Advertisement
American Journal of Kidney Diseases

An Increasingly Complex Relationship Between Salt and Water

Published:September 09, 2017DOI:https://doi.org/10.1053/j.ajkd.2017.07.007
      Commentary on Rakova N, Kitada K, Lerchl K, et al. Increased salt consumption induces body water conservation and decreases fluid intake. J Clin Invest. 2017;127(5):1932-1943.
      One hundred fifty years ago this year, physiologist Moritz Schiff proclaimed from a pulpit at the University of Florence that the sensation of thirst, rather than being secondary to dryness of the throat, is a “general sensation, stemming from lack of water in the blood.” Expounding, he declared “the dryness of the throat that normally accompanies [thirst] is merely a secondary phenomenon, analogous to the weight of the eyelids that accompanies sleepiness.”
      • Schiff M.
      Deuxième Leçon: de la Faim et de la Soif
      Leçons sur la Physiologie de la Digestion.
      Fifty years later, Erich Leschke would demonstrate that intravenous infusion of hypertonic saline in humans provoked a “sudden and violent thirst.”
      • Leschke E.
      Ueber die durstempfindung.
      Subsequent studies revealed that increased dietary salt stimulates fluid consumption in experimental animals, and the role of increased oral fluid intake in mitigating dietary salt–induced hypertonicity while expanding extracellular fluid volume became established renal canon.
      • Richter C.P.
      • Mosier Jr., H.D.
      Maximum sodium chloride intake and thirst in domesticated and wild Norway rats.
      However, studies of humans in the 1980s suggested that the relationship between dietary salt and fluid intake may not be so simple.
      • Luft F.C.
      • Fineberg N.S.
      • Sloan R.S.
      • Hunt J.N.
      The effect of dietary sodium and protein on urine volume and water intake.
      Delving deeper into this subject, Rakova and colleagues now present findings in support of the heretical notion that increased salt intake over the long term decreases fluid consumption in humans.
      • Rakova N.
      • Kitada K.
      • Lerchl K.
      • et al.
      Increased salt consumption induces body water conservation and decreases fluid intake.
      An accompanying report by the same group further explores the metabolic effects of increased salt consumption in mouse models and the mechanisms that allow reduced fluid intake in the context of increased sodium consumption.
      • Kitada K.
      • Daub S.
      • Zhang Y.
      • et al.
      High salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation.
      These findings expand our understanding of the metabolic effects of salt consumption and test our faith in the dogma surrounding the role of water consumption in controlling extracellular tonicity.

      What Does This Important Study Show?

      The Mars500 program provided a unique opportunity to examine fluid and electrolyte balance over extended periods in humans. In these studies, all-male crews were confined to an isolation chamber in Moscow for 105 or 520 days in simulation of interplanetary travel. Participants were provided fixed-calorie diets with salt that varied from 6 to 12 g (equivalent to 2.4-4.7 g of sodium) per day, with each dietary sodium phase lasting at least 29 days. Study participants recorded ad libitum fluid intake and performed daily 24-hour urine collections. Twelve individuals were studied; 2 of these were dropped from the study due to poor data reliability. A previous report from the Mars500 program demonstrated a surprising near-weekly variation in urinary sodium excretion and semiweekly variation in aldosterone and cortisol excretion.
      • Rakova N.
      • Juttner K.
      • Dahlmann A.
      • et al.
      Long-term space flight simulation reveals infradian rhythmicity in human Na(+) balance.
      To prevent these rhythms from obscuring trends in experimental results, data were stratified both by dietary salt level and urinary sodium and adrenal hormone tertiles.
      This research group’s previous report demonstrated that increased dietary sodium resulted in a rapid but transient increase in extracellular fluid volume.
      • Rakova N.
      • Juttner K.
      • Dahlmann A.
      • et al.
      Long-term space flight simulation reveals infradian rhythmicity in human Na(+) balance.
      Although volume status returned to baseline after 2 weeks on the highest sodium diet, blood pressure gradually increased over 4 weeks.
      • Rakova N.
      • Juttner K.
      • Dahlmann A.
      • et al.
      Long-term space flight simulation reveals infradian rhythmicity in human Na(+) balance.
      The present report reveals the surprising finding that a high-salt diet was associated with a decrease in oral fluid consumption.
      • Rakova N.
      • Kitada K.
      • Lerchl K.
      • et al.
      Increased salt consumption induces body water conservation and decreases fluid intake.
      This was possible partly as a result of decreased urinary osmolyte-free water excretion. The accompanying animal model study by Kitada et al
      • Kitada K.
      • Daub S.
      • Zhang Y.
      • et al.
      High salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation.
      showed that increased salt intake in experimental mice stimulated a catabolic shift in metabolism, promoting muscle and fat breakdown and hepatic urea production. When mice were provided ad libitum food intake, increased dietary salt stimulated food consumption, presumably to offset these catabolic effects. The authors suggest that this observation may be driven in part by elevated plasma cortisol concentrations. High salt intake also increased urea transporter UT-A1 expression in the renal medulla. Together, increased urea production and reduced urea excretion augmented medullary urea concentrations and enhanced urinary concentrating ability. Although the higher-salt diet decreased urinary free-water excretion in human participants, urine volumes in the highest salt intake phase were not decreased. The authors conclude that increased metabolic water production compensated for this apparent fluid deficit, though a reduction in insensible losses could not be assessed. The combination of reduced urinary water excretion and enhanced water production was so effective that mice that were given a high-salt diet and only normal saline solution to drink experienced a paradoxical reduction in plasma sodium concentration. Thus, increased sodium intake reduced fluid intake without causing hypertonicity.
      Several factors may influence the generalizability of these findings. The Mars500 program study included only young subjects who were free of overt hypertension, kidney disease, or heart disease. None were women. All were of European or Asian ancestry. Participants consumed a fixed-calorie diet. The dietary sodium intervention was relatively modest compared with the global range of sodium intake levels. The highest daily sodium intake level, 4.7 g, remained lower than mean daily intake in some global studies.
      • Mente A.
      • O'Donnell M.J.
      • Rangarajan S.
      • et al.
      Association of urinary sodium and potassium excretion with blood pressure.
      • O'Donnell M.
      • Mente A.
      • Rangarajan S.
      • et al.
      Urinary sodium and potassium excretion, mortality, and cardiovascular events.
      During the simulated space flight, study participants were found to experience physiologic perturbations, including decreased total sleep time and efficiency, reduced physical activity, dampened parasympathetic circadian rhythms, and increased production of cortisol and inflammatory cytokines.
      • Gemignani A.
      • Piarulli A.
      • Menicucci D.
      • et al.
      How stressful are 105 days of isolation? Sleep EEG patterns and tonic cortisol in healthy volunteers simulating manned flight to Mars.
      • Vigo D.E.
      • Tuerlinckx F.
      • Ogrinz B.
      • et al.
      Circadian rhythm of autonomic cardiovascular control during Mars500 simulated mission to Mars.
      • Yi B.
      • Rykova M.
      • Feuerecker M.
      • et al.
      520-d isolation and confinement simulating a flight to Mars reveals heightened immune responses and alterations of leukocyte phenotype.
      It is not clear whether these specific variables influenced results in the current study, but the study environment appears to have provoked unexpected physiologic and psychological effects. Replicating these findings in a less isolated environment may prove difficult but would help address the generalizability of the study’s findings.

      How Does This Study Compare With Prior Studies?

      This study’s finding that fluid intake did not increase with increased dietary salt seems at odds with studies using experimental animals. One explanation for this discrepancy may lie in the differences in sodium administered. For example, when Richter and Mosier
      • Richter C.P.
      • Mosier Jr., H.D.
      Maximum sodium chloride intake and thirst in domesticated and wild Norway rats.
      observed increased fluid consumption in rats consuming a 2% sodium chloride diet, the rats consumed a quantity of sodium that, when normalized for body weight, would be comparable to >27 g/d in a 70-kg human. Even in the accompanying animal study by Kitada et al,
      • Kitada K.
      • Daub S.
      • Zhang Y.
      • et al.
      High salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation.
      mice on a 4% salt diet increased fluid consumption by >50%. Urine data suggest that these mice consumed a quantity of sodium equivalent to >17 g/d for an adult human, far in excess of the 4.7 g/d consumed by Mars500 participants during the highest dietary sodium phase. If humans consumed this much sodium, oral fluid intake might also increase.
      This difference in sodium intake may also influence endocrine findings in these studies. Mice in the Kitada et al
      • Kitada K.
      • Daub S.
      • Zhang Y.
      • et al.
      High salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation.
      study exhibited increased plasma glucocorticoid concentrations on a high-sodium diet. Although the human participants in the Mars500 study exhibited increased urinary cortisol excretion, this does not necessarily indicate that the human participants experienced increased plasma cortisol concentrations. Moderate increases in dietary sodium in humans have previously been observed to cause increased urinary clearance of cortisol with an associated decrease in plasma cortisol concentrations, suggesting that additional mechanisms may have contributed to altered water and urea metabolism in the Mars500 participants.
      • Kerstens M.N.
      • van der Kleij F.G.
      • Boonstra A.H.
      • et al.
      Salt loading affects cortisol metabolism in normotensive subjects: relationships with salt sensitivity.
      • Lewicka S.
      • Nowicki M.
      • Vecsei P.
      Effect of sodium restriction on urinary excretion of cortisol and its metabolites in humans.
      Few studies have addressed the relationship between sodium consumption and fluid intake in humans. One study varied daily sodium intake from about 0.2 to 9.6 g/d in 24 apparently healthy men and saw no difference in fluid intake or urine volume, though baseline variation was significant and intraparticipant changes were not reported.
      • Luft F.C.
      • Fineberg N.S.
      • Sloan R.S.
      • Hunt J.N.
      The effect of dietary sodium and protein on urine volume and water intake.
      In another study examining healthy men with fixed fluid intake, an increase in dietary sodium up to 15 g/d was associated with net negative fluid balance. However, extracellular fluid remained stable, suggesting that water accumulated from sources other than ingestion. These sources could include intracellular water, reduced insensible losses, or metabolism, consistent with results from the Mars500 program.
      • Heer M.
      • Baisch F.
      • Kropp J.
      • Gerzer R.
      • Drummer C.
      High dietary sodium chloride consumption may not induce body fluid retention in humans.

      What are the Implications for Nephrologists?

      The findings in these reports have several clinical implications. These studies challenge the intuitive concept that moderate increases in dietary sodium intake stimulate oral fluid intake and increase extracellular fluid volume in healthy individuals. Further, these findings add credence to recent arguments that mechanisms independent of extracellular fluid volume contribute to the increase in blood pressure promoted by increased dietary sodium.
      • Feng W.
      • Dell'Italia L.J.
      • Sanders P.W.
      Novel paradigms of salt and hypertension.
      • Trott D.W.
      • Harrison D.G.
      The immune system in hypertension.
      • Blaustein M.P.
      • Leenen F.H.
      • Chen L.
      • et al.
      How NaCl raises blood pressure: a new paradigm for the pathogenesis of salt-dependent hypertension.
      The catabolic state observed in animals fed a high-salt diet suggests that increased salt consumption may have long-term metabolic consequences that may influence diabetes, cardiovascular diseases, and hypertension. The enhanced urinary concentrating ability and free water retention provoked by a high-salt diet demonstrate a mechanism to explain how therapies other than oral salt may be more effective for the treatment of hyponatremia. Finally, the observed rhythmicity in adrenal hormone and urinary sodium excretion cast doubt on the validity of a single 24-hour urine collection to estimate an individual’s sodium and fluid intake or adrenal hormone production.
      The present studies suggest that the mechanisms regulating thirst and extracellular fluid volume and tonicity are more complicated than previously understood and likely involve hormonal, metabolic, and other systemic processes. Reformed understanding of these processes may ultimately facilitate improved strategies for management of disorders of extracellular fluid volume, tonicity, and metabolism.

      Acknowledgements

      Support: Supported by grants from the National Institutes of Health ( DK110332 , DK038470 , and DK079407 ).
      Financial Disclosure: The authors declare that they have no relevant financial interests.
      Peer Review: Editorial input from an Associate Editor and Deputy Editor Berns.

      References

        • Schiff M.
        • Deuxième Leçon: de la Faim et de la Soif
        Leçons sur la Physiologie de la Digestion.
        Vol 1. Hermann Loescher, Florence, Italy1867: 41-42
        • Leschke E.
        Ueber die durstempfindung.
        Archiv für Psychiatrie und Nervenkrankheiten. 1918; 59: 773-781
        • Richter C.P.
        • Mosier Jr., H.D.
        Maximum sodium chloride intake and thirst in domesticated and wild Norway rats.
        Am J Physiol. 1954; 176: 213-222
        • Luft F.C.
        • Fineberg N.S.
        • Sloan R.S.
        • Hunt J.N.
        The effect of dietary sodium and protein on urine volume and water intake.
        J Lab Clin Med. 1983; 101: 605-610
        • Rakova N.
        • Kitada K.
        • Lerchl K.
        • et al.
        Increased salt consumption induces body water conservation and decreases fluid intake.
        J Clin Invest. 2017; 127: 1932-1943
        • Kitada K.
        • Daub S.
        • Zhang Y.
        • et al.
        High salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation.
        J Clin Invest. 2017; 127: 1944-1959
        • Rakova N.
        • Juttner K.
        • Dahlmann A.
        • et al.
        Long-term space flight simulation reveals infradian rhythmicity in human Na(+) balance.
        Cell Metab. 2013; 17: 125-131
        • Mente A.
        • O'Donnell M.J.
        • Rangarajan S.
        • et al.
        Association of urinary sodium and potassium excretion with blood pressure.
        N Engl J Med. 2014; 371: 601-611
        • O'Donnell M.
        • Mente A.
        • Rangarajan S.
        • et al.
        Urinary sodium and potassium excretion, mortality, and cardiovascular events.
        N Engl J Med. 2014; 371: 612-623
        • Gemignani A.
        • Piarulli A.
        • Menicucci D.
        • et al.
        How stressful are 105 days of isolation? Sleep EEG patterns and tonic cortisol in healthy volunteers simulating manned flight to Mars.
        Int J Psychophysiol. 2014; 93: 211-219
        • Vigo D.E.
        • Tuerlinckx F.
        • Ogrinz B.
        • et al.
        Circadian rhythm of autonomic cardiovascular control during Mars500 simulated mission to Mars.
        Aviation Space Environ Med. 2013; 84: 1023-1028
        • Yi B.
        • Rykova M.
        • Feuerecker M.
        • et al.
        520-d isolation and confinement simulating a flight to Mars reveals heightened immune responses and alterations of leukocyte phenotype.
        Brain Behav Immun. 2014; 40: 203-210
        • Kerstens M.N.
        • van der Kleij F.G.
        • Boonstra A.H.
        • et al.
        Salt loading affects cortisol metabolism in normotensive subjects: relationships with salt sensitivity.
        J Clin Endocrinol Metab. 2003; 88: 4180-4185
        • Lewicka S.
        • Nowicki M.
        • Vecsei P.
        Effect of sodium restriction on urinary excretion of cortisol and its metabolites in humans.
        Steroids. 1998; 63: 401-405
        • Heer M.
        • Baisch F.
        • Kropp J.
        • Gerzer R.
        • Drummer C.
        High dietary sodium chloride consumption may not induce body fluid retention in humans.
        Am J Physiol Renal Physiol. 2000; 278: F585-F595
        • Feng W.
        • Dell'Italia L.J.
        • Sanders P.W.
        Novel paradigms of salt and hypertension.
        J Am Soc Nephrol. 2017; 28: 1362-1369
        • Trott D.W.
        • Harrison D.G.
        The immune system in hypertension.
        Adv Physiol Educ. 2014; 38: 20-24
        • Blaustein M.P.
        • Leenen F.H.
        • Chen L.
        • et al.
        How NaCl raises blood pressure: a new paradigm for the pathogenesis of salt-dependent hypertension.
        Am J Physiol Heart Circ Physiol. 2012; 302: H1031-H1049