CAP Recommendations to Aid in Adoption of New eGFR Equation

Reports and recommendations from within the medical community have advised implementing the newly developed 2021 CKD-EPI-creatine equation for estimated glomerular filtration rate (eGFR), which eliminates race-based adjustment factors that can delay recognition of chronic kidney disease (CKD). To aid in adoption and implementation of the new equation, the CAP has developed recommendations for practitioners of pathology and laboratory medicine.

CAP Recommendations

1. The CAP recommends that all laboratories implement the new ‘2021 CKD-EPI creatinine’ eGFR equation as quickly as feasible and report this eGFR with all creatinine values. Combined with existing recommendations for use of IDMS-traceable enzymatic methods for creatinine measurement, this approach supports cost-effective and standardized calculation of eGFR regardless of health care setting. Health care providers should still be aware of the potential for systematic population differences when using creatinine-only eGFR equations.¹ The CAP, National Kidney Foundation (NKF), and other professional organizations will be producing additional educational resources to assist with technical implementation of the new equation.
2. Emerging evidence suggests that use of cystatin C with creatinine (‘2021 CKD-EPI creatinine-cystatin C equation’) further minimizes population-specific biases in eGFR and provides a more accurate eGFR for all patients compared to creatinine alone. Use of this equation is significantly limited by lack of widespread cystatin C availability and increased cost of cystatin C relative to creatinine. Laboratories and health care institutions may see increasing interest in access to cystatin C testing as evidence accumulates to support its use.
3. Health care providers should be aware that all eGFR equations provide an estimate of mGFR. While eGFR is one of many important tools in the evaluation of renal function, particularly given its widespread availability, no eGFR equation can accurately represent mGFR (usually measured by iothalamate or iohexol clearance) for all patients under all circumstances. Given eGFR result uncertainty, caution should be used when interpreting results around fixed clinical decision points.^2,3

As outlined in the CAP recommendation above, the CAP supports use of the ‘2021 CKD-EPI creatinine’ equation to eliminate race-based adjustment factors in eGFR reporting, standardization and unification in use of eGFR equations, as well as use of IDMS-traceable enzymatic methods for creatinine measurement incorporated into eGFR calculations.

While the CAP accreditation program does not include specific requirements regarding use or selection of eGFR equations, the accreditation program does include requirements regarding the validation and review of calculations used by the laboratory. For example, GEN.43022 describes record requirements associated with LIS testing, programs, and modifications; GEN.43450 outlines requirements associated with review of calculated results every two years or when system changes are made that may affect calculations; and GEN.43875 describes requirements associated with auto-verification validations.

The New 2021 CKD-EPI Equations

Equations for eGFR that do not incorporate race adjustment factors were developed in an ongoing effort to reduce and eliminate inequity and structural racism from health care. The new equations, as published, use conventional (mg/dL) creatinine units. Conversion factors are available to transform results from SI to conventional units prior to use in the new eGFR equations.

The newly developed equations do not fully eliminate bias observed across populations; less bias, however, is observed with the ‘2021 CKD-EPI creatinine-cystatin C’ equation. Lastly, the newly developed equations were established using patients 18 years and older. Current eGFR equations commonly used in pediatrics (eg, the Bedside Schwartz equation) do not include race adjustment factors.

The complete equations can be found in the 2021 Inker et al. New England Journal of Medicine (NEJM) article (Table 2). Practical guidance for implementing the new equation is also available.⁴ The ‘2021 CKD-EPI creatinine’ equation and recommendations can also be found via the National Kidney Foundation.

Background

For many years, adjustment factors for race have been used in equations for eGFR, including the 1999 MDRD Study equation,⁵ the 2009 CKD-EPI creatinine equation,⁶ and the 2012 CKD-EPI creatinine-cystatin equation.¹ As race is a social construct and not a biological attribute, its use and impact in medical practice, education, and decision-making has come under increasing scrutiny as part of the ongoing efforts and commitment to eliminate bias, inequity, and structural racism from health care.^4,5

Adjustment factors for race were originally incorporated into eGFR equations to account for increased average plasma creatinine concentrations observed in individuals who self-identified or were categorized as Black/African American.⁵ These populations, however, have a 3.7-fold greater prevalence of end-stage renal disease.⁹ Because adjustment factors for race produce a higher eGFR, this may result in a delay in recognition of CKD based on eGFR calculations that incorporate race. Furthermore, the impact of race adjustment factors on classification of CKD stage in individuals can have significant implications for a host of medical issues, including eligibility as an organ transplant donor or recipient, clinical trial enrollment, dosing of medications, and treatment options available across settings.

There is a growing consensus across the medical community that eGFR calculations non-reliant upon race adjustment factors are needed to minimize health disparities associated with CKD. A variety of approaches have been considered or are currently in use in some settings, and this has resulted in eGFR calculation practices that are not standardized across laboratories and medical practices. In 2020, a task force of the NKF and the American Society of Nephrology (ASN) was established to propose recommendations regarding race and eGFR reporting.¹⁰

In September 2021, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) published results in the New England Journal of Medicine comparing the performance of existing and new eGFR equations without race adjustment factors.¹¹ A new creatinine-based eGFR equation without a race adjustment factor—the new ‘2021 CKD-EPI creatinine’—was established and determined to be “sufficiently accurate for clinical practice in many circumstances,” although systematic differences in eGFR results may still be observed with the creatinine-only based equation across populations.¹¹ The authors of this study also concluded that a newly established eGFR equation incorporating both creatinine and cystatin C without a race-adjustment factor—the new ‘2021 CKD-EPI creatinine-cystatin C’ equation—was most accurate when compared to mGFR (eg, urinary clearance of iothalamate or plasma clearance of iohexol) and had smaller result differences across populations.

Concurrent with the release of the NEJM report, the NKF-ASN task force published recommendations regarding a unified approach to eGFR reporting in adults.¹² The task force recommended 1) implementation of the ‘2021 CKD-EPI creatinine’ equation in all laboratories, 2) national efforts dedicated toward increased use of cystatin C, particularly in individuals at increased risk of CKD, and 3) further research on eGFR with new markers dedicated to eliminating race and ethnic disparities.¹²

NOTE: For the complete new 2021 CKD-EPI equations, see Table 2 in the 2021 Inker et al. NEJM article.11 Practical guidance for implementing the new equations is also available.4 The ‘2021 CKD-EPI creatinine’ equation can also be found at: https://www.kidney.org/professionals/kdoqi/gfr_calculator/formula

1. Inker LA et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med. 2012;367(1):20-29, 2021. https://pubmed.ncbi.nlm.nih.gov/22762315/
2. Miller WG. Uncertainty in estimated glomerular filtration rate is much larger than the race adjustment term. Clin Chem. 2021;67(4):693-695. https://pubmed.ncbi.nlm.nih.gov/33543281/
3. Miller WG. Perspective on new equations for estimating glomerular filtration rate. Clin Chem. 2021;67(6):820-822. https://pubmed.ncbi.nlm.nih.gov/33720356/
4. Miller et al. National Kidney Foundation Laboratory Engagement Working Group Recommendations for Implementing the CKD-EPI 2021 Race-Free Equations for Estimated Glomerular Filtration Rate: Practical Guidance for Clinical Laboratories. Clin Chem. 2022, 68(4):511-520. https://pubmed.ncbi.nlm.nih.gov/34918062/
5. Levey AS et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999 Mar 16;130(6):461-70. https://pubmed.ncbi.nlm.nih.gov/10075613/
6. Levey AS et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-612. https://pubmed.ncbi.nlm.nih.gov/19414839/
7. Titus K. A transparent lens on estimated GFR. CAP Today. May 2021.
8. Vyas DA et al. Hidden in plain sight – reconsidering the use of race correction in clinical algorithms. N Engl J Med. 2020;383(9):874-882. https://pubmed.ncbi.nlm.nih.gov/32853499/
9. Kidney Disease Statistics for the United States. National Institute of Diabetes and Digestive and Kidney Diseases. National Institutes of Health. https://www.niddk.nih.gov/health-information/health-statistics/kidney-disease
10. Delgado C et al. Reassessing the inclusion of race in diagnosing kidney diseases: an interim report from the NKF-ASN task force. J Am Soc Nephrol. 2021;32:1305-1317. https://pubmed.ncbi.nlm.nih.gov/33845065/
11. Inker LA et al. New creatinine- and cystatin C-based equations to estimate GFR without race. N Engl J Med. 2021;385(19):1737-1749. https://pubmed.ncbi.nlm.nih.gov/34554658/
12. Delgado C et al. A unifying approach for GFR estimation: recommendations of the NKF-ASN task force on reassessing the inclusion of race in diagnosing kidney disease. Am J Kidney Dis. 2022;79(2):268-288. https://pubmed.ncbi.nlm.nih.gov/34563581/