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April 2002, Volume 16, Number 4, Pages 255-260
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Original Article
Lack of correlation between two methods for the assessment of salt sensitivity in essential hypertension
A de la Sierra, V Giner, E Bragulat and A Coca

Hypertension Unit, Department of Internal Medicine, IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Hospital Clinic, Barcelona, Spain

Correspondence to: A de la Sierra, Hypertension Unit, Department of Internal Medicine, Hospital Clínic. Villarroel 170, 08036Barcelona, Spain. E-mail: asierra@clinic.ub.es

Abstract

The existence of a heterogeneous blood pressure (BP) response to salt intake, a phenomenon known as salt sensitivity, has increasingly become a subject of clinical hypertension research, and has important clinical and prognostic implications. However, two different methodologies are currently used to diagnose salt sensitivity. The aim of the present study was to compare the BP response to intravenous sodium load and depletion on the one hand, and to changes in dietary salt intake on the other, in order to assess salt sensitivity in a group of essential hypertensive patients. Twenty-nine essential hypertensives underwent two different procedures separated by 1 month: a dietary test consisting of a 2-week period of low (20 mmol/day) and high (260 mmol/day) salt intakes, and an intravenous test consisting of a 2 litre saline load over a 4-h period, followed by 1 day of low (20 mmol) salt intake and furosemide (40 mg/8 h orally) administration. BP was registered at the end of every period using 24-h ambulatory BP monitoring. In the whole group of hypertensive patients studied, both low salt intake and furosemide administration significantly (P < 0.01) decreased mean BP. Correlation coefficients of BP changes obtained using the two methodologies were between 0.3 and 0.4. Moreover, coefficients of agreement between the oral and the intravenous tests, using several cut points for BP changes, were systematically below 0.5, thus indicating a misclassification of salt sensitivity greater than 50%, depending on the method used. None of the cut points for BP changes during furosemide administration showed a good combination of sensitivity and specificity compared with changes in response to low dietary salt. The present results indicate that the diagnosis of salt-sensitive hypertension should be based on the BP response to changes in dietary salt intake, while BP response to saline and furosemide administration leads to a systematic misclassification of more than 50% of patients, even using different cutpoints for changes in BP.

Journal of Human Hypertension (2002) 16, 255-260. DOI: 10.1038/sj/jhh/1001375

Keywords

salt-sensitivity; essential hypertension; dietary salt

Introduction

Epidemiological and interventional studies have demonstrated a clear relationship between salt intake and hypertension.1 However, the effect of salt intake on blood pressure (BP) response varies among individuals. While high salt intake raises BP significantly in some subjects, in others there is no variation or even a decrease in BP. This heterogeneity is classified as salt sensitivity (SS) or salt resistance (SR).

SS is well established in both human and experimental hypertension. Clinical studies have shown that between 30% and 60% of essential hypertensive patients are salt-sensitive.2,3,4 Moreover, in recent years, we and others have furthered the understanding of the genetic determinants,5 associated pathophysiological factors6,7 and clinical implications of SS.8,9

Although the clinical importance of SS is well recognised, accurate diagnosis remains problematic, mainly due to the complexity of the dietary manipulation required for its assessment, including at least a 2-week period of low and high salt intake, with additional compliance difficulties in many patients. In order to overcome these obstacles, several authors have used a shorter methodology consisting of a rapid intravenous sodium load and depletion to classify patients as salt sensitive or salt resistant, as previously reported.10

Comparisons of these two methodologies for the assessment of SS are scarce. Weinberger et al11 first reported a significant correlation between them. However, when individual essential hypertensive patients were classified as salt sensitive or salt resistant by one method, this classification changed in some patients when the other method was used. Moreover, Sharma et al12 later confirmed the results reported by Weinberger et al.11 More recently, Galletti et al13 used tertiles of the BP response to rapid sodium load and depletion to predict the blood pressure variation compared with dietary changes on sodium intake. However, only a small subset of these patients underwent both protocols, making it difficult to obtain valid conclusions.

In the present paper we have attempted to quantify the validity of the rapid sodium load and depletion test for the diagnosis of SS in comparison to the dietary approach, which more closely mirrors daily life. To this end, we calculated correlation coefficients of the BP response and coefficients of agreement of the SS diagnosis using several cut points for both rapid sodium load and depletion and the dietary approach. In addition, we calculated sensitivity, specificity, and positive and negative predictive values for the intravenous test in comparison to chronic dietary sodium manipulation.

Patients and methods

Patient selection

Twenty-nine essential hypertensive patients from the Hypertension Unit of the Hospital Clinic, Barcelona, Spain, were studied. All patients had at least three office BP measurements above 140/90 mm Hg after 4 weeks of an unrestricted salt diet and without antihypertensive medication. Written informed consent was obtained from all participants.

Dietary protocol (DP)

Essential hypertensive patients were admitted to a metabolic ward for the duration of the study. A low-salt diet containing 20 mmol sodium daily was given to all participants for 14 days. This baseline diet was supplemented by random, single-blind administration of placebo tablets for 7 days (low-salt period) and NaCl tablets (240 mmol daily) for additional 7 days (high-salt period). Thus, total NaCl intake during the high-salt period was 260 mmol daily.

Dietary compliance was assessed by daily measurement of 24-h urinary Na+ excretion throughout the study. Mean values obtained were 33 ± 13 mmol/24 h at the end of the low-salt period and 244 ± 55 mmol/24 h at the end of the high-salt period.

On the last day of both low and high-salt periods, a 24-h ABPM was performed using an automated, noninvasive oscillometric device (SpaceLabs 90207, SpaceLabs Inc, Redmond, WA, USA). The appropriate cuff was placed on the non-dominant arm and BP was registered automatically at 15-min intervals for a 24-h period.

Intravenous protocol (IP)

The BP response to intravenous saline infusion and furosemide was evaluated at least 1 month after the dietary protocol. Patients were admitted to a metabolic ward and maintained on normal sodium diet (150 mmol/day) for the first day. On the second day, rapid volume expansion was achieved by intravenous administration of 2 litres of 0.9% saline over a 4-h period, between 08.00 and 12.00. A 24-h ABPM was performed on this day, beginning at 08.00. As in the dietary protocol, blood pressure was registered automatically at 15-min intervals with the aid of a SpaceLabs 90207 device. On the third day, volume depletion was accomplished by administration of a low (20 mmol/day) sodium diet and 120 mg furosemide in three seperate doses. A new 24-h ABPM was performed on this day, beginning at 08.00.

Statistical analysis

Values are expressed as mean ± s.d. and absolute frequencies. The relationship between 24-h mean BP changes induced by DP or IP was assessed by means of Pearson's correlation coefficient. Due to the lack of a uniform definition of SS, we used different cut points of 24-h mean BP changes to divide hypertensive patients into salt-sensitive and salt-resistant categories. For 24-h mean BP changes induced by DP, cut points were established at 3, 4 and 5 mm Hg of absolute change, while for changes induced by IP, cut points were established at 5 and 10 mm Hg of absolute change.

We have previously reported that the use of 24-h ABPM (and thus a large number of repeated BP recordings) allows the diagnosis of salt-sensitivity by using the statistical significance of the variation of 24-h mean BP comparing records of the same subject obtained at different levels of salt intake.4 For this reason, we also used this method to compare DP with IP, in addition to comparing the absolute changes.

As the main objective of the study was to compare the results obtained by the two methods, the statistical analysis was performed in two ways: (a) without assuming that one of the methods (DP) was the 'gold standard' and thus calculating coefficients of agreement (kappa) in contingency tables between acute and dietary manipulations using the different criteria mentioned above; and (b) taking DP as the 'gold standard' and calculating sensitivity, specificity, and positive and negative predictive values for every cut point used in the IP for the assessment of SS.

Results

Twenty-nine essential hypertensive patients were compliant, completed both the dietary and intravenous protocols and had evaluable ABPM data from all the different situations. Twelve were male and 17 female, with a mean age of 55 ± 9 years. Baseline office BP was 161 ± 15 mm Hg for systolic BP and 97 ± 8 mm Hg for diastolic BP. Table 1 shows the general characteristics of patients included.

Table 2 shows 24-h systolic, mean and diastolic BP obtained at the end of low and high salt periods and during saline and furosemide administration. Both DP and IP promoted significant changes in 24-h BP. However, the magnitude of changes observed during IP were twice as great as those observed during DP.

Table 3 shows correlation coefficients between individual 24-h BP changes obtained during DP and IP. Correlation coefficients were obtained before and after adjusting for BP at every step of the study. As can be seen, non-adjusted correlation coefficients were lower than 0.5 for systolic, mean and diastolic BP. Adjustment for BP for both low-salt or furosemide infusion periods slightly improved correlation coefficients, whereas adjustment for BP values at both high-salt or saline infusion periods decreased correlations.

Table 4 shows different parameters of agreement between the two methodologies. Coefficients of agreement obtained at different cut points were always below 0.5, with the exception of the 0.512 obtained when a 5-mm Hg BP decrease during the low salt diet was compared with a 10 mm Hg BP decrease from saline to furosemide infusion. Although statistical significance was found in agreement coefficients higher than 0.3, these findings indicate a systematic misclassification of more than 50% of hypertensive subjects into SS or SR categories depending on the methodology used for the assessment of SS.

Table 4 also shows sensitivity, specificity, and positive and negative predictive values for each cut point used in the BP decrease from saline to furosemide administration in comparison with the BP decrease during low salt diet. None of the comparisons performed exhibited good combinations of these four parameters, indicating that the validity of IP for the diagnosis of salt-sensitive hypertension was poor. High indexes of sensitivity and negative predictive value were systematically accompanied by low specificity and positive predictive values, while high specificity and positive predictive values were accompanied by low sensitivity and negative predictive values.

We measured hormonal changes during both the dietary and intravenous protocols. As Table 5 shows, both low salt and furosemide increased mean values of plasma renin activity and serum aldosterone and decreased atrial natriuretic peptide. Plasma noradrenaline changes run in parallel with those observed in PRA and aldosterone, although due to their high variability differences did not reach statistical significance.

Discussion

The present paper compares the acute intravenous sodium load and depletion protocol with the more-frequently used chronic dietary approach for the diagnosis of SS in a group of essential hypertensive patients. Generally speaking, both methods have a poor correlation regarding the BP response obtained. Even using several combinations of the magnitude of BP variation for the diagnosis of salt-sensitive or salt-resistant hypertension, more than 50% of the patients fall into a different category using one method or another. These results indicate that the protocol of rapid sodium load and depletion is not useful for the assessment of SS in essential hypertension.

The importance of SS in hypertension is three-fold. Firstly, SS is an intermediate phenotype that allows the study of both the genetic determinants5,14,15 and physiopathology6,7 of high BP. Secondly, salt-sensitive hypertension is associated with severe hypertension, target organ damage8 and a worse prognosis in terms of cardiovascular morbidity.9 Thirdly, and probably most important, the detection of this phenotype in hypertensive patients is of special importance in the application of salt restriction as a therapeutic measure. Indeed, the effectiveness of salt restriction as a universal measure in treating or preventing hypertension has been challenged16 and it is recognised that a considerable reduction in salt intake is difficult to achieve, especially as processed foods play an important role in modern diets.17 Identification of hypertensive or hypertension-prone subjects sensitive to the pressor effect of salt intake may help to plan preventive therapeutic strategies for both the general population and for individual hypertensives.

Although all these arguments strengthen the importance of SS, the clinical reality is that very few patients know the effect of salt restriction or consumption on their BP and the diagnosis of SS is at present restricted to clinical research, mainly because its assessment is complex and requires dietary manipulations that are difficult to achieve in a large number of patients and strict compliance.

Various studies have used an intravenous protocol with a rapid sodium load and depletion to diagnose SS, in an attempt to show that the effect of this manoeuver was similar to that obtained by changes in salt intake. However, this hypothesis is not supported by the results of the present paper. In fact, although we obtained significant correlation coefficients between changes in BP by the two methodologies used, they were always below 0.5.

Two previous studies have compared the two methodologies for the assessment of SS in hypertensive and normotensive subjects. In 40 hypertensives, Weinberger et al11 found a correlation coefficient between the two methods of 0.4 for changes in mean BP, a figure almost identical to that obtained in the present paper (0.38). Similar results were obtained by Sharma et al12 in a group of 22 young normotensive males. Correlation coefficients of 0.32 and 0.56 were observed for systolic and diastolic blood pressures, respectively.

However, as previously stated, SS should be regarded as an individual diagnosis in order to aid therapeutic decisions in individual patients. In this respect, the comparison between these two methodologies should be regarded in terms of congruence or agreement if we assume that both methodologies are equally valid, or in terms of sensitivity, specificity, and positive and negative predictive values if we assume that the DP is the gold standard. To date, there are no published studies comparing this aspect of the two methodologies. In the study by Weinberger et al11 2/21 patients defined as salt sensitive or indeterminate by the intravenous test showed an increase in BP during low salt diet, whereas 7/19 patients defined as salt resistant showed a decrease in BP during low salt diet. Moreover, in the study by Sharma et al12 of normotensive patients, the percentages classified as salt sensitive by dietary salt restriction or by furosemide administration were quite different. In the present paper, the best agreement (a concordance of only 50% of patients) was obtained by comparing a 5-mm Hg decrease in mean BP with low salt diet and a 10-mm Hg decrease in mean BP with furosemide administration. The remaining comparisons, using several cut points for each protocol or even the statistically significant variation for changes in dietary salt, as we have previously reported,4 gave coefficients of agreement that were repeatedly below 0.5.

We also used another approach to compare the two protocols; assuming that the response to changes in dietary salt is the 'gold standard' method for the diagnosis of SS and thus calculating sensitivity, specificity, and positive and negative predictive values for each combination of cut points for BP change. The results obtained indicate that none of the comparisons showed good combinations of sensitivity and specificity.

We believe that these results agree with those obtained by Weinberger et al11 in hypertensive patients and by those of Sharma et al12 in normotensive subjects. However, our interpretation is quite different. In spite of the presence of statistically significant correlations of BP changes between the two methods, the low agreement coefficients and the poor sensitivity and specificity combination indexes do not support the idea that the intravenous protocol can be used to diagnose SS in large groups of subjects. Therefore, this diagnosis should still be based on the BP response to changes in dietary salt intake which better reflects daily life and is easier to administrate clinically. Moreover, the poor concordance in this small group of subjects does not provide encouragement for a large-scale concordance study in hypertension.

References

1 Muntzel M, Drüeke T. A comprehensive review of the salt and blood pressure relationship. Am J Hypertens 1992; 5: 1S-42S. MEDLINE

2 Campese VM. Salt sensitivity in hypertension. Renal and cardiovascular implications. Hypertension 1994; 23: 531-550. MEDLINE

3 Weinberger MH. Salt sensitivity of blood pressure in humans. Hypertension 1996; 27: 481-490. MEDLINE

4 de la Sierra A et al. Assessment of salt sensitivity in essential hypertension by 24-h ambulatory blood pressure monitoring. Am J Hypertens 1995; 8: 970-977. MEDLINE

5 Giner V et al. Renin-angiotensin system genetic polymorphisms and salt sensitivity in essential hypertension. Hypertension 2000; 35: 512-517. MEDLINE

6 de la Sierra A et al. Fluid, ionic and hormonal changes induced by high salt intake in salt-sensitive and salt-resistant hypertensive patients. Clin Sci 1996; 91: 155-161. MEDLINE

7 Bragulat E, de la Sierra A, Antonio MT, Coca A. Endothelial dysfunction in salt sensitive hypertension. Hypertension 2001; 37: 444-448. MEDLINE

8 de la Sierra A et al. Increased left ventricular mass in salt-sensitive hypertensive patients. J Hum Hypertens 1996; 10: 795-799. MEDLINE

9 Morimoto A et al. Sodium sensitivity and cardiovascular events in patients with essential hypertension. Lancet 1997; 350: 1734-1737. MEDLINE

10 Sullivan JM. Salt sensitivity. Definition, conception, methodology, and long-term issues. Hypertension 1991; 17 (Suppl I): 161-168. MEDLINE

11 Weinberger MH, Stegner JE, Fineberg NS. A comparison of two tests for the assessment of blood pressure responses to sodium. Am J Hypertens 1993; 6: 179-184. MEDLINE

12 Sharma AM, Schorr U, Cetto C, Distler A. Dietary v intravenous salt loading for the assessment of salt sensitivity in normotensive man. Am J Hypertens 1994; 7: 1070-1075. MEDLINE

13 Galletti F et al. Evaluation of a rapid protocol for the assessment of salt sensitivity against the blood pressure response to dietary sodium chloride restriction. Am J Hypertens 1997; 10: 462-466. MEDLINE

14 Cusi D et al. Polymorphisms of alpha-adducin and salt sensitivity in patients with essential hypertension. Lancet 1997; 349: 1353-1357. MEDLINE

15 Poch E et al. Genetic variation of the gamma subunit of the epithelial Na+ channel and essential hypertension. Relationship with salt sensitivity. Am J Hypertens 2000; 13: 648-653. MEDLINE

16 Gradual NA, Galløe AM, Garred P. Effect of sodium restriction on blood pressure, renin, aldosterone, catecholamines, cholesterols, and triglyceride. A meta-analysis. JAMA 1998; 279: 1383-1391. MEDLINE

17 Chobanian AV, Hill M. National Heart, Lung, and Blood Institute Workshop on sodium and blood pressure. A critical review of current scientific evidence. Hypertension 2000; 35: 858-863. MEDLINE

Tables

Table 1 General characteristics of the 29 essential hypertensive patients studied

Table 2 Mean values (±s.d.) of 24-h systolic, mean, and diastolic blood pressures (BP) obtained at the end of low and high salt intakes, and during saline and furosemide administration in the whole group of essential hypertensive patients studied

Table 3 Pearson's correlation coefficients between changes in 24-h systolic, mean, and diastolic blood pressures (BP) obtained by either changes in dietary salt and saline-furosemide administration. Correlation coefficients were calculated non-adjusted, and also after adjustment for the corresponding BP obtained in all four steps of the study

Table 4 Coefficients of agreement (kappa), sensitivity, specificity, and positive and negative predictive values of the diagnosis of salt-sensitive hypertension by different cut off values of 24-h mean blood pressure (BP) change during furosemide-saline administration in comparison with 24-h mean BP changes during low and high salt intakes

Table 5 Changes in hormonal parameters induced by either low and high salt intakes, and by saline furosemide administration

Received 8 June 2001; revised 16 November 2001; accepted 21 November 2001
April 2002, Volume 16, Number 4, Pages 255-260
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