3

Sodium Intake and Intermediate Markers for Health Outcomes

BACKGROUND

In its statement of task, the committee was asked to review evidence for associations between dietary sodium and health outcomes published in the peer-reviewed literature since the last update of the report Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate (IOM, 2005). This chapter first summarizes evidence and findings on sodium intake and intermediate markers for health outcomes reviewed in that report (IOM, 2005) and the 2010 report of the Dietary Guidelines Advisory Committee (DGAC) (HHS and USDA, 2010), then summarizes corresponding evidence published subsequently (from 2003 through 2012). This summary of new evidence is an overview of representative studies and includes only indicators or biomarkers of health outcomes and not clinical outcomes, which are reviewed in the next chapter. The evidence was considered by the committee to provide additional support for its findings and conclusions about associations between sodium intake and health outcomes; it was not used as a primary source of evidence.

Use of Biomarkers as Indicators of Health Outcomes

Biomarkers, as defined by the Biomarkers Definitions Working Group (Atkinson et al., 2001), are “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a[n] … intervention.” Applications of biomarkers include indicators of clinical endpoints (for example,



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3 Sodium Intake and Intermediate Markers for Health Outcomes BACKGROUND In its statement of task, the committee was asked to review evidence for associations between dietary sodium and health outcomes published in the peer-reviewed literature since the last update of the report Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate (IOM, 2005). This chapter first summarizes evidence and findings on sodium intake and intermediate markers for health outcomes reviewed in that report (IOM, 2005) and the 2010 report of the Dietary Guidelines Advisory Committee (DGAC) (HHS and USDA, 2010), then summarizes corresponding evidence published subsequently (from 2003 through 2012). This summary of new evidence is an overview of representative studies and includes only indica- tors or biomarkers of health outcomes and not clinical outcomes, which are reviewed in the next chapter. The evidence was considered by the com- mittee to provide additional support for its findings and conclusions about associations between sodium intake and health outcomes; it was not used as a primary source of evidence. Use of Biomarkers as Indicators of Health Outcomes Biomarkers, as defined by the Biomarkers Definitions Working Group (Atkinson et al., 2001), are “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a[n] . . . intervention.” Applica- tions of biomarkers include indicators of clinical endpoints (for example, 39

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40 SODIUM INTAKE IN POPULATIONS in clinical trials) that denote how a study participant feels, functions, or survives; or in clinical practice, for example in risk stratification, disease prevention, screening, diagnosis, and monitoring. In public health practice, biomarkers serve as a means to track health status and for making recom- mendations for preventing, mitigating, and treating diseases or conditions at the population level (IOM, 2010). A related concept used in public health is the surrogate endpoint. The Institute of Medicine (IOM) Committee on Qualification of Biomarkers and Surrogate Endpoints in Chronic Disease defined surrogate endpoint as “a biomarker that is intended to substitute for a clinical endpoint. A surrogate endpoint is expected to predict clinical benefit (or harm, or lack of benefit or harm) based on epidemiologic, thera- peutic, pathophysiologic, or other scientific evidence” (IOM, 2010, p. 23). This committee further identified blood pressure as “an exemplar surrogate endpoint for cardiovascular mortality and morbidity due to the levels and types of evidence that support its use” (IOM, 2010, p. 39). Although biomarkers have wide utility in research, clinical practice, and public health, the biological complexity and variation among indi- viduals is important to consider as potential sources of error in assessing the link between biomarkers and health outcomes. Further, and of critical importance, with the exception of blood pressure and HIV-1RNA (IOM, 2010), biomarkers predict clinical outcomes but are not necessarily directly correlated with them. Indeed, there are situations where treatment recom- mendations based on biomarkers have led to patient harm, once outcome studies were finally performed. For these reasons, the committee reviewed evidence from its literature search on a range of intermediate markers for health outcomes but did not include these studies in its assessment of rel- evant research in response to the task. Given the limitations associated with most biomarkers as indicators of risk of adverse health outcome, as discussed in the Dietary Reference Intake (DRI) report (IOM, 2005), the DGAC (HHS and USDA, 2010) report, and the report on biomarkers and surrogate endpoints (IOM, 2010), blood pressure is widely recognized as a strong surrogate indicator for primary cardiovascular disease (CVD) clinical endpoints, such as myocardial infarc- tion (MI) and stroke. The committee considered the strength of the evidence for blood pressure as a surrogate endpoint for risk of CVD and stroke and this evidence underpinned its assessment of new evidence on health outcomes. The committee summarizes new evidence for blood pressure as an indirect indicator of risk of CVD in this chapter, but does not include its assessment of this indicator in its comprehensive evidence review and analysis of sodium intake and direct health outcomes in Chapter 4.

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INTERMEDIATE MARKERS FOR HEALTH OUTCOMES 41 BLOOD PRESSURE AS A BIOMARKER FOR CARDIOVASCULAR DISEASE Salt Sensitivity Evidence presented to the committee in its data-gathering workshop (see Appendix C) and reviewed in IOM (2005) reinforces that reduc- ing sodium intake can have widely varying effects among individuals. Nevertheless, the term “salt sensitive” has been used to describe those who experience the greatest reduction in blood pressure in response to decreased sodium intake. Conversely, “salt-resistant” individuals experi- ence little change in blood pressure, even with dramatic changes in sodium intake (Weinberger, 1996). Interindividual heterogeneity in blood pressure in response to dietary sodium is described in IOM (2005, pp. 286-291), and includes findings from Obarzanek and colleagues (2003). This study exam- ined blood pressure differences between two points: when sodium intake was similar and when sodium intake was decreased. A wide statistically normal distribution in measured blood pressure was seen among individu- als at both intake levels. The standard deviation of the distribution change, however, was similar for both distributions, suggesting that the variability in blood pressure responses to reduced sodium intake likely occurred in response to factors unrelated to sodium intake. Biological variation in the physiological response to dietary sodium, mediated through the renin- angiotensin-aldosterone system (RAAS), has been postulated as a possible mechanism (Chamarthi et al., 2010). Genetic Variation and Salt Sensitivity Evidence examining a relationship between genetic variations and salt sensitivity and risk of high blood pressure suggests that such variations may be specific to certain population subgroups. Beeks et al. (2004) conducted a systematic review of reports across population groups on genetic factors associated with salt sensitivity. The review identified several candidate polymorphisms from among the studies reviewed. However, due to meth- odological differences, variations in the way salt sensitivity was defined, and a limited number of studies examining a given polymorphism, definitive conclusions could not be drawn. Other studies examining polymorphisms within specific population subgroups have identified genetic variants associ- ated with racial/ethnic groups and risk of high blood pressure or hyperten- sion, as illustrated in the following studies. These studies also show that multiple pathways are involved in blood pressure response to expression of gene variants. Miyaki et al. (2005) used a food frequency questionnaire to estimate

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42 SODIUM INTAKE IN POPULATIONS salt intake and genotyping for polymorphisms in the endothelial nitric oxide synthase (eNOS) gene, implicated in coronary artery disease and MI, to examine risk for hypertension in 281 healthy Japanese men. This study identified a specific mutation in the eNOS gene that, with a high-salt diet, was associated with a significant increase in blood pressure among affected men. Zhang et al. (2010), in a small (n=329) cross-sectional study, identified the presence of cytochrome P450 3A polymorphisms in a group of Japanese adults. Blood pressure response to sodium intake, estimated by spot analy- sis of 24-hour urinary sodium excretion, was found to be associated with the frequency of expression of two allelic variants: a heterozygous modifier of blood pressure, and a homozygous variant in carriers that resulted in greater sensitivity to salt intake compared to noncarriers. A small intervention study in 39 healthy adults in Sweden examined the influence of genetic variants in RAAS following a protocol of 4 weeks on a high-salt intake followed by 4 weeks on a low-salt intake (Dahlberg et al., 2007). Blood pressure measurements and 24-hour sodium excretions, taken at baseline and at the end of each dietary intervention, suggested enhanced salt sensitivity in normotensive participants carrying two variants of a gene associated with monogenic hypertension. Kelly et al. (2009) and Gu et al. (2010) examined data from GenSalt, a large (n=1,906) 14-day intervention study carried out in rural China between 2003 and 2005, to identify gene variants that function in blood pressure regulation associated with salt sensitivity in a population consum- ing high levels of salt. Study participants consumed a low-sodium (3,000 mg per day) diet for the first 7 days, followed by a high-sodium (18,000 mg per day) diet for 7 days. Three timed urinary specimens were collected, one at baseline, then at the end of each intervention phase. Blood pressure mea- sures were taken and genotyping for genetic polymorphisms was conducted for each participant. Kelly et al. (2009) identified two variants, one in the alpha-adducin gene and one in the guanine nucleotide binding protein beta polypeptide 3 genes. Gu et al. (2010) identified three novel variants from 11 RAAS candidate genes that were significantly associated with blood pressure response to salt intake. Another GenSalt study (Zhao et al., 2010) identified genetic variants in the angiotensin-converting enzyme 2 (ACE-2), a regulator of RAAS and the apelin receptor (a substrate of ACE-2), which were associated with blood pressure response to salt intake. Together, these studies illustrate that a number of genetic variants are associated with salt sensitivity and susceptibility to high blood pressure associated with sodium intake, particularly among certain population sub- groups. Additionally, individuals not seen to be at risk of hypertension may carry genetic polymorphisms that render them salt sensitive.

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INTERMEDIATE MARKERS FOR HEALTH OUTCOMES 43 EVIDENCE ASSOCIATING SODIUM INTAKE WITH BLOOD PRESSURE Reports on Associations Between Sodium Intake and Blood Pressure When it examined possible adverse effects of sodium overconsumption, the Panel on Dietary Reference Intakes for Electrolytes and Water (IOM, 2005) reviewed evidence on cardiovascular outcomes (stroke, coronary heart disease, left ventricular hypertrophy) and kidney disease and their associations with increased blood pressure. Evidence reviewed by the panel from meta-analyses of observational studies and clinical trials provided strong support for a link between high blood pressure and risk of CVD. Additional evidence from intervention studies consistently supported a dose-response relationship between dietary sodium intake and blood pres- sure in both normotensive and hypertensive individuals. Taken together, the panel concluded that reducing sodium intake therefore lowers blood pressure and thereby should decrease risk of CVD (IOM, 2005, pp. 351- 357). However, evidence for other benefits associated with reduced sodium intake was inconclusive. The 2010 DGAC (HHS and USDA, 2010) considered evidence pub- lished since the DRI report on water and electrolytes (IOM, 2005) in a systematic review on adverse effects of sodium on blood pressure, and included discussion related to sodium intake and risk of stroke, coronary heart disease, and kidney disease. This evidence along with previous evi- dence from the 2005 DGAC report (HHS and USDA, 2005) provided sup- port for the committee’s findings and recommendations for sodium intake in the general U.S. population. Although the 2010 DGAC report (HHS and USDA, 2010) also found variability in study design and intake assessment, and inconsistency in sodium measurements among the observational studies reviewed, collectively, the evidence was consistent with that identified in the previous DRI report on water and electrolytes (IOM, 2005) and showed a relationship between reducing sodium intake and lowering blood pressure. In 2012, the World Health Organization (WHO) published its updated report Guideline: Sodium Intake for Adults and Children (WHO, 2012). The evidence base for the supporting literature review included epidemio- logical evidence, three systematic reviews (one of which was of randomized controlled trials [RCTs]) conducted by WHO, and a reanalysis of data from a fourth systematic review. The outcomes examined for associations with sodium intake were blood pressure in adults, all-cause mortality, CVD, stroke, and coronary heart disease in adults, potential adverse effects in adults, blood pressure in children, and potential adverse effects in children. The report found that the evidence for a relationship between sodium intake and blood pressure was of high quality, whereas that for sodium intake and

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44 SODIUM INTAKE IN POPULATIONS all-cause mortality, CVD, stroke, and coronary heart disease was of lower quality. Nevertheless, collectively, the WHO concluded that the evidence reviewed supports the conclusion that any reduction in sodium intake is beneficial for most individuals regardless of initial sodium intake. The report further concluded that even a modest reduction in blood pressure from reducing sodium intake would have significant public health benefits. New Evidence Associating Sodium Intake with Health Outcomes Blood Pressure Response to Sodium Intake in Population Subgroups A unique population identified in the INTERSALT study, the Yanomami Indians, exhibits consistently low systolic and diastolic blood pressures within the population and over their lifetimes (De Jesus Mancilha-Carvalho and De Souza e Silva, 2003). Members of this population maintain an active lifestyle and have a very low salt intake (assessed by 24-hour uri- nary sodium excretion) throughout life and have no indicators of risk of coronary heart disease. The finding that blood pressure in members of this population does not rise with age or stimulation of RAAS suggests the pos- sibility of a relationship between salt intake and blood pressure response that can occur apart from physiological or genetic variation. Studies in more heterogeneous populations subjected to environmental factors not encountered by the Yanomami Indians show less consistency in blood pres- sure response to low sodium intakes. At the other end of the spectrum are population subgroups that are at risk of hypertension, are considered prehypertensive, or have diagnosed hypertension. Evidence published since the report Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate (IOM, 2005) includes additional subanalyses of data from the Dietary Approaches to Stop Hyper- tension (DASH)-Sodium trial as well as new evidence from the GenSalt intervention study in China and the Relationship between Hypertension and Salt Intake in Turkish Population (SALTURK) population-based epi- demiological study in Turkey. Bray et al. (2004) analyzed data collected in the DASH-Sodium trial to determine the effect of stepwise reduction in sodium intake on blood pres- sure as modified by hypertension status. The DASH-Sodium dietary pat- tern and a control diet representative of a typical American eating pattern and changes in blood pressure were compared within hypertensive versus nonhypertensive; non–African American versus African American; women versus men; 45 years of age and younger versus older than 45 years of age; and obese versus nonobese population groups at three sodium intake levels: 150 mmol (3,450 mg) (high), 100 mmol (2,300 mg) (intermediate), and 50 mmol (1,150 mg) (low) per day for 30 days. Changes in blood pressure

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INTERMEDIATE MARKERS FOR HEALTH OUTCOMES 45 were analyzed to determine an overall effect of sodium reduction, as well as the effects of differences between high versus low and between high ver- sus intermediate and intermediate versus low sodium intake levels for each subgroup and for hypertensive status within each subgroup. Analyses by subgroup found that, at each sodium level, the DASH diet significantly reduced systolic blood pressure among African Americans and women on low versus high, low versus intermediate, and intermediate versus high intake levels. Hypertensive participants significantly reduced blood pressure in a stepwise fashion at all sodium intake levels for both the control and DASH diets. Among nonhypertensive participants, significant reductions in systolic blood pressure were found at all levels for those on the control diet but only between the low versus high levels for those on the DASH diet. Analyses of hypertensive and nonhypertensive individu- als within each subgroup found that, for the control diet, the association between stepwise sodium reduction and reduced blood pressure was statisti- cally significant across all subgroups by hypertension status, except those in the 45 years of age or younger subgroup. A subset of participants in the GenSalt study included 1,906 adults 18-60 years of age, who completed a 21-day dietary sodium and potas- sium intervention. The intervention included a low-salt (3,000 mg salt or ~1,200 mg sodium per day) diet for 7 days followed by a high-salt (18,000 mg salt or ~7,200 mg sodium per day) diet for 7 days with a 1,500 mg potassium supplement included with the high-salt diet. Analysis of data col- lected at baseline and during each intervention found that blood pressure and 24-hour urinary sodium excretion in about 75 percent of participants decreased during the low-salt (~1,200 mg sodium per day) intervention and increased during the high-salt (~7,200 mg sodium per day) intervention, providing support for previous observations of salt sensitivity across popu- lations. This study further found that blood pressure response to sodium intake was more pronounced in women compared to men, and among older participants as well as those with higher baseline blood pressure levels, consistent with findings from the DASH trial (He et al., 2009a). The SALTURK population-based epidemiological study examined asso- ciations between dietary salt intake and blood pressure response in 603 normotensive and 213 hypertensive adult men and women. Data on family history of hypertension, dietary habits, and daily salt consumption as well as other medical and demographic information were collected by in-person interview questionnaire. Blood pressure measurement and 24-hour urinary sodium excretion were collected on each participant. The mean intake of salt was estimated to be about 18,000 mg per day (~7,200 mg sodium per day) across the population. Within the population, salt intake was signifi- cantly higher among the obese, those living in rural areas, and those with lower education levels. In addition, men consumed more salt than women

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46 SODIUM INTAKE IN POPULATIONS and salt intake increased significantly with increasing age. After adjusting for these factors, positive linear correlations were found between salt intake and systolic and diastolic blood pressure. More specifically, each 2,000 mg per day intake in salt (~800 mg sodium per day) correlated with an increase in systolic blood pressure of 5.8 mmHg. Cook et al. (2005) examined blood pressure response to reduced dietary sodium intake in a 3-year prospective intervention as part of the Trials of Hypertension Prevention, Phase II (TOHP II) study. Participants with high- normal blood pressure ages 30-54 years with a body mass index (BMI) indicating overweight were randomized into either a sodium-reduction group (n=596) or a usual care control group (n=596). Those in the sodium- reduction group were counseled on how to reduce sodium intake to 3.5 g or less per day while those in the usual care group followed their usual diets. Both groups were assessed for mean blood pressure and urinary sodium excretion at baseline, 18, and 36 months. Analyses of data on the change in blood pressure corresponding with urinary sodium excretion showed a significant dose-response trend in decreasing systolic blood pressure that was strongest for participants who maintained a low sodium intake. A meta-analysis of evidence from RCTs carried out between 1981 and 2004 found a modest but significant association between a reduction in salt intake and decreased blood pressure in children (He and MacGregor, 2006). More recently, He et al. (2008) analyzed data from the National Diet and Nutrition Survey to assess relationships between salt intake and blood pressure in a cross-sectional study of free-living children in the United Kingdom. The study population included a nationally representa- tive sample of 1,658 children and adolescents 4-18 years of age. Dietary salt intake data were obtained from 7-day dietary records. Average intake of salt, excluding salt added in cooking or added at the table, ranged from 4,700 (±200) mg (~1,900 [±800] mg sodium) per day at 4 years of age up to 6,800 (±200) mg (~2,700 mg sodium) per day at 18 years of age. When analyzed by tertile of salt intake for each group 4-8 years of age, 9-13 years of age, and 14-18 years of age, there was a significant association between increasing salt intake and an increase in systolic blood pressure for those 4-8 and 9-13 years of age, but not for those 14-18 years of age. However, a positive association between salt intake and systolic blood pressure was seen when all age groups were analyzed together. No associations were found between salt intake and diastolic blood pressure or between salt use in cooking or at the table and systolic blood pressure, although there was a significant association with increasing pulse pressure compared to those who did not add salt in cooking or at the table.

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INTERMEDIATE MARKERS FOR HEALTH OUTCOMES 47 Blood Pressure Response to Sodium Intake in Normotensive Population Groups Ducher et al. (2003) analyzed data from 296 normotensive young adults participating in a 2-year prospective study that collected blood pres- sure measurements, 24-hour urinary sodium, sodium-to-creatinine ratio, and dietary intake of sodium at the time of entry and exit from the study. At the end of the study period, a multiple regression analysis found, using a linear model, a significant association between both systolic and diastolic blood pressure and age, BMI, sodium intake, and alcohol intake (correla- tion coefficient for systolic blood pressure=0.37 and for diastolic blood pressure=0.47 [p<0.0001]). Considered as an independent variable, there was no significant association between blood pressure and sodium intake. To examine further for relationships between sodium intake and blood pressure within the study population, the investigators conducted a Zrho analysis. This approach is based on an analysis of statistical dependence between values of the two variables (sodium intake and blood pressure) within individuals in the population, thereby allowing detection of a rela- tionship between blood pressure and sodium intake among individuals in the study population when it was not significant for the population as a whole. Using this analytical approach, a significant correlation was found between sodium intake and diastolic blood pressure in 16 percent of the study population. Another epidemiological study (Park et al., 2010) examined associa- tions between dietary sodium, calcium, and potassium, and anthropometric measures of obesity in a subset of Korean adults (n=2,761) from the Korean National Health and Nutrition Examination Survey (KHANES III). Dietary sodium intake data were obtained from 24-hour dietary recall. This study, which included participants who were normotensive as well as prehyperten- sive and hypertensive, also found no correlation between sodium intake and either systolic or diastolic blood pressure, although an inverse correlation was found between calcium intake and blood pressure. Several intervention studies in normotensive population groups exam- ined blood pressure response to variations in dietary sodium intake but study findings were inconsistent. In a small (n=10) 6-week double-blind random- ized crossover study, Starmans-Kool et al. (2011) examined the effect of changes in dietary salt intake on central blood pressure and wave reflection (a measure of dynamic blood flow) in healthy normotensive males, 22-40 years of age. Participants were normalized to 2,200 mg sodium per day the first week, then randomized into either 2,200 mg (128 mmol) sodium per day by capsule or matched placebo controls along with a diet containing 2,600-3,500 mg sodium per day. Data were collected daily on blood pres- sure, heart rate, arterial pressure, and blood flow velocity. The study found

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48 SODIUM INTAKE IN POPULATIONS significantly elevated carotid systolic blood pressure but only small changes in brachial systolic blood pressure in participants receiving the high-sodium intervention in this population of young normotensive men. Todd et al. (2012) used a 4-week single-blind randomized crossover trial to examine the effect of dietary sodium administered as tomato juice containing 0, 4,000, or 8,000 mg sodium per day on blood pressure and other measures of arterial function in 19 normotensive adults. All partici- pants were normalized to a 2,600 mg sodium diet in a 2-week washout period between respective interventions. Blood pressure, urinary sodium, and other analyses were taken at baseline, 1, 2, and 4 weeks for each inter- vention. None of the interventions was found to be significantly associated with either systolic or diastolic blood pressure response despite an increase in urinary sodium corresponding with increased sodium intake. To examine the influence of dietary sodium on nighttime blood pressure “dipping” in salt-sensitive compared to salt-resistant young adults (18-40 years of age, n=41) and children (8-15 years of age, n=28), Simonetti et al. (2010) placed participants on 7 days of a low-salt diet (300 mg [122 mg sodium] per day), followed by 7 days of the same diet with sodium chloride tablets (9,000 mg per day for adults and 120 mg per kg body weight per day for children) and measured 24-hour urine collections and oscillometric 24-hour ambulatory blood pressure during each test week. The low-salt diet was effective in reducing daytime systolic blood pressure among salt- sensitive but not salt-resistant adults and children. However, nighttime dipping in blood pressure was not significantly different between the two age groups, independent of salt sensitivity or salt intake. A study of similar design carried out in an adult Amish population (n=465) obtained different results than those of Simonetti et al. (2010). This study by Montasser et al. (2011) also measured daytime and nighttime sys- tolic blood pressure over two 6-day intervention periods. However, partici- pants were subjected to a high-salt diet (6,440 mg per day) first, followed by a 6- to 14-day washout period, then a low-salt diet (980 mg [~380 mg sodium] per day). Ambulatory blood pressure was measured by a monitor worn by the participant on the last day of each intervention. In contrast to Simonetti et al. (2010), Montasser et al. (2011) found a significant reduc- tion in systolic blood pressure response for both daytime and nighttime measures, particularly among women, older participants, and those with higher systolic blood pressure, following the low-salt intervention. Daytime and nighttime systolic blood pressure response to high- and low-salt diet treatment also was studied in a group of normotensive adults from Sweden (Melander et al., 2007). The study used a randomized double- blind crossover design in which participants were provided a 3,000 mg salt (~1,200 mg sodium) per day baseline diet for 8 weeks. Then, in the cross- over, each participant received a sodium chloride capsule (6,000 mg per

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INTERMEDIATE MARKERS FOR HEALTH OUTCOMES 49 day) with the baseline diet for 4 weeks and a placebo capsule for 4 weeks. Ambulatory systolic blood pressure measures over 24 hours and 24-hour urine collections were taken at baseline and at the end of each treatment period. Similar to Montasser et al. (2011), Melander et al. (2007) found that lowering salt intake by 6,000 mg per day significantly decreased sys- tolic blood pressure for both daytime and nighttime measures. A recent report (Coxson et al., 2013) used computer modeling of three different scenarios to evaluate the effect of sodium reduction over a period of 10 years on blood pressure and related health outcomes in the U.S. popu- lation. The report demonstrates sodium reductions, ranging from 4 to 40 percent, achieved a reduced risk of coronary heart disease, stroke, major CVD events, and all-cause mortality from all three scenarios. The greatest reduction in risk was associated with sodium reduction modeling based on the TOHP trials (discussed in Chapter 4). Summary and Interpretation of Evidence The studies reviewed by the committee, like those reviewed in IOM (2005) and DGAC (HHS and USDA, 2010), also show heterogeneity within and among population groups with regard to a relationship between sodium intake and blood pressure. The studies vary in the methodological approaches used to measure sodium intake, as well as in how they account for bias and potential confounding in their results. Nevertheless, considered collectively, the evidence in the studies reviewed here generally supports prior evidence that links excessive dietary sodium to elevated blood pres- sure in at-risk subgroups, particularly individuals with hypertension or prehypertension. EVIDENCE ASSOCIATING SODIUM INTAKE WITH BIOMARKERS OF PROGRESSION OF PRIOR KIDNEY DISEASE The progression of chronic kidney disease (CKD) appears to be related to dietary sodium intake, either through effects on blood pressure or other mechanisms. Examples of intermediate health outcomes that have addressed the effect of sodium intake in CKD are primarily those evaluating changes in urinary protein or albumin excretion (proteinuria). Studies evaluating the relationship of dietary sodium intake with risk of end-stage renal disease are addressed separately in Chapter 4. Proteinuria Although a reduced sodium intake is typically recommended to lower blood pressure in patients with CKD, the 2005 IOM report Dietary Refer-

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50 SODIUM INTAKE IN POPULATIONS ence Intakes for Water, Potassium, Sodium, Chloride and Sulfate found only one cross-sectional study associating sodium intake with albumin excretion at that time. A systematic review of evidence on the relationship of dietary sodium markers for progression of CKD was published in 2006. The authors concluded that, on the basis of data on the effects of sodium intake on functional, structural, or pathological indicators such as glomerular filtra- tion rate, image scanning, or proteinuria, modest dietary sodium chloride restriction for patients with CKD should be considered, especially for those with hypertension or proteinuria (Jones-Burton et al., 2006). The diversity in methodologies and poor quality of the studies was highlighted in this review. More recently, other studies have emerged linking dietary sodium intake with intermediate markers of kidney disease, such as urinary pro- teinuria. Weir et al. (2012) conducted a large cohort study of kidney disease patients with and without diabetes to explore the relationship between dietary sodium (estimated from 24-hour sodium excretion) and proteinuria. In their regression model, urinary sodium alone explained 12 percent of the urinary protein variation and dietary potassium offset some of the increase in proteinuria. In a small randomized controlled trial in African or African Caribbean hypertensive individuals, protein and protein-to-creatinine ratio excretion fell significantly with a reduced sodium intake diet of 5,000 mg salt (2,000 mg sodium) per day (Swift et al., 2005). This reduction seemed not to be related to a decrease in blood pressure but occurred concomitantly with a significant increase in the level of plasma renin activity (a measure of the activity of the RAAS). Further, a 7-day trial with 43 Chinese hypertensive individuals showed that the sodium-restricted group (average of 96 mmol sodium per day measured by 24-hour urine excretion analysis) had significantly less urine protein when compared with the habitual diet group (average of 149 mmol sodium per day) (Yu et al., 2012). Another marker of CKD progression, urinary TGF-β-1, also decreased. The importance of sodium in the management of CKD was highlighted in an observational study in which the authors correlated the intake of sodium to the use of antihypertensive medications (Boudville et al., 2005). The study suggests that in individuals with CKD and equivalent blood pres- sure control, higher sodium intakes (estimated by 24-hour urinary sodium analysis) are associated with greater use of antihypertensive medications. Effects on proteinuria also have been studied directly in patients treated for hypertension. The relationship between 24-hour urinary sodium (one collection at home) and proteinuria was found again in a cross-sectional study con-

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INTERMEDIATE MARKERS FOR HEALTH OUTCOMES 51 ducted in Japan with individuals under treatment for hypertension (Ohta et al., 2012). In this study, the level of aldosterone, but not of renin activity, was correlated with variations in urinary sodium. In a randomized crossover trial with 169 mildly hypertensive partici- pants, reduction in salt intake estimated from levels in urine of 9,700 (high) to 6,500 (control) mg salt per day (3,880 and 2,600 mg of sodium per day for high and control, respectively) resulted in significant reductions in albumin-to-creatinine ratios after 6-week intervention (He et al., 2009b). Other studies have been designed to explore the interplay of drug therapies with dietary sodium (or salt) intake. For example, the effects on proteinuria of a dietary restriction or combination of an angiotensin recep- tor blocker and an angiotensin-converting enzyme inhibitor was tested in a small randomized controlled study with patients with nephropathy but not diabetes in the Netherlands (Slagman et al., 2011). The results indicated that a reduced-sodium diet (1,200 versus 4,800 mg per day for 6 weeks) was more effective than the angiotensin receptor blocker in reducing pro- teinuria in these patients. These results agree with those from other studies (Vogt et al., 2008). Another small randomized controlled study also indicated that a lower- sodium diet had significant effects on decreasing proteinuria, regardless of the therapeutic intervention with an angiotensin II receptor antagonist, a diuretic, or both (Waanders et al., 2009). Renin-Angiotensin-Aldosterone System The RAAS is related to the progression of kidney disease. It also has been found to be associated with changes in sodium intake (Abiko et al., 2009; Alderman et al., 1991). Among the elements of the RAAS, plasma renin levels or activity have received substantial attention. The IOM report Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate (IOM, 2005) suggested that the inverse relationship between renin and sodium intake appears to be curvilinear and it occurs at levels less than 2,300 mg per day. Below that level, and especially below 1,000 mg per day, renin rises exponentially. Plasma renin activity (PRA) also has been proposed as a predictor of cardiovascular risk. Therefore, increases in PRA due to low sodium intake could have adverse health effects in the population. In a large, stable population of high-risk patients with atherosclerosis and/or diabetes, for example, PRA was an independent predictor of major vascular events and mortality (Verma et al., 2011). PRA also has been related to cardiovascular risk factors (e.g., hypertension, left ventricular hypertrophy, lipid levels) and with insulin resistance. A recent review, however, questions the validity of plasma renin as

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52 SODIUM INTAKE IN POPULATIONS a biomarker for cardiovascular events. The authors concluded that even though most studies have shown a positive association, conclusions are difficult to make based on differences across the studies (Volpe et al., 2012). In the Antihypertensive Lipid-Lowering Treatment to Prevent Heart Attack Trial, participants assigned to diuretics, which increase RAAS, had similar CVD event risk and lower risk of heart failure compared to those on calcium channel blockers (Furberg et al., 2002). A recent Cochrane review update that included 167 RCTs from 1950 to 2011 addressed the effect of sodium intake on blood pressure, renin, aldosterone, catecholamines, cholesterol, and triglyceride in healthy persons with high or normal blood pressure (Graudal, 2012). The sodium intake, in the range of 120 to 150 mmol (2,760 to 3,450 mg) per day in three studies, and less than 120 mmol (2,760 mg) per day in all other studies, was estimated from 24-hour urine collection or from a sample of a minimum of 8 hours. This update high- lighted important results, such as significant increases in urine aldosterone and blood renin that were proportional to estimated sodium intake. These results are in agreement with prior meta-analysis of trials (He and Mac- Gregor, 2002; Jürgens and Graudal, 2003). However, experts still do not agree about the significance for health outcomes of the increases of blood renin levels with lower sodium intake. REFERENCES Abiko, H., T. Konta, Z. Hao, S. Takasaki, K. Suzuki, K. Ichikawa, A. Ikeda, Y. Shibata, Y. Takeishi, S. Kawata, T. Kato, and I. Kubota. 2009. Factors correlated with plasma renin activity in general Japanese population. Clinical and Experimental Nephrology 13(2):130-137. Alderman, M. H., S. Madhavan, W. L. Ooi, H. Cohen, J. E. Sealey, and J. H. Laragh. 1991. Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. New England Journal of Medicine 324(16):1098-1104. Atkinson, A. J., Jr., W. A. Colburn, V. G. DeGruttola, D. L. DeMets, G. J. Downing, D. F. Hoth, J. A. Oates, C. C. Peck, R. T. Schooley, B. A. Spilker, J. Woodcock, and S. L. Zeger. 2001. Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clinical Pharmacology and Therapeutics 69(3):89-95. Beeks, E., A. G. H. Kessels, A. A. Kroon, M. M. Van Der Klauw, and P. W. De Leeuw. 2004. Genetic predisposition to salt-sensitivity: A systematic review. Journal of Hypertension 22(7):1243-1249. Boudville, N., S. Ward, M. Benaroia, and A. A. House. 2005. Increased sodium intake corre- lates with greater use of antihypertensive agents by subjects with chronic kidney disease. American Journal of Hypertension 18(10):1300-1305. Bray, G. A., W. M. Vollmer, F. M. Sacks, E. Obarzanek, L. P. Svetkey, L. J. Appel, and DASH Collaborative Research Group. 2004. A further subgroup analysis of the effects of the DASH diet and three dietary sodium levels on blood pressure: Results of the DASH-Sodium Trial. [Erratum appears in American Journal of Cardiology 2010 Feb 15;105(4):579]. American Journal of Cardiology 94(2):222-227.

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