Practical and valid approaches in quantifying sodium intake in population studies

Sodium (salt in food) plays essential roles in the body's physiology and regulation of body processes in the maintenance of life [1–3]. Prior to the invention of modern technologies enabling food refrigeration and preservation, salt was essential in preserving food, particularly in temperate countries in winter months when fresh food was less readily available and in warm countries where food spoiled quickly. The effectiveness of salt in this regard and its relative scarcity and high cost until modern times has influenced society's beliefs and attitude towards salt in food preparation and nutrition. Its importance is such that although it seems cheap and readily available nowadays, its trade had been a government-controlled monopoly in many places in the past. Thus, it is ironic that today the major debate is on whether we ingest too much of it [4,5]. Excessive sodium is believed by many to be responsible for hypertension [4–7]. It is also believed that if daily intake of sodium is reduced by nearly half from the normal daily intake of approximately 3.5–4.0 g in Western society, hypertension would no longer be a major cardiovascular risk factor [4–7]. This would in turn reduce its contribution to the burden of cardiovascular disease. Others, however, believe that the evidence for this belief, and recommendation to reduce sodium intake to 2.0–2.5 g daily, has not been adequately established to support this recommendation [8–11]. Moreover, it was pointed out that, given its physiological role, excessively low sodium intake could be associated with increased cardiovascular disease (CVD) risk due to unforeseen and unintended consequences of the low sodium intake [1–3,10]. Moreover, reducing sodium intake to such levels on a society-wide approach has not been shown to be practical or feasible [8]. Only through systematic collection of data could we address these questions and settle the debate. To determine whether too much or just enough sodium is ingested by a population, accurate measurements of usual daily intake in large population studies are needed [12,13]. For a long time, the amount of salt or sodium a person takes has been estimated from self-report methods, in the same way that nutritional scientists estimate the amount of ingested fats or carbohydrates in food. Such estimates are necessarily accompanied by measurement errors in assessing absolute intake and generally do not account for discretionary sodium use, that is, at the table or during cooking. Alternatively, direct measurement of the total amount of sodium excreted in the urine over 24 h by an individual has been regarded as more accurate and reproducible. The assumption with this method is that, in the healthy steady state, the amount of sodium excreted over a period of time, that is, over 24 h, would be equal to the amount ingested. With this simple concept and the perception that collection of the total amount of urine produced by an individual could be collected over 24 h, the task would be uncomplicated and easily achievable. This has now become the reference or gold standard against which other methods of estimating 24-h sodium intake are compared [14]. Nevertheless, the 24-h urine collection method does have its drawbacks, which could contribute substantially to the margins of error [14]. The commonest drawback is undercollection for any number of reasons. It is not uncommon for participating individuals to forget collecting one or more voids of urine during the period of collection, thus reducing the volume of urine and therefore the amount of sodium excreted. At other times, perhaps due to misunderstanding of instructions, the participants may have overcollected the volume of urine, leading to an overestimate. In addition to issues of errors in collection, sodium is also lost in sweat, faeces and other bodily fluids and therefore unaccountable in the urine collection. In countries with warm climate, the amount of sodium lost in the sweat may be considerable but unaccounted for in the 24 h of collected urine in the profusely sweating individuals carrying out heavy labour. Furthermore, in addition to high rates of incomplete sample collection, the method involves high participant burden and therefore low response rates. Studies have shown that the number of individuals who do not properly collect 24-h urine samples can be as high as 30% and their data are usually excluded [14–16]. Therefore, when used in epidemiological research, the use of 24-h urines would result in the exclusion of a large number of participants, thereby increasing the risk of bias. It can be concluded that there is no such thing as a ‘best’ method for measuring sodium intake, as different approaches are appropriate for different questions, for example multiple 24-h urine collection is the right approach where one wants to document the absolute level of sodium in a population or in smaller studies to assess the impact on blood pressure (BP). On the other hand, such an approach may not be necessary and in fact may be a hindrance in trying to get reliable estimates of the association between sodium intake and rare clinical outcomes. This is why simple, practical and valid approaches are needed for large population studies. Our own experience in assessing dietary sodium and potassium intake in Canadians using the 24-h urinary collection method has shown to us the challenges in collecting 24-h urine properly from 1700 participants (mean age 59.6 years) in the PURE study [17]. We were aware of the challenges of incomplete collection and we opted to administer para-aminobenzoic acid (PABA), which is a nontoxic substance as a marker of completeness of 24-h collection. It does not undergo metabolism and is almost completely cleared by the kidneys within 24 h. We used PABA in participants who were 65 years or younger and in whom PABA was not contraindicated [17]. In a pilot study, we learned that incomplete collection could be readily detected and the lessons learned allowed us to further instruct participants on the proper urinary collection. Thus, participants were given written instructions and reminders on how to collect the 24-h urine sample and not to ‘miss any single drop’. They were asked to discard the first urine voided on the day of their collection and to collect all urine voided on the day of collection for 24 h, ending with the first urine void the following morning. We found that PABA recovery results showed that 89.4% of individuals who reported taking PABA tablets had a percentage recovery within the reference range (70–110%) and about 10% had amounts that were above or below this range. This showed that in a high-income country like Canada, almost complete collection of 24-h urine was possible when participants are given clear instructions and reminders but that even in this environment, incomplete collection can occur in an educated and motivated population. We found that the average 24-h sodium excretion in this Canadian study population was 3325 mg/day (95% confidence interval 3255–3395 mg/day) and that excretion values appeared slightly higher, but not substantially so, in individuals whose age was over 65 years and not administered the PABA [17]. Although this and other studies have shown that measuring 24-h urine excretion was possible, the challenges in ensuring complete collection are formidable and too complex for adapting to studies of salt (sodium) intake in large populations given the challenges of ensuring the need for complete collection. Further, the logistics of collecting, storing and transporting the 24-h samples for processing in local laboratories and then stored frozen before transportation to central laboratories for longer term storage and analysis of sodium and other substances are similarly formidable. For this reason, the estimation of 24-h excretion (or intake) using spot urine samples has proven to be attractive. In the article published in the current issue of the Journal, Petersen et al.[18] estimated population salt intake in two states in India, comparing the 24-h urine collection method to five different validated spot urine methods using the Tanaka, Mage, INTERSALT, Toft and Kawasaki equations. The authors found that although the first three equations in this list resulted in amounts of sodium that were quite close to the 24-h collection estimates, the latter two had substantially overestimated the excretion. Although some people may think, from these results, that some equations performed better than others due to inherent strengths or weaknesses, other reasons may account for these variations. The equations were originally validated under strict methodology. For example, the Kawasaki method requires a ‘morning fasting urine’ sample, that is the second urine sample voided in the morning before breakfast and after the participant has voided the overnight sample [19]. Unsurprisingly, the use of a random morning sample without adherence to such strict conditions would be associated with wide margins of error. Clearly, strict adherence to the conditions of collection and analyses as described in the validation methods is essential in reducing the margins of error. If one were to compare the procedure of quantifying sodium intake to that of the process of assaying a chemical in a laboratory, then the strict methodology comparable to the strict protocol in place in the laboratory should be followed. Deviations from the protocol, as it appeared to have been the case in this study, would not lead to reliable results. Mente et al.[20] reported on the outcomes on validation and comparison of three formulae in estimating sodium and potassium excretion from a single morning fasting urine compared with 24-h measures in 11 countries. The authors found that the intraclass correlation coefficient (ICC) between estimated and measured sodium excretion was higher with the Kawasaki formula (ICC 0.71 compared with INTERSALT ICC 0.49 and Tanaka 0.54). In the 1083 participants in this study, from the general population in 11 countries with variable economic development, the Kawasaki equation provided the best agreement and least bias. In this study, the BP correlated most closely and similarly with the 24-h and Kawasaki estimates for sodium compared with the other two formulae. Petersen et al.[18] also noted that there were instances of incomplete collections in the 24-h collections the results of which were or were not used in this study. In situations where participants do not recall having missed collecting one or more voids, the results would inevitably be used and could cause underestimation of the levels. The authors also reported that some participants had reported collecting samples for more or less than 24 h, for example 23 or 25 h. The authors then standardized the amount of total sodium over a 24-h period by standardizing the collection time to 24 h. Such adjustment of sodium excretion values from the reference method can contribute to a wide margin of error, when comparing the excretion values to formulae estimates. The study by Petersen et al.[18] did not relate the sodium values from each method (formula-based and 24-h urine collections) to SBP and DBP, an independent physiological measure in the same participants, which could shed light on whether or not any one method is superior in relation to BP and whether it matters if one method is used over another, or if simpler methods give similar or different results compared to 24-h urine. This is an important point, considering three cohort studies using 24-h urine collections also showed that low sodium, versus moderate sodium intake, is associated with increased CVD events or mortality [15,21–23]. More work is needed to validate the different methods against BP measures. It is clear that there is a need for strictly adhering to the methodology in estimation of sodium intake by assessing 24-h collection of urine or by a spot urine sample. It is also clear that 24-h urine collection is not feasible in large population studies. In the ongoing debate on whether the amount of sodium (salt) ingested by most populations is too high or just right, the debate should not be on insisting that the ‘reference standard’ should be 24-h urine collection measurement, and this must be used despite known challenges with the method or that one or another spot urine method are misleading. Just as there are strict rules in the biochemistry or other laboratories, methods in the analyses of chemicals or molecules, strict methodology should be followed in the collection of the spot urine used in estimating sodium intake. Only by using unbiased data following strict methodology could we address the bigger question of sodium intake and its influence on development of hypertension and risk of CVD. ACKNOWLEDGEMENTS Conflicts of interest There are conflicts of interest.

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