Appendix D

Indicators Not Relevant for Establishing Dietary Reference Intake Values

The Agency for Healthcare Research and Quality systematic review, Sodium and Potassium Intake: Effects on Chronic Disease Outcomes and Risks (AHRQ Systematic Review) (Newberry et al., 2018), served as a foundational evidence source for this study. However, the committee needed to consider additional evidence to inform each of the Dietary Reference Intake (DRI) categories. Accordingly, supplemental literature searches were performed.

In the first step of the DRI organizing framework, potential indicators for establishing the reference values are identified and reviewed. The committee used a multipronged approach to create a comprehensive list of indicators that have been assessed for having a relationship with either potassium and/or sodium intake. The list was compiled with the intent of determining which indicators not included in the AHRQ Systematic Review would merit further consideration and, as appropriate, supplemental literature searches. By assessing the scope of evidence on the relationship between the identified indicator and potassium and/or sodium intake and through expert judgment, the committee determined which of the identified indicators had the potential to be relevant for establishing potassium and sodium DRI values.

This appendix describes the committee’s approach to compiling the comprehensive list of indicators and performing scoping literature searches for the identified indicators. For each indicator the committee determined to be not relevant for establishing potassium or sodium DRI values, a brief description of the evidence gathered and the committee’s rationale for not further evaluating the indicator are provided.

METHODOLOGICAL APPROACH

The committee first compiled a comprehensive list of indicators not included in the AHRQ Systematic Review by gathering information from a variety of sources. Then, through its assessment of the evidence coupled with expert judgment, the committee determined which indicators were not relevant for establishing potassium or sodium DRI values.

Creating a Comprehensive List of Indicators Not Included in the AHRQ Systematic Review

To approach the first step of the DRI organizing framework, the committee undertook several efforts to identify a wide range of indicators that could potentially inform potassium or sodium DRI values. The multipronged approach included reviewing relevant Institute of Medicine (IOM) reports, conducting an abbreviated search of recent systematic reviews, reviewing international reference intake values reports, and circulating a call for relevant grey literature. These efforts informed the comprehensive list of potential indicators.

Reviewing Relevant Institute of Medicine Reports

The committee reviewed indicators included in three key reports from the IOM: Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate (2005 DRI Report) (IOM, 2005); Strategies to Reduce Sodium Intake in the United States (IOM, 2010); and Sodium Intake in Populations: Assessment of Evidence (Sodium Intake in Populations) (IOM, 2013). Indicators not included in the AHRQ Systematic Review were added to the comprehensive list.

Conducting an Abbreviated Search of Recent Systematic Reviews

An abbreviated literature search of recent systematic reviews was conducted to identify additional indicators not included in the AHRQ Systematic Review. Because the intent was only to identify indicators, systematic reviews were not assessed for quality and the strength of evidence in the relationship with the nutrient was not considered at this stage. Searches were conducted in PubMed using the sodium and potassium search strings

presented in the AHRQ Systematic Review.^1,2 Using PubMed filters, the searches were limited to systematic reviews published between January 1, 2012, through December 31, 2017 (for sodium), and systematic reviews published between January 1, 2003, through December 31, 2017 (for potassium). The article type was selected to facilitate an efficient identification of indicators of current interest and investigation that would potentially have a sufficient amount of evidence that could inform the derivation of DRI values. The date range of the searches was selected based on the most recent review of the evidence for the nutrients by an IOM consensus committee. For sodium, Sodium Intake in Populations (IOM, 2013) served as the most recent evaluation. As such, a start date of January 1, 2012, was selected to account for articles that were in press or published during the production of the Sodium Intake in Populations report. For potassium, the 2005 DRI Report (IOM, 2005) was the most recent IOM review of the evidence. Accordingly, a start date of January 1, 2003, was selected. The potassium and sodium searches of recent systematic reviews resulted in 559 and 386 results, respectively.

The titles and abstracts of the systematic reviews were screened for relevance. Citations were excluded if they were not published in English, if they did not assess the relationship between one or more indicators and either or both of the nutrients, or if the only relationship(s) assessed were explored in the AHRQ Systematic Review. For reviews that passed the initial screening, the indicator was drawn from the title, abstract, and, when ambiguous from the title and abstract, the full text article. For sodium, 35 articles addressed one or more indicators not included in the AHRQ Systematic Review, while 18 articles contained an additional indicator for potassium. Several of the articles assessed the same indicator. Accordingly, fewer than 35 and 18 indicators were identified for sodium and potassium, respectively, through this abbreviated literature search of systematic reviews.

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¹ The PubMed search was conducted using the systematic review filter and the following search string: (((“Sodium Chloride”[Mesh] OR “Sodium Glutamate”[Mesh] OR “monosodium glutamate”[Title/Abstract] OR salt[Title/Abstract] OR salt[Text Word] OR sodium[Title/Abstract] OR sodium[Text Word]) AND (diet[MeSH Terms] OR diet[Title/Abstract] OR diet[Text Word] OR food[Text Word] OR food[Title/Abstract] OR intake[Title/Abstract] OR intake[Text Word] OR “urinary excretion”) OR “Diet, Sodium-Restricted”[Mesh] OR “Sodium, Dietary”[Mesh])).

² The PubMed search was conducted using the systematic review filter and the following search string: (“Potassium, Dietary”[Mesh] OR potassium[tiab] OR KLOR-CON[tiab] OR KCL[tiab]).

Reviewing International Reference Intake Values Reports

The committee also reviewed international nutrient intake value reports for potassium and sodium to identify indicators that have been used by other groups, including the European Food Safety Authority (EFSA, 2017; EFSA et al., 2016); the Australian Government Department of Health and the New Zealand Ministry of Health (NHMRC, 2006, 2017); reference values for nutrient intake for Austria, Germany, and Switzerland (Strohm et al., 2017a,b); and the DRIs for Koreans (Paik, 2008).

Circulating a Public Call for Relevant Grey Literature

The committee gathered grey literature by asking sponsors, stakeholders, and interested members of the public for relevant reports that do not appear in the peer-reviewed literature. The request was posted to the National Academies of Sciences, Engineering, and Medicine website and an email announcement was circulated through the study listserv. This public call for information was in addition to the existing public comment mechanism, in which the public could provide written comments for the committee’s consideration throughout the duration of the study.

Integrating Expert Input

To gain additional insight, the committee hosted a 1-day public workshop in Washington, DC, on March 7, 2018, and a 1-hour open session on March 9, 2018 (for agendas of these public sessions, see Appendix B). The workshop and open session included presentations on a variety of topics relevant to the committee’s Statement of Task and included a range of scientific perspectives. In-person workshop attendees had an opportunity to address the committee by providing remarks up to 3 minutes in length. Interested members of the public were also able to submit written public comment throughout the duration of the study. Indicators revealed through the workshop, public comments, and information-gathering public sessions were compared to the comprehensive list of indicators, and indicators not previously identified were added.

Compiling the Comprehensive List of Indicators Not Included in the AHRQ Systematic Review

The comprehensive list of indicators not included in the AHRQ Systematic Review was compiled from the information-gathering activities described in the preceding sections (see Table D-1).

TABLE D-1 Comprehensive List of Potential Indicators Not Included in the AHRQ Systematic Review That Have Been Recently Assessed in Relation to Sodium and/or Potassium, Presented in Alphabetical Order

^aIncludes cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein.

^bIncludes bone mineral density and osteoporosis.

^cSerum or plasma creatinine.

^dIncludes insulin sensitivity and glucose intolerance.

^eIncludes miscarriage, preeclampsia, and other adverse pregnancy or birth outcomes.

^fIncludes asthma.

Determining Which Indicators Have Potential Relevance

A wide range of indicators have been assessed in the literature as potentially having a relationship with potassium and/or sodium. The committee, therefore, decided to triage the identified indicators to determine which indicators potentially had relevance for establishing potassium or sodium DRI values. The steps included an initial assessment through expert judgment, then a broad assessment of the literature through scoping searches.

Using Expert Judgment

In the first wave of consideration, the committee used its expert judgment to remove from consideration any indicator that would not fit the DRI paradigm. Consideration was given as to whether the relationship between the indicator and the nutrient had biological underpinnings or if the indicator only exists in a disease state or population (i.e., would not be relevant to an apparently healthy population). The committee also used expert judgment to identify indicators that merited a more thorough consideration.

Reviewing Evidence Collected Through Information-Gathering Activities

In the next wave of considerations, the committee reviewed the remaining indicators in light of findings in previous IOM consensus study reports—specifically the 2005 DRI Report (IOM, 2005) and Sodium Intake in Populations (IOM, 2013)—and evidence presented at the March 2018 public workshop and public session.

The committee also conducted scoping searches. The searches sought to provide an overview of evidence on the relationship between the nutrients

and the identified indicators, beyond what was provided in the previous consensus study reports. The scoping searches were performed in PubMed. The committee followed the general approach described in the AHRQ Systematic Review, which consisted of three different types of searches per indicator in PubMed. One search type was to identify systematic reviews for reference mining. A second search type was intended to identify evidence of effect of the nutrient on the indicator. Aligned with the approach taken in the AHRQ Systematic Review, this consisted of searching for parallel arm or crossover randomized controlled trials. A third search type was intended to identify evidence of the association between the nutrient and the indicator. Aligned with the approach taken in the AHRQ Systematic Review, this consisted of searching for prospective cohort studies and nested case-control studies.

The structure of the searches aligned with those presented in the AHRQ Systematic Review, with the indicator-specific search terms varying across the searches. Table D-2 presents the general search strategy. Indicator-specific search strings are presented as footnotes in the presentation of the evidence. The timeframe of literature assessed varied depending on if and when the indicator was last reviewed in an IOM consensus study report. For example, if the indicator was included in Sodium Intake in Populations (IOM, 2013), the scoping search only extended to January 1, 2012. For all other indicators, the scoping searches extended to January 1, 2003.

Two independent reviewers screened the titles and abstracts of the results from each of the searches for relevance, with disagreements resolved through discussion. The criteria for the title and abstract screening were broad, as to be generally inclusive. A citation was included if it was a study of humans that included an assessment of a relationship between the nutrient and indicator (for systematic reviews), an effect of the nutrient on the indicator, or an association between the nutrient and the indicator. An article was excluded if it exclusively reported on patients with end-stage renal disease, heart failure, HIV, or cancer, or reported on intake in which sodium and/or potassium could not be disaggregated from other components of the diet (e.g., studies that assess dietary patterns in which sodium is not the only component). Articles that remained after the title and abstract screening went on to full-text screening, using the same criteria as the title and abstract screening. Information about the population, intervention/intake, comparators/outcomes, timing, setting, and study design were extracted from each of the included articles. As is common for scoping review-type searches, risk of bias for each article was not formally assessed, although information on key components that would affect risk of bias (population, measurement of exposure, and measurement of outcome) was captured through data extraction.

TABLE D-2 General Search Strategy Used for Conducting Scoping Searches in PubMed, as Informed by Search Strategy Used in the AHRQ Systematic Review

^aThe search terms were specific to each indicator under consideration and are noted as footnotes throughout this appendix.

SOURCE: Search strings adapted from Newberry et al., 2018.

The committee reviewed the evidence from previous IOM reports, the March 2018 public workshop and public session, and the scoping searches to make a determination about whether the indicator potentially had relevance for deriving potassium or sodium DRI values. Indicators the committee determined to have evidence to suggest it may be of relevance progressed to a more thorough consideration and, as necessary, comprehensive literature search (see Appendix E). Evidence and rationale for not further pursuing indicators are described in the section that follows.

INDICATORS NOT RELEVANT FOR ESTABLISHING POTASSIUM OR SODIUM DIETARY REFERENCE INTAKE VALUES

Through the methodology described in the preceding section, the committee made an informed decision regarding the relevance of the identified indicators for the purposes of establishing potassium and sodium DRI values. The sections that follow provide the evidence and rationale that support those decisions.

Relevance Determined by Expert Scientific Judgment

In its initial review of the comprehensive list of indicators, the committee used its collective expert judgment to identify seven indicators that

were relevant to its task: blood lipids, bone health, catecholamines, diabetes, headaches, the renin-angiotensin-aldosterone system, and serum or plasma levels of the nutrients.³ The committee also had clear rationale for not further pursuing several of the indicators, in context of the evidence provided in the AHRQ Systematic Review and in context of the type of evidence needed to derive DRI values. Rationale for those decisions are provided below.

Arterial Stiffness

Arterial stiffness was identified as a potential sodium and potassium indicator through the abbreviated search of recent systematic reviews. The relationship between sodium and arterial stiffness was not explored in the 2005 DRI Report (IOM, 2005) or in Sodium Intake in Populations (IOM, 2013). Measures of arterial stiffness have become more frequently used in research and in clinical settings in the past 20 years (Townsend, 2017). The rapid expansion and use of measures of arterial stiffness created a need for standardization of methodologies, for which guidelines were recently released (Townsend et al., 2015). If it were to be considered as a potential

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³ This text was revised since the prepublication release.

indicator, arterial stiffness would likely be used for establishing a DRI based on chronic disease, namely cardiovascular disease. Given the strength of evidence for blood pressure and for the hard endpoints of cardiovascular disease morbidity and mortality, the committee determined that currently available evidence on arterial stiffness would not further inform the derivation of the sodium DRI values. For potassium, arterial stiffness would need to be considered a qualified surrogate marker in context of potassium (see Chapter 2). Given the limited data on the relationship between potassium intake and cardiovascular disease risk, the committee determined that current evidence does not support considering arterial stiffness for the derivation of a potassium DRI based on chronic disease.

Ascites

Ascites is a condition in which fluid accumulates in the peritoneal cavity and occurs when an excess of sodium and fluid is retained in the body. Ascites is often caused by liver disease, but it is also found in other patient populations including those with congestive heart failure, advanced kidney disease, or advance cancers of abdominal organs. Because it occurs as a complication to a chronic disease and generally necessitates medical management, ascites does not fit the paradigm of an indicator that could inform a DRI value for the apparently healthy population.

Cancer

The Continuous Update Project of the World Cancer Fund and the American Institute for Cancer Research summarizes current evidence on factors related to the development and progression of cancer. The third expert report, Diet, Nutrition, Physical Activity and Cancer: A Global Perspective, reported that there was strong, probable evidence that consumption of Cantonese-style salted fish increases the risk of nasopharyngeal cancer and that consumption of foods preserved by salting increases the risk of stomach cancer (WCRF/AICR, 2018b). With respect to the DRIs, the committee determined that the evidence related to the Cantonese-style salted fish (which is consumed as part of a traditional diet in the Pearl River Delta region in southern China) does not have broad public health relevance to U.S. and Canadian populations. Furthermore, the evidence supporting the relationship between salt-preserved foods and stomach cancer was primarily from studies conducted in Asian populations with heterogeneous classification of what qualified as a salt-preserved food (WCRF/AICR, 2018a). It was reported that there was insufficient evidence to conduct an intake–response meta-analysis. The systematic literature review that supported the conclusion on stomach cancer also investigated total salt intake

(Norat et al., 2015). Six studies were identified, and all collected sodium exposure through food frequency questionnaires. The meta-analysis of the six studies resulted in no significant relationship between total salt intake and stomach cancer; no intake–response meta-analysis was conducted. The findings in the 2018 edition of the Diet, Nutrition, Physical Activity and Cancer: A Global Perspective report are in contrast to those in the 2007 edition, which indicated that it was probable that “total salt consumption, from processed foods, including salty and salted foods, and also salt added in cooking and at the table” increases the risk of stomach cancer (WCRF/AICR, 2007, p. 141). Based on this collection of evidence, the committee determined that the evidence currently does not support the use of stomach or nasopharyngeal cancer as a potential indicator for a sodium DRI.

Creatinine (Serum or Plasma)

Creatinine was identified as a potential indicator for potassium through the abbreviated search of recent systematic reviews. The relationship was not explored in the 2005 DRI Report (IOM, 2005). Serum or plasma creatinine levels are used as markers of kidney function. The AHRQ Systematic Review included evidence on the relationship between potassium intake and risk of kidney stones and kidney disease morbidity and mortality. A recent meta-analysis of potassium supplementation trials found that moderate supplementation did not lead to changes in circulating creatinine levels (Cappuccio et al., 2016). Based on the evidence included in the AHRQ Systematic Review and the finding from Cappuccio et al. (2016), the committee determined that the evidence currently does not support the use of serum or plasma creatinine as a potential indicator for establishing potassium DRI values.

Endothelial Dysfunction

Endothelial function is a broad category that has been assessed using a variety of measures and techniques, each with noted advantages and disadvantages (Flammer et al., 2012). The American College of Cardiology Foundation and the American Heart Association joint practice guidelines do not recommend an endothelial function test as a tool for risk prediction or risk classification of cardiovascular disease in asymptomatic adults (Greenland et al., 2010). If it were to be considered as a potential indicator for sodium, measures of endothelial dysfunction would likely be used for deriving DRIs based on chronic disease. Endothelial dysfunction would need to be considered a qualified surrogate marker of cardiovascular disease in the context of sodium reduction. Given the strength of evidence for blood pressure and for the hard endpoints of cardiovascular disease morbidity

and mortality, the committee determined that the evidence currently does not support the use of measures of endothelial dysfunction as a potential indicator for establishing sodium DRI values.

Heart Rate

Heart rate is often measured and reported in trials related to sodium intake. The committee identified one recent systematic review that reported reduced dietary sodium intake increases heart rate (Graudal et al., 2016). Given that the systematic review included 63 randomized controlled trials, the committee did not think it was efficient to use the review for reference mining, as was done for other potential indicators under consideration. Instead, the committee assessed the quality of the review using the AMSTAR 2 tool.⁴ Based on its appraisal, the committee identified critical weaknesses in the systematic review, particularly in the description and documentation of the search strategy. Furthermore, the criteria used in the systematic review did not align with the inclusion and exclusion criteria for the AHRQ Systematic Review (e.g., at least 4 weeks in duration, crossover trials with at least 2 weeks of washout).

If it were to be considered as a potential indicator, heart rate would likely be used for establishing DRIs based on chronic disease, namely cardiovascular disease. Given the strength of evidence for blood pressure and for the hard endpoint of cardiovascular disease, the committee determined that the evidence currently does not support the use of heart rate as a potential indicator for establishing sodium DRI values.

One recent meta-analysis of randomized controlled trials (Gijsbers et al., 2016), identified through the committee’s literature scan, assessed evidence on the relationship between increased potassium intake (through potassium supplementation) and heart rate in healthy adults. Gijsbers et al. (2016) reported that the meta-analysis of 22 trials (1,086 participants) yielded no overall effect, no intake–response relationship, and no subgroup differences. The evidence, therefore, does not support considering heart rate for the derivation of potassium DRI values.⁵

Left Ventricular Mass

Increased left ventricular mass, a subclinical form of cardiovascular disease, is considered to be a structural adaptation of the heart as a compensatory mechanism for increased blood pressure and wall stress. Factors that are associated with blood pressure, such as sodium and potassium

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⁴ AMSTAR stands for A Measurement Tool to Assess Systematic Reviews.

⁵ This text was revised since the prepublication release.

intake, are also associated with increased left ventricular mass. Direct evidence, particularly from longitudinal studies and randomized controlled trials, is sparse.

In the 2005 DRI Report, left ventricular mass was explored as an adverse effect of overconsumption of sodium. Nearly all of the identified observational studies reported a statistically significant positive relationship between urinary sodium excretion and left ventricular mass (Daniels et al., 1990; du Cailar et al., 1989, 1992, 2002; Kupari et al., 1994; Langenfeld et al., 1998; Liebson et al., 1993; Schmieder et al., 1988, 1990, 1996). Four clinical trials were also identified. The comparison group in three of the trials received antihypertensive drug therapy (Fagerberg et al., 1991; Ferrara et al., 1984; Liebson et al., 1995). The fourth trial specifically assessed the effect of sodium reduction and reported significant reductions in left ventricular mass, as compared to a nonintervention group (Jula and Karanko, 1994). The 2005 DRI Report noted that while the cross-sectional studies consistently showed an association between urinary sodium excretion and left ventricular mass, additional trials were needed. Left ventricular mass, therefore, was not used to derive the sodium Tolerable Upper Intake Level (UL) in the 2005 DRI Report.

Through the scoping searches, three articles on crossover clinical trials and two articles on prospective cohort studies were identified as exploring the relationship between sodium intake and left ventricular mass. For the crossover trials, Williams et al. (2005) and Vaidya et al. (2009) reported on the results from participants with hypertension from an international consortium (HyperPath Project), while Larson et al. (2012) reported on results from normotensive adults. All three reports used the same protocol for high (≥ 200 mmol/d) and low (≤ 10 mmol/d) sodium exposure, which consisted of participants consuming 1 week of each diet, in random order. There was some indication that the low-sodium diet had a beneficial effect on left ventricular hypertrophy among the participants with hypertension, but such a finding was not reported among the evaluated normotensive adults. The high- and low-sodium diet intervention in these crossover trials only lasted for 1 week, which is unlikely to alter left ventricular mass. In addition, these trials used electrocardiography to measure left ventricular hypertrophy (LVH), which has low sensitivity; the majority of cases with true anatomical LVH could be misclassified by using electrocardiography criteria of LVH (Bacharova et al., 2014).

In the Coronary Artery Risk Development in Young Adults study, Rodriguez et al. (2011) reported that higher urinary sodium excretion and sodium-to-potassium ratio were significantly associated with greater left ventricular mass among relatively healthy young adults. These relationships were independent of blood pressure and persisted through 5 years of follow-up. Urinary sodium and potassium excretion were assessed using

the average of three 24-hour urinary samples. The Strong Heart Study, conducted in American Indian communities, reported that baseline sodium intake, as ascertained by a food frequency questionnaire, was not associated with changes in left ventricular mass over a 4-year period among normotensive participants (Haring et al., 2015). Sodium-to-potassium ratio, however, was associated with left ventricular mass index among participants with prehypertension and hypertension. The evidence from the Strong Heart Study was limited by use of a food frequency questionnaire to gather dietary sodium intake exposure data.

The committee determined that, although there is some evidence to suggest that lower dietary sodium intake or sodium-to-potassium ratio is related to lower left ventricular mass or risk of LVH, there is insufficient evidence at this time to support an intake–response relationship. Therefore, the evidence currently does not support the use of left ventricular mass as a potential indicator for establishing potassium or sodium DRI values. The committee, however, notes that future clinical trials are warranted to clarify the relationship between sodium intake and left ventricular mass.

Obesity

Obesity as an outcome was identified as a potential indicator for sodium and potassium through the abbreviated search of recent systematic reviews. The relationship between potassium and sodium and obesity was not explored in the 2005 DRI Report (IOM, 2005) or in Sodium Intake in Populations (IOM, 2013). Potassium and sodium are not energy-providing nutrients but are correlated with energy intake (see Chapter 3). The majority of sodium intake in the diet comes from processed foods (see Chapter 11), whereas major contributors to potassium intake are fruits and vegetables. The interpretation of evidence on an apparent relationship between either nutrient and incident obesity is complicated, and has a high likelihood of being confounded. Accordingly, the committee elected to review evidence on obesity as a subpopulation who could be differentially affected by potassium or sodium intake (i.e., weight status as an effect modifier on relationships between intake and chronic disease outcomes), but determined it was not an appropriate indicator to inform the potassium or sodium DRI values.

Quality of Life

Quality of life is a broad, multidimensional concept. The instruments, scales, and tools used to assess quality of life capture an individual’s or a group’s perceptions. Owing to the lack of a biological mechanism to support the relationship between the nutrients and quality of life, the commit-

tee determined that such a subjective measure does not fit the paradigm of an indicator that could inform a DRI value for the apparently healthy population.

Severe Acute Malnutrition

Severe acute malnutrition is a condition characterized by severe wasting, caused by sudden shortage of food. Severe acute malnutrition contributes to the burden of disease globally, particularly among young children. The prevalence of wasting among children younger than 5 years of age in the United States is 0.5 percent (UNICEF/WHO/World Bank Group, 2017); it does not appear to be a widespread public health issue in North America.⁶ In contrast, the prevalence of wasting among young children in Southern Asia is 15.4 percent. Accordingly, the committee determined that severe acute malnutrition would not have relevance for establishing DRI values for populations in the United States and Canada, but it acknowledges that it may have implications for nutrient reference values in other regions of the world.

Relevance Determined by Committee’s Review of Evidence

To make an informed decision regarding the remaining indicators on the comprehensive list, the committee assessed a broad range of evidence. Information gathered on each of the indicators and the committee’s rationale for why each was determined to not have relevance for establishing potassium or sodium DRI values is presented in the sections that follow.

Age-Related Cataracts, Age-Related Macular Degeneration, and Diabetic Retinopathy

Three eye-related conditions were identified as being potential indicators for sodium and potassium from the abbreviated search of recent systematic reviews. The potential indicators included age-related cataracts, age-related macular degeneration, and diabetic retinopathy. None of the eye-related indicators were reviewed in the 2005 DRI Report (IOM, 2005) or in Sodium Intake in Populations (IOM, 2013).

Sodium Through the scoping searches and reference mining of three systematic reviews for sodium (Dow et al., 2018; Wong et al., 2016, 2018), three articles that analyzed prospective cohort data were identified (Cundiff

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⁶ No estimate was available for Canada.

and Nigg, 2005; Horikawa et al., 2014; Roy and Janal, 2010).⁷ Two of the studies were conducted in individuals with type 1 diabetes (Cundiff and Nigg, 2005; Roy and Janal, 2010), and were considered to have limited applicability for the purposes of establishing DRI values for the apparently healthy population. Horikawa et al. (2014) followed 1,588 Japanese patients who had type 2 diabetes, 40–70 years of age, for 8 years. Intake was assessed by food frequency questionnaires collected at baseline and 5 years after registration. Odds of incident retinopathy were not significantly different when those in the highest quartile of sodium intake were compared to those in the lowest quartile of sodium intake (odds ratio [OR]: 1.10 [95% confidence interval {CI}: 0.75, 1.61], p = .64). Based on this scoping search, the committee determined that the evidence currently does not support the use of age-related cataracts, age-related macular degeneration, or diabetic retinopathy as indicators to inform the sodium DRI values.

Potassium Through the scoping searches and reference mining of one systematic review for potassium (Dow et al., 2018), one relevant prospective cohort analysis was identified (Tanaka et al., 2013).⁸ The analysis assessed 978 Japanese patients, 40–70 years of age, with type 2 diabetes. Dietary intake was collected through food frequency questionnaires and 24-hour dietary recall. The relationship between potassium intake and incidence diabetic retinopathy was not significant. The committee, therefore, determined that the evidence currently does not support the use of age-related cataracts, age-related macular degeneration, or diabetic retinopathy as indicators to inform the potassium DRI values.

Depression

Depression was assessed as an outcome in Sodium Intake in Populations (IOM, 2013), in which it was determined that conclusions about the relationship could not be drawn because only one study that prospectively

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⁷ The different scoping searches (see Table D-2) returned 3 results for the systematic review search, 26 results for the association search, and 25 results for the effect search, which were screened for relevance. The indicator-specific search string was (((((“eye”[MeSH Terms] OR “eye”[All Fields]) AND (“health”[MeSH Terms] OR “health”[All Fields])) OR (“eye diseases”[MeSH Terms] OR (“eye”[All Fields] AND “diseases”[All Fields]) OR “eye diseases”[All Fields] OR (“eye”[All Fields] AND “disease”[All Fields]) OR “eye disease”[All Fields])) OR (“retinal diseases”[MeSH Terms] OR (“retinal”[All Fields] AND “diseases”[All Fields]) OR “retinal diseases”[All Fields] OR “retinopathy”[All Fields])) OR (“cataract”[MeSH Terms] OR “cataract”[All Fields]).

⁸ The different scoping searches (see Table D-2) returned 4 results for the systematic review search, 71 results for the association search, and 43 results for the effect search, which were screened for relevance. The indicator-specific search string was the same as for the sodium search.

assessed patients with heart failure was identified (Song, 2009). The relationship between sodium intake and depression was not explored in the 2005 DRI Report (IOM, 2005).

Sodium The scoping searches did not reveal any publications on trials, prospective cohorts, or nested case-control studies on the independent relationship between sodium intake and depression that have been published since January 1, 2012.⁹ This committee therefore determined that the evidence currently does not support the use of depression as an indicator to inform the sodium DRI values.

Gastroesophageal Reflux

Gastroesophageal reflux was assessed as an outcome in Sodium Intake in Populations (IOM, 2013), in which it was determined that conclusions about the relationship could not be drawn because only two studies on the topic were identified (Aanen et al., 2006; Nilsson et al., 2004). The relationship was not explored in the 2005 DRI Report (IOM, 2005).

Sodium The scoping searches did not reveal any publications on trials, prospective cohorts, or nested case-control studies on this topic that have been published since January 1, 2012.¹⁰ Accordingly, the committee determined that the evidence currently does not support the use of gastroesophageal reflux as an indicator to inform the sodium DRI values.

Genitourinary Symptoms

Genitourinary symptoms (including kidney stone formation and urinary tract infection) were assessed in both in the 2005 DRI Report (IOM, 2005) and in Sodium Intake in Populations (IOM, 2013). The AHRQ Systematic Review included renal-related outcomes in key questions 3 and 4 for sodium and in key questions 5–8 for potassium (for the list of key

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⁹ The different scoping searches (see Table D-2) returned 0 results for the systematic review search, 9 results for the association search, and 8 results for the effect search, which were screened for relevance. The indicator-sepcific search string was ((((“depressive disorder”[MeSH Terms] OR (“depressive”[All Fields] AND “disorder”[All Fields]) OR “depressive disorder”[All Fields] OR “depression”[All Fields] OR “depression”[MeSH Terms])) OR depressed)).

¹⁰ The different scoping searches (see Table D-2) returned 2 results for the systematic review search, 2 results for the association search, and 1 result for the effect search, which were screened for relevance. The indicator-specific search string was ((“gastroesophageal reflux”[MeSH Terms] OR (“gastroesophageal”[All Fields] AND “reflux”[All Fields]) OR “gastroesophageal reflux”[All Fields] OR (“gastroesophageal”[All Fields] AND “reflux”[All Fields] AND “disease”[All Fields]) OR “gastroesophageal reflux disease”[All Fields]) OR “acid reflux”[All Fields])).

questions in the AHRQ Systematic Review, see Chapter 1, Box 1-3). This section, therefore, only describes the evidence on the relationship between sodium intake and urinary tract infection, which was not captured by the AHRQ Systematic Review.

Sodium In Sodium Intake in Populations (IOM, 2013), four articles on the relationship between sodium intake and genitourinary symptoms were identified, but only one was on the topic of urinary tract infections. In a cross-sectional assessment of 1,545 men 30–79 years of age in the Boston Area Community Healthy survey (2002–2005), Maserejian et al. (2009) reported that sodium intake, as measured by a food frequency questionnaire, had a significant positive association with lower urinary tract symptoms (p for trend = .007). In Sodium Intake in Populations (IOM, 2013), it was concluded that, given the inconsistent methodological approach and results, there was insufficient evidence to draw conclusions regarding the relationship between sodium intake and genitourinary symptoms. The scoping searches did not reveal any new randomized controlled trials, prospective cohorts, or nested case-cohort studies.¹¹ Accordingly, the committee determined that the evidence currently does not support the use of urinary tract infections as an indicator to inform the sodium DRI values.

Hyperhomocysteinemia

Hyperhomocysteinemia was identified as a potential indicator for sodium through the abbreviated search of recent systematic reviews. The relationship was not explored in the 2005 DRI Report (IOM, 2005) or in Sodium Intake in Populations (IOM, 2013).

Sodium Through the scoping searches, one study was identified as exploring the relationship between sodium intake and hyperhomocysteinemia.¹² Wan et al. (2017) conducted a trial in rural China among 47 normotensive adults. Participants consumed three different diets in sequence, each for

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¹¹ The different scoping searches (see Table D-2) returned 4 results for the systematic review search, 46 results for the association search, and 36 results for the effect search, which were screened for relevance. The indicator-specific search string was (urinary tract infection OR lower urinary tract OR cystitis).

¹² Instead of three individual scoping searches, a single search was conducted and led to 40 total results that were screened for relevance. The search string was (((((“Sodium Chloride”[Mesh] OR “Sodium Glutamate”[Mesh] OR “monosodium glutamate”[Title/Abstract] OR salt[Title/Abstract] OR salt[Text Word] OR sodium[Title/Abstract] OR sodium[Text Word]) AND (diet[MeSH Terms] OR diet[Title/Abstract] OR diet[Text Word] OR food[Text Word] OR food[Title/Abstract] OR intake[Title/Abstract]OR intake[Text Word] OR “urinary excretion”) OR “Diet, Sodium-Restricted”[Mesh] OR “Sodium, Dietary”[Mesh]))) AND ((Hyperhomocysteinemia) OR homocysteine)) AND ((humans[MESH]) OR (inprocess[sb] OR publisher[sb] OR pubmednotmedline [sb] NOT (mice[ti] OR mouse[ti] OR rats[ti] OR dogs[ti]))).

1 week (low salt [3 grams sodium chloride per day], high salt [18 grams sodium chloride per day], and high salt with potassium supplementation [18 grams sodium chloride per day and 4.5 grams potassium chloride per day]); there was no washout period between the diets. Plasma homocysteine increased during salt loading among salt-sensitive participants (n = 19), whereas it did not significantly change among salt-resistant subjects (n = 28). The effects of salt loading among the salt-sensitive participants were ameliorated by the potassium supplementation.

Although the Wan et al. (2017) study suggests there is a relationship between sodium intake and plasma homocysteine levels in salt-sensitive individuals, the duration of the dietary intervention was short and there was no washout period between the different diets. Furthermore, given challenges in identifying salt-sensitive individuals (see Chapter 3), the committee did not use salt sensitivity as a characteristic to define subpopulations. Accordingly, the committee determined that the evidence currently does not support the use of hyperhomocysteinemia as an indicator to inform the sodium DRI values.

Leg Cramps

Leg cramps were identified as a potential indicator for sodium through the abbreviated search of recent systematic reviews. The relationships between the nutrients and leg cramps were not explored in the 2005 DRI Report (IOM, 2005) or in Sodium Intake in Populations (IOM, 2013).

Sodium The scoping search revealed two systematic reviews published since January 1, 2003, that explore the relationship between leg cramps and sodium intake (Young, 2009, 2015).¹³ The only primary study cited in the systematic reviews was Robinson (1947), and it was noted in those reviews that this study was of poor quality. No other articles were identified. Given the lack of recent data, the committee determined that the evidence currently does not support the use of leg cramps as an indicator to inform the sodium DRI values.

Maternal and Birth Outcomes

Maternal and birth outcomes (e.g., miscarriage, preeclampsia) were identified as a potential indicator for sodium through the abbreviated search of recent systematic reviews. In the 2005 DRI Report (IOM, 2005,

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¹³ The different scoping searches (see Table D-2) returned 2 results for the systematic review search, 0 results for the association search, and 1 result for the effect search, which were screened for relevance. The indicator-specific search string was (leg cramp*).

p. 383), it was determined that the “available evidence indicates that reducing sodium intake has little impact on preventing hypertensive disorders of pregnancy or their complications.” Pregnancy-related outcomes were not addressed in Sodium Intake in Populations (IOM, 2013).

Sodium Through the scoping searches and reference mining of three systematic reviews (Duley, 2008, 2011; Duley et al., 2005), five studies were identified as exploring the relationship between sodium intake and maternal and birth outcomes (see Table D-3).¹⁴ The outcomes explored were varied and provided limited evidence of effect of sodium intake. The committee determined that the evidence currently does not support the use of maternal or birth outcomes as indicators to inform the sodium DRI values.

Metabolic Syndrome

Metabolic syndrome as an outcome was identified as a potential indicator for sodium and for potassium through the abbreviated search of recent systematic reviews. The relationships between the nutrients and metabolic syndrome were not explored in the 2005 DRI Report (IOM, 2005). In Sodium Intake in Populations (IOM, 2013), two cross-sectional studies examining the association between sodium intake and risk of metabolic syndrome were identified, but the studies did not meet the criteria for further evaluation (Rodrigues et al., 2009; Teramoto et al., 2011).

Sodium The scoping searches and reference mining of three systematic reviews (Cai et al., 2016; Kang et al., 2016; Soltani et al., 2017) did not reveal any articles on trials, prospective cohorts, or nested case-control studies exploring the relationship between sodium intake and metabolic syndrome.¹⁵ Accordingly, the committee determined that the evidence cur-

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¹⁴ The different scoping searches (see Table D-2) returned 4 results for the systematic review search, 27 results for the association search, and 20 results for the effect search, which were screened for relevance. The indicator-specific search string was (((((“pre-eclampsia”[MeSH Terms] OR “pre-eclampsia”[All Fields] OR “preeclampsia”[All Fields]) OR (“abortion, spontaneous”[MeSH Terms] OR (“abortion”[All Fields] AND “spontaneous”[All Fields]) OR “spontaneous abortion”[All Fields] OR “miscarriage”[All Fields])) OR (“pregnancy outcome”[MeSH Terms] OR (“pregnancy”[All Fields] AND “outcome”[All Fields]) OR “pregnancy outcome”[All Fields])) OR “pregnancy-induced hypertension”[All Fields]) OR “hypertensive pregnancy”[All Fields])).

¹⁵ The different scoping searches (see Table D-2) returned 6 results for the systematic review search, 36 results for the association search, and 34 results for the effect search, which were screened for relevance. The indicator-specific search string was ((“metabolic syndrome”[MeSH Terms] OR (“metabolic”[All Fields] AND “syndrome”[All Fields]) OR “metabolic syndrome”[All Fields]) OR MetS[All Fields])).

rently does not support the use of metabolic syndrome as an indicator to inform the sodium DRI values.

Potassium The scoping searches and reference mining of one systematic review (Cai et al., 2016) did not reveal any articles on trials, prospective cohorts, or nested case-control studies exploring the relationship between potassium intake and metabolic syndrome.¹⁶ Accordingly, the committee determined that the evidence currently does not support the use of metabolic syndrome as an indicator to inform the potassium DRI values.

Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease was identified as a potential indicator for sodium through the abbreviated search of recent systematic reviews. The relationship between sodium and nonalcoholic fatty liver disease was not explored in the 2005 DRI Report (IOM, 2005) or in Sodium Intake in Populations (IOM, 2013).

Sodium The scoping searches and reference mining of one systematic review (Wong et al., 2017) did not reveal any articles on trials, prospective cohorts, or nested case-control studies exploring the relationship between sodium intake and nonalcoholic fatty liver disease.¹⁷ Accordingly, the committee determined that the evidence currently does not support the use of nonalcoholic fatty liver disease as an indicator to inform the sodium DRI values.

Pulmonary Function

Pulmonary function was assessed in both in the 2005 DRI Report (IOM, 2005) and in Sodium Intake in Populations (IOM, 2013).

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¹⁶ The different scoping searches (see Table D-2) returned 3 results for the systematic review search, 45 results for the association search, and 38 results for the effect search, which were screened for relevance. The indicator-specific search string was the same as for the sodium search.

¹⁷ The different scoping searches (see Table D-2) returned 1 result for the systematic review search, 6 results for the association search, and 6 results for the effect search, which were screened for relevance. The indicator-specific search string was (“non-alcoholic fatty liver disease”[MeSH Terms] OR (“non-alcoholic”[All Fields] AND “fatty”[All Fields] AND “liver”[All Fields] AND “disease”[All Fields]) OR “non-alcoholic fatty liver disease”[All Fields] OR (“nonalcoholic”[All Fields] AND “fatty”[All Fields] AND “liver”[All Fields] AND “disease”[All Fields]) OR “nonalcoholic fatty liver disease”[All Fields])).

TABLE D-3 Evidence on the Relationship Between Sodium Intake and Maternal and Birth Outcomes, Identified Through Scoping Searches

NOTE: CI = confidence interval; NaCl = sodium chloride; OR = odds ratio; PPROM = preterm premature rupture of membranes.

^aPregnancy-induced hypertension defined as gestational hypertension (rise in BP to v 140/90 mm Hg); preeclampsia (newly developed hypertension v 140/90 mm Hg with proteinuria v 300 mg/day); or superimposed preeclampsia after the 20th gestational week on chronic hypertension (BP rise to v 160/110 mm Hg, and/or new-onset or worsening proteinuria v 300 mg/day).

Sodium In the 2005 DRI Report, pulmonary function was explored as an adverse effect of overconsumption of sodium. The five cross-sectional analyses on the topic identified had mixed results regarding the relationship between pulmonary function and sodium intake (Britton et al., 1994; Burney et al., 1986; Schwartz and Weiss, 1990; Tribe et al., 1994; Zoia et al., 1995). Evidence from three trials suggested that high salt intake adversely affected people with asthma (Carey et al., 1993; Gotshall et al., 2000; Medici et al., 1993). The evidence on the relationship between sodium intake and pulmonary function ultimately was characterized as sparse and was not used in the derivation of the UL in the 2005 DRI Report.

In Sodium Intake in Populations (IOM, 2013), four articles on the relationship between sodium intake and pulmonary function were identified (Gotshall et al., 2004; Hirayama et al., 2010; Mickleborough et al., 2005; Sausenthaler et al., 2005). It was concluded that, given the inconsistent methodological approach and results, there was insufficient evidence to draw conclusions regarding the relationship between sodium intake and pulmonary function.

The scoping searches and reference mining of one systematic review (Forte et al., 2018) did not reveal any additional articles on trials, pro-

^bDuring the second trimester, women with PPROM were also reported to consume more energy, saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, vitamin A, vitamin C, beta-carotene, carotenoids, calcium, and iron.

^cAdjusted for energy intake, maternal age, maternal education, parity, maternal height, prepregnancy body mass index, pregravid oral contraceptive use, smoking during pregnancy, exact gestational age at delivery, and gender of the baby.

spective cohorts, or nested case-control studies exploring the relationship between sodium intake and pulmonary function as being published since January 1, 2012.¹⁸ Accordingly, the committee determined that the evidence currently does not support the use of pulmonary function as an indicator to inform the sodium DRI values.

Potassium In the 2005 DRI Report, prevention of impaired pulmonary function was explored as an indicator for estimating the requirement for potassium. The evidence on the relationship between potassium and pulmonary function was mixed for adults (Tribe et al., 1994; Zoia et al., 1995) and for children (Gilliland et al., 2002; Pistelli et al., 1993). Pulmonary function was not used in the derivation of the potassium Adequate Intake values.

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¹⁸ The different scoping searches (see Table D-2) returned 5 results for the systematic review search, 34 results for the association search, and 29 results for the effect search, which were screened for relevance. The indicator-specific search string was ((((((((((((((Asthma) OR Chest tightness) OR Cough) OR Dyspnoea) OR FEV1) OR Forced expiratory volume) OR Forced vital capacity) OR FVC) AND Lung function) OR PEF) OR Pulmonary function) OR Respiratory symptoms) OR Spiromet*) OR wheez*))).

The scoping searches and reference mining did not reveal any articles on randomized controlled trials, prospective cohorts, or nested case-cohort studies exploring the relationship between potassium intake and pulmonary function.¹⁹ Accordingly the committee determined that the evidence currently does not support the use of pulmonary function as an indicator to inform the potassium DRI values.

Rheumatoid Arthritis

Rheumatoid arthritis was identified as a potential indicator for sodium through the abbreviated search of recent systematic reviews. The relationship between sodium and rheumatoid arthritis was not explored in the 2005 DRI Report (IOM, 2005) or in Sodium Intake in Populations (IOM, 2013).

Sodium Through the scoping searches and reference mining of one systematic review (Wong et al., 2016), one nested case-control study was identified as exploring the relationship between sodium intake and rheumatoid arthritis.²⁰ The analysis included 386 cases of rheumatoid arthritis examined for a median of 7.7 years before the onset of symptoms and 1,886 matched controls (Sundström et al., 2015). The cases and controls were drawn from data collected through the Västerbotten Intervention Programme, a population-based screening and health counseling program in Sweden. Sodium intake was assessed by a semiquantitative food frequency questionnaire. Risk of developing rheumatoid arthritis did not significantly differ by tertile of sodium intake. When stratified by smoking status, however, the risk for developing rheumatoid arthritis was elevated among smokers in the highest tertile of sodium intake, as compared to the lowest tertile of intake (OR = 2.26 [95% CI: 1.06, 4.81], p = .036).

It was estimated that 54 percent of the increased risk of developing rheumatoid arthritis was attributed to the interaction between high sodium intake and smoking. Despite the statistically significant finding among smokers reported in Sundström et al. (2015), the study had limitations, including the methodology for capturing sodium intake. The com-

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¹⁹ The different scoping searches (see Table D-2) returned 6 results for the systematic review search, 263 results for the association search, and 180 results for the effect search, which were screened for relevance. The indicator-specific search string was the same as for the sodium search.

²⁰ The different scoping searches (see Table D-2) returned 2 results for the systematic review search, 9 results for the association search, and 1 result for the effect search, which were screened for relevance. The indicator-specific search string was (“arthritis, rheumatoid”[MeSH Terms] OR (“arthritis”[All Fields] AND “rheumatoid”[All Fields]) OR “rheumatoid arthritis”[All Fields] OR (“rheumatoid”[All Fields] AND “arthritis”[All Fields]))).

mittee, therefore, determined that the evidence currently does not support the use of rheumatoid arthritis as an indicator to inform the sodium DRI values.

Sarcopenia

Sarcopenia was identified as a potential indicator for sodium and for potassium through the abbreviated search of recent systematic reviews. The relationship between sodium and sarcopenia was not explored in the 2005 DRI Report (IOM, 2005) or in Sodium Intake in Populations (IOM, 2013).

Sodium The scoping searches and reference mining of one systematic review (van Dronkelaar et al., 2018) did not reveal any randomized controlled trials, prospective cohorts, or nested case-control studies published since January 1, 2003, on the relationship between sodium intake and sarcopenia.²¹ The committee, therefore, determined that the evidence currently does not support the use of sarcopenia as an indicator to inform the sodium DRI values.

Potassium Through the scoping searches and reference mining of one systematic review (van Dronkelaar et al., 2018), two primary research articles were identified as exploring the relationship between sodium intake and sarcopenia-related measures that had been published since January 1, 2003.²²

Ceglia and Dawson-Hughes (2017) conducted an 84-day randomized, placebo-controlled potassium bicarbonate (KHCO₃) trial among 233 men and women, 60 years of age and older. Participants were randomized to a placebo arm, a low-dose arm (1 mmol/kg/d KHCO₃), or a high-dose arm (1.5 mmol/kg/d KHCO₃). Using a ratio of urinary nitrogen excretion to concurrent nitrogen intake as a marker of muscle breakdown, the study found greater reductions in the marker with escalating doses of KHCO₃, although only the comparison between the highest dose and placebo arms was significant. The premise of this study, however, was not to investigate the effect of potassium, but rather the conjugate anion (bicarbonate) as a

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²¹ The different scoping searches (see Table D-2) returned 1 result for the systematic review search, 21 results for the association search, and 13 results for the effect search, which were screened for relevance. The indicator-specific search string was (((“sarcopenia”[MeSH Terms] OR “sarcopenia”[All Fields]) OR ((“muscles”[MeSH Terms] OR “muscles”[All Fields] OR “muscle”[All Fields]) AND loss[All Fields])))).

²² The different scoping searches (see Table D-2) returned 16 results for the systematic review search, 48 results for the association search, and 18 results for the effect search, which were screened for relevance.

means for reducing metabolic acidosis. Measures and assessment of potassium intake or excretion were not reported.

In an analysis of prospective cohort data from 3,122 adults 65 years of age and older living in Hong Kong, dietary intake was assessed at baseline using a validated food frequency questionnaire (Chan et al., 2015). The investigators assessed the relationship of dietary protein-to-potassium ratio (as a measure of net endogenous acid production [NEAP]) and declines in muscle mass over a 4-year period. The results found slower declines with lower measure of NEAP. The premise of the study was to use the measure of NEAP, rather than evaluating the independent effect of potassium. The investigators also demonstrated that the energy-adjusted NEAP estimates were significantly correlated with the intake of several nutrients (e.g., vitamin C, calcium, fiber) and food groups (e.g., fish and shellfish, fruits and dried fruits, vegetables).

The scoping literature search revealed that studies on sarcopenia, as they relate to intake of potassium, focus on metabolic acidosis and the role of bicarbonate that is associated with potassium, as part of the supplement (KHCO₃) or in potassium-containing foods (e.g., assessed by NEAP). As the independent relationship between potassium intake and sarcopenia does not appear to be pervasive in the literature, the committee determined that the evidence currently does not support the use of sarcopenia as an indicator to inform the potassium DRI values.

Small Vessel Disease

Small vessel disease was identified as a potential indicator for sodium through the abbreviated search of recent systematic reviews. The relationships between sodium and small vessel disease was not explored in the 2005 DRI Report (IOM, 2005) or in Sodium Intake in Populations (IOM, 2013).

Sodium The scoping searches and reference mining of a systematic review (Makin et al., 2017) did not reveal any articles on trials, prospective cohorts, or nested case-control studies exploring the relationship between

sodium intake and small vessel disease.²³ Accordingly, the committee determined that the evidence currently does not support the use of small vessel disease as an indicator to inform the sodium DRI values.

SUMMARY

A wide range of intermediates, surrogates, and clinical outcomes have been assessed as having a relationship with sodium and with potassium. While each may be of scientific and clinical interest, not all are relevant for the purposes of informing the potassium or sodium DRI values. Through expert judgment and scoping literature searches for recent evidence, the committee determined that several of the potential indictors that exist in the literature do not align with the DRI paradigm or have limited data at present, and as such do not support their use as indicators to inform the potassium or sodium DRI values.

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²³ Instead of three individual scoping searches, a single search was conducted and led to 25 total results that were screened for relevance. The search string was (((((“Sodium Chloride”[Mesh] OR “Sodium Glutamate”[Mesh] OR “monosodium glutamate”[Title/Abstract] OR salt[Title/Abstract] OR salt[Text Word] OR sodium[Title/Abstract] OR sodium[Text Word]) AND (diet[MeSH Terms] OR diet[Title/Abstract] OR diet[Text Word] OR food[Text Word] OR food[Title/Abstract] OR intake[Title/Abstract]OR intake[Text Word] OR “urinary excretion”) OR “Diet, Sodium-Restricted”[Mesh] OR “Sodium, Dietary”[Mesh]))) AND ((((“Small”[Journal] OR “small”[All Fields]) AND (“blood vessels”[MeSH Terms] OR (“blood”[All Fields] AND “vessels”[All Fields]) OR “blood vessels”[All Fields] OR “vessel”[All Fields]) AND (“disease”[MeSH Terms] OR “disease”[All Fields]))) OR (((“small vessel disease”) OR “microvascular Disease”) OR “small artery disease”))) AND ((humans[MESH]) OR (inprocess[sb] OR publisher[sb] OR pubmednotmedline [sb] NOT (mice[ti] OR mouse[ti] OR rats[ti] OR dogs[ti]))).

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Cappuccio, F. P., L. A. Buchanan, C. Ji, A. Siani, and M. A. Miller. 2016. Systematic review and meta-analysis of randomised controlled trials on the effects of potassium supplements on serum potassium and creatinine. BMJ Open 6(8):e011716.

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