Percentage of ingested sodium excreted in 24‐hour urine collections: A systematic review and meta‐analysis

High dietary sodium is estimated to be the leading dietary risk for death and disability according to the Global Burden of Disease Study.1, 2 The health risk associated with dietary sodium is largely related to a direct relationship between increasing dietary sodium and increasing blood pressure. Notably, increased blood pressure is a leading global risk factor for death and disability causing approximately 50% of cardiovascular disease.3 In both observational and interventional studies, 24-hour urine sodium excretion is often used as the “gold standard” to estimate dietary sodium. Although it is generally stated that approximately 90% of dietary sodium is excreted in 24-hour urine collections,4 to our knowledge, there has been no systematic review of the percentage of ingested sodium excreted in the urine. Previous studies in healthy people have reported that 24-hour urine sodium excretion accounts for 61%-107% of ingested sodium.5 We have conducted a systematic review of studies that examined the percentage of sodium excreted in 24-hour urine collections in study participants ingesting known quantities of sodium. Accurately defining the percentage of dietary sodium excreted in urine is important to assess the validity of using urine excretion studies as the best evidence for assessing relationships between dietary sodium and health. This systematic review was conducted with the support of the TRUE consortium.6 The TRUE consortium formed because of concerns that low-quality research was causing controversy about the health impact of dietary sodium.7 Specifically, studies that inadequately assess dietary sodium may be susceptible to drawing false conclusions between sodium intake and health outcomes. The TRUE consortium will provide recommendations about minimum and desirable standards for the conduct of research and also conduct systematic reviews of outcome studies that meet the minimum standards as part of a process to ensure clinical and population recommendations for dietary sodium are based on reliable, reproducible research. To establish the percentage of ingested sodium that is excreted in urine, we included only studies that rigorously assessed the amount of sodium ingested and the amount of sodium excreted in 24-hour urine collections in individuals on a prescribed intake of dietary sodium. To ensure adherence to prescribed dietary sodium, eligible studies had to either provide meals with known content of sodium to participants or record the weight of food ingested and the food samples be subsequently analyzed for sodium content. To be included, studies had to have adult participants and ensure adherence to a constant quantity of dietary sodium for a minimum of 3 days, to ensure participants were at a “steady state” of urine sodium excretion relative to ingested sodium. Additionally, studies were excluded if the participants had any acute or major chronic illnesses (eg, heart failure), or acute change in physical activity or heat exposure or ingestion of drugs (eg, furosemide) that may have altered sodium absorption, metabolism, or excretion. Studies involving participants with stable chronic health risks such as hypertension were included. Medline, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and the World Health Organization (WHO) International Clinical Trials Registry Platform were searched to identify potential studies. Search terms were developed with a librarian and tailored for each database (see Appendix A). The search terms for each database were developed to capture studies that evaluated our surrogate measure (24-hour urine sodium excretion) and our reference standard (sodium/salt, dietary consumption). The WHO Clinical Trials database used a broader set of terms because of restrictions caused by the search engine user interface. No language or date restrictions were applied. All searches were performed on October 3, 2016. All studies identified were initially screened using a title-abstract review, followed by a full-text review. Disagreements for article inclusion were resolved through consensus between 2 reviewers (AL and CD). Studies identified as suitable through the full-text review were subject to data extraction for the following variables: (1) health status; (2) sex; (3) study design; (4) sample size; (5) the duration of dietary intervention; (6) prescribed daily sodium intake; (7) 24-hour urine sodium excretion; (8) prescribed potassium intake or excretion; and (9) study environment (controlled study [conducted in a research facility] vs uncontrolled study [conducted in free living subjects]. Cochrane Collaboration tool for assessing risk of bias was used to score biases and quality of each study8. Cochrane's tool contains measures that identify selection, performance, detection, attrition, and reporting bias. The percentage of daily sodium intake excreted in 24-hour urine samples was calculated by dividing sodium excreted in mg by daily sodium intake in mg and multiplying by 100. Once the percentage of daily sodium excreted was calculated, the standard error of the amount of excreted urine was used to calculate the 95% confidence interval (CI) for the percentage of daily sodium excreted. To calculate the 95% CI, the mean sodium excreted was added or subtracted (for the upper and lower ranges of confidence) to the z value of 1.96, multiplied by the standard error divided by the daily sodium intake. Studies that did not provide standard errors were excluded from the meta-analysis as it was not possible to calculate the confidence intervals (n = 2), but these studies were included in the descriptive analysis9, 10. A meta-analysis was performed on all percentages of sodium excretion provided in each study (n = 35). A random effects model with inverse-variance weighting was used, as we expected that each of the study point estimate(s) would differ based on varying study conditions and characteristics (eg, age of participants across studies differed). Heterogeneity was assessed using the I2 statistic. Subgroup analysis was performed on the following variables: potassium intake (calculated as either having a potassium intake above or below the sample mean of 77.6 mmol/d (n = 22) and also calculated as a continuous variable, study environment (controlled [study conducted in a research facility] vs uncontrolled [study conducted in free living subjects outside of a research facility]), sex (male, female), sodium intake range, health status, dietary sodium changes (low to high, high to low, and no direction), length of steady state (3, 4-5, and 7 or more days), and study rigor. An additional subgroup analysis was conducted on those studies with sodium intake < 1000 mg/d, and length of steady state. A random effects metaregression was also performed on all subgroup analyses to obtain P values for the differences between subgroups. Sodium intake levels were as previously defined by Campbell and colleagues, based on the paleolithic diets human evolved on, long-term physiologic studies, and the World Health Organization dietary recommendations, where low daily sodium intake was defined as < 100 mg, normal-physiological intake as 100 to < 1000 mg, recommended intake as 1000 mg to < 2000 mg, high intake as ≥ 2000 mg to 4000 mg, very high intake as > 4000 to 6000 mg, and extremely high intake as > 6000 mg.11 Study rigor was considered high if dietary intake was assessed with a known unbiased reference measure (denominator) and the 24-hour urine collections were high quality. Known unbiased reference measures for sodium intake include (1) controlled feeding studies or (2) direct observation.12 Controlled feeding studies provide meals and carefully monitor the amount of food consumed.13 High-quality 24-hour urine collections were arbitrarily defined as including provision of explicit instructions for collection, an assessment of completion of 24-hour urine collection (eg, creatinine criteria, para-aminobenzoic acid recovery) and at least 80% of urine specimens meeting completion criteria.14 Age was not assessed as a subgroup as there was inconsistent reporting of age across studies. Studies that may have potentially influenced the final estimates and heterogeneity (ie, high risk of bias, studies that did not assess completeness of 24-hour urine collections or that included incomplete 24-hour urine samples, and studies with larger changes in sodium intake over a shorter period in time where steady state sodium excretion may not have been achieved) were removed as part of the sensitivity analysis to assess whether the findings were robust. In most cases, studies assessed sodium excretion as a secondary rather than primary objective. Therefore, we did not consider publication bias. The search of the 5 electronic databases retrieved 6754 articles (Figure 1). After removing duplicate studies in the literature searches, 5264 unique studies were identified for the title/abstract search. The title and abstract search identified 392 (95% consensus between 2 reviewers) relevant articles that then underwent a full-text review. Of those, 359 were excluded because they did not meet the inclusion criteria for sodium intake and 24-hour urine excretion measurements. Two more articles were excluded from the meta-analysis because the data they provided did not allow a confidence interval to be calculated.9, 10 Two studies were also removed because they included participants or used methodologies that may have affected sodium steady state.15, 16 These 2 articles were still included during data extraction but not in the meta-analysis. Six additional studies were found from the reference lists of review articles that were identified during the literature search. A final 35 articles were included in the meta-analysis (Appendix B)17-51. All studies included in the analysis were prospective and were either randomized controlled parallel group trials (n = 10) or randomized crossover trials (n = 25). Participants in each study ranged from 18 to 80 years of age and were considered to be either healthy (n = 22) or have chronic health risks such as hypertension (n = 13). The studies used different schedules for urine sample collection, different methods for assessing completeness of 24-hour urine collections and for ensuring dietary adherence. Only 2 of the studies17, 18 included had a primary objective of assessing the quantity of ingested sodium excreted in urine. Figure 2 provides a forest plot for the pooled percentage of dietary sodium excretion in each study. The pooled estimate for the percentage of sodium excreted in urine for all studies included in the meta-analysis was 92.8% (95% CI 90.7, 95.0, heterogeneity 95.1%, P < 0.001). Several studies reported levels for potassium intake, or potassium excretion. Studies that reported potassium intake exhibited a mean potassium intake or excretion of < 77.6 mmol/d (n = 10) yielded a pooled estimate of 90.1% (95% CI 84.9, 95.3, heterogeneity 93.7, P < 0.001) for percentage of ingested sodium that was excreted in urine. The pooled estimate of sodium excretion for studies with potassium intake or excretion > 77.6 mmol/day (n = 12) was 106.6% (95% CI 100.7, 112.6, heterogeneity 95.1%, P < 0.001). Dietary potassium (as a continuous variable) was not significantly related to the percentage of sodium excreted (P = 0.257). Studies that took place in controlled research facilities (eg, metabolic wards, sealed chambers, hospitals; n = 7) demonstrated a percentage excretion of ingested sodium of 83.6% (95% CI 80.5, 86.7, heterogeneity 72.3%, P < 0.001). In comparison, participants in studies that were conducted in uncontrolled environments (n = 28) excreted 100.6% (95% CI 97.6, 103.7, heterogeneity 96.8%, P < 0.001) of ingested sodium intake. The percentage of sodium excreted did not differ between the study environments (controlled vs uncontrolled, P = 0.056). Studies with controlled environments did not appear to have any systematic differences in methodology (eg, low dietary sodium, short dietary periods, etc.) compared to studies with uncontrolled environments. In studies that reported sex-specific data, sex-specific estimates of urine sodium excretion were calculated. In studies that reported data in males only (n = 16), the pooled estimate of ingested sodium that was excreted in 24-hour urine was 97.4% (95% CI 94.2, 100.6, heterogeneity 95.6% P < 0.001). Only 3 studies reported data in female participants; the percentage of dietary sodium excreted in urine was 93.2% (95% CI 86.1, 100.2, heterogeneity 79.1% P < 0.001). The percentages of sodium excreted by males and females were not significantly different (P = 0.481). Many studies reported sodium excretion, with differing levels of sodium intake.11 Sodium intakes were categorized according to standardized nomenclature in the following ranges: low (< 100 mg sodium/d, n = 0), normal-physiologic (100-< 1000 mg sodium/day, n = 17), recommended (1000 -< 2000 mg sodium/d, n = 6), high (≥ 2000-4000 mg sodium/d, n = 13), very high (≥ 4000-6000 mg sodium/d, n = 11), and extremely high (> 6000 mg sodium/d, n = 10). Within the normal-physiologic range of sodium intake (100 to < 1000 mg/d), mean urine sodium excretion was 140.6% (95% CI 123.1, 158.1, heterogeneity 96.3%, P < 0.001). Studies that fell into the recommended (1000 to < 2000 mg/d) and high ranges of sodium intake (2000-4000 mg/d) reported pooled estimates of sodium excretion of 104.5% (95% CI 88.9, 120.1, heterogeneity 95.2%, P < 0.001) and 90.1% (95% CI 85.7, 94.4, heterogeneity 97.9%, P < 0.001), respectively. Studies with very high intake (sodium > 4000 to 6000 mg/d) reported pooled estimates of sodium excretion of 98.8% (95% CI 92.0, 105.5, heterogeneity 88.4%, P < 0.001) and the studies with extremely high levels of sodium intake (sodium > 6000 mg/d) had a pooled estimate of 86.4% (95% CI 81.2, 91.6, heterogeneity 94.7%, P < 0.001). The percentage of sodium excreted was not different for recommended, very high, and extremely high compared to high sodium intake (P = 0.093, P = 0.284, P = 0.641 respectively). However, normal-physiological sodium intake had a higher percentage excretion of sodium compared with high levels of sodium intake (P < 0.001). Studies assessing healthy populations (n = 25) had a pooled 24-hour excretion of ingested sodium estimate of 93.7% (95% CI 90.5, 96.8, heterogeneity 97.1%, P < 0.001). Comparatively, in the studies with participants who had chronic health risks, such as diabetes and hypertension (n = 9), the pooled estimate of urine sodium excretion was 109.7% (95% CI 102.8, 116.7, heterogeneity 96.2%, P < 0.001). The presence of health risks did not significantly affect the percentage of sodium excreted (P = 0.073). Studies that had dietary protocols that changed from low sodium intake to high sodium intake (n = 13) had a pooled estimate of 100.5% (95% CI 94.4, 106.7, heterogeneity 95.5%, P < 0.001) sodium excretion compared to studies with no directionality to dietary changes (n = 22) with a pooled estimate of 97.2% (95% CI 93.9, 100.4, heterogeneity 97.0%, P < 0.001). There were no significant differences in percentage of urine sodium excretion between the diets that increased sodium intake and those with no change in sodium intake (P = 0.745). There were no studies that had dietary protocols that changed from high to low sodium intake. Studies with stable dietary sodium intervention periods of 3 days before urine sampling (n = 5) had a pooled estimate of 114.4% (95 CI 95.1, 33.6, heterogeneity 96.4% P < 0.001). Studies that had stable dietary sodium intervention periods of 4 or 5 days before sampling (n = 9) had a pooled estimate of 109.9% (95% CI 101.5, 118.3, heterogeneity 95.4%, P < 0.001) excretion, whereaas studies with 7 days or more days of stable dietary sodium intervention before sampling (n = 21) had pooled estimates of 93.9% (95% CI 90.8, 96.9, heterogeneity 97.1%, P < 0.001). The length of dietary intervention did not significantly affect the percentage of sodium excreted (P = 0.742). Studies that had high-quality dietary assessment methods and 24-hour urine sodium excretion measures (n = 3) reported a pooled estimate of 91.8% (95% CI 89.1, 94.5, heterogeneity 79.8%, P = 0.001), whereas studies that did not meet the criteria for high-quality diets and 24-hour urine sodium excretion measures (n = 32) reported a pooled estimate of 100.3% (95% CI 96.4, heterogeneity P < 0.001). Studies categorized as having low sodium intake were analyzed with to assess the between the length of steady state and sodium excretion (Figure The length of steady state did not affect the percentage of sodium excreted (P = studies were removed from the pooled as as each of the to to identify potential of heterogeneity and Studies were removed for not incomplete urine a high risk of and for having a change in sodium intake of over The heterogeneity of the pooled estimate did not change by more than each of the studies was removed from the The sensitivity analysis was also to each of the where the change in heterogeneity was from to was removed on a very change in sodium intake in the high potassium intake All heterogeneity changed by than during the sensitivity studies were to the analysis but still included data that be the conclusions of Two of these studies did not meet criteria because of an intervention the participants to a 16 The 2 studies did not include data for urine sodium excretion and not be used in the 10 The studies ranged between and with 2 studies 16 Two studies urine sodium on a stable for 5 days or 2 urine sodium at either 3 or 4 days of a stable Two of the studies assessed 10 and had 3 sodium intake levels of and during acute heat exposure and urine sodium excretion ranged from to and had and sodium intake levels during acute heat exposure and a sodium excretion range of to and and and both had 2 levels of sodium intake of and and and mg/d, and sodium excretion values between to and to 10 The pooled estimate from meta-analysis that on 92.8% of 24-hour dietary sodium was excreted in 24-hour urine This meta-analysis included only studies where participants had a constant amount of sodium in diets for a minimum of 3 participants in studies that included assessment of dietary sodium and collection of 24-hour urine, percentages of dietary sodium were excreted in reported of sodium ingested was excreted in 24-hour urine on a dietary during a study that included 4 of assessment of dietary sodium intake and urine excretion and reported of sodium was excreted in 24-hour in a there is a change in dietary sodium, it 3 or more days before a steady state urine excretion of sodium is Therefore, in the of changes in dietary sodium, meta-analysis 24-hour urine sodium is a estimate of 24-hour dietary sodium in a study However, most people sodium intake to to and often to a very carefully conducted study found and in sodium excretion people were on a constant sodium there is no to a 24-hour urine sodium to an long-term sodium intake. Several studies support the for 24-hour urine to for daily of dietary intake and long-term changes in sodium excretion to assess an sodium The 24-hour urine sodium included in the percentage of sodium excreted between studies leading to high the excretion of ingested sodium from to (Figure The heterogeneity be the is that in sodium in the and in 24-hour urine accounts of of the heterogeneity in the percentage of dietary sodium excreted. The studies were based on criteria that collection of 24-hour and assessment of the amount of dietary sodium that was However, we there was a of quality to ensure the of and adherence to dietary sodium and criteria to assess and incomplete 24-hour urine The of dietary assessment of sodium intake have been and include and and in food In at least study that reported the sodium content in the there was from the amount of sodium the study to most studies did not the diets and there is no that additional sodium was not added to the or that more or food was than In it is that there was in the completeness of 24-hour urine samples individuals and between studies. 24-hour urine collections are in research studies and will to of the amount of sodium urine is and in of sodium excretion. We in methods used to incomplete urine The different methods for incomplete urine collections in differences in estimated dietary we examined the 3 studies that most carefully assessed dietary sodium and completeness of urine the excretion was to that in the meta-analysis vs 92.8% of ingested sodium excreted in 24-hour in dietary sodium and incomplete 24-hour urine collections that have been reported to affect estimates of sodium excretion include health status, status, and dietary that may have not been reported in the in sodium excretion has also been during between and studies, with studies relationships between dietary and sodium We did not an impact of different levels of stable potassium intake on the percentage of dietary sodium excreted but not an of changes in potassium intake. Studies for potential reporting sodium excretion and 24-hour urine There was also in the mean percentage excretion of dietary sodium in the subgroup analysis normal-physiological sodium intake to the high intake Studies included in the sodium intake group (100 to < 1000 mg/d) often had > of ingested sodium excreted. The > sodium excretion found in studies may a of adherence to the lower dietary sodium or in sodium excretion. is also possible because of a of sodium intake as part of the participants had not a steady state of sodium excretion relative to intake. In our subgroup analysis the length of steady state at lower sodium intake it was whether are to steady state. Previous studies changes in intake of sodium approximately 3 days are to a steady state for the study sodium In our subgroup of all levels of dietary sodium, steady state diets than 3 days did not the percentage of dietary sodium excreted. An important of study is the of The on dietary protocols to ensure metabolic steady state may not participants who have varying dietary protocols (eg, change in sodium individuals with acute health physical exposure to high that affect sodium excretion, or chronic may different percentages of Therefore, 24-hour urine sodium during acute dietary acute changes in physical or may not be to sodium intake The meta-analysis found that approximately of dietary sodium is excreted in urine. The primary and subgroup analyses had heterogeneity that may in part be by a of quality in assessing dietary intake of sodium and the completeness of 24-hour urine the percentage excretion of each subgroup analysis was to support for using 24-hour urine collections to assess dietary sodium intake for the of approximately of dietary is that changes to and to to a intake, 24-hour urine samples are The would to the of in the search terms used in as as and for on the of the TRUE consortium include the and of the World International of and International of International of of Clinical Health Health Organization on Dietary World World The findings and conclusions in article are those of the and not the of the for Disease and is a of on Health and World on Health and are and not any support from or is of of and on and are not any support from any of these was a to the to support to hypertension in of low to support for and a to a has provided on blood pressure assessment to and is an of World on and Health is a to has no of to The is not for the content or of any by the than be to the for the

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