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Clinical Chemistry 55:7 1347–1353 (2009) Proteomics and Protein Markers Impact of Left Ventricular End-Diastolic Wall Stress on Plasma B-Type Natriuretic Peptide in Heart Failure with Chronic Kidney Disease and End-Stage Renal Disease Shinichiro Niizuma,1,3 Yoshitaka Iwanaga,4* Takaharu Yahata,2 Yodo Tamaki,3 Yoichi Goto,2 Hajime Nakahama,1 and Shunichi Miyazaki4 BACKGROUND: Plasma B-type natriuretic peptide (BNP) is a diagnostic and prognostic marker in heart failure (HF). Although renal function is reported as an important clinical determinant, precise evaluations of the relationships of renal function with hemodynamic factors in determining BNP have not been performed. Therefore, we evaluated the association of plasma BNP concentrations with LV end-diastolic wall stress (EDWS) in a broad range of HF patients including those with chronic kidney disease (CKD) and endstage renal disease (ESRD). METHODS: In 156 consecutive HF patients including those with CKD and ESRD, we measured plasma BNP and performed echocardiography and cardiac catheterization. LV EDWS was calculated as a crucial hemodynamic determinant of BNP. RESULTS: Plasma BNP concentrations increased progressively with decreasing renal function across the groups (P ⬍ 0.01) and were correlated with LV EDWS (r ⫽ 0.47) in the HF patients overall. This relationship was also present when patients were subdivided into systolic and diastolic HF (P ⬍ 0.01). In multivariable analysis, higher EDWS was associated with increased BNP concentration independently of renal dysfunction (P ⬍ 0.01). Anemia, systolic HF, and decreased BMI also contributed to increased BNP concentrations. CONCLUSIONS: These results suggest that LV EDWS is a strong determinant of BNP even in patients with CKD and ESRD. Anemia, obesity, and HF type (systolic or diastolic) should also be considered in interpreting plasma BNP concentrations in HF patients. These find- 1 Division of Hypertension and Nephrology; and 2 Division of Cardiology, National Cardiovascular Center, Suita, Japan; 3 Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan; 4 Division of Cardiology, Department of Internal Medicine, Kinki University School of Medicine, Osakasayama, Japan. * Address correspondence to this author at: Division of Cardiology, Department of Internal Medicine, Kinki University School of Medicine, 377–2 Ohno-Higashi, Osakasayama 589-8511, Japan. Fax ⫹81-72-368-2378; e-mail yiwanaga@ med.kindai.ac.jp. Received November 28, 2008; accepted March 24, 2009. ings may contribute to the clinical management of HF patients, especially those complicated with CKD and ESRD. © 2009 American Association for Clinical Chemistry Chronic kidney disease (CKD)5 is frequently associated with a progressive decrease in glomerular filtration rate (GFR), which leads to end-stage renal disease (ESRD) (1 ). The number of patients with CKD as well as ESRD is increasing markedly worldwide (2, 3 ). Several investigators have documented that patients with CKD are at higher risk of cardiovascular disease than the general population, and show a higher rate of cardiovascular mortality (4–6 ). In particular, ESRD patients have a 500-fold greater rate of cardiovascular mortality than age-matched controls with normal renal function (7 ). Heart failure (HF) is also an increasingly prevalent condition and the leading cause of death among cardiovascular diseases in patients with CKD and ESRD (8 ). There may be some interaction between heart disease and kidney disease, and HF patients who have CKD or ESRD show a worse prognosis (9, 10 ). Thus, early diagnosis and aggressive management of HF are needed in patients with CKD and ESRD. Conversely, early recognition and management of CKD are also necessary in patients with HF. B-type natriuretic peptide (BNP) is synthesized in the ventricular myocardium in response to ventricular stretching and wall stress (11 ). BNP and N-terminal pro-BNP (NT-proBNP), which are associated with the severity of HF and left ventricular (LV) function, are useful markers for diagnosis, management, and prog- Previously published online at DOI: 10.1373/clinchem.2008.121236 5 Nonstandard abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate; ESRD, end-stage renal disease; HF, heart failure; BNP, B-type natriuretic peptide; NT-proBNP, N-terminal pro-BNP; LV, left ventricular; EDWS, end-diastolic wall stress; NYHA, New York Heart Association; Cr, creatinine; Hb, hemoglobin; eGFR, estimated GFR; EF, ejection fraction; RWT, relative wall thickness; LVMI, LV mass index; EDP, end-diastolic pressure; BMI, body mass index; AF, atrial fibrillation; HF, heart failure; LVEDVI, LV end-diastolic volume index; SHF, systolic HF; DHF, diastolic HF. 1347 nosis in patients with normal renal function (11–14 ). Recently, the prognostic potential of plasma BNP concentrations has been investigated in several studies on patients with CKD and patients on hemodialysis and peritoneal dialysis (15, 16 ). However, the diagnostic accuracy of plasma BNP and NT-proBNP concentrations for HF has been reported to be reduced in this setting (17 ). It is not yet clear whether, in HF patients with CKD and ESRD, increased plasma BNP concentrations might be due to more hemodynamic stimuli or might result from other factors such as anemia, obesity and cachexia, or impaired renal clearance of natriuretic peptide, despite similar hemodynamic stimuli. Accordingly, we conducted the present study to clarify the relationship between plasma BNP concentrations and possible determinants, including severity of renal dysfunction, anemia, obesity/cachexia, and hemodynamic factors in HF patients across all CKD groups, including ESRD. In particular, we performed an analysis of left ventricular end-diastolic wall stress (EDWS), which we previously found to be a crucial hemodynamic determinant of plasma BNP concentrations (11 ), to clarify the precise contribution of hemodynamic factors to the regulation of plasma BNP in this setting. Materials and Methods STUDY PATIENTS One hundred fifty-six patients who had been referred for HF [New York Heart Association (NYHA) ⱖ class II] between October 2003 and May 2005 were enrolled in the present study. The diagnosis of HF was based on the European Society of Cardiology criteria. For all participants, cardiac catheterization and echocardiograms were performed at a compensated congestive heart failure stage (before discharge). Patients who did not undergo LV catheterization were excluded. Plasma BNP, serum creatinine (Cr), and hemoglobin (Hb) were measured on the day before cardiac catheterization. RENAL FUNCTION Serum creatinine values obtained for all patients were used to estimate GFR using the abbreviated Modification of Diet in Renal Disease study formula (18 ): estimated GFR (eGFR, mL/min/1.73 m2) ⫽ 186 ⫻ Cr⫺1.154 ⫻ age⫺0.203 (⫻ 0.742 if female). The severity of renal dysfunction was classified as normal, CKD, or ESRD by using eGFR. CKD and ESRD were defined as 15 ⱕ eGFR ⬍60 and eGFR ⬍15, respectively. Among the patients with ESRD, 38 underwent regular 4-h sessions of hemodialysis 3 times weekly. Plasma BNP concentrations were measured in blood samples drawn from the arteriovenous fistula immediately before a he1348 Clinical Chemistry 55:7 (2009) modialysis session on the day before coronary cardiac catheterization. The underlying disease etiologies in patients with ESRD were chronic glomerulonephritis in 13, nephrosclerosis in 13, diabetic nephropathy in 13, and other causes in 2. CARDIAC CATHETERIZATION Left ventricular pressure was recorded with a 5-F pigtail catheter connected to a fluid-filled transducer. Left ventricular volume and ejection fraction (EF) were determined by left ventriculography with contrast medium using the Kennedy’s formula (19 ). ECHOCARDIOGRAPHY We performed echocardiographic examinations in all patients using a Sonos 5500 machine equipped with a 2.5-MHz probe. M-mode images were obtained to measure left atrial and ventricular dimensions (20 ). Relative wall thickness (RWT) was defined as 2 ⫻ (posterior wall thickness)/(LV end-diastolic dimension). The left ventricular mass index (LVMI) was estimated using the formula of Devereux et al. (21 ). In patients with sinus rhythm, the pulsed Doppler transmitral flow velocity was recorded to measure the ratio of peak mitral E-wave velocity to peak mitral A-wave velocity (E/A ratio) and the deceleration time of the mitral E-wave velocity. Based on hemodynamic and echocardiographic data, end-diastolic and systolic meridional wall stresses were calculated as follows: WS ⫽ 0.334 ⫻ P(LVID)/WT(1 ⫹ WT/LVID), where WS is wall stress, P is LV pressure [i.e., peak systolic pressure or enddiastolic pressure (EDP), which was obtained during cardiac catheterization], LVID is left ventricular internal dimension, and WT is wall thickness (11 ). STATISTICAL ANALYSIS We compared groups using 2 tests for proportions and Mann–Whitney U tests or ANOVA for continuous variables, as appropriate. We assessed the linearity of a relationship between 2 variables by linear regression analysis and calculated the Pearson correlation coefficient. Further multivariable analysis was performed to evaluate the independent relationship between the severity of renal dysfunction and plasma BNP concentrations in concert with demographic variables, hemodynamic indexes, and laboratory data using JMP version 8.0. Variables included in the analysis were sex, age, body mass index (BMI), NHYA class, hypertension, diabetes, hyperlipidemia, atrial fibrillation (AF), heart failure (HF) etiology, medications, hemodynamic and echocardiographic indexes, and laboratory data; P ⬍ 0.05 was considered significant. Results are expressed as mean ⫾ SE. BNP and Chronic Kidney Disease in Heart Failure Table 1. Patient characteristics.a n Age, years Female BMI, kg/m2 Normal CKD ESRD 58 57 41 Table 2. Echocardiographic and hemodynamic parameters.a P 60.4 (2.0) 69.2 (1.8) 65.0 (1.3) ⬍0.01 19 (32) 16 (28) 11 (27) 0.81 22.1 (0.6) 22.0 (0.4) 21.1 (0.4) 0.28 b LVEDD, mm PWT, mm Normal CKD ESRD P 58.8 (1.0) 63.4 (1.2) 54.8 (1.4) ⬍0.01 9.7 (0.3) 9.2 (0.2) 10.4 (0.4) ⬍0.01 RWT 0.33 (0.01) 0.29 (0.01) 0.40 (0.02) ⬍0.01 LAD, mm 44.3 (1.1) eGFR, mL/min/ 1.73m2 78 (2) 44 (1) 5 (0) ⬍0.001 E/A 1.64 (0.22) 1.68 (0.16) 1.21 (0.14) 0.18 Hypertension 24 (41) 31 (55) 33 (83) 0.08 DCT, msec 194 (12) 195 (13) 0.64 Diabetes 14 (24) 29 (51) 21 (53) 0.06 LVMI, g/m2 165 (6) 176 (7) 179 (9) 0.41 Hyperlipidemia 21 (36) 30 (53) 16 (40) 0.18 EF, % 37.8 (1.9) 36.6 (2.0) 39.4 (2.4) 0.68 DHF 16 (28) 14 (25) 11 (27) 0.94 LVEDVI, mL/m 120 (6) 123 (6) 116 (9) 0.42 AF 18 (31) 16 (29) 11 (27) 0.92 LVSP, mmHg 121 (5) 122 (4) 149 (6) ⬍0.01 0.18 LVEDP, mmHg 14.3 (0.7) 17.2 (1.0) 17.1 (1.0) 0.04 EDWS, kdynes/cm2 40.6 (2.3) 56.0 (3.6) 47.1 (6.0) 0.01 Diagnosis b OMI or ICM 18 (31) 25 (44) 21 (51) Valvular heart disease 19 (32) 18 (32) 13 (32) HHD 9 (14) 2 (4) 2 (5) DCM 14 (24) 12 (21) 5 (12) ACE inhibitor or ARB 37 (63) 39 (68) 11 (26) Beta blocker 22 (37) 30 (54) 22 (55) 0.13 Diuretics 36 (62) 49 (81) 7 (17) ⬍0.001 Aldosterone receptor blocker 20 (34) 21 (36) 1 (2) ⬍0.001 a b Medication ⬍0.001 Laboratory a b 2 512 (48) 1947 (391) ⬍0.001 BNP, ng/L 287 (31) Cr, mg/L 7.3 (1.7) 12.1 (1.7) 79.5 (2.1) ⬍0.001 Hb, g/L 135 (3) 130 (3) 100 (6) ⬍0.001 Values are mean (SE) or n (%). OMI, old myocardial infarction; ICM, ischemic cardiomyopathy; HHD, hypertensive heart disease; DCM, dilated cardiomyopathy; ARB, angiotensin receptor blocker. Results 49.3 (1.4) 181 (12) 44.3 (1.1) 0.06 Values are mean (SE). LVEDD, left ventricular end-diastolic dimension; PWT, posterior wall thickness; LAD, left atrial dimension; E/A, ratio of peak mitral E-wave velocity to peak mitral A-wave velocity; DCT, deceleration time of early diastolic filling; LVSP, left ventricular peak systolic pressure; LVEDP, left ventricular end-diastolic pressure. sterone receptor blockers, or diuretics. Hb levels were significantly lower in ESRD patients than in normal and CKD patients (P ⬍ 0.01). Geometric and functional parameters obtained by echocardiography or cardiac catheterization are shown in Table 2. In all of the patients, mean (SD) EF was 47.8% (1.2%) and mean LVMI, LV end-diastolic volume index (LVEDVI), and LV EDWS were 172.7 (5.3) g/m2, 119.9 (4.0) mL/m2, and 47.9 (2.3) kdynes/cm2, respectively. Among the 3 groups, although there was no significant difference in EF, LVEDVI, or LVMI, patients with CKD showed higher EDWS than those in the normal and ESRD groups. Patients with ESRD showed higher RWT (more concentric remodeling) and left ventricular systolic pressure than those in the normal and CKD groups. PATIENT CHARACTERISTICS The baseline clinical characteristics in HF patients according to the degree of renal dysfunction [normal (n ⫽ 58), CKD (n ⫽ 57), ESRD (n ⫽ 41)] are shown in Table 1. The proportion of patients with eGFR between 15 and 29 (i.e., stage 4 CKD) was only 12% in the CKD group. In all of the patients, the mean age was 64.7 (1.1) years, and 29% of the patients were female. Patients with CKD and ESRD showed a high prevalence of old myocardial infarction or ischemic cardiomyopathy. Patients in the ESRD group were less likely to be taking ACE inhibitors or angiotensin receptor blockers, aldo- ASSOCIATION BETWEEN PLASMA BNP CONCENTRATIONS AND THE SEVERITY OF RENAL FUNCTION As shown in Fig. 1A, plasma BNP concentrations increased progressively with the degree of renal dysfunction [normal, 287 (31) ng/L; CKD, 512 (48) ng/L; ESRD, 1947 (391) ng/L; P ⬍ 0.01]. Overall, 102 patients had an LV EF of ⱕ45%. These comprised the systolic heart failure (SHF) group. The diastolic heart failure (DHF) group comprised 54 patients with preserved systolic function (LV EF ⬎45%) (22 ). Mean EFs were 28.9% (0.9%) and 54.6% (0.8%), respectively. Clinical Chemistry 55:7 (2009) 1349 A * B * 10 Log [BNP (ng/L)] Log [BNP (ng/L)] 10 * 9 8 7 6 5 * * 7 6 5 4 3 2 2 ESRD * 8 3 CKD * 9 4 Normal * Normal CKD ESRD Normal CKD ESRD SHF DHF Fig. 1. (A), Analysis of BNP concentration according to the severity of renal dysfunction; normal (n ⴝ 58), CKD (n ⴝ 57), ESRD (n ⴝ 41); (B), subgroup analysis in SHF (n ⴝ 102) vs DHF (n ⴝ 54); *P < 0.05. Plasma BNP concentrations were significantly higher in SHF than in DHF groups [SHF, 997 (144) ng/L; DHF, 445 (71) ng/L; P ⬍ 0.01]. As shown in Fig. 1B, plasma BNP concentrations increased progressively with the degree of renal dysfunction even when patients were divided into 2 groups: SHF and DHF (P ⬍ 0.01). In patients with DHF, however, no significant difference was observed between the normal and CKD groups. CORRELATION OF PLASMA BNP CONCENTRATIONS WITH HEMODYNAMIC PARAMETERS AND OTHER FACTORS Log LV EDWS, EF, and EDP were moderately correlated with log plasma BNP concentrations (r ⫽ 0.47, 0.45, 0.40, respectively; P ⬍ 0.01) and LVMI was significantly, but poorly, correlated (r ⫽ 0.17, P ⫽ 0.03) (Fig. 2). When anemia was defined as Hb ⬍12 g/dL for women and Hb ⬍13 for men, it was present in 51% (n ⫽ 79) of the total patients and in 26%, 44%, and 95% of those in the normal, CKD, and ESRD groups. There were no differences in BMI among the 3 groups. Both hemoglobin concentrations and BMI were moderately correlated with log plasma BNP concentrations (r ⫽ ⫺0.44 and ⫺0.35, P ⬍ 0.01). LV EDWS were significantly higher in SHF than in DHF groups [SHF, 55.7 (3.1) kdynes/cm2; DHF, 33.1 (1.7) kdynes/cm2; P ⬍ 0.01]. Although log LV EDWS was positively correlated with the log BNP concentrations in the SHF group (r ⫽ 0.54, P ⬍ 0.01), no association was observed in the DHF group (P ⫽ 0.76). The individual correlation coefficients for each renal category (normal, CKD, ESRD) between log BNP and echocardiographic/hemodynamic parameters are shown in Supplemental Table 1, which accompanies the online version of this article at www.clinchem.org/ 1350 Clinical Chemistry 55:7 (2009) content/vol55/issue7. The correlation between log BNP and log EDWS appears weak in patients with ESRD compared with the other 2 groups (r ⫽ 0.400, 0.704, 0.782, respectively). RELATIONSHIP OF RENAL FUNCTION, EDWS, AND OTHER CONFOUNDERS WITH PLASMA BNP CONCENTRATIONS The plasma BNP concentrations in all HF patients according to the groups of renal dysfunction and tertiles of the EDWS level are shown in Fig. 3. Plasma BNP concentrations increased progressively with the grade of EDWS in both the normal and CKD groups. In the ESRD group, there were no significant differences between the low and middle EDWS groups. However, patients with ESRD and high EDWS showed the highest plasma BNP concentrations. Multivariable linear regression analysis revealed that the group defined in terms of renal dysfunction and the levels of log EDWS were both independent determinants of log BNP concentrations (P ⬍ 0.01). In addition, HF type (systolic vs diastolic), hemoglobin concentrations, and BMI were independently associated with the log BNP level. In contrast, LVMI was unrelated to plasma BNP once the effects of renal dysfunction, log EDWS, HF type, Hb, and BMI were considered (Table 3). The fit (R2) of the model including these variables was 0.63. The results of a multivariable linear regression analysis in the ESRD group vs the CKD combined normal group are shown in online Supplemental Table 2. Only log EDWS remained a significant predictor for log BNP concentrations in HF patients with ESRD. No other confounder variables were found to be significant in this population. BNP and Chronic Kidney Disease in Heart Failure A B 10 r = 0.47, P < 0.01 9 Log [BNP (ng/L)] Log [BNP (ng/L)] 10 8 7 6 5 4 3 8 7 6 5 4 3 2 2 2.5 3 3.5 4 Log [EDWS C 4.5 5 (kdynes/cm2) 2 5.5 ] 0 50 100 150 200 250 300 350 LVMI (kg/m2) D 10 10 r = –0.44, P < 0.01 9 8 7 6 5 4 3 Log [BNP (ng/L)] Log [BNP (ng/L)] r = 0.17, P = 0.03 9 r = –0.35, P < 0.01 9 8 7 6 5 4 3 2 2 60 80 100 120 140 160 180 200 13 18 23 28 33 38 BMI (kg/m2) Hb (g/L) Fig. 2. Correlations between log BNP concentration and log LV EDWS (A), LVMI (B), Hb concentration (C), and BMI (D) in all patients. ‚, patients with normal GFR; 䡬, CKD; }, ESRD. Discussion HF is one of the leading causes of death in patients with CKD and ESRD (7 ). There may be some interaction between heart disease and kidney disease, and HF patients who have CKD and ESRD show a worse prognosis (9, 10 ). In our study population with HF, only 37% of the patients had eGFR ⱖ60 mL/min/1.73 m2, and the remainder had eGFR ⬍60 or were receiving chronic dialysis. In terms of the diagnosis and management of HF, it is essential to consider the existence of renal dysfunction. BNP and NT-proBNP are currently the most widely used markers in the clinical setting of HF. However, in most previous studies on the diagnostic and prognostic roles of BNP or NT-proBNP in HF, 8 Table 3. Predictors for log BNP concentrations in multivariable regression analysis.a 7.5 7 6.5 6 Log [BNP (ng/L)] Log BNP 5.5 5  Coefficient Parameter 4.5 4 3.5 2nd tertile 3 ESRD 1st tertile CKD EDWS Normal Renal function Fig. 3. Relationship of renal function (normal, CKD, ESRD) and LV EDWS with log BNP concentration. Patients were divided into tertiles according to the EDWS level (first tertile: ⬍33 kdynes/cm2, second tertile: 33–55, third tertile: ⬎55). P NSb LVMI 3rd tertile BMI ⫺0.068 Hb ⫺0.065 0.023 HF type (SHF vs DHF) 0.260 ⬍0.001 Log EDWS 0.678 ⬍0.001 ⫺0.017 ⬍0.001 eGFR ⬍0.001 a Significant univariable predictors were included in the multivariable regression model as continuous variables, and HF type was included as a binary variable. b NS, not significant. Clinical Chemistry 55:7 (2009) 1351 patients with CKD and ESRD have been excluded because of potentially increased BNP concentrations. Thus, the utility of BNP measurement in HF has been obviously limited in patients with renal dysfunction. It is well known that the hemodynamic load is the most important stimulus for BNP secretion in the myocardium based on the results of both basic and clinical studies. We have recently shown that plasma BNP concentrations strongly reflect LV EDWS in HF patients with normal creatinine concentrations, and this relationship was more robust than any other parameter previously reported (11 ). Although several studies have already demonstrated the association between BNP and renal function in patients with HF or without HF, hemodynamic factors were not adequately considered in the analysis (23–25 ). Accordingly, we performed this study in a wide spectrum of HF patients with a concomitant analysis of EDWS and showed that both EDWS and renal dysfunction may contribute to the increased BNP concentrations independently in this setting. In the clinical setting, heterogeneity in BNP concentrations among individuals with HF has been recognized, and this has caused some confusion in interpreting results (11 ). A number of nonhemodynamic factors such as age, sex, atrial fibrillation, obesity (BMI), and anemia are presumed to have some contribution to the interindividual variability of plasma BNP concentrations in the diagnosis and management of HF patients (26–29 ). In the present study, anemia, lower BMI, and SHF, in addition to EDWS and renal dysfunction, contributed to increased BNP levels to some extent. Anemia is a common phenomenon in HF and is related to its severity. HF is strongly related to CKD, and renal dysfunction is a well-known cause of anemia. This vicious cycle has been described as the cardiorenal anemia syndrome (30 ). Because all 3 conditions could closely influence each other and increase BNP concentrations independently or mutually, it has not been clear what increased BNP concentrations reflect in this complicated setting. In the present study, hemoglobin added significant value to the multivariable linear regression model of BNP determinants in addition to EDWS and renal dysfunction. This is consistent with the results reported by Hogenhuis et al. (28 ), although their study did not adequately consider hemodynamic factors. The high prognostic value of BNP might be derived from the fact that BNP is an integrated marker of cardiohemodynamic function, renal function, and anemia, as demonstrated in the present study. Currently, the clinical utility of measurements of BNP in HF patients with ESRD is very limited because of lack of data. In the present study, the findings in ESRD patients were clearly different from the other 2 groups, not only in terms of patient characteristics, 1352 Clinical Chemistry 55:7 (2009) echo and hemodynamic data, but also in the relationship of BNP with other variables. In a subanalysis shown in online Supplemental Table 2, only EDWS remained a significant determinant of BNP concentrations in HF patients with ESRD. However, there might be unknown factors or hidden confounders unique to this population. Epidemiological data indicate that up to 50% of patients with HF symptoms suffer from DHF. Moreover, the prognosis of patients suffering from DHF is as ominous as that of patients suffering from SHF (31 ). However, little is known about the relationship between CKD and DHF. The contribution of LV diastolic function to plasma BNP concentrations and the usefulness of BNP in the diagnosis of DHF have been demonstrated (32 ), and we also have shown that EDWS could account for the increase in plasma BNP concentrations even in patients with DHF and normal renal function (11 ). It has been suggested, however, that the diagnostic accuracy of BNP may be lower in patients with DHF than in those with SHF (33 ). In subanalyses in the present study, there was no significant difference in BNP concentrations between DHF patients with normal renal function and those with CKD, and no correlation of BNP concentrations with LV EDWS in DHF patients. However, these findings might be a reflection of the lower diagnostic accuracy of BNP in patients with DHF, and clinicians are therefore advised to interpret BNP concentrations in the diagnosis and management of patients with DHF with caution. Several limitations should be considered in interpreting our results. First, the study population was relatively small. Second, only plasma BNP concentrations were considered in our study. Recently, the measurement of NT-proBNP increasingly has been used clinically because of its longer half-life and larger size. NTproBNP might be more dependent on renal clearance than BNP (34 ). To date, most studies have demonstrated that both are equally useful, even in CKD and HD patients (35 ). Finally, the study population was comprised of patients who were in stable condition and could tolerate LV cardiac catheterization; thus patients who could not bear cardiac catheterization (e.g., patients with NYHA class IV HF) or would be at high risk for contrast nephropathy were excluded. In particular, our study design led to exclusion of some patients with more severe CKD not on renal replacement therapy. Therefore, the applicability of our results to the patients with more severe CKD not requiring dialysis might be uncertain. Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, BNP and Chronic Kidney Disease in Heart Failure acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article. Authors’ Disclosures of Potential Conflicts of Interest: Upon manuscript submission, all authors completed the Disclosures of Potential Conflict of Interest form. Potential conflicts of interest: Honoraria: None declared. Research Funding: This study was supported by a research grant from the Takeda Science Foundation and a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (18590774). Expert Testimony: None declared. Employment or Leadership: None declared. Consultant or Advisory Role: None declared. Stock Ownership: None declared. Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or preparation or approval of manuscript. References 1. Jones CA, McQuillan GM, Kusek JW, Eberhardt MS, Herman WH, Coresh J, et al. Serum creatinine levels in the US population: third National Health and Nutrition Examination Survey. Am J Kidney Dis 1998;32:992–9. 2. National Kidney Foundation (NKF) Kidney Disease Outcome Quality Initiative (K/DOQI) Advisory Board. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification: Kidney Disease Outcome Quality Initiative. Am J Kidney Dis 2002;39:S17–31. 3. Lysaght MJ. Maintenance dialysis population dynamics: current trends and long-term implications. J Am Soc Nephrol 2002;13:S37– 40. 4. Cardiovascular Disease in Dialysis Patients Work Group. Clinical practice guidelines for cardiovascular disease in dialysis patients. Am J Kidney Dis 2005;45 (Suppl 4):S7–153. 5. Berl T, Henrich W. Kidney-heart interactions: epidemiology, pathogenesis, and treatment. Clin J Am Soc Nephrol 2006;1:8 –18. 6. Ninomiya T, Kiyohara Y, Kubo M, Tanizaki Y, Doi Y, Okubo K, et al. Chronic kidney disease and cardiovascular disease in a general Japanese population: the Hisayama Study. Kidney Int 2005; 68:228 –36. 7. Schiffrin EL, Lipman ML, Mann JF. Chronic kidney disease: effects on the cardiovascular system. Circulation 2007;116:85–97. 8. U.S. Renal Data System, USRDS 2006 annual data report. Bethesda (MD): NIH, National Institute of Diabetes and Digestive and Kidney Diseases; 2007. 9. Manjunath G, Tighiouart H, Ibrahim H, MacLeod B, Salem DN, Griffith JL, et al. Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J Am Coll Cardiol 2003;41:47–55. 10. Muntner P, He J, Hamm L, Loria C, Whelton PK. Renal insufficiency and subsequent death resulting from cardiovascular disease in the United States. J Am Soc Nephrol 2002;13:745–53. 11. Iwanaga Y, Nishi I, Furuichi S, Noguchi T, Sase K, Kihara Y, et al. B-type natriuretic peptide strongly reflects diastolic wall stress in patients with chronic heart failure: comparison between systolic and diastolic heart failure. J Am Coll Cardiol 2006;47:742– 8. 12. Maisel AS, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P, et al. Breathing Not Properly Multinational Study Investigators. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161–7. 13. Anand IS, Fisher LD, Chiang YT, Latini R, Masson 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. S, Maggioni AP, et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation 2003;107: 1278 – 83. O’Donoghue M, Januzzi JL Jr. N-terminal proBNP: a novel biomarker for the diagnosis, risk stratification and management of congestive heart failure. Expert Rev Cardiovasc Ther 2005;3:487–96. Naganuma T, Sugimura K, Wada S, Yasumoto R, Sugimura T, Masuda C, et al. The prognostic role of brain natriuretic peptides in hemodialysis patients. Am J Nephrol 2002;22:437– 44. Wang AY, Lam CW, Yu CM, Wang M, Chan IH, Zhang Y, et al. N-terminal pro-brain natriuretic peptide: an independent risk predictor of cardiovascular congestion, mortality, and adverse cardiovascular outcomes in chronic peritoneal dialysis patients. J Am Soc Nephrol 2007;18:321–30. Vanderheyden M, Bartunek J, Filippatos G, Goethals M, Vlem BV, Maisel A. Cardiovascular disease in patients with chronic renal impairment: role of natriuretic peptides. Congest Heart Fail 2008;14(4 Suppl 1):38 – 42. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461–70. Kennedy JW, Trenholme SE, Kasser IS. Left ventricular volume and mass from single-plane cineangiocardiogram. A comparison of anteroposterior and right anterior oblique methods. Am Heart J 1970;80:343–52. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. J Am Soc Echocardiogr 1989;2:358 – 67. Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986;57: 450 – 8. Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 2008;359:2456 – 67. deFilippi CR, Seliger SL, Maynard S, Christenson RH. Impact of renal disease on natriuretic peptide testing for diagnosing decompensated heart failure and predicting mortality. Clin Chem 2007;53: 1511–9. Schou M, Gustafsson F, Kistorp CN, Corell P, 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. Kjaer A, Hildebrandt PR. Effects of body mass index and age on N-terminal pro brain natriuretic peptide are associated with glomerular filtration rate in chronic heart failure patients. Clin Chem 2007;53:1928 –35. Takami Y, Horio T, Iwashima Y, Takiuchi S, Kamide K, Yoshihara F, et al. Diagnostic and prognostic value of plasma brain natriuretic peptide in non-dialysis-dependent CRF. Am J Kidney Dis 2004;44:420 – 8. Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett JC Jr. Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll Cardiol 2002;40: 976 – 82. Silvet H, Young-Xu Y, Walleigh D, Ravid S. Brain natriuretic peptide is elevated in outpatients with atrial fibrillation. Am J Cardiol 2003;92:1124 –7. Iwanaga Y, Kihara Y, Niizuma S, Noguchi T, Nonogi H, Kita T, et al. BNP in overweight and obese patients with heart failure: an analysis based on the BNP-LV diastolic wall stress relationship. J Card Fail 2007;13:663–7. Hogenhuis J, Voors AA, Jaarsma T, Hoes AW, Hillege HL, Kragten JA, et al. Anaemia and renal dysfunction are independently associated with BNP and NT-proBNP levels in patients with heart failure. Eur J Heart Fail 2007;9:787–94. Silverberg DS, Wexler D, Blum M, Wollman Y, Schwartz D, Sheps D, et al. The interaction between heart failure, renal failure and anemia: the cardio-renal syndrome. Blood Purif 2004;22:277– 84. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006;355:251–9. Bursi F, Weston SA, Redfield MM, Jacobsen SJ, Pakhomov S, Nkomo VT, et al. Systolic and diastolic heart failure in the community. JAMA 2006; 296:2209 –16. Dahlström U. Can natriuretic peptides be used for the diagnosis of diastolic heart failure? Eur J Heart Fail 2004;6:281–7. McCullough PA, Sandberg KR. B-type natriuretic peptide and renal disease. Heart Fail Rev 2003; 8:355– 8. Clerico A, Fontana M, Zyw L, Passino C, Emdin M. Comparison of the diagnostic accuracy of brain natriuretic peptide (BNP) and the N-terminal part of the propeptide of BNP immunoassays in chronic and acute heart failure: a systematic review. Clin Chem 2007;53:813–22. Clinical Chemistry 55:7 (2009) 1353