The thirst switch: how kidneys keep the body’s water in balance

Part 1: Water in, water out

1Water makes up about 60 per cent of the mass of an adult human body. Every day we gain water from drinks, from food and from respiration, and we lose it in urine, sweat, faeces and exhaled air. These gains and losses rarely match exactly, yet the water potential of the blood plasma stays within narrow limits. The organs that make this possible are the kidneys, which can change both the volume and the concentration of the urine within minutes.

2Each kidney has an outer cortex and an inner medulla, and contains about a million nephrons. Blood enters the kidney in the renal artery, which divides into smaller and smaller vessels until each nephron receives blood through its own afferent arteriole. Together the two kidneys receive about a fifth of the blood pumped by the heart, even though they make up less than one per cent of body mass. This huge blood flow is not needed to supply the kidney cells with oxygen. It is needed because the kidneys process the plasma itself, removing urea and excess ions and adjusting the water content before the blood returns to the heart in the renal vein.

3Urine formation begins in the glomerulus, a knot of capillaries inside the cup-shaped Bowman’s capsule. The efferent arteriole leaving the glomerulus is narrower than the afferent arteriole entering it, so the hydrostatic pressure of the blood in the glomerulus is high. Water and small solutes are forced out through pores in the capillary walls, through the basement membrane and between the podocytes lining the capsule. Blood cells and most plasma proteins are too large to pass through. About 180 litres of filtrate are produced every day.

4Almost all of that filtrate is reabsorbed. In the proximal convoluted tubule, the cells lining the tubule have microvilli and many mitochondria. Sodium ions are actively transported out of these cells into the blood, and glucose and amino acids are carried back into the cells from the filtrate by co-transport with sodium ions. Water follows by osmosis. By the end of the proximal tubule, about two-thirds of the water and all of the glucose have usually been returned to the blood.

The countercurrent multiplier

5The loop of Henle dips down into the medulla and back up again. Cells in the wall of the ascending limb actively transport sodium and chloride ions out of the filtrate into the surrounding tissue fluid, but this part of the wall is impermeable to water. The descending limb is permeable to water, so water leaves it by osmosis into the salty tissue fluid. Because fluid flows in opposite directions in the two limbs, a gradient of water potential builds up, with the lowest water potential deep in the medulla.

6The longer the loop of Henle, the steeper this gradient can be. Kangaroo rats living in North American deserts have exceptionally long loops and can produce urine about five times more concentrated than the most concentrated human urine. Many of these rodents never drink at all, surviving on water from the seeds they eat and from their own respiration. Beavers, which live in fresh water, have short loops and produce dilute urine. In general, the thickness of the medulla compared with the size of the kidney is greater in mammals from drier habitats.

The hormone that saves water

7The concentration of urine is controlled by antidiuretic hormone, ADH. ADH is made by neurosecretory cells in the hypothalamus and stored in the posterior pituitary gland. Osmoreceptors in the hypothalamus detect a fall in the water potential of the blood: water leaves the osmoreceptor cells by osmosis and they shrink, which increases their rate of firing. Nerve impulses then pass along the axons of the neurosecretory cells to the posterior pituitary, which releases ADH into the blood. The same fall in water potential also stimulates a separate group of cells in the hypothalamus that create the sensation of thirst.

8ADH travels in the blood to the kidney, where it binds to receptors on the cell surface membranes of cells lining the collecting ducts. Binding sets off a series of reactions, using cyclic AMP as a second messenger, that causes vesicles containing water channel proteins called aquaporins to move to the membrane facing the lumen and fuse with it. With more aquaporins in place, more water leaves the collecting duct by osmosis into the medulla, where the water potential is low.

9When the water potential of the blood returns to normal, the osmoreceptors fire less often and less ADH is released. Aquaporins are taken back into the cells by endocytosis and stored in vesicles again. The collecting duct becomes less permeable to water, and larger volumes of dilute urine are produced. This is an example of negative feedback, in which a change from the normal level triggers a response that reverses that change.

10In an illustrative study, sixteen trained cyclists rode for 90 minutes in a room kept at 30 °C without drinking. Their mean body mass fell from 72.0 kg to 70.2 kg, almost all of this being water lost as sweat. Over the same period, the mean concentration of ADH in their blood plasma rose from 2.1 to 7.6 picograms per cm³, and the volume of urine produced in the hour after exercise fell to less than a third of the volume produced on a rest day.

11"Sweat is made from plasma, so heavy sweating lowers the water potential of the blood very quickly," explains Dr Anika Sørensen, who led the illustrative study. "The kidneys respond within minutes. But they can only reduce water loss, they cannot replace water. Only drinking can do that, which is why thirst is triggered by the same osmoreceptors. In our study, the riders who started the session already slightly dehydrated had the highest ADH concentrations of all."

Part 2: When the switch fails

12In diabetes insipidus, the body cannot concentrate its urine, and a person may produce more than 15 litres of very dilute urine a day and feel constantly thirsty. In central diabetes insipidus, too little ADH is released, often after damage to the hypothalamus or pituitary gland. In nephrogenic diabetes insipidus, ADH is released normally but the collecting duct cells do not respond to it. Doctors can tell the two forms apart by giving a synthetic form of ADH and measuring whether the urine becomes more concentrated over the next few hours.

13Most inherited cases of nephrogenic diabetes insipidus are caused by mutations in a gene called AVPR2, which codes for the ADH receptor. The AVPR2 gene is found on the X chromosome, and almost all of the people affected are male. A smaller number of cases are caused by mutations in the gene for aquaporin-2 itself. Some of these mutations change a single amino acid, so the aquaporin folds incorrectly and is broken down before it ever reaches the cell surface membrane.

14Central diabetes insipidus is usually treated with desmopressin, a synthetic molecule with a structure similar to ADH that binds to the same receptor. It can be taken as a tablet or a nasal spray and lasts longer in the body than natural ADH. Desmopressin does not help people with nephrogenic diabetes insipidus, whose treatment relies on diet and on drugs that reduce the volume of filtrate reaching the collecting ducts.

15Researchers are searching for drugs that could move aquaporins into the membrane without acting through the ADH receptor. In an illustrative series of experiments, a team used CRISPR gene editing to give mice the same AVPR2 mutation found in an affected family. When the mice were given one candidate drug, their urine volume fell by about 40 per cent over 24 hours, although the effect wore off within two days. A drug of this kind would need to act mainly on the collecting duct cells, because other types of aquaporin are found in many other tissues of the body.

16Other everyday substances act on this system too. Alcohol reduces the release of ADH from the posterior pituitary, which is one reason why drinking alcohol increases urine production and can lead to dehydration. Some recreational drugs have the opposite effect and cause ADH to be released, so a person who also drinks large volumes of water may retain too much of it. Caffeine has a much smaller effect on urine output than is often claimed, and regular coffee drinkers show almost no change at all.

17Drinking too much water can be as dangerous as drinking too little. During very long endurance events, a few athletes drink far more water than they lose in sweat. Their blood plasma becomes dilute, a condition called hyponatraemia, and water moves into body cells by osmosis. Cells in the brain swell, which can cause confusion and, in rare cases, death. Guidance for athletes now recommends drinking according to thirst rather than to a fixed schedule. Sports drinks contain some salt, but not enough to prevent the condition in someone who drinks several litres more than they need.

18Measuring hydration accurately is harder than it sounds. Urine colour charts are cheap and quick but are affected by diet and vitamin supplements. Laboratories can measure the solute concentration, or osmolality, of urine or plasma, and the change in body mass before and after exercise is used as an estimate of sweat loss. In one illustrative survey of 200 school pupils, about a third arrived at school with concentrated urine.

19"We tend to think of the kidney as a filter, but really it is a recycling plant," says Dr Sørensen. "It filters the entire plasma volume many times a day and then decides, minute by minute, how much water to give back. ADH is the switch that makes that decision. When the switch fails, as it does in diabetes insipidus, you see just how much water the kidneys normally save for us."