# 5.7 Coupling of the Osmoreceptor & the Kidneys

The role of the hypothalamic osmoreceptor in the control of water balance has been experimentally determined and the quantitative aspects of its function will be discussed here.

A graph of plasma ADH levels versus plasma osmolality is depicted below. The points to note are:

• Below an osmolality of about 280 mOsm/l, ADH levels are very low
• The curve starts to rise very sharply and linearly at osmolalities above 280 mOsm/l

The value of 280 mOsm/l is the threshold value (or set-point) of the osmoreceptor. The slope of the line above 280 mOsm/l represents the sensitivity of the receptor. This rising line can be described by the equation:

##### [ADH] = 0.38 x ( POsm - 280 )

where: [ADH] is the plasma ADH concentration and POsm is the plasma osmolality.

The sensitivity (the slope of the line) is 0.38 pg of ADH/ml per mOsm/kg. [ADH] will increase by 0.38 pg/ml for every 1 mOsm/kg increase in plasma osmolality.

The extreme sensitivity of the osmoreceptor can be better appreciated if this is stated another way: A 1% increase (2.9 mosm/kg) in plasma osmolality will increase [ADH] by about 1 pg/ml. This increase is enough to have significant effects on urinary osmolality.

[insert Fig here]

The next step is to consider the relationship between the [ADH] and the urine osmolality. This is displayed in the figure below. As the [ADH] increases the antidiuretic effect increases and the urine osmolality increases up to the limit set by the maximal concentrating ability of the kidney. For young adults, this maximal urine osmolality is somewhere between 1200 to 1400 mOsm/kg. The line can be described by the equation:

##### UOsm = 250 ( [ADH] - 0.25 )

where: [ADH] is the plasma ADH concentration and UOsm is the urine osmolality.

The slope of the line (250) is the sensitivity of the renal mechanism which responds to ADH. The threshold [ADH] is 0.25 pg/ml. To state this another way: An increase in [ADH] of just 1 pg/ml will cause urine osmolality to rise by 250 mOsm/kg. The renal response to ADH is very sensitive.

[insert Fig here]

The overall sensitivity of this system for controlling plasma osmolality and water balance is referred to as the gain of the system. The gain is high because there is a sensitive mechanism for responding to changes in plasma osmolality which is coupled to a sensitive mechanism for changing urine osmolality in response to changes in [ADH].

The sensitivity of the osmoreceptor (0.38) is such that a rise in plasma osmolality of 2.63 mOsm/kg (ie 1/0.38) will result in a rise of 1 pg/ml in [ADH]. The sensitivity of the renal response is 250 so the overall gain of the system is 95 (ie 250 divided by 2.63). This means that an increase in plasma osmolality of 1 mOsm/kg will result in a rise in urine osmolality of 95 mOsm/kg!

The two limits imposed on the system must be recognised:

• the threshold of the osmoreceptor (280 mOsm/kg)
• the maximal urine concentration of the kidney (1200 to 1400 mOsm/kg in a young adult)

The sensitivity of the system is so high that it exceeds our ability to accurately measure the osmolality.

The [ADH] at the threshold of the osmoreceptor is 0.5 pg/ml. The [ADH] at the maximal urine concentration is 5 pg/ml. The plasma osmolality in healthy adults averages 287 mOsm/kg and this is associated with a [ADH] of 2 to 2.5 pg/ml. The significance of this is that it is at about the midpoint of the renal response line: sensitivity to changes in plasma osmolality is thus high in both directions.

Maximal anti-diuresis occurs at a plasma osmolality of 294 mOsm/kg. This is about the average osmolality at which the thirst mechanism is activated. This illustrates the interaction btween the ADH and the thirst mechanisms for control of water balance. The threshold of thirst for osmotic stimuli has a higher set-point then that for ADH release: thirst is considered by some to act as a ‘back-up’ mechanism if changes in ADH are not sufficient of themselves to keep plasma osmolality constant.

At the threshold of the osmoreceptor (280 mOsm/kg), the [ADH] is less than 0.5 pg/ml and urine osmolality is at its minimal value. The formula predicts minimal urine osmolality of about 60 mOsm/kg {ie 250 x (0.5 - 0.25) } if basal [ADH] is 0.5 pg/ml. The minimum urine osmolality that is measured in young adults is in the range 40 to 100 mOsm/kg. To excrete a daily solute load of 600 mOsm at a minimum urine osmolality of 60 mOsm/kg requires a urine volume of 10 liters (over 400 mls/hr). The significance of this is that the urine production can increase to such high levels when [ADH] is low, that hypotonic hyponatraemia cannot persist other then briefly if the kidney’s ability to excrete dilute urine is normal.

The response of the osmoreceptor can be affected by several other factors:

• Intravascular volume
• The rate of change of the osmolality
• The type of blood solute present

The response of the osmoreceptor is partially rate-dependent: a rapid increase in plasma osmolality will result in a much higher [ADH] initially then if the plasma osmolality has risen slowly. This effect is noticeable if the plasma osmolality increases at a rate of 2% or more per hour.

Some blood solutes are less effective than others in stimulating the osmoreceptor. Sodium and its associated anions normally account for about 92% of plasma tonicity; so under normal conditions the osmoreceptor responds to changes in sodium concentration. Glucose & urea contribute to plasma osmolality but they cross cell membranes easily and are ‘ineffective’ solutes which do not contribute to plasma tonicity (see Section 1.2.3). An increase in urea concentration can have marked effects on plasma osmolality but minimal effects on blood tonicity and thus does not affect [ADH]. The osmoreceptor senses blood tonicity and not blood osmolality. In the presence of insulin, glucose can enter the osmoreceptor cells and is an ineffective osmole. In cases of hyperglycaemia due to insulin deficiency, glucose cannot enter cells so it now is effective in altering plasma tonicity and can cause appropriate release of ADH.