Risk Stratification of Acute Kidney Injury Using the Blood Urea Nitrogen/Creatinine Ratio in Patients With Acute Decompensated Heart Failure

Abstract

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)

There is increased focus on cardiorenal syndrome because of its association with adverse outcomes.^1,2 An increase in serum creatinine levels during acute decompensated heart failure (ADHF) therapy has emerged as one of the most potent prognostic factors.^3–9 However, because there are multiple mechanisms underlying increases in serum creatinine levels, conflicting results have been reported. For example, relief of congestion following aggressive diuresis results in increased serum creatinine levels, but is associated with better outcomes.¹⁰ An increase in serum creatinine levels has prognostic value only in patients with persistent congestion.¹¹ Therefore, although attending physicians must not make blind assumptions and need to evaluate the clinical significance of increased serum creatinine levels, few clinical markers have been identified to enable such assessment. Recently, we reported that late (≥5 days from admission) but not early (≤4 days from admission) onset of acute kidney injury (AKI) was linked with a high mortality rate, and that blood urea nitrogen (BUN) levels at admission were related to the late onset of AKI.¹²

Editorial p 1446

Serum creatinine levels primarily reflect glomerular filtration rate, because creatinine essentially passes through the renal tubules without being reabsorbed. Activation of neurohormonal factors, such as the sympathetic nervous system, renin-angiotensin-aldosterone system, and arginine vasopressin, results in the disproportionate reabsorption of urea,^13–15 leading to an increase in the BUN/creatinine ratio (Cr). Elevated BUN/Cr, which is a surrogate marker for severe heart failure,^16–19 may identify a form of AKI associated with mortality. In the present study, we hypothesized that the BUN/Cr is useful for attending physicians to assess the risk stratification of AKI during ADHF therapy. The aim of the present study was to determine whether clinical markers of renal function, such as the BUN/Cr or BUN or creatinine values alone, stratify the risk of AKI for mortality in patients with ADHF.

Methods

Study Population

We retrospectively investigated 433 consecutive patients with ADHF admitted to the Cardiac Care Unit of the National Cerebral and Cardiovascular Center (Osaka, Japan) between May 2006 and April 2009, as described previously.¹² Briefly, ADHF was diagnosed on the basis of the guidelines of the European Society of Cardiology.²⁰ All patients had New York Heart Association functional Class III or IV and were treated with intravenous diuretics. To assess AKI caused exclusively on the basis of the pathophysiology and treatment of 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), as well as those on intermittent renal replacement therapy since prior to admission (n=11). Patients discharged within 48 h of admission due to non-cardiac complications were also excluded (n=6). The present study was performed according to the principles of the Declaration of Helsinki and was approved by the Ethics Committee of the National Cerebral and Cardiovascular Center (approval ID: M22-25). All patients provided written informed consent.

Clinical Assessments

All patients were systematically characterized with regard to demographics, medical history, physical examinations, and medications during hospitalization. Decisions regarding the intravenous administration of agents were made on the basis of clinical indications. Laboratory measurements were performed on admission for all patients. After admission, the timing of laboratory measurements was left to the discretion of the attending physicians.

AKI was defined as absolute serum creatinine ≥0.3 mg/dl or a 1.5-fold increase in serum creatinine levels within 48 h according to the AKI Network creatinine criteria.²¹ Serum creatinine levels were monitored during ADHF therapy, and changes within 48 h were calculated. AKI was identified when serum creatinine levels increased to ≥0.3 mg/dl or there was a 1.5-fold increase compared with values measured within the past 48 h, as described previously.¹² The BUN/Cr and BUN and creatinine values were evaluated at the time of admission. Patients were divided into 4 groups according to the presence of AKI and median values of the BUN/Cr, BUN, or creatinine.

Endpoint

The study endpoint was defined as all-cause mortality. A 12-month follow-up was performed during a clinical visit or via telephone interviews with the patient, his or her relatives, or physicians. Independent investigators who had no role in patient follow-up and treatment obtained information regarding outcomes.

Statistical Analysis

Data are presented as mean±SD for continuous variables and as a number and percentage for categorical variables. The significance of differences in clinical characteristics among the 4 groups was analyzed using 1-way analysis of variance for continuous variables and the Chi-squared test for categorical variables. Factors related to AKI were assessed using multivariate analysis. Variables (ie, age, sex, systolic blood pressure, left ventricular ejection fraction, BUN levels, creatinine levels, BUN/Cr, plasma B-type natriuretic peptide [BNP] levels, intravenous administration of dobutamine, and intravenous administration of vasodilators) were entered using a P value of <0.10 as the selection criterion. Odds ratios (ORs) are presented with 95% confidence intervals (CIs). Survival rates were estimated using Kaplan-Meier analysis, and the significance of differences was analyzed using the log-rank test. Predictors of 12-month mortality were assessed using Cox proportional hazard analysis. In multivariate analysis, we entered variables, including age, sex, systolic blood pressure, hemoglobin levels, plasma BNP levels, and intravenous administration of dobutamine, as well as the combination of AKI with either BUN/Cr, BUN, or creatinine, using a P value of <0.10 as the selection criterion. Hazard ratios (HRs) are presented with 95% CIs. Statistical analysis was performed with JMP version 8.0 (SAS Institute Inc, Cary, NC, USA) and significance was defined as P<0.05.

Results

Study Population

After excluding patients (see Methods) and the loss of a further 10 patients at the 12-month follow-up, 371 patients remained in the study. The clinical characteristics of the study population are given in Table 1. The mean patient age was 73±13 years, and 60% of patients were male; 55 patients died during the 12-month follow-up period.

Table 1. Clinical Characteristics

	All patients (n=371)	Non-AKI+low BUN/Cr (n=133)	Non-AKI+high BUN/Cr (n=139)	AKI+low BUN/Cr (n=51)	AKI+high BUN/Cr (n=48)	P value
Age (years)	73±13	71±13	75±12	73±11	76±12	0.029
No. males (%)	221 (60)	104 (78)	56 (40)	32 (63)	29 (60)	<0.001
BMI (kg/m2)	22.9±4.0	23.4±3.7	22.2±4.0	23.2±4.0	23.3±4.7	0.067
Etiology of heart failure
Ischemia	127 (34)	52 (39)	35 (25)	24 (47)	16 (33)	0.016
Non-ischemia	244 (66)	81 (61)	104 (75)	27 (53)	32 (67)
History of heart failure hospitalization	156 (42)	59 (44)	49 (35)	26 (51)	22 (46)	0.179
Clinical scenario 1	197 (53)	65 (49)	82 (59)	33 (65)	17 (35)	0.008
Clinical scenario 2	117 (32)	46 (35)	42 (30)	11 (22)	18 (38)	0.266
Clinical scenario 3	57 (15)	22 (17)	15 (11)	7 (14)	13 (27)	0.072
SBP (mmHg)	140±37	141±37	144±35	149±38	122±36	0.002
DBP (mmHg)	79±22	79±21	80±22	86±23	70±21	0.011
Heart rate (beats/min)	94±26	93±25	93±28	98±29	94±24	0.782
LVEF (%)	36±16	35±15	39±17	33±12	35±17	0.368
Physical examinations
Rales (>1/2 lung fields)	113 (30)	35 (26)	42 (30)	20 (39)	16 (33)	0.367
Jugular venous distension	236 (64)	80 (60)	94 (68)	30 (59)	32 (67)	0.379
Peripheral edema	222 (60)	74 (56)	90 (65)	25 (49)	33 (69)	0.051
Laboratory measurements
Hemoglobin (g/dl)	11.7±2.2	12.2±2.2	11.6±2.3	11.1±2.2	11.0±2.0	0.001
Hematocrit (%)	34.7±6.6	36.1±6.4	34.6±6.7	32.9±6.2	32.9±6.2	0.003
Albumin (g/dl)	3.5±0.4	3.6±0.4	3.5±0.4	3.4±0.4	3.4±0.5	0.067
Sodium (mEq/L)	138±4	138±4	138±4	137±5	137±4	0.197
BUN (mg/dl)	27±15	19±8	27±10	33±16	42±21	<0.001
Creatinine (mg/dl)	1.23±0.67	1.13±0.43	0.94±0.34	2.04±0.94	1.50±0.78	<0.001
BUN/Cr	23.3±8.3	17.1±3.0	29.6±6.8	16.6±4.1	29.3±7.1	<0.001
eGFR (ml/min/1.73 m2)	50±24	53±20	57±22	31±18	43±31	<0.001
Log BNP (pg/ml)	2.82±0.42	2.76±0.39	2.78±0.44	3.08±0.30	2.85±0.45	<0.001
Medications during hospitalization
ACEI and/or ARBs	249 (67)	96 (72)	92 (66)	30 (59)	31 (65)	0.380
β-blockers	241 (65)	91 (68)	85 (61)	34 (67)	31 (65)	0.657
Aldosterone antagonists	168 (45)	61 (46)	62 (45)	19 (37)	26 (54)	0.509
Intravenous diuretics dose (mg)	272±835	141±533	184±716	462±1,177	398±820	0.023
Intravenous dopamine	30 (8)	6 (5)	7 (5)	8 (16)	9 (19)	0.004
Intravenous dobutamine	69 (19)	21 (16)	13 (9)	16 (31)	19 (40)	<0.001
Intravenous nitrates	164 (44)	59 (44)	60 (43)	29 (57)	16 (33)	0.187
Intravenous vasodilators	232 (63)	83 (62)	90 (65)	27 (53)	32 (67)	0.458

Data are presented as the mean±SD or as n (%). ACEI, angiotensin-converting enzyme inhibitors; AKI, acute kidney injury; ARBs, angiotensin receptor blockers; BMI, body mass index; BNP, B-type natriuretic peptide; BUN, blood urea nitrogen; Cr, creatinine ratio; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; SBP, systolic blood pressure.

AKI

AKI occurred in 99 patients during ADHF therapy. Multivariate analysis revealed that AKI was independently related to BUN levels, creatinine levels, and intravenous administration of dobutamine (Table 2).

Table 2. Factors Related to AKI

	Univariate analysis		Multivariate analysis
	OR (95% CI)	P value	OR (95% CI)	P value
Age >75 years	1.38 (0.87–2.20)	0.175
Male	1.12 (0.70–1.81)	0.627
SBP <100 mmHg	1.61 (0.87–2.91)	0.128
LVEF <35%	1.04 (0.66–1.65)	0.857
BUN >24 mg/dl	3.99 (2.43–6.69)	<0.001	2.36 (1.30–4.36)	0.005
Creatinine>1.0 mg/dl	3.67 (2.22–6.27)	<0.001	1.93 (1.04–3.60)	0.036
BUN/Cr >22.1	0.90 (0.57–1.43)	0.656
BNP >500 pg/ml	2.56 (1.52–4.48)	<0.001	1.57 (0.88–2.87)	0.126
Intravenous dobutamine	3.66 (2.14–6.32)	<0.001	2.79 (1.58–4.95)	<0.001
Intravenous vasodilators	0.84 (0.53–1.36)	0.482

CI, confidence interval; OR, odds ratio. Other abbreviations as in Table 1.

Combination of AKI and BUN/Cr

Patients were group according to the presence of AKI and a median value of the BUN/Cr at admission of 22.1 into the following groups: non-AKI+low BUN/Cr (n=133), non-AKI+high BUN/Cr (n=139), AKI+low BUN/Cr (n=51), and AKI+high BUN/Cr (n=48). The AKI+high BUN/Cr group had lower systolic blood pressure, hemoglobin and hematocrit levels, higher BUN levels, and was more frequently treated with intravenous dopamine and dobutamine than the other groups (Table 1).

Kaplan-Meier survival curves showed that the AKI+high BUN/Cr group had a significantly higher 12-month mortality rate than the other groups (log-rank test, P<0.001; Figure A). The mortality rate was significantly higher in the AKI+high BUN/Cr group than in the AKI+low BUN/Cr group (long-rank test, P=0.025). Univariate Cox proportional hazard analysis revealed that the risk of mortality was significantly higher in the AKI+high BUN/Cr and AKI+low BUN/Cr groups compared with the non-AKI+low BUN/Cr group. Multivariate analysis revealed that the relative risk remained significantly higher in the AKI+high BUN/Cr group, whereas that for the AKI+low BUN/Cr group did not reach statistical significance (Table 3).

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.

Combination of AKI and BUN or Creatinine

When patients were grouped according to the presence of AKI and a median BUN value at admission of 23.0 into non-AKI+low BUN (n=164), non-AKI+high BUN (n=108), AKI+low BUN (n=24), and AKI+high BUN (n=75) groups, Kaplan-Meier survival curves showed that the AKI+high BUN group had a higher 12-month mortality rate than the other groups (log-rank test, P<0.001; Figure B). However, there were no significant differences in mortality rate between the AKI+high BUN and AKI+low BUN groups (log-rank test, P=0.350). Multivariate Cox proportional hazard analysis revealed that both the AKI+high BUN and AKI+low BUN groups were associated with 12-month mortality (Table 4).

Table 4. Risk Stratification of AKI for 12-Month Mortality Using BUN

	Univariate analysis		Multivariate analysis
	HR (95% CI)	P value	HR (95% CI)	P value
Non-AKI+low BUN	1 (reference)		1 (reference)
Non-AKI+high BUN	1.88 (0.81–4.45)	0.141	1.33 (0.56–3.23)	0.518
AKI+low BUN	4.77 (1.62–12.9)	0.006	3.83 (1.27–10.6)	0.019
AKI+high BUN	7.34 (3.67–15.9)	<0.001	4.26 (1.99–9.76)	<0.001

Adjusted for age, sex, SBP, hemoglobin levels, plasma BNP levels, and intravenous administration of dobutamine. Abbreviations as in Tables 1–3.

When patients were divided according to the presence of AKI and a median creatinine value at admission of 1.04 into non-AKI+low creatinine (n=149), non-AKI+high creatinine (n=123), AKI+low creatinine (n=25), and AKI+high creatinine (n=74) groups, Kaplan-Meier survival curves showed that the AKI+high creatinine and AKI+low creatinine groups had a higher 12-month mortality rate (log-rank test, P<0.001; Figure C). The mortality rate in the AKI+high creatinine group was similar to that in the AKI+low creatinine group (log-rank test, P=0.828). Multivariate Cox proportional hazard analysis revealed that both the AKI+high creatinine and AKI+low creatinine groups were associated with 12-month mortality (Table 5).

Table 5. Risk Stratification of AKI for 12-Month Mortality Using Creatinine

	Univariate analysis		Multivariate analysis
	HR (95% CI)	P value	HR (95% CI)	P value
Non-AKI+low creatinine	1 (reference)		1 (reference)
Non-AKI+high creatinine	1.80 (0.78–4.36)	0.171	1.39 (0.59–3.39)	0.454
AKI+low creatinine	6.32 (2.37–16.5)	<0.001	4.88 (1.71–13.3)	0.004
AKI+high creatinine	6.90 (3.34–15.6)	<0.001	4.15 (1.90–9.81)	<0.001

Adjusted for age, sex, SBP, hemoglobin levels, plasma BNP levels, and intravenous administration of dobutamine. Abbreviations as in Tables 1–3.

Discussion

The major findings of the present study are that the combination of AKI with an elevated BUN/Cr at admission was linked with an increased risk of mortality in patients with ADHF, and that BUN or creatinine values alone at admission did not influence the risk of AKI for mortality. Our findings suggest that the BUN/Cr is useful for risk stratification of AKI.

AKI is not always related to mortality in patients with ADHF. Several studies have shown that increases in serum creatinine levels caused by relief of congestion are not associated with permanent renal damage and adverse outcomes.^{10,11,22–25} Therefore, the mechanisms underlying the development of AKI are important to determine clinical outcomes in patients with ADHF. The present study provides important evidence that an elevated BUN/Cr at admission, which reflects neurohormonal activation, identifies a form of AKI associated with mortality in patients with ADHF. Furthermore, because risk stratification for AKI can be prepared at the time of admission, it could provide useful information for attending physicians to make decisions regarding continuing decongestion therapy for ADHF in patients with a lower BUN/Cr despite increased creatinine levels, in contrast with consideration of additional strategies for ADHF in AKI patients with a higher BUN/Cr.

Although it has been established that creatinine and estimated glomerular filtration rate portend adverse outcomes in patients with HF,¹⁶ the BUN/Cr is reported to be strongly associated with adverse outcomes, especially in the setting of acute decompensation of HF.¹⁹ In the setting of ADHF, activation of neurohormonal factors, such as the sympathetic nervous system and renin-angiotensin-aldosterone system, causes renal vasoconstriction and decreases glomerular filtration rate, which reduces urea excretion. Neurohormonal activation also increases flow- and concentration-dependent urea absorption. Arterial underfilling secondary to low cardiac output stimulates the release of arginine vasopressin, which promotes urea reabsorption.^13–15,27 Under the condition of neurohormonal activation, creatinine is freely filtered through the glomerulus and is not reabsorbed, whereas urea is disproportionately reabsorbed, leading to an elevated BUN/Cr. Therefore, an elevated BUN/Cr more closely reflects neurohormonal activation than elevated creatinine or decreased estimated glomerular filtration rate, and is linked with adverse outcomes in patients with ADHF.^16,19,28 Furthermore, the BUN/Cr has been used for the differentiation of HF-induced renal dysfunction from intrinsic renal disease.^13,14,16 In the setting of fluid and sodium excess, such as in HF, urea excretion is disproportionately reduced in relation to decreased glomerular filtration rate and urea absorption is promoted, leading to an elevated BUN/Cr. Conversely, the cause of intrinsic renal disease is irreversible nephron loss and urea clearance is thus reduced in parallel to the glomerular filtration rate, resulting in a normal BUN/Cr. Therefore, an elevated BUN/Cr may be useful for detecting severe HF-induced AKI, which is associated with an increased risk of mortality. In addition, the present study showed that the incidence of AKI was related to both BUN and creatinine levels, but not the BUN/Cr, at baseline. These results suggest that a high BUN/Cr may stratify AKI patients according to the risk of mortality, but not stratify ADHF patients at risk of AKI.

Study Limitations

First, the present study was a retrospective observational study in a single center. Our findings need to be confirmed in larger trials. Second, the BUN/Cr is influenced by non-neurohormonal factors, such as protein diet, cachexia, and muscle wasting, but these factors were not assessed in this study. Third, because the timing of laboratory measurements was left to the discretion of the treating physicians, the time interval for measurements of serum creatinine was not just 48 h, resulting in potential underestimation of the incidence of AKI. Fourth, AKI defined by the AKI Network criteria includes serum creatinine and urine output data,²¹ but we used only serum creatinine. Data regarding volume depletion were not obtained. Fifth, urinalysis was performed in only 121 (33%) patients. This rate was too low to clarify the clinical significance of the urinalysis data. Finally, direct hemodynamic parameters were not obtained.

Conclusions

The combination of AKI with an elevated BUN/Cr at admission, but not with values of BUN or creatinine individually, is linked with an increased risk of mortality in patients with ADHF. Our findings suggest that the prognostic value of AKI is dependent on the BUN/Cr at admission, and that the BUN/Cr is useful for risk stratification of AKI. Further studies are needed to validate these findings and investigate therapeutic strategies to improve clinical outcomes in patients with ADHF.

Acknowledgments

This work was supported by the Program for Promotion of Fundamental Studies in Health Sciences of the Pharmaceuticals and Medical Devices Agency in Japan.

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