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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2009  |  Volume : 20  |  Issue : 4  |  Page : 560-569
Sodium balance-an integrated physiological model and novel approach

Salford Royal Foundation Trust, Manchester, United Kingdom

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Date of Web Publication8-Jul-2009


Various physiological mechanisms regulate sodium and water balance in the human body. These processes achieve acute and chronic sodium regulation and the simultaneous or se­quential changes can be explained using a single physiological model. Steady intracellular water and osmolality is necessary for cell membrane integrity and cellular processes. Body fluids protect circulatory blood volume by altering Na + and water balance. This is the most vital homeostatic function of the body. Changes in ECF volume are sensed by various cardinal sensors. Physio­logically, the main aim of Na + and water balance is to permit variable salt and water intake without large fluctuations in blood pressure or volume status. Homeostatic processes act in an integrated fashion to protect against any perturbations. Characteristically, these mechanisms are sequential as well as parallel. These may be synergistic or antagonistic to each other. Rapidity, sensitivity and potency of these powerful feedback systems differ. Various physiological and pathological insults determine the magnitude of response of these systems.

How to cite this article:
Patel S. Sodium balance-an integrated physiological model and novel approach. Saudi J Kidney Dis Transpl 2009;20:560-9

How to cite this URL:
Patel S. Sodium balance-an integrated physiological model and novel approach. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2022 Jan 23];20:560-9. Available from: https://www.sjkdt.org/text.asp?2009/20/4/560/53242

   Introduction Top

Various physiological mechanisms regulate sodium and water balance in the human body. These processes achieve acute and chronic so­dium regulation by simultaneous or sequential changes. Sodium homeostasis can be explained by using a single physiological model.

Water is an important biological solvent that provides an ideal environment for biochemical reactions. Intracellular (IC) water is 2/3 of total body (TB) water. The remaining 1/3 of TB water is extracellular (EC) of which plasma is 1/4 and interstitial (IS) is 3/4. The main barrier between intravascular (IV) and IS fluid is the capillary endothelium and between the IS and IC fluid compartment is cell membrane. Water moves freely across these membranes from low to high solute concentration.

Sodium (Na + ) is restricted mainly to extra­cellular fluid (ECF), and is a major determinant of its osmolality and volume. Normal body Na + content is essential to maintain ECF homeo­stasis. The fraction of ECF volume in the vas­cular system partly determines pressure on both arterial and venous circulations. Adequate car­diac output and mean arterial blood pressure are major determinants of Na + and water homeo­stasis. [1] Thus, mechanisms that regulate Na + , water, and blood pressure form a loop, which is completed on one side by "sensors" and on the other by "effectors" [Figure 1].

The physiological factors that protect balance of Na + , water, adequate blood pressure and car­diac output interact in an integrated and inter­dependent fashion, [Figure 2]. [2]

   Cellular Water and Sodium Control Top

Steady intracellular water and osmolality are necessary to ensure normal cell membrane in­tegrity and cellular processes. In health IC osmo­lality is constant so IC water movement is usually due to changes in EC osmolality. water redis­tribution occurs if there is an osmotic disequi­librium across the cell membrane, i.e. an increase or decrease in Na + concentration in ECF. As a result, cells shrink or swell in order to adapt to changes in osmolality of the environment. [3] On the other hand, if osmolality is increased equally in all body fluids due to urea, cellular volume does not change because an osmotic gradient does not develop.

Acute osmolar stresses elicit electrolytes trans­portation across the cell membrane and return the cell volume back to normal within minutes. Cells adapt to chronic changes in tonicity by altering their osmolal constituents. Chronic ECF tonicity causes the accumulation or loss of small IC organic molecules termed osmolytes (ex. sorbitol) and amino acids. Both compensatory mechanisms occur over a different time scale. Clinically, correction of Na + imbalance should be carried out gradually to allow time for re­versal of these compensatory processes. Rapid reversal of serum Na + level back to normal can cause serious cellular water, and volume changes particularly in the neuronal cells of the brain.

Role of Na + -K + -ATPase pump

The Na + -K + -ATPase pump is a membrane bound enzyme that carries out the active elec­trogenic translocation of Na + and K ions across the plasma membrane of most cells. In a normal isoosmolar environment, the cellular volume is maintained by Na + -K + -ATPase. [4] It indirectly controls ionic balance and epithelial transport. There are hundreds to thousands of Na + -K +­ATPase pumps per cell bound to its membrane. Na + -K + -ATPase pumps indirectly control the cell water at a "local" level. The activity of this enzyme is under multifactorial control. At the cellular level, changes in cytoplasmic concen­tration of Na + , K and calcium can modulate the activity of the pumps. Various hormones, nota­bly aldosterone, increase the activity and numbers of these pumps. Their function is also affected by diseases and drugs.

One of the main functional activities of the Na + -K + -ATPase pumps is to create an electro­chemical gradient in luminal cells of the intes­tine and nephron.

   Role of the Cardiovascular System Top

Body fluids protect circulatory blood volume by altering Na + and water balance. This is the most vital homeostatic function of the body. Changes in ECF volume are sensed by various cardinal sensors. These sensors in turn send sig­nals, which lead to various effective changes via neural, hormonal and physical responses. In fact, as mentioned earlier, the mean arterial blood pressure is a major determinant of Na + output [Figure 2].

Starling forces

Plasma and ISF are continuously interchanged because of starling forces (SF) operating at the capillary level. These forces are hydrostatic and osmotic within the vascular and interstitial com­partments. Dynamically, the balance between these two opposite forces determines distribu­tion of water between the interstitial fluid and plasma.

Single layer capillary endothelial cells permit free movement of water and other solutes. Out­ward movement of fluid from capillaries at the arteriolar end occurs at one liter per hour be­cause hydrostatic forces are greater than osmotic forces. About 85% of this filtered fluid is re­turned directly at the venule end as hydrostatic pressure falls. The remaining almost 15% (nearly 3.5 to 4.0 L per day) returns to the circulation via the lymphatic system.

Fluid exchange in capillary beds varies in dif­ferent tissues and under different conditions. Capillaries can be opened up and closed off by precapillary sphincters. The balance of these forces across the capillaries can be disturbed by diseases such as cardiac failure and nephrotic syndrome. Consequently, fluid accumulates ab­normally in the interstitial spaces. Starling forces and their importance in renal function are discussed later.

Effective Circulatory Blood Volume (ECBV)

This physiological concept, which cannot be exactly quantified and measured, is related to "effective" perfusing pressure within tissues. ECBV normally relates to ECF volume, systemic blood pressure and cardiac output. [5] If ECBV is low and tissue perfusion inadequate, various Na + and water retaining mechanisms are activated in order to "normalize" the ECBV. For example, in diseases such as cirrhosis and congestive cardiac failure, excess Na + and water is retained in the body. The reduction in ECBV may be due to a pump problem (ex. cardiac failure) or disturbances in starling forces (ex. cardiac fai­lure, nephrotic syndrome) [Figure 2].

Low pressure (volume) sensors

Right and left atrial myocytes release atrial natriuretic peptide (ANP) in response to stretch or distension. [6] This endogenous peptide hor­mone is released if there is 5 to 10% increase in BV. ANP has various physiologic effects. Low pressure sensors signal the medulla and result in a decrease in sympathetic activity in response to the increased BV. The opposite occurs if hypo­volemia develops. Volume sensors are also pre­sent in pulmonary vessels. Additionally, in the presence of hypovolemia and hypotension, low pressure sensors also mediate ADH release via vagal afferents to the medulla [Figure 2].

High Pressure sensors

In response to fluctuations in the mean arterial blood pressure, baroreceptors located in the ca­rotid sinus and aortic arch send signals to me­dulla via the glossopharyngeal and vagus nerves, respectively. This reflex acts to modulate auto­nomic nervous system activity rapidly. These high pressure receptors also influence ADH re­lease if ECF loss is severe enough to affect the blood pressure.

It is clear that pathways, which mediate hemo­dynamic regulation of ADH release via baro­receptors, are entirely different from those in­ 6 volved in osmoregulation [Figure 2].

   Renal and Neuroendocrine Mechanisms Top

The kidney has two important functions for Na + and water balance: filtration and reabsorp­tion. Multiple local and systemic mechanisms directly or indirectly achieve these functions. Normally filtration is autoregulated, so it is the reabsorptive mechanisms that adjust to variable input and output.

Every minute 125 mL (180 L/day) of filtrate containing 17 mmoL of Na + (daily 25,000 mmoLs) enters the proximal tubule (PT); 99% is reabsorbed and 1% excreted. The kidney can handle large variation in salt and water intake with enormous efficiency. Daily, it can excrete 0.5 to 25 L of urine with osmolality varying from 40-1400 mosm/L. Thus, depending on the demands from the body for conservation or ex­cretion, urine volume can vary 50-fold and urine osmolality 35-fold.

Reabsorption of filtered Na + load varies quan­titatively and qualitatively in the different parts of the nephron; 65%, 20%, 10% and 4% of filtered Na + is reabsorbed from the PT, thick ascending part of loop of Henle (aLOH), the distal tubule (DT), and collecting duct (CD) respectively. There is an abundance of Na + -K +­ATPase pumps at the basolateral membrane of all cells in the nephron, which actively shift Na + out of the cells. At the luminal border an elec­trochemical gradient drives Na + into the cells via Na + -cotransporters in the PT, Na+-K+-2 Cl¯cotransporters in the thick aLOH, Na+- Cl¯cotransporters in the DT and epithelial Na + cha­nnels in the CD [Figure 2]. Na + is also reab­sorbed in a significant amount via paracellular pathway in later part of proximal tubule. Na + is also exchanged with H + in via Na + - H + exchanger in the PT, which are stimulated by angiotensin II. [8] Water diffuses passively from all parts of the nephron except the LOH.

Intrarenal Hemodynamics

In the kidney, starling forces at the glomeruli control glomerular filtration rate. The hydro­static and colloid osmotic forces of the renal interstitium provide an important link between circulatory function and renal tubular reabsorp­tion. [9] Hydrostatic and oncotic forces within the peritubular capillaries (PTC) also influence re­absorption. [10] Conversely, these reabsorptive me­chanisms alter the fluid in the medulla by changing its osmolality.

Rapid and large volume solute reabsorption in the early part of the PT is favored by high oncotic pressures in the peritubular capillaries (PTC), which originate from the efferent arte­riole. PTC in this part of nephron has a high concentration of proteins because they are not filtered. Relative afferent and efferent arterioles (AA/EA) vosoconstriction or vasodilatation can alter hydrostatic forces both within glomeruli and PTC. Such changes in arterioles modify the filtration into and reabsorption from the PT. For example, selective EA constriction increases both filtered (by an increase of hydrostatic force in glomeruli) and reabsorbed (by a decrease of hydrostatic force in the PTC) load. Moreover, both filtered and reabsorbed loads increase in response to selective afferent arteriolar vaso­constriction (hydrostatic forces are reduced both within glomeruli and PTC).

Medullary blood flow (MBF) is also a regu­latory mechanism for water and Na + reabsorp­tion. [11] For example, if MBF is increased due to increased ECF volume, medullary hypertonicity is lost, which results in less water reabsorption. Na + is diluted and is absorbed less in the thick aLOH and thus more Na + and water is excreted.

JG Cells

Renin is released from modified fenestrated and granular endothelial cells [12] in the AA in res­ponse to a decrease in actual (e.g., hemorrhage) or effective (e.g. hypotension due to peripheral vasodilatation) blood volume. These barorecep­tors detect perfusion pressure in the AA. In­creased sympathetic activity or catecholamines also stimulate renin release, which leads to increased angiotensin II levels in blood.

Renal Sympathetic Aactivity

Increased renal sympathetic activity causes (1) a decrease of renal blood flow and GFR (2) a decrease of perfusion pressure in the AA and indirect release of renin (3) a direct release of renin via 01 receptors located on JG cells in the AA (4) an increase of absorption of Na + in the PT via a1 receptors located at basolateral mem­brane. [13]

Tubuloglomerular Feedback

The distal tubule has specialized epithelial cells (macula densa) situated directly opposite the JG cells. These cells act as chemoreceptors. They sense the Na + and Cl¯ load delivered in the DT. [14] Depending on this signals are conveyed to JG cells in the AA. Accordingly, AA tone is altered and the amount of Na + filtered is changed. This is a continuous feedback mechanism at the individual nephron level. For example, if Na + deli­very in the DT is less, vasodilatation in the AA will occur and more Na + will pass into the PT. Thus, there is a negative feedback relationship between the afferent arterioles and the volume of fluid filtrate that enters the DT.

Angiotensin II (AT II)

In addition to increased SNS activity and de­ creased Na + delivery in the DT, low perfusion pressure in the AA directly releases renin from the JG cells. Renin converts angiotensiongen to angiotensin I, which is further cleaved by ACE in vascular endothelium to AT II. AT II has a variable effect on GFR. [15] It increases GFR by EA vasoconstriction. It decreases GFR by redu­cing the filtration surface area due to mesangial cell contraction. It also reduces medullary blood flow. AT II increases Na + reabsorption in the PT by stimulating Na + -H + exchanger. [8] AT II is a potent stimulus for synthesis of aldosterone. It has a negative feedback mechanism on its own actions. Inhibition of the Na + retaining actions of A II is clinically useful in various patholo­gical conditions such as hypertension and car­diac failure [Figure 2], [Table 1].


It is a potent hormone for Na + reabsorption. Low oral Na + intake or plasma Na + level increases the synthesis and release of aldosterone. Na + reab­sorption by aldosterone is a slow process and may take hours to be effective. Aldosterone is responsible for reabsorption of 2% of filtered load of Na + . In other words, absence of aldos­terone results in renal loss of Na + in excess of 500 mmols/day. On the other hand, if aldos­terone is secreted in excess amounts, final Na + concentration in urine will be close to nil [Figure 2], [Table 1].


ECF osmolality is delicately and continuously sensed by osmoreceptors (OR). These receptors increase or inhibit release of ADH immediately resulting in an increase or decrease in plasma osmolality respectively. [16] Despite a wide varia­tion in water intake the body preserves plasma osmolality within 1-2% of normal range. Supra­optic (SO) and paraventricular (PV) nuclei in the hypothalamus synthesize ADH which is trans­ported along the axons to the posterior pituitary where it is stored [Figure 2], [Table 1]. ADH is released linear proportion to increasing plasma osmolality. A 10-15% decrease in BV will also stimulate ADH secretion but in an exponential fashion.

The thick ascending loop of juxtamedullary nephrons (the counter-current multiplier) and vasa recta (counter-current exchanger) create hypertonicity of medullary interstitium. This is essential for water reabsorption from the CD by ADH. In certain clinical conditions, increased ADH release may occur despite normal ECF osmolality. This causes water retention and di­lutional hyponatremia.

Atrial Natriuretic Peptide (ANP)

ANP is a counter-regulatory mechanism to the renin angiotensin system. It has an important role in regulation of Na + and water balance, blood volume, and blood pressure. [17] ANP exhibits di­verse direct and indirect physiological actions [Figure 2], [Table 1] on the kidney and cardiovas­cular systems thereby protecting against volume overload. It also decreases sympathetic tone. ANP has a specific role in volume overload conditions such as CCF, where increased levels may prevent the development of complications due to volume over load. Thus, ANP is an endo­genous diuretic.

Prostaglandins (PGs)

PGs (e.g. PGE2) have an important role in maintaining renal blood flow particularly under conditions of stress. Their production is increa­sed in response to hypotension and renal ische­mia. PGs play a defensive role by promoting renal vasodilatation and preserving intrarenal hemodynamics. They have also been shown to influence water and Na + excretion.

Nitric Oxide (NO)

In the kidney, NO is synthesized in vascular endothelium as well as tubular cells. It increa­ses GFR and medullary blood flow. NO has also been shown to inhibit Na + reabsorption in the CD. [19] It opposes the renal vasoconstrictor effects of AT II and the sympathetic nervous system and decreases renal vascular resistance.

   Gastrointestinal and Other Factors Top

For a 70 kg adult daily Na + intake is 100-150 mmols in addition to 1.5-2.5 L of oral daily in­take of fluids. Approximately 8 L more are pro­duced and secreted by various parts of GIT. These secretions contain 1200-1400 mmol of Na + . 6 to 6.5 L is reabsorbed in the small intes­tine and the remainder passes to the large intes­tine where further absorption occurs. Only 100­200 mL of fluid and 4-5 mmol of Na + are ex­creted in the stool. Similarly to the kidney, Na +­K + -ATPase pumps at the basolateral membrane of intestinal epithelial cells plays a crucial role which appears to be stimulated by aldosterone.

Water is also lost insensibly through the skin and lungs (approximately 400 mL via each) but partly compensated by water gain due to meta­bolic processes (nearly 400 mL).

   ECF Volume vs Osmoregulation Top

Water regulation is dependent on (1) appro­priate ADH synthesis, transport, release, and func­tion, (2) counter-current multiplier and exchanger system, and (3) functioning thirst mechanism.

Three discrete areas are located in hypothala­mus (1) osmoreceptors (OR) (2) thirst center and (3) SO and PV nuclei responsible for ADH synthesis [Figure 2]. Afferent input from OR to SO and PV nuclei is essential for a normal ADH response.

Maintenance of ECF osmolality is necessary to keep the relative ratio of Na + to water nor­mal. If either the osmolality or volume of ECF are individually disturbed independent mecha­nisms for osmoregulation or volume control are activated. For example, 1 L of drinking water is readily absorbed from GIT into plasma and then distributed to interstitial fluid and cells. It re­duces plasma osmolality and secretion of ADH from the posterior pituitary. Within the next hour of drinking this excess water dilute urine is excreted without altering its solute concentra­tion. However, with 1 L of saline in-fusion, ECF osmolality is not changed, but an increase in its volume will lead to activation of baroreceptors, [Figure 2]. Consequently, ANP is released and sympathetic activity is reduced; while AT II and aldosterone formation is inhibited. Ultimately, more Na + and water excretion occurs to adjust for the extra Na + and water load.

In contrast to the above scenario, hypovolemia severe enough to drop blood pressure can acti­vate volume restoring processes where ANP release is inhibited. Even if there is a relative increase in osmolality in this condition, volume mediated release of ADH will inhibit water ex­cretion from distal parts of nephron. Hemody­namic responses override those of osmolality in an attempt to restore tissue perfusion [Figure 2].

   Hypo and Hypernatremia Top

Pathophysiology and corrective measures are summarized in [Table 2] and [Figure 3].

   Conclusion Top

Physiologically, the main aim of Na + and wa­ter balance is to permit variable salt and water intake without large fluctuations in blood pres­sure or volume status. Homeostatic processes act in an integrated fashion to protect against any disturbances. Characteristically, these mecha­nisms are sequential as well as parallel. As feed­back systems, they may be synergistic or antagonistic, and their speed, sensitivity, and poten­cy may differ. Various physiological and patho­logical insults determine the magnitude of res­ponse of these systems.

   References Top

1.Guyton AC: Blood pressure control: special role of the kidneys and body fluids. Science 1991; 252:1813-6.  Back to cited text no. 1    
2.Granger JP. Regulation of extracellular fluid volume by integrated control of sodium excre­tion. Adv Physiol Edu 1998; 20:S157-S68.  Back to cited text no. 2    
3.McManus ML, Charchwell KB, Strange K. Regulation of cell volume in health and disease. N Eng J Med 1995;333:1260-6.  Back to cited text no. 3    
4.Koko JP. Fluids and electrolytes. In: Goldman L, Ausielho D, eds. Cecil textbook of medicine. 22 nd ed. Philadelphia: Saunders, 2004:669-88.  Back to cited text no. 4    
5.Manning RD Jr, Coleman TG, Samar RE: Auto­regulation, cardiac output, total peripheral resis­tance and the "quantitative cascade" of the kidney­blood volume system for pressure control. In Guyton AC ed. Arterial Pressure and Hyper­tension. Philadelphia: WB Saunders Co;1980: 139-55.  Back to cited text no. 5    
6.Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med 1998; 339:321-8.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]
7.Ganong WF. Review of medical physiology.20 th ed. New York: McGraw-Hill 2001:26-237.  Back to cited text no. 7    
8.Hall JE, Hall MW. The rennin angiotensin aldos­terone systems: renal mechanisms and circula­tory homeosatsis. In: Seldin DW, Geibish G eds. The kidney, physiology and pathophysiology. 2 nd ed. New York: Raven press, 1992:1455.  Back to cited text no. 8    
9.Granger JP. Role of renal interstitial hydrostatic pressure in the regulation of sodium excretion. Federation Proc. 1986; 45:840-4.  Back to cited text no. 9    
10.Hall, JE, Granger JP. Role of sodium and fluid excretion in hypertension. In: Swales JD ed. Text-book of Hypertension. Oxford: Blackwell Scientific, 1994:360-87.  Back to cited text no. 10    
11.Roman RJ, Zou AP. Influence of the renal me­dullary circulation on the control of sodium excretion. Am J Physiol 1993;265:R963-73.  Back to cited text no. 11    
12.Briggs JP. Whys and the wherefores of juxta­glomerular apparatus functions. Kidney Int 1996,49:1724-6.  Back to cited text no. 12    
13.DiBona GF. The functions of the renal nerves. Rev Physiol Biochem Pharmacol 1982;94:76-181.  Back to cited text no. 13    
14.Wright FS, Okusa MD. Functional role of tubu­loglomerular feedback control of glomerular fil­tration. Adv Nrphrol Necker Hosp 1990;19:119­34.  Back to cited text no. 14    
15.Johnson CI, Fabris B, Jandeleit K. Intrarenal renin angiotensin system to the control of intra­renal haemodynamics. Kidney Int 1993;44:S59­63.  Back to cited text no. 15    
16.Bie P. Osmoreceptors, vasopressin and control of renal water secretion. Physiol Rev 1980;60: 961-1048.  Back to cited text no. 16    
17.Goetz KL. Physiology and pathophysiology of atrial peptides. Am J Physiol 1988; 254:E1-15.  Back to cited text no. 17    
18.Moncada, SR, Palmer MJ, Higgs EA. Nitric oxide: physiology, pathophysiology and phar­macology. Pharmacol Rev 1991;43:109-42.  Back to cited text no. 18    
19.Schnackenberg CG, Kirchner K, Patel A, Granger JP. Nitric oxide, the kidney, and hypertension. Clin ExpPharmacol Physiol 1997;24:600-6.  Back to cited text no. 19    

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  [Table 1], [Table 2]

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