BNP and NT-proBNP: how they differ, what it means

Of 1,296 ED patients, 933 had diagnostically concordant BNP and NT-proBNP results (72 percent), 340 (26 percent) were partially discordant, and 23 (two percent) were fully discordant. (The weighted kappa statistic for concordance between BNP and NT-proBNP in the acute ED setting was 0.695 [95 percent CI, 0.688–0.723].) “It’s not dramatic,” he said of the two percent. “It’s not 50 percent of patients, but it’s not zero. There are clearly going to be different answers in some populations.”

“So for institutions that are transitioning to a different biomarker for natriuretic peptides for heart failure analysis, you just have to know you can’t just switch from one assay to the other.”

In the case of the 72-year-old patient with a BNP of 90 pg/mL and an NT-proBNP of 1,100 pg/mL, “NT-proBNP is saying ‘this patient has heart failure,’ and BNP is saying ‘maybe you have to do a little more work.’” A slightly different workup was done for this patient, and he was ruled in for heart failure.

The reasons these molecules can be discordant sometimes are clear, he says. In another case, a 65-year-old male with a history of end-stage renal disease had an eGFR of <15 mL/min/1.73m² and stage four heart failure with an ejection fraction of 38 percent. He was taking ACE inhibitors, diuretics, and a beta blocker. “How much did his end-stage renal disease or his impaired kidney function really impact [HF] biomarkers?” Dr. Farnsworth asked.

The most significant impact of ESRD would be on NT-proBNP, he said, “and it actually has almost everything—at least we think it has everything—to do with the mechanisms of clearance” (Lafontan M, et al. Arterioscler Thromb Vasc Biol. 2005;25[10]:​2032–2042).

BNP is receptor mediated and proteolytic in clearance, Dr. Farnsworth said. “It’s a hormone,” so it will be endocytosed by its receptor and then degraded, or proteolytically cleaved and broken down as it circulates in the plasma. NT-proBNP, in contrast, is believed to be a relatively inert molecule. Since it’s mostly cleared renally, patients with impaired renal function have reduced renal clearance of NT-proBNP.

In their study, Dr. Farnsworth and his coauthors broke patients down by CKD stage, from one—indicating relatively normal if not completely normal kidney function—to five, which was ESRD. “These patients are generally on dialysis or awaiting a transplant or had a transplant,” he said. Fig. 1 shows the increased NT-proBNP concentrations relative to BNP concentrations in patients with CKD. “Normal patients should be around three or four—so four times higher NT-proBNP relative to BNP,” Dr. Farns­worth said.

But as renal function decreases, NT-proBNP increases relative to BNP concentrations, he said, “to the point where it jumps almost to a four- or fivefold increase relative to baseline.”

Farnsworth, et al., wrote, “CKD had a profound negative effect on concordance between the two methods.”

Fig. 2 shows the increased NT-proBNP relative to BNP in patients with CKD. He and his coauthors wrote that “these results indicate that diagnostic concordance between natriuretic peptides is decreased, at least in part, by increased NT-proBNP relative to BNP in patients with CKD. This suggests that different cutoffs may be required in patients with CKD.”

A study published in 2020 of CKD patients with and without atrial fibrillation reaffirmed the impact, Dr. Farns­worth said (Rørth R, et al. Circ Heart Fail. 2020;13[2]:e006541). Similar to his group’s data, patients with end-stage renal disease (eGFR<60 and with AF) had a ratio of NT-proBNP to BNP of about 10:1, when the expectation would be around 3:1 or 4:1, he said. For patients with improved or normal renal function, Rørth, et al., found the ratio of NT-proBNP to BNP to be closer to 6:1, Dr. Farnsworth said.

As in the case of the 65-year-old male with ESRD and stage four heart failure, “what you see in patients with end-stage renal disease is the NT-proBNP is going to be higher relative to the BNP,” he said.

Dr. Farnsworth presented a third case: a 58-year-old female with a history of stage three heart failure (ejection fraction 39 percent) and on an angiotensin receptor-neprilysin inhibitor (ARNI). Does it matter whether BNP or NT-proBNP is used?

An ARNI, he explained, is usually a mixture of two drugs: sacubitril and valsartan. Valsartan is an angiotensin II receptor blocker and works like an ACE (angiotensin-converting enzyme) inhibitor, helping to lower blood pressure and improve diuresis. It’s given with sacubitril, a neprilysin inhibitor. “Neprilysin is one of the primary enzymes that proteolytically cleaves BNP,” so the thought is that sacubitril will inhibit neprilysin along with BNP to remain elevated for a longer time, he said. “Since BNP is a circulating hormone, it has important physiologic direct effects, such as improved diuresis.”

ARNI therapy was compared with an ACE inhibitor in a double-blind trial of 8,399 patients with heart failure and reduced ejection fraction (Packer M, et al. Circulation. 2015;131[1]:54–61). The authors measured NT-proBNP in randomized patients at entry and again eight months later. At eight months, they found levels of NT-proBNP in the ARNI group had decreased significantly, from a median of around 1,200 pg/mL to around 900 pg/mL, Dr. Farnsworth said, while NT-proBNP concentrations in the ACE inhibitor group did not change across the population.

Contrasted with BNP measured in the same patients, using the same protocol, at the same time, no decrease of BNP concentrations was found in the ARNI group, he said. “There’s actually a slightly significant increase, which physiologically and chemically makes sense” because patients received a drug that should increase BNP concentration. In contrast, BNP levels in the ACE inhibitor group decreased slightly.

Packer, et al., wrote, “[b]ecause BNP (but not NTproBNP) is a substrate for neprilysin, levels of BNP will reflect the action of the drug, whereas levels of NTproBNP will reflect the effects of the drug on the heart.”

“What they’re saying is, ‘If you want to monitor how well these patients are doing, you should monitor NT-proBNP, not BNP,’” Dr. Farns­worth said. “You’re expecting that BNP is not going to change, so you should use NT-proBNP as your primary marker.” A close look at the data revealed: “Just intuitively speaking, across a population level, there’s clearly a difference,” Dr. Farnsworth said. “But patient to patient, the difference is not all that clear based on the study data.”

In a study published this year of 335 patients with advanced heart failure treated with a sacubitril/valsartan combination or with valsartan alone, the authors found “no statistically significant difference between sacubitril/valsartan and valsartan with respect to reducing NT-proBNP levels” (Mann DL, et al. JAMA Cardiol. 2022;7[1]:17–25).

“What this implies, at least to me perhaps, is that NT-proBNP is not necessarily more helpful than BNP for monitoring patients on ARNI therapy, and maybe it’s not the reason we should be choosing biomarkers,” Dr. Farnsworth said.

In the case of the 58-year-old female patient with stage three heart failure and who was treated with ARNI, Dr. Farnsworth said this of the choice of biomarker: “I personally don’t think it matters.”

The Barnes-Jewish Hospital core laboratory has platforms for both assays—BNP and NT-proBNP—but its primary instrument on the automated line uses the NT-proBNP assay. “It helped a little with turnaround time and helped increase throughput,” Dr. Farnsworth tells CAP TODAY.

“Whichever platform your hospital has is probably the one you should use,” he advises. “It’s going to be more dependent on which instruments you use and less dependent on studies,” like those he highlighted, “and perhaps some physiologic differences.”

Of his laboratory’s switch to NT-proBNP in 2017, he says: “It’s difficult to switch to an assay that has at best modest correlation with the previous assay. Interestingly, we received almost no feedback from the providers,” likely owing to the “significant education” provided pre-transition and the three-month overlap.

What might lie ahead for the BNP and NT-proBNP biomarkers? An emerging area, he says, is the appropriate use of cutpoints and reference intervals in pediatrics. He and his coauthors wrote a paper (Tawiah KD, et al. Clin Biochem. Published online Aug. 5, 2022. doi:10.1016/j.clinbiochem.​2022.08.003) on a similar study comparing BNP and NT-proBNP in a pediatric population.

“The problem is that the biomarkers are used for dramatically different purposes and there are not established cutpoints or reference intervals like those for adults,” which he notes is generally true across all pediatric reference intervals. “They are not particularly well defined,” he says. While it’s far rarer that pediatric patients would need BNP or NT-proBNP testing than adults, “for those who do, it is important for monitoring of various cardiac pathologies. Applying the correct reference intervals for each test will be crucial to how providers interpret results,” he says, “especially when institutions change assays or children move between institutions.”

Amy Carpenter Aquino is CAP TODAY senior editor.