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European Journal of Heart Failure 2002 4(5):597-603; doi:10.1016/S1388-9842(02)00097-1
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© 2002 European Society of Cardiology

Serum to urinary sodium concentration ratio is an estimate of plasma renin activity in congestive heart failure

GianCarlo Marenzi*, Gianfranco Lauri, Emilio Assanelli, Marco Grazi, Jeness Campodonico, Gabriella Famoso and Piergiuseppe Agostoni

Centro Cardiologico Monzino, IRCCS, Institute of Cardiology, University of Milan via Parea 4, 20138 Milan, Italy

* Corresponding author. Tel.: +39-02-580021; fax: +39-02-504667. E-mail address: giancarlo.marenzi{at}cardiologicomonzino.it


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
We investigated the relationship between plasma renin activity (PRA) and serum ([sNa+]) and urinary ([uNa+]) sodium concentrations in 124 congestive heart failure (CHF) patients (II–IV NYHA class) and 20 healthy subjects. According to PRA (> or <3 ng ml–1 h–1) and [sNa+] (> or <135 mEq l–1), patients were classified as Group A (normal PRA and normal [sNa+], n=39), Group B (increased PRA and normal [sNa+], n=62) and Group C (low [sNa+], n=23). Measurements were performed at rest and, in 26 cases, after extracorporeal ultrafiltration (UF). At rest, [sNa+] and [uNa+], and their difference ([sNa+]–[uNa+]), were linearly correlated with PRA, but the values did not allow differentiation of control subjects from patients or differentiation of patients with from those without renin–angiotensin system (RAS) activation. Conversely, the [sNa+]/[uNa+] ratio showed the best correlation with PRA (r=0.79, P<0.0001). UF-induced PRA changes were linearly correlated with [sNa+]/[uNa+] ratio changes (r=0.67, P=0.002), but not with those of [sNa+], [uNa+] and [sNa+]–[uNa+]. In CHF, the [sNa+]/[uNa+] ratio best correlates with PRA and reflects the basal activity as well as the rapid changes (as those induced by UF) of the RAS. Therefore, it can be considered a strong and easily available marker of PRA.

Key Words: Sodium concentration • Plasma renin activity • Heart failure • Ultrafiltration

Received April 19, 2001; Revised January 24, 2002; Accepted February 4, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
The renin–angiotensin system (RAS) plays a central role in the regulation of systemic blood pressure, electrolyte and fluid balance, and blood volume [1,2]. In congestive heart failure (CHF), activation of the RAS is involved in fluid retention, and its blockade by angiotensin-converting enzyme inhibitors has been shown to prevent or delay disease progression and improve prognosis [3–6]. The results of the Studies of Left Ventricular Dysfunction (SOLVD) Register demonstrate a correlation between left ventricular ejection fraction and plasma renin activity (PRA), even when corrected for the effect of diuretic agents and angiotensin-converting enzyme inhibitor therapy [7]. Therefore, monitoring of RAS activity might be useful for assessing CHF severity and response to therapy [7–10]. Unfortunately, PRA measurements are expensive and not immediately available to most clinicians, and are therefore rarely used to guide CHF treatment. Hence, the possibility of identifying a reliable, easily repeatable and low-cost marker of PRA is a stimulating incentive.

Hyponatremia, defined as a serum sodium concentration ([sNa+]) <136 mEq l–1, often complicates the clinical course of patients with CHF [11]. It is considered an index of compromised renal perfusion, increased RAS activity and poor CHF prognosis [11–15]. Nevertheless, hyponatremia is detectable in only a few patients with advanced CHF. Therefore, its potential clinical and prognostic value as a marker of PRA is limited and cannot be applied to all CHF patients, most of whom have a serum sodium concentration within the normal range.

In the present study we investigated whether the combination of simple parameters related to renal sodium metabolism, such as [sNa+] and urinary sodium concentration ([uNa+]), for which changes might precede hyponatremia development, can reflect RAS activity in CHF. To test this hypothesis we measured [sNa+], [uNa+] and PRA at rest, during RAS stimulation and RAS inhibition. We also investigated patients undergoing extracorporeal ultrafiltration (UF), a procedure used for CHF treatment [16,17], because the PRA response to fluid removal by UF is characterized by a transient increase in patients with moderate fluid retention [18,19], and by a remarkable decrease in those with severe fluid overload and oligoanuria [19,20].


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patients
The study involved 124 patients, 98 men and 26 women, aged from 33 to 79 years, with chronic CHF. A total of 79 had coronary and 45 had idiopathic cardiac muscle disease; none had primary valvular heart disease or hypertension. All were in a stable clinical condition. According to the New York Heart Association (NYHA) functional classification, 38 patients were in class I, 47 in class III and 39 in class IV. All patients had cardiac dysfunction with a left ventricular ejection fraction (echocardiogram) <35%. All patients received furosemide, 21 patients were also given thiazides, 36 spironolactone and 15 received both thiazide and spironolactone in addition to furosemide; 74% of patients were taking angiotensin-converting enzyme (ACE) inhibitors and 12% beta-blockers. According to their PRA and [sNa+], patients were classified as Group A (PRA<3 ng ml–1 h–1 and [sNa+]>135 mEq l–1; n=39), Group B (PRA>3 ng ml–1 h–1 and [sNa+]>135 mEq l–1; n=62) and Group C ([sNa+]<136 mEq l–1; n=23).

We included 20 healthy individuals (17 men and three women, mean age 52±11 years) as a reference group. The investigation conformed with the principles outlined in the Declaration of Helsinki. Informed consent was obtained from all subjects, and the local Ethics Committee approved the protocol.

2.2. Study protocol
All patients were hospitalized during the study and continued on their usual oral doses of furosemide, other diuretics and digoxin; none of these was administered in the 12 h preceding blood and urine sampling. All vasodilator drugs, including ACE inhibitors, had been discontinued at least 5 days before the study. During this period patients received a low sodium diet (60–80 mmol day–1) and had free access to water.

Studies were performed in the morning after an overnight fast. Patients were instructed to remain supine for at least 1 h before blood and urine collection for PRA (radioimmunoassay), plasma norepinephrine (high-performance liquid chromatography) [19], and [sNa+] and [uNa+] analysis.

2.3. Extracorporeal ultrafiltration
A total of 26 patients (14 in NYHA class III and 12 in class IV) underwent a single UF as part of CHF treatment. All had normal [sNa+]. The procedure was performed during temporary admission to the intensive care unit, according to methods previously described in detail [16–20]. Briefly, a double lumen catheter was introduced into the femoral vein for blood withdrawal and reinfusion and connected with a by-pass circuit. Blood was driven by a peristaltic pump (Diapact CRRT, B Braun Carex, Italy), and a Renaflo HF700 diafilter (Minntech, Minneapolis, MN) was inserted into the circuit. This particular filter contains fine hollow capillaries arranged in a parallel configuration having membranes with pores of an inner diameter that allows subtraction of water and of solutes with a molecular weight lower than 50 000 Da. Because of this, the procedure reduces total plasma water and increases serum colloid osmotic pressure, thus promoting a net flow of fluid from the interstitial to the intravascular phase [21]. A new steady state is achieved according to the amount of fluid filtered and the protein interstitial concentration relative to the plasma protein concentration. Since sodium moves freely with water through the membrane pores, ultrafiltrate sodium concentration is similar to that in the plasma (isotonic), and the procedure does not significantly alter [sNa+] [16,19]. The rate of UF was regulated to remove 300–500 ml h–1 of plasma water and the procedure was interrupted when hemoconcentration started to appear, as signaled by an increase in hematocrit. PRA, [sNa+] and [uNa+] were determined before and soon after the UF session.

2.4. Statistical analysis
Analysis of variance with the Student–Neuman–Keuls test was used for group differences. Changes in sodium concentrations and PRA following UF were evaluated with Student's t-test for paired data. Linear regression analysis was used for correlation coefficients. Significance was taken at the 5% level. Results are presented as mean±standard deviation.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
The clinical characteristics of patients and control subjects are shown in Table 1. In the three patient groups, the percentages of ischemic and primary heart diseases were similar. PRA was normal in Group A and augmented in Group B by selection; in Group C it was significantly higher than in the other two groups. Resting plasma norepinephrine paralleled the PRA value. Serum creatinine was similar in the three groups, whereas blood urea nitrogen (BUN) and BUN/serum creatinine ratio, an index of prerenal azotemia, were increasingly greater from Group A through Group C. Mean systemic arterial pressure was significantly lower from Group A through Group C. Patients in Group C received greater daily amounts of furosemide.


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  		Table 1 Clinical and biochemical variables in the four study groups

 
Fig. 1 shows [sNa+], [uNa+], and the differences and the ratios between the two in reference subjects and in CHF groups. According to the grouping criteria, [sNa+] was normal in Groups A and B and low in Group C; [uNa+] was lower in patients than in control subjects, and in patients was increasingly lower from Group A through C. As compared to [sNa+], [uNa+] was greater in normal subjects and lower in Groups B and C; the two values were similar in Group A. The [sNa+]/[uNa+] ratio was 0.72±0.2 (range 0.57–1.17) in control subjects and was 1.48±0.6 (range 0.43–2.89), 5.86±11.5 (range 2.47–51.5) and 20.6±43 (range 2.84–57) in Groups A, B and C, respectively. Indeed, the ranges of this parameter showed only a small overlap between subjects with normal (control subjects and Group A) and those with high PRA (Groups B and C). In particular, in cases with normal PRA (<3 ng ml–1 h–1), the [sNa+]/[uNa+] ratio never exceeded the value of 3.


Figure 1
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  		Fig. 1 Serum sodium concentration ([sNa+]), urinary sodium concentration ([uNa+]), their difference ([sNa+]–[uNa+]) and ratio ([sNa+]/[uNa+]) in control subjects and in the three heart failure groups. *P<0.01 vs. control subjects; §P<0.01 vs. Group A; #P<0.01 vs. Group B.

 
In the whole study population, PRA was correlated with [sNa+] (r=–0.35, P<0.001), with [uNa+] (r=–0.26, P<0.001), with the [sNa+]–[uNa+] difference (r=0.23, P=0.03) and, to a greater extent, with the [sNa+]/[uNa+] ratio (r=0.79, P<0.0001) (Fig. 2). The relationships between sodium concentrations and the other biochemical indexes are reported in Table 2. Notably, the [sNa+]/[uNa+] ratio was also strongly related to plasma norepinephrine, mean systemic arterial pressure and dose of furosemide.


Figure 2
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  		Fig. 2 Correlation between serum/urinary concentration ratio ([sNa+]/[uNa+]) and plasma renin activity (PRA) in patients with heart failure.

 


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  		Table 2 Correlation coefficients of sodium values with the other variables analyzed in patients with congestive heart failure

 
3.1. Extracorporeal ultrafiltration
We measured PRA, [sNa+] and [uNa+] in 26 patients undergoing UF. In all patients the procedure produced relief of edema and dyspnea. The amount of isotonic fluid removed by UF averaged 1823±600 ml in the 14 NYHA class III patients and 4480±930 ml in the 12 class IV patients (P<0.001). As expected [19], PRA was different in the two groups of patients according to the different degree of severity of the disease, and its response to UF was different as well, with a rise in class III (from 2.3±5 to 6.6±8 ng ml–1 h–1, P<0.0001), and a fall in class IV (from 30.7±14 to 12.1±10 ng ml–1 h–1, P<0.0001). At baseline, [sNa+] was similar in the two groups and, in both, did not significantly change (Fig. 3). Before UF, [uNa+] was higher, while the [sNa+]–[uNa+] difference and [sNa+]/[uNa+] ratio was lower in class III than in class IV patients. All these three parameters were affected by UF; however, changes had a different behavior according to CHF severity (Fig. 3). Ultrafiltration-induced PRA changes and [sNa+]/[uNa+] ratio changes were linearly related to each other (r=0.67, P=0.002; Fig. 4). No relationship was found between PRA changes and [sNa+], [uNa+] and [sNa+]–[uNa+] difference changes.


Figure 3
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  		Fig. 3 Serum sodium concentration ([sNa+]), urinary sodium concentration ([uNa+]), their difference ([sNa+]–[uNa+]) and ratio ([sNa+]/[uNa+]), before and after extracorporeal ultrafiltration (UF) in patients with moderate (black bars) and severe (white bars) heart failure. *P<0.01 vs. before UF; #P<0.01 between the two groups.

 


Figure 4
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  		Fig. 4 Correlation between ultrafiltration-induced plasma renin activity changes ({Delta}PRA) and serum/urinary concentration ratio changes ({Delta}[sNa+]/[uNa+]).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
In CHF many neurohormonal systems are activated as cardiac output declines [3–6,22]. The RAS has an important role in the maintenance of normal blood pressure when the ‘effective’ filling of the arterial circulation decreases [4,23]. By physiologically regulating proximal nephron sodium chloride transport, angiotensin II is considered an independent determinant of extracellular volume regulation. In normal conditions, ~70% of filtered sodium chloride and water and 95% of filtered NaHCO3 are reabsorbed along the proximal tubule. Angiotensin II, by virtue of its control over both glomerular and proximal tubule function, is a major mediator of this response [24,25]. Direct consequences of a change in angiotensin II activity include modification of glomerular filtration, by resetting glomerular vascular resistances and the hydraulic permeability coefficient, and by altering absolute sodium chloride reabsorption in the proximal convolute tubule [24–27]. In addition, angiotensin II modifies two other factors that control sodium chloride transport, neurogenic tone and peritubular hydrostatic and oncotic forces [25,28]. Such parallel control of glomerular and tubular function by RAS would thus directly affect the amount of sodium emerging from the nephron, and natriuresis and diuresis.

The parameters we considered as possibly related to PRA were serum and urinary sodium concentrations, their difference and their ratio. As glomerular filtrate resembles plasma composition, the concentration of sodium in the Bowman's capsule is similar to that in the serum. Therefore, the difference between sodium concentration in serum and that in urine reflects the total changes in sodium concentration during fluid transit through the proximal and distal tubules under both angiotensin II and aldosterone control. The contribution of the tubule in sodium handling can be assessed not only as an absolute value, but also as a fraction of the filtered sodium load that is excreted into the urine ([sNa+]/[uNa+] ratio). All these variables could possibly reflect RAS activity. This issue is particularly important in CHF, where the degree of RAS activation is closely related to severity and prognosis of the disease [7–10,29]. Yet, the greatest benefit on hemodynamics and mortality with ACE inhibitors is obtained in patients having the highest baseline RAS activation [30].

In our study, as well as in others [11,13], [sNa+] was related to PRA, but its clinical utility as an index of PRA is restricted to only a few patients with advanced CHF, namely those with hyponatremia, while most CHF patients with increased PRA show normal [sNa+] values (Group B, Table 1). Our data confirm that patients with hyponatremia (Group C) have a marked RAS activation and a low renal perfusion pressure, as suggested by the increased BUN/serum creatinine ratio and the reduced mean arterial systemic pressure (Table 1). Therefore, the presence of hyponatremia indicates the existence of RAS overactivity, proportional to the degree of [sNa+] reduction. On the contrary, when [sNa+] is normal, activation of the RAS cannot be excluded.

Similar considerations can be applied to urinary sodium concentration. A significant relationship between [uNa+] and PRA was found in our study, but [uNa+] did not allow discrimination of patients with an abnormal PRA value (Groups B and C) from those with a normal one (Group A and control subjects; Fig. 1). Therefore, both [sNa+] and [uNa+], when considered separately, are poor indicators of RAS activity in CHF patients.

A more reliable evaluation of RAS activity can be obtained from the combination of these two parameters. In our study, the [sNa+]–[uNa+] difference increased from normal subjects to those with increased PRA (from control subjects to Group C, Fig. 1), suggesting a progressive enhancement of sodium tubular reabsorption as RAS activity increases. However, the relationship between the [sNa+]–[uNa+] difference and PRA was weak, with a broad overlap among groups. All patients were receiving diuretics. These drugs, by antagonizing sodium reabsorption in the renal tubule and by increasing its urinary excretion, can narrow the difference between serum and urinary concentrations. At the same time, diuretics stimulate RAS [11,31], with consequent tubular sodium retention and an opposite effect on the [sNa+]–[uNa+] difference. These contrasting tubular effects could explain the lack of a clear relationship between PRA and the [sNa+]–[uNa+] difference in our population. In particular, the [sNa+]–[uNa+] difference was similar in Groups B and C, despite a lower mean PRA value in the former than in the latter group. A higher furosemide requirement in Group C may have counterbalanced the difference in PRA between the two groups. If a similar increase in [sNa+] and in [uNa+] does not influence their difference, it will affect their ratio (except if they have the same value), as in the present study, where a significant correlation between [sNa+]/[uNa+] ratio and PRA (Fig. 2) was shown. This is particularly evident above a [sNa+]/[uNa+] ratio of 10. It should be noted that our measurements were taken in the post-diuretic phase to avoid the impact of these drugs on urinary sodium concentration.

We studied patients undergoing UF to evaluate whether RAS activity changes can be detected by [sNa+], [uNa+] and their combination. In the two CHF populations undergoing UF, opposite changes in PRA were observed. After UF, PRA increased in patients with moderate CHF and lowered in those with severe CHF [18–20]. In the former, the mechanism of this response is the transient reduction in circulating volume [18], whereas in the latter the apparent paradoxical PRA inhibition following fluid subtraction seems to be due to a complex interplay of hemodynamic and renal factors, such as improvement in renal perfusion pressure, possibly due to right atrial pressure reduction and circulating volume optimization [19].

Changes in PRA during UF were associated with changes in all sodium parameters, except [sNa+] (Fig. 3); however, only changes in the [sNa+]/[uNa+] ratio were significantly correlated with those of PRA (Fig. 4). As isotonic fluid is removed from the circulation during UF, [sNa+] is not significantly affected by the procedure [16,19]. Therefore, the changes observed in the [sNa+]/[uNa+] ratio were related to changes in [uNa+], due to increase, in moderate CHF, or decrease, in severe CHF, of tubular sodium reabsorption under the influence of angiotensin II. Accordingly, in patients with moderate CHF, decrease in [uNa+] following UF-induced transient hypovolemia can be completely antagonized by ACE inhibitors [33].

Notably, in all cases of our study population having a normal PRA value (control subjects and Group A), the [sNa+]/[uNa+] ratio never exceeded the value of 3, while only a few patients of Groups B and C showed a [sNa+]/[uNa+] ratio lower than 3. In other words, the [sNa+]/[uNa+] ratio overlap among subjects with and those without PRA activation is negligible. Therefore, a [sNa+]/[uNa+] ratio greater than 3 is a strong indicator of RAS activation. Based on these observations, it appears that angiotensin II and aldosterone-induced tubular changes in sodium concentration are better reflected by the fraction of the filtered sodium load rather than by the absolute difference along the tubule, and that the [sNa+]/[uNa+] ratio can be utilized as an index of RAS activity in CHF patients. A disproportionately high tubular sodium reabsorption for a given concentration in the serum seems to better reflect RAS activity than the simple, transtubular sodium concentration difference. The inverse relationship between [sNa+]/[uNa+] ratio and mean systemic arterial pressure observed in our population suggests that reduced renal perfusion pressure, rather than disturbance in sodium excretion, is the major stimulus to RAS activation in CHF, and that the [sNa+]/[uNa+] ratio increase can estimate this reduction.

In our study, the [sNa+]/[uNa+] ratio was also closely related to norepinephrine plasma concentration (Table 2). This was not unexpected, as the sympathetic adrenergic system activity is facilitated by angiotensin II [32], and plasma norepinephrine concentration and PRA have a parallel role in reflecting the severity and the prognosis of the disease [22,30]. As a consequence, the [sNa+]/[uNa+] ratio could be effectively considered as an index of general neurohumoral activation in CHF. Finally, the strong relationship observed between this parameter and the furosemide dosage is in agreement with the recognized relevant contribution of diuretic drugs in sustaining RAS activity in CHF [11,31].

We were not able to measure angiotensin II plasma concentration on a routine basis, and therefore we have used PRA as an indirect index of this parameter. Therefore, we were obliged to temporarily withdraw ACE inhibitor treatment at least 5 days before measurements were performed. Our results cannot therefore be applied in a straightforward manner to the majority of CHF patients who are treated with ACE inhibitors. Nevertheless, as renal tubular activity is under the influence of angiotensin II, and not of renin, the [sNa+]/[uNa+] ratio should reflect angiotensin II activity, regardless of either the presence or absence of ACE inhibition.

In conclusion, we propose that the [sNa+]/[uNa+] ratio may be used to monitor RAS activity in CHF, being a rapid, readily available and inexpensive way to evaluate PRA.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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