What factors can make B-type Natriuretic Peptide (BNP) levels unreliable, falsely high, or low?

Factors Affecting BNP Reliability

BNP and NT-proBNP levels can be falsely elevated by renal dysfunction, advanced age, female sex, atrial fibrillation, and sepsis, while obesity, nesiritide therapy, and certain presentations of HFpEF can cause falsely low values that may mislead clinical decision-making. 1, 2

Factors Causing Falsely Elevated BNP/NT-proBNP

Renal Impairment

• Renal dysfunction significantly elevates NT-proBNP more than BNP due to reduced clearance, with severe renal failure (GFR <30 mL/min/1.73 m²) making both detection and exclusion of heart failure less accurate despite adjusted cutoffs 1, 3
• Adjusted thresholds of 1200 pg/mL for NT-proBNP should be used when GFR <60 mL/min/1.73 m² 3
• Renal impairment increases NT-proBNP concentrations to a greater extent than BNP 1

Age and Sex

• Age substantially influences what may be considered physiological concentrations, with older patients (>75 years) having higher baseline BNP levels 1, 3
• Age-adjusted cutoffs are recommended: 450 pg/mL for patients <50 years, 900 pg/mL for patients 50-75 years, and 1800 pg/mL for patients >75 years 3
• Female sex is associated with higher BNP levels compared to males at any given level of cardiac dysfunction 1, 2

Cardiac Arrhythmias

• Atrial fibrillation significantly affects BNP levels and interpretation, with median NT-proBNP levels 20-30% higher in patients with atrial fibrillation 1, 3, 2
• The diagnostic accuracy for detecting heart failure is reduced in the setting of atrial fibrillation, warranting careful interpretation 1

Non-Cardiac Conditions

• Pulmonary conditions including pulmonary embolism, pulmonary hypertension, and severe COPD can cause marked elevation of natriuretic peptides 1, 3
• Sepsis and systemic inflammation can contribute to elevated levels, especially with cardiac involvement 1, 2
• Hyperthyroidism overestimates BNP values 2

Assay-Related Issues

• BNP assays detect proBNP in addition to mature BNP, meaning current BNP values represent proBNP plus BNP, which can lead to higher measured values 1, 2
• Macro-proBNPemia (high molecular weight immunoreactive proteins) can cause false positive results in specific assay platforms 2, 4
• No peer-reviewed literature has demonstrated that two natriuretic peptide assays are analytically equivalent, so caution is needed when comparing results from different assays 1

Factors Causing Falsely Low BNP/NT-proBNP

Obesity

• Obesity has an inverse relationship with BNP and NT-proBNP concentrations, with each unit increase in BMI correlating with lower natriuretic peptide levels 1, 3
• Patients with BMI >30 kg/m² have significantly lower BNP levels (median 332 pg/mL) compared to those with BMI <20 kg/m² (median 747 pg/mL) despite similar cardiac dysfunction 1
• Severe obesity (BMI >35 kg/m²) reduces sensitivity for detecting heart failure, and obese patients with HFpEF may have BNP levels of only 60-100 pg/mL despite symptomatic heart failure 1, 3
• Some of this variability is related to lean body mass, perhaps as a manifestation of testosterone metabolism, as androgens reduce BNP and NT-proBNP levels 1

Heart Failure with Preserved Ejection Fraction (HFpEF)

• Patients with HFpEF have lower BNP levels than those with HFrEF because they have a small LV cavity and thick LV walls with end-diastolic wall stress being much lower, producing less stimulus for BNP production 1, 5
• Increased clearance and enhanced degradation of natriuretic peptides in HFpEF contribute to lower BNP levels 5
• Reduced myocardial wall stress in HFpEF is associated with low BNP compared to HFrEF 5

Medication Effects

• Nesiritide (human recombinant BNP) therapy can confound BNP results since it is molecularly identical to endogenously released BNP, potentially causing false increased concentrations if measured before appropriate clearance 1
• Conversely, nesiritide does not directly confound NT-proBNP measurements 1

Specific Clinical Scenarios

• Flash pulmonary edema may present with only slightly elevated BNP at initial presentation, though levels can rise markedly over time despite adequate treatment 1
• Immediately after acute coronary syndrome onset, BNP values may be underestimated 2
• Pericardial effusion can underestimate BNP values 2

Ethnic Variations

• NT-proBNP levels vary by ethnicity, with African American patients exhibiting lower levels, potentially linked to salt-sensitive hypertension and left ventricular hypertrophy 5

Critical Interpretation Considerations

Biological Variability

• Both BNP and NT-proBNP exhibit high intra-individual biological variability (30-50%), requiring changes of approximately 85% for increases and 46% for decreases to be considered clinically significant 1
• Only changes >50% in NT-proBNP or >70% in BNP should be considered clinically significant when monitoring serial measurements 1, 3

Timing of Measurement

• Adequate diuresis may be required before evaluating natriuretic peptide levels, as euvolemic BNP/NT-proBNP levels may be more accurate for prognostic assessment and therapy guidance 1, 3
• In the perioperative setting, normal fluctuations differ significantly from stable heart failure patients, with median increases of 238-292% regardless of cardiac events 1

Clinical Context Requirements

• BNP and NT-proBNP should never be used as standalone tests but rather as confirmation biomarkers integrated with comprehensive clinical assessment and confirmatory cardiac imaging 1, 3
• The diagnostic accuracy requires integration with clinical assessment, as specificity is variable across the range of values 3