Correspondence Validation and comparison of three formulae to estimate sodium and potassium excretion from a singlemorning fasting urine compared to 24-h measures in 11 countries Norm Campbell
M
ente et al. [1] provide additional data to support the utility of different equations based on ‘spot’ urine sodium to estimate 24-h urine sodium in diverse populations. Nevertheless, there are several issues with the study that require clarification and raise concerns about the study findings. Mente et al. utilized a ‘first void’ (overnight) urine sample as their ‘spot’ sample and this can represent a substantive proportion of the 24-h period. If 24-h urine samples are incomplete, there will be a higher proportion of the ‘24-h’ urine collection represented by the first void sample and the result will likely be a falsely high correlation. The strikingly high rate of incomplete urine collections (50%) reported by Mente et al. is concerning. Further, Kawasaki et al.’s method used by Mente et al. excluded 24-h urine samples as incomplete if the predicted creatinine exceeds 15% of the measured creatinine value while Mente et al. altered the method without justification to exclude samples at 25% [2]. Thus Mente et al.’s study likely included many 24-h urine samples as complete that would have been excluded by Kawasaki et al.’s original method. The potential inflation of the correlation is likely further accentuated as indirect methods of assessing completeness of 24-h urines underestimate incomplete collection compared to methods that use the ‘gold standard’ para amino benzoic acid (PABA) [3]. The Kawasaki equation was also designed to assess second void morning samples [2,4]. Reporting the rate of incomplete collections and correlations found using the 15% used by Kawasaki et al. would allow interpretation of the impact of incomplete collections on their study findings. Indicating the rate of incomplete collections in the subsample that was retested would also allow interpretation of the validity of the reproducibility results. Mente et al. should clarify if the alteration to the Kawasaki et al. method was determined a priori and provide rationale. Mente et al. showed the average bias that is present in estimating 24-h sodium with the different formulae. This bias is likely inaccurate based on the very high rate of incomplete 24-h urine samples. Furthermore, the bias is more marked at higher levels of ‘24-h’ urine sodium. Differences in bias at different levels of urinary sodium may in part be due to differences in completeness of the 24-h urine samples with bias at lower and higher urine
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sodium potentially explained by incomplete and over collections. Further, the three formulae tested may also be differentially impacted by incomplete 24-h urine collection, so the conclusion that the equation used by Kawasaki et al. has less bias is uncertain. Complete 24-h urine collections are required to assess the bias of the different formulae and are especially important in assessing differential bias at different levels of dietary salt. Mente et al.’s study utilizes the correlation between the first pass morning (overnight) urine sodium and 24-h urine sodium from the same 24-h period. The fundamental biological question, however, is the relationship of estimated sodium intake from spot urine sodium to usual daily dietary sodium and this requires correlation of the spot urine sodium to a different day’s 24-h urine sodium. The appropriate analysis would be to relate the spot urine sodium from the initial sample to the 24-h urine sodium in the retest substudy participants (and the spot urine sodium from the retest substudy to the initial 24-h urine sodium). These additional correlations are required to understand the relationship between the spot urine sodium and usual sodium intake. The reported study analysis inflates the association between the spot urine and biologically relevant indicator – usual sodium intake. The results of the more relevant analyses should be provided. The study by Mente et al. did find a relationship between spot urine sodium and blood pressure, and this is startling given the biological variability of blood pressure, salt intake, and daily sodium and creatinine excretion. On the basis of analysis of multiple studies, it is estimated that spot urine sodium samples from approximately 300 representative people can estimate average daily population intake of sodium (conclusions from a WHO meeting to assess sodium intake in surveys 2013, Campbell, personal communication). That fewer spot urine samples are required to estimate an individual’s usual sodium intake is currently unknown. Further, the stability over time of formulae to estimate 24-h urine sodium from spot urine samples has not been established. In addition sodium, creatinine and blood pressure are highly impacted by variation in assessment methods, also making relations between spot urine sodium and blood pressure and health outcomes difficult to discern. This is specifically concerning as the blood pressure data from the Prospective Urban Rural Epidemiology (PURE) study do not match well to rigorously conducted population surveys [5,6]. The association of spot urine sodium to blood pressure indicated by Mente et al. may not be the cause and effect, given the PURE study methods. The equation used by Kawasaki et al. utilizes creatinine (reflecting both muscle mass and renal function) which may also be related to blood pressure, and it is also possible that associations could be created by the multifactorial adjustments. The other equations to estimate salt intake from spot urine sodium have similar limitations. The robust association of dietary salt and blood pressure has been established be rigorous randomized controlled trials [7].
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ACKNOWLEDGEMENTS Conflicts of interest N.C. is a member of World Action on Salt and Health, CoChair of the Pan American Health Organization/World Health Organization Technical Advisory Group on Dietary Salt and the HSF CIHR Chair in Hypertension Prevention and Control. N.C. received travel support in 2012 from Novartis (Russia) to present on hypertension control.
REFERENCES 1. Mente A, O’Donnell MJ, Dagenais G, Wielgosz A, Lear SA, McQueen MJ, et al. 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. J Hypertens 2014; 32:1005–1014. 2. Kawasaki T, Itoh K, Uezono K, Sasaki H. A simple method for estimating 24 h urinary sodium and potassium excretion from second morning voiding urine specimen in adults. Clin Exp Pharmacol Physiol 1993; 20:7–14. 3. Murakami K, Sasaki S, Takahashi Y, Uenishi K, Watanabe T, Kohri T, et al. Sensitivity and specificity of published strategies using urinary creatinine to identify incomplete 24-h urine collection. Nutrition 2008; 24:16–22. 4. Ji C, Sykes L, Paul C, Dary O, Legetic B, Campbell NRC, et al. Systematic review of studies comparing 24-h and spot urine collections for estimating population salt intake. Rev Panam Salud Publica 2012; 32:307–315. 5. Chow CK, Teo KK, Rangarajan S, Islam S, Gupta R, Avezum A, et al. Prevalence, awareness, treatment, and control of hypertension in rural and urban communities in high-, middle-, and low-income countries. JAMA 2013; 310:959–968. 6. Rahman MM, Gilmour S. Prevention and control of hypertension in different countries. JAMA 2014; 311:418–419. 7. World Health Organization. WHO guideline: sodium intake for adults and children [Report, i-46]. Geneva, Switzerland: WHO Press; 2012.
Journal of Hypertension 2014, 32:2499–2503 Departments of Medicine, Physiology and Pharmacology and Community Health Sciences, The University of Calgary, Calgary, Alberta, Canada Correspondence to Norm Campbell, Libin Cardiovascular Institute of Alberta, University of Calgary, 3280 Hospital Drive NW, Calgary, Alberta, Canada, T2N 4Z6 E-mail: [email protected] J Hypertens 32:2499–2503 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000404
Can sodium excretion from single fasting morning urine really be used for estimation of dietary sodium intake? Christof J. Majoor and Liffert Vogt
T
he relation between sodium intake and cardiovascular health is a subject of an ongoing, sometimes heated, discussion [1]. An important issue contributing to this discussion is the way by which sodium intake
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is assessed among the many studies. In this regard, the study by Mente et al. [2] recently published in Journal of Hypertension fuels the debate. They presented data from the PURE (Prospective Urban Rural Epidemiology) cohort a large-scale epidemiological study in 17 low, middle and high-income countries around the world, in which urinary sodium excretion from 24-h collections was compared with estimated 24-h sodium excretion from single morning fasting urines. Three equations to estimate 24-h urinary sodium excretion were validated against 24-h collections, that is, the Kawasaki, INTERSALT (International Study of Salt and Blood Pressure), and Tanaka formulas, showing that the Kawasaki formula had maximum agreement and the minimum bias compared with the other two formulas. The data may have important impact as the use of morning fasting urines offers a more convenient way to estimate 24-h sodium intake. It may even serve epidemiological studies on sodium intake and health outcomes under more difficult circumstances that one may face in rural communities or in low-income countries. We, however, have several concerns. First of all, Mente et al. seem to have applied the Kawasaki formula incorrectly. The calculation for prediction of urinary creatinine excretion for men was mixed up with the formula for women. As a consequence, on the basis of the baseline characteristics provided in the study, we calculated that the estimated 24-h sodium excretion was underestimated by 27% in men and overestimated by 36% in women. Second, one should consider that measurement of urinary sodium excretion in a 24-h collection may not reflect sodium intake. This may not only occur because of sampling errors or urinary bladder retention. Also, the presence of recently demonstrated rhythmic sodium excretory and retention patterns influences the interpretation of sodium excretion using 24-h collections. Amongst others, the group of Rakova et al. [3] showed that at a stable sodium intake 24-h sodium excretion into the urine displayed day-to-day fluctuations. In fact, 24-h sodium excretion exhibited a weekly rhythm [3]. Thus, neither single 24-h collections nor 48-h urine collections can be used as ‘gold standard’ for assessment of daily sodium intake. Consequently, the use of formulas that estimate a wobbly parameter like 24-h urinary sodium excretion based on just one urine sample seems to introduce additional bias, also when applied at a population level. Moreover, in light of the discussion on health outcomes, estimations by formulas do not provide the information on the parameter in which we are really interested, namely, dietary sodium intake.
ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.
REFERENCES 1. He FJ, Appel LJ, Cappuccio FP, de Wardener HE, MacGregor GA. Does reducing salt intake increase cardiovascular mortality? Kidney Int 2011; 80:696–698. 2. Mente A, O’Donnell MJ, Dagenais G, Wielgosz A, Lear SA, McQueen MJ, et al. 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. J Hypertens 2014; 32:1005–1015.
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Correspondence 3. Rakova N, Ju¨ttner K, Dahlmann A, Schro¨der A, Linz P, Kopp C, et al. Long-term space flight simulation reveals infradian rhythmicity in human Naþ balance. Cell Metab 2013; 17:125–131.
Journal of Hypertension 2014, 32:2499–2503 Departments of Respiratory Medicine and Internal Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands Correspondence to Liffert Vogt, MD, PhD, Department of Internal Medicine, Room F4-215, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. Tel: +31 20 566 5990; fax: +31 20 566 9583; e-mail: [email protected] J Hypertens 32:2499–2503 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000405
Reply to both letters Andrew Mente a,b, Martin J. O’Donnell a,c,d, and Salim Yusuf a,b,c
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e thank Dr Campbell for the issues raised in his letter [1] many of which have already been addressed in the ‘Discussion’ section of our paper. However, Dr Campbell fails to consider that the approach to measuring sodium intake should be tailored to the purpose and design of any study. As this has been a recurring theme, we believe it is important to provide additional context to our international validation study. Our goal was to validate a method that can be used reliably in large international populations to either study the associations of measures of sodium intake with blood pressure (BP), or sodium intake with clinical outcomes, or to track levels of sodium intake in populations over time. This requires reliable and innovative approaches that would be widely feasible in a range of settings (including resource-challenged regions, in remote communities and all parts of the world) and at low costs. The intent of our approach is analogous to that of most epidemiologic studies which relate risk factors such as BP, cholesterol or glucose to cardiovascular disease (CVD; where simple approaches to risk factor measurement have been used and have resulted in major advances in our understanding of the causes of CVD). The initial large studies in the field of sodium were focused on demonstrating an association between sodium intake and BP (not clinical events). To address this question, investigators chose to use 24-h urinary collections, and even in the highly regarded INTERSALT (International Study of Sodium, Potassium, and Blood Pressure) study (n ¼ 10 079, 52 centres), a high proportion of incomplete 24-h collections likely occurred, based on their table on 24-h creatinine excretion. This was particularly noticeable in more primitive populations, making the estimates of sodium consumption from these populations especially suspect [2]. Therefore, the use of 24-h urine collections is an obstacle to completing large international cohort studies, which are necessary to truly understand the epidemiology
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of salt intake and health. Dr Campbell identifies the appreciable proportion of participants with incomplete 24-h collections, but this is not unique to our study, and exemplifies the major limitation of completing 24-h urine collection in large studies. Rather than being a limitation of our approach, it demonstrates the major advantage of our approach, as it indicates low rates of ‘incompleteness’ and minimal selection biases due to the burden of 24-h urine collection. Indirect comparisons, including meta-analyses of studies relating sodium intake to BP, suggest substantial heterogeneity in those with and without hypertension, and, although based on limited data, across different geographic regions. For example, no significant association between sodium intake and BP was reported in the large Scottish Health study [3]. To verify and understand these differences, we need large international studies, using methods that are feasible, inexpensive and can be standardized across a large number of centres, in order to determine whether there is true heterogeneity in the association among key subgroups. Our recent publication of the larger PURE (Prospective Urban Rural Epidemiologic) study cohort illustrates this issue, where we report heterogeneity in the association between sodium intake and BP, by age, sex and level of sodium intake. A next step is to reliably demonstrate the association of sodium intake with CVD events. In order to explore this association in populations at average risk, much larger studies – several times larger than the INTERSALT study – are required. Using 24-h urine collections in such studies is impractical, but such studies are essential to determine the association between sodium intake and CVD, and to quantify the magnitude of risk. Using this approach, we have demonstrated the pattern of association between sodium intake and CVD, which is J-shaped. Some prior prospective cohort studies were not large enough to demonstrate the true pattern of association, although meta-analyses of these studies did report a J-shaped association [4] and so did the large ONTARGET (Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial) study [5]. We used two approaches to our validation and attempted to test the validity and the reliability of three formula-based approaches (Kawasaki, Tanaka and INTERSALT formula) to estimate sodium intake. First, each method was assessed for its validity versus estimates of sodium consumption utilizing 24-h urine collections. As 24-h urine collection is the ‘reference’. and not the ‘gold’ standard, any correlation between the two would reflect the limitation of either or both methods, and one cannot infer that any one method is inferior to the other. The second approach was to test each of the estimates (the three from formula-based approaches and the 24-h urine) versus an independent physiologic measure (in this case blood pressure), for which an association has been established. In the first analysis, the Kawasaki formulabased approach showed high intra-class correlation coefficient (ICC 0.71) versus 24-h estimates of sodium and little bias (a 10% overestimate), compared to the other formulabased approaches. Note that the correlation of sodium intake using the Kawasaki formula versus the 24-h collection is similar to that of a single BP versus 24-h BP [6], or a www.jhypertension.com
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single fasting glucose versus HbA1c [5] glycosylated hemoglobin (HbA1c) [7]. Further, the reliability (i.e. the correlations between the same measure obtained at two time points) was similar for the estimates using the Kawasaki formula versus that seen with 24-h urine. Second, the association of sodium intake using the Kawasaki formula or the 24-h estimates of sodium versus BP was of similar strength. This indicates that the Kawasaki and the 24-h estimates of sodium intake provide parallel information and are of similar validity and reliability. Therefore, the value of either method has to be considered in the context of what the estimates of sodium would be used for. In our case, we wanted to identify reliable and valid methods that could be used for the conduct of large studies. This requires methods that are more feasible (i.e. lower risk of volunteer or selection bias, or incomplete collections). Whereas 24-h collections are prone to under-collection, this particular issue does not affect the results of our study. With a more restrictive inclusion criteria (observed creatinine at 15% of expected value; n ¼ 411), the ICC for the Kawasaki formula estimate versus measured 24-h sodium excretion remains unchanged [0.71; 95% confidence interval (CI) 0.65–0.76], as does the degree of bias [Kawasaki formula (þ304 mg/day; 95% CI 152 to 456); INTERSALT formula (892 mg/day; 95% CI 722 to 1061) and Tanaka formula (553 mg/day; 95% CI 391 to 716), respectively]. We acknowledge that our method differed from that originally reported by Kawasaki (used second fasting urine), and this was the rationale for completing the current validation study, which now extends its use to any fasting morning urine (FMU). We are encouraged that Dr Campbell accepts our approach for measuring sodium intake at a group level; he reports that a minimum sample of 300 is required (we await published details of his assertions so that they can be independently scrutinized), but the studies we are interested in will involve some tens of thousands (or even >100 000) of individuals so that several thousand CVD events will accrue [8,9]. We clarify that we utilized a FMU sample, rather than a ‘spot’ random urine (which Dr Campbell misleadingly states). The distinction is important, as is the distinction between a fasting glucose and a spot random glucose test, or a fasting cholesterol versus a non-fasting cholesterol. Our approach ensures measurement of ‘basal’ fasting excretion of sodium that can be collected in a standardized manner across centres and is less prone to variability in the method of collection than 24-h urine collections. Sodium intake likely varies day to day, making repeated measurements desirable, to gain an estimate (irrespective of the method used for any single day’s measure) of ‘usual’ sodium intake. Dr Campbell’s suggestion that a single assessment should be able to provide a measure of ‘usual’ intake is not supported by any data that we are aware of, or in theory. Rather, one needs to measure urinary estimates of sodium excretion on a number of occasions, which further highlights the practical advantage of using FMUs in large population-level studies. Utilizing the association between two measures of sodium intake on two separate occasions, we can mathematically correct for the variability over time in a group of individuals, and this approach has been used in studies relating BP or cholesterol to CVD. In all of our 2502
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studies relating sodium intake to BP or clinical outcomes, we address the issue of variability over time by estimating the degree of regression dilution bias and mathematically correct for it [5,8,9]. Unlike Dr Campbell’s unsubstantiated claim that our sample size was insufficient to detect an association between sodium intake and BP, our recently published results in the New England Journal of Medicine [8], based on over 100 000 people from 18 countries (10 times larger than the INTERSALT study), provide the most clear demonstration of the modest link between sodium intake and BP, with results similar to that of the meta-analysis of randomized controlled trials (RCTs) by He et al. [10] (2.4/1.2 mmHg per 1 g/day). This indicates the internal and external validity and reliability of our method, the consistency with external data and the value of our method when used globally for large population surveys. Our current study sample was far larger than all BP clinical trials combined, which provide the evidence-base for current guidelines recommending low sodium intake [8]. Does Dr Campbell also dispute the findings of these trials on similar grounds, that is, that they were too small? We do not. In addition, his concern that inclusion of creatinine in the formula may have led to a type 1 error is unlikely, as adjustment and/or collinearity generally bias estimates towards the null. With respect to the contention that ‘BP data from the PURE study do not match well with rigorously conducted population surveys’, this is incorrect, as described by our prior publication based on more than 140 000 people [11]. Moreover, the population included in the PURE cohort (>100 000 people from 18 low, middle and high-income countries) is vastly more representative of a general population than those included in clinical trials of sodium intake and BP (total of only 3230, all from North America and Europe only, which is only 3% of the size of the PURE cohort) [10]. If Dr Campbell wants to be consistent in his arguments, he will need to completely discount the results of all the RCTs of sodium reduction (which we certainly do not). We thank Drs Majoor and Vogt [12] for identifying that the formulae for men and women were interchanged in our manuscript, which was a typographical error in one sentence of the publication. This was detected immediately by us and we corresponded with the Journal, who have immediately corrected this and published an erratum [13]. They raise the issue of whether single 24-h measurements provide a valid estimate of sodium intake, as a recent very small study (n ¼ 10) has challenged that changes in sodium intake are reflected in subsequent 24-h urine collections. In that study of astronauts in simulated flight, sodium intake was controlled and changed over time in an artificial environment (with altered sleep–wake patterns). We agree that their findings may have important implications for the validity of individual-level estimates and for interpreting results of small interventional clinical trials of sodium reduction, with short-term follow-up. We also entirely agree that 24-h urinary assessment should not be considered the ‘gold’ standard. However, in large studies, the variability between different people will be at random and so the averaged estimates across many thousands of people will provide reliable estimates of average sodium intake (for groups, but not individuals). In our study, we Volume 32 Number 12 December 2014
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report a test–retest reliability of ICC value equal to 0.68 (ICC ¼ 0.70 for individuals with creatinine at 15% of expected value) for fasting morning urine estimates, which argues against there being large misclassification error when estimating group-level sodium intake in large observational studies. As discussed above, however, their point further re-enforces the need for convenient assessment methods to permit repeated measures of sodium intake over time, to measure ‘usual’ sodium intake. In summary, the Kawasaki estimates when applied to FMU provide reliable estimates of sodium intake for large population studies and permit the conduct of studies of the size needed to detect modest effects of sodium on BP and on CVD [6,7] in the population. Such large studies need to include several tens and perhaps even more than 100 000 individuals to be reliable. More complex and involved approaches to measuring sodium may compromise the feasibility and at times even the validity of such studies.
ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.
REFERENCES 1. Campbell N. 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. J Hypertens 2014; 32:2499– 2500. 2. INTERSALT: an international study of electrolyte excretion and blood pressure. Results for 24 h urinary sodium and potassium excretion. Intersalt Cooperative Research Group. BMJ 1988; 297:319–328. 3. Smith WC, Crombie IK, Tavendale RT, Gulland SK, Tunstall-Pedoe HD. Urinary electrolyte excretion, alcohol consumption, and blood pressure in the Scottish heart health study. BMJ 1988; 297:329–330. 4. Graudal NA, Hubeck-Graudal T, Ju¨rgens G. Effects of low-sodium diet vs. high-sodium diet on blood pressure, renin, aldosterone, catecholamines, cholesterol, and triglyceride (Cochrane Review). Am J Hypertens 2012; 25:1–15.
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5. O’Donnell MJ, Yusuf S, Mente A, Gao P, Mann JF, Teo K, et al. Urinary sodium and potassium excretion and risk of cardiovascular events. JAMA 2011; 306:2229–2238. 6. Bottini PB1, Carr AA, Rhoades RB, Prisant LM. Variability of indirect methods used to determine blood pressure. Office vs. mean 24-h automated blood pressures. Arch Intern Med 1992; 152:139–144. 7. Ghazanfari Z, Haghdoost AA, Alizadeh SM, Atapour J, Zolala F. A comparison of HbA1c and fasting blood sugar tests in general population. Int J Prev Med 2010; 1:187–194. 8. Mente A, O’Donnell MJ, Rangarajan S, McQueen MJ, Poirier P, Wielgosz A, et al. PURE Investigators. Association of urinary sodium and potassium excretion with blood pressure. N Engl J Med 2014; 371: 601–611. 9. O’Donnell M, Mente A, Rangarajan S, McQueen MJ, Wang X, Liu L, et al. PURE Investigators. Urinary sodium and potassium excretion, mortality, and cardiovascular events. N Engl J Med 2014; 371:612–623. 10. He FJ, Li J, Macgregor GA. Effect of longer term modest salt reduction on blood pressure: Cochrane systematic review and meta-analysis of randomised trials. BMJ 2013; 346:f1325. 11. Chow CK, Teo KK, Rangarajan S, Islam S, Gupta R, Avezum A, et al. PURE (Prospective Urban Rural Epidemiology) Study investigators. Prevalence, awareness, treatment, and control of hypertension in rural and urban communities in high-, middle-, and low-income countries. JAMA 2013; 310:959–968. 12. Majoor CJ, Vogt L. Can sodium excretion from single fasting morning urine really be used for estimation of dietary sodium intake? J Hypertens 2014; 32:2500–2501. 13. 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: Erratum.[Correction]. J Hypertens 2014; 32:1915.
Journal of Hypertension 2014, 32:2499–2503 a Population Health Research Institute, Hamilton Health Sciences, McMaster University, bDepartment of Clinical Epidemiology and Biostatistics, cDepartment of Medicine, McMaster University, Hamilton, Ontario, Canada and dHRB-Clinical Research Facility, NUI Galway, Galway, Ireland
Correspondence to Andrew Mente, PhD, Population Health Research Institute, Hamilton, Ontario, Canada. E-mail: [email protected] J Hypertens 32:2499–2503 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000406
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M
ente et al. [1] provide additional data to support the utility of different equations based on ‘spot’ urine sodium to estimate 24-h urine sodium in diverse populations. Nevertheless, there are several issues with the study that require clarification and raise concerns about the study findings. Mente et al. utilized a ‘first void’ (overnight) urine sample as their ‘spot’ sample and this can represent a substantive proportion of the 24-h period. If 24-h urine samples are incomplete, there will be a higher proportion of the ‘24-h’ urine collection represented by the first void sample and the result will likely be a falsely high correlation. The strikingly high rate of incomplete urine collections (50%) reported by Mente et al. is concerning. Further, Kawasaki et al.’s method used by Mente et al. excluded 24-h urine samples as incomplete if the predicted creatinine exceeds 15% of the measured creatinine value while Mente et al. altered the method without justification to exclude samples at 25% [2]. Thus Mente et al.’s study likely included many 24-h urine samples as complete that would have been excluded by Kawasaki et al.’s original method. The potential inflation of the correlation is likely further accentuated as indirect methods of assessing completeness of 24-h urines underestimate incomplete collection compared to methods that use the ‘gold standard’ para amino benzoic acid (PABA) [3]. The Kawasaki equation was also designed to assess second void morning samples [2,4]. Reporting the rate of incomplete collections and correlations found using the 15% used by Kawasaki et al. would allow interpretation of the impact of incomplete collections on their study findings. Indicating the rate of incomplete collections in the subsample that was retested would also allow interpretation of the validity of the reproducibility results. Mente et al. should clarify if the alteration to the Kawasaki et al. method was determined a priori and provide rationale. Mente et al. showed the average bias that is present in estimating 24-h sodium with the different formulae. This bias is likely inaccurate based on the very high rate of incomplete 24-h urine samples. Furthermore, the bias is more marked at higher levels of ‘24-h’ urine sodium. Differences in bias at different levels of urinary sodium may in part be due to differences in completeness of the 24-h urine samples with bias at lower and higher urine
Journal of Hypertension
sodium potentially explained by incomplete and over collections. Further, the three formulae tested may also be differentially impacted by incomplete 24-h urine collection, so the conclusion that the equation used by Kawasaki et al. has less bias is uncertain. Complete 24-h urine collections are required to assess the bias of the different formulae and are especially important in assessing differential bias at different levels of dietary salt. Mente et al.’s study utilizes the correlation between the first pass morning (overnight) urine sodium and 24-h urine sodium from the same 24-h period. The fundamental biological question, however, is the relationship of estimated sodium intake from spot urine sodium to usual daily dietary sodium and this requires correlation of the spot urine sodium to a different day’s 24-h urine sodium. The appropriate analysis would be to relate the spot urine sodium from the initial sample to the 24-h urine sodium in the retest substudy participants (and the spot urine sodium from the retest substudy to the initial 24-h urine sodium). These additional correlations are required to understand the relationship between the spot urine sodium and usual sodium intake. The reported study analysis inflates the association between the spot urine and biologically relevant indicator – usual sodium intake. The results of the more relevant analyses should be provided. The study by Mente et al. did find a relationship between spot urine sodium and blood pressure, and this is startling given the biological variability of blood pressure, salt intake, and daily sodium and creatinine excretion. On the basis of analysis of multiple studies, it is estimated that spot urine sodium samples from approximately 300 representative people can estimate average daily population intake of sodium (conclusions from a WHO meeting to assess sodium intake in surveys 2013, Campbell, personal communication). That fewer spot urine samples are required to estimate an individual’s usual sodium intake is currently unknown. Further, the stability over time of formulae to estimate 24-h urine sodium from spot urine samples has not been established. In addition sodium, creatinine and blood pressure are highly impacted by variation in assessment methods, also making relations between spot urine sodium and blood pressure and health outcomes difficult to discern. This is specifically concerning as the blood pressure data from the Prospective Urban Rural Epidemiology (PURE) study do not match well to rigorously conducted population surveys [5,6]. The association of spot urine sodium to blood pressure indicated by Mente et al. may not be the cause and effect, given the PURE study methods. The equation used by Kawasaki et al. utilizes creatinine (reflecting both muscle mass and renal function) which may also be related to blood pressure, and it is also possible that associations could be created by the multifactorial adjustments. The other equations to estimate salt intake from spot urine sodium have similar limitations. The robust association of dietary salt and blood pressure has been established be rigorous randomized controlled trials [7].
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Correspondence
ACKNOWLEDGEMENTS Conflicts of interest N.C. is a member of World Action on Salt and Health, CoChair of the Pan American Health Organization/World Health Organization Technical Advisory Group on Dietary Salt and the HSF CIHR Chair in Hypertension Prevention and Control. N.C. received travel support in 2012 from Novartis (Russia) to present on hypertension control.
REFERENCES 1. Mente A, O’Donnell MJ, Dagenais G, Wielgosz A, Lear SA, McQueen MJ, et al. 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. J Hypertens 2014; 32:1005–1014. 2. Kawasaki T, Itoh K, Uezono K, Sasaki H. A simple method for estimating 24 h urinary sodium and potassium excretion from second morning voiding urine specimen in adults. Clin Exp Pharmacol Physiol 1993; 20:7–14. 3. Murakami K, Sasaki S, Takahashi Y, Uenishi K, Watanabe T, Kohri T, et al. Sensitivity and specificity of published strategies using urinary creatinine to identify incomplete 24-h urine collection. Nutrition 2008; 24:16–22. 4. Ji C, Sykes L, Paul C, Dary O, Legetic B, Campbell NRC, et al. Systematic review of studies comparing 24-h and spot urine collections for estimating population salt intake. Rev Panam Salud Publica 2012; 32:307–315. 5. Chow CK, Teo KK, Rangarajan S, Islam S, Gupta R, Avezum A, et al. Prevalence, awareness, treatment, and control of hypertension in rural and urban communities in high-, middle-, and low-income countries. JAMA 2013; 310:959–968. 6. Rahman MM, Gilmour S. Prevention and control of hypertension in different countries. JAMA 2014; 311:418–419. 7. World Health Organization. WHO guideline: sodium intake for adults and children [Report, i-46]. Geneva, Switzerland: WHO Press; 2012.
Journal of Hypertension 2014, 32:2499–2503 Departments of Medicine, Physiology and Pharmacology and Community Health Sciences, The University of Calgary, Calgary, Alberta, Canada Correspondence to Norm Campbell, Libin Cardiovascular Institute of Alberta, University of Calgary, 3280 Hospital Drive NW, Calgary, Alberta, Canada, T2N 4Z6 E-mail: [email protected] J Hypertens 32:2499–2503 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000404
Can sodium excretion from single fasting morning urine really be used for estimation of dietary sodium intake? Christof J. Majoor and Liffert Vogt
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he relation between sodium intake and cardiovascular health is a subject of an ongoing, sometimes heated, discussion [1]. An important issue contributing to this discussion is the way by which sodium intake
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is assessed among the many studies. In this regard, the study by Mente et al. [2] recently published in Journal of Hypertension fuels the debate. They presented data from the PURE (Prospective Urban Rural Epidemiology) cohort a large-scale epidemiological study in 17 low, middle and high-income countries around the world, in which urinary sodium excretion from 24-h collections was compared with estimated 24-h sodium excretion from single morning fasting urines. Three equations to estimate 24-h urinary sodium excretion were validated against 24-h collections, that is, the Kawasaki, INTERSALT (International Study of Salt and Blood Pressure), and Tanaka formulas, showing that the Kawasaki formula had maximum agreement and the minimum bias compared with the other two formulas. The data may have important impact as the use of morning fasting urines offers a more convenient way to estimate 24-h sodium intake. It may even serve epidemiological studies on sodium intake and health outcomes under more difficult circumstances that one may face in rural communities or in low-income countries. We, however, have several concerns. First of all, Mente et al. seem to have applied the Kawasaki formula incorrectly. The calculation for prediction of urinary creatinine excretion for men was mixed up with the formula for women. As a consequence, on the basis of the baseline characteristics provided in the study, we calculated that the estimated 24-h sodium excretion was underestimated by 27% in men and overestimated by 36% in women. Second, one should consider that measurement of urinary sodium excretion in a 24-h collection may not reflect sodium intake. This may not only occur because of sampling errors or urinary bladder retention. Also, the presence of recently demonstrated rhythmic sodium excretory and retention patterns influences the interpretation of sodium excretion using 24-h collections. Amongst others, the group of Rakova et al. [3] showed that at a stable sodium intake 24-h sodium excretion into the urine displayed day-to-day fluctuations. In fact, 24-h sodium excretion exhibited a weekly rhythm [3]. Thus, neither single 24-h collections nor 48-h urine collections can be used as ‘gold standard’ for assessment of daily sodium intake. Consequently, the use of formulas that estimate a wobbly parameter like 24-h urinary sodium excretion based on just one urine sample seems to introduce additional bias, also when applied at a population level. Moreover, in light of the discussion on health outcomes, estimations by formulas do not provide the information on the parameter in which we are really interested, namely, dietary sodium intake.
ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.
REFERENCES 1. He FJ, Appel LJ, Cappuccio FP, de Wardener HE, MacGregor GA. Does reducing salt intake increase cardiovascular mortality? Kidney Int 2011; 80:696–698. 2. Mente A, O’Donnell MJ, Dagenais G, Wielgosz A, Lear SA, McQueen MJ, et al. 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. J Hypertens 2014; 32:1005–1015.
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Correspondence 3. Rakova N, Ju¨ttner K, Dahlmann A, Schro¨der A, Linz P, Kopp C, et al. Long-term space flight simulation reveals infradian rhythmicity in human Naþ balance. Cell Metab 2013; 17:125–131.
Journal of Hypertension 2014, 32:2499–2503 Departments of Respiratory Medicine and Internal Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands Correspondence to Liffert Vogt, MD, PhD, Department of Internal Medicine, Room F4-215, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. Tel: +31 20 566 5990; fax: +31 20 566 9583; e-mail: [email protected] J Hypertens 32:2499–2503 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000405
Reply to both letters Andrew Mente a,b, Martin J. O’Donnell a,c,d, and Salim Yusuf a,b,c
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e thank Dr Campbell for the issues raised in his letter [1] many of which have already been addressed in the ‘Discussion’ section of our paper. However, Dr Campbell fails to consider that the approach to measuring sodium intake should be tailored to the purpose and design of any study. As this has been a recurring theme, we believe it is important to provide additional context to our international validation study. Our goal was to validate a method that can be used reliably in large international populations to either study the associations of measures of sodium intake with blood pressure (BP), or sodium intake with clinical outcomes, or to track levels of sodium intake in populations over time. This requires reliable and innovative approaches that would be widely feasible in a range of settings (including resource-challenged regions, in remote communities and all parts of the world) and at low costs. The intent of our approach is analogous to that of most epidemiologic studies which relate risk factors such as BP, cholesterol or glucose to cardiovascular disease (CVD; where simple approaches to risk factor measurement have been used and have resulted in major advances in our understanding of the causes of CVD). The initial large studies in the field of sodium were focused on demonstrating an association between sodium intake and BP (not clinical events). To address this question, investigators chose to use 24-h urinary collections, and even in the highly regarded INTERSALT (International Study of Sodium, Potassium, and Blood Pressure) study (n ¼ 10 079, 52 centres), a high proportion of incomplete 24-h collections likely occurred, based on their table on 24-h creatinine excretion. This was particularly noticeable in more primitive populations, making the estimates of sodium consumption from these populations especially suspect [2]. Therefore, the use of 24-h urine collections is an obstacle to completing large international cohort studies, which are necessary to truly understand the epidemiology
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of salt intake and health. Dr Campbell identifies the appreciable proportion of participants with incomplete 24-h collections, but this is not unique to our study, and exemplifies the major limitation of completing 24-h urine collection in large studies. Rather than being a limitation of our approach, it demonstrates the major advantage of our approach, as it indicates low rates of ‘incompleteness’ and minimal selection biases due to the burden of 24-h urine collection. Indirect comparisons, including meta-analyses of studies relating sodium intake to BP, suggest substantial heterogeneity in those with and without hypertension, and, although based on limited data, across different geographic regions. For example, no significant association between sodium intake and BP was reported in the large Scottish Health study [3]. To verify and understand these differences, we need large international studies, using methods that are feasible, inexpensive and can be standardized across a large number of centres, in order to determine whether there is true heterogeneity in the association among key subgroups. Our recent publication of the larger PURE (Prospective Urban Rural Epidemiologic) study cohort illustrates this issue, where we report heterogeneity in the association between sodium intake and BP, by age, sex and level of sodium intake. A next step is to reliably demonstrate the association of sodium intake with CVD events. In order to explore this association in populations at average risk, much larger studies – several times larger than the INTERSALT study – are required. Using 24-h urine collections in such studies is impractical, but such studies are essential to determine the association between sodium intake and CVD, and to quantify the magnitude of risk. Using this approach, we have demonstrated the pattern of association between sodium intake and CVD, which is J-shaped. Some prior prospective cohort studies were not large enough to demonstrate the true pattern of association, although meta-analyses of these studies did report a J-shaped association [4] and so did the large ONTARGET (Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial) study [5]. We used two approaches to our validation and attempted to test the validity and the reliability of three formula-based approaches (Kawasaki, Tanaka and INTERSALT formula) to estimate sodium intake. First, each method was assessed for its validity versus estimates of sodium consumption utilizing 24-h urine collections. As 24-h urine collection is the ‘reference’. and not the ‘gold’ standard, any correlation between the two would reflect the limitation of either or both methods, and one cannot infer that any one method is inferior to the other. The second approach was to test each of the estimates (the three from formula-based approaches and the 24-h urine) versus an independent physiologic measure (in this case blood pressure), for which an association has been established. In the first analysis, the Kawasaki formulabased approach showed high intra-class correlation coefficient (ICC 0.71) versus 24-h estimates of sodium and little bias (a 10% overestimate), compared to the other formulabased approaches. Note that the correlation of sodium intake using the Kawasaki formula versus the 24-h collection is similar to that of a single BP versus 24-h BP [6], or a www.jhypertension.com
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single fasting glucose versus HbA1c [5] glycosylated hemoglobin (HbA1c) [7]. Further, the reliability (i.e. the correlations between the same measure obtained at two time points) was similar for the estimates using the Kawasaki formula versus that seen with 24-h urine. Second, the association of sodium intake using the Kawasaki formula or the 24-h estimates of sodium versus BP was of similar strength. This indicates that the Kawasaki and the 24-h estimates of sodium intake provide parallel information and are of similar validity and reliability. Therefore, the value of either method has to be considered in the context of what the estimates of sodium would be used for. In our case, we wanted to identify reliable and valid methods that could be used for the conduct of large studies. This requires methods that are more feasible (i.e. lower risk of volunteer or selection bias, or incomplete collections). Whereas 24-h collections are prone to under-collection, this particular issue does not affect the results of our study. With a more restrictive inclusion criteria (observed creatinine at 15% of expected value; n ¼ 411), the ICC for the Kawasaki formula estimate versus measured 24-h sodium excretion remains unchanged [0.71; 95% confidence interval (CI) 0.65–0.76], as does the degree of bias [Kawasaki formula (þ304 mg/day; 95% CI 152 to 456); INTERSALT formula (892 mg/day; 95% CI 722 to 1061) and Tanaka formula (553 mg/day; 95% CI 391 to 716), respectively]. We acknowledge that our method differed from that originally reported by Kawasaki (used second fasting urine), and this was the rationale for completing the current validation study, which now extends its use to any fasting morning urine (FMU). We are encouraged that Dr Campbell accepts our approach for measuring sodium intake at a group level; he reports that a minimum sample of 300 is required (we await published details of his assertions so that they can be independently scrutinized), but the studies we are interested in will involve some tens of thousands (or even >100 000) of individuals so that several thousand CVD events will accrue [8,9]. We clarify that we utilized a FMU sample, rather than a ‘spot’ random urine (which Dr Campbell misleadingly states). The distinction is important, as is the distinction between a fasting glucose and a spot random glucose test, or a fasting cholesterol versus a non-fasting cholesterol. Our approach ensures measurement of ‘basal’ fasting excretion of sodium that can be collected in a standardized manner across centres and is less prone to variability in the method of collection than 24-h urine collections. Sodium intake likely varies day to day, making repeated measurements desirable, to gain an estimate (irrespective of the method used for any single day’s measure) of ‘usual’ sodium intake. Dr Campbell’s suggestion that a single assessment should be able to provide a measure of ‘usual’ intake is not supported by any data that we are aware of, or in theory. Rather, one needs to measure urinary estimates of sodium excretion on a number of occasions, which further highlights the practical advantage of using FMUs in large population-level studies. Utilizing the association between two measures of sodium intake on two separate occasions, we can mathematically correct for the variability over time in a group of individuals, and this approach has been used in studies relating BP or cholesterol to CVD. In all of our 2502
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studies relating sodium intake to BP or clinical outcomes, we address the issue of variability over time by estimating the degree of regression dilution bias and mathematically correct for it [5,8,9]. Unlike Dr Campbell’s unsubstantiated claim that our sample size was insufficient to detect an association between sodium intake and BP, our recently published results in the New England Journal of Medicine [8], based on over 100 000 people from 18 countries (10 times larger than the INTERSALT study), provide the most clear demonstration of the modest link between sodium intake and BP, with results similar to that of the meta-analysis of randomized controlled trials (RCTs) by He et al. [10] (2.4/1.2 mmHg per 1 g/day). This indicates the internal and external validity and reliability of our method, the consistency with external data and the value of our method when used globally for large population surveys. Our current study sample was far larger than all BP clinical trials combined, which provide the evidence-base for current guidelines recommending low sodium intake [8]. Does Dr Campbell also dispute the findings of these trials on similar grounds, that is, that they were too small? We do not. In addition, his concern that inclusion of creatinine in the formula may have led to a type 1 error is unlikely, as adjustment and/or collinearity generally bias estimates towards the null. With respect to the contention that ‘BP data from the PURE study do not match well with rigorously conducted population surveys’, this is incorrect, as described by our prior publication based on more than 140 000 people [11]. Moreover, the population included in the PURE cohort (>100 000 people from 18 low, middle and high-income countries) is vastly more representative of a general population than those included in clinical trials of sodium intake and BP (total of only 3230, all from North America and Europe only, which is only 3% of the size of the PURE cohort) [10]. If Dr Campbell wants to be consistent in his arguments, he will need to completely discount the results of all the RCTs of sodium reduction (which we certainly do not). We thank Drs Majoor and Vogt [12] for identifying that the formulae for men and women were interchanged in our manuscript, which was a typographical error in one sentence of the publication. This was detected immediately by us and we corresponded with the Journal, who have immediately corrected this and published an erratum [13]. They raise the issue of whether single 24-h measurements provide a valid estimate of sodium intake, as a recent very small study (n ¼ 10) has challenged that changes in sodium intake are reflected in subsequent 24-h urine collections. In that study of astronauts in simulated flight, sodium intake was controlled and changed over time in an artificial environment (with altered sleep–wake patterns). We agree that their findings may have important implications for the validity of individual-level estimates and for interpreting results of small interventional clinical trials of sodium reduction, with short-term follow-up. We also entirely agree that 24-h urinary assessment should not be considered the ‘gold’ standard. However, in large studies, the variability between different people will be at random and so the averaged estimates across many thousands of people will provide reliable estimates of average sodium intake (for groups, but not individuals). In our study, we Volume 32 Number 12 December 2014
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report a test–retest reliability of ICC value equal to 0.68 (ICC ¼ 0.70 for individuals with creatinine at 15% of expected value) for fasting morning urine estimates, which argues against there being large misclassification error when estimating group-level sodium intake in large observational studies. As discussed above, however, their point further re-enforces the need for convenient assessment methods to permit repeated measures of sodium intake over time, to measure ‘usual’ sodium intake. In summary, the Kawasaki estimates when applied to FMU provide reliable estimates of sodium intake for large population studies and permit the conduct of studies of the size needed to detect modest effects of sodium on BP and on CVD [6,7] in the population. Such large studies need to include several tens and perhaps even more than 100 000 individuals to be reliable. More complex and involved approaches to measuring sodium may compromise the feasibility and at times even the validity of such studies.
ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.
REFERENCES 1. Campbell N. 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. J Hypertens 2014; 32:2499– 2500. 2. INTERSALT: an international study of electrolyte excretion and blood pressure. Results for 24 h urinary sodium and potassium excretion. Intersalt Cooperative Research Group. BMJ 1988; 297:319–328. 3. Smith WC, Crombie IK, Tavendale RT, Gulland SK, Tunstall-Pedoe HD. Urinary electrolyte excretion, alcohol consumption, and blood pressure in the Scottish heart health study. BMJ 1988; 297:329–330. 4. Graudal NA, Hubeck-Graudal T, Ju¨rgens G. Effects of low-sodium diet vs. high-sodium diet on blood pressure, renin, aldosterone, catecholamines, cholesterol, and triglyceride (Cochrane Review). Am J Hypertens 2012; 25:1–15.
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5. O’Donnell MJ, Yusuf S, Mente A, Gao P, Mann JF, Teo K, et al. Urinary sodium and potassium excretion and risk of cardiovascular events. JAMA 2011; 306:2229–2238. 6. Bottini PB1, Carr AA, Rhoades RB, Prisant LM. Variability of indirect methods used to determine blood pressure. Office vs. mean 24-h automated blood pressures. Arch Intern Med 1992; 152:139–144. 7. Ghazanfari Z, Haghdoost AA, Alizadeh SM, Atapour J, Zolala F. A comparison of HbA1c and fasting blood sugar tests in general population. Int J Prev Med 2010; 1:187–194. 8. Mente A, O’Donnell MJ, Rangarajan S, McQueen MJ, Poirier P, Wielgosz A, et al. PURE Investigators. Association of urinary sodium and potassium excretion with blood pressure. N Engl J Med 2014; 371: 601–611. 9. O’Donnell M, Mente A, Rangarajan S, McQueen MJ, Wang X, Liu L, et al. PURE Investigators. Urinary sodium and potassium excretion, mortality, and cardiovascular events. N Engl J Med 2014; 371:612–623. 10. He FJ, Li J, Macgregor GA. Effect of longer term modest salt reduction on blood pressure: Cochrane systematic review and meta-analysis of randomised trials. BMJ 2013; 346:f1325. 11. Chow CK, Teo KK, Rangarajan S, Islam S, Gupta R, Avezum A, et al. PURE (Prospective Urban Rural Epidemiology) Study investigators. Prevalence, awareness, treatment, and control of hypertension in rural and urban communities in high-, middle-, and low-income countries. JAMA 2013; 310:959–968. 12. Majoor CJ, Vogt L. Can sodium excretion from single fasting morning urine really be used for estimation of dietary sodium intake? J Hypertens 2014; 32:2500–2501. 13. 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: Erratum.[Correction]. J Hypertens 2014; 32:1915.
Journal of Hypertension 2014, 32:2499–2503 a Population Health Research Institute, Hamilton Health Sciences, McMaster University, bDepartment of Clinical Epidemiology and Biostatistics, cDepartment of Medicine, McMaster University, Hamilton, Ontario, Canada and dHRB-Clinical Research Facility, NUI Galway, Galway, Ireland
Correspondence to Andrew Mente, PhD, Population Health Research Institute, Hamilton, Ontario, Canada. E-mail: [email protected] J Hypertens 32:2499–2503 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000406
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