Reassessing the Inclusion of Race in Diagnosing Kidney Diseases: An Interim Report from the NKF-ASN Task Force - JASN
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SPECIAL ARTICLE www.jasn.org
Reassessing the Inclusion of Race in Diagnosing Kidney
Diseases: An Interim Report from the NKF-ASN Task
Force
Cynthia Delgado,1 Mukta Baweja,2 Nilka Ríos Burrows,3 Deidra C. Crews ,4
Nwamaka D. Eneanya ,5 Crystal A. Gadegbeku,6 Lesley A. Inker,7 Mallika L. Mendu,8
W. Greg Miller,9 Marva M. Moxey-Mims,10 Glenda V. Roberts,11 Wendy L. St. Peter ,12
Curtis Warfield,13 and Neil R. Powe14
Due to the number of contributing authors, the affiliations are listed at the end of this article.
ABSTRACT
For almost two decades, equations that use serum creatinine, age, sex, and race to On a national scale, eGFR is used for
eGFR have included “race” as Black or non-Black. Given considerable evidence of important surveillance and regulatory
disparities in health and healthcare delivery in African American communities, some purposes, including population tracking
regard keeping a race term in GFR equations as a practice that differentially influ- of kidney diseases by the Centers for Dis-
ences access to care and kidney transplantation. Others assert that race captures ease Control and Prevention and the
important GFR determinants and its removal from the calculation may perpetuate United States Renal Data System, re-
other disparities. The National Kidney Foundation (NKF) and American Society of search supported by the National Insti-
Nephrology (ASN) established a task force in 2020 to reassess the inclusion of race in tutes of Health (NIH) and other public
the estimation of GFR in the United States and its implications for diagnosis and and private funding agencies (including
subsequent management of patients with, or at risk for, kidney diseases. This interim ongoing clinical trials), and eligibility for
report details the process, initial assessment of evidence, and values defined re- kidney-disease education or nutritional
garding the use of race to estimate GFR. We organized activities in phases: (1) clarify supplementation under the Medicare
the problem and examine evidence, (2) evaluate different approaches to address program.2–5 Although GFR estimation
use of race in GFR estimation, and (3) make recommendations. In phase one, we has remained an important guide for
constructed statements about the evidence and defined values regarding equity clinical decision making and population
and disparities; race and racism; GFR measurement, estimation, and equation per- tracking, derived equations, like many
formance; laboratory standardization; and patient perspectives. We also identified other tools in medicine, have undergone
several approaches to estimate GFR and a set of attributes to evaluate these ap-
proaches. Building on evidence and values, the attributes of alternative approaches
to estimate GFR will be evaluated in the next phases and recommendations will C.D. and N.R.P. are co-chairs of the NKF-ASN Task
Force.
be made.
This article is being published concurrently in the
JASN 32: ccc–ccc, 2021. doi: https://doi.org/10.1681/ASN.2021010039 Journal of the American Society of Nephrology and
American Journal of Kidney Diseases. The articles
are identical except for stylistic changes in keeping
with each journal’s style. Either of these versions
may be used in citing this article.
The measurement of creatinine, the tomography scans or cardiac catheteriza-
muscle protein metabolite, in serum is tions. Almost all clinical laboratories in the Published online ahead of print. Publication date
available at www.jasn.org.
used to estimate kidney function as United States now report eGFR with any
eGFR and has served as a major marker laboratory metabolic panel that contains Correspondence: Dr. Cynthia Delgado, San Fran-
for the detection, diagnosis, and manage- serum creatinine, with one estimate for Af- cisco VA Medical Center, Nephrology Section,
111J4150 Clement Street, San Francisco, CA
ment of kidney diseases. Creatinine-based rican Americans and another for non- 94121, or Dr. Neil R. Powe, Department of Medi-
eGFR (eGFRcr) thresholds guide clinical African Americans.1 Use of race in medical cine, Priscilla Chan and Mark Zuckerberg San
practice, including estimation of surgical practice has come under scrutiny in light of Francisco General Hospital and University of Cal-
ifornia San Francisco, San Francisco, CA 94110. Email:
complication risk; initiation, discontin- the most recent reckoning with racism and Cynthia.delgado@ucsf.edu or neil.powe@ucsf.edu
uation, and dosing of medications; and publicly displayed atrocities against racial
Copyright © 2021 by the American Society of
utilization of certain contrast-based and ethnic minorities across the United Nephrology and the National Kidney Foundation,
tests and procedures, such as computed States that has been longstanding. Inc. All rights reserved.
JASN 32: ccc–ccc, 2021 ISSN : 1046-6673/3205-ccc 1SPECIAL ARTICLE www.jasn.org
a nearly 50-year history of re-evaluation, measured GFR as their White adult Estimated GFR from cystatin C is not
adaptation, and refinement. This evolu- counterparts, indicating that determi- more accurate than eGFRcr; however,
tion continues in the reassessment of the nants of serum creatinine levels, other the equation reported in 2012, with a
use of race in estimating GFR. than GFR, differed between the groups.8 combination of the two markers, pro-
Race was among the 16 factors con- vides more accurate estimates.12 A term
sidered in the derivations and refine- for African American race is included in
EVOLUTION OF KIDNEY ment of the Modification of Diet in this combined marker equation that is
FUNCTION–ESTIMATING Renal Disease (MDRD) Study equation substantially smaller than in the
EQUATIONS reported in 1999.8 In regression models creatinine-only equations (1.08). In the
to predict GFR from serum creatinine report of the equation, the investigators
Since 1976, equations developed to esti- levels, a term (and coefficient) for self- noted an insufficient number of African
mate the clearance or filtration function identified African American race was Americans were included in the valida-
of the kidney from serum creatinine found to be a substantial and statistically tion datasets, prohibiting validation of
concentration have included, and ad- significant predictor of carefully mea- the effect of this coefficient in a separate
justed for, various factors, including sured GFR.8 The MDRD equation was population outside of the development
age, sex, African American race, and/or validated in the African American Study population.
body weight. These equations were of Kidney Disease.9 At the time, this ad- Clinical practice guidelines from Kid-
largely developed using clinical, epidemi- justment was thought to be an advance ney Disease Improving Global Out-
ologic, and statistical methods that were, because an important group, with high comes (KDIGO) recommend that,
at the time of equation derivation, con- risk for CKD progression, was included whenever serum creatinine is measured
sidered to be scientifically state of the art. in studies of measured GFR. in clinical practice, an eGFR should be
The Cockcroft–Gault equation, one In 2009, the Chronic Kidney Disease reported with an eGFRcr, using the
of the initial equations, used data from Epidemiology Collaboration (CKD- CKD-EPI 2009 creatinine equation or a
249 White males with measured creati- EPI) equation using creatinine was de- similarly accurate equation. When a
nine clearance ranging from 30 to veloped in a subsequent analysis with more accurate assessment of GFR is re-
130 ml/m2 to estimate creatinine clear- pooled studies of individual partici- quired, or there are concerns about the
ance.6 Although this equation represents pants. Meta-analytic regression was accuracy of eGFRcr, this initial test
one of the initial attempts to approxi- used in a more heterogeneous partici- should be followed by a confirmatory
mate kidney function without needing pant population, which combined data test using eGFR computed by cystatin
to undergo laborious and potentially in- from thousands of individuals (includ- C (alone or in combination with creati-
complete urine collection, the derivation ing White, African American, and—to a nine), measured creatinine clearance, or
cohort was limited by lack of both race far lesser extent—Asian, Hispanic/La- measured GFR.13 Since the first eGFR
and sex diversity. tino, and Native American individuals) equations were introduced two decades
from ten different independent studies. ago, data from laboratories in the United
Results were validated in a pooled group States show continual growth in the re-
RACE IN EGFR ASSESSMENT IN of 16 separate studies. 10 Across these porting of eGFR along with serum cre-
THE UNITED STATES studies, investigators found a similar atinine and, despite KDIGO guidelines,
result for African American race as a pre- the MDRD equation is the most fre-
After the publication and use of the dictor of measured GFR, with the mag- quently used.14
Cockcroft–Gault equation and before nitude of the coefficient slightly less than
the derivation of subsequent equations, that in the MDRD Study equation (1.20
published research by the National Insti- compared with White individuals for the PROBING THE RATIONALE FOR A
tute of Diabetes and Digestive and MDRD Study equation, and 1.16 com- RACE COEFFICIENT
Kidney Diseases (NIDDK) showed that pared with non-Black individuals for the
serum creatinine concentrations were CKD-EPI equation). In studies of mea- Although the biologic rationale for in-
higher among non-Hispanic Black sured GFR in the United States, other cluding coefficients (such as age, sex,
adults when compared with non- racial and ethnic groups were not and body weight) in eGFR equations
Hispanic White adults.7 This research included in large enough numbers to seem apparent, the reasons for including
was based on the Third National Health understand whether differences in non- race on the basis of serum creatinine ob-
and Nutrition Examination Survey, a na- GFR determinants of creatinine are servational data, muscle mass, and/or
tionally representative sample of the US present in persons of non-White and other factors are questionable.15 It may
population. Subsequent research by non-Black race or ethnicity.11 be problematic to rely on a correction
Levey and others found that serum cre- An alternative filtration marker, cys- without completely understanding
atinine levels were higher among African tatin C, is available and does not include what factors are being captured together,
American adults who had the same race in its estimating equation for GFR. and with an underappreciation of the
2 JASN JASN 32: ccc–ccc, 2021www.jasn.org SPECIAL ARTICLE
ancestral diversity among African Amer- DISPARITIES IN HEALTH AND related to kidney disease. Multifaceted
icans which exists in other racial and HEALTHCARE initiatives beyond an examination of
ethnic groups. 16 There is well-known GFR-estimating equations are impor-
exploitation and inhumane experi- Studies have shown disparities in tant to address, and ultimately eliminate,
mentation to which racial and ethnic health and healthcare disproportion- disparities.
minority individuals, particularly Afri- ately affect African Americans. When
can Americans, have been subjected.17 compared with non-Hispanic White
As a small, but growing, number of US individuals, African Americans have
FORMATION OF THE NKF-ASN
individuals self-identify as being of nearly double the prevalence of hyper-
TASK FORCE
mixed racial background, the complex- tension, a common etiology of kidney
ity of a changing racial and ethnic com- disease. 30–32 Decline in GFR among
The National Kidney Foundation (NKF)
position makes the use of race in the African Americans occurs at an earlier
and the American Society of Nephrology
practice of medicine further problem- age and at a faster annualized rate when
(ASN) announced on July 2, 2020 plans
atic. Recent calls for social justice re- compared with non-Hispanic White
to establish a task force to reassess the
form have galvanized segments of the Americans, even by cystatin C–based
inclusion of race in diagnosing kidney
medical community into further dis- GFR assessment.33 African Americans
disease. Representing patients, health-
course and action toward achieving with advanced kidney disease are youn-
care professionals, and other advocates
greater healthcare equity, including ger, with an incidence of ESKD nearly
across the world,42 NKF and ASN are
the assertion of race as a social, non- three times that of their non-Hispanic
two leading organizations dedicated to
biologic, construct.18–24 White counterparts.5
preventing, treating, and ultimately cur-
Many assert that removing race from Such disparities go beyond the bur-
ing kidney disease. During the past two
estimating GFR would achieve better den of kidney diseases and extend into
decades, both organizations have
health and healthcare equity by miti- differences in kidney-disease treatment.
championed health equity and health-
gating disparities, particularly for Before the widespread use of GFR esti-
care disparities in kidney disease. The
African American patients who experi- mation, it was documented that African
formation of the joint task force is a
ence faster progression to kidney fail- Americans were more likely to receive a
strong affirmation of both organiza-
ure and lower rates of transplantation. late referral for an evaluation by a ne-
tions’ commitment to health equity, di-
This rationale posits that such a change phrologist, a finding that is associated
versity, and scientific evidence.
would result in earlier identifica- with decreased survival after the devel-
A decision to remove race from the
tion and management of kidney dis- opment of ESKD.34 Documented since
estimation of GFR is not trivial and
eases for African American patients, the 1980s and 1990s, African Americans
could have consequences. As such,
referral for specialist care by nephrolo- are less likely to be treated with home
NKF and ASN charged the task force
gists, and earlier referral for kidney dialysis therapies and to be waitlisted
with:
transplantation. 2 5 –2 7 Others assert for kidney transplant, with even fewer
that, even if previously observed racial being transplanted.5,35–38 The reasons c Examining the inclusion of race in the
differences are poorly understood, race for observed disparities are multifac- estimation of GFR and its implica-
is capturing important determinants of torial and may be attributed to inter- tions for the diagnosis and subsequent
measured GFR. This rationale posits nalized, personal, or institutionalized management of patients with, or at
that removing race may create or per- racism.39,40 To date, disparities in health risk for, kidney disease.
petuate other disparities by assigning and healthcare have not been conclu-
the value for non-African Americans sively attributed to race correction in c Recognizing that any change in eGFR
to African Americans.17,28,29 There is eGFR equations, although research is reporting must consider the multiple
also a concern of subjectivity in regards ongoing. social and clinical implications, be
to applying the African American race Whereas Medicare spends approxi- based on rigorous science, and be
coefficient on healthcare decision mak- mately $120 billion annually on people part of a national conversation about
ing, and personal and/or provider bias with kidney diseases (including .$70 uniform reporting of eGFR across
in transparency with patient-physician billion for people with non–dialysis- healthcare systems.
communication. These points of view, dependent kidney disease), the NIH
along with others, have highlighted the budget on kidney research is ,$700 mil- c Incorporating the concerns of pa-
need to find an approach to GFR esti- lion, and little has been allocated to the tients and the public, especially in
mation that embraces the substantial understanding of racial disparities in marginalized and disadvantaged
diversity of the US population and pro- kidney-disease care and outcomes.5,41 communities, while rigorously as-
motes social and health equity without Reassessing race in eGFR should be the sessing the underlying scientific and
creating new, or worsening current, start of reassessing race in other areas of ethical issues embedded in current
health disparities. diagnosis and management decisions practice.
JASN 32: ccc–ccc, 2021 Reassessing Race in eGFR 3SPECIAL ARTICLE www.jasn.org
c Ensuring that GFR estimation equa- deliberations, including: (1) embracing forward to final recommendations. Task
tions provide an unbiased assessment a holistic approach that examines the force moderators devised goals for each
of GFR so that laboratories, clinicians, clinical, psychosocial, and financial session, an agenda, and an outline of
patients, and public-health officials tradeoffs of benefits and harms, balanc- specific questions for which the task
can make informed decisions to en- ing them across racial/ethnic groups force sought information. For example,
sure equity and personalized care for with particular attention to how kidney a session on race and racism included an
patients with kidney disease. diseases affect different races; (2) being in-depth review of the definitions of race
data driven and generating a solution and racism, and the effect of internal-
c Keeping laboratories, clinicians, and driven by science and evidence; and (3) ized, personal, and institutional racism
other kidney health professionals ap- engaging in effective listening, respect- on health and healthcare disparities. The
prised of any potential long-term ing different ideas and opinions, and task force defined and discussed genetic
implications of removing race from having a willingness to learn after hear- ancestry and its relation with self-
the eGFR formula. ing all perspectives. reported race; examined studies on the
Importantly, the NKF-ASN leader- relation of genetic ancestry to serum cre-
The task force was created to include
ship and the members of the task force atinine levels; and evaluated the history
a variety of health professionals and pa-
collectively agreed on the confidentiality of GFR measurement and the underly-
tients, including individuals with exper-
of deliberations (including refraining ing physiology, study design, popula-
tise in diagnosis, management, and
from social media commentary) to pro- tions, and statistical methods used for
treatment of kidney disease; measure-
mote candid opinions and exchange of the derivation of the most commonly
ment and estimation of GFR; healthcare
ideas. Members also mutually agreed to used GFR-estimating equations.
disparities; epidemiology and clinical re-
work toward the goal of agreement in Equation examination included an
search; laboratory medicine; pharmacy;
instances where there were differences intensive review of the race, ethnicity,
health services research; patient safety;
of opinion. All task force weekly sessions and socioeconomic and clinical charac-
patient experience with care; patient
were held virtually due to social distanc- teristics of participants in the studies in-
quality of life; medical education; and
ing directives during the coronavirus corporating the gold standard of direct
prevention/public health. The NKF and
disease 2019 pandemic. measurement of GFR included in equa-
ASN leadership selected the cochairs and
To undertake a comprehensive and tion derivation. Substantial heterogene-
initial members, recognizing the need
in-depth exploration of several issues ity exists across individual studies and,
for varying perspectives and back-
germane to race and GFR estimation, therefore, the task force evaluated ap-
grounds, requisite expertise, interest,
the task force organized its activities proaches for pooling data from different
and ability to commit to the intensive
into three phases (Table 1). This interim cohorts (i.e., meta-analysis) for a more
deliberations that lie ahead. The cochairs
report focuses on phase one. comprehensive and diverse sample of
additionally suggested to NKF and ASN
people for equation derivation. The
that they appoint patients, an expert in
Phase One task force also explored past efforts to
drug dosing and US Food and Drug Ad-
In phase one, the task force clarified achieve consistency in eGFR measure-
ministration (FDA) considerations, and
the problem and evidence by examining ment and reporting across US clinical
an expert on public-health surveillance.
information, including testimony, laboratories and institutions through
Patients were explicitly included as
lectures, and literature from experts standardization of laboratory measure-
members because of the importance of
(Table 2). First, the members of the ments and promulgation of clinical
their voice and the effects any potential
task force collectively identified and de- practice guidelines. Finally, the task force
change could have on their health and
cided upon the domains to be consid- considered patients’ perspectives and the
well-being. Task force members are not
ered and the panelists and discussants role of shared decision making in the de-
remunerated. Disclosures are included
to be formally invited by the cochairs livery of healthcare. After each session,
at the end of the manuscript.
and NKF-ASN leadership to provide ex- members of the task force debriefed pri-
pert testimony. We sought a wide range vately to discuss and summarize invited
of evidence and views, as illustrated by testimony and independent literature re-
NKF-ASN TASK FORCE PROCESS representation across the United States. viewed. On the basis of this informa-
We assured confidentiality to individuals tion, the task force developed a series
During the initial meeting of the task who provided testimony, in some in- of statements that summarized the evi-
force, members stated their familiarity stances due to sharing of unpublished dence and values held by its members
and involvement with the issues and bia- information. Members of the task force regarding health and healthcare equity,
ses so that other members of the task with subject-matter expertise served as disparities, race and racism, GFR, stan-
force were aware of individual initial subject moderators so that no one task dardization, and patients’ perspectives
leanings. The task force then established force member unduly influenced the en- (Table 3). All members of the task force
principles to guide its interactions and tire process, an approach to be followed actively participated in constructing the
4 JASN JASN 32: ccc–ccc, 2021www.jasn.org SPECIAL ARTICLE
Table 1. Overview of work phases and activities of the NKF-ASN Task Force
Phase One Phase Two Phase Three
Clarifying the problem and evidence Evaluating the approaches Making recommendations
eGFR and measurement Clinical consequences of different approaches Issuance of recommendations
Race, racism, and genetic ancestry. System and societal consequences of different approaches Comment on recommendations
Body composition and populations Implementation
used in eGFR estimation
Standardization and guidelines
Patients’ perspective and shared
decision making
Possible approaches to address race in
GFR estimation (Table 4)
statements of evidence and value, scru- kidney diseases in African Americans approaches on patient safety and health
tinizing and revising them. Revisions in- and all other races/ethnicities, how equity put forth in this report (https://
cluded a series of iterations regarding such changes might affect US FDA ap- form.jotform.com/210244230676145).
content, language, and perspective. proval and labeling of therapies, and the All of this information will be used to
The task force then assembled an in- possible effect on the federal govern- make future recommendations.
clusive inventory of potential approaches ment’s tracking of kidney diseases In phase three, the task force will de-
to GFR estimation or measurement require further examination. The avail- velop recommendations on the basis of
that included approaches in which race ability in communities of assays for a number of attributes (Table 5). These
is considered and not considered in newer, raceless biomarkers (e.g., cystatin attributes include biomarker choice, in-
derivation and/or reporting of eGFR C, b-trace protein, b2 microglobulin) puts and their availability for estimation
(Table 4). The approaches included also need evaluation.76,96 and reporting, representation of diver-
those (1) currently in widespread use sity in participants in research founda-
(including race in eGFR equations), (2) Phases Two and Three tional to equation development, and
recently adopted at some institutions, Recognizing the use of race in estimat- equation bias and accuracy compared
(3) currently available that might be am- ing equations is problematic, the task with measured GFR for different race
plified more broadly, and (4) recently force has focused on identifying a path and ethnic groups. Importantly, attri-
suggested that are currently under devel- forward. In phase two, on the basis of butes also include consequences for
opment or could be developed. testimony, lectures from additional ex- clinical decisions with regard to evalua-
Final recommendations will be made perts, literature, and input from the tion and management of patients’ GFR
after the task force examines the community of interested individuals and feasibility of standardization. Fi-
strengths and weaknesses of existing and organizations, the task force will nally, it is very important that any rec-
and newer approaches to estimating evaluate each of the possible ap- ommended approach incorporates the
GFR. The downstream consequences of proaches that could be recommended patient perspective and be patient
changes from current reporting are un- with regard to its patient, clinical, centered.97
known and could be profound. Changes health system, and societal effects Recommendations will be reviewed
could lead to overdiagnosis or under- (Supplemental Materials 1 and 2). and informed by an advisory board, in-
diagnosis of kidney diseases as a result The deliberations and conclusions of cluding members of the NKF’s and
of GFR estimation bias and inaccuracy these meetings will be presented in de- ASN’s governing bodies, committees on
for any ethnic group. Conclusive evidence tail in the final report. diversity and inclusion, policy and advo-
on outcomes from well-conducted studies The task force held a series of forums cacy panels, and experts in patient safety
will likely take years to produce. The re- in January 2021 to invite input from and healthcare quality. The task force is
sultant effects in terms of the numbers of the broader kidney community (Public committed to continuing its transpar-
African Americans affected and the Forums to Provide Input to eGFR ent, open, and community-based pro-
safety and effectiveness of pharmacother- Joint Task Force, NKF). Over the course cess through phases two and three.
apy use and dosing need appraisal. Addi- of three sessions, the task force heard
tionally, effect on managing risk factors from (1) students and trainees; (2)
(e.g., hypertension), nephrology referral, clinicians, scientists, and other health SUMMARY AND IMPLICATIONS
transplant waitlisting, and kidney dona- professionals; and (3) patients, family
tion will also warrant evaluation. members, and other public stake- Estimation of GFR is a major underpin-
The ramifications of changes in eGFR holders. The task force also seeks input ning of many clinical decisions in med-
equations on research studies examining regarding the effect of particular icine. The use of race to estimate GFR
JASN 32: ccc–ccc, 2021 Reassessing Race in eGFR 5SPECIAL ARTICLE www.jasn.org
Table 2. Topics and panelists/discussants during phase one
Topic Moderators and Panelists/Discussants Location
GFR: history and evolution of kidney Neil Powe, MD, MPH, MBA; Cynthia Delgado, MD
function measurement over the past Andrew S. Levey, MD Boston, Massachusetts
50 years
GFR: measurement, estimation, Lesley Inker, MD
performance in the United States Josef Coresh, MD, MPH Baltimore, Maryland
Susan L. Furth, MD, PhD Philadelphia, Pennsylvania
Andrew S. Levey, MD Boston, Massachusetts
Julia B. Lewis, MD Nashville, Tennessee
Robert G. Nelson, MD, PhD Bethesda, Maryland
Derek K. Ng, PhD Baltimore, Maryland
Andrew D. Rule, MD Rochester, Minnesota
George Schwartz, MD Rochester, New York
Race and racism; genetic ancestry and Deidra Crews, MD, ScM
race; creatinine, race and ancestry Camara Phyllis Jones, MD, PhDa Atlanta, Georgia
David R. Williams, PhDa Boston, Massachusetts
Dorothy E. Roberts, JDa Philadelphia, Pennsylvania
Nora Franceschini, MD Chapel Hill, North Carolina
Alicia R. Martin, PhD Boston, Massachusetts
Miriam S. Udler, MD, PhD Baston, Massachusetts
Esteban G. Burchard, MD San Francisco, California
Jeffery B. Kopp, MD Bethesda, Maryland
Opeyemi A. Olabisi, MD, PhD Durham, North Carolina
Body composition and populations used Cynthia Delgado, MD
in eGFR estimation Kamyar Kalantar Zadeh, MD, PhD Los Angeles, California
Andrew D. Rule, MD Rochester, Minnesota
Glen M. Chertow, MD Palo Alto, California
Kirsten L. Johansen, MD Minneapolis, Minnesota
Baback Roshanravan, MD Davis, California
Flor Alvorado, MD Baltimore Maryland
Abinet M. Aklilu, MD New Haven, Connecticut
Laboratory standardization issues with Greg Miller, PhD; Mukta Baweja, MD
markers and guidelines Adeera Levin, MD, FRCPC Vancouver, British Columbia
Amy D. Karger, MD, PhD Minneapolis, Minnesota
Andrew S. Narva, MD Washington, DC
Harvey Kaufman, MD, FCAP, MBA Short Hills, New Jersey
Holly J. Kramer, MD, MPH Maywood, Illinois
James Fleming, PhD, FACB Greensboro, North Carolina
Joseph A. Vassalotti, MD New York, New York
Neil Greenberg, PhD, DABCC Cleveland, Ohio
Ravi I. Thadhani, MD, MPH Boston, Massachusetts
Wolfgang C. Winkelmayer, MD, ScD Houston, Texas
W. Greg Miller, PhD Richmond, Virginia
Patient perspective and participatory Glenda Roberts, BSc; Curtis Warfield, MS
decision-making experience and Monica Peek, MD, MPH Chicago, Illinois
patient centered considerations David White Brooklyn, New York
Richard Knight Bowie, Maryland
Keren Ladin Medford, Massachusetts
Kevin Fowler Chicago, Illinois
Rajnish Mehrotra, MD Seattle, Washington
Allison Tong, PhD, MPHb Sydney, Australia
L. Ebony Boulware, MD Durham, North Carolina
H. Gilbert Welch, MD Boston, Massachusetts
Possible approaches to address race in Neil Powe, MD, MPH, MBA; Cynthia Delgado, MD
GFR estimation Task Force Members
a
Previously disseminated video talks were reviewed for these individuals due to their availability.
b
Video talk was reviewed for this individual due to their availability.
6 JASN JASN 32: ccc–ccc, 2021www.jasn.org SPECIAL ARTICLE
Table 3. NKF-ASN Task Force agreed upon statements of evidence and value
Statement: Evidence or Value
Equity and disparities
(1) Equitya in kidney health and kidney healthcare is a fundamental and important goal. (V)
(2) Disparities in kidney health and kidney health care should not exist. (V)
(3) Equity in healthcare, as defined by the NAM is care that does not vary in quality on the basis of personal characteristics, such as sex, race/
ethnicity, geographic location, or socioeconomic status.43 (E)
(4) A disparity in healthcare, as defined by NAM, is a difference in care that arises through operation of the healthcare system; legal or regulatory
climate; or discrimination, biases, stereotyping, and uncertainty; but is not due to clinical appropriateness or patient preference.44 (E)
(5) A variety of factors influence kidney health across racial and ethnic groups, including delivery of healthcare, clinical/health policies,
environment, genetics, and health behaviors.45–51 (E) These factors act with a different degree of influence along the life span of individuals
and along the continuum from health to kidney disease.45–49 (E) There are gaps in our understanding of these influences and how to interrupt
their effect on creating health disparities.52 (E) To eliminate disparities, multifaceted initiatives beyond an examination of estimating
equations must be developed. (V)
(6) Differences in health exist across racial and ethnic groups in the United States, and not all of these differences are accounted for by
socioeconomic status, geographic regions (including urban versus rural setting), insurance, lifestyle, and clinical factors.53 (E) Disparities in
healthcare exist across racial and ethnic groups and geographic regions (including urban versus rural setting) in the United States, even after
accounting for insurance status, income, age, and disease severity.44,54 (E)
(7) Disparities across racial and ethnic groups in the United States exist in kidney disease. These disparities exist with regard to kidney-disease risk
factors, comorbidities, and progression to kidney failure.2,5,55 (E) Disparities across racial and ethnic groups in the United States exist in kidney-
disease care, including diabetes and BP control, nephrology referral, dialysis modality, and transplantation, and with regard to both living and
deceased kidney donation.56–58 (E) Disparities across racial and ethnic groups in the United States in healthcare exist for diagnostics and
therapeutics, which rely on GFR assessment (e.g., radiocontrast administration; metformin, anticoagulant, and chemotherapeutic use).59–62 (E)
(8) Racial and ethnic diversity in participants in health and healthcare research is an important component of equity for studies and their data to be
useful and generalizable to decisions in routine clinical practice.17,63,64 (E) Research studies should focus on a diversity of racial and ethnic
groups to allow for greater generalizability. (V)
Race and racism
(9) Race is defined as a construct of human variability based on perceived differences in biology, physical appearance, and behavior.65 (E) Race
and ethnicity are social and not biologic constructs.17,66,67 (E)
(10) Racism is defined as an organized system, rooted in an ideology of inferiority that categorizes, ranks, and differentially allocates societal
resources to human population groups.68 (E) Racism can be internalized, personal, or institutional.40 (E) As such, racism can be a part of the
environment/behavior, delivery of healthcare, and clinical/health policy factors, respectively.69 (E) Racism can impede prevention and clinical
care along the continuum from healthy kidneys, to kidney disease, to treatment.39,70 (E) Implicit bias has also been shown to negatively affect
patient outcomes, particularly among African American patients in the United States.71 (E) Approaches proven to minimize implicit bias in
healthcare delivery should be used. (V) The effects of racism can be long lasting and this effect may even be carried forward over
generations.72–74 (E)
(11) Although race and genetic ancestry are related, race captures factors beyond genetic ancestry. The relation between race, ancestry, and
observed biology is poorly understood.17 (E) Research is ongoing to elucidate the relation between genetic ancestry and race.17 (E)
(12) According to 2019 US Census population estimates, the self-identified racial and ethnic composition of individuals was 76.3% White, 13.4%
African Americans, 5.9% Asian, 1.3% American Indian/Native American and Alaskan Native, 0.2% Native Hawaiian and Other Pacific Islander,
with approximately 18.5% Hispanic/Latinx ethnicity.75 (E) Approximately 2.9% of US individuals self-identified as being of mixed racial
background.75 (E) The complexity of changing racial and ethnic makeup makes the use of race in the practice of medicine challenging and
potentially problematic. (V)
GFR measurement, estimation, and equation performance
(13) Creatinine and cystatin C are the most commonly used and studied filtration markers for use in estimating GFR.13 (E) Creatinine is used more
commonly, is more widely available, and has a longer history of study than cystatin C.8,10,76 (E) The determinants of serum concentrations of
creatinine are not completely understood, and those of cystatin C are even less well understood.77 (E) Assays for cystatin C have greater
analytical variation than do assays for creatinine.78 (E)
(14) Over 250 million serum creatinines are performed each year in the United States. The cost for serum creatinine is currently low relative to
serum cystatin C (Medicare reimbursement rates in 2020, $5.12 and $18.52, respectively).79 (E) With more widespread adoption and use of
cystatin C, costs could decrease. (V)
(15) Multiple studies among the US population, including national health statistics studies across age groups, show African American men and
African American women have higher serum creatinine concentrations than their White counterparts. Not all factors that might affect serum
creatinine concentrations were accounted for in these studies.7,80 (E) Studies have also shown African Americans have higher serum creatinine
concentrations than White individuals at the same measured GFR in the United States.81 (E) The reasons for these differences are not
understood.81 (E)
(16) Studies have shown the proportion of African ancestry is related to the level of creatinine in US adults.82,83 (E) Studies have not examined the
relation of genetic ancestry to measured GFR. (E) These studies are desired. (V)
JASN 32: ccc–ccc, 2021 Reassessing Race in eGFR 7SPECIAL ARTICLE www.jasn.org
Table 3. Continued
Statement: Evidence or Value
(17) All estimates of GFR are subject to bias, imprecision, and inaccuracy.8,10,76,84 (E) Equations should not differentially induce bias and
inaccuracy by age, sex, or race; i.e., they should not have disproportionate bias, imprecision, or inaccuracy for a particular group according to
age, sex, or race. (V)
(18) Clinical algorithms to assess eGFR with additional predictors are a better indicator of GFR than serum creatinine concentration alone.13 (E)
(19) Individual studies of adults with measured GFR and eGFRcr or eGFRcys have been limited in the diversity of participants with regard to age,
sex, race, ethnicity, geography, socioeconomic status, comorbidity, and other risk factors for kidney disease. These individual studies have
also been limited in diversity of participants with regard to absence, severity, and etiology of kidney disease.8,10,76,81 (E) Individual studies of
adults are also limited in measurements of body composition and chronic or acute illness.8,12,76 (E) Future studies should seek more diversity in
participants with regard to many patient characteristics (age; sex; race; ethnicity; geography; socioeconomic status; comorbidity; risk factors
for kidney disease; absence, severity, and etiology of kidney disease; diet; and body composition). (V)
(20) Estimating equations that were not developed in diverse populations (including race and ethnicity) leads to questions as to how applicable
they are to populations not included in the developmental phase without further validation. (V)
(21) To estimate GFR, it is useful to pool data on participants from individual studies (i.e., meta-analysis) to obtain a more comprehensive and
diverse sample of people (age; sex; race; ethnicity; geography; socioeconomic status; comorbidity; risk factors for kidney disease; absence,
severity, and etiology of kidney disease; and body composition) for whom eGFR can be applied in clinical practice. (V)
(22) To approximate measured GFR with greater accuracy and to minimize bias in all groups, creatinine-based estimating equations (MDRD and
CKD-EPI eGFRcr or eGFRcr-cys) have included a coefficient for age, sex, and race; whereas cystatin C–based equations (CKD-EPI) have
included coefficients for age and sex alone.12 (E)
(23) Data in adult ambulatory outpatients show that the most validated equations (CKD-EPI; eGFRcr, eGFRcys, and eGFRcr-cys) perform with
different degrees of bias and accuracy.12 (E) With regard to accuracy, CKD-EPI 2012 eGFRcr-cys has the highest available accuracy (P30,
accuracy measured as the percentage of estimates within 30% of measured GFR) at 91.5%, with similar accuracy for CKD-EPI 2009 eGFRcr at
87.2% and CKD-EPI 2012 eGFRcys at 86.9%.12 (E) Precision (interquartile range) is best for eGFRcr-cys (13.4) and less for eGFRcr (15.4) and
eGFRcys (16.4), all in ml/min per 1.73 m2.12 (E) Bias (measured minus estimated GFR) is similar among equations: eGFRcr-cys (3.9), GFRcr (3.7),
and eGFRcys (3.4), all in ml/min per 1.73 m2.12 (E) Bias and inaccuracy of estimated GFR equations are greater at higher measured GFR.12 (E)
There is no differential accuracy, precision, or bias in equations between Black and non-Black individuals using these equations.12 (E)
(24) Inclusion of height and total body weight did not improve performance of eGFR estimation in adults.11,85 (E) Validated equations for use in
children include height, serum creatinine, cystatin c, and BUN, but do not include race.86 (E) Although methods for measuring body
composition have been useful in research settings, no single method has been widely standardized and adapted for routine clinical use for
adults in the United States or evaluated for use with eGFR equations. (V)
Laboratory standardization
(25) Standardization of measurement and reporting of GFR in the United States is important. (V)
(26) Standardization can be achieved through issuance and adherence to clinical practice guidelines.87 (E)
(27) Reference materials, methods, and accounting for interfering substances are important in achieving assay equivalence.1,88,89 (E) Results for
analytes used to estimate GFR should be standardized. (V)
(28) Implementation efforts to achieve standardization, and adoption and adherence to practice guidelines, are important for uniform practices.
(V)
(29) Clinical laboratories and the manufacturers of laboratory equipment and supplies must be engaged to achieve standardization. (V)
Patients’ perspective
(30) Patients prefer to have shared decision making with their physician, rather than the patient or the physician being the sole decision maker.90
(E) Given the diversity of the patient populations within and across healthcare settings, patient education on the clinical implications of eGFR
should include a discussion on how the equation was derived, its limitations, and how it applies to them. (V)
The task force actively participated in constructing the statements of evidence and value, the statements then underwent scrutiny and revision by all of the members
of the task force. The task force went through a series of iterations regarding content, language, and perspective. V, value; NAM, National Academy of Medicine; E,
evidence; eGFRcys, estimated GFR from cystatin C; eGFRcr-cyst, estimated GFR from creatinine and cystatin C; P30, accuracy measured as the percentage of
estimates within 30% of measured GFR.
a
See Supplemental Material 2 for terms and definitions.
and possible replacements have short- Because these differing approaches public-health professionals—the task
comings that the task force is currently may have varying effects for patients force would like to offer a careful and
examining. Nationwide, many institu- treated and followed by clinicians— judicious review to guide implementa-
tions have made independent decisions including but not limited to primary tion efforts for a standardized and equi-
to address race in estimation of GFR, but care physicians, medical specialists table approach to care. The task force
these approaches vary and, therefore, GFR (e.g., nephrologists, hospitalists, endo- understands how high the stakes are for
estimates and subsequent care decisions crinologists, cardiologists, oncologists), African Americans, recognizes that ex-
are not standardized. surgical specialists, pharmacists, and peditious recommendations are needed,
8 JASN JASN 32: ccc–ccc, 2021www.jasn.org SPECIAL ARTICLE
Table 4. Inventory of possible approaches to estimating and reporting GFR for general use
Creatinine Used as Biomarker Noncreatinine Biomarker Used
Estimation and reporting with creatinine and race using existing Estimation with cystatin C, creatinine, and race using existing
equations equations
(1) eGFRcr (MDRD or CKD-EPI) (age, sex, race) with “Black” estimate (13) eGFRcr-cys (CKD-EPI) (age, sex, race) with “Black” estimate
reported for self-identified African Americans and “non-Black” reported for self-identified African Americans and “non-Black”
estimate reported for persons from other communities8,10,a estimate reported for persons from other communities12
Estimation with creatinine and race using existing equations but Estimation with cystatin, creatinine, and race using existing
reporting without specification of race equations but reporting without specification of race
(2) eGFRcr (CKD-EPI) (age, sex, race) with “Black” estimate reported as (14) eGFRcr-cys (CKD-EPI) (age, sex, race) with “Black” estimate
“high muscle mass,” and “non-Black” estimate reported as “low reported as “high muscle mass,” and non-Black estimate reported
muscle mass”a as “low muscle mass”
(3) eGFRcr (CKD-EPI) (age, sex, race) with “Black” estimate reported as (15) eGFRcr-cys (CKD-EPI) (age, sex, race) with “Black” estimate
“high value,” and “White” reported as “low value”a reported as “high value,” and “White” reported as “low value”a
(4) eGFRcr (CKD-EPI) (age, sex, race) with the Black coefficient ignored (16) eGFRcr-cys (CKD-EPI) (age, sex, race) with the Black coefficient
and eGFR value for White/other is reported for alla ignored and value for White/Other is reported for all
(5) eGFRcr (CKD-EPI) (age, sex, race), with the Black coefficient used (17) eGFRcr-cys (CKD-EPI) (age, sex, race), with the Black coefficient
and eGFR value for African Americans is reported for all used and value for African Americans is reported for all
(6) Blended eGFRcr (CKD-EPI) (age, sex, race) using a single coefficient (18) Blended eGFRcr-cys (CKD-EPI) (age, sex, race) using a single
weighted for percentage of African Americans in the specific coefficient weighted for percentage of African Americans in the
population is reported for all specific population is reported for all
Estimation with creatinine that do not include race Estimation with cystatin C only
(7) CG estimated creatinine clearance (age, sex, weight)6,a,b (19) eGFRcys (CKD-EPI) (age, sex)76,a
(8) eGFRcr (FAS) (age, sex)91 (20) eGFRcys (FAS) (age, sex)92
(9) eGFRcr (EKFC) (age, sex)93 (21) eGFRcys (CAPA) (age)94
(10) eGFR (LM) (age, sex)95
Equations to be developed to estimate GFR with creatinine that do Equations to be developed to estimate GFR with creatinine and
not include race cystatin C that do not include race
(11) eGFRcr refit without race variable (22) eGFRcr-cys refit without race variable
(12) eGFRcr refit with height and weight without race variable
Estimation with creatinine only that does not include race
(23) eGFRcr-cys (FAS) (age, sex)92
Estimations with new filtration markers in combination with
creatinine or cystatin C that do not include race
(24) eGFRcys-b2m-btp (age, sex)96
(25) eGFRcr-cys-b2m-btp (age, sex)96
(26) Any of the above either in combination or in sequence with measured GFR using exogenous filtration markers or measured creatinine
clearance, to be used generally or by clinical indication (e.g., donation, diagnosis, prescription, referral, transplant): Example: One of the
above approaches followed by another approach for confirmation.
Parentheses indicate coefficients included in the development of the equation. eGFRcr-cys, estimated GFR with creatinine and cystatin C; CG, Cockcroft–Gault;
FAS, full age spectrum; EKFC, European Kidney Function Consortium; CAPA, Caucasian and Asian Pediatric and Adult; LM, Lund–Malmo; b2m, b2 microglobulin;
btp, b-trace protein.
a
Used or in use in at least one US setting.
b
CG creatinine clearance is reported in ml/min, eGFR results are standardized (or indexed) to a body surface area of 1.73 m2 and are reported in ml/min per 1.73 m2.
and that a careful review of the evidence education and sustained efforts to kidney health and to eliminate health
must guide its recommendations. The monitor and assure patient safety and disparities.
task force also recognizes that alignment health equity. Assessing the inclusion
of US clinical laboratories is critical to of race in estimating GFR is part of a
maintain the success achieved over the larger conversation in addressing ra- DISCLOSURES
past two decades in reporting of eGFR, cial disparities in kidney health. NKF,
which has improved the quality of care ASN, and the task force encourage M. Baweja reports having interests/relationships
for millions of Americans. the community of healthcare profes- with Physicians for Human Rights, Young Center
NKF, ASN, and the task force ap- sionals, scientists, medical educa- for Immigrant Children’s Rights, and Premier, Inc.
preciate that issuing recommenda- tors, students, health professionals in D.C. Crews reports serving on the Nephrology
Board of the American Board of Internal Medi-
tions is only the beginning of change. training, and patients to join in the cine, on the Council of Subspecialist Societies at
Implementing recommendations of larger, comprehensive effort needed the American College of Physicians, on the Bayer
this magnitude will require extensive to address the entire spectrum of HealthCare Pharmaceuticals Inc, Patient and
JASN 32: ccc–ccc, 2021 Reassessing Race in eGFR 9SPECIAL ARTICLE www.jasn.org Table 5. Sample of attributes to be considered in making a recommendation among alternative approaches to estimation of kidney function (eGFR) Attribute Filtration biomarker availability Input variable for computation (race, filtration biomarker, age, sex, body composition measure) Representation in development and validation of a diverse population with regard to race, ethnicity, sex, age, body composition, severity and cause of kidney disease, and socioeconomic status Bias compared with measured kidney function for different race and ethnic groups Accuracy compared with measured kidney function for different race and ethnic groups Consequences of equation used for clinical decisions with regard to evaluation and management of patients’ kidney function, including health disparities and bias Availability of input variables for reporting (race, filtration biomarker, age, sex, body composition measure) Feasibility of standardization across the United States Patient-centered perspectives on approaches Physician Advisory Board Steering Committee for technical expert panel for Quality Insights Kidney Centers for Disease Control and Prevention, At- Disparities in CKD Project, on the editorial board Care Pilot project; serving as a scientific advisory lanta, Georgia. The findings and conclusions in this of CJASN and Journal of Renal Nutrition, as asso- board member of the NKF and ASN Task Force on report are those of the authors and do not neces- ciate editor for Kidney360 as cochair of Kidney360, EGFR and Race; and having consultancy agree- sarily represent the official position of the Centers and on the Board of Directors of the NKF of Mary- ments with Total Renal Care, Inc. N.R. Powe re- for Disease Control and Prevention. Because land/Delaware; receiving research funding from ports serving as a JASN associate editor; reports Marva M. Moxey-Mims and Neil R. Powe are As- Somatus, Inc.; and having consultancy agreements receiving honoraria from the Patient Centered sociate Editors of JASN, they were not involved in with Yale New Haven Health Services Corporation Outcomes Research Institute, Robert Wood John- the peer review process for this manuscript. An- Center for Outcomes Research and Evaluation son Foundation, University of Washington, Yale other editor oversaw the peer review and decision- (CORE). C. Delgado reports her contribution is University, and Vanderbilt University; and serving making process for this manuscript. in part supported with the resources and the use as a scientific advisor for the Patient Centered Out- of facilities at the San Francisco VA Medical Center. comes Research Institute, Robert Wood Johnson N.D. Eneanya reports receiving honoraria from Foundation, University of Washington, Vanderbilt Columbia University Medical Center, Gerson University, and Yale University. G.V. Roberts re- SUPPLEMENTAL MATERIAL Lehrman, Harvard University, Partner’s Health- ports serving on a speakers bureau with American care, Quality Insights, SCAN Healthcare, Univer- Association of Kidney Patients; receiving honoraria This article contains the following supplemental sity of California Irvine, and Wake Forest School of from APOLLO; serving on the APOLLO NIDDK material online at http://jasn.asnjournals.org/ Medicine; serving as a scientific advisor for, Study Community Advisory Committee, Can- lookup/suppl/doi:10.1681/ASN.2021010039/-/ or member of, Healthcare: The Journal of Delivery SOLVE CKD International Research Advisory Com- DCSupplemental. Science and Innovation and Kidney Medicine; and mittee, International Nephrology Society (ISN) Patient Supplemental Material 1. Topics and informants having consultancy agreements with Somatus. Group, University of Washington (UW) Center for during phase 2. C. Gadegbeku reports receiving research funding Dialysis Innovation Patient Advisory Board, and UW Supplemental Material 2. Terms and definitions. from Akebia and Vertex; serving as scientific advi- Kidney Research Institute Patient Advisory Commit- sor for, or member of, the ASN Council; and hav- tee; having other interests/relationships with the ASN ing consultancy agreements with Fresenius Kid- COVID-19 Response Team and Transplant Subcom- ney Care as medical director. L.A. Inker reports mittee and Kidney Health Initiative Patient and REFERENCES serving as scientific advisor or member of, Alport’s Family Partnership Council; serving as an advisory Foundation, Goldfinch, and Diametrix; member of committee member for Home Dialyzors United; 1. Miller WG, Jones GRD: Estimated glomerular the ASN and member of National Kidney Disease and having ownership interest in Microsoft. filtration rate; laboratory implementation and Education Program; having consultancy agree- C. 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