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 80รข€“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,
