Glomerular Filtration Rate

The glomerular filtration rate (GFR) is the rate at which an ultrafiltrate of plasma is produced by glomeruli per unit of time. It is the best estimate of the number of functioning nephrons or functional renal mass. Accurate measurement of GFR is time-consuming and expensive, but a number of filtered substances may be measured to estimate GFR, including blood urea nitrogen (BUN) and serum creatinine and measurement of creatinine clearance by the kidney.

Serum Creatinine

Creatinine, an end product of muscle metabolism, is excreted solely by the kidneys. Its production rate is proportional to the patient's muscle mass and is, therefore, relatively stable over time. In adults, the normal range for plasma creatinine is 0.8 to 1.3 mg/dL (70 to 114 mmol/L) in men and 0.6 to 1.0 mg/dL in women. However, a creatinine level of 1.4 may represent normal renal function in a muscular man but may represent markedly decreased function in a cachectic person.
Creatinine excretion can be used to estimate the GFR because creatinine is freely filtered at the glomerulus and is not reabsorbed. However, tubular secretion of creatinine does occur; although not clinically significant when renal function is normal, it accounts for an increasingly greater percentage of urinary creatinine as serum creatinine concentrations increase. As the true GFR falls to 40 mL/min (as measured by inulin clearance), the absolute amount of creatinine secreted can rise by more than 50%, accounting for as much as 35% of urinary creatinine.
The plasma creatinine concentration (PCr) varies inversely with the GFR. The relation between plasma creatinine and GFR is not linear. Figure 163-1 demonstrates that significant renal function is lost before the PCr rises and that with early renal dysfunction, relatively small changes in PCr reflect large diminutions of GFR. In advanced renal failure, large changes in PCr reflect relatively small changes in GFR.
PCr may also rise acutely without a change in GFR due to decreased creatinine secretion or interference with the plasma assay. At physiologic pH, creatinine is an organic cation and is secreted by the organic cation secretory pump in the proximal tubule. This pump may be inhibited by other organic cations, notably trimethoprim and the H2-blocker cimetidine. PCr may rise by as much as 0.4 to 0.5 mg/dL (35 to 44 mmol/L) but reverses on discontinuation of the drug. When PCr is measured by the Jaffe reaction, which involves complexing creatinine with alkaline picrate and measuring a colorimetric change, chromogens other than creatinine may be measured in addition to the PCr. The accumulation of acetoacetate in diabetic ketoacidosis may cause a false rise in PCr of 0.5 to 2 mg/dL (44 to 176 mmol/L) or more. Cefoxitin and flucytosine may produce a similar effect. When an enzymatic method is used to measure PCr, spurious noncreatinine chromogens are not measured, thus permitting accurate quantification of the creatinine concentration. However, patients receiving intravenous lidocaine or hyperalimentation fluid containing proline may have an increase in the PCr of up to 0.3 mg/dL. N-acetylcysteine has been reported to interfere with the creatinine assay such that serum creatinine is underestimated.

Blood Urea Nitrogen

The BUN also varies inversely with the GFR but is a less useful marker of changes in the GFR than the PCr because the BUN can change independent of the GFR. Unlike creatinine, the rate of urea production is not constant and increases with a high-protein diet and tissue breakdown due to hemorrhage, trauma, or glucocorticoids. A low-protein diet, malnutrition, and liver disease may lower the BUN without a change in the GFR (Table 163-2). Urea is reabsorbed in the proximal and distal nephrons. Urea reabsorption in the medullary collecting duct is influenced by the patient's volume status. In the absence of antidiuretic hormone (ADH), the medullary collecting duct is relatively impermeable to urea, and hence urea reabsorption is minimal at this site. However, in volume depletion, ADH is stimulated, the medullary collecting duct's permeability to urea rises, and urea reabsorption increases, with the result that the BUN rises out of proportion to the decline in GFR.

Creatinine Clearance

Creatinine clearance, the most useful clinical estimate of GFR, is defined as the volume of plasma that is cleared of creatinine by the kidney per unit of time:

creatinine clearance = U creat conc x V / P creat conc

Creatinine clearance is usually determined from a 24-hour urine collection; shorter collections give less accurate results. The accuracy of the creatinine clearance may be limited by an incomplete urine collection and increasing creatinine secretion. The completeness of a timed collection can be estimated by calculating the total amount of creatinine in the urine specimen and comparing it to the predicted creatinine excretion. Under age 50, men normally excrete 20 to 25 mg/kg lean body weight/day (177 to 221 mmol/kg), whereas women excrete 15 to 20 mg/kg lean body weight/day (133 to 177 mmol/kg).
Because creatinine is also secreted by the proximal tubule, in addition to being freely filtered, creatinine clearance overestimates GFR. As previously noted, the percentage contribution of creatinine secretion increases with declining renal function, thus increasing the error. Inhibition of creatinine secretion by cimetidine may minimize the overestimation of GFR. A loading dose of 1200 to 2000 mg (with doses adjusted for renal insufficiency) is given on day 1, followed by 400 mg for 3 to 4 days. A 1.5-hour urine collection is then obtained. This has been shown to be as accurate as a 24-hour collection.
An alternative method for estimating GFR in patients with moderate to severe renal dysfunction is to take the average of the creatinine and urea clearances. The clearance of creatinine overestimates the GFR due to creatinine secretion, but the urea clearance underestimates GFR, as about 40% to 50% of the filtered urea is reabsorbed. Because the magnitude of the two errors tends to be similar, the average of both clearances is more accurate.

Direct Measurement of the GFR

To measure GFR accurately, a marker is required that is filtered but not secreted, reabsorbed, or metabolized, such that the GFR is equal to the urinary clearance of the marker after its intravenous infusion. Inulin is a fructose polymer that is not metabolized and is cleared only by glomerular filtration. A constant intravenous infusion with carefully timed urine collections, therefore, allows an accurate determination of the GFR. 131I-iothalamate has similar properties to inulin. The major drawback to both inulin and 131I-iothalamate clearances is that they require constant intravenous infusions and are thus time-consuming and expensive. For this reason, they are generally used only as research tools when an accurate measurement of GFR is required.
Nuclear medicine techniques are also available to measure GFR. 99mTechnetium diethylene triaminopentaacetic acid (DTPA) is excreted by glomerular filtration, and GFR can be estimated after a single injection of radioisotope by estimating the amount in plasma samples obtained 60 and 180 minutes after injection. Camera-based clearances are more commonly used because of their convenience. This is done by measuring the increase in counts over the kidney for 3 to 6 minutes and doing a mathematical analysis that takes into account renal accumulation of radioisotope, tissue depth, and background counts. Correlation coefficients for camera-based techniques versus the reference methods have ranged from 0.48 to 0.97. A small fraction of the radiopharmaceutical may be bound to protein, but this is not a problem for routine clinical applications. The extraction fraction (the percentage of the agent extracted with each pass through the kidney) is about 20%; hence, impaired renal function adversely affects the utility of this method.
Recently, iohexol has been evaluated as an exogenous marker of GFR. Iohexol, a nonionic, low osmolar radiocontrast agent, may be measured in minute quantities by high-performance liquid chromatography. Extrarenal elimination is trivial. GFR may be determined by single-sample iohexol clearance 3 to 4 hours after the injection of 3 to 5 mL of iohexol. Initial investigations have suggested that renal clearance may be accurately measured in patients with GFRs as low as 2 to 3 mL/min.

Estimation of Renal Blood Flow

Under normal conditions, the kidneys receive about 25% of the cardiac output. Experimentally, renal blood flow (RBF) is calculated by measuring paraaminohippurate (PAH) clearance in a fashion similar to creatinine or inulin clearance. PAH is an organic acid that is both filtered at the glomerulus and extensively secreted by the proximal tubule, resulting in a first-pass clearance (up to a saturation concentration) that approaches 100%. Administering PAH by constant infusion to achieve a steady-state plasma level and carefully collecting timed urine samples allows for the calculation of RBF. 99mTc-mercaptoacetyltriglycine (MAG3) and iodine-123 orthoiodohippurate (OIH) are highly protein bound and, therefore, are not cleared by glomerular filtration but are cleared mainly by the proximal tubule. Clearance of these agents has been highly correlated to PAH estimation of RBF. Reliable estimation of RBF has not been achieved using 99mTc-DTPA. 131I-OIH produces a high-energy 364-keV photon that has suboptimal imaging characteristics; moreover, a high dose of radiation is delivered to the kidney. 123I-OIH is an excellent radiopharmaceutical but is limited by its 13-hour half-life and is no longer available in the United States. 99mTc-MAG3 has a much higher extraction fraction than 99mTc-DTPA and hence provides better scintigraphic images, especially in patients with impaired renal function. It is the radiopharmaceutical of choice in the presence of impaired renal function.