What are the new recommendations regarding estimation of glomerular filtration rate without the variable for race, and what effects might this have on drug dosing?

Introduction

Estimates of kidney function are performed in clinical practice to diagnose and stage chronic kidney disease (CKD) and to appropriately dose drugs eliminated by the kidney.1 Many methods of estimating kidney function have been developed over recent decades, including the commonly used Cockcroft-Gault and Modification of Diet in Renal Disease (MDRD) equations. In 2009, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was introduced and implemented in routine care following recommendations for its widespread use.1,2 Despite incremental advancements in these equations’ accuracy, the inclusion of a variable for race in the MDRD and CKD-EPI equations can perpetuate biases related to race and contribute to health disparities.3,4

Recently, a Task Force including members of the National Kidney Foundation (NKF) and American Society of Nephrology (ASN) reassessed the inclusion of the variable for race in estimating kidney function.3,4 The Task Force recommended use of the CKD-EPI equation refit without the variable for race.4 Because this recommendation may generate questions regarding its impact on dosing of drugs based on glomerular filtration rate (GFR), this summary reviews the rationale, characteristics, and potential clinical impact of the Task Force’s recommendation for use of the CKD-EPI equation without the variable for race.

Background

Kidney function is commonly described using GFR, which represents the sum of all filtration rates in functioning nephrons.5 It is considered the most useful method to identify and stage CKD.6 Measurement of GFR involves determining renal clearance of a substance that is filtered by the glomerulus but that does not undergo tubular secretion or absorption. Exogenous compounds that possess these characteristics, such as inulin and iothalamate, facilitate accurate calculation of GFR; however, their measurement is tedious and requires specialized methods.6 In contrast, endogenous compounds such as creatinine or cystatin C require fewer technical resources and are easier to measure, but are not as accurate as external filtration markers. While GFR is considered the best overall estimate of kidney function, estimating equations that use more accessible clinical and demographic variables are used to approximate GFR.7

Creatinine is the endogenous compound most commonly used in GFR estimation.4 It is a by-product of muscle metabolism, and therefore is readily measured.6 Because creatinine is freely filtered at the glomerulus and neither reabsorbed nor metabolized by the kidney, creatinine clearance (CrCl) is often used as a surrogate measurement of GFR. However, creatinine undergoes tubular secretion and is eliminated by other routes; it is therefore a less accurate filtration marker than exogenous compounds.6,8 Additionally, creatinine concentrations may be elevated in patients with greater muscle mass or dietary meat consumption, resulting in higher serum creatinine concentrations and underestimation of renal function. While CrCl may provide an estimate of GFR, the two are not interchangeable, and CrCl may overestimate GFR by approximately 10% to 20%.9

Original CKD-EPI Equation

Over time, new equations for estimating GFR have been developed and adopted into clinical practice. The Cockcroft-Gault equation was developed in 1976 to estimate CrCl based on variables for age, weight, and serum creatinine.1,5 The data used in its development, however, were from 249 hospitalized White men. In 1999, the MDRD equation was introduced, representing greater diversity because of its development using data from males, females, and Black and non-Black patients.5 One way in which the MDRD equation differed from Cockcroft-Gault was that the equation incorporated an additional variable for race. The MDRD equation became the most widely used method for reporting GFR, although it systematically underestimated GFR at higher levels of kidney function because all individuals in its cohort had CKD.

In 2009, the CKD-EPI 2009 equation was developed to more accurately estimate GFR in individuals with higher kidney function while providing similar accuracy in individuals with GFR less than 60 mL/min/1.73 m2.7 The equation was developed and validated using data from multiple studies that utilized direct measurement of GFR with external filtration markers and represented greater diversity, including patients with and without CKD.5,7 Like MDRD, the CKD-EPI 2009 equation included variables for serum creatinine, age, sex, and race (defined as Black versus non-Black). Compared with non-Black patients, the CKD-EPI 2009 equation calculates an estimated GFR that is 15.9% higher for Black patients of the same sex and similar age and serum creatinine concentration to account for the higher observed GFR in Black patients.10,11 Overall, the CKD-EPI 2009 equation was more accurate than the MDRD equation, although the latter performed better at lower levels of GFR.12,13 Shortly after the introduction of the CKD-EPI 2009 equation, the Kidney Disease Improving Global Outcomes (KDIGO) guideline recommended that clinical laboratories report estimated GFR using this method or a similarly accurate alternative.2

Rationale for the Change

In 2020, the NKF and ASN announced a Task Force to reassess the inclusion of the variable for race in the estimation of GFR in the US.4 The initiative was rooted in efforts to avoid the use of race in medical care. Studies have demonstrated race-based disparities in healthcare, which disproportionately affect Black persons in the US. In nephrology outcomes alone, these individuals on average experience earlier and more rapid declines in GFR, are more likely to receive a late referral to a nephrologist, and are less likely to be waitlisted for kidney transplant compared with non-Hispanic White individuals. The reasons for these disparities are multifactorial and include personal and/or institutionalized racism.

Another reason for avoiding the use of race that was considered by the Task Force is that race is a social rather than a biological construct.4 Growing numbers of individuals self-identify as being of mixed racial background, which could complicate the use of self-reported race in medicine. Overall, removing a term for race in GFR estimating equations can help mitigate healthcare disparities and reduce bias in the process of care.

Recommendations of the NKD-ASN Task Force

After reviewing 26 distinct approaches for estimating GFR without consideration of race, the NKF-ASN Task Force determined that a refit CKD-EPI equation without the race variable (CKD-EPI Creatinine Equation [2021]) best fit predefined criteria.4,14 This new equation was developed using the same data set as the CKD-EPI 2009 equation and was validated using new data sets.14 In addition to not including race in the calculation and reporting, the new equation included diversity in its development, is immediately available to all laboratories in the US, and has acceptable performance characteristics and potential consequences that do not disproportionately affect any one group of individuals.4 The Task Force recommended that the CKD-EPI Creatinine Equation (2021) be implemented immediately for US adults.

The Task Force also recommended expanded efforts to increase use of cystatin C.4 Like creatinine, cystatin C is an endogenous filtration marker, but offers greater accuracy and less variability because it produced by all nucleated cells, not just muscle cells.1,6 The Task Force noted that equations that included both creatinine and cystatin C were more accurate than those using either marker alone and could improve clinical decision-making.4 However, measurement of cystatin C is expensive and not widely available.6 Greater access to this marker can help confirm estimated GFR in adults who are at risk for or have CKD.4 Acknowledging this potential benefit, the Task Force recommended that if equations including cystatin C alone or in combination with creatinine demonstrate acceptable performance, these should be adopted to provide more accurate testing.

Implications and Implementation

The Task Force considered potential consequences of the candidate approaches to estimating GFR without race.4 Using the CKD-EPI Creatinine Equation (2021), measured GFR was underestimated in Black patients by a median 3.6 mL/minute/1.73 m2 and overestimated in non-Black patients by a median 3.9 mL/minute/1.73 m2.14 Consistent with these changes, the Task Force considered there to be greater potential harm to Black adults related to inappropriate drug discontinuation and underdosing, while non-Black adults may be at greater risk for harms due to inappropriate drug continuation or overdosing.4

Some investigators have evaluated the effect on drug therapy of omitting the race variable in estimates of GFR. For example, removal of race from the original CKD-EPI equation was associated with 1% to 5% more Black patients with cancer being ineligible for chemotherapy and 1% to 18% more patients receiving dose reductions.10,11 Similarly, a study assessed the discordance in dosing recommendations between the CKD-EPI 2009 equation with and without race versus recommendations derived from Cockcroft-Gault for renally dose-adjusted antimicrobials.15 Estimates of GFR using the CKD-EPI equation without race was less frequently discordant with Cockcroft-Gault than was the CKD-EPI equation with race (12.5% vs 18.5%). Notably, while the equations used to calculate GFR in these studies did not consider race, they were not equivalent to the refit CKD-EPI Creatinine Equation (2021) recommended by the NKF-ASN Task Force.10,15

Further study of the effects on dosing of renally eliminated drugs can elucidate the effects of the new CKD-EPI Creatinine Equation (2021) once it is more widely adopted. For now, experts recommend that estimation of GFR should be an initial rather than a conclusive determinant in decision-making.11 In situations demanding the most accurate assessment, GFR should be measured using exogenous filtration markers, consistent with KDIGO recommendations.2 Settings in which this may be indicated include extremes of age or body size, paraplegia or quadriplegia, persons with a vegetarian diet, pregnancy, rapidly changing kidney function, severe malnutrition or obesity, and skeletal muscle disorders.1

Consistent with new recommendation for immediate implementation, the Task Force anticipates reasonably rapid uptake of the CKD-EPI Creatinine Equation (2021) at time frames ranging from 6 months in settings where the change was anticipated to up to 2 years in others.16 Until results from the CKD-EPI Creatinine Equation (2021) become integrated and reported in electronic medical records, clinicians can use a free online calculator available at the NKF website.17

Conclusion

In 2021, a Task Force composed of members of the NKF and ASN reviewed various equations to estimate GFR that do not include a variable for race. The Task Force recommended use of the CKD-EPI Creatinine Equation (2021) because the calculation incorporates the readily accessible measure of serum creatinine, included diversity in its development, and its potential consequences do not disproportionately impact any particular group of individuals. It is unknown to what degree the new equation may influence dosing of drugs eliminated by the kidney, although the equation performed adequately and similarly to the CKD-EPI 2009 equation. In situations demanding greater accuracy of GFR estimation, direct measurement of GFR using exogenous filtration markers is recommended. Overall, implementation of the new CKD-EPI Creatinine Equation (2021) can mitigate biases and promote greater equity in care by removing race from medical decision-making.

References

  1. National Kidney Foundation. Frequently asked questions about GFR estimates. National Kidney Foundation. Accessed December 14, 2021. https://www.kidney.org/sites/default/files/docs/12-10-4004_abe_faqs_aboutgfrrev1b_singleb.pdf
  2. Kidney Disease Improving Global Outcomes CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. 2013;3(Suppl):1-150.
  3. Delgado C, Baweja M, Burrows NR, 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. doi:10.1681/ASN.2021010039
  4. Delgado C, Baweja M, Crews DC, 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. J Am Soc Nephrol. 2021. doi:10.1681/asn.2021070988
  5. Lyas C, Zuber K, Davis J. Reevaluating race and the glomerular filtration rate calculator. Jaapa. 2021;34(12):59-61. doi:10.1097/01.JAA.0000800284.39341.3b
  6. Dowling TC. Evaluation of kidney function. In: DiPiro JT, Yee GC, Posey LM, Haines ST, Nolin TD, Ellingrod V, eds. Pharmacotherapy: A Pathophysiologic Approach. 11th ed. McGraw-Hill Education; 2020. accesspharmacy.mhmedical.com/content.aspx?aid=1182440159
  7. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-612. doi:10.7326/0003-4819-150-9-200905050-00006
  8. Bauer LA. Drug dosing in special populations: renal and hepatic disease, dialysis, heart failure, obesity, and drug interactions. In: Bauer LA, ed. Applied Clinical Pharmacokinetics. 3rd ed. McGraw-Hill Medical; 2015. accesspharmacy.mhmedical.com/content.aspx?aid=1106302753
  9. Shahbaz H, Gupta M. Creatinine clearance. In: StatPearls Publishing, ed. StatPearls. StatPearls Publishing; December 16, 2021. https://www.ncbi.nlm.nih.gov/books/NBK544228/
  10. Casal MA, Ivy SP, Beumer JH, Nolin TD. Effect of removing race from glomerular filtration rate-estimating equations on anticancer drug dosing and eligibility: a retrospective analysis of National Cancer Institute phase 1 clinical trial participants. Lancet Oncol. 2021;22(9):1333-1340. doi:10.1016/s1470-2045(21)00377-6
  11. Levey AS, Powe NR. eGFR and chemotherapy: will removing race create disparities? Lancet Oncol. 2021;22(9):1208-1209. doi:10.1016/s1470-2045(21)00391-0
  12. Kilbride HS, Stevens PE, Eaglestone G, et al. Accuracy of the MDRD (Modification of Diet in Renal Disease) study and CKD-EPI (CKD Epidemiology Collaboration) equations for estimation of GFR in the elderly. Am J Kidney Dis. 2013;61(1):57-66. doi:10.1053/j.ajkd.2012.06.016
  13. Stevens LA, Schmid CH, Greene T, et al. Comparative performance of the CKD Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease (MDRD) Study equations for estimating GFR levels above 60 mL/min/1.73 m2. Am J Kidney Dis. 2010;56(3):486-495. doi:10.1053/j.ajkd.2010.03.026
  14. Inker LA, Eneanya ND, Coresh J, et al. New creatinine- and cystatin C-based equations to estimate GFR without race. N Engl J Med. 2021;385(19):1737-1749. doi:10.1056/NEJMoa2102953
  15. Miller J, Knorr JP. Impact of removing the race coefficient in renal function estimate equations on drug dosage recommendations. Ann Pharmacother. 2022;56(1):44-51. doi:10.1177/10600280211010228
  16. Seaborg E. New race-free eGFR equation welcomed, focus turns to implementation. KidneyNewsOnline. Published October 1, 2021. Accessed December 18, 2021. https://www.kidneynews.org/view/journals/kidney-news/13/10/11/article-p1_1.xml
  17. National Kidney Foundation. eGFR Calculator. National Kidney Foundation. Published 2021. Accessed December 16, 2021. https://www.kidney.org/professionals/kdoqi/gfr_calculator

Prepared by:
Ryan Rodriguez, PharmD, BCPS
Clinical Associate Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

January 2022

The information presented is current as December 14, 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.