Association of N-Terminal Pro-B-Type Natriuretic Peptide With Left Ventricular Structure and Function in Chronic Kidney Disease (from the Chronic Renal Insufficiency Cohort [CRIC])

doi:10.1016/j.amjcard.2012.10.019

The American Journal of Cardiology

Volume 111, Issue 3, 1 February 2013, Pages 432-438

https://doi.org/10.1016/j.amjcard.2012.10.019 Get rights and content

We evaluated the cross-sectional associations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) with cardiac structural and functional abnormalities in a cohort of patients with chronic kidney disease without clinical heart failure, the Chronic Renal Insufficiency Cohort (n = 3,232). The associations of NT-proBNP with echocardiographically determined left ventricular (LV) mass and LV systolic and diastolic function were evaluated using multivariate logistic and linear regression models. Reclassification of participants' predicted risk of LV hypertrophy (LVH), systolic and diastolic dysfunction was performed using a category-free net reclassification improvement index that compared a clinical model with and without NT-proBNP. The median NT-proBNP was 126.6 pg/ml (interquartile range 55.5 to 303.7). The greatest quartile of NT-proBNP was associated with a nearly threefold odds of LVH (odds ratio 2.7, 95% confidence interval [CI] 1.8 to 4.0) and LV systolic dysfunction (odds ratio 2.7, 95% CI 1.7 to 4.5) and a twofold odds of diastolic dysfunction (odds ratio 2.0, 95% CI 1.3 to 2.9) in the fully adjusted models. When evaluated alone as a screening test, NT-proBNP functioned modestly for the detection of LVH (area under the curve 0.66) and LV systolic dysfunction (area under the curve 0.62) and poorly for the detection of diastolic dysfunction (area under the curve 0.51). However, when added to the clinical model, NT-proBNP significantly reclassified participants' likelihood of having LVH (net reclassification improvement 0.14, 95% CI 0.13–0.15; p <0.001) and LV systolic dysfunction (net reclassification improvement 0.28, 95% CI 0.27 to 0.30; p <0.001) but not diastolic dysfunction (net reclassification improvement 0.10, 95% CI 0.10 to 0.11; p = 0.07). In conclusion, in this large chronic kidney disease cohort without heart failure, NT-proBNP had strong associations with prevalent LVH and LV systolic dysfunction.

Section snippets

Methods

The present study was a cross-sectional analysis from the Chronic Renal Insufficiency Cohort (CRIC) study, which was established by the National Institute of Diabetes and Digestive and Kidney Diseases in 2001 as an observational study to evaluate the determinants of progression to end-stage renal disease and cardiovascular disease among those with CKD.⁸ Participants were recruited from 7 clinical centers from July 2003 to March 2007. The inclusion criteria were an estimated glomerular

Results

Of the 3,232 participants included in the present analysis, the distribution of the NT-proBNP levels was skewed rightward; the median was 126.6 pg/ml (interquartile range 55.5 to 303.7), and the 90th percentile was 734.4 pg/ml (Figure 1). The mean age of the participants was 59 ± 11 years; 45% were women and 43% were non-Hispanic white. Compared to those with the lowest levels of NT-proBNP, the participants with the greatest level of NT-proBNP were older and more likely to be Hispanic (Table 1

Discussion

Given the high prevalence of elevated NT-pro-BNP levels in patients with CKD and its association with a poor prognosis in end-stage renal disease,17, 18 we evaluated the associations between NT-pro-BNP and prognostically meaningful cardiac structural and functional abnormalities across a wide range of renal function. In the present study of a large, diverse population of ambulatory patients at various stages of CKD without HF, our principal findings were as follows. First, the NT-proBNP levels

Disclosures

The authors have no conflicts of interest to disclose.

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Cited by (52)

FGF-23, Left Ventricular Hypertrophy, and Mortality in Patients With CKD: A Revisit With Mediation Analysis
2024, JACC: Advances
In patients with chronic kidney disease (CKD), fibroblast growth factor (FGF)-23 is suspected to cause death or cardiovascular disease by inducing left ventricular hypertrophy (LVH).
This study aims to quantify the mediational effect of LVH in the hypothetical causal pathway from FGF-23 to long-term adverse outcomes.
From 3,939 adults with CKD stages 2 to 4 enrolled in the CRIC (Chronic Renal Insufficiency Cohort) study, 2,368 participants with available data of FGF-23, left ventricular mass index at 1 year, and covariates were included. We employed linear and Cox proportional hazards regression models to investigate the association between FGF-23 and LVH, all-cause mortality, atrial fibrillation (AF), or congestive heart failure (CHF). Mediation analysis was used within a counterfactual framework to decompose the effect of FGF-23 into natural direct and indirect effects.
Among 2,368 participants (mean age: 57.7 years, 1,252 males, median FGF-23 level: 138.8 RU/mL), left ventricular mass index was positively correlated with FGF-23. During a median of 12.0, 11.1, and 11.1 years, FGF-23 was associated with all-cause mortality (HR: 1.62, 95% CI: 1.24-2.12), AF (HR: 1.58, 95% CI: 1.12-2.24), and CHF (HR: 1.32, 95% CI: 0.95-1.84) when the highest quartile was compared to the lowest quartile. LVH mediated 7.4%, 11.2%, and 21.9% of the effect of FGF-23 on all-cause mortality, AF, and CHF, respectively.
In CKD patients, FGF-23 had a minor effect on the development of long-term adverse outcomes through LVH. Other potential mediators and the validity of negative effect of FGF-23 should be explored.
Descriptions and Determinants of N-Terminal Pro–B-Type Natriuretic Peptide in Pediatric CKD: The Chronic Kidney Disease in Children (CKiD) Study
2023, American Journal of Kidney Diseases
Change in Cardiac Biomarkers and Risk of Incident Heart Failure and Atrial Fibrillation in CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study
2021, American Journal of Kidney Diseases
Circulating cardiac biomarkers may signal potential mechanistic pathways involved in heart failure (HF) and atrial fibrillation (AF). Single measures of circulating cardiac biomarkers are strongly associated with incident HF and AF in chronic kidney disease (CKD). We tested the associations of longitudinal changes in the N-terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), galectin-3, growth differentiation factor 15 (GDF-15), and soluble ST-2 (sST-2) with incident HF and AF in patients with CKD.
Observational, case-cohort study design.
Adults with CKD enrolled in the Chronic Renal Insufficiency Cohort study.
Biomarkers were measured at baseline and 2 years later among those without kidney failure. We created 3 categories of absolute change in each biomarker: the lowest quartile, the middle 2 quartiles, and the top quartile.
The primary outcomes were incident HF and AF.
Cox proportional hazards regression models were used to test the associations of the change categories of each cardiac biomarker with each outcome (with the middle 2 quartiles of change as the referent group), adjusting for potential confounders and baseline concentrations of each biomarker.
The incident HF analysis included 789 participants (which included 138 incident HF cases), and the incident AF analysis included 774 participants (123 incident AF cases). In multivariable models, the top quartile of NT-proBNP change (>232 pg/mL over 2 years) was associated with increased risk of incident HF (HR, 1.79 [95% CI, 1.06-3.04]) and AF (HR, 2.32 [95% CI, 1.37-3.93]) compared with the referent group. Participants in the top quartile of sST2 change (>3.37 ng/mL over 2 years) had significantly greater risk of incident HF (HR, 1.89 [95% CI, 1.13-3.16]), whereas those in the bottom quartile (≤−3.78 ng/mL over 2 years) had greater risk of incident AF (HR, 2.43 [95% CI, 1.39-4.22]) compared with the 2 middle quartiles. There was no association of changes in hsTnT, galectin-3, or GDF-15 with incident HF or AF.
Observational study.
In CKD, increases in NT-proBNP were significantly associated with greater risk of incident HF and AF, and increases in sST2 were associated with HF. Further studies should investigate whether these markers of subclinical cardiovascular disease can be modified to reduce the risk of cardiovascular disease in CKD.
Cardiac Biomarkers and Risk of Mortality in CKD (the CRIC Study)
2020, Kidney International Reports
Cardiovascular disease (CVD) is the leading cause of mortality among individuals with chronic kidney disease (CKD). Cardiac biomarkers of myocardial distention, injury, and inflammation may signal unique pathways underlying CVD in CKD. In this analysis, we studied the association of baseline levels and changes in 4 traditional and novel cardiac biomarkers with risk of all-cause, CV, and non-CV mortality in a large cohort of patients with CKD.
Among 3664 adults with CKD enrolled in the Chronic Renal Insufficiency Cohort Study, we conducted a cohort study to examine the associations of baseline levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), cardiac high-sensitivity troponin T (hsTnT), growth differentiation factor−15 (GDF-15), and soluble ST-2 (sST-2) with risks of all-cause and cardiovascular (CV) mortality. Among a subcohort of 842 participants, we further examined the associations between change in biomarker levels over 2 years with risk of all-cause mortality. We used Cox proportional hazards regression models and adjusted for demographics, kidney function measures, cardiovascular risk factors, and medication use.
After adjustment, elevated baseline levels of each cardiac biomarker were associated with increased risk of all-cause mortality: NT-proBNP (hazard ratio [HR] = 1.92, 95% confidence interval [CI] = 1.73−2.12); hsTnT (HR = 1.62, 95% CI = 1.48, 1.78]); GDF-15 (HR = 1.61, 95% CI = 1.46−1.78]); and sST-2 (HR = 1.26, CI = 1.16−1.37). Higher baseline levels of all 4 cardiac biomarkers were also associated with increased risk of CV. Declines in NT-proBNP (adjusted HR = 0.55, 95% CI = 0.36−0.86) and sST2 (HR = 0.55, 95% CI = 0.36−0.86]) over 2 years were associated with lower risk of all-cause mortality.
In a large cohort of CKD participants, elevations of NT-proBNP, hsTnT, GDF-15, and sST-2 were independently associated with greater risks of all-cause and CV mortality.
Estimated Glomerular Filtration Rate, Activation of Cardiac Biomarkers and Long-Term Cardiovascular Outcomes: A Population-Based Cohort
2019, Mayo Clinic Proceedings
Citation Excerpt :
In comparison with prior studies, these data suggest lower thresholds of both biomarkers for prediction of poor outcomes. Although these biomarkers are often used in cases of acute manifestations of CHF or coronary syndromes in the general population,28-30 there has been considerable reluctance to clinically use these in patients with CKD, given concerns that they may be falsely elevated due to impaired renal clearance.29,31,32 However, we examined tertiles of NT-proBNP and hs-TnT and their interactions with eGFR with regards to the clinical endpoints of CHF, MI, stroke, and all-cause mortality; we did not find significant interactions between eGFR and levels of NT-proBNP and hs-TnT.
To classify subjects in a general population per their renal function and characterize the cardiac biomarker levels, left ventricular function and cardiovascular outcomes over a 10.2 year follow-up period (interquartile range, 5.1–11.4 years).
This was a retrospective review of a population-based random sample of residents aged ≥45 years. Data were collected between January 1, 1997, and December 31, 2000. One thousand nine hundred eighty-one individuals were classified based on estimated glomerular filtration rate (eGFR) into group I (>90 mL/min/1.73 m²), group II (60 to 89 mL/min/1.73 m²) and group III (<60 mL/min/1.73 m²; chronic kidney disease [CKD]). Age/sex-adjusted baseline characteristics, tertiles of N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT) and their interactions with eGFR were examined. Outcomes measured included incident myocardial infarction (MI), congestive heart failure, stroke, and all-cause mortality.
Eight hundred nineteen patients were classified as group I, 1036 as group II, and 126 of 1981 (6.4%) as group III or CKD. Subjects in group III were older and had a higher incidence of hypertension, diabetes, and MI at baseline. Over a 10.2-year follow-up period, CKD was associated with an increased risk of MI (hazard ratio, 1.95; 95% CI, 1.2-3.14; P=.006) and composite cardiovascular outcomes including MI, congestive heart failure, stroke, and all-cause mortality (hazard ratio, 1.38; 95% CI, 1.05-1.83 ;P=.02). Subjects with NT-proBNP or hs-TnT in the third tertile were at greater risk of cardiovascular events without significant interactions between eGFR and levels of NT-proBNP and hs-TnT.
Subjects with CKD had significantly elevated cardiac biomarkers and were at an increased risk of MI and adverse cardiovascular events. This warrants future studies to investigate whether these cardiac biomarkers could identify high-risk CKD patients for aggressive management of cardiovascular risk factors.
Correlations of Plasma Biomarkers and Imaging Characteristics of Cerebral Small Vessel Disease
2024, Brain Sciences

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: This project was supported by R01 DK066488 award (to principal investigator M. G. Shlipak); and in part by the Chronic Renal Insufficiency Cohort General Clinical Research Center and Clinical and Translational Science Award grants: UL1 RR-024134 to the University of Pennsylvania (Philadelphia, Pennsylvania), UL1 RR-025005 to Johns Hopkins University (Baltimore, Maryland), M01RR-16500 to University of Maryland (College Park, Maryland), UL1 RR-024989 to Case Western Reserve University (Cleveland, Ohio), M01 RR-000042 and UL1 RR-024986 to University of Michigan (Ann Arbor, Michigan), UL1 RR-029879 to University of Illinois at Chicago (Chicago, Illinois), and 2 U01 DK060902 to the Kaiser Permanente Division of Research in Oakland (Oakland, California).

: Drs. Mishra and Shlipak had full access to all the data in the present study and take responsibility for the integrity of the data and the accuracy of the data analysis.

: See page 438 for disclosure information.

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MiscellaneousAssociation of N-Terminal Pro-B-Type Natriuretic Peptide With Left Ventricular Structure and Function in Chronic Kidney Disease (from the Chronic Renal Insufficiency Cohort [CRIC])

Section snippets

Methods

Results

Discussion

Disclosures

J Am Coll Cardiol

Am J Kidney Dis

Am J Cardiol

Am J Kidney Dis

Am J Kidney Dis

J Am Soc Echocardiogr

J Am Coll Cardiol

J Am Soc Echocardiogr

Kidney Int

Am J Kidney Dis

Clin Chim Acta

J Am Coll Cardiol

J Card Fail

J Cardiol

Miscellaneous
Association of N-Terminal Pro-B-Type Natriuretic Peptide With Left Ventricular Structure and Function in Chronic Kidney Disease (from the Chronic Renal Insufficiency Cohort [CRIC])