Khalifeh, Neda; Haider, Dominik; Hörl, Walter H.
The 3 major natriuretic peptides, namely atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide play a major role in sodium and body volume homeostasis, thereby protecting the cardiovascular system from the effects of volume overload.1 The biological actions of natriuretic peptides are mediated through membrane-bound natriuretic peptide receptors (NPRs). Natriuretic peptide receptor-A preferentially binds ANP and BNP, whereas NPR-B preferentially binds C-type natriuretic peptide. Clearance of natriuretic peptides from blood is mediated by NPR-C. B-type natriuretic peptide has emerged as a superior biomarker to ANP for clinical applications. This is the explanation why BNP and associated metabolites are widely used. The natriuretic peptide receptors responsible for the metabolism of BNP are located in the liver, lung, kidney and vascular endothelium. In addition, BNP is degraded by neutral endopeptidase.2-4 Glomerular filtration and passive renal excretion might be responsible for some BNP clearance as well.1 A number of triggers, such as ventricular wall stretch, derangements in systemic blood pressure as well as increases in extracellular volume and sodium balance initiates the synthesis of pre-proBNP(134 amino acids) in left ventricular myocytes. Subsequently, the peptide is cleaved first to proBNP(1-108) and a 26 amino acids containing peptide. ProBNP is then secreted from myocytes and further cleaved by a membrane-bound serine protease (corin) to the biologically active BNP(77-108) and the 76 amino acids containing inactive amino-terminal fragment (NT-proBNP).1,5,6 NT-proBNP clearance is believed to occur solely in the kidney.7 Thus, its levels show stronger correlation with estimated glomerular filtration rate (eGFR) than do BNP levels.8 The different routes of elimination and degradation are reflected in different circulating half-lives for BNP (20 minutes) and NT-proBNP (120 minutes).5 Thus, NT-proBNP level may be more stable.6 B-type natriuretic peptide and NT-proBNP have a molecular weight of approximately 3.5 kDa and 8.5 kDa, respectively.
BNP AND NT-PROBNP IN CHRONIC KIDNEY DISEASE
If BNP and NT-proBNP are used for in vitro diagnostics, one has to consider that circulating BNP and NT-proBNP levels depend on kidney function.9,10 Even in patients with impairment of kidney function, however, natriuretic peptides parallel the presence and severity of cardiac dysfunction and offer powerful prognostic information.11 Among 831 dyspnea patients (393 with kidney disease defined as eGFR <60 mL/min/1.73 m2), NT-proBNP and BNP were equivalent predictors of decompensated heart failure across a spectrum of renal function, but NT-proBNP was a superior predictor of mortality.12 Compared with the lowest quartile, quartile 4 of BNP had an adjusted hazards ratio (HR) of 2.6 and quartile 4 of NT-proBNP had an HR of 4.5. Only NT-proBNP remained a predictor of death after adjustment for comorbidities, renal function, diagnosis of decompensated heart failure, and other natriuretic peptide markers.12 Direct comparison of BNP and NT-proBNP in a large population of patients with chronic and symptomatic heart failure indicated that NT-proBNP was superior to BNP for predicting mortality and morbidity or hospitalization for heart failure.13 NT-proBNP and BNP levels were found to be significant and equivalent indicators of coronary artery disease and left ventricular hypertrophy (LVH) not only in the general population but also in asymptomatic patients with chronic kidney disease (CKD).14 In the setting of impaired renal function, NT-proBNP was predictive of 60-day outcome in patients presenting with acute decompensated heart failure.15 NT-proBNP did predict mortality in a group of 140 renal transplant candidates at a cut-off value of 350 pg/ml. Patients with raised NT-proBNP had a larger left ventricular (LV) cavity, reduced systolic function and higher LV filling pressure than those without.16 These data indicate that raised NT-proBNP concentrations are in part due to reduced renal excretion, but also reflect cardiac damage (Table 1).
In patients with CKD and particularly in those with end-stage renal disease (ESRD), plasma BNP, and especially NT-proBNP levels are by far higher as compared with subjects with normal kidney function due to the fact that predominantly NT-proBNP accumulates with the decline in kidney function.7,17 B-type natriuretic peptide and its metabolites are normally excreted by the kidneys.18,19 As mentioned previously, however, the reduced renal clearance is not the sole cause of the markedly elevated BNP and NT-proBNP levels seen in patients with ESRD.1 Several factors, such as comorbidity, the type of the dialyzer used for hemodialysis (HD), total body water, extracellular water content, rate of ultrafiltration, residual renal function, changes in blood pressure, medications, and/or intradialytic body changes may influence circulating levels of natriuretic peptides in ESRD patients and the dialysis patient population. Accordingly, 99% of ESRD patients20 and 100% of the HD patients21 have elevated plasma NT-proBNP levels. Plasma levels of natriuretic peptides are considered to be significant predictors of LV dysfunction, cardiac events, and survival in patients with ESRD.22
Austin et al.23 compared 2 BNP assays (Biosite Incorporated, San Diego, CA; Bayer, Leverkusen, Germany) with the NT-proBNP assay (Roche, Mannheim, Germany) in 171 patients with CKD and a mean serum creatinine level of 2.3 mg/dL (mean GFR 41 mL/min/1.73 m2). NT-proBNP correlated well with BNP in all cases (r = 0.911; P < 0.01), regardless of degree of renal impairment or type of left ventricular dysfunction. A BNP level of 175 pg/mL and an NT-proBNP level of 1,250 pg/mL identified in this study patients with CKD stage III at high risk for mortality or cardiac hospitalization.23 Nevertheless, there are differences with clinical relevance between BNP and NT-proBNP/BNP, at least in CKD patients: As mentioned previously, NT-proBNP appears to be affected more than BNP by declining kidney function due to the fact that its clearance is exclusively renal. Vickery et al.24 found in a cohort of 213 patients with CKD and a median eGFR of 18 mL/min/1.73 m2 that mean plasma BNP concentration increased by 20.6% per 10 mL/min/1.73 m2 reduction in eGFR compared with 37.7% for NT-proBNP. NT-proBNP/BNP ratio increased with CKD stage from 3.7 in stage 3, to 5.9 in stage 4 and to 7.7 in stage 5. In HD patients, NT-proBNP ratio was 28.0 before HD treatment and increased further to 36.0 after HD.17 In ambulatory patients with heart failure, a mean NT-proBNP/BNP ratio of 8.53 has been reported.25 In the study by Vickery et al.,24 more than two thirds of the cohort had LVH and, as in other studies, the presence of LVH was associated with increased natriuretic peptide concentrations. B-type natriuretic peptide increased by 0.3% per 1 g/m2 increase in left ventricular mass index (LVMI) but NT-proBNP increased by 0.5% per 1 g/m2 increase in LVMI in this patient population.
In a study with 142 CKD patients (mean age 60 ± 11 years, mean LVEF 71 ± 6%, eGFR 38 ± 14 mL/min/1.73m2) eGFR, β-blocker usage, and hemoglobin level were predictors of NT-proBNP, whereas plasma BNP was independently predicted by LVMI and β-blocker usage but not eGFR. The authors concluded that BNP may be the more appropriate biomarker than NT-proBNP to screen for cardiac dysfunction in CKD.26 In contrast, Mark et al.27 found across a spectrum of renal dysfunction including nondialysis CKD patients stages 1 to 4, HD patients, and renal transplant recipients that GFR was a more important determinant of serum BNP than ventricular function. Because serum BNP levels were significantly confounded by GFR, albumin, hemoglobin, β-blocker, and age in this study, the authors concluded that the use of BNP (or ANP) in renal dysfunction to diagnose LV dysfunction may be of limited value.27 However, in the study of Vickery et al.,28 NT-proBNP and high-sensitivity C-reactive protein but not BNP or the NT-proBNP/BNP ratio independently predicted all-cause mortality in a nondialysis CKD population. In the study of deFilippi et al.,29 NT-proBNP level elevation in asymptomatic patients with CKD not on dialysis therapy reflected underlying ischemic heart disease and hypertrophy independent of renal function.
In patients with systolic heart failure, anemia was closely associated with NT-proBNP levels above the median (1381 pg/ml) after adjustment for traditional confounders. Patients with anemia and high NT-proBNP levels had a fivefold increased risk for mortality (HR 4.77, 95% confidence 2.47 to 9.18, P < 0.001).30 Correction of anemia with subcutaneous erythropoietin for 4 months and oral iron for 12 months resulted in an improvement of LV systolic function and a decrease in circulating BNP.31
Spanaus et al.32 examined the relevance of BNP and NT-proBNP as predictors of CKD progression (Fig. 1). BNP and NT-proBNP were significantly higher among the 65 nondiabetic CKD patients who received the combined end point, defined as doubling of baseline serum creatinine or ESRD requiring renal replacement therapy, than the 112 CKD patients who did not. Each increment of 1 SD in log-transformed BNP and NT-proBNP increased the risk for CKD progression by HRs of 1.38 [95% confidence interval (CI), 1.09-1.76; P = 0.009] and 2.28 (95% CI, 1.76-2.95; P < 0.001), respectively. After adjustment for other established prognostic factors of CKD progression, NT-proBNP but not BNP remained a significant independent predictor of the combined renal end point.32 Proteinuria and/or immunosuppression contribute to enhanced plasma levels and increased urinary excretion of natriuretic peptides.33
Differences between BNP and NT-proBNP include not only renal function but also age.6 NT-proBNP is more affected than BNP probably because of a decrease in GFR with increasing age.34 The optimal cut-points for NT-proBNP for diagnosing acute congestive heart failure with increasing age are
- 450 pg/mL for patients younger than 50 years
- 900 pg/mL for patients in an age between 50 and 75 years
- 1800 pg/mL for patients older than 75 years.5,35,36
In the Val-HeFT study, however, the increase in BNP and NT-proBNP with age was comparable.13
Taken together, circulating BNP and particularly NT-proBNP levels depend on kidney function but also on the age of CKD patients. Nevertheless, these biomarkers correlate with cardiovascular morbidity and mortality. Both parameters predict also CKD progression.
THE HD PATIENT
Natriuretic hormones are used as markers of volume status and cardiovascular risk in ESRD patients.6 In a large cohort of dialysis patients, ANP and BNP were linked independently to LV mass and function, and predicted total and cardiovascular mortality.37 In this study, ANP and BNP were increased moderately in the absence and markedly in the presence of alterations in LV mass and function. This study also showed that BNP is a better indicator of geometric alterations of the heart mass in dialysis patients than ANP.37 These data extended to the uremic patient population observations made already before in patients with essential hypertension.38,39 Matayoshi et al.40 confirmed that BNP is a good predictor in cardiac function even in HD patients. B-type natriuretic peptide, however, did not predict a fall in blood pressure during HD.40 Cardiovascular disease in terms of LVH and reduced LVEF determine circulating BNP and also NT-proBNP levels. In this study, postdialytic levels of NT-proBNP were lower than predialytic NT-proBNP, but both pre- and postdialytic NT-proBNP levels were predictive of mortality. By Kaplan-Meier analysis, HD patients with NT-proBNP levels above a median cut-off value had a 40% higher total mortality.41 Naganuma et al.42 found a HR of 51.9 for cardiac death in HD patients with BNP levels greater than 700 pg/mL as compared with HD patients whose BNP levels were less than 200 pg/ml. A recent study of Roberts et al.43 confirmed that BNP and NT-proBNP strongly predict mortality in patients who are treated with long-term dialysis. Serial estimations will help in the identification of occult cardiac disease in the dialysis patient.22
Zeng et al.44 found a significant increase of plasma BNP from 596 ± 401 pg/mL (predialysis) to 705 ± 454 pg/mL (10-minute postdialysis) and from 116 ± 110 pg/mL to 172 ± 187 pg/mL in maintenance HD patients with and without LV failure, respectively. In a subset of 15 dialysis patients without LVH or other concomitant diseases, Cataliotti et al did not find an increase in plasma BNP concentrations compared with controls, suggesting that ESRD per se is not responsible for the elevated BNP levels in most dialysis patients. Again, plasma ANP and BNP levels were associated with a greater risk of cardiovascular death. The cutoff levels of ANP and BNP were 58 pg/mL and 390 pg/mL, respectively. These data clearly indicate that elevation of circulating BNP levels seen in ESRD patients cannot be explained solely by reduced renal clearance but appear to represent counterregulatory responses from left ventricle.45 In the study of Zeng et al.,44 BNP decreased significantly 3 and 6 hours after HD in both groups and started to increase again 24 hours after HD treatment. The authors interpreted this finding by the HD-induced transient reduction of plasma volume initially, followed by the relief of hypervolemia and finally by the occurrence of volume repletion.44
In the study of Biasioli et al.,46 median BNP levels decreased from 335 to 232 pg/mL during HD. Postsession BNP levels decreased by 29% in 73.1% and increased by 14% in 26.9% of the 52 HD patients. In this study, 34 HD patients (65.4%) were dialyzed with a high-flux membrane, whereas 18 HD patients (34.6%) were dialyzed with a low-flux membrane. It remains, however, unclear from this study whether the decrease and increase of plasma BNP levels were membrane-dependent. Interestingly, the proportion of deaths observed during the 28 months of follow-up was found to be higher in patients showing an intradialytic BNP increase as compared with those showing an intradialytic BNP decrease.46 In patients with refractory congestive heart failure, intermittent hemodiafiltration caused a marked decrease in circulating BNP levels.47 The rapid and significant decrease of circulating BNP by intermittent hemofiltration may be the result of plasma volume reduction. However, it is probably more likely that BNP reduction by intermittent hemodiafiltration is mainly related to its removal by filtration.48 In several studies, there was not any correlation between volume overload and NT-proBNP and also not any correlation between NT-proBNP and acute changes in preload during dialysis.41,49
In contrast, Sommerer et al.18 found mean plasma NT-proBNP levels of 3247 pg/mL (range 1619-5574 pg/ml) in HD patients without hypervolemia but mean plasma NT-proBNP levels of 11,988 pg/mL (range 5307-19,242 pg/ml; P < 0.001) in HD patients with hypervolemia. The area under the NT-proBNP receiver operator characteristic curve was 0.815 (95% CI, 0.740-0.889). The point at which sensitivity and specificity were equal (at 77%) was a plasma NT-proBNP concentration of 5300 pg/ml. In this study, both NT-proBNP and cardiac troponin T (cTnT) levels were found to be independent predictors of the composite end point death or cardiovascular events.18 NT-proBNP level, however, is more strongly associated with mortality than cTnT level in asymptomatic HD patients.50
In an elderly maintenance HD patient population (mean age 72.3 ± 6.2 years), predialysis concentration for BNP was 738 ± 120 pg/mL and for NT-proBNP 25,316 ± 9062 pg/mL, respectively.17 In this study, mean BNP and NT-proBNP levels decreased during HD by 22.5 ± 9.4% and by 18.4 ± 2.3% with a high-flux membrane. Using a low-flux dialyzer, however, plasma BNP decreased by 18.5 ± 1.9% but NT-proBNP increased by 16.8 ± 4.9%. The amount of BNP eliminated by a high-flux or low-flux dialyzer was 3603 ± 1106 or 2238 ± 900 ng pro HD, whereas the amount of NT-proBNP eliminated by a high-flux or low-flux membrane was 49,910 ± 18,674 or 9416 ± 4416 ng pro HD, respectively.17 A decrease of circulating BNP and NT-proBNP during HD with high-flux membranes and an increase of NT-proBNP with low-flux dialyzers was also reported by other investigators.49,51 In the study of Dautin et al.,52 NT-pro-BNP concentration was comparable after and before dialysis in HD patients dialyzed with a membrane whose ultrafiltration coefficient was less than or equal to 12. In HD patients with a membrane whose ultrafiltration coefficient was greater than or equal to 40, however, NT-proBNP decreased by 35% from 18,574 ± 31,862 to 11,983 ± 21,819 ng/mL (P < 0.0001) during dialysis. Madsen et al.41 found markedly elevated median plasma NT-proBNP levels before (4079 pg/ml; 1893-15,076) and after (2759 pg/ml; 1078-11,070) HD using high-flux filters. The mean reduction in circulating NT-proBNP during dialysis was 38.8 ± 13.6%. In this study, there was no correlation between the amount of fluid drawn during dialysis and the difference in pre- and postdialysis levels of NT-proBNP. The mean reduction in pre- to postcartidge levels of NT-proBNP, however, was only 7% suggesting that reduced generation of NT-proBNP may also occur during HD as a result of an abrupt fall in intra-vascular volume.41 In contrast, Safley et al.53 found in agreement with the study of Biasioli et al.46 an increase of BNP in 33.3% and a fall of BNP in 66.7% during HD. In this study, the BNP reduction ratio correlated with the volume removed, change in body weight, and Kt/V. In patients who changed from conventional HD (3 × 4 hours a week) to daily dialysis (6 × 2 hours a week) predialysis BNP levels decreased from 194 ± 51 pg/mL to 113 ± 45 pg/mL (P = 0.001) within 4 weeks, while maintaining a total weekly time on dialysis of 12 hours. The authors explained this finding by a reduction of cardiac distress due to daily dialysis.54
Van de Pol et al.55 compared BNP, NT-proBNP, and blood volume changes in HD patients both during regular dialysis and during an ultrafiltration pulse. Blood volume changes during these procedures depend on the rate of fluid removal and the refill of fluid from interstitial tissues to the intravascular compartment. In this study, vena cava diameter index, total body water, and BNP decreased significantly during HD, whereas NT-proBNP did not.55 Unlike BNP, NT-proBNP was not able to detect acute changes in fluid status.49
Although BNP levels drop during each HD session, the decline does not correlate with changes in clinical parameters related to volume status, such as ultrafiltration volume or blood pressure in all studies. Interestingly, Sheen et al.56 observed a steady and significant decline in pre- and postdialysis BNP values over the course of the week even in the absence of changes in plasma volume during dialysis. Time is probably needed both to establish a steady state and to allow the left ventricle to sense a new established steady state.56 Changes in BNP levels with HD correlate with extracellular fluid retention and volume change independent of left ventricular function.57-61 Iwashima et al.62 showed that creation of an arteriovenous fistula has significant effects on cardiac systolic and diastolic performance. The increase in cardiac output was associated with elevation of ANP levels but not BNP levels, indicating that ANP release was induced by volume loading. Conversely, the increase in the ratio of the peak velocity of early diastolic to atrial filling correlated with BNP levels but not ANP levels, indicating that BNP release is stimulated by left ventricular dysfunction.62 Lee et al.58 found that inferior cava diameter correlates significantly with postdialytic BNP levels. Predialytic BNP level correlated significantly with postdialytic BNP levels, postdialytic diastolic blood pressure, pulse pressure, and the ratio of extracellular fluid to total body water.
In a huge diabetic HD patient population, patients with NT-proBNP greater than or equal to 9252 pg/mL (fourth quartile) exhibited a more than 4-fold risk of stroke, and a more than 2-fold risk of sudden death and mortality as compared with patients with NT-proBNP less than or equal to 1433 pg/mL (first quartile). Doubling of NT-proBNP increased the risk of death by 46%, but neither baseline nor change in NT-proBNP was significantly associated with myocardial infarction in this study.63 Whether BNP and/or NT-proBNP-guided management of the hydration status and pharmacotherapy of CKD patients improves outcome needs to be determined.64 Metoprolol therapy did not only cause a fall in circulating ANP and BNP levels in 14 HD patients within 4 months but also improve left ventricular function.65 A substantial decline in natriuretic peptide may occur also in CKD patients treated with ACE inhibitors and/or angiotensin II blockers. Improved blood pressure and volume control should result in improved LV function and lower BNP and NT-proBNP levels.6
Taken together, fluctuations of circulating BNP and NT-proBNP levels during HD represent clearance of these markers depending on the dialysis membrane used. Nevertheless, BNP and NT-proBNP are markers of LV mass and function as well as volume status in this patient population. Both biomarkers predict also total and cardiovascular mortality in the HD patient population (Table 2).
The Peritoneal Dialysis Patient
Lee et al.66 investigated the association between serum NT-proBNP levels and extracellular water as well as left ventricular dysfunction in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Serum NT-proBNP levels were linked to LVMI and LVEF but not to extracellular water suggesting that NT-proBNP is not a useful marker for the assessment of extracellular fluid in CAPD patients. Determination of circulating BNP levels is also not helpful for the evaluation of volume status in chronic peritoneal dialysis (PD) patients.67 Wang et al.68 followed serum NT-proBNP levels together with echocardiography and dialysis indices in 230 chronic PD patients over a period of 3 years or until death. NT-proBNP was a significant predictor of cardiovascular congestion, all-cause mortality and cardiovascular death and event in this patient population. Its predictive power seemed stronger than that of measurements of left ventricular mass and systolic function. Figure 2 shows the Kaplan-Meier estimates of the composite end point of all fatal or nonfatal cardiovascular event-free survival in relation to quartiles of NT-proBNP as recently published by Wang et al.68 In this study, NT-proBNP was found to be also a marker of extracellular volume expansion apart from reflecting cardiac morphology and function. CAPD patients with LVMI above or below median had higher plasma NT-proBNP levels in the presence of subsequent cardiovascular congestion as compared with those without cardiovascular congestion.68 Mak et al.69 found a correlation between BNP and left ventricular filling pressure, a marker of left ventricular volume status.
The PD population enrolled in the ADEMEX (ADEquacy of peritoneal dialysis in MEXico) trial offered the opportunity to evaluate natriuretic peptides and their predicting outcomes in the largest clinical trial ever performed in PD.70 The findings of this study can be summarized as follows: plasma levels of atrial natriuretic peptides are elevated in patients on PD; the levels observed correlate with the level of residual renal function and systolic blood pressure; NT-proBNP (but neither proANP1-98) nor proANP(1-30) or proANP(31-67) is a powerful predictor of total as well as cardiovascular mortality.71 As in other studies, it remained unclear why NT-proBNP predicted all-cause mortality and not specifically cardiovascular mortality.6 Diabetic and nondiabetic anephric CAPD patients had significantly higher plasma levels of NT-proBNP, proANP(1-30), and proANP(31-67) as compared with diabetic and nondiabetic nonanephric CAPD patients. In this study, there was a direct relation between NT-proBNP and systolic blood pressure and an inverse correlation between NT-proBNP and both urine volume and GFR. NT-proBNP correlated also with inflammatory markers (inversely with albumin and directly with interleukin-6 and C-reactive protein).71
Few small studies tried to compare circulating BNP levels between HD and PD patients. BNP levels were found to be markedly lower in PD patients (probably due to better residual renal function) as compared with HD patients.72,73 As in HD patients plasma BNP concentration correlated with LVMI and LVEF also on PD patients. The lower BNP concentration in CAPD patients as compared with HD patients suggests that cardiac load in CAPD patients may be lower than that in HD patients.72 However, prospective controlled trials with carefully selected ESRD patients are needed before any conclusions based on natriuretic peptide measurements in patients receiving different types of dialysis should been made.
Taken together, circulating BNP and NT-proBNP levels are linked to LV mass and function but not to extracellular water. Both biomarkers correlate with residual renal function, blood pressure, and inflammatory parameters. B-type natriuretic peptide and NT-proBNP are significant predictors of cardiovascular congestion and mortality in PD patients (Table 2).
Circulating BNP and particularly NT-proBNP levels depend on kidney function but also on many additional risk factors such as heart failure, LVH, hypervolemia, anemia or age. Both peptides parallel the presence and severity of cardiac dysfunction and offer powerful prognostic information even in patients with severe impairment of kidney function. Monitoring of natriuretic peptide levels might not only improve patient care and outcome in patients with heart failure or coronary artery disease but also in patients at different stages of CKD and in those on renal replacement therapy. In non-CKD patients, BNP- or NT-proBNP-guided therapy has been shown to improve outcome in heart failure. Such studies, however, are so far not available in the CKD or dialysis patient population.74,75
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