Natriuretic regulation of extracellular fluid volume homeostasis includes suppression of the renin-angiotensin-aldosterone system, pressure natriuresis, and reduced renal nerve activity, actions that concomitantly increase urinary Na+ excretion and lead to increased urine volume. The resulting natriuresis-driven diuretic water loss is assumed to control the extracellular volume. Here, we have demonstrated that urine concentration, and therefore regulation of water conservation, is an important control system for urine formation and extracellular volume homeostasis in mice and humans across various levels of salt intake. We observed that the renal concentration mechanism couples natriuresis with correspondent renal water reabsorption, limits natriuretic osmotic diuresis, and results in concurrent extracellular volume conservation and concentration of salt excreted into urine. This water-conserving mechanism of dietary salt excretion relies on urea transporter–driven urea recycling by the kidneys and on urea production by liver and skeletal muscle. The energy-intense nature of hepatic and extrahepatic urea osmolyte production for renal water conservation requires reprioritization of energy and substrate metabolism in liver and skeletal muscle, resulting in hepatic ketogenesis and glucocorticoid-driven muscle catabolism, which are prevented by increasing food intake. This natriuretic-ureotelic, water-conserving principle relies on metabolism-driven extracellular volume control and is regulated by concerted liver, muscle, and renal actions.
Kento Kitada, Steffen Daub, Yahua Zhang, Janet D. Klein, Daisuke Nakano, Tetyana Pedchenko, Louise Lantier, Lauren M. LaRocque, Adriana Marton, Patrick Neubert, Agnes Schröder, Natalia Rakova, Jonathan Jantsch, Anna E. Dikalova, Sergey I. Dikalov, David G. Harrison, Dominik N. Müller, Akira Nishiyama, Manfred Rauh, Raymond C. Harris, Friedrich C. Luft, David H. Wasserman, Jeff M. Sands, Jens Titze
Submitter: Richard Sterns | firstname.lastname@example.org
Authors: Richard Sterns (1) and Lise Bankir (2)
(1) University of Rochester School of Medicine and Dentistry and (2) Inserm Unit 1138, Centre de Recherche des Cordeliers, Paris, France.
Published September 27, 2017
According to the New York Times , a recent study published in the Journal  “contradicts much of the conventional wisdom about how the body handles salt and suggests that high levels may play a role in weight loss”. Before we throw away our Physiology Textbooks, we would offer a much simpler explanation for the study’s findings than the authors have proposed.
Table 1 of Kitada’s paper  provides averaged data for cosmonauts on 6 and 12 g sodium diets (LSD and HSD, respectively). As expected, doubling dietary sodium doubles urinary sodium (56±24 vs 108±34 mmol/d). Consistent with data reviewed by Bankir et al , increased sodium excretion in cosmonauts was accomplished by increasing urine sodium concentration (56±24 vs 108±34 mmol/l) with no increase in urine volume (22±8 vs 22±7 ml/kg/d). Surprisingly, fluid intake was significantly lower on HSD (31±7 vs 35±7 ml/kg/day). Bolstered by studies in mice the authors conclude that metabolic water must have compensated for diminished fluid intake on HSD.
Classic physiological principles would attribute the 13 ml/kg daily difference between fluid intake (35 ml/kg) and urine volume (22 ml/kg) on LSD to insensible loss. Similarly, insensible loss on HSD would be estimated to be 9 ml/kg (31–22 ml/kg/d) . The differences between input and output on the two diets cannot be attributed to protein catabolism (urine urea excretion was actually lower on HSD). Moreover, if the subjects were really turning 4 ml/kg of their flesh into water each day, and, if the study lasted 250 days, they would have disappeared!
The studies in mice that appear to support the authors’ hypothesis are seriously flawed. The mice were not in steady state. They were not adapted to metabolic cages and were deprived of food for the 20-h of urine collection which, given their high metabolic rate, would have led to extreme stress and catabolism, making the data uninterpretable.
How then, can the observations in humans be explained? Doubling salt intake would be expected to stimulate vasopressin, which increases both water and urea reabsorption from the collecting duct, increasing urine osmolality, with a sodium + potassium concentration (158 mmol/L) higher than plasma sodium. This should generate positive electrolyte-free water balance. Vasopressin also plays a role in thermoregulation, reducing insensible losses that dissipate heat . Renal generation of electrolyte-free water along with reduced insensible losses, explain the slight reduction in water intake on the higher salt diet.
Submitter: Jens Titze | jens.m.titze@Vanderbilt.Edu
Authors: Jens Titze
Vanderbilt University Medical Center
Published September 27, 2017
Drs. Sterns and Bankir have found a simple answer to the question why 10 young men living in a carefully controlled environment drank less when they ate 6 grams of salt more per day: in line with what was discussed in the original paper (1), „renal generation of electrolyte-free water along with reduced insensible losses, might explain the slight reduction in water intake on the higher salt diet“.
Were things really that simple? A 6 g/d increase in salt intake increased glucocorticoid levels in the subjects. What happened when glucocorticoid levels were high? The subjects showed elevated urine volumes, but did not increase fluid intake – and urine osmolality decreased. Where did the surplus water they excreted come from, if they did not drink it? Suddenly our simple answer becomes shaky. A water surplus may theoretically have been acquired earlier as a result of successful free-water reabsorption in the extrarenal barriers skin, gut, and lung when glucocorticoid levels were high. But why on earth would these three barriers generate water – just to have the kidneys happily lose it? Which hormonal signal would induce free-water generation in the skin, the gut, or the lungs - and at the same time allow the kidney to excrete the generated water load? Could parallel vasopressin release again explain this rather anomalous water exretion pattern? Most likely not.
So why not testing the alternative hypothesis, namely that glucocorticoid release increases metabolic water production, because its catabolic action promotes protein, fat, and sugar breakdown (2)? Mice with elevated glucocorticoid levels on an experimental high-salt diet ate 20-30% more food. But they did not increase body weight. Where did the energy go to? Did they mask a salt-driven catabolic state by increasing food intake? Reducing their energy intake to the level of the low-salt group, high-salt fed animals stole the energy and nitrogen from skeletal muscle, resulting in catabolic muscle wasting. Why? Because the mice now utilized endogenous, and not exogenous fuels to generate more metabolic water (3). And additonally, the mice produced the urea that was necessary for osmolyte gradient-driven free-water generation in the kidney, mediated by vasopressin-dependent water transport – as suggested by Drs. Sterns and Bankir.
Last question: is this research flawed? Neither Dr. Sterns, nor Dr. Bankir, nor myself know the answer. Future investigators will. I am looking forward to their findings.
1. Rakova N, Kitada K, Lerchl K, Dahlmann A, Birukov A, Daub S, Kopp C, Pedchenko T, Zhang Y, Beck L, et al. Increased salt consumption induces body water conservation and decreases fluid intake. J Clin Invest 2017;127(5):1932-43.
2. Kitada K, Daub S, Zhang Y, Klein JD, Nakano D, Pedchenko T, Lantier L, LaRocque LM, Marton A, Neubert P, et al. High salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation. J Clin Invest. 2017;127(5):1944-59.
3. Rabelink TJ. Renal physiology: Burning calories to excrete salt. Nature Reviews Nephrology. 2017;13(6):323-4.