A randomized trial of 67 acute heart failure patients found that low-dose BNP infusion with or without sildenafil increased plasma cGMP levels but did not improve kidney function or sodium excretion — an important negative result for peptide-based cardiorenal therapy.
cGMP increased but kidney function did not improveBNP plus sildenafil boosted plasma cGMP by 61% versus standard care, but this biochemical response failed to translate into better kidney function — demonstrating a disconnect between the signaling pathway and clinical outcome
What the researchers found
In 67 patients hospitalized with acute heart failure and renal dysfunction, both BNP alone and BNP combined with sildenafil (PDE-V inhibitor) significantly increased plasma cGMP at 24 hours: +25.6% with BNP and +60.8% with BNP/sildenafil versus -13.5% with standard care (P=0.001).
However, this biochemical response did not translate to clinical improvement. The coprimary endpoints showed no significant differences: eGFR change was 0% (standard care) vs 0% (BNP) vs -8.8% (BNP/sildenafil) (P=0.60), and BUN change was -1.4% vs -5.9% vs +6.9% (P=0.38). Urinary sodium and cGMP excretion also did not improve. Hypotension was more common in the BNP/sildenafil group, representing a safety concern.
Why it matters
Cardiorenal syndrome — simultaneous heart and kidney failure — is one of the deadliest complications of acute heart failure, with no specific approved therapy. BNP was a biologically rational choice because it's the body's own cardiac peptide hormone designed to protect the kidneys. The hypothesis that PDE-V upregulation in heart failure degrades the cGMP signal needed for kidney protection was mechanistically sound. This well-designed negative result is important because it closes a therapeutic hypothesis and redirects research effort toward other approaches.
How the study worked
Open-label randomized clinical trial (NCT00972569) with 67 patients hospitalized for acute heart failure with renal dysfunction, randomized to three arms: standard care, low-dose IV BNP (0.005 µg/kg/min), or combination BNP plus sildenafil (25 mg every 12 hours) for 48 hours. Coprimary endpoints were percent change in eGFR and BUN from baseline to 48 hours. Secondary endpoints included plasma cGMP, urinary sodium, and urinary cGMP excretion.
What this study cannot tell us
The study was open-label (not blinded), which could introduce bias in clinical management. The sample size of 67 patients limits statistical power for detecting modest treatment effects. Only one BNP dose was tested — higher doses might produce different results but were avoided due to hypotension risk. The 48-hour treatment duration may be too short for renal effects to manifest. The patient population was heterogeneous, and specific heart failure subtypes may respond differently.
How to read the evidence
This is a randomized clinical trial, a high level of evidence. However, it was open-label (not blinded), had a modest sample size (67 patients), and produced a negative result. The study is well-designed for a proof-of-concept investigation but lacks the power of larger blinded trials.
When this study was published
Published in 2024 in Circulation: Heart Failure, this is a very recent trial reflecting current understanding of natriuretic peptide physiology and the challenges of translating cardiorenal peptide therapy from bench to bedside.
The bigger picture
Natriuretic peptides (ANP, BNP, CNP) have long been attractive therapeutic candidates for heart failure because of their natural role in sodium excretion, vasodilation, and cardiac protection. Nesiritide (synthetic BNP) was previously approved for heart failure but fell out of favor after trials showed no mortality benefit and potential harm. This study represents another attempt to leverage the natriuretic peptide pathway — this time by combining BNP with PDE-V inhibition to amplify its signal — but the negative result suggests that the kidney's resistance to natriuretic peptide signaling in heart failure may be more complex than simple cGMP degradation.
Questions still open
- Is the kidney's resistance to BNP signaling in heart failure caused by mechanisms beyond PDE-V upregulation that sildenafil cannot address?
- Would longer treatment duration or different BNP dosing strategies produce different renal outcomes?
- Should future cardiorenal peptide therapies target neprilysin inhibition (as in sacubitril/valsartan) rather than direct natriuretic peptide infusion?
Common questions
What is BNP and why would infusing it help the kidneys?
Why did raising cGMP not improve kidney function?
Read the original research
Renal Effects of Combination Phosphodiesterase V Inhibition and Low-Dose B-Type Natriuretic Peptide in Acute Heart Failure: A Randomized Clinical Trial.
Circulation. Heart failure, 17(12), e011761
Citation
Hubers, Scott A; Benike, Sherry L; Johnson, Bradley K; McKie, Paul M; Scott, Christopher; Chen, Horng H. (2024). Renal Effects of Combination Phosphodiesterase V Inhibition and Low-Dose B-Type Natriuretic Peptide in Acute Heart Failure: A Randomized Clinical Trial.. Circulation. Heart failure, 17(12), e011761. https://doi.org/10.1161/CIRCHEARTFAILURE.124.011761