CONCENTRATION OF URINE.pdf

CONCENTRATION OF URINE DR SAMUEL AA INTRODUCTION Every day 180 L of glomerular filtrate is formed with large quantity of water. If this much of water is excreted in urine, body will face serious threats. So the concentration of urine is very essential Thus the kidney doesn’t only excrete waste pro...

CONCENTRATION OF URINE DR SAMUEL AA INTRODUCTION Every day 180 L of glomerular filtrate is formed with large quantity of water. If this much of water is excreted in urine, body will face serious threats. So the concentration of urine is very essential Thus the kidney doesn’t only excrete waste product but helps to maintain water balance i.e. they determine the amount of water that should accompany those wastes So how do the kidneys determine how much water is to be excreted? The secret lies in the osmolarity of the extracellular fluid (ECF). The body tries to maintain an ECF osmolarity of 300mOsm/L, because if it is higher than that, the cells will shrink; if it's lower than that, the cells will swell. This ECF osmolarity is brought about by the salt and water content, therefore, if the salt content increases, or the water content reduces, the osmolarity will rise, and the kidneys will try to bring it back to normal in two ways - stimulating thirst so that you drink more water, and reducing the excretion of water through urine (resulting in concentrated urine). INTRODUCTION As stated previously, by the time the tubular fluid gets to the late distal tubule and collecting ducts, over 90% of the water has already been reabsorbed. However, the water that is still left at that point can either be reabsorbed or not, depending on the osmolarity of the plasma through the actions of ADH and a high osmotic gradient in the medullary interstitium in order to drive the reabsorption of water FORMATION OF DILUTE URINE When, water content in the body increases, kidney excretes dilute urine. This is achieved by inhibition of ADH secretion from posterior pituitary so that water reabsorption from the distal renal tubules does not take place leading to excretion of large amount of water. This makes the urine dilute. FORMATION OF CONCENTRATED URINE When the water content in body decreases, kidney retains water and excretes concentrated urine formation of concentrated urine is not as simple as that of dilute urine. It involves two processes: 1. Development and maintenance of medullary gradient by countercurrent system 2. Secretion of ADH MEDULLARY GRADIENT MEDULLARY HYPEROSMOLARITY Quickly recall that the kidneys have two main segments - cortex and medulla. Also, we have two types of nephrons - cortical and juxtamedullary nephrons, and the loop of Henle of juxtamedullary nephrons go all the way down to the medulla, and even renal papilla. The interstitial fluid surrounding the cortical nephron has the same osmolarity as that of plasma (i.e 300 mOsm/L), Osmolarity of juxtamedullary nephrons interstitial fluid near the cortex is also 300 mOsm/L. However, while proceeding from outer part towards the inner part of medulla, the osmolarity increases gradually and reaches the maximum at the inner most part of medulla near the renal sinus. Here, the interstitial fluid is hypertonic with osmolarity of 1,200 mOsm/L. This type of gradual increase in the osmolarity of the medullary interstitial fluid is called the medullary gradient. It plays an important role in the concentration of urine. MEDULLARY GRADIENT DEVELOPMENT AND MAINTENANCE OF MEDULLARY GRADIENT Kidney has some unique mechanism called countercurrent mechanism, which is responsible for the development and maintenance of medullary gradient and hyperosmolarity of interstitial fluid in the inner medulla COUNTERCURRENT MECHANISM A countercurrent system is a system of ‘U’shaped tubules (tubes) in which, the flow of fluid is in opposite direction in two limbs of the ‘U’shaped tubules. The countercurrent system is a bit complex to understand, but one can still grasp the fundamental principle behind it. Let us always keep in mind that the sole aim of this system is to create a high osmotic gradient in the medullary interstitium. This gradient is produced by the operation of the loops of Henle as countercurrent multipliers and maintained by the operation of the vasa recta as countercurrent exchangers. Thus, countercurrent mechanism can be said to be made up of; 1. Countercurrent multiplier and 2. Countercurrent exchanger COUNTERCURRENT MULTIPLIER Loop of Henle functions as countercurrent multiplier. It is responsible for development of hyperosmolarity of medullary interstitial fluid and medullary gradient. There are three structural factors of the loop of henle that ensure that the osmolarity of the medullary interstitium is increased and multiplied: 1. Shape of the loop of Henle: The 'U' shape of loop of Henle ensures that two segments of the tubule with opposite characteristics face each other and envelop the interstitium. 2. Water impermeability of ascending limb and Active NaCl reabsorption in ascending limb: Since water is not reabsorbed with NaCl, this increases the concentration of the medullary interstitium. 3. Water reabsorption in descending limb: The water reabsorption here helps to concentrate the descending tubular fluid by reaching equilibrium with the already concentrated medullary interstitium. COUNTERCURRENT MULTIPLIER Now, let us discuss how exactly the osmolarity of the interstitium is multiplied. The operation of each loop of Henle as a countercurrent multiplier depends on the high permeability of the thin descending limb to water (via aquaporin-1), the active transport of Na+ and Cl− out of the thick ascending limb, and the inflow of tubular fluid from the proximal tubule, with outflow into the distal tubule. The fluid that flows from the proximal tubule into the descending limb is isotonic to plasma, because equal amounts of solutes and water are reabsorbed in the proximal tubule. So, the fluid entering the descending limb is still 300mOsm/L. Also understand this, Assume first a condition in which osmolarity of 300 mOsm/L is present throughout the descending and ascending limbs and the medullary interstitium. COUNTERCURRENT MULTIPLIER Let us now turn our attention to the ascending limb because what happens in the descending limb can only be understood from what happens in the ascending limb. The ascending limb actively pumps NaCl into the medullary interstitium, but it is impermeable to water. These solutes accumulate in the medullary interstitium and increase the osmolarity of the interstitium (because of NaCl) while that of the fluid in the ascending limb decreases (because of retention of water). However, only a gradient of 200mOsm/L can exist between them. So the osmolarity of the fluid in the ascending limb decreases to about 200mOsm/L while that of the interstitium increases to about 400mOsm/L So, about the descending limb, what happens there? Since the descending limb is freely permeable to water, the water from the fluid in the thin descending limb then moves out COUNTERCURRENT MULTIPLIER Also, new fluid from proximal tubule entering descending limb containing more sodium and chloride This results in contents of the descending loop of Henle reaching equilibrium with the medullary interstitial fluid, making the fluid in the descending limb to now become 400mOsm/L (from 300mOsm/L) This fluid, now of 400mOsm/L from the descending limb flows to the ascending limb, and more NaCl is pumped out of it, retaining water. This makes the medullary interstitial fluid to rise even further to an osmolarity of about 500mOsm/L. This process now repeats itself again and again until the medullary interstitium reaches a maximum osmolarity of about 1200 mOsm/L (at the level of the hairpin bend) This constant increase or multiplication of the osmolarity of medullary interstitial fluid is called countercurrent multiplier COUNTERCURRENT MULTIPLIER As you would have noticed, there are just three major steps that are repeated over and over again in the countercurrent multiplier: Pump step: This is where NaCl is continuously pumped into the medullary interstitium, and increases its osmolarity. Equilibration step: This is where the fluid in the descending limb reaches equilibrium with the medullary interstitium. Shift step: This is where new glomerular fluid flows into the descending limb from the PCT, and 'pushes' the previous fluid further down. COUNTERCURRENT MULTIPLIER COUNTERCURRENT EXCHANGER Vasa recta functions as countercurrent exchanger. It is responsible for the maintenance of medullary gradient, which is developed by countercurrent multiplier As you know, the renal tubules are surrounded by peritubular capillaries; but the loop of henle of the juxtaglomerular nephrons, because of their special function in urine concentration, their capillaries are called vasa recta. Vasa recta acts like countercurrent exchanger because of its position. Like the loop of henle, It is also ‘U’shaped tubule with a descending limb, hairpin bend and an ascending limb. Vasa recta runs parallel to loop of Henle. Its descending limb runs along the ascending limb of Henle loop and its ascending limb runs along with descending limb of Henle loop. COUNTERCURRENT EXCHANGER The sodium chloride reabsorbed from ascending limb of Henle loop enters the medullary interstitium. From here it enters the descending limb of vasa recta. Simultaneously water diffuses from descending limb of vasa recta into medullary interstitium. The blood flows very slowly through vasa recta. So, a large quantity of sodium chloride accumulates in descending limb of vasa recta and flows slowly towards ascending limb. By the time the blood reaches the ascending limb of vasa recta, the concentration of sodium chloride increases very much. This causes diffusion of sodium chloride into the medullary interstitium. Simultaneously, water from medullary interstitium enters the ascending limb of vasa recta. And the cycle is repeated By so doing, the osmolarity of the medullary interstitium is preserved without being washed out by the flowing blood in the vasa recta. COUNTERCURRENT EXCHANGER THE ROLE OF UREA IN URINE CONCENTRATION (UREA CYCLING) In actual sense, half of the 1200 mOsm/L osmolarity of the medullary interstitium is contributed by urea, but in the renal interstitium around the inner medullary collecting ducts. Yes, that's right. You thought it was only NaCl, but urea has an equal role to play in that region. Fifty percent of urea filtered in glomeruli is reabsorbed in proximal convoluted tubule. Almost an equal amount of urea is secreted in the loop of Henle. So the fluid in distal convoluted tubule has as much urea as amount filtered. Collecting duct is impermeable to urea. However, due to the water reabsorption from distal convoluted tubule and collecting duct in the presence of ADH, urea concentration increases in collecting duct. Now due to concentration gradient, urea diffuses from inner medullary part of collecting duct into medullary interstitium. THE ROLE OF UREA IN URINE CONCENTRATION (UREA CYCLING) Diffusion of urea from collecting duct into medullary interstitium is carried out by urea transporters, UT-A1 and UT-A3, which are activated by ADH Due to continuous diffusion, the concentration of urea increases in the inner medulla resulting in hyperosmolarity of interstitium in inner medulla. Again, by concentration gradient, urea enters the ascending limb. From here, it passes through distal convoluted tubule and reaches the collecting duct. Urea enters the medullary interstitium from collecting duct. By this way urea recirculates repeatedly and helps to maintain the hyperosmolarity of inner medullary interstitium. Only a small amount of urea is excreted in urine. ROLE OF ADH Diuresis means passage of urine; so antidiuresis simply means prevention of urine passage. Antidiuretic hormone (ADH) is secreted by the paraventricular cells of the posterior pituitary gland in response to a high plasma osmolarity. They act on the late distal tubule and collecting ducts to increase water reabsorption by increasing the number of water channels known as aquaporins through which the water will be transported. Without ADH, those segments of the nephron are impermeable to water. The more the osmolarity of the plasma, the more ADH is secreted, and the more water is reabsorbed in those segments, resulting in more concentrated urine. Therefore, ADH is the final determinant of the concentration of urine. APPLIED PHYSIOLOGY 1. Osmotic Diuresis; Diuresis is the excretion of large quantity of water through urine. Osmotic diuresis is the diuresis induced by the osmotic effects of solutes like glucose. It is common in diabetes mellitus. 2. Polyuria; Polyuria is the increased urinary output with frequent voiding. It is common in diabetes insipidus. In this disorder, the renal tubules fail to reabsorb water because of ADH deficiency. 3. Syndrome of Inappropriate Hypersecretion of ADH (SIADH); It is a pituitary disorder characterized by hypersecretion of ADH is the SIADH. Excess ADH causes water retention, which decreases osmolarity of ECF APPLIED PHYSIOLOGY 4. Nephrogenic Diabetes Insipidus; Sometimes, ADH secretion is normal but the renal tubules fail to give response to ADH resulting in polyuria. This condition is called nephrogenic diabetes insipidus. 5. Bartter Syndrome; Bartter syndrome is a genetic disorder characterized by defect in the thick ascending segment. It is a renal tubular salt-wasting disorder in which the kidneys cannot reabsorb sodium and chloride in the thick ascending limb of the loop of Henle. This leads to increased distal delivery of salt and excessive salt and water loss from the body.