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(Hypertension. 1995;25:1339-1344.)
© 1995 American Heart Association, Inc.

Articles

Salt-Induced Increases in Systolic Blood Pressure Affect Renal Hemodynamics and Proteinuria

Matthew R. Weir; Donald R. Dengel; M. Theresa Behrens; Andrew P. Goldberg

From the Division of Nephrology and Clinical Research Unit, Division of Gerontology, Geriatrics Service and Geriatric Research, Education and Clinical Center, Department of Medicine, University of Maryland School of Medicine and Baltimore VA Medical Center, Baltimore, Md.

	Abstract

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Abstract Nine white and 13 black hypertensive patients with normal serum creatinine were randomized to receive either 2 weeks of a low-salt (40 mEq Na⁺/d) or high-salt (200 mEq Na⁺/d) diet followed by 2 weeks of the other diet separated by a 1-week washout on their regular diet. The entire study was conducted in an outpatient setting with intensive dietary instruction and monitoring of blood pressure and 24-hour collections of urine for analysis. Urine electrolyte measurement showed that the patients were able to achieve only a modestly reduced (100±14 mEq Na⁺/24 h [mean±SEM]) low-salt diet as outpatients, while the higher-salt diet (236±22 mEq Na⁺/24 h) was more easily achieved. Eleven patients (8 black, 3 white) were classified as modestly salt sensitive on the basis of an increase or decrease in mean arterial pressure of 3 mm Hg going from lower- to high- or high- to lower-salt diets, respectively. In the salt-sensitive patients, the increase in dietary salt intake increased glomerular filtration rate by 29% (71.2±6.6 to 85.8±7.3 mL · min^-1 · 1.73 m², P=.05), with no significant change in renal plasma flow (412.7±36.4 to 399.6±27.8 mL · min^-1 · 1.73 m²). There were no changes in these parameters in the salt-resistant patients. Increased dietary salt intake in the salt-sensitive patients was associated with a 15% increase in glomerular filtration fraction (0.18±0.02 to 0.22±0.01, P=.09), whereas in the salt-resistant group, glomerular filtration fraction did not change (0.16±0.01 to 0.17±0.02, P=.47). Greater dietary salt intake also resulted in an increase in 24-hour urine protein excretion in the salt-sensitive population (74.0±8.3 to 139.0±31.3 mg/24 h), while there was no significant change in the salt-resistant population (115.5±16.6 to 86.4±14.3 mg/24 h, P=.03 versus salt sensitive). The salt-induced increase in proteinuria was related to the increase in systolic blood pressure on the high-salt diet (r=.54, P=.04). These studies demonstrate that in the presence of modest salt sensitivity (mean arterial pressure increase 3 mm Hg), an increase in systolic blood pressure is predictive of potentially adverse renal hemodynamic responses to higher dietary salt in essential hypertensive patients. Consequently, modest salt restriction may reduce the risk for acute changes in renal hemodynamics in salt-sensitive patients, which may be important for long-term protection and prevention of deterioration of renal function.

Key Words: blood pressure • hypertension, salt-dependent • salt • kidney • proteinuria

	Introduction

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Patients with essential hypertension exhibit varied blood pressure responses to dietary salt intake.^{1 2 3 4 5 6 7 8} Investigators classify patients as being salt sensitive or salt resistant on the basis of absolute changes in mean arterial pressure (MAP).^{5 6 7 8 9 10 11} Some investigators choose an arbitrary value of a 5 to 10 mm Hg increase in MAP in response to a 10-fold increase in dietary salt.^{5 6 7 8 9 10 11} Most of these investigators either have admitted patients to inpatient clinical research centers or have provided all meals to patients in an ambulatory setting during these studies; however, these methods are not applicable in clinical medicine settings. Usually 20 mEq Na⁺/d on the low-salt diet is followed by 200 mEq Na⁺/d or more on the high-salt diet. Using these techniques, investigators have demonstrated important abnormalities in renal hemodynamics and carbohydrate and lipid metabolism during high dietary salt intake in salt-sensitive patients.^{9 10 11}

The practicality of using these observations for diagnostic purposes in the outpatient setting is not known. The study was designed to examine, in an outpatient setting and using only dietary outpatient instruction, the effects of modestly restricted and high dietary salt recommendations on blood pressure, renal hemodynamics, and proteinuria in hypertensive patients classified by their salt-sensitive or -resistant status responses.

	Methods

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Subjects
Patients were eligible for the study if, during a 4-week lead-in period of placebo medication, their diastolic blood pressure (DBP) was 95 and 114 mm Hg. Patients were excluded from the study if they had clinically significant concurrent medical conditions such as cardiac, renal (creatinine >135 mmol/L), hepatic, or gastrointestinal illnesses or diabetes (fasting glucose >7.8 mmol/L or 2-hour glucose after 75-g glucose tolerance test >11.1 mmol/L). Also excluded were patients with a recent history of smoking or drug or alcohol abuse or clinically relevant mental disorders and use of concomitant medications that might interfere with blood pressure or renal function within 4 weeks before entering this study. These medications included monoaminoxidase inhibitors, antiarrhythmic drugs, digitalis, sedative hypnotics, minor tranquilizers, psychotropic drugs, or nonsteroidal anti-inflammatory drugs. All patients signed an informed consent as approved by the Institutional Review Board of the University of Maryland School of Medicine.

Experimental Design
A single-blind, crossover study was designed to evaluate the influence of dietary salt on blood pressure, renal hemodynamics, and proteinuria in patients with normal renal function and mild-to-moderate essential hypertension (Fig 1). During the 4-week placebo lead-in phase, patients were maintained on a normal diet and discontinued any prior therapy with antihypertensive medication. Patients with qualifying hypertension (sitting DBP between 95 and 114 mm Hg on two consecutive visits) continued into the second phase and were randomized to either a low-salt (40 mEq Na⁺/d) or high-salt (200 mEq Na⁺/d) diet plus placebo for 2 weeks. We purposely prescribed a lower-salt diet than we expected the patients to comply with in the expectation that they would ingest a diet containing 3 g Na⁺, which is in line with the American Heart Association step I recommendations. All patients were instructed to follow a low-salt diet prescribed by a registered dietitian throughout the study; patients on the high-salt diet were given an additional 160 mEq Na⁺/d in the form of sodium chloride tablets. Those on the low-salt diet received placebo tablets. No attempt was made to alter either dietary calcium or potassium. Patients were classified as salt sensitive on the basis of a modest increase or decrease in MAP [diastolic+0.33(systolic-diastolic)] of 3 mm Hg going from low-salt to higher-salt diet or from high-salt to lower-salt diet, respectively. Compliance was assessed during weekly dietary reviews with a dietitian, weekly pill counts, and five 24-hour urinary sodium analyses to determine dietary salt compliance by measurement of urinary sodium, creatinine, and protein. After 2 weeks of either high- or lower-salt diet, patients were crossed over to the other salt diet for a period of 2 weeks.

View larger version (18K): [in this window] [in a new window]   Figure 1. Diagram showing experimental design of the study. Numbers refer to weeks.

Study Procedures
Study procedures included medical history, physical examination (weekly), 12-lead electrocardiogram (beginning and end of study), chest radiograph, clinical laboratory evaluation (beginning and end of the study), and blood pressure and pulse rate measurements (weekly). Blood pressure was measured in the morning by the same nurse-clinician throughout the study by mercury sphygmomanometer in the same arm in the sitting position, with three consecutive blood pressure measurements taken at no less than 30-second intervals. The recorded blood pressure was the average of the three measurements. Korotkoff sounds I and V were used to record systolic blood pressure (SBP) and DBP, respectively. Glomerular filtration rate (GFR) (^99mTc-DTPA), renal plasma flow (RPF) (¹³¹I-hippuran serum disappearance), and filtration fraction (GFR/RPF) were performed at baseline (after placebo lead-in) and at the conclusion of each 2-week dietary intervention.

Analytical Methods
GFR and effective RPF were measured after an overnight fast, as follows. One hour before the study, the patients consumed an oral water load of 10 to 15 mL/kg body wt to establish a brisk urine flow. An intravenous bolus injection of 100 µCi of ^99mTc-DTPA was then given, and after a 60-minute wait, the patients voided, blood samples were drawn, and three timed sequential 1-hour urine collections were obtained, after which additional blood samples were drawn.¹² The ^99mTc-DTPA activity in the samples was determined by liquid scintillation counting. Urinary clearances of ^99mTc-DTPA were calculated for each 1-hour collection period as urine activity times urine flow rate divided by average plasma activity. Average plasma activity was calculated as the mean of the plasma values over the interval from the beginning to the end of each urinary collection. The GFR was expressed as the average of the three 1-hour collection values. RPF was determined by measuring the disappearance from serum of 60 µCi of ¹³¹I-hippuran at precisely 44 minutes after injection, as previously described.¹³

Statistical Analyses
Data were analyzed with standard statistics software packages (STATVIEW, Abacus Concepts). ANOVA was used to determine differences in baseline or final values between study groups and to determine the significance of absolute changes between study groups. Significance of changes between low-salt and high-salt diets within groups was determined by paired t tests. The relationships (correlation coefficients) between salt-related changes in proteinuria and changes in SBP and DBP were determined by Pearson product moment linear regression analysis. Statistical significance was set as P<.05. All results are expressed as mean±SEM.

	Results

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Twenty-two patients (14 men, 8 women; 13 black, 9 white) with essential hypertension and normal renal function as determined by serum creatinine concentration (99±1.8 mmol/L) were included in this study (Table 1). Eleven patients were classified as being salt sensitive and 11 as salt resistant based on a 3 mm Hg increase or decrease in MAP during low- to higher- or high- to lower-salt diets, respectively. There were no significant differences in age, race, sex, body mass index, or baseline (pre–diet intervention) blood pressures (Table 1). The known duration of hypertension averaged 10.1 years and did not differ between the two groups.

View this table: [in this window] [in a new window]   Table 1. Study Population

The salt-sensitive patients had a mean 6.8 mm Hg increase in DBP (P=.012), 8.7 mm Hg increase in SBP (P=.003), and 7.4 mm Hg increase in MAP (P=.001) in response to higher dietary salt (Fig 2). In contrast, the blood pressure of salt-resistant patients declined or did not change: DBP (-4.1 mm Hg, P=.008), SBP (-4.3 mm Hg, P=.34), and MAP (-3.8 mm Hg, P=.01) in response to higher salt intake. The differences in the changes in DBP, SBP, and MAP in response to dietary salt between the two groups were significant (DBP, P=.0003; SBP, P=.01; MAP, P=.0001) (Fig 2).

View larger version (21K): [in this window] [in a new window]   Figure 2. Bar graph showing changes (mean±SEM) in diastolic (DBP), systolic (SBP), and mean arterial (MAP) pressures (mm Hg) in response to increasing dietary salt in salt-sensitive (hatched bars) and salt-resistant (open bars) patients.

The changes in renal hemodynamics and proteinuria in response to changes in dietary salt intake are depicted in Table 2. There was an increase in the GFR of the salt-sensitive patients (+14.6±6.5 mL · min^-1 · 1.73 m², P<.05) in response to higher dietary salt intake, but there was no change in GFR in the salt-resistant group (-4.6±6.1 mL · min^-1 · 1.73 m², P=NS). On the other hand, there were no significant changes in RPF (P=NS) in either the salt-sensitive (-13.0±31.1 mL · min^-1 · 1.73 m²) or salt-resistant (-28.8±25.4 mL · min^-1 · 1.73 m²) group in response to higher dietary salt intake. The net result of the increase in GFR with no change in RPF (Fig 3) was a 15% increase in glomerular filtration fraction in the patients in the salt-sensitive group (0.18±0.02 to 0.22±0.01, P=.09), which approached statistical significance, but no change in the filtration fraction in the salt-resistant group (0.16±0.01 to 0.17±0.02, P=NS). There was a 69% increase in urinary protein excretion in the salt-sensitive patients (+60.5±24.2 mg/24 h, P=.01) in response to greater salt intake but no change in the salt-resistant patients (-23.9±10.6 mg/24 h, P=NS). The salt-induced difference in protein excretion was statistically significant between the two groups (P<.03). The salt-induced changes in urinary protein correlated directly with changes in SBP (r=.54, P=.04), but there was no correlation between changes in proteinuria with DBP (r=.34, P=.21) (Fig 4).

View this table: [in this window] [in a new window]   Table 2. Changes in Renal Hemodynamics in Response to Alterations of Dietary Salt Intake

View larger version (27K): [in this window] [in a new window]   Figure 3. Graphs showing individual data points for corrected glomerular filtration rate (left) and corrected renal plasma flow (right) for each patient (salt sensitive, ; salt resistant, ) on low- and higher-salt diets.

View larger version (14K): [in this window] [in a new window]   Figure 4. Scatterplots showing correlation between dietary salt–mediated increase in systolic and diastolic blood pressures with change in proteinuria (systolic, r=.54, P=.04; diastolic, r=.34, P=.21).

	Discussion

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The results of this outpatient clinical trial demonstrate that even modest changes in dietary salt (going from 100 to 200 mEq Na⁺/d) can have a significant influence on renal hemodynamics and proteinuria in patients with essential hypertension who are mildly salt sensitive. Moreover, the increased proteinuria observed with increased dietary salt directly correlated with an increase in SBP but not DBP. SBP has recently been recognized as a significant risk factor for cardiovascular disease,¹⁴ as well as for hypertensive renal injury.¹⁵

These observations are consistent with results of studies in a highly controlled inpatient setting with strict dietary provision of salt (low-salt diet, 20 mEq Na⁺/d; high-salt diet, 200 to 250 mEq Na⁺/d), which demonstrate that increasing dietary salt in salt-sensitive patients leads to an increase in glomerular filtration fraction and increasing proteinuria.^{10 11} In those studies, salt sensitivity was defined as an increase in MAP of 10 mm Hg in response to higher dietary salt intake; however, we observed the same renal physiological responses using a more modest cutoff point of 3 mm Hg MAP increase in response to greater dietary salt intake. Furthermore, there was a significant correlation between the salt-induced increase in proteinuria with the change in systolic blood pressure, a relationship never before reported.

The salt-sensitive patients in this study demonstrated significant renal hemodynamic changes in response to only a twofold increase in dietary salt, which is an increase of much smaller magnitude compared with the 10-fold increase in studies by Campese et al¹⁰ and Bigazzi et al.¹¹ Thus, in an ambulatory setting, these results show that even with a twofold increase in dietary salt in modestly salt-sensitive patients, there is a potentially detrimental influence on renal function that occurs parallel to the rise in SBP. This is relevant clinically when one considers that the typical American diet usually contains about 150 mEq Na⁺/d.¹⁶

An increase in glomerular filtration fraction and urinary protein excretion in mildly salt-sensitive patients in response to a relatively small increase in dietary salt could be indicative of a potentially heightened risk for the development of renal dysfunction. Elevated glomerular filtration fraction could reflect hyperfiltration and increased glomerular capillary pressure, conditions identified as risk factors for the development of glomerulosclerosis in experimental models of renal disease and diabetes mellitus.¹⁷ This scenario occurred in studies in which increasing glomerular hyperfiltration in nondiabetic experimental models of renal disease in response to greater dietary salt intake increased disease progression,^{18 19 20} whereas decreasing dietary salt corrected glomerular hyperfiltration in another experimental hypertensive rat model.²¹

The mechanism for the increase in glomerular filtration fraction observed in salt-sensitive patients with higher dietary salt is not well understood. It could be a result of a salt-mediated increase in efferent glomerular arteriolar resistance through primary or secondary activation of a neuroendocrine system,^{22 23} such as the renin-angiotensin system, or the sympathetic nervous system, or a relative deficiency of an endogenous renal dilator such as insulin, dopamine,²⁴ kallikrein,²⁵ or nitric oxide²⁶ ; or it could be the result of inadequate autoregulation of afferent glomerular arteriolar resistance in response to higher systemic arterial pressure. These alterations in glomerular hemodynamics may perpetuate salt sensitivity by increasing renal tubular sodium reabsorption through a salt-induced rise in peritubular colloid osmotic pressure and a reduction in peritubular hydrostatic pressure.²⁷

There is experimental evidence that inbred strains of rats that are both genetically predisposed to developing hypertension and also salt sensitive are at greater risk for renal injury.^{28 29} The spontaneously hypertensive rat (SHR) responds to increasing blood pressure with an increase in preglomerular resistance, thereby avoiding glomerular capillary hypertension.²² In the Dahl salt-sensitive rat, dietary sodium–mediated increases in blood pressure are not associated with an increase in preglomerular resistance. These adaptations in renal hemodynamics could explain why the Dahl salt-sensitive rat is more susceptible to the development of proteinuria and glomerulosclerosis than the SHR model.²⁸ It is possible that similar changes might also occur in salt-sensitive humans.

To support these theories, Parmer et al³⁰ reported significant racial differences in GFR and its autoregulation in response to dietary salt alterations. Fifty-nine white and 22 black age- and blood pressure–matched hypertensive men were studied on a metabolic ward with low-salt (approximately 40 mEq Na⁺/d) and higher-salt (approximately 160 mEq Na⁺/d) diets. The MAP increased by 6 to 7 mm Hg in response to higher-salt diet in both racial groups. However, the black patients consistently exhibited greater GFR increases in response to greater dietary salt than the white patients. The parallel increase in GFR and RPF, coupled with decreased renal vascular resistance, was consistent with afferent arteriolar vasodilation. These investigators theorized that these salt-induced changes in renal hemodynamics could predispose to renal injury. In contrast to their observations, the results of our study and the study of Bigazzi et al¹¹ suggest that salt sensitivity, independent of race, is associated with salt-induced adverse changes in renal hemodynamics. We cannot explain these disparate observations.

Thus, our results provide additional evidence that even small increases in dietary salt may have potentially detrimental effects on glomerular hemodynamics and proteinuria in salt-sensitive hypertensive patients. The corollary to this observation is that modest salt restriction may be helpful by reducing the risk for adverse renal hemodynamic changes in these patients. The ability to detect subtle changes in systemic arterial pressure and urinary protein excretion in an outpatient setting in response to modest changes in dietary salt may be useful for screening patients at high risk for renal and cardiovascular complications. This may be particularly relevant in the elderly, diabetic, obese, and hypertensive patients of African-American descent who have a high prevalence of salt sensitivity.^{31 32 33 34} Our ability to demonstrate these pathophysiological relationships in an outpatient setting enhances the clinical importance and potential utility of these observations in clinical practice.

	Acknowledgments

 
This work was supported by an educational grant by Sandoz Research Institute, Inc, E Hanover, NJ (Dr Weir), an American Heart Association Grant-in-Aid, Maryland Affiliate (Dr Weir), a grant from the Fraternal Order of Eagles, Maryland (Dr Weir), National Institutes of Health National Research Service Award grant KO1 AG000655-01 (Dr Dengel), and Baltimore VA Geriatric Research, Education and Clinical Center support from the Department of Veterans Affairs (Dr Goldberg). We wish to thank Pamela Sue Hall, RN, MS, for her dedicated efforts in patient care and the conduct of research tests and Karyl Fleck and Rosemaria Jackson for their dedicated and expert secretarial assistance.

	Footnotes

 
Reprint requests to Matthew R. Weir, MD, Nephrology Division, University of Maryland Hospital, 22 S Greene St, Baltimore, MD 21201.

Received September 23, 1994; first decision November 7, 1994; accepted January 24, 1995.

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