关于盐，我们所知的一切可能都错了
两百多年来一直被传授给医生的水盐平衡，并不是个难理解的理论。人类的身体依赖这种必不可少的矿物质实现各种机能，包括血压和传递神经脉冲。我们必须小心地维持血液中的钠浓度。如果食用了很多盐（氯化钠）就会口渴、会喝水，这样就会稀释血液，使之保持适当的钠浓度，最终会通过尿液排出大部分多余的盐和水。这个理论直观简单，但是或许完全是错误的。
2017年5月1日，美国临床研究学会官方期刊《临床研究杂志》正式发表德国柏林洪堡大学和柏林自由大学联合医学院、马克斯德尔布吕克分子医学中心、埃尔朗根纽伦堡大学、美茵茨大学、雷根斯堡大学、德国航空航天中心、美国范德堡大学、埃默里大学、日本香川大学的两项研究报告，否定了有关身体如何处理盐分的许多传统认知，并表明高浓度的盐分或许有助减肥。
该研究的项目负责人和通讯作者为延斯·蒂策（Jens Titze）。1991年，还是柏林大学医学生的蒂策，上了一门有关极端环境下人体生理的课程。这门课的教授与欧洲太空计划合作，展示了一项为期28天的模拟飞行任务的数据。在这项任务中，全体宇航员都生活在一个小太空舱里。这项任务的主要目标是了解宇航员们会如何相处，但是科学家们也收集了他们的尿液和其他生理指标。蒂策在这些数据中注意到了一些令人困惑的地方：宇航员们的尿量以七天为一个周期上下波动。这与他在医学院学到的东西是完全矛盾的：不应该有这样的时间周期。
1994年，俄罗斯太空计划决定在和平号空间站进行为期135天的生命模拟实验。蒂策设法去了俄罗斯，研究宇航员的尿液变化规律，以及饮食中的盐如何影响这些变化。结果他有了一个惊人的发现：宇航员身体中的钠浓度以28天为周期进行变化，而且这些变化与他们的尿量多少无关。此外，钠浓度的变化规律也比尿样变化更加显著，钠浓度本应随着尿量变化而增减。虽然这项研究不够完美，宇航员的钠摄入量没有经过精确的校准，但是蒂策确信，有液体摄取之外的其他东西在影响船上宇航员体内的钠存储。他意识到，这样的结论是“异端邪说”。
2006年，俄罗斯太空计划又宣布了两项模拟研究，一项持续105天，另一项520天。蒂策看到一个机会，可以让他搞清楚这些异常的发现是否是真的。在时间较短的那个模拟项目中，宇航员最初的饮食每天摄入12克盐，之后是每天9克，然后变成每天6克的低盐饮食，每个阶段持续28天。在时间更长那个任务里，宇航员们也会多一个每天摄入12克盐的饮食周期。跟我们大多数人一样，这些宇航员也喜欢吃咸的。33岁的德国人奥利弗·克尼克尔（Oliver Knickel）如今是斯图加特的汽车工程师，当年参加了那个项目。据他回忆，即使是每天提供12克盐的食物对他而言也不够咸，当盐含量下降到每天6克时，就不怎么好吃了。真正让人震惊的事情发生在蒂策测量全体宇航员的尿量、尿钠、血钠时，诡异的尿量变化规律依然存在，但是一切似乎都与教科书一致，当宇航员摄入更多盐，就在尿液中排出更多盐，血液中的钠含量保持不变，但是他们的尿量会增加。然而，观察他们的液体摄入量后，结果大吃一惊。长时间看，当宇航员摄入更多盐分时，他们并没有摄入更多液体，反倒喝得更少。那他们排泄出去的水是从哪里来的？只有一种办法可以解释这种现象：当盐摄入量增加时，身体很可能自己生成或制造了水分。
为此，蒂策等人开始在实验室里用小鼠做研究。果然，他在这些动物的饮食中添加越多的盐，它们的饮水量就会越小。他找到了其中的原因，这些动物是在获得水分，但是并非通过饮用。糖皮质激素水平增高，促使体内脂肪和肌肉分解，由此释放出水分，供身体使用。但是蒂策等人也发现，这个过程需要消耗能量，所以小鼠在高盐分饮食期间进食量增加了25%。这些激素或许也是导致尿量从长期看出现异常波动的一个原因。科学家们知道人体饥饿时会燃烧脂肪和肌肉以维持生命，但是意识到采用高盐饮食也会出现类似的情况。
这些结果令肾脏专家感到震惊。哈佛医学院医学助理教授梅拉妮·霍尼格（Melanie Hoenig）称：研究做得十分严谨。匹兹堡大学教授詹姆斯·R·约翰斯顿（James R. Johnston）在两篇文章的页边标出了每个意想不到的发现，结果两篇论文都被涂满了，他说：的确很酷，不过他也提到，这些发现需要重复验证。
对此，哈佛医学院贝斯以色列女执事医疗中心肾脏内科马克·泽德尔（Mark Zeidel）发表同期评论，其中指出：人类的做法和骆驼是一样的。骆驼要穿越没水的沙漠，作为替代，它分解驼峰中的脂肪以获得水分。在这个发现带来的诸多启示中，有一个是我们也许可以利用盐以减肥。科学家们通常认为高盐饮食会促使身体摄入更多液体，进而令体重增加。但是如果平衡更高的盐分摄入会促使身体分解组织，那它或许也能增加能量消耗。
不过，蒂策表示他不会建议通过摄入很多盐以减肥。如果他的结果是正确的，那么从长期看，摄入更多的盐会感觉更加饥饿，所以必须确保自己不会吃更多的食物，不然就把额外燃烧的热量抵消掉了。而且，高糖皮质激素水平与骨质疏松症、肌肉减少、2型糖尿病等代谢问题存在相关性。
J Clin Invest. 2017 May 1;127(5):1932-1943.
Increased salt consumption induces body water conservation and decreases fluid intake.
Rakova N, Kitada K, Lerchl K, Dahlmann A, Birukov A, Daub S, Kopp C, Pedchenko T, Zhang Y, Beck L, Johannes B, Marton A, Müller DN, Rauh M, Luft FC, Titze J.
Charité Medical Faculty, Max-Delbrück Center for Molecular Medicine, Berlin, Germany; University Clinic Erlangen, Erlangen, Germany; Vanderbilt University Medical Center, Nashville, Tennessee, USA; University Medical Center Mainz, Mainz, Germany; German Aerospace Center, Cologne, Germany.
BACKGROUND: The idea that increasing salt intake increases drinking and urine volume is widely accepted. We tested the hypothesis that an increase in salt intake of 6 g/d would change fluid balance in men living under ultra-long-term controlled conditions.
METHODS: Over the course of 2 separate space flight simulation studies of 105 and 205 days' duration, we exposed 10 healthy men to 3 salt intake levels (12, 9, or 6 g/d). All other nutrients were maintained constant. We studied the effect of salt-driven changes in mineralocorticoid and glucocorticoid urinary excretion on day-to-day osmolyte and water balance.
RESULTS: A 6-g/d increase in salt intake increased urine osmolyte excretion, but reduced free-water clearance, indicating endogenous free water accrual by urine concentration. The resulting endogenous water surplus reduced fluid intake at the 12-g/d salt intake level. Across all 3 levels of salt intake, half-weekly and weekly rhythmical mineralocorticoid release promoted free water reabsorption via the renal concentration mechanism. Mineralocorticoid-coupled increases in free water reabsorption were counterbalanced by rhythmical glucocorticoid release, with excretion of endogenous osmolyte and water surplus by relative urine dilution. A 6-g/d increase in salt intake decreased the level of rhythmical mineralocorticoid release and elevated rhythmical glucocorticoid release. The projected effect of salt-driven hormone rhythm modulation corresponded well with the measured decrease in water intake and an increase in urine volume with surplus osmolyte excretion.
CONCLUSION: Humans regulate osmolyte and water balance by rhythmical mineralocorticoid and glucocorticoid release, endogenous accrual of surplus body water, and precise surplus excretion.
FUNDING: Federal Ministry for Economics and Technology/DLR; the Interdisciplinary Centre for Clinical Research; the NIH; the American Heart Association (AHA); the Renal Research Institute; and the TOYOBO Biotechnology Foundation. Food products were donated by APETITO, Coppenrath und Wiese, ENERVIT, HIPP, Katadyn, Kellogg, Molda, and Unilever.
PMID: 28414302
PMCID: PMC5409798
DOI: 10.1172/JCI88530
J Clin Invest. 2017 May 1;127(5):1944-1959.
High salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation.
Kitada K, Daub S, Zhang Y, Klein JD, Nakano D, Pedchenko T, Lantier L, LaRocque LM, Marton A, Neubert P, Schroder A, Rakova N, Jantsch J, Dikalova AE, Dikalov SI, Harrison DG, Müller DN, Nishiyama A, Rauh M, Harris RC, Luft FC, Wassermann DH, Sands JM, Titze J.
Vanderbilt University Medical Center, Nashville, Tennessee, USA; University Medical Center Mainz, Mainz, Germany; Emory University, Atlanta, Georgia, USA; Kagawa University, Kagawa, Japan; Vanderbilt University, Nashville, Tennessee, USA; University Clinic Erlangen, Erlangen, Germany; Charité Medical Faculty, Max-Delbrueck Center for Molecular Medicine, Berlin, Germany; University Clinic Regensburg, University Regensburg, Regensburg, Germany.
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.
PMID: 28414295
PMCID: PMC5409074
DOI: 10.1172/JCI88532
J Clin Invest. 2017 May 1;127(5):1625-1626.
Salt and water: not so simple.
Zeidel ML.
Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
It has long been viewed that the maintenance of osmotic balance in response to high salt intake is a passive process that is mediated largely by increased water consumption to balance the salt load. Two studies in this issue of the JCI challenge this notion and demonstrate that osmotic balance in response to high salt intake involves a complex regulatory process that is influenced by hormone fluctuation, metabolism, food consumption, water intake, and renal salt and water excretion. Rakova et al. report the unexpected observation that long-term high salt intake did not increase water consumption in humans but instead increased water retention. Moreover, salt and water balance was influenced by glucocorticoid and mineralocorticoid fluctuations. Kitada et al. extend upon these findings in mouse models and determined that increased urea and a corresponding increase in urea transporters in the renal medulla as the result of increased protein intake promote the water retention that is needed to achieve osmotic homeostasis. Together, the results of these two studies lay the groundwork for future studies to determine how, in the face of chronic changes in salt intake, humans maintain volume and osmotic homeostasis.
PMID: 28414294
PMCID: PMC5409062
DOI: 10.1172/JCI94004