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TREATMENT REVIEW
Diagnostic and Therapeutic
Utility of B-Type Natriuretic
Peptide in Patients With
Renal Insufficiency and
Decompensated Heart Failure
Peter A. McCullough, MD, MPH, FACC, FACP, FCCP FAHA,* Kuncheria Joseph, MD,† Vandana S. Mathur, MD‡ *Divisions of Cardiology, Nutrition and Preventive Medicine, William Beaumont Hospital, RoyalOak, MI, †Bon Secours Hospital, Venice, FL, ‡Department of Medicine, Department of Nephrologyand Renal Transplantation, University of California San Francisco, San Francisco, CA Chronic kidney disease (CKD) and congestive heart failure (CHF) are epidemiologicallyand pathophysiologically linked. A recent study in patients with severe CHF demonstratedthat renal plasma flow was inversely correlated with pulmonary capillary wedge pres-sure, right atrial pressure, pulmonary pressure, and right ventricular ejection fraction.
This article reviews the utility of B-type natriuretic peptide (BNP) levels in assessingcardiac function and volume status in patients with CKD and examines the safetyand efficacy of BNP therapy in patients with renal insufficiency and decompensatedheart failure. [Rev Cardiovasc Med. 2004;5(1):16-25] Key words: Congestive heart failure • Renin-angiotensin-aldosterone system •
B-type natriuretic peptide • Nesiritide • Chronic kidney disease
Only 16% of chronic kidney disease (CKD) patients who have reached end-stage renal disease (ESRD) have echocardiographically normal leftventricles,1 and 40% have clinically diagnosed congestive heart failure (CHF).2 The activation of the renin-angiotensin-aldosterone system (RAAS),sympathetic nervous system (SNS), and endothelin-1 by heart failure reduces VOL. 5 NO. 1 2004 REVIEWS IN CARDIOVASCULAR MEDICINE Utility of B-Type Natriuretic Peptide
losclerosis, tubulointerstitial fibrosis, patients with glomerular filtrationrates (GFRs) of 50 mL/min to 75mL/min, 25 mL/min to 50 mL/min, Chronic CHF and CKD may aggravate the progression of each other, leading to an inexorable vicious cycle and accelerated cardiac and renal fibrosis. approximately 30%, 33%, and 49%,respectively. Chronic Kidney Disease and
Congestive Heart Failure
past 15 years.19 According to the U.S.
VOL. 5 NO. 1 2004 REVIEWS IN CARDIOVASCULAR MEDICINE 17 Utility of B-Type Natriuretic Peptide continued
presentation with acute decompen-sated CHF are typically due to renal Aldosterone
Angiotensin II
acute CHF. IV diuretics have beenshown to cause significant increases Figure 1. Central role of the renin-angiotensin-aldosterone axis in progressive cardiomyopathy and chronic kidney
disease. CHF, congestive heart failure; CKD, chronic kidney disease; LVH, left ventricular hypertrophy. within 20 minutes of administra-tion.36 Hence, while helpful in clear- ulation is reflected by studies ofpatients with advanced CHF (andmean serum creatinine (Cr) of Hence, while helpful in clearing pulmonary congestion, the early and singular use of IV loop diuretics further activates the RAAS and SNS while leading to elevations in Cr in many patients. from universal (VMAC, 69%15;OPTIME, 69%28). Renal Function as a Predictor
of Outcome
Natriuretic Peptides and Acute
Neurohormonal Activation
Heart Failure
strongest independent predictors ofmortality among U.S. patients whowere hospitalized with a primary Adverse Consequences of Chronic Systemic and
Tissue Level RAAS Activation
60-day hospital readmissions amonga Medicare cohort (N = 2176) with • Coronary atherosclerosis vasoconstriction • Prothrombotic effects/increased plasminogen RAAS, renin-angiotensin-aldosterone system Data from: Epstein M,5 Brewster UC, et al,6 and Hostetter TH, et al.23 VOL. 5 NO. 1 2004 REVIEWS IN CARDIOVASCULAR MEDICINE Utility of B-Type Natriuretic Peptide
Correlation of Systemic Hemodynamic Parameters to
Renal Plasma Flow in Heart Failure Patients45
epithelial and mesangial cells insmaller quantities.7 Both peptidesagonize the guanylate cyclase-cou- Hemodynamic Parameter
r-value for Correlation With RPF
P Value
Renal plasma flow did not correlate significantly with cardiac index, systemic vascular resistance PCWP, pulmonary capillary wedge pressure; PAP, pulmonary artery pressure; RAP, right atrialpressure; RVEF, right ventricular ejection fraction. Data from: Kos, et al.45 BNP, but not ANP.37,38 Both ANP andBNP are cleared by neutral endopep-tidase (NEP 24.11), which is found differences in physiologic response.
VOL. 5 NO. 1 2004 REVIEWS IN CARDIOVASCULAR MEDICINE 19 Utility of B-Type Natriuretic Peptide continued
Figure 2. (A) Effect of nesiritide
(NES) on urine volumes over 6 hours.
(B) Effect of nesiritide on clinical
by blinded patients (PT) and physi- BNP Levels in Patients With
Physiologic Effects of B-Type Natriuretic Peptide
Renal Disease
A number of studies have examined
Observed Physiologic
or Clinical Effect
Known or Presumed Mechanism
Reference
Direct inhibition of aldosterone, renin, secondary to improvements in cardiac function and inhibition of endothelin-1, Enhanced potassium secretion secondary 55 to natriuretic effects balanced by aldosterone inhibition Arterial dilatation and potential reflexive VOL. 5 NO. 1 2004 REVIEWS IN CARDIOVASCULAR MEDICINE Utility of B-Type Natriuretic Peptide
that BNP is not significantly (if at all) reduction in BNP with a dialysis ses-sion may prove to be an importantindicator of optimally reduced left Nesiritide was significantly better at reducing PCWP than placebo plus standard therapies and intravenous nitroglycerin plus standard therapies. Physiologic Effects of BNP
BNP has myriad physiologic and
ics, they either reduce renal filtrationfunction or activate adverse neuro- Hemodynamic Effects of Nesiritide
Improvements in
Nesiritide Nesiritide
Cardiopulmonary
0.015 µg/kg/min
0.030 µg/kg/min
P Value
Hemodynamics and Heart
Failure Symptoms
Nesiritide consistently and rapidly
and pulmonary artery pressures,and it increases cardiac index in a Values are means + SD. P values are for the comparison among all three groups, calculated with the * P < .001 for the pairwise comparison with placebo, by the F test. † P < .05 for the pairwise comparison with placebo, by the F test.
PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; SVR, systemic vascular resistance; CI, cardiac index; SBP, systolic blood pressure. VOL. 5 NO. 1 2004 REVIEWS IN CARDIOVASCULAR MEDICINE 21 Utility of B-Type Natriuretic Peptide continued
even in the absence of urine output.
effects predicts that its use as a natri- conducted. It may be possible, withthe early use of nesiritide in com-bined kidney failure and CHF, to It may be possible, with the early use of nesiritide in combined kidney failure and CHF, to reduce the use of additional therapies, including pies, including inodilators. Thus,the use of additional hospital resources and risks of invasive hemo-dynamic monitoring and arrhyth- Management of Patients With
or GFR occurred (despite natriuresis).
Chronic Kidney Disease and
Chronically Decompensated
Heart Failure
Natriuresis and Renal
Function Preservation in
Heart Failure
VOL. 5 NO. 1 2004 REVIEWS IN CARDIOVASCULAR MEDICINE Utility of B-Type Natriuretic Peptide
days (10% vs 23%, P = .06), and the > 65, history of sustained ventriculartachycardia, ischemic etiology ofCHF, history of diabetes, outpatient FUSION data suggest that serial outpatient infusions of nesiritide given to patients with advanced heart failure who are at high risk for hospitalization potentially reduces morbidity and mortality due to heart failure. ly infusions of nesiritide in an out-patient setting in patients with VOL. 5 NO. 1 2004 REVIEWS IN CARDIOVASCULAR MEDICINE 23 Utility of B-Type Natriuretic Peptide continued
plasma endothelin-1 levels in patients withdecompensated congestive heart failure. Am J Stevens TL, Burnett JC, Kinoshita M, et al. Afunctional role for endogenous atrial natri- uretic peptide in a canine model of early left ventricular dysfunction. J Clin Invest. 1995;95:1101-1108.
Full Prescribing Information for NATRECOR Maisel A, Cremo R, Gardetto N. The effects of nesiritide on serum levels of B-type natriuretic peptide (BNP) in patients admitted for decom-pensated congestive heart failure [abstract]. J References
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Main Points
• B-type natriuretic peptide (BNP), produced by the cardiac ventricles and, to a small degree, by the renal glomerular
epithelial and mesangial cells, is a counter-regulatory hormone that physiologically opposes and suppresses the RAASendothelin-1 and the SNS.
• Baseline renal function and renal functional changes are important predictors of outcome in acute heart failure. • Independent of age, left ventricular ejection fraction, diabetes, and discharge Cr level, even small deteriorations in renal function (Cr elevations of 0.2 mg/dL) during hospitalization for acute CHF, are predictors of increased mortality.
• As a therapy, BNP is the only available compound that creates improvements in both renal and cardiac function when • The ability of nesiritide to suppress sodium retentive and renal vasoconstrictive neurohormonal systems while exerting natriuretic effects predicts that its use as a natriuretic should not be hindered by worsening renal function,as occurs with conventional diuretics.
• In patients with acute worsening of renal function in the setting of acute CHF, nesiritide would be expected to improve renal function by inhibiting renal vasoconstrictive hormones that are mediating the renal functional decline.
• FUSION demonstrated that weekly infusions of nesiritide in an outpatient setting in patients with advanced CHF were • There may be a role for long-term intermittent treatment with nesiritide in high-risk patients with advanced VOL. 5 NO. 1 2004 REVIEWS IN CARDIOVASCULAR MEDICINE Utility of B-Type Natriuretic Peptide
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