SCIENCE REVIEW


‘Free water excretion is regulated by the circulating concentration of the antidiuretic hormone arginine vasopressin’


products of metabolism that must be eliminated from the body. This minimal urinary water loss is obligatory and unregulated. However, free water loss (ie water lost in excess of this obligatory volume) is regulated, so that urine volume in health can vary from 500 mL/day to 3000 mL/day or more if necessary to ensure a water balance in the context of decreased or increased water intake. Free water excretion is regulated by the


circulating concentration of the antidiuretic hormone arginine vasopressin (AVP; also known as antidiuretic hormone [ADH]). This is a nine amino acid peptide synthesised in specialised neural cells located in two discrete areas of the hypothalamus. From its sites of synthesis, AVP is delivered via neural axons to the posterior pituitary, where it is stored. Pituitary release of AVP to the circulation is stimulated, like the thirst response, by increasing plasma osmolality, although the threshold for secretion of AVP (around 280 mOsmol/kg) is significantly lower than that which invokes the thirst response (closer to 290 mOsmol/kg). The antidiuretic (water conserving)


action of AVP operates via V2 receptors located on the basolateral membrane of renal collecting duct tubule cells. Thus, AVP binding of these V2 receptors promotes activation of a sequence of intracellular molecular events that results in translocation of aquaporin 2 (AQP2) water channels from vesicles within the cytoplasm to the apical membrane of the tubule cell. The previously watertight membrane is rendered permeable by the insertion of AQP2, and water flows from the tubule lumen through the tubule cell and out via the AQP3 and AQP4 water channels located on the basolateral membrane to the renal vasculature. In summary, AVP action results in reabsorption of water from tubule to blood, urine volume is reduced, and, as solute excretion does not alter, urine concentration (osmolality) increases. The water reabsorbed to blood reduces plasma osmolality and the stimulus to AVP secretion is thereby reduced. As AVP concentration is reduced, AQP2 returns to cytoplasmic vesicles and the water impermeability of tubule cell membrane is restored. Arginine vasopressin has a half-life in the


circulation of just 15–20 minutes before rapid metabolism in the liver. Thus, AVP- mediated control of free water excretion is able to operate continuously, responding minute by minute to small (1%) changes in plasma osmolality. As a consequence, despite large variation in water intake


THE BIOMEDICAL SCIENTIST AUGUST 2016


AVP CRH


Hypothalamus


Pituitary gland


ACTH CORT


Adrenal gland


Although in a few cases of central diabetes insipidus no identifiable cause for reduced AVP secretion can be found, damage to, or disease of, the hypothalamic-posterior pituitary axis (part of the hypothalamo-pituitary- adrenal stress axis), located in the brain, is usually the reason.


throughout the day, plasma osmolality (reference range 285–295 mOsmol/kg) and total body water does not normally vary by more than 1–2%. In contrast, urine volume and therefore urine osmolality vary enormously according to fluid (water) intake.


Thirst response and AVP secretion The differing osmolality thresholds for AVP secretion (280 mOsmol/kg) and sensation of thirst (290 mOsmol/kg) reflects the fact that in the normal course of events it is only AVP- mediated control of free water excretion that ensures a balance between water intake and water loss. If fluid is restricted, however, there comes a point at which, despite maximal AVP-mediated water conservation (ie maximally concentrated urine – osmolality 1200 mOsmol/kg), free water excretion slows and eventually ceases. In order to maintain the obligatory


minimum urine flow required to excrete solutes, a potential ECF water deficit develops and plasma osmolality rises above 290 mOsmol. At this point, the thirst response is triggered and the increased fluid intake that it induces saves the body from the potential water deficit becoming real. Thus, both AVP (primarily) and the thirst response (secondarily) are involved in protecting the body from dehydration. Diabetes insipidus is a condition in which, as a result of AVP deficiency, thirst becomes the primary protector against water deficit and dehydration.


Diabetes insipidus Diabetes insipidus (DI) is a consequence of either inadequate secretion of AVP from the posterior pituitary (usually referred to as central DI) or decreased response to AVP by the kidney tubule cells (nephrogenic DI). Although in a few cases of central DI no


identifiable cause for reduced AVP secretion can be found, damage to, or disease of, the hypothalamic-posterior pituitary axis, located in the brain, is usually the reason. Damage may be a consequence of traumatic head injury or can arise as a complication of pituitary surgery. Hypothalamic/pituitary tumours or


interruption of the blood supply to the axis due to cerebral haemorrhage/thrombosis may be the cause in particular cases, and central DI may arise secondary to viral or bacterial infection of the meninges (meningitis). Many individually extremely rare inherited defects of the gene that codes for AVP have been described. These are grouped together under the umbrella term familial or inherited central DI and account for just 1–2% of all cases. For those with nephrogenic DI, the


hypothalamic-pituitary axis is functionally normal but the kidney tubule collecting duct cells are unable to respond adequately to circulating AVP. Nephrogenic DI, like central DI, can be either acquired or inherited. Advanced chronic renal failure and other renal diseases (eg polycystic kidney disease, pyelonephritis) account for


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