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(Circulation. 1996;94:1629-1634.)
© 1996 American Heart Association, Inc.

Articles

Inverse Relation of Dietary Protein Markers With Blood Pressure

Findings for 10 020 Men and Women in the INTERSALT Study

J. Stamler, MD; P. Elliott, MB, PhD; H. Kesteloot, MD; R. Nichols, MS; G. Claeys, PhD; A.R. Dyer, PhD; R. Stamler, MA; for the INTERSALT Cooperative Research Group

the Department of Preventive Medicine (J.S., A.R.D., R.S.), Northwestern University Medical School, Chicago, Ill; Department of Epidemiology and Public Health (P.E., R.N.), Imperial College School of Medicine at St Mary's, London, England; and Department of Epidemiology (H.K., G.C.), School of Public Health, St Raphael University Hospital, Catholic University of Leuven, Belgium.

Correspondence to Jeremiah Stamler, MD, Department of Preventive Medicine; Northwestern University Medical School; 680 N Lake Shore Dr, Suite 1102; Chicago, IL 60611. E-mail hwe216@lulu.acns.nwu.edu.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background The purpose of this study was to assess relations to blood pressure (BP) in individuals of markers of dietary protein in their 24-hour urine collections.

Methods and Results INTERSALT (INTERnational study of SALT and blood pressure) was a cross-sectional study of 10 020 men and women aged 20 to 59 years in 52 population-based samples in 32 countries worldwide, with quality-controlled standardized procedures and assessment of multiple possible confounders. Three measurements of dietary protein in 24-hour urine of each individual participant were studied: total nitrogen and urea as indexes of total protein intake, and sulfate as an index of sulfur-containing dietary amino acids. Repeat examination was performed in a random 8% of participants to assess reliability and to correct for regression-dilution bias. Significant independent inverse relationships were found between BP (systolic and diastolic) and both 24-hour urinary total nitrogen and urea nitrogen, with adjustment for age, sex, alcohol intake, body mass, and 24-hour urinary sodium, potassium, calcium, and magnesium. With adjustment for regression-dilution bias, it was estimated that systolic and diastolic BP were on average 3.0 and 2.5 mm Hg lower, respectively, for persons with dietary total protein intake 30% above the overall mean than for those whose dietary protein intake was 30% below the overall mean (12.94 versus 6.96 g/d urinary total nitrogen, equivalent to 81 versus 44 g/d dietary protein, respectively). For the association of these markers with diastolic BP, results were similar for younger (20- to 39-year-old) and older (40- to 59-year-old) persons and for women and men. For their relation to systolic BP, regression coefficients were larger both for those aged 40 to 59 years than for those aged 20 to 39 years and for women than for men. Nonsignificant inverse relations were recorded for urinary sulfate and BP.

Conclusions These INTERSALT findings lend support to the hypothesis that higher dietary protein intake has favorable influences on BP.

Key Words: blood pressure • diet • proteins • population • epidemiology

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
This report deals with data on a long-standing unsolved problem: the relationship of dietary protein to BP. It brings to bear on this issue the final results from biochemical analyses of 24-hour urine collections in INTERSALT. These findings on urinary markers of dietary protein and BP are for 10 020 men and women aged 20 to 59 years from all 52 INTERSALT population samples in 32 countries worldwide.

INTERSALT is an epidemiological investigation of the relations of dietary and other factors to BP. Its analyses have focused on relations to BP of 24-hour sodium and potassium excretion, BMI, and alcohol consumption in the 10 079 participants in the study as well as their implications for medical care and public health.^{1 2 3 4 5} In individuals, urinary sodium excretion and the sodium/potassium ratio were directly and significantly related to BP, and potassium excretion was inversely related, with control for age, sex, and each of the other major variables. There was also a significant direct, independent relation of BMI and heavy alcohol use to BP.

With these INTERSALT results in hand in the late 1980s, it was then postulated that other nutritional factors, measurable with the INTERSALT data set, were related to BP of individuals, particularly dietary protein. The present study presents final INTERSALT findings on associations of BP with 24-hour urinary excretion of total nitrogen, urea nitrogen, and sulfate—all markers of dietary protein intake.^{6 7 8 9 10 11}

	Methods

Top Abstract Introduction Methods Results Discussion References

 
INTERSALT design and methods have been reported in detail.^{1 2 5 12} In brief, INTERSALT used a standardized protocol, with field methods and materials common to all 52 centers, centralized training, and certification of key local personnel. Each local center was asked to recruit, with informed consent, a representative sample of 200 men and women aged 20 to 59 years, stratified into eight equal sex-decade groups, from a defined population. Standardized methods have been published for assessment of BP, weight, height, alcohol intake, demographic and other possible confounding variables, and electrolytes (sodium, potassium, calcium, and magnesium) in a single, carefully timed 24-hour urine collection. Within-person variability was estimated from repeat urine collections obtained from a random 8% of participants.

Intake of total dietary protein was estimated centrally by 24-hour total urinary nitrogen and urea excretion, and intake of sulfur-containing amino acids in dietary protein was assessed by 24-hour urinary sulfate assayed chromatographically in an automated high-performance ion chromatograph (HPIC; Dionex 4000 i system). Urinary total nitrogen excretion is an established index of dietary total protein intake by healthy persons.^{6 7 8 9 10 11} Urinary total nitrogen and urea were both measured for methodological reasons: urea is determined simply and inexpensively, whereas the opposite is true for total nitrogen. Therefore, INTERSALT undertook to acquire detailed data on its >10 000 participants from 52 diverse population samples worldwide as to the scientific validity of using 24-hour urea rather than total nitrogen as a urinary marker of total protein intake.

Individual 24-hour analyte excretion was the product of analyte concentration in the urine and urinary volume corrected to 24 hours. Urinary urea (C₁H₄N₂O₁) was converted to urea nitrogen with the multiplier 0.4667 (two nitrogen molecular weight=28; urea molecular weight=60; 28/60=0.4667). To estimate the proportion of total nitrogen derived from ingested and metabolized sulfur-containing amino acids in dietary protein, the following calculations were performed: urinary 24-hour sulfate excretion was divided by 3 to obtain its sulfur content (molecular weight of sulfate=96; molecular weight of sulfur=32; 32/96=1/3). Urinary sulfur was then multiplied by 14/32 because the sulfur-containing amino acids (methionine, cysteine, and cystine) each contain one atom of nitrogen (molecular weight=14) and one atom of sulfur (molecular weight=32). Thus, the measured 24-hour sulfate excretion of each individual was multiplied by 0.1458 (1/3x14/32).

Statistical Analysis
Relations between urinary protein markers and BP of individuals were assessed by the same statistical methods used to evaluate relations of BP to sodium, potassium, sodium/potassium ratio, BMI, and alcohol.^{1 3 5} In brief, within-sample multiple regression coefficients of BP of individuals on their total nitrogen, urea nitrogen, and sulfate were computed, with adjustment first for age and sex, then adjustment for age, sex, BMI, alcohol intake, and 24-hour urinary sodium, potassium, calcium, and magnesium, because previous analyses showed each of these variables to be a possible confounder. For each of the urinary protein markers, the resultant within-sample regression coefficients were then averaged (pooled) to obtain overall estimates for individuals from all 52 samples. In this computation, the coefficient for each sample was weighted by the inverse of its variance. Data presented here include regression coefficients both without and with correction for attenuation of true coefficients because of misclassification of individual participants on the basis of a single 24-hour urinary collection (regressiondilution bias).^{1 3 5 13 14} Two-sided tests of significance are presented throughout. Standard errors and z scores for pooled coefficients adjusted for regression-dilution bias are approximations based on bootstrap estimates.¹⁴

	Results

Top Abstract Introduction Methods Results Discussion References

 
Percent technical errors of the laboratory measurements, based on ongoing external surveillance with blinded split samples (total number, 1020), were 3.2% for urinary total nitrogen, 5.3% for urea, and 3.7% for sulfate. Age- and sex-adjusted estimates of reliability¹³ of the three urinary markers of dietary protein, based on repeat 24-hour urine collections by 8% of participants, were 0.472 for total nitrogen, 0.460 for urea nitrogen, and, 0.455 for sulfate.

Descriptive Statistics: Means and Simple Correlations
Table 1 presents age and sex sample-adjusted mean values and SDs for the 10 020 individual INTERSALT participants for SBP and DBP; for the three urinary markers of dietary protein intake; for height, weight, BMI, and pulse; for age and education; and for 24-hour urinary sodium, potassium, calcium, and magnesium excretions. Data on alcohol intake are also presented.

View this table: [in this window] [in a new window]   Table 1. Descriptive Statistics for All 10 020 Individual Participants

Overall, 24-hour total nitrogen excretion averaged 9.95 g. For each sample, SDs were sizable, which indicates considerable interindividual variability. Urea nitrogen averaged 8.17 g. Mean urinary nitrogen derived from sulfur-containing amino acids in dietary protein was estimated to be 0.257 g, ie, on average 2.6% of 24-hour total nitrogen. This variable and urea nitrogen were highly correlated, with an age and sex sample-adjusted r=.886 for all 10 020 individuals.

Each of the three indexes of dietary protein intake was positively correlated with 24-hour urinary sodium, potassium, calcium, and magnesium (r=.41 to .52) and correlated with BMI (r=.26 to .27), weight (r=.32 to .33), and height (r=.16 to .17). With adjustment for age, sex, and BMI and in analyses for four age-sex groups, urinary total nitrogen, urea nitrogen, and sulfate remained positively correlated with sodium, potassium, calcium, and magnesium.

Relation Between 24-Hour Excretion of Total Nitrogen and Urea Nitrogen: Results of the Methodological Study
For all individuals, urea nitrogen made up on average 82% of total nitrogen. This proportion ranged from 70% to 92% across the 52 samples. For all participants and for those in most of the 52 samples considered separately, the SD for this ratio was small, ie, 5%, with a consequent coefficient of variation of 6%; for a few of the samples, it was larger, eg, the Kenya sample individuals, who had a coefficient of variation of 12%. Spearman's rank order correlation coefficients for 24-hour urinary total nitrogen and urea nitrogen were uniformly high; the average of these coefficients for the 52 samples was .985, .961 for those in the sample with the lowest correlation (People's Republic of China), .994 for those in the sample with the highest correlation (Belgium), .983 for men, .987 for women, .985 for persons aged 20 to 39 years, and .984 for persons aged 40 to 59 years.

Regression of SBP and DBP of Individuals on 24-Hour Urinary Excretion of Total Nitrogen, Urea Nitrogen, and Sulfate
Results for All 10 020 Participants
With adjustment for age and sex only, there was a positive relation between each of the dietary protein markers and both SBP and DBP (Table 2). With adjustment for age, sex, BMI, alcohol intake, and urinary sodium, potassium, calcium, and magnesium, these relations became inverse and were statistically significant for total nitrogen–SBP, urea nitrogen–SBP, total nitrogen–DBP, and urea nitrogen–DBP (P<.001 for coefficient not corrected for reliability). Repetition of the multiple linear regression analyses with addition of one confounder at a time showed that BMI was the key variable responsible for the shift from a direct to an inverse relation.

View this table: [in this window] [in a new window]   Table 2. Relations of 24-Hour Urinary Total Nitrogen, Urea Nitrogen, and Sulfate to SBP and DBP, INTERSALT Men and Women Aged 20 to 59 Years: Multiple Linear Regression Analyses

With adjustment for regression-dilution bias,^{13 14} the pooled regression coefficient was -0.495 mm Hg per gram of total nitrogen for SBP and -0.414 for DBP (Table 2). Thus, persons with 24-hour total nitrogen excretion higher by 5.970 g/d (eg, 12.935 compared with 6.965 g, 30% above and 30% below the overall mean of 9.95 g, respectively; Table 1) were estimated to have group mean SBP and DBP that were lower by 3.0 and 2.5 mm Hg, respectively (0.495x5.97 and 0.414x5.97). Similarly, on the basis of pooled regression coefficients of -0.570 and -0.494 mm Hg for SBP and DBP per gram of urea nitrogen, persons with an excretion of 10.62 g/d versus those with 5.72 g/d (again, 30% above and 30% below the overall mean of 8.17 g; Table 1) were estimated to have group mean SBP and DBP that were lower by 2.8 and 2.4 mm Hg, respectively.

Results for Older (40- to 59-Year-Old) and Younger (20- to 39-Year-Old) Persons
Particularly for the relations of total nitrogen and urea nitrogen to SBP, the inverse associations noted above were stronger for older than for younger persons. For SBP, the coefficient, adjusted for age, sex, BMI, alcohol, and 24-hour urinary sodium, potassium, calcium, and magnesium and adjusted for regression-dilution bias, was -0.924 mm Hg per gram of 24-hour urinary total nitrogen for persons aged 40 to 59 years (P<.01), whereas for persons aged 20 to 39 years, it was -0.196, about one fifth as large. Thus, with mean 24-hour urinary total nitrogen of 9.97 g, for persons aged 40 to 59 years with total nitrogen of 12.96 g/d compared with those at 6.98 g/d (30% higher and lower, respectively, than the group mean of 9.97 g/d), SBP was estimated to be lower by 5.5 mm Hg.

For DBP, the pooled regression coefficient was -0.484 mm Hg per gram of total nitrogen for persons aged 40 to 59 years (P<.05) and -0.376 for persons aged 20 to 39 years (P<.05). Thus, for those aged 40 to 59 years with 24-hour total excretion of 12.96 g/d versus those at 6.98 g/d, DBP was estimated to be lower by 2.9 mm Hg. For those aged 20 to 39 years with mean 24-hour urinary total nitrogen of 9.93 g/d, DBP was estimated to be 2.2 mm Hg lower for those at 12.91 g/d versus those at 6.95 g/d (again, 30% above and below the group mean, respectively).

Findings were qualitatively similar to the foregoing for corresponding age-specific, multivariate-adjusted linear regression analyses of SBP and DBP on urea nitrogen.

Results for Men and for Women
In multivariate-adjusted analyses of SBP regressed on total nitrogen and on urea nitrogen, coefficients were 2 to 4x larger for women than for men. For DBP regressed on these two urinary markers of total protein intake, regression coefficients were 1.2 to 1.3x larger for women than for men. With mean 24-hour urinary total nitrogen of 11.06 for men and 8.84 for women, for those with values 30% above compared with 30% below the mean, DBP was estimated to be lower on average by 2.9 mm Hg for men and 2.7 mm Hg for women.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The main findings from these INTERSALT analyses are the significant inverse associations that exist between BP of individual adults and their 24-hour urinary excretions of markers of dietary total protein. Both markers of total protein intake, total nitrogen and urea nitrogen output in 24-hour urine, were significantly related to SBP and DBP in multiple linear regression analyses adjusted for age, sex, BMI, alcohol intake, and 24-hour urinary excretions of sodium, potassium, calcium, and magnesium.

Detailed methodological assessment consistently showed that 24-hour urinary urea nitrogen and total nitrogen were very highly correlated in the analyses for the 52 population samples worldwide, including those for younger (20- to 39-year-old) and older (40- to 59-year-old) persons and for women and men. It is therefore a reasonable conclusion that 24-hour urea nitrogen, the less expensive and less complex measurement, can be used to measure dietary total protein intake of individuals in population studies rather than total nitrogen, hitherto a "gold standard."^{6 7 8 9 10 11}

In the 1990s, in part as a result of the stimulus provided by presentation of INTERSALT initial findings in 1991 and 1992, the relation between dietary protein and BP has been explored in other large samples. Findings have been summarized in a report for Circulation¹⁵ and have been reviewed in JAMA.¹⁶ The latter includes three tables that present results from human observational studies, trials, and animal experimentation. In brief, therefore, in addition to INTERSALT, eight other cross-sectional surveys of American and British adults found an inverse relation between dietary total protein and BP or prevalence of hypertension (one study); another study of Americans found an inverse relation of vegetable protein to BP; and three studies of Chinese or Japanese adults found an inverse relation of animal protein to BP. One study of monozygotic American twins reported a nonsignificant low-order inverse relation of total protein to BP for individuals but a significant direct association of intertwin differences in protein intake with their differences in DBP. A prospective study of middle-aged, employed American men found a relation of baseline vegetable protein to BP change; however, another prospective study of American young adults found no significant association of dietary protein (total, vegetable, or animal) to BP change. Thus, most of these results are broadly concordant with INTERSALT findings reported herein, but there are inconsistencies in regard to total versus animal versus vegetable protein as possible producers of lower BP and unresolved issues about possible confounding by other dietary variables (eg, fiber and/or magnesium). Data from the few trials and the limited animal-experimental studies leave unresolved the matter of a possible etiologically significant inverse relation of dietary protein, as well as specific amino acids, to BP.^{15 16}

Accordingly, comment is in order as to possible confounding of the protein-BP relation, which is not accounted for in the INTERSALT analyses. Because these analyses included age, sex, BMI, alcohol intake, and urinary sodium, potassium, calcium, and magnesium, these variables were controlled for as confounders. Another possibility, not amenable to assessment with the INTERSALT data because no dietary data were collected, is that the findings reported here were confounded by dietary lipids. Thus, in many (but not all) population samples, at least in Western countries, higher protein intake of individuals (% kcal) is associated with higher intake of total fat, saturated, monounsaturated, and polyunsaturated fatty acids (% kcal), and cholesterol (mg/1000 kcal) and lower intake of total carbohydrate and complex carbohydrate (% kcal) as well as fiber.¹⁷ However, with control for energy intake, correlations between protein and several of these other dietary variables are not large (eg, for the large cohort of men randomized into MRFIT, correlations with the cited neutral fats were in the range of r=.019 to .067).^{15 17} Furthermore, as recent reviews have noted, data from both observational and interventional studies are limited and inconsistent in regard to the effects of any of these dietary variables on BP.^{15 18} As MRFIT and other data indicate,¹⁵ the relation is direct, not inverse, for dietary lipids such as saturated fatty acids, cholesterol, the ratio of saturates to polyunsaturates, Keys score,¹⁹ and influence on BP. Therefore, any possible higher levels of intake of these lipids that accompany higher protein intake would tend to obscure an inverse relation of protein to BP, ie, they could not be confounders responsible for the observed protein-BP inverse association. Moreover, MRFIT data indicate persistence of a significant inverse relation of protein to BP with control for the cited macronutrients as well as BMI and intake of alcohol, caffeine, sodium, potassium, calcium, and other variables.¹⁵ Therefore, it does not seem likely that the INTERSALT findings of significant inverse relations of urinary markers of dietary protein to SBP and DBP are spurious, ie, attributable to unmeasured dietary confounders. However, additional data sets from other studies are needed on this matter.¹⁶

Given a tentative inference that the INTERSALT results reported in the present study and similar findings from other recent studies reflect an independent, etiologically significant, inverse relation between dietary protein and BP, two questions follow: First, is the level of intake of total dietary protein the critical factor, or do specific components of that intake influence BP? Second, what are the mechanisms of this effect? In regard to the first of these questions, available data leave the matter unresolved because they are inconsistent as to whether total protein, vegetable protein, or animal protein relates inversely to BP.^{15 16} Further work is needed to clarify and verify the independence and reproducibility of the relation. This is essential to resolve the etiologic issue definitively. Also, research is needed on the association of individual dietary amino acids (singly and in combination) with BP.

As to mechanisms whereby dietary protein influences BP, the possibilities are legion, and almost all are hypothetical at present.^{15 16} It has been known for years that an increase in protein intake induces increases in renal plasma flow, glomerular filtration rate, and sodium excretion in the short term and increases in renal size, renal plasma flow, and glomerular filtration rate over the long term. Several individual amino acids have been shown to be capable of stimulating these effects on the kidney.^{15 16} Furthermore, as recent work has shown, dietary protein and other macronutrients influence catecholamine metabolism.^{15 16 20 21} Also, there are possible implications for BP regulation of recent demonstrations that the amino acid L-arginine is the source in cells for nitric oxide and the amino acid cysteine influences nitric oxide metabolism.^{15 16 22 23} Other areas of current research include work on inotropic excitatory amino acid receptors^{24 25} and work on proteins that make up cellular ion (sodium, potassium, and calcium) channels,^{26 27 28 29} which are implicated in BP regulation. Hypotheses can be formulated readily that dietary protein and specific amino acids influence these pathways and thereby BP.

Finally, concerning possible practical implications if an etiologically significant inverse relation is established, as noted in "Results," for those individuals with 24-hour urinary excretion of total nitrogen 30% above the group mean compared with those 30% below the group mean, SBP and DBP were estimated to be lower on average by 3.0 and 2.5 mm Hg, respectively, with correction for regression-dilution bias. This is equivalent to 37 g more of ingested dietary protein per day.¹⁰ As previously documented,^{3 4 5} a shift downward in population BP of this size, over and above reductions from prevention and control of adverse levels of body mass, alcohol and salt intake, and dietary sodium/potassium ratio,^{1 2 3 4 5 30 31} can be expected to lead to meaningful declines in age-specific rates of incidence and mortality from coronary heart disease, stroke, and cardiovascular diseases for adults and in mortality from all causes. Hence, further work to verify the findings presented here and their etiologic import would relate significantly to public policy on prevention and control of high BP and achievement of optimal BP levels throughout the population.^{15 16 30 31 32} This is particularly so given that current nutritional recommendations for prevention and control of the major adult cardiovascular and other chronic diseases do not include any reference to the possible value of increased protein intake.^{10 33 34}

	Selected Abbreviations and Acronyms

 

BMI = body mass index BP = blood pressure DBP = diastolic blood pressure INTERSALT = INTERnational study of SALT and blood pressure SBP = systolic blood pressure

	Acknowledgments

 
The INTERSALT Study was launched under the auspices of the Council on Epidemiology and Prevention of the International Society and Federation of Cardiology. The work was supported by grants from the National Heart, Lung, and Blood Institute (United States); the Wellcome Trust (United Kingdom); the International Society of Hypertension; the World Health Organization; the Heart Foundations of Canada, Great Britain, Japan, and The Netherlands; the Chicago Health Research Foundation; the FWGO-FMRS (Belgian National Research Foundation); the ASLK-CGER (Parastatal Insurance Co, Brussels); and grants in most of the 32 countries to the Principal Investigators responsible for the surveys of the 52 population samples. It is a pleasure to acknowledge the fine contributions of the leadership and staffs of the 52 INTERSALT field research groups, as well as those of the staffs of the Central Laboratory and the two Coordinating Centers. Listings of those individuals are published in the British Medical Journal (See Reference 1) and in the Journal of Human Hypertension (See Reference 2).

	Footnotes

 
Initial data from this study were presented at the 64th Scientific Sessions of the American Heart Association, Anaheim, Calif, November 11-14, 1991, and at the 14th Scientific Meeting of the International Society of Hypertension, Madrid, Spain, June 1992, and published in abstract form (Circulation. 1991;84[suppl II]:II-698).

Received April 16, 1996; revision received June 17, 1996; accepted June 20, 1996.

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