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Next Lesson - Control of Potassium
Contents
Abstract
- Osmoreceptors in the hypothalamus are responsible for detecting changes in plasma osmolarity.
- Changes in plasma osmolarity can be corrected through the release of antidiuretic hormone (ADH) from the posterior pituitary gland, or through the feeling of thirst.
- The release of ADH and its actions on the kidney can only correct for small changes in plasma osmolarity. Large changes are compensated for through thirst (the urge to drink).
- The medullary counter-current mechanism (the way the kidney builds up a salt gradient in its inner part, the medulla) allows the kidney to reabsorb water selectively.
Core
Plasma Osmolarity and Plasma Osmolality
Osmolality and osmolarity are different measurements of the body’s electrolyte-water balance (how concentrated the plasma is). They are functionally the same in practice, even though they are technically different.
Before working out the difference, one first has to understand the ‘osmole’. An osmole is a unit that counts the number of moles of solute particles contributing to the osmotic concentration of a solution. For example, one mole of sodium chloride (NaCl) in solution would produce two osmoles (Na+ and Cl-).
Osmolarity (with an ‘R’) is defined as the number of osmoles per litre of solution.
Osmolality (with an ‘L’) is defined as the number of osmoles per kilogram of solvent.
Basically, a larger number when measuring osmolarity or osmolality means a higher concentration.
Neurohormonal Mechanisms to Control Plasma Osmolarity
Changes in plasma osmolarity indicate that there is a disorder of overall water balance in the body. There are two neurohormonal mechanisms (mechanisms involving both nerves and hormones) by which the body controls plasma osmolarity: antidiuretic hormone (ADH) and thirst.
Osmoreceptors are located in the hypothalamus. These detect changes in plasma osmolarity and trigger two responses. The first is the release of ADH, which causes increased reabsorption of water from the filtrate (the fluid filtered from the blood into the kidney tubules), leaving small amounts of very concentrated urine. The second is thirst.
ADH is released when plasma osmolarity rises by about 1% above its threshold (the threshold varies between people). Thirst is stimulated at a slightly higher level, a few per cent above that point. ADH therefore acts first, and thirst is the backup.
When plasma osmolarity rises, osmoreceptors stimulate the release of antidiuretic hormone from the posterior pituitary gland. This leads to decreased renal water excretion (remember: anti-diuresis = conserving water). Conversely, when plasma osmolarity decreases, ADH secretion is inhibited. ADH release when osmolarity rises, and its inhibition when it falls, together form a negative feedback loop (a loop that corrects any change) which stabilises osmolarity.
ADH increases the permeability (how easily substances pass through) of the collecting duct to water and urea. The collecting duct is the final tube that carries urine from the nephrons, and it is where urine is concentrated. An increase in ADH means more water is reabsorbed by the kidney and plasma osmolarity will decrease. ADH increases the insertion of aquaporin-2 (AQP2) channels (water channels) into the apical membrane (the surface facing the inside of the duct) of the cells of the collecting duct.
Whilst this control of plasma osmolarity is important, it can be overridden. When the volume of blood in the vessels (the intravascular volume) is low, the kidneys will conserve water in an attempt to maintain blood pressure, even if this means the osmolarity of body fluids changes.
Diabetes insipidus is a condition in which water is inadequately reabsorbed from the collecting ducts, so a large quantity of urine is produced. There are two types of diabetes insipidus: central and nephrogenic.
Central diabetes insipidus occurs when plasma levels of ADH are too low. This can have many causes, such as:
- Damage to the hypothalamus or pituitary gland, for example from a skull fracture, a tumour or an aneurysm.
- Sarcoidosis (an inflammatory disease in which small clumps of immune cells form in the organs) or tuberculosis.
- Some forms of encephalitis (inflammation of the brain) or meningitis.
- Langerhans cell histiocytosis (a disorder of immune cells), although this is rare.
Nephrogenic diabetes insipidus is caused by insensitivity of the kidney to ADH. It can be inherited (most often an X-linked fault in the gene for the ADH receptor, AVPR2) or acquired, for example from lithium, a high blood calcium level (hypercalcaemia) or a low blood potassium level (hypokalaemia).
Central diabetes insipidus is managed with desmopressin, a synthetic form of ADH. It can be given by mouth, under the tongue, as a nasal spray or by injection. A common side-effect is hyponatraemia (low plasma sodium).
Nephrogenic diabetes insipidus does not respond to ADH. Management includes adequate water intake and a low-sodium diet. If symptoms persist, a thiazide diuretic (a drug that makes the kidneys pass more salt and water) is used. Paradoxically, it reduces urine output in this condition: it causes mild volume depletion, so the kidney reabsorbs more sodium and water early in the nephron (in the proximal tubule) and less fluid reaches the collecting ducts. NSAIDs (non-steroidal anti-inflammatory drugs, such as indomethacin) are sometimes added, but they can harm the kidneys and the gut.
Syndrome of Inappropriate ADH Secretion
Syndrome of inappropriate ADH secretion (SIADH) is another condition in which ADH secretion is abnormal. In SIADH there is excessive release of ADH from the posterior pituitary gland (or from another source, such as a neuroendocrine tumour, which is a tumour of hormone-producing cells). This results in abnormal retention of water from the urine, causing a dilutional hyponatraemia (the plasma sodium is low because it is diluted by the extra water). Total body water rises slightly, but there are no obvious signs of fluid overload such as swelling (oedema), so the circulating volume is normal (euvolaemic).
Neural (Behavioural) Mechanism
Large changes in plasma osmolarity can only be partially compensated for by the kidney through the action of ADH.
The urge to drink water is induced by an increase in plasma osmolarity. Drinking increases the amount of free water (water without solutes), which in turn lowers plasma osmolarity. When sufficient fluid has been consumed, this urge stops. Experiments, mostly in animals, show that thirst eases as soon as fluid passes through the mouth and throat, before the water has been absorbed, and that signals from the gut about the fluid’s osmolarity also help.
The Medullary Counter-Current Mechanism
The medullary counter-current mechanism refers to the functional organisation of the kidney which allows the kidney to concentrate urine. This is achieved largely by the creation of a vertical osmotic gradient. This means that the osmolarity of the renal medulla (the inner part of the kidney) is greater (more concentrated) than that of the renal cortex (the outer part). There are many parts that make up this mechanism:
- Juxtamedullary Nephrons (nephrons that lie next to the medulla) - these account for around 20% of all nephrons (the other 80% being cortical nephrons). They have a particularly long loop of Henle (the U-shaped section of the nephron) which ‘dips’ into the renal medulla, allowing the creation of the vertical osmotic gradient.
- Vasa Recta - long, straight capillaries that surround juxtamedullary nephrons and help to maintain the vertical osmotic gradient.
- Collecting Ducts of All Nephrons - all collecting ducts pass through the renal medulla so use the vertical osmotic gradient, along with ADH to produce urine of varying concentrations.
- Urea - adds to the osmolarity of the inner medulla (the deepest part of the medulla) and is needed for the kidney to concentrate urine fully.
The descending limb of the loop of Henle is highly permeable to water due to the presence of AQP-1 channels in the membrane which are always open. The descending limb is not permeable to sodium, so sodium remains in the descending limb and the filtrate concentration (osmolarity) increases as water moves into the interstitium (the tissue space around the tubules). The maximum concentration of the filtrate is at the tip of the loop of Henle.
The ascending limb is impermeable to water. In the thin ascending limb, NaCl leaves passively down its concentration gradient; in the thick ascending limb, salt reabsorption is driven by active transport. Salt leaves while water remains, so tubular fluid becomes more dilute before entering the distal convoluted tubule (DCT), the twisted tubule that follows the loop of Henle.
Together, water loss from the descending limb and salt loss from the ascending limb mean that a large vertical osmotic gradient is established in the interstitial fluid of the renal medulla. The interstitial fluid becomes more concentrated (higher osmolarity) the deeper it lies in the medulla.
This process is called counter-current multiplication (the small concentration difference made at each level of the loop builds up into a large gradient) and the loop of Henle is referred to as a counter-current multiplier.
As previously mentioned, the vertical osmotic gradient is initially set up by the loop of Henle, but it is maintained by the vasa recta. The vasa recta act as a counter-current exchanger, which means that blood runs in opposite directions in two neighbouring vessels and swaps water and solutes between them.
Blood flows in opposite directions in the descending and ascending limbs of the vasa recta. As blood descends into the medulla it gains solutes and loses water; as it ascends it loses solutes and gains water. This counter-current exchange limits medullary solute washout (loss of solutes from the medulla into the blood) while returning reabsorbed water to the circulation. It minimises solute loss rather than eliminating it.
Blood entering the descending vasa recta from the cortex becomes progressively more concentrated as it passes into the hyperosmotic medulla (more concentrated than the blood): water leaves the blood and sodium chloride and urea enter it.
As blood returns towards the cortex in the ascending vasa recta, the surrounding interstitium becomes progressively less concentrated. Solutes diffuse out of the blood and water enters it. This exchange helps preserve the medullary osmotic gradient while allowing reabsorbed water to be carried away.
Urea is a major contributor to the vertical osmotic gradient in the inner medulla (the deepest part of the medulla), alongside sodium chloride. Urea is reabsorbed from the medullary portion of the collecting ducts, and it then moves into the interstitium before diffusing back into the loop of Henle (mainly its thin descending limb). This cycle is called urea recycling.
While urea is in the interstitium, it increases the osmolarity of the interstitium, further increasing the vertical osmotic gradient. In the kidney, urea can act as an “effective osmole”, meaning a solute that influences the movement of water. (In plasma, urea is usually called an “ineffective osmole”, because it crosses most cell membranes freely and so does not shift water between cells and plasma.)
The release of ADH promotes more urea moving into the interstitium, allowing it to draw more water into the interstitium.
As mentioned before, the medullary counter-current mechanism allows the collecting ducts to concentrate urine, and the above points show how this is created and maintained.
These factors make the medulla hyperosmotic. The collecting ducts pass through the hyperosmotic renal medulla, so the increased osmolarity of the interstitium draws water out of the collecting ducts. This removal of water concentrates the urine, and the amount can be modulated by ADH.
When changes in plasma osmolarity are too large to be compensated for by the kidney alone, thirst helps to regulate plasma osmolarity: drinking adds free water, which lowers the osmolarity.
Edited by: Dr. Maddie Swannack
Reviewed by: Dr. Thomas Burnell and Dr. Marcus Judge
Quiz
- 8069
