Part of the TeachMe Series

Sodium Regulation

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Original Author(s): Laurie Peters
Last updated: 18th December 2021
Revisions: 10

Original Author(s): Laurie Peters
Last updated: 18th December 2021
Revisions: 10

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Sodium (Na) is the most abundant cation in the extracellular fluid (ECF) compartment. The normal plasma sodium concentration is 135-145 mmol/L, while the intracellular fluid (ICF) concentration is approximately 10-12 mmol/L.

Maintaining this transmembrane concentration gradient is necessary for generating the resting membrane potential and for action potential propagation. Sodium is also the main osmotic solute in the ECF, meaning that water travels in the direction of increasing sodium concentration via osmosis.

Na+ is therefore essential in regulating intravascular volume and is highly linked to fluid balance and blood pressure.

In this article, we will look at the mechanisms involved in controlling sodium balance and the consequences of its dysregulation.

Overview of Sodium Balance

Sodium intake is determined by dietary intake and absorption in the colon and distal small bowel. Na+ is widely abundant in many foodstuffs and modern diets generally incorporate an excess of sodium in the form of salt (NaCl).

Output is predominantly via urinary excretion but there are also insensible losses, particularly in the sweat and faeces.

Urinary sodium concentration is highly variable, depending on the amount of reabsorption occurring in the nephrons. This allows for the variable intake of water and sodium seen day to day to not drastically alter blood pressure or intravascular volume, i.e. maintenance of homeostasis.

Renal Sodium Reabsorption

Approximately 180L of fluid is filtered through the kidneys each day. Typically, 99% of sodium ions which pass through the glomerulus are reabsorbed, however urinary osmolality and excretion volume can vary significantly in order to regulate sodium balance.

Sodium reabsorption varies at different parts of the nephron, but in each section, it is driven across the basolateral membrane by Na-K-ATPase pumps. This allows the maintenance of an electrochemical gradient driving Na+ into cells across the apical membrane.

Section of nephron

Percentage of Na+ reabsorption Method of reabsorption

Proximal convoluted tubule (PCT)

65% Apical Na+/Amino Acid cotransporter

Na+/H+ antiporter

Paracellular reabsorption (between cells)

Thick ascending Loop of Henle


Apical Na+/K+/2 Cl¯ cotransporter

Distal convoluted tubule (DCT)


Apical Na+/Cl+ cotransporter

Collecting duct (CD)


Apical ENaC (epithelial sodium channels)


Renal Sympathetic Nerve Activity

Hypotension (detected by baroreceptors in the carotid and aortic arch) and hypovolaemia (detected by reduced distension of atrial myocytes) stimulate activation of the sympathetic nervous system.

One of the many effects of renal sympathetic nerve activity is the increased reabsorption of sodium in the PCT by activation of a1 and a2 adrenoceptors. This increases fluid retention, thereby increasing intravascular volume and blood pressure, maintaining homeostasis.

Renin-Angiotensin-Aldosterone System (RAAS)

Reduced renal perfusion and/or reduced sodium delivery to the nephron stimulates renin release from granular cells of the juxtaglomerular apparatus. Renin release leads to the production of angiotensin II, which itself stimulates aldosterone secretion.

RAAS activation has numerous effects which work synergistically to increase blood pressure. Particularly pertinent to sodium balance is increased Na+ reabsorption in the nephron. This occurs as:

  • Angiotensin II stimulates the Na+/H+ antiporter in the PCT.
  • Aldosterone increases the expression of ENaC in the CD.

Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP)

Raised blood volume causes an increase in venous return, which stretches atrial myocytes. This stimulates the myocytes to release ANP and BNP.

These hormones promote natriuresis (urinary excretion of sodium) in order to reduce circulating blood volume. ANP and BNP act to reduce aldosterone secretion (from the adrenal glands) and renin secretion (from the juxtaglomerular apparatus), thereby decreasing sodium reabsorption in the DCT and CD.

They also increase glomerular filtration by dilating the afferent glomerular arterioles and constricting the efferent arterioles, meaning more blood passes through the components of the nephron.

Antidiuretic Hormone (ADH)

An increase in plasma osmolality (e.g. from dehydration), detected by osmoreceptors in the hypothalamus, stimulates thirst and the release of ADH from the posterior pituitary gland. A significant reduction in effective circulating volume (≈15%), detected by baroreceptors also stimulates ADH production.

ADH causes insertion of aquaporins (water channels) in the DCT and CD, increasing the amount of water reabsorbed by osmosis. Thirst increases water intake and ADH reduces water output by making urine more concentrated. This additional water dilutes the plasma, reducing sodium concentration and plasma osmolality.

Figure 1 – Schematic of sodium handling in the nephron

Clinical Relevance – Hyponatraemia

Hyponatraemia (serum sodium <135mmol/L) arises when the proportion of sodium in the body decreases relative to the proportion of total body water.

In acute hyponatraemia (<48 hours), the abrupt reduction of plasma osmolality results in cerebral oedema as water moves into the brain via osmosis. This results in neurological symptoms including confusion, seizures, coma, or even death. Other symptoms include nausea, vomiting, headache and muscle cramps.

Chronic hyponatraemia is more common, especially in elderly patients with polypharmacy or poor oral intake. The brain adapts over time to the new osmolality by decreasing levels of certain osmolytes within the neurones. This allows the neurones to remain relatively isotonic and avoid development of cerebral oedema.

Patients may therefore be asymptomatic. It is very important to not correct sodium too quickly in patients with chronic hyponatraemia.  Sudden increases in ECF osmolality can result in osmotic demyelination syndrome, which is associated with significant morbidity and mortality.

Hyponatraemia can be subclassified according to the fluid status of the patient.

Type of hyponatraemia

Mechanism Causes

Hypovolaemic hyponatraemia

Significant loss of intravascular volume (>15%) stimulates baroreceptors, triggering an increased release of ADH, despite there being no rise in osmolality. ADH secretion results in increased nephron water reabsorption while thirst stimulates increased water intake, lowering serum sodium concentration. Gastrointestinal loss (diarrhoea or vomiting)


Osmotic diuresis, e.g. hyperglycaemia

Euvolaemic hyponatraemia

a) High water intake means the kidneys are unable to excrete urine dilute enough to match, so, overall, sodium is lost.

b) ADH secretion despite normal plasma volume and osmolality

a) Drinking excessive water (primary/psychogenic polydipsia or when using illicit drugs such as MDMA)

b) Syndrome of inappropriate antidiuretic hormone (SIADH) – may be due to central nervous system disorders or paraneoplastic

Hypervolaemic hyponatraemia Development of oedema (fluid lead into the interstitium), causing a loss of effective intravascular volume, triggering release of ADH and consequently hyponatraemia

Nephrotic syndrome (reduced intravascular oncotic pressure)

Cardiac failure (increased hydrostatic pressure)

Liver failure (both reduced intravascular oncotic pressure and increased hydrostatic pressure)

Poor fluid management (iatrogenic)

Renal failure (impairs kidneys’ ability to produce dilute urine)


Clinical Relevance – Hypernatraemia

Hypernatraemia (serum sodium >145mmol/L) occurs when total body sodium increases relative to total body water.

This usually occurs with dehydration due to a lack of water intake (e.g. due to dementia) or from increased water losses (e.g. burns or diarrhoea). Less commonly it arises from sodium gain (e.g. iatrogenic causes or poisoning).

When managing patients with hypernatraemia, fluid status must be assessed and any dehydration corrected, with oral fluids if possible, after calculating the patient’s water deficit. It is important to correct acute hypernatraemia (developed over <24 hours) rapidly to reduce the risk of osmotic demyelination.

On the contrary, in chronic hypernatraemia neurones have had time to adapt to the increased ECF osmolality, so correcting chronic hypernatraemia too quickly can cause cerebral oedema.