The potential difficulty in obtaining accurate urine collections is one reason to consider plasma clearance methods to measure GFR. Avoiding a timed urine collection is particularly advantageous in certain populations including very young children who are not yet fully toilet trained and/or incontinent patients who would require use of a urinary catheter. The Brochner-Mortensen formula is commonly used to calculate mGFR in plasma disappearance protocols
While urinary clearance may be the most physiologic and accurate method to measure the filtering capacity of the kidney, it is time consuming and prone to errors in the measurement of urinary flows. Plasma clearance methods represent the best compromise between physiology and feasibility, both in clinical routine and research. Monitoring plasma clearance is far less cumbersome and costly, especially in older adults or diabetic patients with bladder dysfunction and young children for whom urine collection remains challenging . In addition, the single-sample plasma clearance technique is more cost-effective procedure for population studies and renal function monitoring in large cohorts of patients. If feasible, the multiple-sample plasma clearance method is probably the most effective approach to monitor intra-patient GFR changes over time in the context of clinical trials and every-day clinical practice in individual patients [7, 8].
Exogenous GFR biomarkers: Which one to choose?
Kidney clearance of inulin is often referred to as the “gold standard” measurement procedure for GFR determination. This inert fructose polymer meets all requirements for an ideal glomerular filtration marker since it is freely filtered by the glomerulus. However, inulin is expensive, difficult to handle, without standardized dosage, inaccurate for plasma clearance and currently unavailable in the United States . There is also a report of anaphylaxis following intravenous administration of inulin .
Iothalamate (125I-Iothalamate) is commonly administered as a radioactive iodine for measurement of GFR. 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 shellfish or iodinated contrast media. Different studies comparing urinary clearance of iothalamate to inulin showed a small positive bias, probably because of tubular secretion of iothalamate. Iothalamate is most commonly used in the United States. Iothalamate is also available as a cold method (iothalamate alone, without 125I). Iothalamate can also be measured by HPLC or Mass spectrometry.
Concern about radiation led to the use of the nonradioactive radiographic contrast agent iohexol. It is most often used as a bolus intravenous 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. Major limitations are the possible complexity and expense of the HPLC assay or mass spectrometry. Iohexol is the most commonly used GFR biomarker in Europe.
The 51Cr-EDTA marker is not commercially available in the United States, as well as in many European countries. Although 51Cr-EDTA is easy for measure, it is expensive and there is a requirement for storage, administration, and disposal of radioactive substances when 51Cr is used as tracer.
Diethethylenetriaminopenta-acetic acid (DTPA), is an analog of EDTA, usually labeled with 99mTc. Advantages include a short half-life (6 h) that minimizes radiation exposure and high counting efficiency of 99mTc. DTPA is thought to be freely filtered at the glomerulus, with minimal tubular reabsorption, but may undergo extrarenal elimination. Its major limitation is the potential for dissociation of 99mTc from DTPA and binding to plasma proteins, leading to underestimation in GFR. The extent of dissociation is not predictable, leading to imprecision and bias. .
Studies that compared mentioned biomarkers showed that Iohexol and 51Cr-EDTA are comparable as GFR markers for multiple-point clearance measurements, and there is an acceptable concordance between iohexol and iothalamate plasma clearance compared to the intraindividual variation of measured GFR of approximately 10% [11, 12]. One systematic review also found strong evidence suggesting that renal clearance of 51Cr-EDTA or iothalamate and plasma clearance of 51Cr-EDTA or iohexol are sufficiently accurate methods to measure GFR .
It is Prof. Delanaye’s opinion that iohexol should be regarded as a marker of choice. It is available worldwide, there are no concerns about radiation and need for nuclear medicine departments, it is safe and very stable from the analytical point of view and can be used for both plasma and urinary clearance. Finally, it is the only marker that has External Quality Assurance in Laboratory Medicine (EQUALIS) available .