CORRESPONDENCE: RESEARCH CORRESPONDENCE
Nonhypotensive Low-Dose Nesiritide Has Differential Renal Effects Compared With Standard-Dose Nesiritide in Patients With Acute Decompensated Heart Failure and Renal Dysfunction
Henry G. Riter, MD,
Margaret M. Redfield, MD,
John C. Burnett, MD and
Horng H. Chen, MB, BCh*
* Cardiorenal Research Laboratory, Mayo Clinic and Foundation, Guggenheim 915, 200 First Street SW, Rochester, Minnesota 55905 (Email: chen.horng{at}mayo.edu).
To the Editor: Brain natriuretic peptide (BNP) is a cardiac peptide with vasodilating, renin-inhibiting, natriuretic, and diuretic properties (1). Human recombinant BNP (nesiritide) has been approved by the Food and Drug Administration for the management of acute decompensated congestive heart failure (CHF) (2). The standard recommended dose of nesiritide is a bolus of 2 µg/kg followed by infusion of 0.01 µg/kg/min. Although preclinical studies have demonstrated the renal-enhancing effects of systemic intravenous (IV) administration of BNP, the clinical trials that led to the Food and Drug Administration approval of BNP for the management of acute CHF have been conflicting with regards to the renal-enhancing properties of BNP (2–4). A recent study by Wang et al. (5) indicates that the standard recommended dose of nesiritide does not improve renal function in patients treated for acute decompensated CHF. Furthermore, a meta-analysis of the clinical trials suggested that nesiritide might even be detrimental to renal function in patients with acute decompensated CHF (6). One explanation for the discrepancy between the preclinical and clinical data could be in part that the dose used in these clinical studies resulted in significant decreases in blood pressure (BP) and hence renal perfusion pressure, attenuating the renal-enhancing effects. Supporting this hypothesis is our previous study in experimental CHF, which demonstrated that a low-dose subcutaneously administered BNP, which did not lower blood pressure, had a more beneficial renal hemodynamic profile than a higher dose that lowered BP (7).
The objective of the current study was to determine whether low-dose IV nesiritide would have greater renal-enhancing properties than standard-dose IV nesiritide in acute decompensated CHF. To address this question, we performed a retrospective review on consecutive patients admitted to Mayo Clinic Heart Failure Hospital Service for acute decompensated CHF from July 2001 to December 2004 who received nesiritide at doses lower than the standard dose. We identified a total of 15 patients: 13 received 0.005 µg/kg/min and 2 received 0.0025 µg/kg/min of nesiritide without bolus. We also compared these results with a group of patients (n = 13) who received the standard dose of nesiritide (2 µg/kg bolus followed by 0.01 µg/kg/min) and a group of patients (n = 12) who received diuretic therapy without nesiritide, matching for ejection fraction and calculated creatinine clearance (CrCl). Creatinine clearance was calculated using the Modification of Diet in Renal Disease formula: 
Results are expressed as mean ± SEM. Unpaired Student t test was used for comparisons between groups; comparisons within each group were done using paired Student t test.
Baseline demographics including age, ejection fraction, calculated creatinine clearance, plasma creatinine, and blood urea nitrogen (BUN) were similar among the three groups. The background medical therapy was also similar. The patients who received low-dose nesiritide had lower baseline systolic BP compared with patients who received standard-dose or no nesiritide (97 ± 3 mm Hg vs. 121 ± 6 mm Hg vs. 115 ± 6 mm Hg; p < 0.005).
Low-dose nesiritide was well tolerated without a significant decrease in systolic BP (from 97 ± 3 mm Hg to 99 ± 3 mm Hg; p > 0.05), whereas systolic BP decreased significantly with standard-dose nesiritide (from 121 ± 6 mm Hg to 112 ±6 mm Hg; p < 0.05) and no nesiritide (from 115 ± 6 mm Hg to 106 ± 6 mm Hg; p < 0.05).
Patients in the low-dose nesiritide group had improvement in renal function as measured by improvement of plasma Cr recorded at baseline documented before the start of IV therapy compared with the values after IV therapy (Fig. 1). This improvement of plasma creatinine was also associated with a decrease in BUN (from 78 ± 9 mg/dl to 57 ± 8 mg/dl; p < 0.005) in the low-dose nesiritide group. Renal function as measured by plasma creatinine and BUN did not improve in the standard-dose nesiritide and no-nesiritide groups. Patients in the low-dose nesiritide group received less furosemide dose compared with the standard-dose nesiritide and no-nesiritide groups (150 ± 39 mg vs. 389 ± 71 mg vs. 345 ± 115 mg of furosemide) while achieving similar diuresis (–1,601 ± 600 ml vs. –1,677 ± 910 ml vs. –1,052 ± 679 ml) during the IV therapy period.
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Figure 1 Plasma creatinine at baseline (open bars) and after therapy (solid bars) with low-dose nesiritide (Low Nes), standard-dose nesiritide (Standard Nes) and no-nesiritide (No Nes) groups. *p < 0.05 versus baseline.
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The mechanism of the associated improvement in renal function observed in the low-dose nesiritide group is most likely multifactorial, and we hypothesize that the improvement was due in part to the fact that systolic BP was not reduced in this group. The significant reduction in systolic BP observed in the standard-nesiritide and no-nesiritide groups may have resulted in activation of counter-regulatory mechanisms, such as the sympathetic and the renin-angiotensin systems, thus attenuating the renal enhancing properties of nesiritide. Supporting this hypothesis is a study by Brunner-La Rocca et al. (8) that demonstrated that the sympathoinhibitory effects of BNP were greater with low-dose (0.003 µg/kg/min) infusion, which did not alter hemodynamics, as compared with a higher dose (0.015 µg/kg/min) infusion, which reduced BP.
In conclusion, further prospective randomized controlled studies are warranted to test the efficacy of non-hypotensive low-dose nesiritide such as 0.005 µg/kg/min and the current dose of 0.01 µg/kg/min without the bolus of 2 µg/kg/min in enhancing renal function in patients with acute decompensated CHF and renal dysfunction as well as defining the mechanisms of the renal-enhancing actions of such a strategy.
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Footnotes
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Please note: Dr. Redfield, Dr. Burnett, and Horng H. Chen have all received research grants from Scios Inc. However, no research grant was received for this study.
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References
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1. Chen HH, Burnett Jr JC. The natriuretic peptides in heart failurediagnostic and therapeutic potentials. (review) Proc Assoc Am Physicians 1999;111:406-416.[Web of Science][Medline]2. Publication Committee for the VMAC Investigators Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failurea randomized controlled trial. JAMA 2002;287:1531-1540.[Abstract/Free Full Text] 3. Colucci WS, Elkayam U, Horton DP, et al. Nesiritide Study Group Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure(erratum appears in N Engl J Med 2000;343:896) N Engl J Med 2000;343:246-253.[Abstract/Free Full Text] 4. Marcus LE, Hart D, Packer M, et al. Hemodynamic and renal excretory effects of human brain natriuretic peptide infusion in patients with congestive heart failure Circulation 1996;94:3184-3189.[Abstract/Free Full Text] 5. Wang DJ, Dowling TC, Meadows D, et al. Nesiritide does not improve renal function in patients with chronic heart failure and worsening serum creatinine Circulation 2004;110:1620-1625.[Abstract/Free Full Text] 6. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure Circulation 2005;111:1487-1491.[Abstract/Free Full Text] 7. Chen HH, Grantham JA, Schirger JA, Michihisa J, Redfield MM, Burnett Jr JC. Subcutaneous administration of brain natriuretic peptide in experimental heart failure J Am Coll Cardiol 2000;36:1706-1712.[Abstract/Free Full Text] 8. Brunner-La Rocca HP, Kaye DM, Woods RL, Hastings J, Esler MD. Effects of intravenous brain natriuretic peptide on regional sympathetic activity in patients with chronic heart failure as compared with healthy control subjects J Am Coll Cardiol 2001;37:1221-1227.[Abstract/Free Full Text]
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