Clearance methods

Urinary Clearance. Urinary clearance is the most direct method for measurement of GFR.  Clearance is calculated as the urine concentration of the exogenous or endogenous filtration marker, multiplied by the volume of the timed urine sample, and divided by the average plasma concentration during the same time period.

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Measurement of creatinine or urea clearance is possible to perform in every clinical center. A long collection period, generally between 6 and 24 hours, is used to avoid the requirement for water loading.

If the patient is in steady state, a single blood sample obtained either at the beginning or end of the collection period may be used to represent the average serum concentration during the urine collection. If the patient is not in steady state, use of the average of the serum concentrations at the beginning and end of the collection period should provide a better estimate of the average concentration.

Timed collections are subject to errors due to inaccurate recording of time and completion of urine collection. Averaging over repeated measurements may minimize the impact of error, but is quite burdensome to the patient. 

It is not possible to perform urinary clearance of cystatin C as it is catabolized and then reabsorbed by the tubules.

Measurements of urinary clearance of exogenous filtration marker are only possible in centers that have been set up to perform such procedures. In general, the protocol is to administer the filtration marker, wait for equilibrium to develop, and then collect the urine over multiple (generally 2-4) 20-30 minute urine collections, with blood samples before and after each 20-30 minute period. Clearance is computed for each urine collection period, and the results are averaged.

Advantages include a relatively short duration of time and comparison of the individual periods allows for an assessment of quality of test results. The marker is administered by intravenous (IV) bolus or subcutaneous bolus injection.

Spontaneous voiding limits its use in populations with impaired urinary incontinence or retention, such as the elderly or children with urinary tract abnormalities.

The protocol is prone to error, particularly related to complete collection of the urine and urinary retention. As such, overall reliability is highly variable across centers, thus limiting its interpretation for any one value.

Plasma clearance. There is increasing interest in measuring plasma clearance to avoid inconvenience and errors from timed urine collections.

In principle, plasma clearance should be unbiased and more precise compared with urinary clearance except for markers that undergo extra-renal elimination. GFR is calculated from plasma clearance following a bolus IV injection of an exogenous filtration marker, with clearance computed from the amount of the marker administered using the area under the curve of plasma concentration over time.

The decline in serum levels is secondary to the immediate disappearance of the marker from the plasma into its volume of distribution (fast component) and to renal excretion (slow component).  This is best estimated using a two-compartment model that requires blood sampling early (usually 2-3 time points until 60 minutes) and late (1-3 time points from 120 minutes forward), but equations have been developed to use only the late time points.26,27

The major disadvantage of plasma clearance is the length of time required (~4 hours at high levels of GFR and 8-24 hours at low levels of GFR).28 Shorter time periods may lead to overestimation of GFR.29 Second, a large volume of distribution, such as edematous conditions, prolongs the initial component leading to an overestimation of GFR.30

Exogenous filtration markers

Iothalamate. Iothalmate is commonly administered as a radioactive iodine label for ease of assay after small doses, but can also be administered in its non-radioactive form and measured using high performance liquid chromotography (HPLC) without impact on its filtration properties. In the radioactive form, it is most commonly administered using bolus subcutaneous injection.

To block thyroidal uptake, cold iodine is administered at the time of 125I-iothalmate administration, thus precluding its use in people with known allergies to iodine, such as iodine in shellfish or iodinated contrast media.

Iohexol. Concern about radiation led to the use of a non-radioactive radiographic contrast agent, iohexol. Iohexol is administered most often using bolus IV injection for plasma clearance, but could be used for urinary clearance, as well.

Other advantages include low expense, wide availability, stability in biologic fluids, and rare adverse reactions when given as a small dose (5 mL 300 mg/ml iodine when assayed with a sensitive HPLC assay). Major limitations are the complexity and expense of the HPLC assay.

Diethethylenetriaminopenta-acetic acid (DTPA). DTPA is usually labeled with 99mTc. Advantages include a short half-life (6 hours) that minimizes radiation exposure, high counting efficiency of 99mTc, and is commonly used in most nuclear medicine departments.

Its major limitation is the potential for dissociation of 99mTc from DTPA and binding to plasma proteins. The extent of dissociation is not predictable, leading to imprecision as well as bias. In addition, chelating kits and technetium generators are not standardized in the U.S., making comparisons of measured GFR among different institutions difficult.