N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) Concentrations in Hemodialysis Patients: Prognostic Value of Baseline and Follow- Up Measurements

Written By: Sam Savage

Published Date: September 5, 2008 Last Edited: September 5, 2008

By Gutierrez, Orlando M Tamez, Hector; Bhan, Ishir; Zazra, James; Tonelli, Marcello; Wolf, Myles; Januzzi, James L; Chang, Yuchiao; Thadhani, Ravi

BACKGROUND: Increased N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations are associated with increased cardiovascular mortality in chronic hemodialysis patients. Previous studies focused on prevalent dialysis patients and examined single measurements of NT-proBNP in time. METHODS: We measured NT-proBNP concentrations in 2990 incident hemodialysis patients to examine the risk of 90-day and 1-year mortality associated with baseline NT- proBNP concentrations. In addition, we calculated the change in concentrations after 3 months in a subset of 585 patients to examine the association between longitudinal changes in NT-proBNP and subsequent mortality.

RESULTS: Increasing quartiles of NT-proBNP were associated with a monotonic increase in 90-day [quartile 1, referent; from quartile 2 to quartile 4, hazard ratio (HR) 1.7-6.3, P

CONCLUSIONS: NT-proBNP concentrations are independently associated with mortality in incident hemodialysis patients. Furthermore, the observation that longitudinal changes in NT-proBNP concentrations were associated with subsequent mortality suggests that monitoring serial NT-proBNP concentrations may represent a novel tool for assessing adequacy and guiding therapy in patients initiating hemodialysis.

Despite substantial advances in the diagnosis and management of cardiovascular disease, patients on chronic hemodialysis manifest significantly higher cardiovascular morbidity and mortality compared with agematched counterparts not on dialysis (1). As a result, current practice guidelines suggest that patients initiating dialysis should be routinely evaluated for cardiovascular disease risk factors to identify those at highest risk for adverse cardiovascular outcomes (2). Given the growing recognition that traditional risk factors, including hypertension, obesity, and hyperlipidemia, remain limited in their ability to define cardiovascular risk in patients with kidney failure (3), novel biomarkers have gained increased attention (4-6).

Natriuretic peptides have emerged as valuable biomarkers of cardiovascular risk in the general population and in patients with cardiac and kidney disease (7-9). N-terminal pro-B-type natriuretic peptide (NT-proBNP),6 in particular, has demonstrated promise as a surrogate marker of cardiovascular disease in kidney failure. Studies have shown that increased NT-proBNP concentrations are strongly associated with left ventricular dysfunction or coronary artery disease in patients with kidney disease (10-12), presumably reflective of prevalent heart disease and volume overload in this population. More recently, increased NT-proBNP concentrations have been shown to independently predict all-cause and cardiovascular mortality in dialysis patients (13-15), suggesting that baseline NT- proBNP measurements may facilitate efforts to stratify risk in patients initiating hemodialysis.

Previous studies, however, primarily examined prevalent dialysis patients, and extrapolating results from these studies to patients initiating dialysis maybe problematic, especially since incident hemodialysis patients have significantly higher rates of mortality in the short term compared with those who survive for 2 to 3 months on dialysis (16-18). Indeed, incident hemodialysis patients are exposed to numerous competing risks of mortality in the first several months of dialysis that become less pronounced in patients who survive past this period of time. Thus, whether the association between NT-proBNP and early (90-day) mortality is similar to that between NT-proBNP and longer-term mortality in prevalent dialysis patients is unclear and has not previously been examined. In addition, while single, cross-sectional measurements of NT-proBNP may provide prognostic information, few studies have examined the diagnostic utility of serial assessments of NT-proBNP. Therefore, we measured NT-proBNP concentrations in approximately 3000 patients randomly selected from a nationally representative, prospective cohort of incident hemodialysis patients to test the hypotheses that increased NT-proBNP concentrations at baseline are independently associated with 90day and 1-year mortality, and that in a subset of patients with serial measurements, longitudinal changes in NT- proBNP concentrations are associated with subsequent mortality.

Materials and Methods

STUDY POPULATION

Accelerated Mortality on Renal Replacement (ArMORR) is a nationally representative, prospective cohort study of 10 044 patients who initiated chronic hemodialysis between July 1, 2004, and June 30, 2005, at any of 1056 US dialysis centers operated by Fresenius Medical Care North America (FMC). ArMORR contains detailed demographic and clinical data including comorbidities, laboratory results, and serum and plasma samples from all participants at the initiation of dialysis and every 90 days thereafter to 1 year. All blood samples collected for clinical care are uniformly shipped to and processed by a central laboratory, Spectra East. Remnant blood samples that were to be discarded after being processed for routine clinical testing were shipped on ice to the ArMORR investigators, where the samples were divided into aliquots and stored in liquid nitrogen tanks. Informed consent to collect residual blood samples was waived since these samples were considered discarded human samples and were stripped of personal identifiers before being collected by the investigators. For the current study, 2990 consecutive patients who had remnant blood samples available for measurement of NT-proBNP constituted the study sample-no patients were excluded. Clinical data were collected prospectively by practitioners and entered into a central database that undergoes rigorous quality assurance/quality control auditing mandated by FMC. Comorbidities were abstracted from Centers for Medicare and Medicaid Services (CMS)-2728 medical evidence forms as well as International Classification of Diseases, Ninth Revision (ICD-9) codes from hospital discharge summaries. Patients enrolled in the study underwent one year of prospective follow-up unless they died (15%), underwent kidney transplantation (3%), discontinued hemodialysis (owing to recovery of kidney function or voluntary withdrawal, 4%), or transferred to a non-FMC unit before completing their first year on hemodialysis (12%). This study was approved by the Institutional Review Board of the Massachusetts General Hospital.

EXPOSURES AND OUTCOMES

The primary predictor variable was serum concentrations of NT- proBNP measured at baseline (0-14 days after initiating hemodialysis) in all 2990 patients, and at approximately day 90 (range 80-100) in a random subset of 585 patients who had remnant 90- day serum samples available for testing. We measured NTproBNP concentrations in predialysis blood samples using the Roche Elecsys 2010 analyzer (Roche Diagnostics), with interrun CV

STATISTICAL ANALYSIS

We compared baseline characteristics of patients who died with patients who survived using standard descriptive statistics. We compared baseline characteristics of the entire study population across quartiles of NT-proBNP (determined by its distribution in the control population) using 1-way ANOVA for continuous variables or Pearson chi^sup 2^ test for categorical variables. We plotted 90- day and 1-year survival curves for each quartile of NT-proBNP using the Kaplan-Meier method, and we calculated the change in NT-proBNP over the first 3 months of dialysis in each of the 585 patients who had baseline and 90-day values by subtracting NT-proBNP concentrations at baseline from NT-proBNP concentrations at 90 days (DeltaNT-proBNP).

Table 1. Baseline characteristics as a function of survival during the first year of hemodialysis.2

The primary analysis used Cox proportional-hazards regression to examine 90-day and 1-year all-cause and cardiovascular mortality on hemodialysis according to quartiles of NT-proBNP concentrations at baseline, with the lowest quartile serving as the reference group. NT-proBNP was also analyzed as a continuous variable, using a multivariable fractional polynomial to determine the most appropriate transformation of NT-proBNP values (20). Subjects were censored if they underwent kidney transplantation, transferred to a non-FMC dialysis unit, recovered kidney function, withdrew from dialysis, or reached the end of followup, whichever came first. We used multivariable models to adjust for other predictors including the following case-mix variables: age, sex, race (white, black, or other), ethnicity (Hispanic or non-Hispanic), etiology of end-stage renal disease (ESRD), systolic blood pressure, body mass index (BMI), dialysis access at initiation, dialysis dose assessed by the urea reduction ratio, facility-specific standardized mortality rates (21), and comorbidities at the initiation of dialysis (diabetes, hypertension, coronary artery disease, and congestive heart failure) and the following laboratory variables: albumin, calcium, phosphate, and parathyroid hormone (PTH) as time-varying covariates in these models. We also conducted additional analyses further adjusting for baseline cardiac troponin-T measurements. Covariates in the final multivariable models were chosen if they had been associated with mortality on dialysis in previous studies. Multiple imputation was used to account for missing data points. In addition, we assessed the impact of NT-proBNP on the discriminatory power of the model and the calibration of the model by calculating the c-statistic of the final Cox regression model and constructing a clinical risk reclassification table before and after adding baseline log NT- proBNP concentrations (22, 23). Table 2. Baseline characteristics of the study sample compared across quartiles of NT-proBNP.a

The secondary analysis used Cox regression to examine the association between DeltaNT-proBNP and subsequent all-cause and cardiovascular mortality in the subset of patients who had both baseline and 90-day NT-proBNP values. DeltaNT-proBNP was analyzed categorically in tertiles (tertile 1, raw change in NT-proBNP 429 ng/L), with tertile 1 serving as the reference group. Multivariable models were used to adjust for other predictors as listed above. Baseline log NTproBNP concentrations were included in the crude and multivariable adjusted models to account for possible regression to the mean. To identify which factors were associated with change in NT-proBNP, we examined the correlation between DeltaNT-proBNP and a number of demographic, clinical, and laboratory variables, including age, sex, race, ethnicity, comorbidities, and contemporaneous changes in laboratory concentrations (albumin, hemoglobin, creatinine, bicarbonate, calcium, phosphorus, PTH), systolic blood pressure, urea reduction ratio, and weight, using Spearman correlation coefficient or linear regression. Baseline and 90-day predialysis weights in kilograms were used to examine the association between DeltaNT-proBNP and change in weight. A 2-sided P value

Results

BASELINE CHARACTERISTICS

The study sample consisted of 2990 patients, 442 (15%) of whom died within the first year of initiating dialysis. Of the 442 deaths, 248 (56%) were categorized as related to cardiovascular disease according to ICD-9 coding. Baseline characteristics of the study population are depicted in Table 1. There were no significant differences in baseline characteristics comparing the patients randomly selected for the current study with the overall ArMORR population (data not shown).

Baseline characteristics of the study sample are compared across quartiles of NT-proBNP in Table 2. Compared with patients in lower quartiles of NTproBNP, patients in the higher NT-proBNP quartiles were older, less likely to be black, and more likely to have a history of coronary artery disease and/or heart failure. In addition, BMI and mean concentrations of albumin, creatinine, hemoglobin, and cholesterol decreased with increasing quartiles of NT-proBNP (P

NT-proBNP CONCENTRATIONS AND SURVIVAL ON HEMODIALYSIS

The overall 1-year mortality rate in the study sample was 19.2 deaths per 100 patient-years at risk. Consistent with previous studies (16, 17), the mortality rate in the first 3 months of dialysis was significantly higher than in the subsequent 9 months of follow-up-22.7 vs 14.9 deaths per 100 patient-years at risk, P

Fig. 2 depicts the crude and adjusted Cox regression survival analyses. In the crude models, increasing quartiles of NT-proBNP were associated with a monotonic increase in both 90-day and 1 – year all-cause mortality. When restricted to cardiovascular deaths, these associations were accentuated. When further adjusted for case- mix and laboratory variables, increasing quartiles of NT-proBNP remained independently associated with increased 90-day and 1-year all-cause and cardiovascular mortality. In addition, when adjusted for baseline cardiac troponin-T concentrations, the monotonic increase in mortality associated with increasing quartiles of NT- proBNP remained qualitatively the same (data not shown). When analyzed using a multivariable fractional polynomial, baseline log NT-proBNP concentrations were significantly associated with increased 90-day [hazard ratio (HR) per unit increase in log NT- proBNP 1.5, 95% CI 1.3-1.7] and 1-year (HR per unit increase in log NT-proBNP 1.4, 95% CI 1.3-1.5) all-cause mortality. Furthermore, the addition of log NT-proBNP concentrations increased the c-statistic of the model from 0.73 (95% CI 0.70-0.75) to 0.76 (95% CI 0.73- 0.78), suggesting that the addition of NT-proBNP improved the model’s discriminatory power for predicting 1-year mortality among incident hemodialysis patients. When the calibration of the model was further evaluated using a clinical risk reclassification table, the model with log NT-proBNP was more accurate in classifying patients’ mortality risk than the model without log NT-proBNP, particularly within the lowest and highest risk categories of 1- year all-cause mortality (/=20%, respectively, see the Data Supplement that accompanies the online version of this article at www.clinchem.org/content/vol54/issue8) .

Fig. 1. Kaplan-Meier estimates of 90-day survival by baseline quartile of NT-proBNP (A); 1-year survival by baseline quartile of NT-proBNP (B); and 9-month survival by tertile of DeltaNT-proBNP (C).

Fig. 2. Crude, case mix adjusted, and multivariable adjusted hazard ratios of mortality according to quartiles of NT-proBNP.

HRs of 90-day all-cause mortality (A); 90-day cardiovascular mortality (B); 1-year all-cause mortality (C); and 1-year cardiovascular mortality (D). Case-mix analyses adjusted for age, sex, race, etiology of ESRD1 initial vascular access, baseline systolic blood pressure, facility standardized mortality rates, and history of diabetes, coronary artery disease, and heart failure. Multivariable analyses adjusted for case-mix variables plus albumin, phosphorus, calcium, and PTH. Quartile 1 is the reference group in all models. Vertical lines represent 95% CIs.

CHANGE IN NT-proBNP AND SURVIVAL ON HEMODIALYSIS

Change in NT-proBNP was examined relative to subsequent mortality in the 585 patients with baseline and 90-day NT-proBNP measurements. Table 3 depicts the characteristics of these patients according to tertile of DeltaNT-proBNP. Mean log NT-proBNP concentrations at 90 days were 2% lower than mean log NT-proBNP concentrations at baseline in this subset (P 0) included weight gain (r = 0.16, P

Table 3. Baseline characteristics by tertile of DeltaNT-proBNP.3

Kaplan-Meier estimates of survival were significantly worse in subjects with a net increase compared to those with a net decrease in NT-proBNP concentrations after the first 3 months of dialysis (Fig. 1C). When examined in Cox regression analysis adjusted for baseline log NT-proBNP concentrations, patients in the highest tertile of DeltaNT-proBNP had a 2.4-fold greater risk of all-cause mortality and a 2.9-fold greater risk of cardiovascular mortality than patients in the lowest tertile (Fig. 3). When further adjusted for age, sex, race, etiology of ESRD, and albumin concentrations, these associations were only marginally attenuated.

Discussion

In this analysis of nearly 3000 incident hemodialysis patients, increased NT-proBNP concentrations at baseline were independently associated with all-cause and cardiovascular mortality. In addition, increases in NT-proBNP concentrations after 3 months of dialysis were associated with subsequent mortality. To our knowledge, this is the largest study to examine the association between baseline NT- proBNP concentrations and mortality in incident dialysis patients, and the first to examine the potential utility of following changes in NT-proBNP over time. Furthermore, this is the first study to demonstrate a strong, independent association between increased baseline NT-proBNP concentrations and early mortality in patients initiating dialysis. These findings suggest that obtaining NT- proBNP concentrations at the initiation of hemodialysis may help identify patients at highest risk for adverse cardiovascular outcomes, especially within the first 3 months of starting dialysis, independent of established markers of cardiovascular disease. Furthermore, the observation that longitudinal changes in NT-proBNP were associated with mortality suggests that serial NT-proBNP measurements may represent novel end points for guiding therapy in patients on chronic hemodialysis. Fig. 3. Crude and multivariable- adjusted hazard ratios of all-cause (A) and cardiovascular (B) mortality according to tertiles of Delta-proBNP.

NT-proBNP is an established marker of cardiovascular risk in the general population and in patients with cardiac or kidney disease (7- 9). Increased concentrations of NT-proBNP have been associated with left ventricular dysfunction and coronary artery disease in patients with predialysis kidney disease (10-12), and more recent studies have shown that increased NT-proBNP concentrations are independently associated with systolic dysfunction, left ventricular hypertrophy, and mortality in patients on peritoneal or hemodialysis (13-15). However, these latter studies were of relatively modest size and primarily focused on prevalent dialysis patients. Therefore, generalizing the results of these studies to patients initiating hemodialysis, who have significantly higher risks of short-term mortality than patients who survive the first several months on dialysis (16-18), may be inappropriate.

The present data represent the largest study to demonstrate that increased NT-proBNP concentrations in patients initiating hemodialysis are strongly associated with 1-year mortality independent of other established markers of cardiovascular disease. Furthermore, this is the first study to show that increased NT- proBNP concentrations are independently associated with mortality in the first 3 months of dialysis, when dialysis patients are at the highest risk of dying. This is particularly noteworthy given the increasing recognition that “traditional” cardiovascular risk factors, such as hypertension, obesity, and increased cholesterol, remain limited in their ability to define cardiovascular risk in kidney disease, and in some cases are paradoxically linked with improved survival in patients on hemodialysis (24 ). Indeed, we observed that patients who survived in this study sample were more likely to have higher systolic blood pressure, BMI, and cholesterol concentrations than patients who died. Thus, these results suggest that routine assessments of NT-proBNP concentrations at the initiation of dialysis may help identify patients who are at the highest risk of adverse cardiovascular outcomes above and beyond traditional markers of cardiovascular disease.

Whereas there is growing enthusiasm for following natriuretic peptide concentrations longitudinally in patients with cardiac disease to help guide therapy (25-29), it is unclear whether employing a similar strategy would be advantageous in hemodialysis patients. Thus, our finding that rising NT-proBNP concentrations are significantly associated with subsequent mortality suggests that monitoring serial NT-proBNP concentrations may indeed provide important prognostic information that could potentially be used for assessing adequacy and adjusting therapy during hemodialysis. Interestingly, change in weight was only weakly associated with DeltaNT-proBNP in univariate analysis, and this association was attenuated in multivariable-adjusted analysis. This suggests that DeltaNT-proBNP may be more strongly influenced by factors other than volume shifts in dialysis patients. For example, very high or rising NT-proBNP concentrations may reflect worsening ventricular wall stress, and thus may help to identify patients who would benefit from earlier diagnostic imaging or more aggressive applications of medical therapies – such as angiotensin-converting enzyme inhibitors or aldosterone inhibitors – that can attenuate ventricular remodeling (30-33), are associated with a mortality benefit (34, 35), and are underutilized in patients with kidney failure (36, 37). Further studies are needed to determine whether specific therapeutic interventions driven by longitudinal changes in NT-proBNP can significantly improve outcomes in hemodialysis patients.

We acknowledge several limitations in this study. First, deaths from cardiovascular causes were determined from ICD-9 codes, which maybe less specific for ascertaining the precise cause of death than clinical chart review (38 ). We would have liked to have corroborated ICD-9 codes with clinical chart data but were unable to do so since all subject information was stripped of personal identifiers before transfer to ArMORR investigators. Second, we did not have any assessments of left ventricular structure or function by echocardiography. Therefore, we were unable to determine whether NT-proBNP concentrations provide important prognostic information that is independent of known markers of mortality in dialysis such as left ventricular hypertrophy. Nevertheless, even if NT-proBNP is simply a surrogate of increased left ventricular wall stress, it may still serve as an important marker of left ventricular dysfunction in both symptomatic and asymptomatic patients on dialysis. Third, we did not have any direct or indirect measurements of volume status apart from predialysis weights and so were limited in our ability to directly evaluate the value of NT-proBNP as a marker of volume overload in dialysis patients. However, previous investigators have reported similarly disappointing correlations between BNP concentrations and noninvasive measures of volume overload in hemodialysis patients (39). Fourth, although NT-proBNP is eliminated to a small extent during hemodialysis (13), the clearance of NT- proBNP is higher with the use of high-flux hemodialysis membranes than low-flux membranes (40). Thus, changes in NT-proBNP concentrations over time may be influenced by differences in the use of high-flux vs low-flux membranes. We did not obtain pre- and postdialysis NT-proBNP concentrations and thus were unable to evaluate this possibility. However, given that the majority of patients (>90%) in the study sample were treated with high-flux membranes, we believe that differences in hemodialysis membrane utilization are unlikely to explain these findings. Finally, although we used c-statistics to examine the effect of NT-proBNP on the discriminatory power of the model, the c-statistic may be insensitive to capturing the full impact of adding new biomarkers to a prediction model (22), and thus we must interpret with caution the change in c-statistic after adding NT-proBNP to the model.

In conclusion, increased NT-proBNP concentrations in patients initiating dialysis are independently associated with early and 1- year all-cause and cardiovascular mortality, and thus may facilitate the identification and treatment of patients at highest risk of adverse cardiovascular outcomes, especially within the first 3 months of dialysis. In addition, longitudinal changes in NT-proBNP are associated with mortality, which suggests that serial measurements of NTproBNP may provide novel surrogate endpoints for guiding therapy in patients on chronic hemodialysis. Future studies are needed to evaluate whether management strategies driven by serial monitoring of NT-proBNP concentrations can significantly improve the dismal rates of cardiovascular morbidity and mortality among patients on chronic hemodialysis.

Grant/Funding Support: NT-proBNP measurements were made possible by a grant from Roche Diagnostics. This study was supported by NIH DK71674 (R. Thadhani). O. M. Gutierrez was supported by an American Kidney Fund Clinical Scientist in Nephrology Fellowship.

Financial Disclosures: J. L. Januzzi reports receiving grant support from Roche, Dade Behring, and Inverness Medical Innovations and consulting and speaking fees from Roche, Dade Behring, Ortho Biotech, and Biosite. R. Thadhani reports receiving a grant from Roche to support this study. No other authors report a conflict of interest.

6 Nonstandard abbreviations: NT-proBNP, N-terminal pro-B-type natriuretic peptide; ArMORR, Accelerated Mortality on Renal Replacement; FMC, Fresenius Medical Care; ICD-9, International Classification of Diseases, Ninth Revision-, ESRD, end-stage renal disease; BMI, body mass index; PTH, parathyroid hormone; HR, hazard ratio.

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Orlando M. Gutierrez,1* Hector Tamez,1 Ishir Bhan,1 James Zazra,2 Marcello Tonelli,3 Myles Wolf,1 James L. Januzzi,4 Yuchiao Chang,5 and Ravi Thadhani1

1 Nephrology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA; 2 Spectra Laboratories, Rockleigh, NJ; 3 Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; 4 Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA; 5 General Medicine, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

* Address correspondence to this author at: University of Miami, Rosenstiel Medical Science Building. Suite 7168, 1600 NW 10th Avenue, Miami, FL 33136.

Fax 305-243-3506; e-mail [email protected].

Received December 5, 2007; accepted May 1, 2008.

Previously published online at DOI: 10.1373/clinchem.2007.101691

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