PRESENTED BY
PIERRE DELANAYE

Presentation Summary

Written by Jasna Trbojevic-Stankovic
Reviewed by Pierre Delanaye

Glomerular filtration rate (GFR) is typically considered the parameter that best reflects overall kidney health and kidney function. Therefore, a reliable assessment of GFR is of paramount importance in clinical practice as well as epidemiological and clinical research settings. As stated in the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, additional tests for GFR assessment are needed in specific populations where creatinine-based equations are unreliable [1, 2].
The importance of appropriate measurement of GFR in specific situations and individuals
GFR when measured adequately is the most precise measure of glomerular function and can be useful to individualize therapy among patients with chronic kidney disease (CKD). However, errors by GFR estimating equations can be quite large. Specific situations, which are critical hinge on the accurate estimation of GFR include starting dialysis, extreme body size, dosing a potentially nephrotoxic drug or a drug that may have other toxicity due to impaired pharmacokinetics, sarcopenic individuals, young women, patients with decompensated cirrhosis, hyperfiltration states or living kidney donor selection [3].

In order to have a reference measure of renal function that is independent of clinical practice at the time of conduct of the pharmacokinetic study, it is recommended that a method accurately measuring GFR using an exogenous marker is used to determine renal function in the subjects in the pharmacokinetic study, if possible. This may be particularly important for drugs that are expected to be affected by renal impairment to such an extent that dose adjustments will be needed [4].

Over the past 20 years, several GFR estimation equations have been developed, with the Modification of Diet in Renal Disease (MDRD) and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations used most widely. In a recently published study, authors assessed the performance of creatinine-based equations for estimating GFR slope according to patient characteristics and specific CKD diagnosis. This study showed little bias but poor precision in GFR slope estimation for both MDRD and CKD-EPI equations. These equations tended to overestimate the GFR slope in the youngest patients and underestimate it in the oldest, thus producing inverse associations between age and measured GFR (mGFR) versus estimated (eGFR) slope [5].
It is also essential to measure GFR accurately during clinical studies. For example, one study compared the efficacy of belatacept and cyclosporine in preventing acute rejection after renal transplantation. Results showed that the GFR measured by iohexol plasma clearence was significantly higher in belatacept group than it was in cyclosporine group. However, when GFR was calculated with the Cockcroft–Gault equation, there was no significant difference in efficacy between belatacept and cyclosporine groups [6].

How to measure GFR?
An ideal marker of GFR must possess all of the following characteristics in order to accurately represent true GFR: (1) its sole route of elimination must be through the kidney via glomerular filtration, (2) the marker must be freely filtered by the glomerulus (e.g. not subject to protein binding), (3) there is no elimination via tubular secretion, (4) the marker is not reabsorbed after being filtered by the glomerulus and (5) it should be easily measured. When all these conditions are met, kidney clearance of the marker would equal the GFR [7].
Several compounds have been used as exogenous GFR markers including inulin, chromium ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), iothalamate, and iohexol. The adequate choice of clearance measurement procedures including renal or plasma clearance are important too. The concept underlying all renal clearance calculations is that the marker is freely filtered and eliminated only by glomerular filtration. The patient’s urine is collected precisely over a defined time period, with plasma sampling during the urine collection period. After quantitating the marker concentration in the urine and blood, mGFR is calculated via equation shown in Figure 1 below:

Figure 1. mGFR equation. mGFR is the calculated GFR, U is the urinary concentration, V is the flow rate mL of urine produced per minute, and P is the plasma concentration

Figure 2. Surface area corrected mGFR equation. BSA is body surface area

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 [7]. 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 [9]. There is also a report of anaphylaxis following intravenous administration of inulin [10].

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. [9].
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 [13].

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 [14].

References

1. Perrone RD, Madias NE, Levey AS. Serum creatinine as an index of renal function: new insights into old concepts. Clin Chem. 1992;38(10):1933-53

2. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013; 3: 1–150

3. Agarwal R, Delanaye P. Glomerular filtration rate: when to measure and in which patients? Nephrol Dial Transplant. 2018 Dec 6. https://doi.org/10.1093/ndt/gfy363

4. European Medicines Agency: EMA/CHMP/83874/2014 – Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with decreased renal function, 2015, December 17. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-evaluation-pharmacokinetics-medicinal-products-patients-decreased-renal-function_en.pdf

5. van Rijn MHC, Metzger M, Flamant M et al. Performance of creatinine-based equations for estimating glomerular filtration rate changes over time. Nephrol Dial Transplant. 2018 Sep 1. https://doi.org/10.1093/ndt/gfy278

6. Vincenti F, Larsen C, Durrbach A et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med. 2005;353(8):770-81.

7. Seegmiller JC, Eckfeldt JH, Lieske JC. Challenges in Measuring Glomerular Filtration Rate: A Clinical Laboratory Perspective. Adv Chronic Kidney Dis. 2018;25(1):84-92.

8. Delanaye P, Flamant M, Dubourg L et al. Single- versus multiple-sample method to measure glomerular filtration rate. Nephrol Dial Transplant. 2018 Oct 1;33(10):1778-1785.

9. Stevens LA, Levey AS. Measured GFR as a confirmatory test for estimated GFR. J Am Soc Nephrol. 2009;20(11):2305-13. doi: 10.1681/ASN.2009020171.

10. Chandra R, Barron JL. Anaphylactic reaction to intravenous sinistrin (Inutest). Ann Clin Biochem. 2002;39(Pt 1):76.

11. Brändström E, Grzegorczyk A, Jacobsson L, Friberg P, Lindahl A, Aurell M. GFR measurement with iohexol and 51Cr-EDTA. A comparison of the two favoured GFR markers in Europe. Nephrol Dial Transplant. 1998 May;13(5):1176-82.

12. Delanaye P, Jouret F, Le Goff C, Cavalier E. Concordance Between Iothalamate and Iohexol Plasma Clearance. Am J Kidney Dis. 2016;68(2):329-330.

13. Soveri I, Berg UB, Björk J et al. Measuring GFR: a systematic review. Am J Kidney Dis. 2014;64(3):411-24.

14. Delanaye P. Which method to measure GFR and in which clinical conditions?. 56th ERA-EDTA Congress; June 15, 2019; Budapest, Hungary Available on the Congress Virtual Meeting

NDT-E Summary Articles