Correspondence Oxidative stress in patients affected by primary aldosteronism Mohinder P. Sambhi
ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.
REFERENCES
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etramala et al. [1], in the October issue of the Journal, describe an increased oxidative stress in patients with primary aldosteronism. We congratulate the authors on their significant findings being reported for the first time. The methods for the measurement of relevant enzymes in serum and urine are sound and the results statistically valid. Studies with adrenalectomy and removal of adenoma strengthen the conclusions that aldosterone is the culprit. Inclusion of patients with essential hypertension, showing that indices of oxidative stress are higher compared to normal individuals, but lower than patients with primary aldosteronism, adds a further perspective in showing the role of aldosterone beyond the existence of hypertension. We, however, agree with the comments of the reviewers 1 and 3, in pointing out a weakness in the study, which is devoid of any experimental approach, or even a discussion to explain the underlying mechanism of its observations and conclusions. We have recently proposed mechanisms that may account for increased oxidative stress in aldosteronism [2]. The proposed mechanisms are initiated by the hitherto unrecognized propensity of aldosterone, causing an up-regulation of the expression of epidermal growth factor receptor (EGFR) [3]. Increased EGFR expression via its agonist independent actions has been shown to increase oxidative stress [4–7]. And studies have shown that EGFR actions mediate cardiovascular renal damage caused by mineralocorticoids [8–10]. We have proposed that stimulation of EGFR expression by aldosterone accounts for the following recent unexplained observations in the clinical literature: 1. The rate of cardiovascular complications [11]. 2. The appearance of LVH disproportionate to the existing hemodynamic load [12]. 3. The extent of renal damage is greater in patients with primary aldosteronism as compared with patients of essential hypertension [13]. We have recently articulated a comprehensive hypothesis detailing the role of EGFR in the initiation and maintenance of hypertensive cardiovascular–renal disease [2]. We hope the authors will find useful leads to design mechanistic studies of their observations.
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1. Petramala L, Pignatelli P, Carnevale R, Zinnamosca L, Marinelli C, Settevendemmie A, et al. Oxidative stress in patients affected by primary aldosteronism. J Hypertens 2014; 32:2022–2029; [discussion 9]. 2. Sambhi MP. A single initiating cause of hypertension; potential for primary prevention: a hypothesis. J Hypertens 2014; 3:169. doi:10.4172/ 2167-1095.1000169. 3. Krug AW, Grossmann C, Schuster C, Freudinger R, Mildenberger S, Govindan MV, et al. Aldosterone stimulates epidermal growth factor receptor expression. J Biol Chem 2003; 278:43060–43066. 4. Carpenter G. Employment of the epidermal growth factor receptor in growth factor-independent signaling pathways. J Cell Biol 1999; 146:697–702. 5. Moghal N, Sternberg PW. Multiple positive and negative regulators of signaling by the EGF-receptor. Curr Opin Cell Biol 1999; 11:190– 196. 6. Hackel PO, Zwick E, Prenzel N, Ullrich A. Epidermal growth factor receptors: critical mediators of multiple receptor pathways. Curr Opin Cell Biol 1999; 11:184–189. 7. Gschwind A, Zwick E, Prenzel N, Leserer M, Ullrich A. Cell communication networks: epidermal growth factor receptor transactivation as the paradigm for interreceptor signal transmission. Oncogene 2001; 20:1594–1600. 8. Griol-Charhbili V, Fassot C, Messaoudi S, Perret C, Agrapart V, Jaisser F. Epidermal growth factor receptor mediates the vascular dysfunction but not the remodeling induced by aldosterone/salt. Hypertension 2011; 57:238–244. 9. De Giusti VC, Nolly MB, Yeves AM, Caldiz CI, Villa-Abrille MC, Chiappe de Cingolani GE, et al. Aldosterone stimulates the cardiac Na(þ)/H(þ) exchanger via transactivation of the epidermal growth factor receptor. Hypertension 2011; 58:912–919. 10. Rickard AJ, Fuller PJ. Mineralocorticoid and epidermal growth factor receptors: partners in vivo. Hypertension 2011; 57:144–145. 11. Savard S, Amar L, Plouin PF, Steichen O. Cardiovascular complications associated with primary aldosteronism: a controlled cross-sectional study. Hypertension 2013; 62:331–336. 12. Muiesan ML, Salvetti M, Paini A, Agabiti-Rosei C, Monteduro C, Galbassini G, et al. Inappropriate left ventricular mass in patients with primary aldosteronism. Hypertension 2008; 52:529–534. 13. Rossi GP, Bernini G, Desideri G, Fabris B, Ferri C, Giacchetti G, et al. Renal damage in primary aldosteronism: results of the PAPY study. Hypertension 2006; 48:232–238.
Journal of Hypertension 2015, 33:883–890 UCLA School of Medicine, Los Angeles, California, USA Correspondence to Mohinder P. Sambhi, MD, MSc, PhD, FRCP(c), Professor Emeritus; UCLA School of Medicine, 10390 Wilshire Blvd. Apt. 1405, Los Angeles, CA 90024, USA. Tel: +1 310 550 6180; fax: +1 310 550 6342; e-mail: [email protected] or [email protected] J Hypertens 33:883–890 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI:10.1097/HJH.0000000000000523
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Response to‘Oxidative stress in patients affected by primary aldosteronism’ Luigi Petramala, Francesco Violi, and Claudio Letizia
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e thank M.P. Sambhi for his comment [1] related to our study, which was conducted in patients with primary aldosteronism and essential hypertension, and in healthy individuals. We focused attention on high oxidative stress in hypertensive patients, especially in those affected by primary aldosteronism, directly due to action of aldosterone excess [2]. We agree with Sambhi that the high rate of cardiovascular complications observed in primary aldosteronism patients [3] can be due not only to higher blood pressure values and related organ damage, but also to the direct action of aldosterone. Mineral-corticoid receptors can be found in almost all kind of tissues, a finding consistent with the multiple pathophysiological modifications that can be found in primary aldosteronism patients in addition to the well known cardiovascular manifestations, such as a high rate of metabolic syndrome, glucose and lipid metabolic abnormalities [4], obstructive sleep apnoea [5] and reduced bone mineral density [6]. As suggested by Sambhi, oxidative stress can be the pivotal key to link aldosterone excess to the overall pathophysiological modifications occurring in primary aldosteronism patients; in our study we have evaluated oxidative stress via NADPH oxidase [2], but further mechanisms can be involved, as epidermal growth factor receptor (EGFR) expression [7,8]. In fact, aldosterone can induce a higher EGFR expression in human and animal renal tissue, directly by interaction with mineral-corticoid receptors, with activation of ERK-1/2 phosphorylation, a process inhibited by specific pharmacological treatment (spironolactone). Recently [9], further mechanisms were evaluated in order to explain metabolic abnormalities observed in primary aldosteronism patients, and mRNA expression of adipokines (as leptin and adiponectin) was found to be affected by aldosterone levels associated with impairment of glucose and lipid metabolism, suggesting an active role of aldosterone in these metabolic abnormalities. In conclusion, aldosterone excess can induce several pathophysiological modifications through different pathways including oxidative stress (via NADPH and upregulation of EGFR) and expression of adipokines. Further studies are required for complete explanations of overall complications.
ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.
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REFERENCES 1. Sambhi MP. Oxidative stress in patients affected by primary aldosteronism. J Hypertens 2015; 33:883. 2. Petramala L, Pignatelli P, Carnevale R, Zinnamosca L, Marinelli C, Settevendemmie A, et al. Oxidative stress in patients affected by primary aldosteronism. J Hypertens 2014; 32:2022–2029. 3. Catena C, Colussi G, Nadalini E, Chiuch A, Baroselli S, Lapenna R, Sechi LA. Cardiovascular outcomes in patients with primary aldosteronism after treatment. Arch Intern Med 2008; 168:80–85. 4. Iacobellis G, Petramala L, Cotesta D, Pergolini M, Zinnamosca L, Cianci R, et al. Adipokines and cardiometabolic profile in primary hyperaldosteronism. J Clin Endocrinol Metab 2010; 95:2391– 2398. 5. Di Murro A, Petramala L, Cotesta D, Zinnamosca L, Crescenzi E, Marinelli C, et al. Renin-angiotensin-aldosterone system in patients with sleep apnoea: prevalence of primary aldosteronism. J Renin Angiotensin Aldosterone Syst 2010; 11:165–172. 6. Petramala L, Zinnamosca L, Settevendemmie A, Marinelli C, Nardi M, Concistre` A, et al. Bone and mineral metabolism in patients with primary aldosteronism. Int J Endocrinol 2014; 2014:836529. 7. Sambhi MP. A single initiating cause of hypertension; potential for primary prevention: a hypothesis. J Hypertens 2014; 3:18. 8. Krug AW, Grossmann C, Schuster C, Freudinger R, Mildenberger S, Govindan MV, et al. Aldosterone stimulates epidermal growth factor receptor expression. J Biol Chem 2003; 278:43060–43066. 9. Letizia C, Petramala L, Di Gioia CR, Chiappetta C, Zinnamosca L, Marinelli C, et al. Leptin and adiponectin mRNA expression from the adipose tissue surrounding the adrenal neoplasia. J Clin Endocrinol Metab 2015; 100:E101–E-104.
Journal of Hypertension 2015, 33:883–890 Department of Internal Medicine and Medical Specialties, University of Rome ‘Sapienza, Italy Correspondence to Claudio Letizia, University of Rome ‘Sapienza, Italy. E-mail: [email protected] J Hypertens 33:883–890 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI:10.1097/HJH.0000000000000524
Estimation of sodium excretion should be made as simple as possible, but not simpler: misleading papers and editorial on spot urines Feng J. He a, Vanja Ivkovic´ b, Bojan Jelakovic´ b, Joan Morris a, and Graham A. MacGregor a
A
reduction in population salt intake is one of the most cost-effective measures to prevent cardiovascular disease [1,2]. Two recent articles by O’Donnell et al. in the New England Journal of Medicine attempt to cast doubt on this important public health policy by claiming that a salt intake below 7.5 g/day was not associated with lower blood pressure and related to a higher cardiovascular events or total mortality based on the Prospective Urban Rural Epidemiology study [3,4]. However, this claim is invalid because of methodological problems as well as errors in using a mathematical formula to estimate daily salt intake from spot urinary sodium.
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Over the past five decades, there have been numerous inadvertently switched formulae for men and women while attempts to try and simplify the accurate measurements of again writing Kawasaki formula with all of the other errors. individuals’ daily salt intake. However, carefully controlled A recent carefully conducted study in a New Zealand studies showed that, to get a reasonable estimate of salt population demonstrated that the four commonly used intake in one individual, six to 11 consecutive 24-h urine formulae, which are Kawasaki, Tanaka, International Study collections need to be made [5]. This is due to the fact that of Sodium, Potassium and Blood Pressure (INTERSALT) salt consumption varies from day to day in individuals as and Pan American Health Organisation, all showed that a much as it does within the population. So, even an accusingle spot urine is a poor predictor of 24-h urinary sodium rately collected single 24-h urine will not reflect that indiexcretion in individuals [10]. At population level, the mean vidual’s intake, and furthermore, it will not reflect the intake excretion from the Kawasaki estimate was particularly over the following few years. In addition to this, many inaccurate, overestimating salt intake by 32% [10]. studies over the same period have shown that spot urinary The claim by O’Donnell et al. that the Kawasaki intrasodium does not accurately reflect 24-h urinary sodium class correlation coefficient of 0.71 shows good agreement excretion [6]. is in fact well below the established threshold of 0.90 to Spot urine measures urinary sodium concentration that give reasonable reliability for clinical measurements. In depends on fluid intake, time of the day, duration and addition, in their validation article, O’Donnell et al. volume of the collection, individuals’ posture [6], as well as included 24-h urine samples within 25% of predicted when the last sodium-containing meal was consumed. In 24-h urinary creatinine excretion as being complete, addition, different formulae used to predict 24-h urinary whereas the original Kawasaki method called for excluding sodium from spot urines give widely discrepant results. urine that exceeded 15% of predicted creatinine excretion None of these points was addressed in O’Donnell et al.’s [8]. This change in the criteria would have further reduced articles [3,4]. They chose to use the Kawasaki formula, but the reliability of their validation method and consequently then they used the wrong formula in their separate valifurther increase the bias of using spot urine to estimate 24-h dation article [7] that they cited as a reference in the New urinary sodium. Moreover, in the O’Donnell’s own study, England Journal of Medicine articles. there is clear evidence that the Kawasaki formula systemThe Kawasaki formula [8] should be atically underestimates salt intake when it is high and mmol ¼ 16:3 24-hUNaV day ffi vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi u u Spot Na mmol u mg l u hmgi t Predicated 24-h urinary Cr day Spot Cr 10 dl However, Mente et al. [7] used the following formula: vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi ffi u mmol u uSpot Na u l 24-hUNaV ¼ 16:3 u t mmol Spot Cr l mg Predicated 24-h urinary Cr day Comparing the above two formulae, Mente et al. [7] made four major errors: only a part of the expression is under the square root sign; erroneous unit of measurement is used for the spot urinary creatinine (mmol/l instead of mg/dl) with no correction when changing from one unit of measurement to another; spot urinary creatinine is not multiplied with appropriate factor; incongruent units were used for spot urinary creatinine (mmol/l); and the other for predicted 24-h urinary creatinine (mg/day). Furthermore, sex-specific formulae for predicted 24-h urinary creatinine were switched, that is, the one that should be used for men, was used for women and vice versa. An additional concern is that several months after publication, O’Donnell et al. sent an erratum to their validation article in the Journal of Hypertension [9], wherein they pointed out that they
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overestimates salt intake when it is low. This means that if the association between salt intake and blood pressure (or mortality) is examined in a group of people with high levels of salt intake, the slope of the association will be exaggerated, as the actual salt intake is greater than the predicted salt intake used in the model. It also means that in a group of people with low levels of salt intake, the association will be reduced, as the actual salt intake is lower than the predicted salt intake. This major methodological issue has been ignored by O’Donnell et al. In addition to the problems with the formula, O’Donnell et al.’s articles have several other methodological issues that are common in cohort studies, as described by the Science Advisory of the American Heart Association [11,12]. Particularly in this type of studies, it is impossible to correct for reverse causality, that is, people who are ill eat less and consume less salt. O’Donnell et al. tried to address reverse causality by excluding individuals with a history of cardiovascular disease; however, individuals with a potentially high risk for an event such as those with prehypertension, were included. These high-risk individuals were more likely to make an effort to reduce their salt intake. This again would cause reverse causality. In spite of all these problems, O’Donnell et al. tried to make an important public health statement about the dangers of reducing salt
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ACKNOWLEDGEMENTS
4. O’Donnell M, Mente A, Rangarajan S, McQueen MJ, Wang X, Liu L, et al. Urinary sodium and potassium excretion, mortality, and cardiovascular events. N Engl J Med 2014; 371:612–623. 5. Liu K, Cooper R, McKeever J, McKeever P, Byington R, Soltero I, et al. Assessment of the association between habitual salt intake and high blood pressure: methodological problems. Am J Epidemiol 1979; 110:219–226. 6. Ji C, Sykes L, Paul C, Dary O, Legetic B, Campbell NR, 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. 7. 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. 8. 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. 9. Mente A, O’Donnell MJ, Dagenais G, Wielgosz A, Lear SA, McQueen MJ, et al. Erratum. 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; 32:1915. 10. McLean R, Williams S, Mann J. Monitoring population sodium intake using spot urine samples: validation in a New Zealand population. J Hum Hypertens 2014; 28:657–662. 11. Whelton PK, Appel LJ, Sacco RL, Anderson CA, Antman EM, Campbell N, et al. Sodium, blood pressure, and cardiovascular disease: further evidence supporting the American Heart Association sodium reduction recommendations. Circulation 2012; 126:2880–2889. 12. Cobb LK, Elliott AC, Hu P, Liu FB, Neaton K, Whelton JD, et al. Methodological issues in cohort studies that relate sodium intake to cardiovascular disease outcomes: a Science Advisory From the American Heart Association. Circulation 2014; 129:1173–1186. 13. Oparil S. Low sodium intake: cardiovascular health benefit or risk? N Engl J Med 2014; 371:677–679. 14. He FJ, MacGregor GA. Reducing population salt intake worldwide: from evidence to implementation. Prog Cardiovasc Dis 2010; 52:363–382. 15. He FJ, Brinsden HC, MacGregor GA. Salt reduction in the United Kingdom: a successful experiment in public health. J Hum Hypertens 2014; 28:345–352. 16. He FJ, Pombo-Rodrigues S, MacGregor GA. Salt reduction in England from 2003 to 2011: its relationship to blood pressure, stroke and ischaemic heart disease mortality. BMJ Open 2014; 4:e004549. 17. Karppanen H, Mervaala E. Sodium intake and hypertension. Prog Cardiovasc Dis 2006; 49:59–75. 18. First Global Ministerial Conference on Healthy Lifestyles and Noncommunicable Disease Control, 28–29 April 2011, Moscow. http:// www.who.int/nmh/events/moscow_ncds_2011/en/. [Accessed 10 June 2013] 19. Beaglehole R, Bonita R, Horton R, Adams C, Alleyne G, Asaria P, et al. Priority actions for the noncommunicable disease crisis. Lancet 2011; 377:1438–1447. 20. Mozaffarian D, Fahimi S, Singh GM, Micha R, Khatibzadeh S, Engell RE, et al. Global sodium consumption and death from cardiovascular causes. N Engl J Med 2014; 371:624–634.
Conflicts of interest There are no conflicts of interest.
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intake, whereas, in fact, for the above reasons, they are in no position to do so. An accompanying editorial [13] does not consider the above points and accepts O’Donnell et al.’s findings that a single spot urine when used with the wrong formula and all of the above caveats, reflects an individual’s salt intake over a long period of time. There are many other types of evidence (epidemiological, migration, animal, genetic, treatment, outcome, and, now, population studies) that all clearly relate salt intake to blood pressure and cardiovascular outcome [14]. Indeed, the evidence for salt is stronger than for any other dietary constituents. None of this evidence was discussed in O’Donnell et al.’s articles. Furthermore, in Finland and now also in the United Kingdom, population salt intake has been reduced by getting the food industry to slowly reduce the amount of salt added to foods across the board [15]. The reduction in salt intake has caused a fall in population blood pressure both in Finland and the United Kingdom, and is associated with a reduction in cardiovascular deaths [16,17]. The totality of the evidence for population-wide reduction in salt intake is very strong [14]. Indeed, salt reduction is one of the most cost-effective measures to prevent cardiovascular disease in both developed and developing countries [1,2]. At the 2011 United Nations high-level meeting on noncommunicable diseases, salt reduction was recommended as one of the top three priority actions to reduce premature mortality from noncommunicable diseases by 25% by 2025 [18,19]. The WHO, in its recent guideline, recommends a 30% reduction in salt intake by 2025 with an eventual target of 5 g/day for all adults and lower levels for children based on calorie intake. All countries should adopt a coherent and workable strategy to reduce salt intake in the population to meet the target of the WHO. The benefits will be very large with approximately 1.65 million cardiovascular deaths prevented per year [20] along with major cost savings to the health service worldwide. The severely methodologically flawed articles by O’Donnell et al. should not and cannot be used to divert this vital and very cost-effective public health policy.
REFERENCES 1. Bibbins-Domingo K, Chertow GM, Coxson PG, Moran A, Lightwood JM, Pletcher MJ, Goldman L. Projected effect of dietary salt reductions on future cardiovascular disease. N Engl J Med 2010; 362:590–599. 2. Asaria P, Chisholm D, Mathers C, Ezzati M, Beaglehole R. Chronic disease prevention: health effects and financial costs of strategies to reduce salt intake and control tobacco use. Lancet 2007; 370:2044– 2053. 3. Mente A, O’Donnell MJ, Rangarajan S, McQueen MJ, Poirier P, Wielgosz A, et al. Association of urinary sodium and potassium excretion with blood pressure. N Engl J Med 2014; 371:601–611.
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a Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK and bSchool of Medicine, University of Zagreb, and Department of Nephrology, Hypertension, Dialysis and Transplantation, University Hospital Center Zagreb, Zagreb, Croatia
Correspondence to Bojan Jelakovic´, MD, PhD, School of Medicine University of Zagreb, Department of Nephrology, Hypertension, Dialysis and Transplantation, University Hospital Centre Zagreb, Croatia, Zagreb, Kisˇ patic´eva 12, 10000 Zargeb. Tel: +385 1 23 88 271; fax: +385 1 23 88 592; email: [email protected] J Hypertens 32:883–890 ß 2015 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000548
Volume 33 Number 4 April 2015
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Response to‘Estimation of sodium excretion should be made as simple as possible, but not simpler: misleading papers and editorial on spot urines’ Andrew Mente a,b, Martin J. O’Donnell a,c,d, and Salim Yusuf a,b,c
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e et al. [1,2] make a number of incorrect assertions in their letters. We clarify that we utilized a fasting morning urine sample, not a ‘spot’ random urine [3–5]. The distinction is important, as is the distinction between a fasting glucose versus a random glucose test, or a fasting cholesterol versus a nonfasting cholesterol. Furthermore, the intent of our approach is analogous to most epidemiologic studies that relate risk factors such as blood pressure (BP), cholesterol, or fasting glucose (each of which is only an approximation of the ‘usual’ levels) to cardiovascular disease (CVD), in which, using single measure, group-level estimates of these risk factors have been reliably related to CVD outcomes. We agree that sodium intake varies from day to day (as does BP or cholesterol), making repeated measurements desirable to gain an estimate (irrespective of the method used for any single day’s measure) of ‘usual’ sodium intake. However, less-frequent measurements introduce mainly random error and reduce statistical precision and are most likely to bias relationships toward the null, but would not be expected to change the overall pattern of association (i.e. would not change a J-shaped association to a linear association). One way to account for this variability is by obtaining repeated measures in each participant, but this is not feasible for large studies. Instead, the usual approach to account for day-to-day variability in measures in large population studies is to estimate the correlation between measures obtained on two separate days some weeks or months apart and then use the correlation to adjust for the degree of regression–dilution bias. This is widely used to relate cholesterol or BP to CVD and is an accepted approach. We used a similar method for estimating ‘usual’ 24-h urinary sodium excretion and this did not change the shape of the slopes, but instead made the ‘J’-shaped slopes steeper at both ends of the curve [5]. He et al. [1,2] ignore a key consideration in large epidemiologic studies examining the association between exposures and clinical outcomes. Although variations in the measurements of sodium intake in the same individual (which can vary by about 30–50%) should be minimized to the extent feasible, the dominant source of variability is the intersubject variability in sodium intake (which can be several fold – e.g. 500–600%) and the random variations in the rates of the outcomes of interest (e.g. CVD incidence). If the associations are moderate (which is the case for most risk factors for CVD), to demonstrate the shape of the association, large population studies (involving several tens of thousands of individuals) with a broad range of intake of sodium is needed among whom several thousand CVD events occur. This requires methods that are simple, least biased, and applicable to large populations. Because 24-h Journal of Hypertension
urine samples are often not complete, and there is a high rate of participant burden and refusals, it is not only impractical to obtain repeated 24-h urine collections but also the population included may be biased as free-living working populations more often tend to refuse to participate in studies with high burden. So using 24-h measures is not suitable for studies of several tens of thousands of individuals (which requires many centers) and in many countries (to include populations with wide range of sodium intakes). The requirements for very large studies mean that the approach to assessing the association of sodium (or BP or cholesterol) versus CVD requires studies with simple methods of assessing the exposures (which is exactly what we have done), and similar to what has been done and widely accepted epidemiologic approaches to evaluating the exposures such as BP, cholesterol, or glucose [6,7]. He et al. [1,2] ignore the fact that the association between sodium and BP in our study is entirely consistent with findings of a meta-analysis of prior studies relating sodium intake (measured using 24-h urine) to BP and so provide further validation of our approach. So, why would the same method provide valid and reliable information on the association of sodium versus BP, but not for the association between sodium versus CVD? We applied the Kawasaki equation as originally specified [8]. We concur that the formula as provided in the ‘Methods’ should have included an additional set of brackets to show that the full expression is under the square root sign. We did perform the appropriate unit conversions and multiplied fasting morning urine creatinine by the appropriate factor, which we did not indicate in the article. Moreover, the calculations were completed by two independent people and compared. We had extensive discussions about the methodology during the reviews of our three articles involving over 15 separate reviewers, who were satisfied with the validity of our approach and calculations. (It is also noteworthy that application of the formula with any of the four errors described by He et al. would produce implausible mean sodium excretion values between three-fold and 35-fold different than the estimates provided that would be easily identified.) Furthermore, the creatinine formulae for men and women were applied correctly, although as noted previously, a typographical error occurred in one sentence of the publication where the words ‘men’ and ‘women’ were transposed. We detected this immediately after publication and rapidly communicated this to the Journal. So the assertion by He et al. that we used an incorrect formula is incorrect. We have also performed analyses of the relationship between sodium and cardiovascular events/mortality using Tanaka and International Study of Sodium, Potassium, and Blood Pressure (INTERSALT) formulae in the Prospective Urban and Rural Epidemiology (PURE) study. Tanaka showed the same J-shaped relationship (Fig. 1), whereas INTERSALT was inverse only (no increased risk with higher sodium excretion) (Fig. 2). So, all approaches give the same answer at low sodium levels, but some differences are observed with different methods with higher sodium excretion levels. In addition, in both our PURE and Ongoing Telmisartan Alone and in combination with www.jhypertension.com
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Sodium versus systolic BP and CVD events
Sodium/creatinine versus systolic BP and CVD events
Systolic BP
136 134 132 130
1
128 126
ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.
REFERENCES
P
etramala et al. [1], in the October issue of the Journal, describe an increased oxidative stress in patients with primary aldosteronism. We congratulate the authors on their significant findings being reported for the first time. The methods for the measurement of relevant enzymes in serum and urine are sound and the results statistically valid. Studies with adrenalectomy and removal of adenoma strengthen the conclusions that aldosterone is the culprit. Inclusion of patients with essential hypertension, showing that indices of oxidative stress are higher compared to normal individuals, but lower than patients with primary aldosteronism, adds a further perspective in showing the role of aldosterone beyond the existence of hypertension. We, however, agree with the comments of the reviewers 1 and 3, in pointing out a weakness in the study, which is devoid of any experimental approach, or even a discussion to explain the underlying mechanism of its observations and conclusions. We have recently proposed mechanisms that may account for increased oxidative stress in aldosteronism [2]. The proposed mechanisms are initiated by the hitherto unrecognized propensity of aldosterone, causing an up-regulation of the expression of epidermal growth factor receptor (EGFR) [3]. Increased EGFR expression via its agonist independent actions has been shown to increase oxidative stress [4–7]. And studies have shown that EGFR actions mediate cardiovascular renal damage caused by mineralocorticoids [8–10]. We have proposed that stimulation of EGFR expression by aldosterone accounts for the following recent unexplained observations in the clinical literature: 1. The rate of cardiovascular complications [11]. 2. The appearance of LVH disproportionate to the existing hemodynamic load [12]. 3. The extent of renal damage is greater in patients with primary aldosteronism as compared with patients of essential hypertension [13]. We have recently articulated a comprehensive hypothesis detailing the role of EGFR in the initiation and maintenance of hypertensive cardiovascular–renal disease [2]. We hope the authors will find useful leads to design mechanistic studies of their observations.
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1. Petramala L, Pignatelli P, Carnevale R, Zinnamosca L, Marinelli C, Settevendemmie A, et al. Oxidative stress in patients affected by primary aldosteronism. J Hypertens 2014; 32:2022–2029; [discussion 9]. 2. Sambhi MP. A single initiating cause of hypertension; potential for primary prevention: a hypothesis. J Hypertens 2014; 3:169. doi:10.4172/ 2167-1095.1000169. 3. Krug AW, Grossmann C, Schuster C, Freudinger R, Mildenberger S, Govindan MV, et al. Aldosterone stimulates epidermal growth factor receptor expression. J Biol Chem 2003; 278:43060–43066. 4. Carpenter G. Employment of the epidermal growth factor receptor in growth factor-independent signaling pathways. J Cell Biol 1999; 146:697–702. 5. Moghal N, Sternberg PW. Multiple positive and negative regulators of signaling by the EGF-receptor. Curr Opin Cell Biol 1999; 11:190– 196. 6. Hackel PO, Zwick E, Prenzel N, Ullrich A. Epidermal growth factor receptors: critical mediators of multiple receptor pathways. Curr Opin Cell Biol 1999; 11:184–189. 7. Gschwind A, Zwick E, Prenzel N, Leserer M, Ullrich A. Cell communication networks: epidermal growth factor receptor transactivation as the paradigm for interreceptor signal transmission. Oncogene 2001; 20:1594–1600. 8. Griol-Charhbili V, Fassot C, Messaoudi S, Perret C, Agrapart V, Jaisser F. Epidermal growth factor receptor mediates the vascular dysfunction but not the remodeling induced by aldosterone/salt. Hypertension 2011; 57:238–244. 9. De Giusti VC, Nolly MB, Yeves AM, Caldiz CI, Villa-Abrille MC, Chiappe de Cingolani GE, et al. Aldosterone stimulates the cardiac Na(þ)/H(þ) exchanger via transactivation of the epidermal growth factor receptor. Hypertension 2011; 58:912–919. 10. Rickard AJ, Fuller PJ. Mineralocorticoid and epidermal growth factor receptors: partners in vivo. Hypertension 2011; 57:144–145. 11. Savard S, Amar L, Plouin PF, Steichen O. Cardiovascular complications associated with primary aldosteronism: a controlled cross-sectional study. Hypertension 2013; 62:331–336. 12. Muiesan ML, Salvetti M, Paini A, Agabiti-Rosei C, Monteduro C, Galbassini G, et al. Inappropriate left ventricular mass in patients with primary aldosteronism. Hypertension 2008; 52:529–534. 13. Rossi GP, Bernini G, Desideri G, Fabris B, Ferri C, Giacchetti G, et al. Renal damage in primary aldosteronism: results of the PAPY study. Hypertension 2006; 48:232–238.
Journal of Hypertension 2015, 33:883–890 UCLA School of Medicine, Los Angeles, California, USA Correspondence to Mohinder P. Sambhi, MD, MSc, PhD, FRCP(c), Professor Emeritus; UCLA School of Medicine, 10390 Wilshire Blvd. Apt. 1405, Los Angeles, CA 90024, USA. Tel: +1 310 550 6180; fax: +1 310 550 6342; e-mail: [email protected] or [email protected] J Hypertens 33:883–890 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI:10.1097/HJH.0000000000000523
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Response to‘Oxidative stress in patients affected by primary aldosteronism’ Luigi Petramala, Francesco Violi, and Claudio Letizia
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e thank M.P. Sambhi for his comment [1] related to our study, which was conducted in patients with primary aldosteronism and essential hypertension, and in healthy individuals. We focused attention on high oxidative stress in hypertensive patients, especially in those affected by primary aldosteronism, directly due to action of aldosterone excess [2]. We agree with Sambhi that the high rate of cardiovascular complications observed in primary aldosteronism patients [3] can be due not only to higher blood pressure values and related organ damage, but also to the direct action of aldosterone. Mineral-corticoid receptors can be found in almost all kind of tissues, a finding consistent with the multiple pathophysiological modifications that can be found in primary aldosteronism patients in addition to the well known cardiovascular manifestations, such as a high rate of metabolic syndrome, glucose and lipid metabolic abnormalities [4], obstructive sleep apnoea [5] and reduced bone mineral density [6]. As suggested by Sambhi, oxidative stress can be the pivotal key to link aldosterone excess to the overall pathophysiological modifications occurring in primary aldosteronism patients; in our study we have evaluated oxidative stress via NADPH oxidase [2], but further mechanisms can be involved, as epidermal growth factor receptor (EGFR) expression [7,8]. In fact, aldosterone can induce a higher EGFR expression in human and animal renal tissue, directly by interaction with mineral-corticoid receptors, with activation of ERK-1/2 phosphorylation, a process inhibited by specific pharmacological treatment (spironolactone). Recently [9], further mechanisms were evaluated in order to explain metabolic abnormalities observed in primary aldosteronism patients, and mRNA expression of adipokines (as leptin and adiponectin) was found to be affected by aldosterone levels associated with impairment of glucose and lipid metabolism, suggesting an active role of aldosterone in these metabolic abnormalities. In conclusion, aldosterone excess can induce several pathophysiological modifications through different pathways including oxidative stress (via NADPH and upregulation of EGFR) and expression of adipokines. Further studies are required for complete explanations of overall complications.
ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.
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REFERENCES 1. Sambhi MP. Oxidative stress in patients affected by primary aldosteronism. J Hypertens 2015; 33:883. 2. Petramala L, Pignatelli P, Carnevale R, Zinnamosca L, Marinelli C, Settevendemmie A, et al. Oxidative stress in patients affected by primary aldosteronism. J Hypertens 2014; 32:2022–2029. 3. Catena C, Colussi G, Nadalini E, Chiuch A, Baroselli S, Lapenna R, Sechi LA. Cardiovascular outcomes in patients with primary aldosteronism after treatment. Arch Intern Med 2008; 168:80–85. 4. Iacobellis G, Petramala L, Cotesta D, Pergolini M, Zinnamosca L, Cianci R, et al. Adipokines and cardiometabolic profile in primary hyperaldosteronism. J Clin Endocrinol Metab 2010; 95:2391– 2398. 5. Di Murro A, Petramala L, Cotesta D, Zinnamosca L, Crescenzi E, Marinelli C, et al. Renin-angiotensin-aldosterone system in patients with sleep apnoea: prevalence of primary aldosteronism. J Renin Angiotensin Aldosterone Syst 2010; 11:165–172. 6. Petramala L, Zinnamosca L, Settevendemmie A, Marinelli C, Nardi M, Concistre` A, et al. Bone and mineral metabolism in patients with primary aldosteronism. Int J Endocrinol 2014; 2014:836529. 7. Sambhi MP. A single initiating cause of hypertension; potential for primary prevention: a hypothesis. J Hypertens 2014; 3:18. 8. Krug AW, Grossmann C, Schuster C, Freudinger R, Mildenberger S, Govindan MV, et al. Aldosterone stimulates epidermal growth factor receptor expression. J Biol Chem 2003; 278:43060–43066. 9. Letizia C, Petramala L, Di Gioia CR, Chiappetta C, Zinnamosca L, Marinelli C, et al. Leptin and adiponectin mRNA expression from the adipose tissue surrounding the adrenal neoplasia. J Clin Endocrinol Metab 2015; 100:E101–E-104.
Journal of Hypertension 2015, 33:883–890 Department of Internal Medicine and Medical Specialties, University of Rome ‘Sapienza, Italy Correspondence to Claudio Letizia, University of Rome ‘Sapienza, Italy. E-mail: [email protected] J Hypertens 33:883–890 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI:10.1097/HJH.0000000000000524
Estimation of sodium excretion should be made as simple as possible, but not simpler: misleading papers and editorial on spot urines Feng J. He a, Vanja Ivkovic´ b, Bojan Jelakovic´ b, Joan Morris a, and Graham A. MacGregor a
A
reduction in population salt intake is one of the most cost-effective measures to prevent cardiovascular disease [1,2]. Two recent articles by O’Donnell et al. in the New England Journal of Medicine attempt to cast doubt on this important public health policy by claiming that a salt intake below 7.5 g/day was not associated with lower blood pressure and related to a higher cardiovascular events or total mortality based on the Prospective Urban Rural Epidemiology study [3,4]. However, this claim is invalid because of methodological problems as well as errors in using a mathematical formula to estimate daily salt intake from spot urinary sodium.
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Over the past five decades, there have been numerous inadvertently switched formulae for men and women while attempts to try and simplify the accurate measurements of again writing Kawasaki formula with all of the other errors. individuals’ daily salt intake. However, carefully controlled A recent carefully conducted study in a New Zealand studies showed that, to get a reasonable estimate of salt population demonstrated that the four commonly used intake in one individual, six to 11 consecutive 24-h urine formulae, which are Kawasaki, Tanaka, International Study collections need to be made [5]. This is due to the fact that of Sodium, Potassium and Blood Pressure (INTERSALT) salt consumption varies from day to day in individuals as and Pan American Health Organisation, all showed that a much as it does within the population. So, even an accusingle spot urine is a poor predictor of 24-h urinary sodium rately collected single 24-h urine will not reflect that indiexcretion in individuals [10]. At population level, the mean vidual’s intake, and furthermore, it will not reflect the intake excretion from the Kawasaki estimate was particularly over the following few years. In addition to this, many inaccurate, overestimating salt intake by 32% [10]. studies over the same period have shown that spot urinary The claim by O’Donnell et al. that the Kawasaki intrasodium does not accurately reflect 24-h urinary sodium class correlation coefficient of 0.71 shows good agreement excretion [6]. is in fact well below the established threshold of 0.90 to Spot urine measures urinary sodium concentration that give reasonable reliability for clinical measurements. In depends on fluid intake, time of the day, duration and addition, in their validation article, O’Donnell et al. volume of the collection, individuals’ posture [6], as well as included 24-h urine samples within 25% of predicted when the last sodium-containing meal was consumed. In 24-h urinary creatinine excretion as being complete, addition, different formulae used to predict 24-h urinary whereas the original Kawasaki method called for excluding sodium from spot urines give widely discrepant results. urine that exceeded 15% of predicted creatinine excretion None of these points was addressed in O’Donnell et al.’s [8]. This change in the criteria would have further reduced articles [3,4]. They chose to use the Kawasaki formula, but the reliability of their validation method and consequently then they used the wrong formula in their separate valifurther increase the bias of using spot urine to estimate 24-h dation article [7] that they cited as a reference in the New urinary sodium. Moreover, in the O’Donnell’s own study, England Journal of Medicine articles. there is clear evidence that the Kawasaki formula systemThe Kawasaki formula [8] should be atically underestimates salt intake when it is high and mmol ¼ 16:3 24-hUNaV day ffi vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi u u Spot Na mmol u mg l u hmgi t Predicated 24-h urinary Cr day Spot Cr 10 dl However, Mente et al. [7] used the following formula: vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi ffi u mmol u uSpot Na u l 24-hUNaV ¼ 16:3 u t mmol Spot Cr l mg Predicated 24-h urinary Cr day Comparing the above two formulae, Mente et al. [7] made four major errors: only a part of the expression is under the square root sign; erroneous unit of measurement is used for the spot urinary creatinine (mmol/l instead of mg/dl) with no correction when changing from one unit of measurement to another; spot urinary creatinine is not multiplied with appropriate factor; incongruent units were used for spot urinary creatinine (mmol/l); and the other for predicted 24-h urinary creatinine (mg/day). Furthermore, sex-specific formulae for predicted 24-h urinary creatinine were switched, that is, the one that should be used for men, was used for women and vice versa. An additional concern is that several months after publication, O’Donnell et al. sent an erratum to their validation article in the Journal of Hypertension [9], wherein they pointed out that they
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overestimates salt intake when it is low. This means that if the association between salt intake and blood pressure (or mortality) is examined in a group of people with high levels of salt intake, the slope of the association will be exaggerated, as the actual salt intake is greater than the predicted salt intake used in the model. It also means that in a group of people with low levels of salt intake, the association will be reduced, as the actual salt intake is lower than the predicted salt intake. This major methodological issue has been ignored by O’Donnell et al. In addition to the problems with the formula, O’Donnell et al.’s articles have several other methodological issues that are common in cohort studies, as described by the Science Advisory of the American Heart Association [11,12]. Particularly in this type of studies, it is impossible to correct for reverse causality, that is, people who are ill eat less and consume less salt. O’Donnell et al. tried to address reverse causality by excluding individuals with a history of cardiovascular disease; however, individuals with a potentially high risk for an event such as those with prehypertension, were included. These high-risk individuals were more likely to make an effort to reduce their salt intake. This again would cause reverse causality. In spite of all these problems, O’Donnell et al. tried to make an important public health statement about the dangers of reducing salt
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ACKNOWLEDGEMENTS
4. O’Donnell M, Mente A, Rangarajan S, McQueen MJ, Wang X, Liu L, et al. Urinary sodium and potassium excretion, mortality, and cardiovascular events. N Engl J Med 2014; 371:612–623. 5. Liu K, Cooper R, McKeever J, McKeever P, Byington R, Soltero I, et al. Assessment of the association between habitual salt intake and high blood pressure: methodological problems. Am J Epidemiol 1979; 110:219–226. 6. Ji C, Sykes L, Paul C, Dary O, Legetic B, Campbell NR, 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. 7. 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. 8. 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. 9. Mente A, O’Donnell MJ, Dagenais G, Wielgosz A, Lear SA, McQueen MJ, et al. Erratum. 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; 32:1915. 10. McLean R, Williams S, Mann J. Monitoring population sodium intake using spot urine samples: validation in a New Zealand population. J Hum Hypertens 2014; 28:657–662. 11. Whelton PK, Appel LJ, Sacco RL, Anderson CA, Antman EM, Campbell N, et al. Sodium, blood pressure, and cardiovascular disease: further evidence supporting the American Heart Association sodium reduction recommendations. Circulation 2012; 126:2880–2889. 12. Cobb LK, Elliott AC, Hu P, Liu FB, Neaton K, Whelton JD, et al. Methodological issues in cohort studies that relate sodium intake to cardiovascular disease outcomes: a Science Advisory From the American Heart Association. Circulation 2014; 129:1173–1186. 13. Oparil S. Low sodium intake: cardiovascular health benefit or risk? N Engl J Med 2014; 371:677–679. 14. He FJ, MacGregor GA. Reducing population salt intake worldwide: from evidence to implementation. Prog Cardiovasc Dis 2010; 52:363–382. 15. He FJ, Brinsden HC, MacGregor GA. Salt reduction in the United Kingdom: a successful experiment in public health. J Hum Hypertens 2014; 28:345–352. 16. He FJ, Pombo-Rodrigues S, MacGregor GA. Salt reduction in England from 2003 to 2011: its relationship to blood pressure, stroke and ischaemic heart disease mortality. BMJ Open 2014; 4:e004549. 17. Karppanen H, Mervaala E. Sodium intake and hypertension. Prog Cardiovasc Dis 2006; 49:59–75. 18. First Global Ministerial Conference on Healthy Lifestyles and Noncommunicable Disease Control, 28–29 April 2011, Moscow. http:// www.who.int/nmh/events/moscow_ncds_2011/en/. [Accessed 10 June 2013] 19. Beaglehole R, Bonita R, Horton R, Adams C, Alleyne G, Asaria P, et al. Priority actions for the noncommunicable disease crisis. Lancet 2011; 377:1438–1447. 20. Mozaffarian D, Fahimi S, Singh GM, Micha R, Khatibzadeh S, Engell RE, et al. Global sodium consumption and death from cardiovascular causes. N Engl J Med 2014; 371:624–634.
Conflicts of interest There are no conflicts of interest.
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intake, whereas, in fact, for the above reasons, they are in no position to do so. An accompanying editorial [13] does not consider the above points and accepts O’Donnell et al.’s findings that a single spot urine when used with the wrong formula and all of the above caveats, reflects an individual’s salt intake over a long period of time. There are many other types of evidence (epidemiological, migration, animal, genetic, treatment, outcome, and, now, population studies) that all clearly relate salt intake to blood pressure and cardiovascular outcome [14]. Indeed, the evidence for salt is stronger than for any other dietary constituents. None of this evidence was discussed in O’Donnell et al.’s articles. Furthermore, in Finland and now also in the United Kingdom, population salt intake has been reduced by getting the food industry to slowly reduce the amount of salt added to foods across the board [15]. The reduction in salt intake has caused a fall in population blood pressure both in Finland and the United Kingdom, and is associated with a reduction in cardiovascular deaths [16,17]. The totality of the evidence for population-wide reduction in salt intake is very strong [14]. Indeed, salt reduction is one of the most cost-effective measures to prevent cardiovascular disease in both developed and developing countries [1,2]. At the 2011 United Nations high-level meeting on noncommunicable diseases, salt reduction was recommended as one of the top three priority actions to reduce premature mortality from noncommunicable diseases by 25% by 2025 [18,19]. The WHO, in its recent guideline, recommends a 30% reduction in salt intake by 2025 with an eventual target of 5 g/day for all adults and lower levels for children based on calorie intake. All countries should adopt a coherent and workable strategy to reduce salt intake in the population to meet the target of the WHO. The benefits will be very large with approximately 1.65 million cardiovascular deaths prevented per year [20] along with major cost savings to the health service worldwide. The severely methodologically flawed articles by O’Donnell et al. should not and cannot be used to divert this vital and very cost-effective public health policy.
REFERENCES 1. Bibbins-Domingo K, Chertow GM, Coxson PG, Moran A, Lightwood JM, Pletcher MJ, Goldman L. Projected effect of dietary salt reductions on future cardiovascular disease. N Engl J Med 2010; 362:590–599. 2. Asaria P, Chisholm D, Mathers C, Ezzati M, Beaglehole R. Chronic disease prevention: health effects and financial costs of strategies to reduce salt intake and control tobacco use. Lancet 2007; 370:2044– 2053. 3. Mente A, O’Donnell MJ, Rangarajan S, McQueen MJ, Poirier P, Wielgosz A, et al. Association of urinary sodium and potassium excretion with blood pressure. N Engl J Med 2014; 371:601–611.
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a Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK and bSchool of Medicine, University of Zagreb, and Department of Nephrology, Hypertension, Dialysis and Transplantation, University Hospital Center Zagreb, Zagreb, Croatia
Correspondence to Bojan Jelakovic´, MD, PhD, School of Medicine University of Zagreb, Department of Nephrology, Hypertension, Dialysis and Transplantation, University Hospital Centre Zagreb, Croatia, Zagreb, Kisˇ patic´eva 12, 10000 Zargeb. Tel: +385 1 23 88 271; fax: +385 1 23 88 592; email: [email protected] J Hypertens 32:883–890 ß 2015 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000548
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Response to‘Estimation of sodium excretion should be made as simple as possible, but not simpler: misleading papers and editorial on spot urines’ Andrew Mente a,b, Martin J. O’Donnell a,c,d, and Salim Yusuf a,b,c
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e et al. [1,2] make a number of incorrect assertions in their letters. We clarify that we utilized a fasting morning urine sample, not a ‘spot’ random urine [3–5]. The distinction is important, as is the distinction between a fasting glucose versus a random glucose test, or a fasting cholesterol versus a nonfasting cholesterol. Furthermore, the intent of our approach is analogous to most epidemiologic studies that relate risk factors such as blood pressure (BP), cholesterol, or fasting glucose (each of which is only an approximation of the ‘usual’ levels) to cardiovascular disease (CVD), in which, using single measure, group-level estimates of these risk factors have been reliably related to CVD outcomes. We agree that sodium intake varies from day to day (as does BP or cholesterol), making repeated measurements desirable to gain an estimate (irrespective of the method used for any single day’s measure) of ‘usual’ sodium intake. However, less-frequent measurements introduce mainly random error and reduce statistical precision and are most likely to bias relationships toward the null, but would not be expected to change the overall pattern of association (i.e. would not change a J-shaped association to a linear association). One way to account for this variability is by obtaining repeated measures in each participant, but this is not feasible for large studies. Instead, the usual approach to account for day-to-day variability in measures in large population studies is to estimate the correlation between measures obtained on two separate days some weeks or months apart and then use the correlation to adjust for the degree of regression–dilution bias. This is widely used to relate cholesterol or BP to CVD and is an accepted approach. We used a similar method for estimating ‘usual’ 24-h urinary sodium excretion and this did not change the shape of the slopes, but instead made the ‘J’-shaped slopes steeper at both ends of the curve [5]. He et al. [1,2] ignore a key consideration in large epidemiologic studies examining the association between exposures and clinical outcomes. Although variations in the measurements of sodium intake in the same individual (which can vary by about 30–50%) should be minimized to the extent feasible, the dominant source of variability is the intersubject variability in sodium intake (which can be several fold – e.g. 500–600%) and the random variations in the rates of the outcomes of interest (e.g. CVD incidence). If the associations are moderate (which is the case for most risk factors for CVD), to demonstrate the shape of the association, large population studies (involving several tens of thousands of individuals) with a broad range of intake of sodium is needed among whom several thousand CVD events occur. This requires methods that are simple, least biased, and applicable to large populations. Because 24-h Journal of Hypertension
urine samples are often not complete, and there is a high rate of participant burden and refusals, it is not only impractical to obtain repeated 24-h urine collections but also the population included may be biased as free-living working populations more often tend to refuse to participate in studies with high burden. So using 24-h measures is not suitable for studies of several tens of thousands of individuals (which requires many centers) and in many countries (to include populations with wide range of sodium intakes). The requirements for very large studies mean that the approach to assessing the association of sodium (or BP or cholesterol) versus CVD requires studies with simple methods of assessing the exposures (which is exactly what we have done), and similar to what has been done and widely accepted epidemiologic approaches to evaluating the exposures such as BP, cholesterol, or glucose [6,7]. He et al. [1,2] ignore the fact that the association between sodium and BP in our study is entirely consistent with findings of a meta-analysis of prior studies relating sodium intake (measured using 24-h urine) to BP and so provide further validation of our approach. So, why would the same method provide valid and reliable information on the association of sodium versus BP, but not for the association between sodium versus CVD? We applied the Kawasaki equation as originally specified [8]. We concur that the formula as provided in the ‘Methods’ should have included an additional set of brackets to show that the full expression is under the square root sign. We did perform the appropriate unit conversions and multiplied fasting morning urine creatinine by the appropriate factor, which we did not indicate in the article. Moreover, the calculations were completed by two independent people and compared. We had extensive discussions about the methodology during the reviews of our three articles involving over 15 separate reviewers, who were satisfied with the validity of our approach and calculations. (It is also noteworthy that application of the formula with any of the four errors described by He et al. would produce implausible mean sodium excretion values between three-fold and 35-fold different than the estimates provided that would be easily identified.) Furthermore, the creatinine formulae for men and women were applied correctly, although as noted previously, a typographical error occurred in one sentence of the publication where the words ‘men’ and ‘women’ were transposed. We detected this immediately after publication and rapidly communicated this to the Journal. So the assertion by He et al. that we used an incorrect formula is incorrect. We have also performed analyses of the relationship between sodium and cardiovascular events/mortality using Tanaka and International Study of Sodium, Potassium, and Blood Pressure (INTERSALT) formulae in the Prospective Urban and Rural Epidemiology (PURE) study. Tanaka showed the same J-shaped relationship (Fig. 1), whereas INTERSALT was inverse only (no increased risk with higher sodium excretion) (Fig. 2). So, all approaches give the same answer at low sodium levels, but some differences are observed with different methods with higher sodium excretion levels. In addition, in both our PURE and Ongoing Telmisartan Alone and in combination with www.jhypertension.com
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Sodium versus systolic BP and CVD events
Sodium/creatinine versus systolic BP and CVD events
Systolic BP
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1
128 126
