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Dietary Reference Intakes for Sodium and Potassium (2019)

Chapter: 12 Knowledge Gaps and Future Directions

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Suggested Citation:"12 Knowledge Gaps and Future Directions." National Academies of Sciences, Engineering, and Medicine. 2019. Dietary Reference Intakes for Sodium and Potassium. Washington, DC: The National Academies Press. doi: 10.17226/25353.
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Suggested Citation:"12 Knowledge Gaps and Future Directions." National Academies of Sciences, Engineering, and Medicine. 2019. Dietary Reference Intakes for Sodium and Potassium. Washington, DC: The National Academies Press. doi: 10.17226/25353.
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Suggested Citation:"12 Knowledge Gaps and Future Directions." National Academies of Sciences, Engineering, and Medicine. 2019. Dietary Reference Intakes for Sodium and Potassium. Washington, DC: The National Academies Press. doi: 10.17226/25353.
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Suggested Citation:"12 Knowledge Gaps and Future Directions." National Academies of Sciences, Engineering, and Medicine. 2019. Dietary Reference Intakes for Sodium and Potassium. Washington, DC: The National Academies Press. doi: 10.17226/25353.
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Suggested Citation:"12 Knowledge Gaps and Future Directions." National Academies of Sciences, Engineering, and Medicine. 2019. Dietary Reference Intakes for Sodium and Potassium. Washington, DC: The National Academies Press. doi: 10.17226/25353.
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Suggested Citation:"12 Knowledge Gaps and Future Directions." National Academies of Sciences, Engineering, and Medicine. 2019. Dietary Reference Intakes for Sodium and Potassium. Washington, DC: The National Academies Press. doi: 10.17226/25353.
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Suggested Citation:"12 Knowledge Gaps and Future Directions." National Academies of Sciences, Engineering, and Medicine. 2019. Dietary Reference Intakes for Sodium and Potassium. Washington, DC: The National Academies Press. doi: 10.17226/25353.
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Suggested Citation:"12 Knowledge Gaps and Future Directions." National Academies of Sciences, Engineering, and Medicine. 2019. Dietary Reference Intakes for Sodium and Potassium. Washington, DC: The National Academies Press. doi: 10.17226/25353.
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Suggested Citation:"12 Knowledge Gaps and Future Directions." National Academies of Sciences, Engineering, and Medicine. 2019. Dietary Reference Intakes for Sodium and Potassium. Washington, DC: The National Academies Press. doi: 10.17226/25353.
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Suggested Citation:"12 Knowledge Gaps and Future Directions." National Academies of Sciences, Engineering, and Medicine. 2019. Dietary Reference Intakes for Sodium and Potassium. Washington, DC: The National Academies Press. doi: 10.17226/25353.
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Suggested Citation:"12 Knowledge Gaps and Future Directions." National Academies of Sciences, Engineering, and Medicine. 2019. Dietary Reference Intakes for Sodium and Potassium. Washington, DC: The National Academies Press. doi: 10.17226/25353.
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Suggested Citation:"12 Knowledge Gaps and Future Directions." National Academies of Sciences, Engineering, and Medicine. 2019. Dietary Reference Intakes for Sodium and Potassium. Washington, DC: The National Academies Press. doi: 10.17226/25353.
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Suggested Citation:"12 Knowledge Gaps and Future Directions." National Academies of Sciences, Engineering, and Medicine. 2019. Dietary Reference Intakes for Sodium and Potassium. Washington, DC: The National Academies Press. doi: 10.17226/25353.
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Suggested Citation:"12 Knowledge Gaps and Future Directions." National Academies of Sciences, Engineering, and Medicine. 2019. Dietary Reference Intakes for Sodium and Potassium. Washington, DC: The National Academies Press. doi: 10.17226/25353.
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Suggested Citation:"12 Knowledge Gaps and Future Directions." National Academies of Sciences, Engineering, and Medicine. 2019. Dietary Reference Intakes for Sodium and Potassium. Washington, DC: The National Academies Press. doi: 10.17226/25353.
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Suggested Citation:"12 Knowledge Gaps and Future Directions." National Academies of Sciences, Engineering, and Medicine. 2019. Dietary Reference Intakes for Sodium and Potassium. Washington, DC: The National Academies Press. doi: 10.17226/25353.
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12 Knowledge Gaps and Future Directions This chapter presents the committee’s interpretation of the state of the science for deriving Dietary Reference Intakes (DRIs) for potassium and sodium, including strengths, limitations, and research needs. Support from federal agencies and research institutions to address these knowledge gaps is expected to enhance the work of the next DRI committee that reviews the evidence on potassium and sodium. This chapter also includes the committee’s suggestions to enhance the DRI process, based on its experience implementing recommendations from the Guiding Principles for Developing Dietary Reference Intakes Based on Chronic Disease (Guiding Principles Report) (NASEM, 2017) and using an externally commissioned systematic review to inform its work. KNOWLEDGE GAPS AND RESEARCH NEEDS Strengthen Methods to Measure Potassium and Sodium Intake Collection of multiple 24-hour urinary sodium excretions with quality control methods is considered the most accurate method for quantifying usual sodium intake in an individual (Holbrook et al., 1984; Lerchl et al., 2015). Even when conducted correctly, this method has limitations. Like all urinary sodium assessments, 24-hour urinary excretion does not capture all modes of sodium loss (e.g., sweat, fecal), and therefore underestimates the true quantity of sodium consumed. Furthermore, collection of 24-hour urine samples is burdensome for participants, which often makes this assessment method challenging to use in a large, free-living population. Spot urine samples collected at a single point in time are more convenient to collect than 24-hour urinary excretions, but they are subject to multiple errors owing to intra- and inter-day variations in urine osmolality, sodium excretion, meal timing, fluid intake, ambient temperature, physical activity, and diuretic use (Ji et al., 2012). Spot urine samples have also demonstrated systematic bias as compared to 24-hour urine samples—underestimating 24-hour urinary sodium excretion at high intake levels, and overestimating 24-hour urinary sodium excretion at low intake levels—both in the general population and in individuals with chronic kidney disease (Dougher et al., 2016; He et al., 2018; Huang et al., 2016; Mente et al., 2014). PREPUBLICATION COPY: UNCORRECTED PROOFS 12-1

12-2 DIETARY REFERENCE INTAKES FOR SODIUM AND POTASSIUM The alternative to determining sodium intake from urinary samples is to use self-reported dietary intake assessment methods, such as 24-hour dietary recalls or food frequency questionnaires. These methods also have limitations. Sodium intake is highly correlated with energy intake, so under-reporting energy intake is likely to result in under-reporting of sodium intake (Bailey et al., 2007). The majority of sodium is consumed from sources prepared outside the home (Harnack et al., 2017). Unless specific brands of foods and beverages are reported and updated food composition databases are used to analyze the data, the results are subject to inaccuracies. Further, methods are lacking for quantifying sodium added at home during food preparation or during consumption (Anderson et al., 2010). Estimating potassium intake is also challenging. Compared to sodium, a lower proportion of potassium consumed is recovered in urine (Aburto et al., 2013a; Tasevska et al., 2006). This incomplete recovery may systematically differ across population groups and may depend on intake of other nutrients in the diet (Turban et al., 2013; Weaver et al., 2016), making it difficult to control for these differences. Short-term self-reported assessment methods, particularly multiple 24-hour dietary recalls, provide reasonably accurate estimates of usual potassium intake because potassium content in foods is generally naturally occurring and not added during food preparation or consumption, therefore is not as variable and brand-specific as sodium. As discussed in Chapter 3, one of the challenges of attributing health effects to potassium per se is its collinearity with other nutrients in the diet. To strengthen methodological approaches and improve the accuracy for estimating potassium and sodium intake, especially if the two nutrients are considered jointly, future research is needed to do the following: • Identify or develop methods to minimize systematic biases between spot and 24-hour urine collections (e.g., nonlinear modeling). If successful, these data could be used to derive new equations to predict 24-hour potassium and sodium exposure from spot urine samples, by groups defined by sex, age, and ethnicity, if appropriate. • Collect multiple 24-hour urine samples from subsamples of large cohorts to permit calibration of spot urine samples collected from the majority of participants. • Identify individual-level and environment-level attributes (e.g., age, sex, ethnicity, body mass index, physical activity, ambient temperature) that affect the proportion of consumed potassium and sodium excreted in the urine. Using this information, determine whether equations can be developed to adjust each individual’s 24-hour urine excretion information. • Determine whether and to what extent use of multiple spot urine samples collected at various times on different days improve calibration over a single spot urine sample for both potassium and sodium. • Develop methodological approaches for capturing, analyzing, and synthesizing data that can characterize complex dietary interactions, especially between potassium and other nutrients in the diet. Determine Potassium and Sodium Requirements and Toxicological Outcomes Potassium and sodium are physiologically essential nutrients, and their concentrations in the blood are tightly regulated through homeostatic controls. This regulation, coupled with the pervasiveness of these nutrients in the food supply, makes it challenging to characterize the PREPUBLICATION COPY: UNCORRECTED PROOFS

KNOWLEDGE GAPS AND FUTURE DIRECTIONS 12-3 distribution of potassium and sodium requirements in the population. Without such information, the DRI for adequacy for each nutrient will remain an Adequate Intake (AI) rather than an Estimated Average Requirement (EAR) and Recommended Dietary Allowance (RDA). Future DRI committee’s efforts to derive EARs and RDAs for potassium and sodium would be facilitated by rigorously designed balance studies that assess intakes levels of potassium and sodium needed to achieve balance across the lifespan. These balance studies would do the following: • Determine an optimal study duration to accurately assess potassium and sodium balance, accounting for both infradian rhythm (i.e., lasting longer than a day) and potentially high intra-individual variability in urinary excretion. • Provide participants with intakes levels that have been chemically determined so that intake can be accurately assessed. • Measure all excretion modes—including urinary, fecal, and sweat. • Characterize sequestration of sodium in the skin and muscle and its relationship to intake, as well as to characteristics such as life stage and degree of adiposity. The applicability of the potassium AI is uncertain for subpopulations prone to hyperkalemia or hypokalemia, such as individuals taking certain medications (e.g., angiotensin- converting-enzyme [ACE] inhibitors, angiotensin II receptor blockers [ARBs], diuretics) or individuals with adrenal insufficiency, chronic kidney disease, or type 2 diabetes. Health care providers may need to individualize potassium intake recommendations for these individuals, given the clinical context. The committee’s inability to determine the applicability of the potassium AI to such subpopulations is due in part to a lack of data on how key biological and drug effects influence 1) potassium balance and 2) the effect of potassium intake on serum potassium concentrations. Furthermore, individuals with such conditions are typically excluded from potassium supplementation trials. To better characterize the potassium intake needs in these at-risk subpopulations, future research would do the following: • Evaluate the effect of potassium supplementation on balance, serum potassium concentrations, blood pressure, and cardiovascular disease in individuals taking common medications that influence potassium homeostasis (e.g., ACE-I, ARBs, diuretics), and in individuals with chronic kidney disease, diabetes, and heart failure. In the expanded DRI model, the Tolerable Upper Intake Level (UL) is intended to characterize toxicological risk. In an effort to identify a toxicological indicator, the committee reviewed adverse effects from trials and case reports. Ethical considerations preclude human studies that are designed to produce toxic effects as the primary outcome. Thus, secondary reports of adverse events that are observed in studies of beneficial effects are likely to be a critical source of information for future DRI committees. Detailed and systematic collection of such information may elucidiate patterns and trends, and provide evidence for an indicator not previously considered. To further characterize the effects of high intakes of potassium and sodium, future research would do the following: • Support the use of animal and in vitro studies for evaluating potential toxicological effects. PREPUBLICATION COPY: UNCORRECTED PROOFS

12-4 DIETARY REFERENCE INTAKES FOR SODIUM AND POTASSIUM • Collect and report adverse effects in human studies in a systematic manner. • Report and thoroughly describe case studies related to potassium and sodium overconsumption. • Identify reliable indicators of excess sodium and potassium intake. Strengthen the Evidence on the Relationship Between Potassium Intake and Chronic Disease Risk There is moderate strength of evidence for a causal relationship between increased potassium intake (achieved by potassium supplementation) and decreased blood pressure among adults with hypertension. However, a lack of an intake–response relationship, coupled with a lack of direct evidence of a causal relationship between potassium intake and cardiovascular disease, precluded the committee from establishing a Chronic Disease Risk Reduction Intake (CDRR) for potassium. To strengthen the evidence on the relationship between potassium and chronic disease risk, future research would accomplish the following: • Assess the effect of different doses and forms of potassium (e.g., dietary potassium, potassium chloride supplements, potassium bicarbonate supplements) on blood pressure so that an intake–response relationship can be established. • Conduct an adequately powered trial of sufficient duration to study the effect of potassium supplementation on cardiovascular disease with concurrent measures of blood pressure, particularly among populations in which there is minimal risk of adverse effects from potassium supplementation. • Conduct pooled meta-analyses that combine individual-level data to identify subgroup differences and comprehensively evaluate intake–response relationships. • Conduct trials to further evaluate the interrelationships of potassium and other nutrients (e.g., calcium, magnesium), to determine the independent effects of each on blood pressure and cardiovascular disease. Strengthen the Evidence on the Relationship Between Sodium Intake and Chronic Disease Risk The meta-analyses used in this report helped the committee consider the totality of the evidence, but were limited by their ecological nature—that is, the studies were the unit of analysis rather than pooled individual-level data. Without access to individual-level data, the committee was unable to conduct analyses to draw conclusions about the differential effects of sodium reductions among population subgroups. To leverage existing data and overcome this limitation, future research would do the following: • Conduct meta-analyses combining individual-level data across various trials so that subgroup differences, particularly for sodium and blood pressure, can be more comprehensively evaluated (e.g., by age, sex, race/ethnicity, baseline blood pressure, genetics). Both mean effects and differences in the intake–response relationship are of interest. PREPUBLICATION COPY: UNCORRECTED PROOFS

KNOWLEDGE GAPS AND FUTURE DIRECTIONS 12-5 Although the committee characterized the relationship between sodium intake and chronic disease risk as moderate, additional studies are still needed on the effects of sodium intake reductions on chronic disease risk. There are a number of design and execution challenges to such trials, especially those that evaluate long-term effects of behavioral modification of dietary intake on chronic disease endpoints. Given the limitations and uncertainties in the current evidence, future research would do the following: • Explore the feasibility of conducting large, methodologically rigorous randomized controlled trials that study the effect of sodium intake levels (ideally a range) on chronic disease endpoints, with particular attention to subpopulations that may have different responses to sodium intake. Blood pressure changes in response to a sodium intervention are variable, roughly following a bell-shaped curve (He et al., 2009). Defining individuals with moderate to high sodium sensitivity remains a challenge (Elijovich et al., 2016). Sodium sensitivity is most often defined as a proportional change (e.g., ≥ 3 percent, ≥ 10 percent) or an absolute change (e.g., ≥3 mm Hg, ≥10 mm Hg) in mean arterial pressure during sodium intervention. A common method to define sodium sensitivity is to assess acute blood pressure response to rapid sodium loading (e.g., intravenous administration of 2 L normal [0.9 percent] saline over 4 hours) and depletion (e.g., a 10 mmol sodium diet and three doses of oral furosemide over 24 hours). Another common method of assessing sodium sensitivity is to measure the blood pressure response to low (e.g., < 50 mmol/day) and high (e.g., > 250 mmol/day) sodium intake over 1–2 weeks. In general, the dietary approach is considered the most rigorous approach for the characterization of sodium sensitivity, and evidence suggests that the blood pressure response has long-term reproducibility and stability in the general population (Gu et al., 2013). Several genes have been identified as being associated with increased sodium sensitivity, both in rats and humans, which suggests a genetic basis for salt sensitivity (Kelly and He, 2012). The Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study estimated that heritabilities for blood pressure response to high-sodium were 0.22, 0.33, and 0.33, for systolic, diastolic, and mean arterial pressure, respectively (Gu et al., 2007). The ability to accurately characterize sodium sensitivity among individuals could inform future updates to the sodium CDRR. Given current limitations in characterizing sodium sensitivity, future research would do the following: • Characterize how blood pressure response to changes in sodium intake varies by age, sex, race/ethnicity, adiposity, genotype, and clinical conditions such as hypertension, diabetes, and chronic kidney disease. • Identify both rare and common genetic variants that will help identify individuals who are predisposed to sodium sensitivity. • Improve methods for identifying sodium-sensitive individuals—including through discovery and validation of biomarkers in the blood or urine and use of proteomics and metabolomics—to increase accuracy and facilitate implementation in clinical and public health settings. Several prospective cohort studies have reported a significant positive association between sodium intake and cardiovascular disease risk and all-cause mortality, independent of PREPUBLICATION COPY: UNCORRECTED PROOFS

12-6 DIETARY REFERENCE INTAKES FOR SODIUM AND POTASSIUM blood pressure (Cook et al., 2007; He et al., 1999; Mills et al., 2016). Mechanisms underlying this blood pressure-independent association are not well studied. Observational studies have reported significant positive associations between sodium intake and left ventricular hypertrophy, endothelial dysfunction, and arterial stiffness, independent of blood pressure (Avolio et al., 1986; DuPont et al., 2013; Rodriguez et al., 2011; Todd et al., 2010). Little evidence exists from randomized controlled trials on the effect of sodium intake on cardiovascular risk factors other than blood pressure. To better characterize the relationship between sodium intake and chronic disease, future research would do the following: • Test the effects of different sodium intake levels on endothelial and vascular function. Explore Potassium and Sodium in Relation to Each Other and Other Dietary Components Sodium-to-Potassium Ratio If a DRI were established as a sodium-to-potassium ratio, it could potentially convey that increases in potassium intake without a concomitant reduction in sodium intake (thereby decreasing the ratio) would confer health benefits. At this time, the evidence is insufficient to characterize the relationship between the sodium-to-potassium ratio and health outcomes. Limitations in the available data precluded the committee from establishing the potassium and sodium DRIs as a ratio, and from assessing the behavioral implications of recommending a ratio. Nevertheless, potassium and sodium are inextricably biologically linked, and further exploration into their interactions is needed. The sodium-to-potassium ratio may overcome some of the methodological inaccuracies of measuring either nutrient alone. When comparing spot urine samples with 24-hour urine samples, for example, the sodium-to-potassium ratios are more closely aligned than is either nutrient alone (Iwahori et al., 2017). The sodium-to-potassium ratio was more accurately captured in both 24-hour dietary recalls and food frequency questionnaires than either individual nutrient (Freedman et al., 2015). In addition, the sodium-to-potassium ratio has been reported to have a higher correlation with blood pressure than either nutrient alone (Iwahori et al., 2017), although evidence from trials is limited. The ratio may be more robust to systematic errors in urine collection or in self-reported intakes than either nutrient alone. For instance, the sodium-to-potassium ratio may partially account for the confounding effect of energy when estimating the association between the minerals and blood pressure outcomes. Errors that occur during the measurement process (e.g., underreporting, other biases associated with the respondent) tend to be correlated across nutrients, so taking the ratio of the two nutrients partially cancels out these errors. To better characterize the interrelationships of potassium and sodium, future research would do the following: • Determine if and how the infradian rhythms (i.e., lasting longer than a day) of urinary potassium and sodium excretion affect the sodium-to-potassium ratio. • Explore the relationship between the sodium-to-potassium ratio and outcomes and surrogate markers (e.g., blood pressure) at different doses of potassium and sodium intake, and assess whether the ratio is a better measure than either nutrient alone. PREPUBLICATION COPY: UNCORRECTED PROOFS

KNOWLEDGE GAPS AND FUTURE DIRECTIONS 12-7 • Identify individual-level attributes that affect the urinary sodium-to-potassium ratio (e.g., age, race/ethnicity, body mass index, genotype), and determine how that information can be used to calibrate adjustment equations. • Improve statistical methods for estimating the distribution of the usual intake for the sodium-to-potassium ratio. Sodium Density The Dietary Approaches to Stop Hypertension (DASH)-Sodium trial was designed using a sodium density approach (i.e., milligrams sodium per kilocalorie energy intake); the primary results, however, were reported in terms of absolute sodium (milligrams of sodium per day), based on a 2,100 kilocalorie diet (Sacks et al., 2001). A secondary analysis of the study reported that the association between sodium intake and blood pressure varied by energy intake (Murtaugh et al., 2018). Specifically, higher sodium intakes among individuals with lower energy intakes led to a greater increase in blood pressure than higher sodium intakes among individuals with higher energy intakes. This finding suggests that it may be important to consider sodium density in addition to absolute sodium intake when assessing the relationship between sodium intake and health outcomes. This approach has had limited application to date. Valid estimates of sodium density may be difficult to obtain without biomarkers for both sodium and energy, unless carefully controlled feeding studies are conducted. To clarify this relationship, future research would do the following: • Identify biomarkers of sodium and energy intake that would be feasible to collect in large population studies. • Determine the intake–response relationship of different levels of sodium intake with both blood pressure and cardiovascular disease and determine whether optimal levels differ by sex, age, and adiposity corresponding to differences in energy needs or intakes of kilocalories. • Explore the feasibility of directly examining sodium intake density to obtain an estimate of the optimal level of sodium intake, either as an absolute amount (milligrams sodium) or as a density (milligrams sodium per kilocalorie energy). Evaluate Developmental Origins of Health and Disease Related to Sodium and Potassium The developmental origins of health and disease (DoHAD) posits that the in utero and early infant environment, including nutrition or stress, alter the long-term risk for chronic disease of the adult offspring. Studies in both human and animal models demonstrate that it is not only the immediate in utero environment for a fetus, but also the in utero environment of the fetus’ parents that can result in DoHAD-enhanced risk for chronic disease (Mandy and Nyirenda, 2018). Different potassium and sodium intake levels during early life may affect chronic disease risk as one ages. At present, however, the longitudinal effects of potassium and sodium intake are not well characterized. One study reported an increased risk of hypertension in adult- offspring of rats fed either a low-sodium or high-sodium diet during pregnancy and lactation (Koleganova et al., 2011). To clarify the long-term effects of potassium and sodium exposure, future research would accomplish the following: PREPUBLICATION COPY: UNCORRECTED PROOFS

12-8 DIETARY REFERENCE INTAKES FOR SODIUM AND POTASSIUM • Evaluate the first- and second-generation effects of high and low potassium and sodium intakes of both the mother and father in order to identify optimal intakes of these nutrients during reproductive stages of life and characterize the variability of risk for chronic disease in the population. Explore Opportunities in the Food Supply Reducing Sodium Sodium (in the form of salt and other sodium-containing compounds) is added to foods for reasons related to food safety, functionality, and taste. Making lower-sodium foods with high consumer acceptability is critical to reducing population-wide sodium intake, but there are conflicting data on how it is best accomplished (Israr et al., 2016). A prior committee explored food technology considerations and strategies for reducing sodium in the food supply in greater detail (IOM, 2010); these topics are discussed here only briefly. A number of strategies have been implemented to enhance salt taste perception in reduced-sodium products, including use of different forms of salt crystals and addition of certain food additives that either impart salty taste without sodium or enhance the perception of salty taste. For example, hollow salt crystals that are less dense than regular crystals dissolve faster upon consumption and increase sodium perception. These crystals are useful only in dry surface applications (e.g., potato chips) because if they dissolve they lose the advantage of their lower sodium density. Potassium chloride may be used to provide salt taste in lower-sodium products, but this ingredient presents challenges for individuals who have health conditions that reduce clearance of potassium from the blood. It can also have a bitter and metallic taste, but these off- flavors can be decreased by adding flavor modifiers or by blending it with sodium chloride. A flavor enhancer to help reduce sodium is free glutamate, used mainly in the form of monosodium glutamate (MSG). MSG is not believed to pose a health risk at the levels used in a typical serving of food. Given that most sodium comes from foods prepared away from home and that there is a relationship between sodium intake and chronic disease risk, future research would do the following: • Develop novel solutions, including through technological innovations, to decrease sodium in the food supply. Ensuring Iodine Nurtriture The native iodine content of foods and beverages tends to be low and is dependent on the geographic location where the ingredients were grown (Ershow et al., 2018). As a result, Canada has established a mandatory table salt fortification program and the United States allows for the voluntary fortification of salt if products are appropriately labeled (CFIA, 2019; Leung et al., 2012). Efforts to reduce sodium intake have led to concerns that iodine consumption will become inadequate in some individuals. However, available data indicate that sodium reductions have not resulted in inadequate iodine intakes (Musso et al., 2018). This finding may be attributed to the low use rates of iodized salt, both among consumers and in commercially prepared and processed food and to the iodine contribution of some common food additives. To continue to explore the possible effect of sodium reduction efforts on iodine consumption, future research would do the following: PREPUBLICATION COPY: UNCORRECTED PROOFS

KNOWLEDGE GAPS AND FUTURE DIRECTIONS 12-9 • Determine whether current approaches to reducing sodium intake in the population decrease intake of iodized salt from sources such as table salt, salt used in processed foods, or both, and assess whether decreases in sodium intake affects iodine consumption and status. • Monitor the iodine status of the U.S. and Canadian populations, and if some subpopulations are found to have inadequate or marginal iodine intakes, identify potential fortificants other than salt as a vehicle for delivering iodine to these specific subpopulations. • Chemically analyze the iodine content of representative diets (such as the Total Diet Study) and compare these estimated iodine intakes to estimates using food composition tables to determine the accuracy of food composition data for iodine. Because salt is not added to the representative diets, this would provide information on iodine contributed from both naturally occurring sources and from iodine-containing food additives other than iodized salt. OPPORTUNITIES TO ENHANCE THE DRI PROCESS The DRI process has evolved over time, and each iteration has revealed opportunities for improvement. As the first DRI committee to apply the guidance from the Guiding Principles Report, the committee identified the future opportunities summarized below. Defining Healthy Populations Relative to the DRI Model When Prevalence of Chronic Disease Is High The DRI model focuses on healthy populations, but an on-going challenge in both the United States and Canada is the high prevalence of chronic disease including obesity, type 2 diabetes, hypertension, and cardiovascular disease in adults, and the increasing prevalence of obesity and type 2 diabetes in children. In adults, the healthy population is the minority, rather than majority, of the total. Describing the focus of the DRIs as “apparently healthy population” does not fully resolve this challenge; high prevalence of these chronic diseases is accompanied by high prevalence of medication and medical nutrition therapy to manage them. The expansion of the DRI model to include the DRIs based on chronic disease magnifies the challenge of high chronic disease prevalence. The DRIs based on chronic disease focus on primary prevention of chronic disease, but issues of secondary prevention and disease management are also pressing public health problems. An on-going challenge and knowledge gap is how to assess if the DRI specified is relevant to the substantive proportion of the population that might be considered “apparently healthy” with appropriate medical management. A related challenge is discerning when and how to include these populations in the DRI framework of assessment of indicators and intake–response relationships. Future DRIs would benefit from the following: • Further research and evaluation to determine whether the population focus of the DRI for each nutrient should be redefined and, if so, how. PREPUBLICATION COPY: UNCORRECTED PROOFS

12-10 DIETARY REFERENCE INTAKES FOR SODIUM AND POTASSIUM Integrating an Externally Conducted Systematic Review into the DRI Process To enhance the effectiveness of an externally conducted systematic review, alignment of the needs of the DRI committee (evidence users) with the information from evidence providers (e.g., Agency for Healthcare Research and Quality [ARHQ]) is critical. This synchronization requires that the information in the systematic review meet the needs of the DRI committee and that the process minimizes the likelihood that bias or conflicts of interest adversely affect the usefulness and integrity of the systematic review. Involving the DRI committee in the development of the systematic evidence review, to the extent that best practices allow, has the potential to create a more efficient DRI process. This interaction is often handled with protocols that are developed prior to initiation of data collection for the review. Such protocols describe appropriate interactions among the contributors—in this case, between the DRI committee, the sponsors, and the scientists conducting the systematic review. Appropriate interactions may include finalizing key questions related to DRI decisions, identifying inclusion/exclusion criteria, reaching a general agreement on table formats and information to be provided, and discussing the overall approach and methodologies to be applied. Once the appropriate interactions have been completed and protocols agreed upon, the evidence providers would then conduct the review independent of the DRI committee. This independence is necessary to minimize the perception that the evidence users and evidence generators exerted bias in the conduct of the review. To create greater efficiency in the process and usability of the final systematic reviews for DRI applications, future DRI reviews would do the following: • Develop a priori protocols for how and when the DRI committee, the sponsors, and those who design and execute the systematic review coordinate at key points in the process, as guided by systematic review best practices. As described in Chapter 2 and Appendix C, the committee assessed the Agency for Healthcare Research and Quality (AHRQ) systematic review, Sodium and Potassium Intake: Effect on Chronic Disease Outcome and Risks (AHRQ Systematic Review) (Newberry et al., 2018), in a variety of ways prior to using and building on the evidence it provided. The committee determined that this step was necessary, because the AHRQ Systematic Review was externally-conducted and the committee was not involved in its design. The committee’s independent assessment of the AHRQ Systematic Review included evaluating the fidelity of the methodology, the transparency of reporting, and the subjective decisions made. Through this process, the committee identified the need to further investigate sources of heterogeneity in meta-analyses and to reassess the strength of evidence ratings for selected indicators. Moreover, the Guiding Principles Report recommended that intake–response assessment also be evaluated using Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Because key questions in the AHRQ Systematic Review focused only on issues of causality between nutrient intakes and chronic disease indicators, the committee performed additional analyses to evaluate intake–response relationships. For sodium, the CDRR was informed by the committee’s intake–response analyses across multiple chronic disease indicators. Future DRI committee will likely need to critically evaluate the methods and conclusions of the systematic evidence review as they apply to both issues of causality and intake–response. This committee also anticipates that it is unlikely that future DRI committees PREPUBLICATION COPY: UNCORRECTED PROOFS

KNOWLEDGE GAPS AND FUTURE DIRECTIONS 12-11 will be able to avoid conducting some additional analyses, particularly with respect to intake– response assessment. Thus, future systematic reviews could in principle conduct some intake– response analyses, but future DRI committees may need to perform additional or alternative analyses and employ expert judgement. To better integrate externally conducted systematic reviews into the process, future DRI reviews would do the following: • Develop protocols for conducting post-hoc analyses of systematic reviews to confirm the fidelity of the review, to update the externally conduced review, and to meet unanticipated committee needs in a manner that is transparent and justified. Collecting Evidence to Supplement the Externally Conducted Systematic Reviews In the first step of the DRI organizing framework, the committee assessed the current state of the evidence on potential indicators for the DRIs for adequacy, DRIs for toxicity, and DRIs based on chronic disease. The AHRQ Systematic Review was limited to a review of potassium and sodium intakes on chronic disease outcomes and related risk factors. This meant that the committee had comprehensive data summaries for chronic disease (with the exception of a few potential chronic disease indicators not included in the review), but lacked similar systematic reviews or a sufficient context for evaluating indicators of adequacy and toxicity. The committee performed several scoping literature searches to determine if there were indicators not included in the AHRQ Systematic Review that could potentially inform any of the DRI categories for either potassium or sodium (see Appendix D). The literature scans led the committee to perform comprehensive literature searches for select indicators (see Appendix E). To better integrate different sources of information, future DRI reviews would do the following: • Develop approaches for DRI committees to compile and evaluate available evidence for potential indicators not included in the independently conducted systematic review, to ensure the quality and completeness of the review while minimizing the potential for bias or conflicts of interest. Integrating the Recommendations in the Guiding Principles Report into the DRI Process The Guiding Principles Report was indispensable to the committee’s derivation of the sodium CDRR values, as well as its decision not to establish DRIs based on chronic disease for potassium. Nonetheless, as the committee reviewed the evidence for these two nutrients, it needed to adapt some of the approaches and recommendations outlined by the Guiding Principles Report. First, with respect to indicators of chronic disease, the Guiding Principles Report recommended selection of a single outcome indicator on the causal pathway, but acknowledged the possibility of using multiple indicators (NASEM, 2017). Rather than using any single outcome indicator as the basis for the sodium CDRR, the committee integrated evidence from multiple indicators (cardiovascular disease incidence, hypertension incidence, systolic blood pressure, and diastolic blood pressure), particularly because these indicators are known to be causally linked and evidence supports the relationship between sodium and each indicator. Future DRI committees may find it useful to use multiple, causally linked indicators for PREPUBLICATION COPY: UNCORRECTED PROOFS

12-12 DIETARY REFERENCE INTAKES FOR SODIUM AND POTASSIUM establishing DRIs based on chronic disease, to the extent that such evidence is available for the nutrient or food substance under investigation. Second, the Guiding Principles Report provided guidance that is more applicable to situations in which observational data are used to assess intake–response relationships. For sodium, the strongest data were from randomized controlled trials, with the limitation that most trials only involved a single contrast. Thus, the committee needed to adapt existing intake– response meta-analysis methods to combine multiple trials with different sodium intake levels for the control and intervention groups. Future DRI committees will likely refine the approaches to assess intake–response relationships, depending on available evidence. Third, in the case of sodium, the committee adapted the Guiding Principles Report recommendation that the DRIs based on chronic disease be expressed as a range instead of a single number. This recommendation was based on the premise that chronic disease risk varies with intake, and that there is a range over which increasing or decreasing intakes will reduce risk. The Guiding Principles Report noted that expressing the DRI as a single number might misconstrued as suggesting the existence of a sharp dividing line between risk and no-risk. Conversely, expressing the sodium CDRR as a range might lead to the false impression that any intake within that range is acceptable, as opposed to being a range where reducing intakes is beneficial. As it considered the guidance and recommendations in the Guiding Principles Report to develop the new DRI category—the CDRR—the committee saw the need to provide a description how the CDRR would apply to sodium. For the reasons stated in Chapter 2, the committee adapted the guidance in the Guiding Principles Report and expressed the sodium CDRR as the lowest level of intake for which there was sufficient strength of evidence to characterize a chronic disease risk reduction. As more experience with establishing DRIs based on chronic disease is gained, future DRI efforts would do the following: • Balance the need for consistency over time with the need for refinements as new and unanticipated challenges are encountered. • Develop a general or standardized description of the DRI based on chronic disease category. Providing Additional Guidance on the Expanded DRI Model as Experience Is Gained The Guiding Principles Report provided limited comment on how the DRIs based on chronic disease affect or interact with the other DRI categories. The committee’s experience clarified that the review of the evidence and the decisions about the DRIs based on chronic disease can have implications for the other DRI categories. For potassium, the evidence that was previously considered for the AI in the Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate (2005 DRI Report) (IOM, 2005) was considered in this report for the purposes of establishing a DRI based on chronic disease. This shift, caused by the expansion of the DRI model, narrowed the evidence the committee considered for establishing the potassium DRIs for adequacy. Ultimately, the lack of a specific indicator of potassium adequacy or status led the committee to establish AIs for all DRI age, sex, and life-stage groups. For sodium, the committee considered evidence on chronic disease-related indicators as context for the adequacy DRI, to ensure the selected intake levels would not increase chronic disease risk. Pursuant to a recommendation in the Guiding Principles Report, the committee considered only toxicological adverse effects for establishing ULs. The meaning of UL in this report, therefore, is PREPUBLICATION COPY: UNCORRECTED PROOFS

KNOWLEDGE GAPS AND FUTURE DIRECTIONS 12-13 fundamentally different than the definition used in the 2005 DRI Report. Although it was imperative for the committee to use its collective expert judgement regarding the interrelationship between the DRIs based on chronic disease and the other DRI categories for potassium and sodium, it is beyond the scope of this report to determine how future DRI committees can systematically make such decisions. To create more conceptually consistent DRIs moving forward, future DRI efforts would do the following: • Provide additional guidance on how to address the interrelationship between the DRIs based on chronic disease and the other DRI categories, particularly the AI. A decision- making framework that can be consistently applied to various scenarios would have broad application for future DRI committees. The committee’s methodologies reflect the state of the evidence on potassium and sodium, and do not necessarily establish a definitive methodological blueprint for future DRIs. The type and quantity of evidence, as well as specific health outcomes, will vary for each nutrient and food substance considered under the expanded DRI model. Approaches taken by future DRI will be determined on a case-by-case basis at the expense of consistency across nutrients and DRI committees. As future DRI committees gain experience with the expanded DRI model with other nutrients and food substances, there will likely be greater clarity on which approaches are broadly applicable, as well as which recommendations in the Guiding Principles Report need to be adapted. To this end, future DRI efforts would do the following: • Update and revise the guiding principles, as experience establishing DRIs based on chronic disease is gained. It is beyond the scope of this study to provide definitive guidance on the proper clinical, educational, research, and public health applications of the DRI values in the expanded model. As the sodium CDRR and future DRIs based on chronic disease are used, a greater understanding will emerge of the strengths, limitations, usefulness, and misapplications of this new DRI category. Translating this information for DRI users will help bolster the use and understanding of the expanded DRI model. As such, DRI users would likely benefit from receiving the following: • Revised guidance on using the expanded DRI model for dietary assessment and dietary planning. CONCLUDING REMARKS The committee identified a range of knowledge gaps and critical research needs related to the first two steps of the DRI organizing framework. A prevailing theme was that methods for assessing potassium and sodium intake need to be strengthened to improve accuracy. The committee found it challenging to characterize sodium and potassium requirements and toxicological effects. As the first to apply the guidance in the Guiding Principles Report, the committee determined that evidence on the relationship between sodium intake and chronic disease risk was sufficient to introduce a new DRI category. There remains a need to strengthen PREPUBLICATION COPY: UNCORRECTED PROOFS

12-14 DIETARY REFERENCE INTAKES FOR SODIUM AND POTASSIUM the evidence on the relationship between potassium and/or sodium intake and chronic disease risk. With the expansion of the DRI model, opportunities exist to continue to enhance the process and to provide DRI users with additional guidance on proper application of the reference values. REFERENCES Aburto, N. J., S. Hanson, H. Gutierrez, L. Hooper, P. Elliott, and F. P. Cappuccio. 2013a. Effect of increased potassium intake on cardiovascular risk factors and disease: Systematic review and meta-analyses. BMJ 346:f1378. Aburto, N. J., A. Ziolkovska, L. Hooper, P. Elliott, F. P. Cappuccio, and J. J. Meerpohl. 2013b. Effect of lower sodium intake on health: Systematic review and meta-analyses. BMJ 346:f1326. Anderson, C. A., L. J. Appel, N. Okuda, I. J. Brown, Q. Chan, L. Zhao, H. Ueshima, H. Kesteloot, K. Miura, J. D. Curb, K. Yoshita, P. Elliott, M. E. Yamamoto, and J. Stamler. 2010. Dietary sources of sodium in China, Japan, the United Kingdom, and the United States, women and men aged 40 to 59 years: The INTERMAP study. Journal of the American Dietetic Association 110(5):736- 745. Andersson, M., V. Karumbunathan, and M. B. Zimmermann. 2012. Global iodine status in 2011 and trends over the past decade. Journal of Nutrition 142(4):744-750. Avolio, A. P., K. M. Clyde, T. C. Beard, H. M. Cooke, K. K. Ho, and M. F. O'Rourke. 1986. Improved arterial distensibility in normotensive subjects on a low salt diet. Arteriosclerosis 6(2):166-169. Bailey, R. L., D. C. Mitchell, C. Miller, and H. Smiciklas-Wright. 2007. Assessing the effect of underreporting energy intake on dietary patterns and weight status. Journal of the American Dietetic Association 107(1):64-71. CFIA (Canadian Food Inspection Agency). 2019. Labelling requirements for salt. http://www.inspection.gc.ca/food/general-food-requirements-and-guidance/labelling/for- industry/salt/eng/1391790253201/1391795959629?chap=0 (accessed February 8, 2019). Cook, N. R., J. A. Cutler, E. Obarzanek, J. E. Buring, K. M. Rexrode, S. K. Kumanyika, L. J. Appel, and P. K. Whelton. 2007. Long term effects of dietary sodium reduction on cardiovascular disease outcomes: Observational follow-up of the trials of hypertension prevention (TOHP). BMJ 334(7599):885-888. Dougher, C. E., D. E. Rifkin, C. A. Anderson, G. Smits, M. S. Persky, G. A. Block, and J. H. Ix. 2016. Spot urine sodium measurements do not accurately estimate dietary sodium intake in chronic kidney disease. American Journal of Clinical Nutrition 104(2):298-305. DuPont, J. J., J. L. Greaney, M. M. Wenner, S. L. Lennon-Edwards, P. W. Sanders, W. B. Farquhar, and D. G. Edwards. 2013. High dietary sodium intake impairs endothelium-dependent dilation in healthy salt-resistant humans. Journal of Hypertension 31(3):530-536. Elijovich, F., M. H. Weinberger, C. A. Anderson, L. J. Appel, M. Bursztyn, N. R. Cook, R. A. Dart, C. H. Newton-Cheh, F. M. Sacks, and C. L. Laffer. 2016. Salt sensitivity of blood pressure: A scientific statement from the American Heart Association. Hypertension 68(3):e7-e46. Ershow, A. G., S. A. Skeaff, J. M. Merkel, and P. R. Pehrsson. 2018. Development of databases on iodine in foods and dietary supplements. Nutrients 10(1). Freedman, L. S., J. M. Commins, J. E. Moler, W. Willett, L. F. Tinker, A. F. Subar, D. Spiegelman, D. Rhodes, N. Potischman, M. L. Neuhouser, A. J. Moshfegh, V. Kipnis, L. Arab, and R. L. Prentice. 2015. Pooled results from 5 validation studies of dietary self-report instruments using recovery biomarkers for potassium and sodium intake. American Journal of Epidemiology 181(7):473-487. Gu, D., T. Rice, S. Wang, W. Yang, C. Gu, C. S. Chen, J. E. Hixson, C. E. Jaquish, Z. J. Yao, D. P. Liu, D. C. Rao, and J. He. 2007. Heritability of blood pressure responses to dietary sodium and PREPUBLICATION COPY: UNCORRECTED PROOFS

KNOWLEDGE GAPS AND FUTURE DIRECTIONS 12-15 potassium intake in a Chinese population. Hypertension 50(1):116-122. Gu, D., Q. Zhao, J. Chen, J. C. Chen, J. Huang, L. A. Bazzano, F. Lu, J. Mu, J. Li, J. Cao, K. Mills, C. S. Chen, T. Rice, L. L. Hamm, and J. He. 2013. Reproducibility of blood pressure responses to dietary sodium and potassium interventions: The GenSalt study. Hypertension 62(3):499-505. Harnack, L. J., M. E. Cogswell, J. M. Shikany, C. D. Gardner, C. Gillespie, C. M. Loria, X. Zhou, K. Yuan, and L. M. Steffen. 2017. Sources of sodium in US adults from 3 geographic regions. Circulation 135(19):1775-1783. He, J., L. G. Ogden, S. Vupputuri, L. A. Bazzano, C. Loria, and P. K. Whelton. 1999. Dietary sodium intake and subsequent risk of cardiovascular disease in overweight adults. JAMA 282(21):2027- 2034. He, J., D. Gu, J. Chen, C. E. Jaquish, D. C. Rao, J. E. Hixson, J. C. Chen, X. Duan, J. F. Huang, C. S. Chen, T. N. Kelly, L. A. Bazzano, and P. K. Whelton. 2009. Gender difference in blood pressure responses to dietary sodium intervention in the GenSalt study. Journal of Hypertension 27(1):48- 54. He, F. J., N. R. C. Campbell, Y. Ma, G. A. MacGregor, M. E. Cogswell, and N. R. Cook. 2018. Errors in estimating usual sodium intake by the Kawasaki formula alter its relationship with mortality: Implications for public health. International Journal of Epidemiology 47(6):1784-1795. Holbrook, J. T., K. Y. Patterson, J. E. Bodner, L. W. Douglas, C. Veillon, J. L. Kelsay, W. Mertz, and J. C. Smith, Jr. 1984. Sodium and potassium intake and balance in adults consuming self-selected diets. American Journal of Clinical Nutrition 40(4):786-793. Huang, L., M. Crino, J. H. Wu, M. Woodward, F. Barzi, M. A. Land, R. McLean, J. Webster, B. Enkhtungalag, and B. Neal. 2016. Mean population salt intake estimated from 24-h urine samples and spot urine samples: A systematic review and meta-analysis. International Journal of Epidemiology 45(1):239-250. IOM (Institute of Medicine). 2005. Dietary Reference Intakes for water, potassium, sodium, chloride, and sulfate. Washington, DC: The National Academies Press. IOM. 2010. Strategies to reduce sodium intake in the United States. Washington, DC: The National Academies Press. Israr, T., A. Rakha, M. Sohail, S. Rashid, and A. Shehzad. 2016. Salt reduction in baked products: Strategies and constraints. Trends in Food Science & Technology 51:98-105. Iwahori, T., K. Miura, and H. Ueshima. 2017. Time to consider use of the sodium-to-potassium ratio for practical sodium reduction and potassium increase. Nutrients 9(7). Ji, C., L. Sykes, C. Paul, O. Dary, B. Legetic, N. R. Campbell, and F. P. Cappuccio. 2012. Systematic review of studies comparing 24-hour and spot urine collections for estimating population salt intake. Revista Panamericana de Salud Publica 32(4):307-315. Kelly, T. N., and J. He. 2012. Genomic epidemiology of blood pressure salt sensitivity. Journal of Hypertension 30(5):861-873. Koleganova, N., G. Piecha, E. Ritz, L. E. Becker, A. Muller, M. Weckbach, J. R. Nyengaard, P. Schirmacher, and M. L. Gross-Weissmann. 2011. Both high and low maternal salt intake in pregnancy alter kidney development in the offspring. American Journal of Physiology: Renal Physiology 301(2):F344-354. Lerchl, K., N. Rakova, A. Dahlmann, M. Rauh, U. Goller, M. Basner, D. F. Dinges, L. Beck, A. Agureev, I. Larina, V. Baranov, B. Morukov, K. U. Eckardt, G. Vassilieva, P. Wabel, J. Vienken, K. Kirsch, B. Johannes, A. Krannich, F. C. Luft, and J. Titze. 2015. Agreement between 24-hour salt ingestion and sodium excretion in a controlled environment. Hypertension 66(4):850-857. Leung, A. M., L. E. Braverman, and E. N. Pearce. 2012. History of U.S. iodine fortification and supplementation. Nutrients 4(11):1740-1746. Mandy, M., and M. Nyirenda. 2018. Developmental origins of health and disease: The relevance to developing nations. Int Health 10(2):66-70. Mente, A., M. J. O'Donnell, G. Dagenais, A. Wielgosz, S. A. Lear, M. J. McQueen, Y. Jiang, W. Xingyu, B. Jian, K. B. Calik, A. A. Akalin, P. Mony, A. Devanath, A. H. Yusufali, P. Lopez-Jaramillo, A. PREPUBLICATION COPY: UNCORRECTED PROOFS

12-16 DIETARY REFERENCE INTAKES FOR SODIUM AND POTASSIUM Avezum, Jr., K. Yusoff, A. Rosengren, L. Kruger, A. Orlandini, S. Rangarajan, K. Teo, and S. Yusuf. 2014. Validation and comparison of three formulae to estimate sodium and potassium excretion from a single morning fasting urine compared to 24-h measures in 11 countries. Journal of Hypertension 32(5):1005-1014; discussion 1015. Mills, K. T., J. Chen, W. Yang, L. J. Appel, J. W. Kusek, A. Alper, P. Delafontaine, M. G. Keane, E. Mohler, A. Ojo, M. Rahman, A. C. Ricardo, E. Z. Soliman, S. Steigerwalt, R. Townsend, and J. He. 2016. Sodium excretion and the risk of cardiovascular disease in patients with chronic kidney disease. JAMA 315(20):2200-2210. Murtaugh, M. A., J. M. Beasley, L. J. Appel, P. M. Guenther, M. McFadden, T. Greene, and J. A. Tooze. 2018. Relationship of sodium intake and blood pressure varies with energy intake: Secondary analysis of the DASH (Dietary Approaches to Stop Hypertension)-sodium trial. Hypertension 71(5):858-865. Musso, N., L. Conte, B. Carloni, C. Campana, M. C. Chiusano, and M. Giusti. 2018. Low-salt intake suggestions in hypertensive patients do not jeopardize urinary iodine excretion. Nutrients 10(10). NASEM (National Academies of Sciences, Engineering, and Medicine). 2017. Guiding principles for developing Dietary Reference Intakes based on chronic disease. Washington, DC: The National Academies Press. Newberry, S. J., M. Chung, C. A. M. Anderson, C. Chen, Z. Fu, A. Tang, N. Zhao, M. Booth, J. Marks, S. Hollands, A. Motala, J. K. Larkin, R. Shanman, and S. Hempel. 2018. Sodium and potassium intake: Effects on chronic disease outcomes and risks. Rockville, MD: Agency for Healthcare Research and Quality. Rodriguez, C. J., K. Bibbins-Domingo, Z. Jin, M. L. Daviglus, D. C. Goff, Jr., and D. R. Jacobs, Jr. 2011. Association of sodium and potassium intake with left ventricular mass: Coronary artery risk development in young adults. Hypertension 58(3):410-416. Sacks, F. M., L. P. Svetkey, W. M. Vollmer, L. J. Appel, G. A. Bray, D. Harsha, E. Obarzanek, P. R. Conlin, E. R. Miller, 3rd, D. G. Simons-Morton, N. Karanja, and P. H. Lin. 2001. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. New England Journal of Medicine 344(1):3-10. Tain, Y. L., and C. N. Hsu. 2017. Developmental origins of chronic kidney disease: Should we focus on early life? International Journal of Molecular Sciences 18(2). Tasevska, N., S. A. Runswick, and S. A. Bingham. 2006. Urinary potassium is as reliable as urinary nitrogen for use as a recovery biomarker in dietary studies of free living individuals. Journal of Nutrition 136(5):1334-1340. Todd, A. S., R. J. Macginley, J. B. Schollum, R. J. Johnson, S. M. Williams, W. H. Sutherland, J. I. Mann, and R. J. Walker. 2010. Dietary salt loading impairs arterial vascular reactivity. American Journal of Clinical Nutrition 91(3):557-564. Turban, S., C. B. Thompson, R. S. Parekh, and L. J. Appel. 2013. Effects of sodium intake and diet on racial differences in urinary potassium excretion: results from the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial. American Journal of Kidney Diseases 61(1):88-95. Weaver, C. M., B. R. Martin, G. P. McCabe, L. D. McCabe, M. Woodward, C. A. Anderson, and L. J. Appel. 2016. Individual variation in urinary sodium excretion among adolescent girls on a fixed intake. Journal of Hypertension 34(7):1290-1297. PREPUBLICATION COPY: UNCORRECTED PROOFS

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As essential nutrients, sodium and potassium contribute to the fundamentals of physiology and pathology of human health and disease. In clinical settings, these are two important blood electrolytes, are frequently measured and influence care decisions. Yet, blood electrolyte concentrations are usually not influenced by dietary intake, as kidney and hormone systems carefully regulate blood values.

Over the years, increasing evidence suggests that sodium and potassium intake patterns of children and adults influence long-term population health mostly through complex relationships among dietary intake, blood pressure and cardiovascular health. The public health importance of understanding these relationships, based upon the best available evidence and establishing recommendations to support the development of population clinical practice guidelines and medical care of patients is clear.

This report reviews evidence on the relationship between sodium and potassium intakes and indicators of adequacy, toxicity, and chronic disease. It updates the Dietary Reference Intakes (DRIs) using an expanded DRI model that includes consideration of chronic disease endpoints, and outlines research gaps to address the uncertainties identified in the process of deriving the reference values and evaluating public health implications.

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