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(Hypertension. 1996;27:1160-1164.)
© 1996 American Heart Association, Inc.

Articles

Renal Function and Blood Pressure Response to Dietary Salt Restriction in Normotensive Men

Gianvincenzo Barba; Francesco Paolo Cappuccio; Luigina Russo; Francesco Stinga; Roberto Iacone; Pasquale Strazzullo

From the Department of Clinical and Experimental Medicine, "Federico II" University of Naples Medical School (Italy), and Blood Pressure Unit, Department of Medicine, St. Georges's Hospital Medical School, London, UK (F.P.C.).

Correspondence to Pasquale Strazzullo, MD, Department of Clinical and Experimental Medicine, "Federico II" University of Naples, Via S Pansini 5, 80131 Naples, Italy.

	Abstract

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Abstract The interindividual variability of the blood pressure response to changes in dietary sodium intake might be traced in part to heterogeneity in renal adaptation. To further explore this possibility, we evaluated glomerular filtration rate and tubular sodium handling in 47 healthy male volunteers from the Olivetti factory in Naples who were studied on their habitual sodium-rich diet (urinary sodium, 184±9 mmol/24 h) and after 3 days of a salt-restricted diet (urinary sodium, 69±5 mmol/24 h). Individual salt sensitivity, defined as the mean blood pressure change recorded after the shift from habitual to low sodium diet, significantly and directly correlated with glomerular filtration rate and absolute proximal sodium reabsorption during the habitual diet. When the entire population was divided into tertiles of salt sensitivity, the group with the highest salt sensitivity showed higher blood pressure, glomerular filtration rate, and absolute proximal sodium reabsorption during the habitual diet compared with the least salt-sensitive group; however, during the low NaCl diet, no differences were detectable between the groups. Twenty-four-hour urinary sodium was similar across the groups. We conclude that relative hyperfiltration and altered tubular sodium handling may occur in salt-sensitive normotensive individuals on a high sodium diet and that NaCl restriction may offset these abnormalities.

Key Words: hypertension, sodium-dependent • diet • glomerular filtration rate • sodium, dietary • blood pressure • natriuresis • kidney

	Introduction

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Epidemiological studies have detected a statistically significant, albeit weak, relationship between individual habitual dietary NaCl intake and blood pressure (BP).^{1 2} Controlled clinical trials have shown that in both normotensive and hypertensive individuals, dietary NaCl restriction lowers BP³ ; nevertheless, these same studies have documented a marked heterogeneity in the BP response to changes in dietary sodium intake among different subjects.^{1 2 3 4 5} The pathophysiological bases of salt sensitivity have not yet been clarified, although a renal origin for this biological feature has been proposed.^{6 7 8 9 10}

Recently, enhanced glomerular filtration rate (GFR)¹¹ and intraglomerular pressure⁸ have been detected in black hypertensive patients, who are more commonly salt sensitive, versus white hypertensive control subjects while on their habitual sodium-rich diet. Indirect evidence of altered renal tubular sodium handling has also been found in salt-sensitive hypertensive patients.^{12 13 14} However, little information is available on renal function and tubular sodium handling in relation to salt sensitivity in healthy normotensive individuals.

Therefore, the purpose of the present study was to evaluate changes in GFR and tubular sodium handling in normotensive men as a function of their BP response on switching from their customary relatively high sodium diet to a low dietary sodium regimen.

	Methods

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Forty-seven healthy normotensive male volunteers (age, 43.8±0.9 years; range, 27 to 57; BP, 123±2/85±1 mm Hg; range, 101 to 153/73 to 94; body weight, 75.0±1.6 kg; range, 51 to 104) were recruited and gave their informed consent to the study protocol, which was approved by the local ethics committee. Subjects were part of the male workforce of the Olivetti factory in Pozzuoli (Naples) participating in a survey of cardiovascular risk factors in Southern Italy (the Olivetti Study).

The subjects' renal sodium handling was evaluated on two different occasions: during their habitual diet and after 3 days of dietary NaCl restriction (40 mmol/d). On the last day of each regimen, the participants collected 24-hour urine samples for measurement of urinary sodium excretion, which was used as an estimate of their sodium intake. On the evening before the study, the subjects were instructed to fast and refrain from smoking, from vigorous exercise, and from alcohol- or caffeine-containing beverages starting from 7 PM. At 10 PM, they took a 300-mg lithium carbonate capsule (Carbolithium, IFI), providing 8.1 mmol elemental lithium, with 400 mL tap water. On the following morning, the subjects were seen at the Medical Center of the Olivetti factory in Pozzuoli (Naples). They remained seated for 10 minutes in a quiet and comfortable room, and then BP was measured three times at 2-minute intervals with a random-zero mercury sphygmomanometer (Gelman Hawksley Ltd). The average value of the last two measurements was used for analysis. Mean BP was calculated as diastolic pressure plus one third pulse pressure. After subjects ingested 400 mL tap water, a timed urine collection was performed and a venous blood sample drawn at the midpoint of the collection. For both specimens, sodium, lithium, and creatinine concentrations were determined and the respective clearances computed according to standard formulas. The average length of the collection was 210±7 minutes during the habitual diet and 226±3 minutes during the low sodium diet; urine volume was 276±20 mL during the habitual diet and 255±19 mL during the low sodium diet. Creatinine clearance, corrected for body surface area, was taken as an index of GFR. Since lithium physiochemically resembles the sodium ion and is almost exclusively reabsorbed at the proximal sites,¹⁵ exogenous lithium clearance (C_Li) was used as a measure of sodium rejection by the proximal tubule, following a procedure previously validated in our laboratory as well as others.^{16 17} GFR, C_Li, and the clearance of sodium (C_Na) were used for calculation of the following indexes of tubular sodium handling: (1) fractional sodium excretion (the percentage of filtered sodium that escapes reabsorption)=(C_Na/GFR)·100; (2) fractional lithium excretion (the percentage of filtered lithium that escapes reabsorption)=(C_Li/GFR)·100; (3) absolute proximal sodium reabsorption (the absolute amount of filtered sodium reabsorbed in the proximal convoluted tubule)=(GFR-C_Li)·serum Na⁺; (4) fractional proximal sodium reabsorption (the percentage of filtered sodium reabsorbed at proximal sites)=[(GFR-C_Li)/GFR]·100; (5) absolute distal sodium reabsorption (the amount of filtered sodium reabsorbed beyond the proximal convoluted tubule)=(C_Li-C_Na)·serum Na⁺; and (6) fractional distal sodium reabsorption (the percentage of sodium rejected by the proximal tubule that is reabsorbed at more distal sites)=[(C_Li-C_Na)/C_Li]·100.

Statistical evaluation was performed with correlation analysis, paired Student's t test, and one-way ANOVA with Duncan's test for multiple comparisons, as appropriate. All data are expressed as mean±SE.

	Results

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Effect of Low NaCl Diet in the Entire Population
Upon dietary NaCl restriction, 24-hour urinary sodium excretion, sodium fractional excretion, lithium fractional excretion, and BP significantly decreased and a trend toward reduced GFR was observed (Table 1). Both proximal and distal fractional sodium reabsorptions were significantly enhanced during the low sodium diet, whereas absolute distal sodium reabsorption was decreased. These results are consistent with the known effects of dietary sodium restriction on BP and renal sodium handling.

View this table: [in this window] [in a new window]   Table 1. Effect of Low NaCl Diet in the Entire Population

Renal Sodium Handling at Different Sodium Intakes as a Function of BP Response to NaCl Restriction
GFR and absolute proximal sodium reabsorption during the habitual diet were significantly and directly correlated with the percent mean BP decrease upon the shift from the habitual to the NaCl-restricted diet (r=.43, P<.01 and r=.37, P<.01, respectively), ie, the higher the individual salt sensitivity of BP, the higher the GFR and proximal sodium reabsorption during the habitual diet (Fig 1). No correlation was found between salt sensitivity and either GFR (r=-.04, P>.05) or absolute proximal sodium reabsorption (r=.02, P>.05) during the low sodium diet. The percent mean BP change elicited by NaCl restriction was also directly correlated with the concomitant change occurring in GFR (r=.33, P<.05) and inversely related to the change in absolute and fractional proximal sodium reabsorptions (r=-.37, P<.01 and r=-.38, P<.05, respectively).

View larger version (18K): [in this window] [in a new window]   Figure 1. Correlation between mean blood pressure (MBP) response to NaCl restriction and glomerular filtration rate (GFR, left; r=.43, P<.01) or absolute proximal sodium reabsorption (APRNa, right; r=.37, P<.01) in normotensive individuals on their habitual diet.

Since the BP changes after the change in NaCl intake were normally distributed (Kolmogorov-Smirnov=0.73, P>.05), we divided the study population into three groups by tertile of salt sensitivity: a low NaCl sensitivity group (LS; n=16; mean BP change, -3.9% or less), a moderate NaCl sensitivity group (MS; n=15; mean BP change, between -3.9% and -9.6%), and a high NaCl sensitivity group (HS; n=16; mean BP change, -9.7% or more). Table 2 summarizes the main findings concerning the indexes of renal sodium handling by tertile of BP response to NaCl restriction.

View this table: [in this window] [in a new window]   Table 2. Renal Sodium Handling at Different Sodium Intakes According to Salt Sensitivity

The three groups were comparable for family history of hypertension (LS=50%; MS=47%; and HS=50% of subjects having at least one hypertensive parent), body weight (LS=75.4±2.6 kg; MS=73.8±2.9; and HS=75.7±3.0), age (LS=43.8±2.0 years; MS=44.5±1.5; and HS=43.3±1.4), and 24-hour urinary sodium excretion during the habitual diet (Table 2). During dietary NaCl restriction, 24-hour urinary sodium excretion was reduced to the same extent in the three groups, indicating similar compliance to the prescribed diet. During the habitual diet, BP was significantly greater with greater salt sensitivity. A similar pattern was observed for GFR, which was significantly higher during the habitual diet in the third tertile of salt sensitivity (Fig 2). On the other hand, this same group displayed the greatest decrease in GFR during dietary NaCl restriction, so that during the low sodium regimen, GFR became similar in the three groups (Fig 2).

View larger version (23K): [in this window] [in a new window]   Figure 2. Glomerular filtration rate (GFR) during habitual and low NaCl diets in normotensive individuals with different salt sensitivity. Empty bars indicate low NaCl sensitivity group; shaded bars, moderate NaCl sensitivity group; and filled bars, high NaCl sensitivity group. One-way ANOVA: F=6.7; **P<.01 during habitual diet; F=0.75, P>.05 during low NaCl diet.

During the habitual diet, together with GFR, absolute proximal sodium reabsorption was significantly greater in the HS compared with the LS group. Furthermore, a trend was observed toward lower sodium and lithium fractional excretions with increasing salt sensitivity (Table 2). During the low NaCl diet, the absolute proximal reabsorption of sodium fell in the HS group only, together with the fall in GFR, so that no more differences were detectable in either GFR or absolute proximal sodium reabsorption across the three groups.

Absolute distal sodium reabsorption tended to decrease and fractional distal sodium reabsorption to increase upon the switch from the habitual to the low sodium diet in all groups (Table 2); nevertheless, these changes did not reach statistical significance, nor did they differ among groups.

	Discussion

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In this ancillary work of the Olivetti cardiovascular survey, we used a short-term protocol of dietary salt restriction to investigate the relationships between NaCl sensitivity of BP and some indexes of renal sodium handling in a group of middle-aged normotensive male volunteers. Renal sodium handling was evaluated before and after dietary intervention, and the data were analyzed as a function of the BP response to NaCl restriction. This response was normally distributed; thus, to avoid arbitrary definitions of salt sensitivity, we divided the study population a posteriori into three groups by tertile of BP response to salt restriction.

No differences in 24-hour urinary sodium excretion were observed during either dietary regimen among the three groups, suggesting that the heterogeneity of BP response was not due to differences in dietary compliance. The group showing the highest salt sensitivity (HS group) had the highest BP values, albeit in the normal BP range, during the habitual (sodium-rich) diet, in accordance with most studies dealing with salt sensitivity of BP.¹ The first of the two most important findings of the present study is that GFR and absolute proximal sodium reabsorption during the sodium-rich diet were both directly and significantly related to the BP response to salt restriction, ie, to the degree of salt sensitivity of BP. In particular, during the habitual high sodium diet, the group with the highest degree of salt sensitivity (HS group) had the highest values of both GFR and absolute proximal sodium reabsorption. The second important finding is that during the low NaCl diet, all of these parameters, including BP, GFR, and absolute proximal sodium reabsorption, no longer differed among the three groups.

Parmer et al¹¹ reported significant hyperfiltration in black hypertensive patients during a high sodium diet; the higher GFR was associated with increased renal plasma flow, but they did not investigate tubular sodium handling. Campese et al⁸ found increased intraglomerular pressure in black salt-sensitive hypertensive individuals. Furthermore, hyperfiltration was described in animal models of salt-sensitive hypertension (Dahl S rat) during a high sodium diet.¹⁸

Our study population was composed of individuals with BP in the normal range; this suggests that the association between NaCl sensitivity and altered renal function may be independent of long-standing high BP.

An important clinical implication of these findings is that a sizable number of healthy individuals, whose BP and renal function appear to be quite normal during low NaCl intake, undergo a significant increase in BP and GFR when consuming their habitual sodium-rich diet. It thus appears as if, during the high sodium diet, they were able to maintain sodium balance only at the expense of an increase in BP and GFR.

Of course, it is beyond the objectives and possibilities of the present study to elucidate the mechanisms whereby an elevated sodium intake could prompt the unfavorable hemodynamic changes found to be associated with salt sensitivity. Nevertheless, it is tempting to speculate that the higher rate of absolute proximal sodium reabsorption observed in the most salt-sensitive subjects during high sodium intake could be the expression of an inadequacy of the proximal tubular handling of sodium by this group of people. The trend toward enhanced sodium reabsorption could lead to an increase in extracellular fluid volume, as previously suggested in humans¹⁹ and in an animal model of salt-sensitive hypertension.²⁰ This in turn would elicit humoral adaptive responses that could eventually end in an increase in systemic BP and GFR, thus overcoming the difficulty in sodium excretion.^{21 22} This hypothesis is strengthened by the trend toward higher fractional, besides absolute, proximal reabsorption of sodium with increasing salt sensitivity, a trend that was observed in our study with the subjects on their habitual sodium-rich diet (Table 2). However, this trend did not reach statistical significance, possibly because of inherent limitations in the sensitivity of the clearance measurements and the relatively small sample size. Also in keeping with this hypothesis is the common observation of a suppressed renin-angiotensin-aldosterone system in salt-sensitive subjects,^{5 10 23} a compensatory response to the trend toward increased proximal tubular sodium reabsorption and extracellular fluid volume expansion.

Because in our work we measured BP on only one occasion during each of the two diets, the objection could be made that the greater GFR observed in salt-sensitive subjects on a high sodium diet could be merely the result of an occasionally higher BP value rather than a reflection of a stable trend toward increased BP. If this had been the case, however, the resulting greater filtered sodium load should have prompted a rise in the absolute and fractional excretions of sodium in salt-sensitive subjects. However, we observed quite the opposite phenomenon. It thus appears more logical to regard the tubular alteration as the primary defect and to assume that the higher BP levels found in salt-sensitive subjects on a high sodium diet reflect a substantial trend toward increased BP, even though within the range of so-called normal values.

It is also worth mentioning that in the Olivetti cross-sectional survey, which involved a large sample of untreated middle-aged men (N=568), a positive and statistically significant correlation was found between plasma triglyceride concentration and proximal tubular sodium handling estimated from the clearances of uric acid and exogenous lithium, as recently reported.²⁴ Although the participants in the present study were free of major metabolic abnormalities, significantly higher plasma triglyceride levels were indeed observed in the HS group compared with the other two groups (LS=1.25±0.11 mmol/L; MS=1.43±0.15; HS=1.69±0.20, P<.05). As hypertriglyceridemia is frequently an expression of hyperinsulinemia and insulin resistance,²⁵ our present findings should be considered in the light of previous data suggesting a possible association between salt sensitivity of BP and insulin resistance.^{26 27 28}

Hyperfiltration and increased intraglomerular pressure accelerate renal damage^{29 30} by promoting the accumulation of plasma proteins in the mesangium and stimulating mesangial cell and matrix proliferation. Notably, these events appear to be more common among salt-sensitive hypertensive subjects.^{31 32 33} According to Schmieder et al,³⁴ hyperfiltration should indeed be taken as an early predictor of target-organ damage. Therefore, we believe that the results of the present work argue for the need to plan further carefully designed studies to elucidate the actual contribution of salt sensitivity and excess dietary sodium intake to the progressive deterioration of renal function in many hypertensive patients.

	Acknowledgments

 
The authors thank Dr Antonio Scottone, chief of the medical staff of the Olivetti factory in Pozzuoli, and Maria Bartolomei, for in-site nursing assistance. They are also grateful to Rosanna Scala for her skillful editorial assistance in the preparation of the manuscript.

Received October 17, 1995; first decision November 9, 1995; accepted January 28, 1996.

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Barba, G. Articles by Strazzullo, P. Search for Related Content PubMed PubMed Citation Articles by Barba, G. Articles by Strazzullo, P.