Renal clearance

The sieve

 

Renal clearance refers to the volume of plasma that is cleared of a particular substance in a given time, ussually 1 minute. Renal clearance tests are done to determine the glomerulus filtration rate, which allows us to detect glomerular damage and follow the progress of renal disease.

The renal clearance rate (RC) of any substance, in ml/min, is calculated from the equation

RC=UV/P

where

RC=Renal clearance rate

U=concentration of the substance in urine (mg/ml)

V=flow rate of urine formation (ml/min)

P=concentration of the substance in plasma (ml/min)

 

Because it is freely filtered and neither reabsorbed nor secreted by the kidneys, inulin is the standard used to determined the glomerulus filtration rate. a polysaccharide with a molecular weight of approximately 5000, inulin has a renal clearance value equal to the glomerulus filtration rate. When inulin is infused such that its plasma concentration is 1 mg/ml (P=1mg/ml), then generally U=125mg/ml, and V=1ml/min. Therefore, its renal clearance is RC=(125×1)/1=125ml/min, meaning that in 1 minute the kidneys have removed (cleared) all the inulin present in 125 ml of plasma.

The clearance value tell us about the net handling of a substance by the kidneys.

There are three possible cases :

  • A clearance values less than that inulin means that a substance is reabsorbed. An example is urea with an RC of 70 ml/min, meaning that of the 125 ml of glomerular filtrate formed each minute, approximately 70 ml is completely cleared of urea, while the urea in the remaining 55 ml is recovered and returned to the plasma. If the RC is zero (such as for glucose in healthy individuals), reabsorption is complete or the substance is not filtered.

 

  • If the RC is equal to that of inulin, there is no reabsorption or secretion.

 

  • If the RC is greater than that of inulin, the tubule cells are secreting the substance into the filtrate. This is the case with the most drug metabolites. Knowing a drug’s renal  clearance value is essential because of its high, the drug dosage must also be high and administered frequently to maintain a therapeutic level.

 

Creatinin, which has an RC of 140 ml/min. is freely filtered but also secreted in small amounts. It is often used nevertheles to give a “quick and dirty” estimate of glomerulus filtration rate.

 

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DIURETICS

 

Drugs

 

There are several type of diuretics, chemical that enhance urinary output. An osmotic diuretic is a substance that is not reabsorbed and that carries water with it (for example, the high blood glucose levels of a diabetes mellitus patient). Alcohol, essentially a sedative, encourages diuresis by inhibiting release of antidiuretic hormone. Other diuretics increase urine flow by inhibiting Na+ reabsorption and the obligatory water reabsorption that normally follows. Examples include caffeine (found in coffee, tea and colas) and many drugs prescribed for hypertension or the edema of congestive heart failure. Common diuretics inhibit Na+ association symporters. “Loop diuretics” [like furosemide (Lasix)] are powerful because they inhibit formation of the medullary gradient by acting at the ascending limb of Henle’s loop. Thiazides are less potent and act at the distal convoluted tubules.

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Concentrated urine

Countercurrent in the kidney

 

The formation of concentrated urine depends on the medullary osmotic gradient and the presence of antidiuretic hormone. In the distal tubules, the filtrate osmolality is approximately 100 mOsm, but as the filtrate flows  through the collecting ducts and is subjected  to the hyperosmolar conditions in the medulla, water rapidly leaves the filtrate, followed by urea. Depending on the amount of antidiuretic hormone released (which is keyed to the level of body hydration), urine concentration may rise as high as 1200 mOsm, the concentration of the interstitial fluid in the deepest part of the medulla. With maximal antidiuretic hormone secretion, up to 99% of the water in the filtrate is reabsorbed and returned to the blood, and a half liter  per day of highly concentrated urine is excreted. The ability of kidneys to produce such concentrated urine is critically tied to ability to survive without water. Water reabsorption that depends on the presence of antidiuretic hormone is called facultative water reabsorption.

Antidiuretic hormone is released more or less continuosly unless the blood solute concentration drops too low. Released of antidiuretic hormone is enhanced by any event that raises plasma osmolality above 300mOsm, such as sweating or diarrhea, or by greatly reduced blood volume or blood pressure. Although release of antidiuretic hormone is the “signal” to produce concentrated urine that opens the door of water reabsorption (through aquaporins), the kidney’s ability to respond this signal depends on the high medullary osmotic gradient,

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Dilute urine

Countercurrent in the kidney

 

Tubular filtrate is diluted as it travels through the ascending limb of the loop of Henle, so all the kidney needs to do secrete dilute (hypo-osmotic) urine is allow the filtrate to continue on its way into the renal pelvis. When ADH (Antidiuretic hormone)  is not being released by the posterior pituitary, that is exactly what happens, The collecting ducts remain essentially impermeable to water due to absence of aquaporins in their luminal cell membranes, and no further water reabsorption occurs. Moreover, as noted, Na+ and selected other ions can be removed from the filtrate by distal convoluted tubule and collecting duct cells so that urine becomes even more dilute before entering renal pelvis. The osmolality of urine can plunge as low as 50 mOsm, about one-sixth the concentration of lomerular filtrate or blood plasma.

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Formation of dilute or concentrated urine

Countercurrent in the kidney

 

The kidneys go to a great deal of trouble to create the medullary osmotic gradient. What is its purpose? Without this gradient, you would not be able to raise the concentration of urine above 300 mOsm, the osmolality of interstitial fluid. As a result, you would not be able to excrete excess solutes to lower your body osmolality.

Controlling the reabsorption of water from filtrate in the collecting ducts in order to adjust the body’s osmolality is the job of antidiuretic hormone (ADH). ADH inhibits diuresis, or urine output. It accomplishes this via a second messenger system using cyclic AMP that causes insertion of aquaporins into the luminal membrane of the principal cells of the collecting ducts. The amount of the ADH determines the number of aquaporins in the collecting ducts and so the amount of water that is reabsorbed there.

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The countercurrent exchanger

Countercurrent in the kidney

 

The vasa recta function as counter current exchangers, maintaining the osmotic gradient established by the cycling of salt while delivering blood cells in the area and removing reabsorbed water and solutes. These vessels receive only about 10% of the renal blood supply, making blood flow through the vasa recta sluggish. Moreover, they are freely permeable to water and NaCl, allowing blood to make passive exchanges with the surrounding interstitial fluid. Consequently, as the blood flows into the medullary depths, it loses water and gains salt (becomes hypertonic). Then, as it emerges from the medulla into the cortex, the process is reversed. It picks up water and loses salt. The water picked up by the ascending vasa recta includes not only water lost from the descending vasa recta, but also water  reabsorbed from the loop of Henle and collecting duct. As a result, the volume of the blood at the end of the vasa recta is greater than at beginning.

Because blood leaving and reentering the cortex via the vasa recta has nearly the same solute concentration, the vessels of the vasa recta act as countercurrent exchangers. This system does not create the medullary gradient, but it protects it by preventing rapid removal of salt from the medullary interstitial space, and by removing reabsorbed water,

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Urea recycling and the medullary osmotic gradient

Countercurrent in the kidney

 

In addition to Na+, urea forms an important part of the medullary osmotic gradient. Urea enters the filtrate by facilitated diffusion in the ascending thin limb of the loop of Henle. As the filtrate moves on, water is usually reabsorbed in the cortical collecting duct, leaving urea behind. When filtrate reaches the collecting duct in the deep medullary region, urea, now highly concentrated, is transported by facilitated diffussion out of the tubule into the interstitial fluid of the medulla, forming a pool of urea contributes substantially to the high osmolality in the medulla.

Anti diuretic hormone (ADH), which stimulates excretion of highly concentrated urine, enhances urea transport in the medullary collecting duct. When ADH is present, urea recycling is enhanced, the medullary osmotic gradient is enhanced, and more concentrated urine can be formed.

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