Bun PDF
Bun PDF
Bun PDF
Circulation Journal
Official Journal of the Japanese Circulation Society
ORIGINAL ARTICLE
http://www. j-circ.or.jp Heart Failure
Background: Risk stratification of acute kidney injury (AKI) is important for acute decompensated heart failure
(ADHF). The aim of this study was to determine whether clinical markers, such as the blood urea nitrogen/creatinine
ratio (BUN/Cr) or BUN or creatinine values alone, stratify the risk of AKI for mortality.
Methods and Results: In all, 371 consecutive ADHF patients were enrolled in the study. AKI was defined as serum
creatinine ≥0.3 mg/dl or a 1.5-fold increase in serum creatinine levels within 48 h. During ADHF therapy, AKI occurred
in 99 patients; 55 patients died during the 12-month follow-up period. Grouping patients according to AKI and a
median BUN/Cr at admission of 22.1 (non-AKI+low BUN/Cr, non-AKI+high BUN/Cr, AKI+low BUN/Cr, and AKI+high
BUN/Cr groups) revealed higher mortality in the AKI+high BUN/Cr group (log-rank test, P<0.001). Cox’s proportional
hazard analysis revealed an association between AKI+high BUN/Cr and mortality, whereas the association with
AKI+low BUN/Cr did not reach statistical significance. When patients were grouped according to AKI and median
BUN or creatinine values at admission, AKI was associated with mortality, regardless of BUN or creatinine.
Conclusions: The combination of AKI and elevated BUN/Cr, but not BUN or creatinine individually, is linked with
an increased risk of mortality in ADHF patients, suggesting that the BUN/Cr is useful for risk stratification of
AKI. (Circ J 2015; 79: 1520 – 1525)
Key Words: Acute decompensated heart failure; Acute kidney injury; Blood urea nitrogen/creatinine ratio; Prognosis
T
here is increased focus on cardiorenal syndrome because (BUN) levels at admission were related to the late onset of
of its association with adverse outcomes.1,2 An increase AKI.12
in serum creatinine levels during acute decompen-
sated heart failure (ADHF) therapy has emerged as one of the Editorial p 1446
most potent prognostic factors.3–9 However, because there are
multiple mechanisms underlying increases in serum creatinine Serum creatinine levels primarily reflect glomerular filtra-
levels, conflicting results have been reported. For example, tion rate, because creatinine essentially passes through the
relief of congestion following aggressive diuresis results in renal tubules without being reabsorbed. Activation of neuro-
increased serum creatinine levels, but is associated with better hormonal factors, such as the sympathetic nervous system,
outcomes.10 An increase in serum creatinine levels has prog- renin-angiotensin-aldosterone system, and arginine vasopres-
nostic value only in patients with persistent congestion.11 sin, results in the disproportionate reabsorption of urea,13–15
Therefore, although attending physicians must not make blind leading to an increase in the BUN/creatinine ratio (Cr). Ele-
assumptions and need to evaluate the clinical significance of vated BUN/Cr, which is a surrogate marker for severe heart
increased serum creatinine levels, few clinical markers have failure,16–19 may identify a form of AKI associated with mor-
been identified to enable such assessment. Recently, we tality. In the present study, we hypothesized that the BUN/Cr
reported that late (≥5 days from admission) but not early (≤4 is useful for attending physicians to assess the risk stratifica-
days from admission) onset of acute kidney injury (AKI) was tion of AKI during ADHF therapy. The aim of the present
linked with a high mortality rate, and that blood urea nitrogen study was to determine whether clinical markers of renal
Received December 15, 2014; revised manuscript received February 19, 2015; accepted March 8, 2015; released online April 8, 2015 Time
for primary review: 28 days
Department of Cardiology (Y.T., H.Y., H.K., M.K., Y.G., T.A., S.Y., H.O.), Department of Hypertension and Nephrology (F.Y., Y.K.),
National Cerebral and Cardiovascular Center, Suita, Japan
Mailing address: Fumiki Yoshihara, MD, Department of Hypertension and Nephrology, National Cerebral and Cardiovascular Center, 5-7-1
Fujishiro-dai, Suita 565-8565, Japan. E-mail: fyoshi@hsp.ncvc.go.jp
ISSN-1346-9843 doi: 10.1253/circj.CJ-14-1360
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp
function, such as the BUN/Cr or BUN or creatinine values with intravenous diuretics. To assess AKI caused exclusively
alone, stratify the risk of AKI for mortality in patients with on the basis of the pathophysiology and treatment of ADHF,
ADHF. we excluded patients who underwent cardiac surgery (n=8),
invasive procedures requiring contrast administration (n=23),
or continuous renal replacement therapy on admission (n=4),
Methods as well as those on intermittent renal replacement therapy
Study Population since prior to admission (n=11). Patients discharged within
We retrospectively investigated 433 consecutive patients with 48 h of admission due to non-cardiac complications were also
ADHF admitted to the Cardiac Care Unit of the National excluded (n=6). The present study was performed according
Cerebral and Cardiovascular Center (Osaka, Japan) between to the principles of the Declaration of Helsinki and was
May 2006 and April 2009, as described previously.12 Briefly, approved by the Ethics Committee of the National Cerebral
ADHF was diagnosed on the basis of the guidelines of the and Cardiovascular Center (approval ID: M22-25). All
European Society of Cardiology.20 All patients had New York patients provided written informed consent.
Heart Association functional Class III or IV and were treated
Figure. Kaplan-Meier survival curves according to the presence of acute kidney injury (AKI) and median values of the blood urea
nitrogen (BUN)/creatinine ratio (Cr) (A), BUN (B), or creatinine (C).
Table 3. Risk Stratification of AKI for 12-Month Mortality Using the BUN/Cr
Univariate analysis Multivariate analysis
HR (95% CI) P value HR (95% CI) P value
Non-AKI+low BUN/Cr 1 (reference) 1 (reference)
Non-AKI+high BUN/Cr 0.79 (0.34–1.84) 0.591 0.79 (0.33–1.84) 0.583
AKI+low BUN/Cr 3.06 (1.39–6.81) 0.006 2.11 (0.93–4.80) 0.072
AKI+high BUN/Cr 6.34 (3.14–13.4) <0.001 4.71 (2.25–10.2) <0.001
Adjusted for age, sex, SBP, hemoglobin levels, plasma BNP levels, and intravenous administration of dobutamine.
HR, hazard ratio. Other abbreviations as in Tables 1,2.
higher in the AKI+high BUN/Cr group, whereas that for the Meier survival curves showed that the AKI+high BUN group
AKI+low BUN/Cr group did not reach statistical significance had a higher 12-month mortality rate than the other groups
(Table 3). (log-rank test, P<0.001; Figure B). However, there were no
significant differences in mortality rate between the AKI+high
Combination of AKI and BUN or Creatinine BUN and AKI+low BUN groups (log-rank test, P=0.350).
When patients were grouped according to the presence of AKI Multivariate Cox proportional hazard analysis revealed that
and a median BUN value at admission of 23.0 into non- both the AKI+high BUN and AKI+low BUN groups were
AKI+low BUN (n=164), non-AKI+high BUN (n=108), AKI+ associated with 12-month mortality (Table 4).
low BUN (n=24), and AKI+high BUN (n=75) groups, Kaplan- When patients were divided according to the presence of
AKI and a median creatinine value at admission of 1.04 into patients with HF,16 the BUN/Cr is reported to be strongly
non-AKI+low creatinine (n=149), non-AKI+high creatinine associated with adverse outcomes, especially in the setting of
(n=123), AKI+low creatinine (n=25), and AKI+high creati- acute decompensation of HF.19 In the setting of ADHF, activa-
nine (n=74) groups, Kaplan-Meier survival curves showed tion of neurohormonal factors, such as the sympathetic ner-
that the AKI+high creatinine and AKI+low creatinine groups vous system and renin-angiotensin-aldosterone system, causes
had a higher 12-month mortality rate (log-rank test, P<0.001; renal vasoconstriction and decreases glomerular filtration rate,
Figure C). The mortality rate in the AKI+high creatinine which reduces urea excretion. Neurohormonal activation also
group was similar to that in the AKI+low creatinine group increases flow- and concentration-dependent urea absorption.
(log-rank test, P=0.828). Multivariate Cox proportional hazard Arterial underfilling secondary to low cardiac output stimu-
analysis revealed that both the AKI+high creatinine and lates the release of arginine vasopressin, which promotes urea
AKI+low creatinine groups were associated with 12-month reabsorption.13–15,27 Under the condition of neurohormonal
mortality (Table 5). activation, creatinine is freely filtered through the glomerulus
and is not reabsorbed, whereas urea is disproportionately reab-
sorbed, leading to an elevated BUN/Cr. Therefore, an elevated
Discussion BUN/Cr more closely reflects neurohormonal activation than
The major findings of the present study are that the combina- elevated creatinine or decreased estimated glomerular filtra-
tion of AKI with an elevated BUN/Cr at admission was linked tion rate, and is linked with adverse outcomes in patients with
with an increased risk of mortality in patients with ADHF, and ADHF.16,19,28 Furthermore, the BUN/Cr has been used for the
that BUN or creatinine values alone at admission did not influ- differentiation of HF-induced renal dysfunction from intrinsic
ence the risk of AKI for mortality. Our findings suggest that renal disease.13,14,16 In the setting of fluid and sodium excess,
the BUN/Cr is useful for risk stratification of AKI. such as in HF, urea excretion is disproportionately reduced in
AKI is not always related to mortality in patients with ADHF. relation to decreased glomerular filtration rate and urea absorp-
Several studies have shown that increases in serum creatinine tion is promoted, leading to an elevated BUN/Cr. Conversely,
levels caused by relief of congestion are not associated with the cause of intrinsic renal disease is irreversible nephron loss
permanent renal damage and adverse outcomes.10,11,22–25 There- and urea clearance is thus reduced in parallel to the glomerular
fore, the mechanisms underlying the development of AKI are filtration rate, resulting in a normal BUN/Cr. Therefore, an
important to determine clinical outcomes in patients with elevated BUN/Cr may be useful for detecting severe HF-
ADHF. The present study provides important evidence that an induced AKI, which is associated with an increased risk of
elevated BUN/Cr at admission, which reflects neurohormonal mortality. In addition, the present study showed that the inci-
activation, identifies a form of AKI associated with mortality dence of AKI was related to both BUN and creatinine levels,
in patients with ADHF. Furthermore, because risk stratifica- but not the BUN/Cr, at baseline. These results suggest that a
tion for AKI can be prepared at the time of admission, it could high BUN/Cr may stratify AKI patients according to the risk
provide useful information for attending physicians to make of mortality, but not stratify ADHF patients at risk of AKI.
decisions regarding continuing decongestion therapy for ADHF
in patients with a lower BUN/Cr despite increased creatinine Study Limitations
levels, in contrast with consideration of additional strategies First, the present study was a retrospective observational study
for ADHF in AKI patients with a higher BUN/Cr. in a single center. Our findings need to be confirmed in larger
Although it has been established that creatinine and esti- trials. Second, the BUN/Cr is influenced by non-neurohor-
mated glomerular filtration rate portend adverse outcomes in monal factors, such as protein diet, cachexia, and muscle
wasting, but these factors were not assessed in this study. M, et al. Prognostic impact of acute kidney injury in patients with
Third, because the timing of laboratory measurements was left acute decompensated heart failure. Circ J 2013; 77: 687 – 696.
10. Testani JM, Chen J, McCauley BD, Kimmel SE, Shannon RP. Poten-
to the discretion of the treating physicians, the time interval tial effects of aggressive decongestion during the treatment of
for measurements of serum creatinine was not just 48 h, result- decompensated heart failure on renal function and survival. Circula-
ing in potential underestimation of the incidence of AKI. tion 2010; 122: 265 – 272.
Fourth, AKI defined by the AKI Network criteria includes 11. Metra M, Davison B, Bettari L, Sun H, Edwards C, Lazzarini V, et
serum creatinine and urine output data,21 but we used only al. Is worsening renal function an ominous prognostic sign in patients
with acute heart failure? The role of congestion and its interaction
serum creatinine. Data regarding volume depletion were not with renal function. Circ Heart Fail 2012; 5: 54 – 62.
obtained. Fifth, urinalysis was performed in only 121 (33%) 12. Takaya Y, Yoshihara F, Yokoyama H, Kanzaki H, Kitakaze M, Goto
patients. This rate was too low to clarify the clinical signifi- Y, et al. Impact of onset time of acute kidney injury on outcomes in
cance of the urinalysis data. Finally, direct hemodynamic patients with acute decompensated heart failure. Heart Vessels 2014
August 24, doi:10.1007/s00380-014-0572-x.
parameters were not obtained. 13. Lindenfeld J, Schrier RW. Blood urea nitrogen a marker for adverse
effects of loop diuretics? J Am Coll Cardiol 2011; 58: 383 – 385.
14. Schrier RW. Blood urea nitrogen and serum creatinine: Not married
Conclusions in heart failure. Circ Heart Fail 2008; 1: 2 – 5.
15. Kazory A. Emergence of blood urea nitrogen as a biomarker of
The combination of AKI with an elevated BUN/Cr at admis- neurohormonal activation in heart failure. Am J Cardiol 2010; 106:
sion, but not with values of BUN or creatinine individually, is 694 – 700.
linked with an increased risk of mortality in patients with 16. Brisco MA, Coca SG, Chen J, Owens AT, McCauley BD, Kimmel
ADHF. Our findings suggest that the prognostic value of AKI SE, et al. Blood urea nitrogen/creatinine ratio identifies a high-risk
but potentially reversible form of renal dysfunction in patients with
is dependent on the BUN/Cr at admission, and that the BUN/ decompensated heart failure. Circ Heart Fail 2013; 6: 233 – 239.
Cr is useful for risk stratification of AKI. Further studies are 17. Testani JM, Coca SG, Shannon RP, Kimmel SE, Cappola TP. Influ-
needed to validate these findings and investigate therapeutic ence of renal dysfunction phenotype on mortality in the setting of
strategies to improve clinical outcomes in patients with ADHF. cardiac dysfunction: Analysis of three randomized controlled trials.
Eur J Heart Fail 2011; 13: 1224 – 1230.
18. Lin HJ, Chao CL, Chien KL, Ho YL, Lee CM, Lin YH, et al. Ele-
Acknowledgments vated blood urea nitrogen-to-creatinine ratio increased the risk of
This work was supported by the Program for Promotion of Fundamental hospitalization and all-cause death in patients with chronic heart
Studies in Health Sciences of the Pharmaceuticals and Medical Devices failure. Clin Res Cardiol 2009; 98: 487 – 492.
Agency in Japan. 19. Aronson D, Mittleman MA, Burger AJ. Elevated blood urea nitrogen
level as a predictor of mortality in patients admitted for decompen-
sated heart failure. Am J Med 2004; 116: 466 – 473.
References 20. Nieminen MS, Bohm M, Cowie MR, Drexler H, Filippatos GS,
1. Dries DL, Exner DV, Domanski MJ, Greenberg B, Stevenson LW. Jondeau G, et al. Executive summary of the guidelines on the diag-
The prognostic implications of renal insufficiency in asymptomatic nosis and treatment of acute heart failure: The Task Force on Acute
and symptomatic patients with left ventricular systolic dysfunction. Heart Failure of the European Society of Cardiology. Eur Heart J
J Am Coll Cardiol 2000; 35: 681 – 689. 2005; 26: 384 – 416.
2. Smith GL, Lichtman JH, Bracken MB, Shlipak MG, Phillips CO, 21. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock
DiCapua P, et al. Renal impairment and outcomes in heart failure: DG, et al. Acute Kidney Injury Network: Report of an initiative to
Systemic review and meta-analysis. J Am Coll Cardiol 2006; 47: improve outcomes in acute kidney injury. Crit Care 2007; 11: R31.
1987 – 1996. 22. Massie BM, O’Connor CM, Metra M, Ponikowski P, Teerlink JR,
3. Metra M, Nodari S, Parrinello G, Bordonali T, Bugatti S, Danesi R, Cotter G, et al. Rolofylline, an adenosine A1-receptor antagonist, in
et al. Worsening renal function in patients hospitalised for acute acute heart failure. N Engl J Med 2010; 363: 1419 – 1428.
heart failure: Clinical implications and prognostic significance. Eur 23. Metra M, O’Connor CM, Davison BA, Cleland JG, Ponikowski P,
J Heart Fail 2008; 10: 188 – 195. Teerlink JR, et al. Early dyspnoea relief in acute heart failure: Prev-
4. Forman DE, Butler J, Wang Y, Abraham WT, O’Connor CM, alence, association with mortality, and effect of rolofylline in the
Gottieb SS, et al. Incidence, predictors at admission, and impact of PROTECT Study. Eur Heart J 2011; 32: 1519 – 1534.
worsening renal function among patients hospitalized with heart 24. Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW,
failure. J Am Coll Cardiol 2004; 43: 61 – 67. Goldsmith SR, et al. Diuretic strategies in patients with acute decom-
5. Chittineni H, Miyawaki N, Gulipelli S, Fishbane S. Risk for acute pensated heart failure. N Engl J Med 2011; 364: 797 – 805.
renal failure in patients hospitalized for decompensated congestive 25. Costanzo MR, Guglin ME, Saltzberg MT, Jessup ML, Bart BA,
heart failure. Am J Nephrol 2007; 27: 55 – 62. Teerlink JR, et al. Ultrafiltration versus intravenous diuretics for
6. Damman K, Navis G, Voors AA, Asselbergs FW, Smilde TD, patients hospitalized for acute decompensated heart failure. J Am
Cleland JG, et al. Worsening renal function and prognosis in heart Coll Cardiol 2007; 49: 675 – 683.
failure: Systemic review and meta-analysis. J Cardiac Fail 2007; 13: 26. Hillege HL, Nitsch D, Pfeffer MA, Swedberg K, McMurray JJ,
599 – 608. Yusuf S, et al. Renal function as a predictor of outcome in a broad
7. Breidthardt T, Socrates T, Noveanu M, Klima T, Heinisch C, spectrum of patients with heart failure. Circulation 2006; 113:
Reichlin T, et al. Effect and clinical prediction of worsening renal 671 – 678.
function in acute decompensated heart failure. Am J Cardiol 2011; 27. Schrier RW, Abraham WT. Hormones and hemodynamics in heart
107: 730 – 735. failure. N Engl J Med 1999; 341: 577 – 585.
8. Weinfeld MS, Chertow GM, Stevenson LW. Aggravated renal dys- 28. Miura M, Sakata Y, Nochioka K, Takahashi J, Takada T, Miyata S,
function during intensive therapy for advanced chronic heart failure. et al. Prognostic impact of blood urea nitrogen changes during hos-
Am Heart J 1999; 138: 285 – 290. pitalization in patients with acute heart failure syndrome. Circ J
9. Shirakabe A, Hata N, Kobayashi N, Shinada T, Tomita K, Tsurumi 2013; 77: 1221 – 1228.