4/28/15

Dr. Chris Doumen

Collin County Community College

BIOL 2402 Renal Function

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Renal Clearance and GFR

Basic functions of the nephrons is expressed as follows:

Amount excreted in Urine = Glomerular Filtration amount reabsorbed + amount secreted

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Renal Clearance and GFR Amount excreted in Urine per time unit = (Glomerular Filtration per time unit) – (amount reabsorbed per time unit) + (amount secreted per time unit) Thus, if a component is freely filtered, and is neither secreted nor reabsorbed, one obtains an excretion rate which then equals the glomerular filtration rate. In addition, this component should be metabolically inert ( not metabolized anywhere in the body) to keep the concentrations steady. INULIN is such a component ( = plant polysaccharide, extracted from the Jerusalem Artichoke). 3

Renal Clearance and GFR The following relationship holds true when considering what is present in the blood and what ends up in the urine : The concentration of a substance X in the blood multiplied by the amount removed by the kidneys per time unit (= clearance) has to be equal to the concentration in the urine of substance X times the volume of urine formed per time unit . Conc. of X in systemic blood plasma

Conc. of X in urine

Volume of urine formed in given time

Px x Cx = Ux x V Clearance

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Renal Body Clearance Water Content and GFR By re-arranging we obtain : Conc. of X in urine

Cx = Ux x V Clearance

Px

Volume of urine formed in given time Conc. of X in systemic blood plasma

Since concentrations are measured in mg/ml and volume of urine formed in a given time as ml/min, clearance is expressed as C = (mg/ml) x (ml/min) /(mg/ml) = ml/min

Renal Clearance and GFR Concentration in afferent blood

How much removed from blood per time unit (= Clearance)

Concentration in urine

Thus clearance becomes equal to GFR !

Urine formed per time unit

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Renal Clearance and GFR Example calculation for Inulin Plasma conc. : 0.3 mg/ml Urine conc. : 30 mg/ml Urine rate : 1.25 ml/min

Inulin Clearance = (Uin x V) / Pin = (30 mg/ml x 1.25 ml/min) / 0.3 mg/ml = 125 ml inulin cleared from plasma/min

= GFR 7

Drawbacks of INULIN

•  Most reliable method of measuring GFR, but not clinically useful. •  Inulin must be administered by IV to get relatively constant plasma levels. •  Chemical analysis of inulin in plasma and urine is technically demanding. •  Problems of IV infusion of GFR marker avoided by using an endogenous substance with inulin-like properties – CREATININE. 8

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CREATININE •  Creatinine is a by product of muscle metabolism ( not to be confused with creatine) and produced at a fairly constant rate of 2 % of muscle mass /day. •  The use of creatinine avoids IV infusion; just requires venous blood and urine samples. •  It is easily measured by colorimetric spectroscopic means: thus cheap, easy, and fairly reliable. The calculations are similar.

CCr = UCr x V PCr

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CREATININE Problems with use of creatinine : •  Creatinine itself is secreted by tubules, so might overestimate GFR by 20% in humans. •  However, colorimetry methods used to measure creatinine overestimate creatinine concentrations. •  Luckily, these 2 errors cancel each other out, and calculated creatinine clearance ≈ inulin clearance. •  Must remember to take into account if person has muscle disease/damage, or has had large quantities of meat to eat. •  Usually measure over 24 hr period to get reliable results and take samples before breakfast. 10

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CREATININE Creatinine levels should be measured in blood samples and urine samples to get a good indication of kidney function. The reasons are obvious if we look at the diagram below

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RENAL PLASMA FLOW Another important indicator of kidney function is Renal plasma Flow = how much plasma is delivered to the nephrons for filtration. Most substances are NOT cleared completely on 1st pass through the kidney – some amount goes out in venous blood. In this image, only 2 out of 6 are filtered; 4 out of 6 move into the Peritubular capillaries ! 12

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RENAL PLASMA FLOW Theoretically, if a substance is complete cleared from the plasma in one pass, the clearance of that substance is equal to the total renal plasma flow In such case, renal clearance of X = arterial renal plasma flow. PAH (p-aminohippurate ) is such a substance

RPFPAH x PPAH = UPAH x V Delivery for filtration to kidney

Conc. of PAH in systemic blood plasma

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RENAL PLASMA FLOW In such case, renal clearance of X = arterial renal plasma flow. PAH (p-aminohippurate ) is such a substance

RPFPAH x PPAH = UPAH x V Delivery for filtration to kidney

Conc. of PAH in systemic blood plasma

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RENAL PLASMA FLOW •  PAH is an organic acid that is not usually present in the body, so it is given by IV infusion. •  It is both filtered and secreted so that almost none is left in the renal vein. In this example: PPAH = 0.1 mg/ml UPAH = 60 mg/ml V = 1 ml/min RPF = (60 x 1)/0.1 = 600 ml/min

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RENAL PLASMA FLOW •  In reality, clearance of PAH is not 100 % but 90 % •  To correct for this we calculate a normal RPF and then divide by 0.9 •  Thus for the previous example : RPF = 600 ml/min Corrected = 600/0.9 Real RFP = 666 ml/min

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Filtration Fraction •  This now can be used to obtain the Filtration Fraction, which is defined as follows : Glomerular Filtration Rate FF = Renal Plasma Flow •  Since fraction of plasma is roughly equal to (1 – Hct), the Renal blood flow can be calculated as RBF = RPF/ (1-Hct)

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Filtration Fraction

•  Thus for the previous example : FF = (125 ml/min) / (666 ml/min) = 0. 187 or close to 20 % •  And if we assume a normal Hct to be 45 %, then RBF = 666/(1-.45) = 666/0.55 = 1210 ml/min

•  Thus ~ 20 % of the plasma that enters the glomeruli is typically filtered •  And the kidneys receive close to 25 % of blood flow 18

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GFR and CLEARANCE VALUES •  Measuring clearance means you measure OVERALL nephron function i.e. all ~2 million nephrons in both kidneys. •  This gives the SUM of ALL transport processes occurring along nephrons. •  So, no information about precise sites and mechanisms of transport. •  But each individual solute has its own Clearance and this provides information on how the nephrons handle each component. 19

GFR and CLEARANCE VALUES Recall this relationship : Amount excreted in Urine = Renal (Plasma ) Clearance = Glomerular Filtration - amount reabsorbed + amount secreted What additional information does this give us about a solute ? •  If the plasma clearance = GFR, then that substance is neither reabsorbed nor secreted. •  If the plasma clearance > GFR, than it indicates that the solute is filtered and secreted. •  If the plasma clearance < GFR, it indicates that the solute is filtered and reabsorbed.

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Tubular Reabsorption Examples GFR = 125 ml/min

Glucose : PG = 1 mg/ml V = 1 ml/min

UG = 0 mg/ml

Glucose plasma Clearance = (UG x V )/ PG = 0 ml/min Glucose Filtered Load = GFR x PG = 125 mg/min Tubular Reabsorption = Filtered Load - Excreted Load = (GFR x PG ) - (UG x V ) = 125 mg/min

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Tubular Reabsorption Examples GFR = 125 ml/min

Sodium : PG = 140 microg/ml UG = 70 microg/ml V = 1 ml/min Sodium plasma Clearance = (UG x V )/ PG = 0.5 ml/min Sodium Filtered Load = GFR x PG = 17500 ug/min Tubular Reabsorption = (GFR x PG ) - (UG x V ) = 17430 ug/min

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AZOTEMIA Azotemia is a condition known as abnormally high levels of nitrogen-containing compounds such as urea, creatinine and other nitrogen-rich compounds in the blood. It is largely related to insufficient filtering of blood by the kidneys. We will briefly discuss aspects of urea and creatinine.

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Blood Urea Nitrogen •  Blood urea nitrogen (BUN) measures the amount of urea nitrogen, a waste product of protein metabolism, in the blood. •  Urea is formed by the liver and carried by the blood to the kidneys for excretion. •  Because urea is cleared from the bloodstream by the kidneys, a test measuring how much urea nitrogen remains in the blood can be used as a test of renal function. •  However, there are many factors besides renal disease that can cause BUN alterations, including protein breakdown, hydration status, and liver failure. 24

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Blood Urea Nitrogen Increased BUN levels means more urea stays behind in the blood (less urea is cleared by the kidneys) and thus may indicate •  Impaired renal function •  Poor renal perfusion due to low cardiac Output An elevated BUN may also be caused by: * Dehydration (lack of fluid to excrete urea with) * Shock * Hemorrhage into the gastrointestinal tract (digested blood is a source of urea) * Acute myocardial infarction * Stress * Excessive protein intake or protein catabolism 25

Blood Urea Nitrogen A decreased BUN may be seen in: * Liver failure * Malnutrition * Anabolic steroid use * Overhydration, Which can result from prolonged intravenous fluids * Pregnancy (due to increased plasma volume) * Impaired nutrient absorption An assessment of the BUN is used as a gross index of glomerular function. Normal values : •  Adult: 7-20 mg/100 ml; men may have slightly higher values than women •  Pregnancy: values decrease about 25% Because the BUN is affected by the patient's hydration status, it is a less sensitive indicator of declining renal function than a creatinine clearance test. 26 A BUN of over 100 mg/dl is a panic value.

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Blood Creatinine Levels •  Measuring serum creatinine is a useful and inexpensive method of evaluating renal dysfunction (used to measure GFR) ! •  Remember that Creatinine is a non-protein waste product of creatine phosphate metabolism by skeletal muscle tissue. •  Creatinine production is continuous and is proportional to muscle mass.

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Blood Creatinine Levels •  Creatinine is freely filtered and therefore the serum creatinine level depends on the Glomerular Filtration Rate (GFR). •  Renal dysfunction diminishes the ability to filter creatinine and the serum creatinine rises. •  If the serum creatinine level doubles, the GFR is considered to have been halved. A threefold increase is considered to reflect a 75% loss of kidney function.

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Blood Creatinine Levels Reference values for serum creatinine (see dotted line in previous figure). •  Adult males: 0.8 - 1.4 mg/dl: values are slightly higher in males due to larger muscle mass •  Adult females: 0.6 - 1.1 mg/dl: creatinine clearance is increased in pregnancy, resulting in lower serum levels •  Children: 0.2 - 1.0 mg/dl: slight increases with age because values are proportional to body mass •  A panic value for creatinine is 10 mg/dl in nondialysis patients. Increased serum creatinine levels are seen in: * Impaired renal function * Chronic nephritis * Urinary tract obstruction * Muscle diseases such as gigantism, acromegaly, and myasthenia gravis * Congestive heart failure 29 * Shock

Blood Creatinine Levels Decreased creatinine levels may be seen in: •  the elderly, persons with small stature, decreased muscle mass, or inadequate dietary protein. •  Muscle atrophy can also result in decreased serum creatinine level.

Unlike the BUN, the serum creatinine level is not affected by hepatic protein metabolism. •  The serum creatinine level does not rise until at least half of the kidney's nephrons are destroyed or damaged. •  Because creatinine levels rise and fall more slowly than BUN levels, creatinine levels are often preferred to monitor renal function on a long-term basis. 30

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Blood BUN: Creatinine Levels Abnormalities in the BUN: Cr ratio are often referred to Azotemia diseases. Three main azotemia issues are

•  Pre-renal Azotemia •  Intra-renal Azotemia •  Post-renal Azotemia

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Blood BUN: Creatinine Levels

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Pre-renal Azotemia •  Prerenal azotemia is caused by a decrease in blood flow (hypoperfusion) to the kidneys. •  However, there is no inherent kidney disease. •  It can occur following hemorrhage, shock, volume depletion, congestive heart failure, adrenal insufficiency, and narrowing of the renal artery among other things.

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Pre-renal Azotemia During normal conditions •  Most of the Creatinine is filtered and ends up in the filtrate. Once in the nephron, it cannot go back to the peritubular capillaries ( in fact some of it also secreted into the nephrons) •  Urea is filtered as well , but because it is hydrophobic, some of it will leak back into the peritubular capillaries •  Thus, more BUN (urea) will be left in the peritubular capillaries compared to creatinine; under nomral conditions, the ratio of BUN: Cr ratio is about 10 : 1 34

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E. a.

Most of creatinine is filtered, some secreted Once filtered , it will remain in nephron

Cr

A. a.

Most of Urea is filtered as well, but some will ‘leak’ back into the peritubular capillaries

Urea Under normal conditions, the BUN: Cr ratio in the blood will be 10:1

Pre-renal Azotemia When pre-renal azotemia develops, the hypo-perfusion results in a RBF and GFR drop The filtrate will move slower through the nephrons, and more BUN (urea) will escape back into the peritubular capillaries The result is a higher blood BUN : Cr ratio; usually > 20:1

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Intra-renal Azotemia When the filtration apparatus is damaged or clogged up (glomerulus damaged), BUN and creatinine are equally NOT filtered and remain in the blood. Thus, BUN will not get the advantage to “leak” back into the peritubular capillaries and the ratio of BUN: Cr in the blood will drop below 10:1 Values of BUN : Cr