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Exp Clin Cardiol. 2010 Fall; 15(3): e65–e69.
PMCID: PMC2954032
Clinical Cardiology: Original Article

Fractional excretion of sodium predicts worsening renal function in acute decompensated heart failure

Abstract

BACKGROUND:

Renal impairment (RI), defined as an increase in creatinine level of greater than 26.5 mmol/L, develops in more than 30% of acute decompensated heart failure (ADHF) patients. Fractional excretion of sodium (FeNa) reflects sodium handling by the kidneys during diuresis.

AIM:

To study the relationship between FeNa and RI in patients admitted with ADHF.

METHOD:

The hospital course and renal function of all ADHF patients admitted to the hospital were prospectively observed. Patients were included if their admission creatinine level was 176 mmol/L or lower, they had been on a low-salt diet since admission, had urine sodium and creatinine samples collected more than 6 h after a furosemide dose in the first few days of admission, and they were on daily intravenous furosemide doses of 20 mg or more.

RESULTS:

Over six months, 51 patients met the inclusion criteria; the average daily dose of intravenous furosemide was 58.8 mg. RI developed in 39% of patients. A FeNa cut-off point of 0.4% was determined using ROC curve analysis; patients with a FeNa of greater than 0.4% (28 patients) were compared with patients with a lower FeNa (23 patients). Admission creatinine level and furosemide dose were higher in the first group (P=0.01 and P=0.06, respectively). The first group developed RI more frequently (OR=6.3; 95% CI 1.7 to 23.5; P=0.0047; adjusted OR for admission creatinine = 6.18; 95% CI 1.6 to 24.5; P=0.0096; and adjusted OR for furosemide dose = 4.7; 95% CI 1.3 to 16.7; P=0.016). They had a longer hospitalization course (median nine days [interquartile range 6.3 to 13.5 days] versus seven days [interquartile range 4.0 to 9.0 days]; P=0.036) and they were admitted to the cardiac care unit more frequently (OR=6.8; 95% CI 1.3 to 34.9; P=0.02).

CONCLUSION:

A FeNa of greater than 0.4% more than 6 h after a dose of diuretics predicts RI and a complicated hospital course in ADHF patients.

Keywords: Diuretics, Fractional excretion of sodium (FeNa), Furosemide, Heart failure, Renal impairment

Renal impairment (RI) is being recognized as one of the most common and most confounding comorbidities in acute decompensated heart failure (ADHF) patients (1,2). In addition, the presence of the two problems in the same patient, referred to as ‘cardiorenal syndrome’ (36), points toward a worse outcome (1,2,7). Several studies have used the threshold of a 26.5 mmol/L (0.3 mg/dL) rise in serum creatinine level over baseline to define this phenomenon (8). Based on this definition, studies (48) have shown that between 25% and 45% of ADHF patients develop renal dysfunction during hospitalization. Because aggressive diuresis plays a role in worsening kidney function (9), and because fractional excretion of sodium (FeNa) reflects sodium handling by the kidneys, which is also influenced by the renin angiotensin pathway and the drugs that modulate it (10), we studied the relationship between FeNa and RI during hospitalization of patients with ADHF.

METHOD

The investigators used an electronic medical record system to prospectively follow every patient admitted to a 500-bed teaching tertiary-care medical centre in urban northern New Jersey (USA) with a primary diagnosis of ADHF, if they met the inclusion criteria shown in Table 1. The study was conducted between June 1, 2009, and January 1, 2010 in Trinitas Regional Medical Center, where it was approved by the Institutional Review Board. The investigators had no direct contact with the patients, and did not interfere with the management.

TABLE 1
Inclusion criteria

Heart failure was diagnosed based on clinical presentation, physical examination and radiographic findings on a chest x-ray. Causes of heart failure were extracted from cardiology consultations and medical records. Baseline characteristics, comorbidities, ejection fraction estimated by echocardiography and medication information were gathered from medical records during the same admission. FeNa was calculated from random spot urine creatinine and sodium tests, and serum levels of sodium and creatinine were determined within the same 24 h period. All samples were analyzed using the UniCel DxI 800 system (Beckman Coulter Inc, USA). Data regarding the patients’ diet, exact time of urine sample collection and diuretic dose timing were also available in the electronic medical system.

Statistical analysis

Interval variables were tested for normality using the D’Agostino-Pearson omnibus normality test. Groupwise comparisons for normally distributed variables were made using Student’s t test; variables that were not normally distributed were subjected to a nonparametric (Mann-Whitney) test. For non-normally distributed data, medians and interquartile ranges (IQRs) are provided; for normally distributed variables, data are expressed as means and SDs. Categorical data were compared using Fisher’s exact test. Decision levels (cut-offs) to dichotomize interval variables were determined by ROC curves. ORs and 95% CIs are provided. Spearman’s rank correlation coefficient was used to measure the statistical association between two non-normally distributed variables. Logistic regression was used to adjust ORs for differences in baseline characteristics if the P value for the difference between the groups was less than 0.1. For the present study, α was set at 0.05; thus, P<0.05 (two-sided) was considered to be statistically significant. Data were analyzed using Prism software (GraphPad Corp, USA), except for logistic regression, which was performed using an online routine (available at www.stat-pages.org/logistic.html; accessed on February 28, 2009).

RESULTS

Of more than 150 ADHF patients admitted during the study period, 51 subjects met the inclusion criteria. The median FeNa in those patients was 0.5% (IQR 0.1% to 1.2%). The median admission creatinine level was 103 mmol/L (IQR 77 mmol/L to 123 mmol/L), while the mean was 103±33 mmol/L. The median dose of intravenous furosemide was equivalent to 40 mg (IQR 40 mg to 80 mg) per day, while the average was 58.8 mg daily. Despite low doses of diuretics, and apparently normal creatinine levels, 39% of subjects developed RI. Compared with those who did not develop RI, patients with RI did not receive a higher dose of diuretics (P=0.16).

To establish a cut-off level of FeNa, an ROC curve was constructed, from which a cut-off value of 0.4% was determined (Figure 1). Subsequently, the patients were dichotomized to group 1 (FeNa of greater than 0.4%) and group 2 (FeNa of 0.4% or less). Their baseline characteristics (Table 2) and hospital courses were compared.

Figure 1)
ROC curve for fractional excretion of sodium (FeNa) and renal impairment. AUC Area under the curve
TABLE 2
Baseline characteristics

Group 1 (28 patients; mean age 71.0±11 years, 50% men) was not significantly different from group 2 (23 patients; mean age 69.0±14 years, 57% men) in their baseline characteristics. However, when other potential clinical predictors of worsening renal function (11,12) during ADHF hospitalization were compared (Table 3), it was clear that group 1 had a higher admission creatinine level (114±32 mmol/L versus 91±29 mmol/L; P=0.01), and a higher daily dose of diuretics (median dose was 80 mg/day [IQR 40 mg/day to 80 mg/day] for group 1 versus 40 mg/day [IQR 40 mg/day to 80 mg/day] for group 2; P=0.06. The mean was 64.3±29 mg/day for group 1 versus 52.2±30 mg/day for group 2).

TABLE 3
Other potential predictors of renal impairment

Group 1 (FeNa of greater than 0.4%) was found to be at a higher risk of developing RI during hospitalization (OR=6.3; 95% CI 1.7 to 23.5; P=0.0047). This was independent of admission creatinine level (adjusted OR = 6.2; 95% CI 1.6 to 24.5; P=0.0096) and daily furosemide dose (adjusted OR = 4.7; 95% CI 1.3 to 16.7; P=0.016).

The median length of hospital stay for all patients was eight days (IQR five to 12 days). Patients who developed RI stayed longer in the hospital than patients who did not develop RI (median 12 days [IQR seven to 15 days] versus seven days [IQR 4.8 to 8.3 days]). Patients in group 1 had a longer hospitalization course than patients in group 2 (median nine days [IQR 6.3 to 13.5 days] versus seven days [IQR 4.0 to 9.0 days] in group 2; P=0.036). Moreover, they were admitted to the cardiac care unit more frequently than patients in group 2 (OR=6.8; 95% CI 1.3 to 34.9; P=0.02).

In patients with systolic heart failure (25 patients), FeNa had a modest but statistically significant correlation with ejection fraction (r=0.48; P=0.015) that was not seen when isolated diastolic heart failure patients were added to the group (total 51 patients; P=0.95).

DISCUSSION

FeNa was used in various previous studies (1315) to assess diuresis in heart failure. Data included in these studies showed that baseline FeNa in heart failure patients before diuretics is approximately less than 1% (1315). In a subset group of these patients, a baseline FeNa of less than 0.2% was shown to be associated with diuretic resistance (16). Characteristically, loop diuretics produce marked water diuresis and natriuresis in heart failure patients in the first 6 h after the intravenous dose; during this period, FeNa can peak at approximately 20% to 25% (10,17). This is usually followed by minimal natriuresis lasting between 6 h and 24 h (17 mmol/L of sodium in a study of subjects with ascites) (18). For this reason, we included in our analysis a FeNa that was calculated based on urine samples collected 6 h after the dose of diuretic to be as close as possible to baseline FeNa. In the same direction, we excluded patients with a higher baseline creatinine level (greater than 176 mmol/L) and patients who were not on a low-salt diet because of chronic kidney disease (19,20); a high-salt diet increases sodium excretion.

Previous studies (21) have shown that a furosemide dose of more than 160 mg/day was associated with worse hospital outcome and impaired renal function. In our cohort, RI developed in 39% of patients despite a low average dose of furosemide (60 mg/day) and a median ejection fraction of 42% (IQR 25% to 60%). Factors such as increased sympathetic activity from pulmonary edema and renal venous congestion (22) may have played a role.

In our study, we demonstrated that a FeNa of greater than 0.4% is associated with an increased risk of RI or manifest RI during hospitalization. Diuresis and natriuresis are results of interplay among baseline kidney dysfunction, degree of neuro-hormonal activation, sodium intake (10), various medications targeting the renin-angiotensin-aldosterone pathway (10) and, finally, diuretics. This may explain the lack of relationship between diuretic administration alone and RI in our study and previous ones (23). Aggressive natriuresis (as indicated by a FeNa of greater than 0.4% 6 h after a loop diuretic dose) may herald more activation of the renin-angiotensin system and a decrease in effective intravascular volume, and eventually leads to worsening renal function. An infusion of small amounts of hypertonic saline halted the deterioration of renal function in ADHF (24,25).

The median length of stay (LOS) of our patients was longer than the median LOS of patients in American hospitals in recent years (five days) (26). We speculate that this is related to our centre being a teaching hospital in an urban area – both factors that are associated with longer LOS (2729). Knowing that RI is associated with a more complicated hospital course in ADHF patients (14), our finding that patients with a FeNa of greater than 0.4% stayed longer and needed more intensive therapy in the cardiac care unit is not surprising.

FeNa reflects net sodium filtration and reabsorption from multiple nephron segments; loop diuretics block sodium reabsorption on the loop of Henle, while having no effect on the proximal tubule. Decreased renal blood flow in severe systolic heart failure may promote sodium reabsorption from this segment, thus decreasing FeNa. Hasenfuss et al (30) noticed a strong correlation between the cardiac index of heart failure patients measured by the thermodilution method, and their FeNa calculated before starting the loop diuretic piretanide (r=0.85; P<0.01). In our study, FeNa was calculated at least 6 h after a dose of diuretic; nonetheless, it still correlates with ejection fraction in systolic heart failure patients (r=0.48; P=0.015).

As in other studies of RI in heart failure, most of the patients in both groups have received combined antihypertensive medications. None of the differences were considered statistically significant. The present study did not look specifically into the dosages of these medications, whether the patients received the target dose for heart failure or whether the dosages were titrated during admission. Loop diuretics stimulate renin secretion directly via the inhibition of sodium uptake by macula densa cells in the kidney (31). Needless to say, renin is also increased after depleting intravascular volume. Exorbitant activation of the renin-angiotensin-aldosterone system may eventually lead to sodium retention and diuretic resistance that could be potentially ameliorated by angiotenin-converting enzyme (ACE) inhibitors (32) or angiotensin receptor blockers. Unfortunately, in some patients, the glomerular filtration rate (GFR) is dependent on angiotensin to maintain renal blood flow; therefore, kidney function may deteriorate if ACE inhibitors are added to diuretics (31,3335). However, the use of these medications did not emerge as an independent risk factor for cardiorenal syndrome in many of the studies cited earlier (18). It is worth mentioning that Butler et al (36) classified the doses of different ACE inhibitors used in the heart failure therapy of 382 patients into low, medium and high doses, but did not find any relationship between RI and ACE inhibitors at any dose.

Beta-blocker therapy was found to be renoprotective in chronic heart failure patients in the Studies Of Left Ventricular Dysfunction (SOLVD) trial (31). In contrast, when heart failure is severe, the cardiovascular system becomes dependent on tachycardia to maintain cardiac output. At this stage, adding beta-blockers during decompensation may lead to cardiogenic shock and worsening renal function. It is unlikely that beta-blockers affected our results because hypotension and very low ejection fraction were infrequent phenomena in both groups.

Spironolactone corrects diuretic-induced hypokalemia, which aggravates metabolic alkalosis and attenuates natriuresis (37). Its action as a diuretic, and its effect on sodium balance, is dependent on the amount of urine sodium and potassium delivered to collecting ducts (38). However, we assumed that spironolactone was administered solely for heart failure (a non-diuretic dose of 25 mg/day to 50 mg/day); thus, it is unlikely that it affected sodium balance in our patients (39).

The present study is limited by the small number of patients, the use of one loop diuretic (furosemide) and its observational design. The inclusion of patients with apparently normal creatinine levels is consistent with other studies (40,41) that show that RI can develop in patients with normal creatinine levels and can predict adverse outcomes. A FeNa test was ordered in those patients with RI, seemingly due to fluctuating creatinine levels, which limited our ability to estimate their GFR using the Cockcroft-Gault equation. This should not have harmed our analysis because the Cockcroft-Gault equation has less precision when estimating GFR in heart failure patients (42), and was shown to predict RI less often than admission creatinine levels in a previous study (7). Finally, we were unable to obtain accurate information from the records about the New York Heart Association classification and the amount of weight loss during hospitalization.

CONCLUSION

A FeNa of greater than 0.4% more than 6 h after administration of diuretics predicts RI and a complicated hospital course in ADHF patients.

Acknowledgments

None of the authors have any conflicts of interest to acknowledge, or financial or other disclosures.

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