ADH (antidiuretic hormone), also called vasopressin, does most of the work of holding extracellular fluid tonicity within a narrow range. The kidney keeps or loses water according to how much ADH reaches it, so to understand water balance we follow the signal from its source to the kidney.
Two controllers of water balance
What exactly is being held steady? Tonicity, which is the effective osmolality: the part of osmolality that determines water movement across cell membranes.
It is held steady in the extracellular fluid. Across vertebrates, extracellular fluid tonicity varies only slightly, a legacy of the marine environment our ancestors left. Invertebrates, especially water-living ones, tolerate much wider differences in extracellular osmolality.
In humans, plasma and extracellular fluid tonicity ranges from 275 to 295 mOsmol/kg, and the average is about 285 mOsmol/kg.
Two factors hold tonicity in this range: thirst, and the kidney’s retention or excretion of water. They are separate controllers. Thirst has a threshold of 295 mOsmol/kg, so it comes into play at the upper end of the range.
How ADH acts in the kidney
How does the kidney decide? It is controlled by ADH, acting through V2 receptors of the cortical collecting ducts. These are the part of the nephron where ADH acts to make urine concentrated or dilute.
When blood tonicity rises, ADH is secreted and the cortical collecting ducts retain water.
How far the kidney can dilute and concentrate
How concentrated can the urine become? The most concentrated urine the kidney can produce is about 1200 mOsmol/kg. The kidney reaches this once ADH secretion exceeds about 5 pg/ml. Maximal renal concentrating potential is reached when plasma tonicity is at the upper limit of normal, about 290–300 mOsmol/kg.
The opposite also happens. When blood tonicity falls, ADH release is suppressed and the kidney loses water. With no detectable ADH, the most diluted urine is about 40–50 mOsmol/kg.
So the kidney has a range of urine concentration, with a ceiling and a floor. Yet ADH governs only a small part of what the kidney handles in a day. Which part?
Pre-urine and where water is reabsorbed
Pre-urine is the fluid filtered from the blood before the tubules modify it. About 200 litres of it are formed daily. Of this, 90% (about 180 litres) is reabsorbed passively and isotonically. The remaining 10% (about 20 litres) is reabsorbed through the aquaporins, the water channels of the collecting duct that ADH activates.
ADH decides the final urine concentration far more than the urine volume.
Where ADH comes from
Where does the hormone come from? ADH reaches the systemic circulation from two regions of the hypothalamus. Magnocellular neurons of the PVN and SON project to the posterior pituitary gland and supply ADH to the blood.
Parvocellular neurons of the PVN and suprachiasmatic regions project instead to the portal plexus of the pituitary gland, the vascular network that carries hypothalamic signals to the anterior pituitary. This ADH supply stimulates the secretion of ACTH from the anterior pituitary.
How the brain senses osmolality
What tells the hypothalamus to release ADH? Two mechanisms control ADH release. The first depends on osmosensors in the hypothalamus that detect extracellular fluid tonicity.
These osmosensors are sensitive to tonicity (effective osmolality), not to osmolality. So adding a large amount of a hyperosmolar solution that does not contribute to tonicity will not activate them.
They are also sensitive. A tonicity change of less than 1% of total blood osmolality, which is about 3 mOsmol/kg difference from the extracellular fluid tonicity, stimulates them.
Detectable plasma ADH rises in a linear relation to plasma osmolality. Measuring ADH is limited by an assay sensitivity of about 0.3 pg/ml.
Renal saturation and its limit
Does more ADH mean more water retained without limit? The kidney’s response to ADH in the collecting duct is saturable. Above about 5 pg/ml of ADH, no further effect on water reabsorption is added.
Osmolality is the first and most potent stimulus to ADH secretion, but it is not the only one.
Baroreceptors and blood volume
What is the second stimulus? The second mechanism rests on baroreceptors, pressure sensors that respond to stretch of the vessel wall. The most potent baroreceptor for this purpose is in the carotid sinus.
In hypotension, such as occurs critically in patients in shock, ADH release can be augmented up to 500-fold.
When volume overrides osmolality
The two mechanisms can disagree. Take a patient who is both hypovolemic and hypotonic. Does hypovolemia raise ADH secretion, or does low tonicity suppress it? Hypovolemia wins.
So if ADH is high and the patient has low sodium, what must be true about their blood volume?