity at Baseline and in Response to Decreasing Furosemide Dose | Baseline (3 weeks) | 4.3 ng/mL/hr | Standard Deviation 2 |
| Compensated CHF Without Renal Dysfunction | Plasma Renin Activity at Baseline and in Response to Decreasing Furosemide Dose | Approximately 6 weeks | 2.7 ng/mL/hr | Standard Deviation 1.1 |
| Compensated CHF With Renal Dysfunction | Plasma Renin Activity at Baseline and in Response to Decreasing Furosemide Dose | Baseline (3 weeks) | 2.1 ng/mL/hr | Standard Deviation 0.8 |
| Compensated CHF With Renal Dysfunction | Plasma Renin Activity at Baseline and in Response to Decreasing Furosemide Dose | Approximately 6 weeks | 1.4 ng/mL/hr | Standard Deviation 0.5 |
Secondary
Renal Plasma Flow at Baseline and in Response to Decreasing Furosemide Dose
Effective renal plasma flow (eRPF) is a measure used to calculate renal plasma flow (RPF) and hence estimate renal function. Renal plasma flow is the volume of blood plasma that flows through the kidneys per unit time, measured as ml/min.
Time frame: 3 weeks, approximately 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Compensated CHF Without Renal Dysfunction | Renal Plasma Flow at Baseline and in Response to Decreasing Furosemide Dose | Baseline (3 weeks) | 304 ml/min | Standard Deviation 19 |
| Compensated CHF Without Renal Dysfunction | Renal Plasma Flow at Baseline and in Response to Decreasing Furosemide Dose | Approximately 6 weeks | 293 ml/min | Standard Deviation 23 |
| Compensated CHF With Renal Dysfunction | Renal Plasma Flow at Baseline and in Response to Decreasing Furosemide Dose | Baseline (3 weeks) | 198 ml/min | Standard Deviation 20 |
| Compensated CHF With Renal Dysfunction | Renal Plasma Flow at Baseline and in Response to Decreasing Furosemide Dose | Approximately 6 weeks | 214 ml/min | Standard Deviation 21 |