MEASUREMENT OF GLOMERULAR FILTRATION RATE

Several drugs and endogenous substances have been used as markers to measure GFR. These markers are carried to the kidney by the blood via the renal artery and are filtered at the glomerulus. Several criteria are necessary to use a drug to measure GFR:

1. The drug must be freely filtered at the glomerulus.

2. The drug must not be reabsorbed nor actively secreted by the renal tubules.

3. The drug should not be metabolized.

4. The drug should not bind significantly to plasma proteins.

5. The drug should not have an effect on the filtration rate nor alter renal function.

6. The drug should be nontoxic.

7. The drug may be infused in a sufficient dose to permit simple and accurate quantifition in plasma and

in urine.

Therefore, the rate at which these drug markers are filtered from the blood into the urine per unit of time reflects the glomerular filtration rate of the kidney. Changes in GFR reflect changes in kidney function that may be diminished in uremic conditions.

Inulin, a fructose polysaccharide, fulfills most of the criteria listed above and is therefore used as a standard reference for the measurement of GFR. In practice, however, the use of inulin involves a time-consuming procedure in which inulin is given by intravenous infusion until a constant steady-state plasma level is obtained. Clearance of inulin may then be measured by the rate of infusion divided by the steady-state plasma inulin concentration. Although this procedure gives an accurate value for GFR, inulin clearance is not used frequently in clinical practice.The clearance of creatinine is used most extensively as a measurement of GFR. Creatinine is an endogenous substance formed from creatine phosphate during muscle metabolism. Creatinine production varies with the age, weight, and gender of the individual. In humans, creatinine is filtered mainly at the glomerulus, with no tubular reabsorption. However, a small amount of creatinine may be actively secreted by the renal tubules, and the values of GFR obtained by the creatinine clearance tend to be higher than GFR measured by inulin clearance. Creatinine clearance tends to decrease in the elderly patient. As mentioned in , the physiologic

changes due to aging may necessitate special considerations in administering drugs in the elderly.

Blood urea nitrogen (BUN) is a commonly used clinical diagnostic laboratory test for renal disease. Urea is the end product of protein catabolism and is excreted through the kidney. Normal BUN levels range from 10 to 20 mg/dL. Higher BUN levels generally indicate the presence of renal disease. However, other factors, such as excessive protein intake, reduced renal blood flow, hemorrhagic shock, or gastric bleeding, may affect increased BUN levels. The renal clearance of urea is by glomerular filtration and partial reabsorption in the renal tubules. Therefore, the renal clearance of urea is less than creatinine or inulin clearance and does not give a quantitative measure of kidney function.

SERUM CREATININE CONCENTRATION AND CREATININE CLEARANCE

Under normal circumstances, creatinine production is roughly equal to creatinine excretion, so the serum creatinine level remains constant. In a patient with reduced glomerular filtration, serum creatinine will accumulate in accordance with the degree of loss of glomerular filtration in the kidney. The serum creatinine concentration alone is frequently used to determine creatinine clearance, Cl Cr. Creatinine clearance from the serum creatinine concentration is a rapid and convenient way to monitor kidney function. Creatinine clearance may be defined as the rate of urinary excretion of creatinine/serum creatinine. Creatinine clearance can be calculated directly by determining the patient's serum creatinine concentration and the rate of urinary excretion of creatinine. The approach is similar to that used in the determination of drug clearance. In practice, the serum creatinine concentration is determined at the midpoint of the urinary collection period and the rate of urinary excretion of creatinine is measured for the entire day (24 hr) to obtain a reliable excretion rate. Creatinine clearance is expressed in mL/min and serum creatinine concentration in mg/dL or mg%. Other Cl Cr methods based solely on serum creatinine are generally compared to the creatinine clearance obtained from the 24-hour urinary creatinine excretion. The following equation is used to calculate creatinine clearance in mL/min when the serum creatinine

          EQUATION 1

where C Cr = creatinine concentration (mg/dL) of the serum taken at the 12th hour or at the midpoint of the urine-collection period, V = volume of urine excreted (mL) in 24 hours, C u = concentration of creatinine in urine (mg/mL), and Cl Cr = creatinine clearance in mL/min.

Creatinine is eliminated primarily by glomerular filtration. A small fraction of creatinine also is eliminated by active secretion and some nonrenal elimination. Therefore, Cl Cr values obtained from creatinine measurements overestimate the actual glomerular filtration rate. Creatinine clearance has been normalized both to body surface area, using 1.73 m2 as the average, and to body weight for a 70-kg adult male. Creatinine distributes into total body water, and when clearance is normalized to a standard V D, similar drug half-lives in adults and children correspond to identical clearances.

Creatinine clearance values must be considered carefully in special populations such as the elderly, obese, and emaciated patients. In elderly and emaciated patients, muscle mass may have declined, thus lowering the production of creatinine. However, serum creatinine concentration values may appear to be in the normal range, because of lower renal creatinine excretion. Thus, the calculation of creatinine clearance from serum creatinine may give an inaccurate estimation of the renal function. For obese patient, generally defined as patients more than 20% over ideal body weight, IBW, creatinine clearance should be based on ideal body weight. Estimation of creatinine clearance based on total body weight, TBW, would exaggerate the Cl Cr values in the obese patient. Women with normal kidney function have smaller creatinine clearance values than men, approximately 80–85% of that in men with normal kidney function.

For the purpose of dose adjustment in renal patients, normal creatinine clearance is generally assumed to be between 100 and 125 mL/min per 1.73 m2 for a subject of ideal body weight: for a female adult, Cl Cr = 108.8 ± 13.5 mL/1.73 m2, and for an average adult male, Cl Cr = 124.5 ± 9.7 mL/1.73 m2.

Creatinine clearance is affected by diet and salt intake. As a convenient approximation, the normal clearance has often been assumed by many clinicians to be approximately 100 mL/min.

Calculation of Creatinine Clearance from Serum Creatinine Concentration

EQUATION 2

The problems of obtaining a complete 24-hour urine collection from a patient, the time necessary for urine collection, and the analysis time preclude a direct estimation of creatinine clearance. Serum creatinine concentration,C Cr, is related to creatinine clearance and is measured routinely in the clinical laboratory. Therefore, creatinine clearance, Cl Cr, is most often estimated from the patient's C Cr. Several methods are available for the calculation of creatinine clearance from the serum creatinine concentration. The more accurate methods are based on the patient's age, height, weight, and gender. These methods should be used only for patients with intact liver function and no abnormal muscle disease, such as hypertrophy or dystrophy.

Moreover, most of the methods assume a stable creatinine clearance. The units for Cl Cr are mL/min. ADULTS

The method of shown in Equation 2. is used to estimate creatinine clearance from serum creatinine concentration. This method considers both the age and the weight of the patient. For males,