Clearance Tests

Clearance is a theoretical concept and is defined as the volume of plasma from which a measured amount of substance can be completely eliminated (cleared) into the urine per unit of time. This depends on the plasma concentration and excretory rate, which, in turn, involve the glomerular filtration rate (GFR) and renal plasma flow (RPF). Clearance tests in general are the best available means for estimating mild to moderate diffuse glomerular damage (e.g., acute glomerulonephritis [AGN]). Serum levels of urea or creatinine respond only to extensive renal disease. Renal clearance is estimated by UV/P, when U is the urine concentration of substance cleared (in mg/100 ml), V is the urine flow rate (in ml/minute), and P is the plasma or serum concentration of the substance cleared (in mg/100 ml). Each of the three variables in the equation can be separately or collectively influenced by extrarenal and intrarenal conditions, thus altering the clearance result (discussed in more detail later).

Urea clearance

Urea is a nitrogen-containing waste product of protein metabolism synthesized in the liver from ammonia (derived predominantly from the metabolism of protein by intestinal bacteria) and from various amino acids (of which alanine is the most important). Urea is filtered at the glomerulus, but approximately 40% is reabsorbed in the tubules by passive back-diffusion. Thus, under usual conditions, urea clearance values parallel the true GFR at about 60% of it. However, two factors may adversely influence this situation. First, the test is dependent on rate of urine flow. At low levels (<2 ml/minute), the values are very inaccurate, even with certain correction formulas. Second, levels of blood urea change to some extent during the day and vary according to diet and other conditions.

Creatinine clearance

Creatinine is a metabolic product of creatine-phosphate dephosphorylation in muscle. It has a relatively (although not completely) constant hourly and daily production and is present at fairly stable blood levels. Excretion is by a combination of glomerular filtration (70%-80%) and tubular secretion. It usually parallels the true GFR by ± 10% (however, it can exceed inulin clearance values by 10%-40%, even in normal persons). At low filtration rates (<30% of normal), creatinine clearance values become increasingly inaccurate because the tubular secreted fraction becomes a larger proportion of total urinary creatinine (sometimes comprising up to 60% of urinary creatinine in severe renal insufficiency). Creatinine clearance has an advantage over urea clearance because creatinine has a more constant production rate than urea. Since the serum value is part of the clearance formula, less fluctuation in the serum value permits larger urine time interval collections and more reproducible results. In addition, there is less non-filtered alteration of creatinine excretion than urea. Theoretical and clinical considerations have shown creatinine clearance to be a better estimate of the GFR than urea clearance. Thus, creatinine clearance has replaced urea clearance in most laboratories.

Creatinine clearance has certain drawbacks. The reference limits (90-120 ml/minute) were established for young adults. The GFR has been shown to decrease with age; one report indicates a 4 ml/ minute decrease for each decade after age 20. Several studies found creatinine clearances as low as 50 ml/minute in clinically healthy elderly persons, and one study found values between 40% and 70% of normal. Creatinine production and excretion also diminish with age, although serum creatinine usually remains within population reference limits. Whether age-related normal values should be applied depends on whether these changes are regarded as physiologic (because they occur frequently in the population) or pathologic (because they are most likely due to renal arteriolar nephrosclerosis). Several nonrenal factors influence creatinine clearance. One major problem is shared by all clearance tests: the necessity for very accurately timed urine collections without any loss of urine excreted during the collection period. Incomplete urine collection will usually falsely decrease apparent clearance values. Another factor to be considered is serum creatinine origin from muscle and therefore dependence on muscle mass, which can vary considerably in different individuals. Decreased muscle mass (as seen in the elderly, persons with chronic renal failure, or malnourished persons) can produce a decrease in apparent clearance values. This exaggerates any decrease due to glomerular filtration decrease. Conversely, dietary meat in sufficiently large quantity can potentially increase serum creatinine and also decrease creatinine clearance. Finally, there are laboratory variables. Certain substances (e.g., ketones) can interfere with the widely used Jaffe biochemical assay of creatinine. Kinetic alkaline picrate methods (used on many automated chemistry instruments) and enzymatic methods for creatinine assay produce serum creatinine values about 20 mg/100 ml (1768 µmol/L) lower than the more nonspecific Jaffe method. This results in clearance values 20-30 ml/min higher in normal persons using these assay methods than clearance values using the Jaffe creatinine assay method. Using any method, day-to-day variation in assay of the same creatinine specimen produces differences in results of 15%-20% in most laboratories (representing ±2 standard deviations from the mean value). Variation in repeated creatinine clearance is reported to be about 20%-25% (range, 20%-34%). Also, once the creatinine clearance falls to very low levels (e.g., less than 20 ml/min), the values become so inaccurate that interpretation is very difficult. To conclude, creatinine clearance is a useful estimate of the GFR, but there are problems in collection, measurement, and body physiology (normal or disease induced) that can produce inaccuracy.

The standard urine collection time for creatinine clearance is 24 hours. Several reports indicate that a 2-hour collection period provides results that correlate reasonably well with those of 24-hour collection. The 2-hour collection should be performed in the early morning with the patient fasting, since there is a postprandial increase in creatinine blood and urine levels of 10%-40%.

Some investigators believe that creatinine clearance results are more accurate if patient weight, surface area, age, or some combination of these variables is included in the clearance computation. One frequently used correction formula is the following:

Renal Function Tests

Various nomograms and formulas have been published based on serum creatinine levels alone plus some of the variables just listed to predict creatinine clearance without requiring urine collection. However, all such formulas assume that patient renal function is stable. None has been widely accepted to date. The formula of Gault and Cockcroft seems reasonably simple and is reported to be fairly reliable:

Renal Function Tests

Clearance values for women determined by using this formula are 90% of those for men. All predictive formulas give some results that are at variance with measured clearances.

Creatinine clearance has been reported to be one of the most sensitive tests available to warn of renal failure, since the clearance falls swiftly to low levels. However, many conditions produce a fall in creatinine clearance, and if the clearance is already decreased, a further fall would be difficult to interpret. The most useful information would be provided if the clearance were known to be normal or close to normal before testing. A major drawback is the nonspecificity of a clearance decrease, which cannot be used to differentiate between the etiologies of abnormality.

Creatinine clearance determinations are most commonly used in three situations: (1) in AGN, to follow the clinical course and as a parameter of therapeutic response, (2) to demonstrate the presence of acute, strictly glomerular disease in contrast to more diffuse chronic structural damage, and (3) as a measurement of overall renal functional impairment. In AGN, there frequently (but not always) is a decrease in the GFR due to primary glomerular involvement. When this is true, the clearance tests have been used to evaluate the length of time that bed rest and other therapy are necessary. However, the erythrocyte sedimentation rate (ESR) gives the same information in a manner that is cheaper, simpler, and probably more sensitive. Therefore, the ESR seems preferable in most cases. Concerning the second category, it is not so easy to demonstrate strictly glomerular disease because many diseases reduce renal blood flow and thus the GFR. Also, some patients with AGN may have some degree of tubular damage. One situation in which clearance tests may be used to diagnostic advantage is the rare case of a young person with sudden gross hematuria but without convincing clinical or laboratory evidence of AGN. Since one expects normal clearance values in a young person, a reduced creatinine clearance rate could be some evidence in favor of nephritis.