Urinary Concentrating and Diluting PDF

**"Urinary Concentrating and Diluting"** - Describe how water is excreted and reabsorbed in the kidney tubule   - Describe the structure, function and location of aquaporins in the renal tubule.   - List the key factors that affect the resorption of water by the kidneys - Explain...

**"Urinary Concentrating and Diluting"** - Describe how water is excreted and reabsorbed in the kidney tubule   - Describe the structure, function and location of aquaporins in the renal tubule.   - List the key factors that affect the resorption of water by the kidneys - Explain how ADH functions to influence water resorption and urine concentration  - Define the terms isosthenuria, hyposthenuria and hypersthenuria.  - List some of the factors that may lead to iso-, hypo- and hypersthenuric urine being made. **["Urinary Concentrating and Diluting" ]** All cells in the body need to exist in the right environment. This means that the extracellular fluid around them must contain the right amounts of the right substances. The osmolarity of the fluid must also be tightly controlled and is dependent upon the concentrations of each substance in the ECF, ie the amount of substrate and the volume it is dissolved in. For this reason, control of body water is just as important as control of things like sodium and potassium by the nephron. Body water volume is also important to maintain circulating volume, blood pressure and body mass. Normally functioning kidneys have an enormous capacity to vary the relative amounts of solutes and water in urine. Urine concentration (and osmolarity), [and] urine volume are finely controlled depending on what the body needs in order to maintain homeostasis. The [volume] and [concentration] of many substrates in urine are also largely controlled **independently**. Generally, large volumes of urine are dilute (think of the effect of drinking 2 pints of water), and small urine volumes are concentrated (think of a day when you've not drunk much and done some exercise). However, if you ate 3 packets of salty crisps with your 2 pints of water, the kidneys would excrete excess salts as well as excreting the excess water: the volume of urine will be high but the sodium concentration may also be significant. Equally important, the kidneys can excrete large volumes of dilute urine or small volumes of concentrated urine without major changes in rates of excretion of solutes like sodium and potassium. Functional kidneys are very clever! **Kidneys excrete excess water by forming dilute urine** The kidneys can also [dilute] the urine. This is often termed "active dilution but the term is quite confusing! Water is not actively pumped into the urine, rather the main process is that ions are resorbed along the nephron as normal but (due to low ADH) water does not follow in the DCT and collecting ducts. Due to active resorption of ions along the nephron, the urine gets more dilute from the thin LoH and through the DCT. If no water is able to follow via aquaporin channels, then the urine that is excreted is significantly more dilute than the glomerular ultrafiltrate (which is representative of protein-free plasma, ie isotonic). By this mechanism, urine can be more dilute (up to one sixth) than extracellular fluid. **Kidneys conserve water by excreting concentrated urine** When there is a deficit of water and ECF osmolarity is high, the kidney can resorb lots of the water filtered and therefore excrete very concentrated urine (up to 5 times that of ECF). **Water moves passively across the tubule wall in several areas of the nephron, always following a concentration gradient. This gradient is sometimes the result of lots of solutes being resorbed and water "following" eg the PCT, and sometimes the concentration gradient is amplified by resorption of ions and changes in water permeability eg the counter-current system in the LoH.** In the proximal convoluted tubule, solutes are rapidly resorbed. This means that they are transported out of the tubule, thus their concentration drops inside and increases "outside" in the renal interstitium. This creates a concentration gradient and water follows by osmosis. This is [isotonic] water resorption and is significantly affected by sodium resorption. This active movement of solutes (mostly sodium) followed by water reduces the filtrate volume by about 65% but it [does not affect its osmolality]. **Water permeability in the PCT is always high.** Moving down the nephron, water is also resorbed by osmosis along the descending Loop of Henle. \*revision of the counter- current exchange mechanism\* The descending limb is permeable to water but not ions and so overall water moves out of the tubule towards the "salty" interstitium. Once the nephron turns the corner and approaches the ascending limb, it becomes permeable to ions but not water. Sodium and chloride are actively transported out of the thick ascending limb, raising the osmolality in the interstitium. This promotes the concentration gradient for water to move out of the thin descending limb by osmosis (it makes the "salty interstitium" even "saltier"). In the LoH, about 25% of filtered sodium and chloride is resorbed but only about 10% of filtered water follows. This produces a dilute urine and a hypertonic medullary interstitium. The movement of ions and water between the descending and ascending limbs creates a gradient of osmolality which increases with depth in the medulla. **Water permeability in LoH varies with location but is overall lower than the PCT.** The distal convoluted tubule (DCT) is largely impermeable to water. In its first part is the macula densa (epithelial cells packed closely together containing renin that is part of the JGA and provides feedback control of GFR). In the next part of the DCT, the tubule is highly convoluted and has many of the same resorptive properties of the thick segment of the ascending LoH. It resorbs lots of ions and the urine gets even more dilute (it is sometimes called the "diluting segment"). Water permeability as we move into the collecting tubules and collecting ducts varies. The cells and tight junctions are fairly impermeable to the osmosis of water BUT the permeability is affected by **[Antidiuretic hormone (ADH).]** This is a hormone that acts mainly on the collecting tubules and collecting ducts to increase water permeability through channels called **[aquaporins]**. **Water permeability in the distal tubules, collecting tubules and collecting ducts depends on ADH.** **Antidiuretic Hormone (ADH) controls urine concentration** ADH (also called [vasopressin]) is part of a control system for *regulating plasma osmolarity and sodium concentration independent of the rate of solute excretion*. It only affects water resorption and does this by increasing the permeability of the distal tubules and collecting ducts to water. ADH is made in the hypothalamus and released from the posterior pituitary gland when osmolarity of the body fluids increases above normal (ie the ECF is "too concentrated"). Osmoreceptors in the hypothalamus detect a rise in plasma osmolality and trigger ADH release. Other stimuli for ADH release include: - Volume depletion - Angiotensin II - Hypoxia - Hypercapnia - Adrenaline - Cortisol. Sex steroids - Pain, trauma - Temperature - Psychogenic stimuli ADH binds V2 receptors on collecting duct cells and triggers a number of intracellular reactions that result in water channels (aquaporins, specifically AQP2) being inserted from intracellular vesicles and into the cell membrane. The aquaporins then allow water to flow through. The concentration gradient is strong, meaning that water readily moves from out of the tubules and into the interstitium. The urine "loses" water and gets more concentrated as a result. To help you remember it: ADH = ANTI-diuretic hormone "diuresis" means "loss of water", *anti-diuretic hormone* therefore reduces water loss from the body ADH also binds to V1 receptors on vascular smooth muscle à vasoconstriction It also enhances the effect of aldosterone on sodium resorption in DCT. Both of these effects support the system as it tries to reduce water loss and maintain perfusion, for example if it is volume-depleted. It also works the other way around: as well as ADH enhancing aldosterone activity, the RAAS system (specifically AngII) also triggers ADH release (as listed above). Think about it like the body springing into action when volume is depleted -- the systems are positively feeding into one another to maximise the reaction to increase fluid volume and correct the problem.    If water permeability is low (no ADH) there is no, or little, water resorption. Sodium and chloride continue to be resorbed and so the urine gets even more dilute. If the permeability of the collecting system is high (lots of ADH), then lots of water moves out of the hypotonic tubular fluid and into the interstitium. Remember the setting of this area: *Overall sodium and chloride transport out of the ascending limb of the LoH creates a hypertonic medullary interstitium.* There is therefore a strong concentration gradient between the dilute urine and the concentrated interstitium. Overall the drive here is for water to leave the descending limb and the collecting duct when water channels are open. In the cortical collecting duct, tubular fluid equilibrates with the cortical interstitium. The collecting duct then descends into the medulla where the interstitial osmolality gets even higher. If permeability continues to be high, the tubular fluid will equilibrate here too. This will create a very concentrated urine. **[What role does Urea play?]** As we have said, sodium and chloride are very important in the creation of the concentration gradient as you move down into the renal medulla. However, urea also contributes significantly to the hyperosmotic renal medullary interstitium and formation of concentrated urine. \*Revision of the Urea SDL\* Urea is passively resorbed in the PCT. However, the nephron beyond this and up to the medullary collecting duct is mostly impermeable to urea. In the presence of ADH, lots of water is resorbed and therefore the urea concentration within the tubule increases rapidly. As the tubule moves into the inner medullary collecting duct even more water is resorbed so the urea concentration gradient continues to get larger. This large gradient allows urea to start diffusing out of the tubule, greatly aided by urea transporters. ADH activates even more of these transporters. Some of the urea is then secreted back into the tubule in the thin loop of Henle, where it starts the journey towards the collecting ducts again. \`in this way, urea can recirculate through the end portion of the nephron several times before it is excreted. Each time, it adds to the hyperosmolar environment in the inner medulla and so favours resorption of water under the effect of ADH, and the production of concentrated urine.  **[Vasa recta and counter-current exchange ]** \*revision from "Renal Blood Flow lecture"\* These are the specialist blood vessels that branch from the efferent arterioles and supply the medulla. They are in pairs: a descending and an ascending vessel, which act as counter-current exchangers. The descending vessels dive into the medulla and water moves out into the concentrated surroundings, while solutes move in down their concentration gradient. The opposite happens as the vessel turns and climbs out of the medulla: water diffuses back into the vessels and solutes are able to move out of the vessels. The result is no net change in the medullary water and solute concentrations. This means that the medulla remains hyperosmotic and the concentration gradients that help water movement and the creation of concentrated urine are maintained. This can be confusing!! Think about it another way, what if the vasa recta didn't exist and there were just "normal" vessels supplying the medulla? Answer: given that it would travel through the concentrated medulla, water would diffuse out and solutes in. As a result, the environment would steadily become less "extreme" in its hyperosmolarity. The effect would be that the kidneys would not be able to make very concentrated urine if it needed to: the steep water concentration gradient would not be present. **[Urine Specific Gravity]** If the kidneys are working well then regular changes in urine concentration are usually appropriate, eg a large volume of dilute urine after you drink 2 pints of water, or a small amount of concentrated urine if you are dehydrated. In many diseases, urine concentration is [inappropriate], eg in chronic renal disease animals often have large amounts of dilute urine in the face of dehydration. Measuring the urine concentration can therefore be very useful clinically in order to identify if there is a problem with concentrating ability. USG is measured using a refractometer... not urine dipsticks, they are inaccurate! Urine specific gravity (USG) is used in lots of clinical settings to provide an estimate of urine solute concentration. Generally, USG increases linearly with osmolarity but it is also affected by solute weight too. This means that the relationship isn't linear if there are lots of heavy molecules eg glucose. It is measured with a refractometer in g/ml. **Hyposthenuria:** The formation of hyposthenuric urine means that the kidneys are [actively diluting] the urine. Dilution mainly occurs in the loop of Henle where water follows solutes (mostly sodium) out of the tubule. An example of when hyposthenuric urine would be expected is in situations where the body is volume-overloaded: the body needs to actively dilute urine beyond that of ECF in order to maintain homeostasis. Hyposthenuric urine is anything \