Tangram of Sodium and Fluid Balance

Abstract

Homeostasis of fluid and electrolytes is a tightly controlled physiological process. Failure of this process is a hallmark of hypertension, chronic kidney disease, heart failure, and other acute and chronic diseases. While the kidney remains the major player in the control of whole-body fluid and electrolyte homeostasis, recent discoveries point toward more peripheral mechanisms leading to sodium storage in tissues, such as skin and muscle, and a link between this sodium and a range of diseases, including the conditions above. In this review, we describe multiple facets of sodium and fluid balance from traditional concepts to novel discoveries. We examine the differences between acute disruption of sodium balance and the longer term adaptation in chronic disease, highlighting areas that cannot be explained by a kidney-centric model alone. The theoretical and methodological challenges of more recently proposed models are discussed. We acknowledge the different roles of extracellular and intracellular spaces and propose an integrated model that maintains fluid and electrolyte homeostasis and can be distilled into a few elemental players: the microvasculature, the interstitium, and tissue cells. Understanding their interplay will guide a more precise treatment of conditions characterized by sodium excess, for which primary aldosteronism is presented as a prototype.

Sodium, Interstitium, Lymphatics and Hypertension—A Tale of Hydraulics

“…Available evidence suggests that lymphatics may not be implicated in all forms of hypertension, but become more prominently involved under conditions of salt loading, when other salt-retentive hits are already in place, and when more severe disease progresses toward organ damage and more overtly disturbed sodium and fluid balance. 3 Phases of adaptive and later maladaptive (or inadequate-to-the-load) lymphatic remodeling seem to occur, although their timing and determinants and end capacity to remediate BP, remain unclear. In this regard, future research investigating lymphatic function should take into account not only fluid drainage but also the actual load to the interstitium including blood microvascular function, autoregulation, density, permeability and interstitial factors altogether.…”

“…48 However, the phenomenon has been recently reconsidered to reflect subclinical extracellular volume expansion in many cases. 3 Even minimal volume changes induce steep pressure changes in the interstitium (Figure 1) and could activate TonEBP, as biomechanical stretch and compressive strain do in vascular smooth muscle cells 49 and macrophages, 50 regardless of osmolarity. In fact, others have previously noted how the cell signaling pathways activated by dietary salt are reminiscent of mechanoreceptor signaling.…”

“…he role that sodium plays in the pathophysiology of hypertension and associated organ damage is prominent but heterogeneous across individuals. 1 This suggests a matter of handling and distribution 2,3 beyond sole intake. Most of our body sodium is confined to the extracellular volume, and its homeostasis largely relies on the kidneys via multiple mechanisms that continuously operate and adapt to changes in renal perfusion-a correlate and surrogate of body sodium and water.…”

“…In fact, our recognition of this volume component has recently expanded to incorporate body volumes other than the vascular space. 3,6 Sodium was found to accumulate in tissues in mineralocorticoid or severe forms of hypertension and other cardiovascular conditions, and to induce local responses that contribute to blood pressure (BP) control. 3 These may include accumulation of sodium in the vascular wall 7 and explain, at least in part, the early increase in vascular resistance observed in forms of hypertension that were classically identified as volume-dependent.…”

“…3,6 Sodium was found to accumulate in tissues in mineralocorticoid or severe forms of hypertension and other cardiovascular conditions, and to induce local responses that contribute to blood pressure (BP) control. 3 These may include accumulation of sodium in the vascular wall 7 and explain, at least in part, the early increase in vascular resistance observed in forms of hypertension that were classically identified as volume-dependent. 8 This shift of attention toward the interstitium has renewed the interest in lymphatic vessels, traditionally neglected because of their anatomic elusiveness.…”