The Genesis of the Estimated Glomerular Filtration Rate (eGFR)

In the beginning there was urine, creatinine and 3-liter jugs.

Originally, in order to measure renal function, clearance assays were performed. These procedures required the collection of 24-hour urine or a timed urine and the measurement of either urine creatinine or an intravenous radioactive tracer such as ¹²⁵I-iothalamate or ⁵¹Cr-EDTA. Although the use of isotopic procedures were considered “the gold standard,” for routine use, these procedures were cumbersome, expensive, invasive (for use of isotopes), and non-standardized.

In the early 1970s, attempts to simplify this procedure were made. These were based on the measurement of serum creatinine, height, weight, age, etc., and required complex formulas in an attempt to approximate the values of clearance tests. These formulas, collectively, are referred to as “Estimated Glomerular Filtration Rate” or eGFR. These formulas included, for pediatric populations, the Schwartz equation, the Leger equation, the Bedside equation, and the Counaham-Barrett (C-B) equation, among others.^1,5 For adults, the Cockcroft-Gault (C-G) formula was established. Over the years, these formulas have been modified as creatinine assay calibrations were standardized by the adoption of the IDMS procedures. Today, most current serum creatinine procedures are calibrated against this standard regardless of the use of the Jaffe procedure or more current enzymatic procedures. However, the C-G is no longer recommended for use because it has not been expressed using standardized creatinine values. Other formulas (MDRD, CKD-EPI, CKD-EPI 2021) have replaced the C-G formula.^1,2,3

Thus, currently the Bedside equation and the C-B formulas are recommended for pediatric, with the Bedside being the most popular and supported by the U.S. National Kidney Foundation on line calculator (Pediatric GFR Calculator | National Kidney Foundation). These 2 equations are very similar and both give similar results in mL/min and are relatively accurate (+/-30%) to the gold standard procedures.

For adult populations, the CKD-EPI (2021) equation is recommended by the National Kidney Foundation including the American Nephrology Association, as well as other international organizations (eGFR Calculator | National Kidney Foundation). With or without Cystatin-C, this calculation is relatively accurate (+/-7%) to the gold standard procedures.^2,3

In addition to these formulae, there are some regional adjusted calculations. For example, the Japanese Society of Nephrology has made modifications to the MDRD, CKD-EPI, and provided a specific formula for the Japanese population.^6,7

A bit about Reference Ranges and “Clinical Cut-off”

Population Reference Ranges are usually established by measuring an analyte in a large population of apparently healthy individuals and consider the central 95% as within the reference range or normal. For example, the central 95% for K+ is 3.5 to 5.0 mEQ/L (3.5 to 5.0 mmol/L). Likewise, if you look at cholesterol levels pre-NCEP, the range would be between 180 mg/dL and 230 mg/dL. However, since NCEP, the desired upper limit is now defined as 200 mg/dL which is based on a risk analysis for cardiovascular disease. For eGFR various studies have suggested reference ranges of 80/90 to 120/130 mL/min/1.73m².

Likewise, for renal function, a referent value of 60 mL/min/1.73m² has been recommended by the National Kidney Foundation. In 2012, international guidelines were published by KDIGO (Kidney Disease Improving Global Outcomes) re-classified Chronic Kidney Disease (CKD) into six GFR categories

• G1: Kidney damage with a normal or high GFR (>90 mL/min/1.73m²)
• G2: Mild reduction in GFR (60-89 mL/min/1.73m²)
• G3a: Mild to moderate reduction in GFR (45-59 mL/min/1.73m²)
• G3b: Moderate to severe reduction in GFR (30-44 mL/min/1.73m²)
• G4: Severe reduction in GFR (15-29 mL/min/1.73m²)
• G5: Kidney failure - GFR <15 mL/min/1.73m²)

The key “cut-off” value remains at 60 mL/min/1.73m². The reasoning is that in the absence of kidney damage (e.g., albuminuria), G1 and G2 cannot/should not be considered CKD. G3a however, is always considered CKD and only the GFR criterion is relevant for the diagnosis of CKD. Since all of the eGFR formulas give clinically similar, but not identical, absolute values, the "cut-off" of 60 mL/min/1.73m² remains.³ A recent publication recommended a cut-off of 75 ml/min/1.73m². This study was a retrospective study from a hospital in Belgium. Since the hospital records did not have the patient height required for the Bedside calculation, the authors developed a pediatric calculation that did not require height and was based in the median of normal serum creatinine values obtained in a “normal” age related population. The retrospective study did not include albuminuria as an indication of kidney damage.⁴

Thus, the recommendation for children > 2 years old (and adult) “cut-off” still remains > 60 mL/min/1.73m². This cut-off should be used for all National Kidney Foundation recognized formulas.^2,3

To learn more, read our latest insight brief on Renal Function and Race in Clinical Trials and the new recommended guidelines for estimated glomerular filtration (eGFR) calculations.

Authors:

Steven Lobel, PhD, D-ABMLI, MBA, FACB, Clinical Immunology, Pediatric/Endocrinology
Patrice Hugo, Ph.D., Chief Scientific Officer
Michael DiMaio, M.D., FACP, Laboratory Director

References:

1. Carlton, KKL, et al. Evaluation of serum creatinine concentration-based glomerular filtration rate equation in pediatric patients with chronic kidney disease. Pharmacotherapy 2012;32(7):642–648
2. National Kidney Foundation (2002) K/DOQI Clinical practice guidelines for chronic kidney disease evaluation, classification and stratification. Am J Kid Disease 39:S1-S266
3. Kidney Disease Improving Global Outcomes (KDIGO) (2013) KDGIO 2012 Clinical practice guidelines for chronic kidney disease evaluation, classification and stratification. Kidney Int Suppl 3: 1 – 150
4. Pottel, H., et al. A simple height-independent equation for estimating glomerular filtration rate in children. Pediatric Nephrol. 27:973-979 (2012)
5. Counahan, R., et al. Estimation of glomerular filtration rate from plasma creatinine concentration in children. Arch Dis Child. 51: 875-878 (1976)
6. Enyu I, et al. A Decade After the KDOQI CKD Guidelines: A Perspective from Japan. Am J Kid Disease. 60:729-730 (2012)
7. Boon Wee Teo, et al. Glomerular Filtration Rates in Asians. Adv Chronic Kidney Dis..25:41-48 (2018)