Glomerular Filtration Rate and Renal Blood Flow
Endogenous Marker
*Creatinine* -Derived from the skeletal muscle *Creatine* -Production proportional to muscle mass and is CONSTANT -Plasma concentration is stable unless there are: >Changes in production: ->Malnutrition= Decrease ->Rhabodmyolysis (muscle breakdown)= Increase >Changes in excretion ->Decrease in Acute Kidney Injury (AKI) -The amount of creatinine in the plasma is proportional to muscle mass and is relatively CONSTANT in a healthy individual. -Plasma creatinine concentrations may change a result of altered production or altered excretion. -Another problem associated with creatinine is that there is some tubular secretion in addition to the filtration. -In a healthy individual this secretion introduces little error but the relative error increases in renal disease as GFR decreases. -As kidney disease progresses creatinine clearance overestimates GFR.
Serum Creatinine
*Endogenous marker* Creatinine -Serum creatinine correlates INVERSELY with GFR >In steady state: creatinine excretion equals production Normal values for serum creatinine in adults: -Men: 0.8-1.3 mg/dl -Women: 0.6-1.0 mg/dl (less muscle mass than man) Normal values in children with increasing muscle mass -Boys = 0.35 + age (yrs)/40 -Girls = 0.35 + age (yrs)/55 -Serum creatinine concentration increase with age. -Kidney Disease: GFR decreases >Concentration of serum creatinine will increase.
Given a GFR of 130 ml/min and a eRPF of 650 ml/min, what is the filtration fraction?
*Filtration Fraction = GFR/eRPF* Filtration Fraction = (130 ml/min)/650 ml/min) Filtration Fraction = 0.2
Glomerular Filtration Rate
*GFR* What is GFR? -GFR is the amount of plasma filtered through all the glomeruli per unit of time (typically mL/min) -Essential for determining the renal function in patients with renal disease What is the clinical significance of the GFR? -GFR is the best index of *functioning renal mass* -GFR also helps determine appropriate dosages of drugs EXCRETED by the kidney What are normal values for GFR in adults? The range of normal values for GFR are: - Men: 115-125 ml/min - Women: 90-100 ml/min -Renal replacement therapy is generally needed when GFR falls below 10-15 ml/min.
Exogenous Marker
*Inulin* -Filtered in glomerulus -No tubular transport -Gold standard in clinical research: Infused to measure -DRAWBACK: Technically challenging and expensive >Not used in clinical practice
An investigator establishes the renal clearance rates for the substances shown in the table below. For which of these substances is the greatest net secretion measured?
---- high clearance above GFR means secretion= PAH
Patient A (Problem)
-Urine flow rate (V̇) = 1.2 L/24 hour (must be complete) -Urine creatinine concentration (UCr) = 100 mg/dL -Plasma creatinine concentration (PCr) = 0.6 mg/dL --- Must take care of units!!! -If you are given a urine volume in L/day you might have to convert to mL/min. -Another common mistake is not making sure that the concentrations are in the same units. >For example, concentration might be expressed as either mg/dL or mg/mL.
Formulas Used to Estimate GFR Based on Serum Creatinine
-While serum creatinine concentration is routinely measured, 24 hour urine collection is NOT commonly ordered. -Several formulas have been developed and continue to be modified to estimate GFR on the *basis of serum creatinine*. -Note that serum creatinine concentration, age, and sex are common to both equations. -Weight is the third parameter in the Cockroft-Gault equation. -Being black and BUN concentration factor into the modification of diet in renal disease (MDRD) equation. Not need to know equation on the slide
A 55 yo man previously diagnosed with early stage renal failure secondary to unregulated hypertension is being re-evaluated. The following labs are obtained: Plasma creatinine = 4 mg/dL; Urine creatinine = 200 mg/dL; Urine flow rate = 1 ml/minWhat is the patient's rate of creatinine clearance?
1. 25 mL/min 2. 50 mL/min 3. 100 mL/min 4. 200 mL/min 5. 800 mL/min --- 2. -In this graph of serum creatinine concentration as a function of GFR we see that at a normal GFR of 120 ml/min the serum creatinine concentration is 1 mg/dL. -If GFR falls to 60 ml/min the serum creatinine concentration increases to 2 mg/dL. -This seemingly small increase in serum creatinine concentration reflects a 50% loss in functional kidney capacity. -In the ABSENCE of an explanation for an acute increase in serum creatinine due to increases creatinine production, the increase in serum creatinine concentration must reflect an acute kidney INJURY
Effective Renal Blood Flow Sample Calculation: Given an eRPF of 650 ml/min and a hematocrit of 0.5, what is the eRBF?
1. 325 ml/min 2. 433 ml/min 3. 650 ml/min 4. 975 ml/min 5. 1300 ml/min ---- 1300 ml/min= 1.3 L/min
Quantification of Renal Clearance
Clearance is the *volume of plasma* from which a substance is completely removed by the kidneys per unit *time* (mL/Min) -To calculate renal clearance one needs to know the *plasma and urine concentrations* of the substance in question and the *urine flow rate.* -In practice a patient is often asked to provide a 24 hour urine collection from which the concentration of the substance can be measured and the plasma concentration is then measured from blood drawn at the time of the office visit.
Effective Renal Blood Flow
Effective renal blood flow (eRBF) is calculated by correcting eRPF to account for the volume of red blood cells. eRBF = (eRPF)/(1.0 - hematocrit) -By correcting for the hematocrit it is possible to calculate the effective renal blood flow from the effective renal plasma flow.
Staging Chronic Kidney Disease Based on GFR
GFR is one of the best measures to chart the progression of chronic kidney disease. -Five stages are recognized from: LOW (stage 1: GFR ≥ 90 ml/min ) TO SEVERE (stage 5: GFR < 15 ml/min) -But for purposes of patient education a simplified chart shows the GFR ranges for Normal-> Kidney Disease-> Kidney Failure (dialysis needed)
GFR vs eRPF vs Renal Clearance
GFR: Substance must be FREELY filtered, not reabsorbed, and NOT secreted >Use creatinine or inulin eRPF: Substance must be FREELY filtered, not reabsorbed BUT COMPLETELY SECRETED at LOW concentrations >Paraaminohippuric acid (PAH) is used to calculate eRPF. Renal clearance: Makes NO assumptions about filtration, reabsorption, or secretion.
Hyperbolic Relationship between GFR and Serum [creatinine]
In this graph of *serum creatinine concentration* as a function of GFR we see that at a normal GFR of 120 ml/min the serum creatinine concentration is 1 mg/dL. -If GFR falls to 60 ml/min the serum creatinine concentration increases to 2 mg/dL. >This seemingly small increase in serum creatinine concentration reflects a 50% loss in functional kidney capacity. -In the absence of an explanation for an acute increase in serum creatinine due to increases creatinine production, the INCREASE in serum creatinine concentration must reflect an *acute kidney injury.* -If MORE serum creatinine then less GFR rate= LOSS of nephrons present at that point of time
Creatinine Clearance (CCr) aka Glomerular Filtration Rate
Note that calculation of the glomerular filtration rate uses exactly the same clearance equation BUT renal clearance only equals GFR when the substance is FREELY filtered, not reabsorbed, not secreted, and not metabolized by the kidney. -Creatinine (or inulin) are used to measure GFR because these endogenous and exogenous markers, respectively, meet the criteria for measuring GFR. -An adequate collection of urine creatinine is 15-20 mg/kg/day for women and 20-25 mg/kg/day for men. -Using GFR calculations based on plasma creatinine concentration are quite reliable within the same individual and can be used to longitudinally monitor GFR. -1/SCr vs. time is sometimes used to predict the course of renal failure.
Which of the following best depicts the volume of glomerular filtrate produced by an adult per day?
PIC! Daily urine excretion is HIGHLY variable but typically falls in the range of 1-2 L -GFR will work with 47 gallons per day total! b is answer
Rate of GFR decline impacts onset of End-Stage Renal Disease
Rate of glomerular filtration rate (GFR) DECLINE in normal and in hypothetical patients with onset of progressive renal disease at age 25. -The course of GFR decline with normal aging (top curve) is based on a cross-sectional study of iothalamate clearance in 357 patients aged 17 to 70 years. -Note that a GFR loss of 2 mL/min/year or greater beginning at age 25 can *result in end-stage renal disease within a normal lifespan*. -Note also that small differences in rates of GFR decline can result in LARGE differences in time to onset of end-stage renal disease.
Effective Renal Plasma Flow (eRPF)
The amount of plasma flowing to the parts of the kidney that function in the production of urine. -Measured using the clearance of *para-aminohippuric acid (PAH)*. >With knowledge of the serum and urinary concentrations of PAH and the urinary flow rate it is possible to estimate the total blood flow through the kidneys -Freely filtered, completely secreted at low plasma concentrations, and NOT reabsorbed. -Produced in the body in very small amounts: end product aromatic amino acid metabolism. -Not used clinically; must be infused to steady-state (IV).
Effective Renal Plasma Flow (Renal Clearance of PAH)
The calculation of PAH clearance is identical to any other clearance determination.
Changes in GFR with Age
This table is included to illustrate the declines in GFR noted with aging. -Note that under the age of 40 nearly 90% of the test subjects had GFRs over 80 mL/min. -For the population 70 years or older the situation was nearly opposite with approximately 87% having a GFR of under 80 mL/min
Typical Clearance Values
This table reveals the wide range of clearance values that are noted for different compounds. -*Albumin* is very poorly filtered so there is very little in the urine and essentially NO renal clearance. -Glucose is freely FILTERED but is avidly REABSORBED to such an extent that the typical clearance value in a healthy individual is also ZERO >Appearance of glucose in the urine of poorly regulated *diabetics* results when tubular transporters are SATURATED -Sodium and water clearance values are LOW but greater than zero indicating that EXCESS dietary sodium and water are REMOVED by the kidneys. >Both of these values can be expected to increase as the dietary load of either sodium or water increases. -Urea is a waste product produced through the metabolism of nitrogenous substances. >The kidney clears ALL of the urea found in the 55 ml of plasma per minute. -Inulin and creatinine are *freely filtered and not reabsorbed.* >The slight difference in the clearance values for these two compounds can be explained by the observation that while inulin is not secreted, there is a small amount of creatinine secretion into the tubule. -P-Amino-hyppurate (PAH) has the *highest clearance* rate from the plasma. >PAH is *freely filtered and secreted *into the tubule. >At low plasma concentrations essentially all of the PAH that is not filtered at the glomerulus is secreted from the peritubular capillaries into the proximal convoluted tubule.
Measurement of GFR based on Exogenous or Endogenous Markers
To estimate GFR, one must measure the renal clearance of a substance that is: 1. *freely filtered* at the glomerulus 2. has a STABLE plasma concentration (Partially filtered/Reabsorbed) 3. NOT reabsorbed, secreted, or metabolized by the kidney
Renal Clearance
What is renal clearance? -Clearance is the volume of plasma completely cleared of a compound in given time >Units typically milliliters per minute (mL/min) What is the clinical significance of the renal clearance? -Clearance is an index of FUNCTIONING renal mass What are normal values for renal clearance? -Renal clearance rates are highly depended on the substance being considered but range from 0 ml/min to 650 ml/min (per kidney)
Effective Renal Plasma Flow: Sample Calculation
What is the effective renal plasma flow if the urine PAH concentration is 13 mg/ml, the plasma PAH concentration is 0.02 mg/ml and the urine flow rate is 1.0 ml/min?
