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.
B-type natriuretic peptide and its inactive fragment, N-terminal pro-B-type natriuretic peptide (NT-proBNP), are co-secreted in equimolar amounts from cardiac myocytes into the circulation in response to myocardial stretch. In the general population, elevated NT-proBNP levels predict poor outcomes in both asymptomatic and dyspneic subjects, irrespective of renal function. The prevalence of elevated levels of NT-pro-BNP in asymptomatic patients with chronic kidney disease (CKD) is high. This is likely due to some combination of extracellular volume expansion, concomitant heart disease, and, possibly, reduced renal clearance ; however, the clinical implications are not clear. In previous studies of asymptomatic patients with CKD, NT-proBNP was associated with prevalent ischemic heart disease and left ventricular (LV) hypertrophy (LVH), but not LV systolic or diastolic dysfunction. However, controversy remains regarding the extent to which renal dysfunction confounds the association between NT-proBNP levels and LVH in patients with CKD. In addition, the diagnostic role of NT-pro-BNP for the detection of cardiac structural and functional abnormalities has not been defined in a large cohort of patients with CKD. If NT-proBNP were to be highly predictive of pathologic cardiac abnormalities, it could be used to select patients with CKD who might benefit from additional evaluation with echocardiography and targeted care to prevent heart failure (HF). To understand the clinical significance of elevations in NT-pro-BNP levels and to better define the diagnostic role of NT-proBNP, we examined the associations of circulating NT-proBNP with LV structure and function in a large, diverse population of ambulatory patients without HF at various stages of CKD.
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. Participants were recruited from 7 clinical centers from July 2003 to March 2007. The inclusion criteria were an estimated glomerular filtration rate of 20 to 70 ml/min/1.73 m 2 for those aged 21 to 44 years, 20 to 60 ml/min/1.73 m 2 for those aged 45 to 64 years, and 20 to 50 ml/min/1.73 m 2 for those aged 65 to 74 years. The exclusion criteria included previous transplantation, polycystic kidney disease, multiple myeloma, use of immunosuppression, and severe co-morbid illnesses such as cirrhosis, human immunodeficiency virus disease, and severe HF. For the present analysis, we excluded participants who reported prevalent HF on the CRIC medical history questionnaire (n = 443) and those who had more than mild mitral regurgitation or significant aortic valve disease, as determined by transthoracic echocardiography (n = 196 after exclusion of participants with chronic HF). A total of 3,232 participants with NT-proBNP measurements were included after exclusion.
The primary predictor for the present study was NT-proBNP, measured using the Elecsys 2010 analyzer (Roche Diagnostics, Indianapolis, Indiana) at the University of Maryland (Baltimore, Maryland). The coefficient of variation for the NT-proBNP assay was 3.5% during the testing period, and the analytical measurement range for NT-proBNP was 5 to 35,000 pg/ml. For adjusted models, we chose covariates that would be available clinically; these included demographic characteristics (age, gender, race, and clinical site); clinical characteristics (body mass index, systolic and diastolic blood pressure, hypertension, diabetes, hypercholesterolemia, current smoking, alcohol and illicit drug use, coronary artery disease [previous myocardial infarction or revascularization], and peripheral vascular disease); hemoglobin level; high-sensitivity C-reactive protein; and estimated glomerular filtration rate using cystatin C.
Transthoracic echocardiography was performed in all CRIC participants at 1 year of follow-up according to the American Society of Echocardiography guidelines, and the data were sent to a core echocardiography laboratory for measurement and analysis (University of Pennsylvania, Philadelphia, Pennsylvania). For the present analysis, we excluded participants with more than mild mitral regurgitation or significant aortic valve disease, as determined by the transthoracic echocardiography, because these valvular abnormalities could potentially confound the relation between NT-proBNP and cardiac structural and functional abnormalities in CKD.
The LV mass was calculated using the area-length method and indexed to height 2.7 . LVH was defined as a LV mass/height 2.7 ≥47 g/m 2.7 in women and ≥50 g/m 2.7 in men. The LV end-diastolic and end-systolic volumes were calculated using the modified biplane method and ejection fraction was calculated as (end-diastolic volume − end-systolic volume)/end-diastolic volume. LV systolic dysfunction was defined as an ejection fraction <0.45. The mitral inflow E- and A-wave velocities, E-wave deceleration time, and pulmonary venous reverse A-wave duration were used to categorize LV diastolic function into normal, mildly, moderately, or severely abnormal. Because 1 center was unable to evaluate diastolic function, these measures were unavailable in 564 participants.
We first depicted the distribution of NT-proBNP in this cohort of participants with CKD. We then categorized NT-proBNP into quartiles to allow an unbiased portrayal of the levels. The demographic, laboratory, and echocardiographic values were compared across categories of NT-proBNP using analysis of variance or Kruskal-Wallis tests for continuous variables and chi-square test for categorical variables.
NT-proBNP was modeled as a continuous variable after log-transformation because of its skewed distribution. The association of NT-proBNP with LV mass/height 2.7 was assessed by multivariate linear regression analysis. The demographic and laboratory covariates were entered into the multivariate-adjusted models according to the strength of their bivariate association with the outcome (p <0.05). We dichotomized LVH and systolic and diastolic dysfunction and used multivariate logistic regression for these analyses. Diastolic dysfunction was dichotomized, with normal and mildly abnormal function as the referent category.
We evaluated the C-statistic, which is equivalent to the area under the receiver operating characteristics curve, for NT-proBNP as the single predictor of each outcome. We then determined the sensitivity, specificity, and positive and negative likelihood ratios for NT-proBNP as a predictor of LVH and LV systolic and diastolic dysfunction using cutpoints of the 75th and 90th percentiles of the NT-proBNP distribution. We also evaluated the clinical effect of NT-proBNP using the category-free net reclassification improvement (NRI) analysis. A baseline multivariate logistic regression model with clinical predictors was used to generate the probability of each participant having LVH, LV systolic dysfunction, or LV diastolic dysfunction (P 0 ). The covariates included age, race, gender, body mass index, estimated glomerular filtration rate using cystatin C, albuminuria, diabetes, current smoking, any cardiovascular disease, and hemoglobin. These probabilities were then recalculated for each outcome with the addition of NT-proBNP into the clinical model (P 1 ). If P 1 > P 0 , the person was considered to have an upward reclassification; if P 1 < P 0 , the reclassification was downward, and if P 1 = P 0 , no change occurred with the addition of NT-proBNP to the clinical model. The NRI was then calculated using the following formula: NRI = P (up|outcome) − P (down|outcome) + P (down|non-outcome) − P (up|non-outcome). Improvement in net reclassification was indicated by an NRI significantly >0. STATA, version 11 (StataCorp, College Station, Texas) was used for analysis.
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 ). Greater levels of NT-proBNP were also associated with a greater prevalence of diabetes, hypertension, hyperlipidemia, tobacco use, cardiovascular and peripheral vascular disease, with greater systolic blood pressure and urine albumin/creatinine ratio and lower hemoglobin and estimated glomerular filtration rate using cystatin C. NT-proBNP and estimated glomerular filtration rate using cystatin C were moderately correlated (−0.49, p <0.001).
| Characteristic | Quartile | p Value | |||
|---|---|---|---|---|---|
| 1 (n = 808) | 2 (n = 809) | 3 (n = 807) | 4 (n = 808) | ||
| N-terminal-pro-B-type natriuretic peptide cutpoint | 2.5–55.4 | 55.5–126.6 | 126.9–303.6 | 303.7–33,742.0 | <0.001 |
| Age (yrs) | 54 ± 12 | 58 ± 11 | 60 ± 11 | 62 ± 10 | <0.001 |
| Women | 35% | 48% | 52% | 47% | <0.001 |
| Race/ethnicity | |||||
| Non-Hispanic white | 43% | 44% | 47% | 39% | <0.001 |
| Non-Hispanic black | 46% | 41% | 36% | 36% | <0.001 |
| Hispanic | 7% | 10% | 13% | 21% | <0.001 |
| Other | 4% | 5% | 4% | 3% | <0.001 |
| Diabetes mellitus | 33% | 41% | 49% | 60% | <0.001 |
| Hypertension | 79% | 87% | 90% | 96% | <0.001 |
| High cholesterol ∗ | 82% | 86% | 85% | 89% | <0.01 |
| Current smoker | 10% | 9% | 15% | 18% | <0.001 |
| Alcohol intake (diet history questionnaire, g) | 6.0 ± 12.4 | 7.0 ± 19.7 | 6.4 ± 31.4 | 6.4 ± 24.1 | <0.001 |
| Cardiovascular disease | 14% | 20% | 29% | 47% | <0.001 |
| Peripheral vascular disease | 3% | 3% | 6% | 13% | <0.001 |
| Body mass index (kg/m 2 ) | 32.0 ± 7.4 | 32.0 ± 7.5 | 32.0 ± 8.4 | 31.8 ± 8.1 | 0.86 |
| Systolic blood pressure (mm Hg) | 128 ± 18 | 131 ± 18 | 134 ± 21 | 140 ± 22 | <0.001 |
| Diastolic blood pressure (mm Hg) | 75 ± 12 | 76 ± 11 | 75 ± 13 | 74 ± 13 | 0.07 |
| Estimated glomerular filtration rate using cystatin C (ml/min/1.73 m 2 ) | 63.5 ± 20.5 | 52.9 ± 18.1 | 46.4 ± 16.6 | 38.7 ± 14.1 | <0.001 |
| Serum creatinine-based estimated glomerular filtration rate (ml/min/1.73 m 2 ) | 50.5 ± 13.6 | 43.5 ± 13.5 | 39.4 ± 13.7 | 33.2 ± 13.3 | <0.001 |
| Urine albumin/creatinine ratio (μg/mg) | 17 (5–117) | 30 (7–316) | 48 (9–447) | 240 (29–1,329) | <0.001 |
| Hemoglobin (g/dl) | 13.6 ± 1.7 | 12.9 ± 1.6 | 12.6 ± 1.7 | 12.1 ± 1.8 | <0.001 |
| High-sensitive C-reactive protein (mg/L) | 4.7 ± 9.1 | 4.7 ± 6.7 | 6.1 ± 11.9 | 6.1 ± 10.4 | 0.01 |
∗ Defined as total cholesterol ≥240 mg/dl, low-density lipoprotein ≥160 mg/dl, high-density lipoprotein ≤40 mg/dl, triglycerides ≥200 mg/dl, or self-reported use of cholesterol-lowering drug.
Across deciles of NT-proBNP, the prevalence of LVH increased incrementally ( Figure 2 ). In the multivariate-adjusted linear regression model, the highest 3 quartiles of NT-proBNP had a significantly greater LV mass/height 2.7 (quartile 2, β 1.7 g/m 2.7 , p = 0.011; quartile 3, β 3.2 g/m 2.7 , p <0.001; and quartile 4, β 6.4 g/m 2.7 , p <0.001).
Overall, the prevalence of LVH in this cohort was high, and the prevalence doubled from the lowest to the highest NT-proBNP quartiles ( Table 2 ). The greatest quartile of NT-proBNP was associated with a nearly fourfold odds of LVH after demographic adjustment; however, this was attenuated to approximately threefold after multivariate adjustment ( Table 2 ). In the clinical model, we repeated this by deciles of NT-proBNP and the multivariate-adjusted associations of the top 3 deciles with LVH were odds ratio (OR) 1.9 (95% confidence interval [CI] 1.1 to 3.4), OR 2.7 (95% CI 1.0 to 4.9), and OR 4.3 (95% CI 2.3 to 8.3) compared to the lowest decile.
| Variable | Quartile | |||
|---|---|---|---|---|
| 1 | 2 | 3 | 4 | |
| Left ventricular hypertrophy | ||||
| Prevalence (%) | 32 | 44 | 55 | 68 |
| Demographic-adjusted ∗ | Reference | 1.6 (1.2–2.0) | 2.4 (1.8–3.0) | 3.6 (2.8–4.6) |
| Multivariate-adjusted † | Reference | 1.3 (0.9–1.8) | 2.1 (1.4–3.0) | 2.7 (1.8–4.0) |
| Systolic dysfunction | ||||
| Prevalence (%) | 6 | 5 | 7 | 14 |
| Demographic-adjusted ∗ | Reference | 1.1 (0.7–1.7) | 1.6 (1.0–2.5) | 3.7 (2.5–5.6) |
| Multivariate-adjusted ‡ | Reference | 0.9 (0.5–1.5) | 1.2 (0.7–2.0) | 2.7 (1.7–4.5) |
| Diastolic dysfunction § | ||||
| Prevalence (%) | 8 | 9 | 8 | 10 |
| Demographic-adjusted ∗ | Reference | 1.3 (0.9–1.9) | 1.2 (0.8–1.8) | 1.9 (1.3–2.8) |
| Multivariate-adjusted ¶ | Reference | 1.3 (0.9–1.9) | 1.2 (0.8–1.9) | 2.0 (1.3–2.9) |
∗ Adjusted for age, gender, race, and cause of renal disease.
† Adjusted for age, gender, race, cause of renal disease, diabetes, hypertension, high cholesterol, previous peripheral vascular disease, any cardiovascular disease, height, weight, body mass index, echocardiographic systolic and diastolic blood pressure, hemoglobin, estimated glomerular filtration rate using cystatin C, and high-sensitive C-reactive protein.
‡ Adjusted for age, gender, race, cause of renal disease, any cardiovascular disease, height, weight, and echocardiographic diastolic blood pressure.
§ This analysis for diastolic dysfunction did not include 564 participants without echocardiographic assessment of diastolic function.
¶ Adjusted for age, sex, race, cause of renal disease, height, and diabetes.
Of the entire cohort of 3,232 subjects, 229 had LV systolic dysfunction (ejection fraction <0.45). Participants in the highest decile of NT-proBNP level had the greatest prevalence of LV systolic dysfunction, more than double the prevalence of any other decile ( Figure 2 ). The median NT-proBNP level was 209.0 pg/ml (interquartile range 81.4 to 680.4) in participants with systolic dysfunction compared with 114.4 pg/ml (interquartile range 52.5 to 266.2) in those with normal systolic function (p <0.001). A nearly threefold greater adjusted odds of systolic dysfunction was apparent when comparing the highest NT-proBNP quartile to the lowest quartile ( Table 2 ). In the clinical model, we repeated this by decile of NT-proBNP and the multivariate-adjusted associations of the top 3 deciles with systolic dysfunction were OR 1.7 (95% CI 0.7 to 4.0), OR 2.2 (95% CI 0.9 to 5.2), and OR 6.3 (95% CI 2.7 to 14.5).
No significant difference was seen in the median NT-proBNP level between the participants with moderate or severe diastolic dysfunction (129.1 pg/ml, interquartile range 59.6 to 330.4) and those with normal or mildly abnormal diastolic function (123.8 pg/ml, interquartile range 55.5 to 286.8; p for comparison = 0.83). However, the NT-proBNP quartiles were associated with the prevalence of moderate to severe diastolic dysfunction, and the greatest quartile was associated with a twofold odds of moderate or severe diastolic dysfunction compared to the lowest quartile in the multivariate-adjusted model ( Table 2 ).
When evaluated as a screening test, NT-proBNP functioned only modestly for the detection of LVH ( Table 3 ). Performance was slightly worse for the detection of LV systolic dysfunction and the combined outcome of LVH and LV systolic or diastolic function and was substantially worse for LV diastolic dysfunction alone. For each of these structural and functional abnormalities, we identified no optimal threshold value for NT-proBNP. The 90th percentile of NT-proBNP had moderately high positive likelihood ratios for detecting LVH, systolic dysfunction, and the combined outcome of LVH and LV systolic or diastolic dysfunction. However, the negative likelihood ratios were uniformly poor owing to the limited sensitivity at each cutpoint ( Table 3 ).
