PERS PE C T IV E
ogy, the vaccine-development pro- understanding of the immune
cess is also being condensed.
Experimental vaccines were de-
veloped and ready for phase 1
clinical trials in 20 months for
SARS after the epidemic began in
2003 and in slightly more than
3 months for Zika virus in 2016.
The response to the Covid-19
pandemic is a prime example of
how rapidly new vaccines can
now be designed. By the time the
WHO declared Covid-19 a pan-
demic on March 11, 2020, at least
37 groups from biotechnology
companies and academic institu-
tions were working on vaccine
candidates.5 These candidates in-
clude live attenuated, inactivated,
DNA, messenger RNA, viral vec-
tor, and spike-protein–based vac-
cines. Less than 1 year later, the
first Covid-19 vaccine-efficacy
trials have now been completed,
and the first vaccines are author-
ized for emergency use.
Many approved vaccines, such
as those against measles and
polio, were made using attenuat-
ed or killed versions
An audio interview
with Dr. Gerberding
of the virus without
detailed knowledge
is available at NEJM.org
of viral pathogenesis.
In contrast, current strategies for
vaccine design rely on new tech-
nologies that lead to a deeper
In Search of a Better Equation
In Search of a Better Equation — Performance and Equity
in Estimates of Kidney Function
James A. Diao, B.S., Lesley A. Inker, M.D., Andrew S. Levey, M.D., Hocine Tighiouart, M.S.,
Neil R. Powe, M.D., M.P.H., M.B.A., and Arjun K. Manrai, Ph.D.​​
G rassroots activism and the
resurgent focus on racism
in the United States have led
medical centers to revisit their
approaches to estimating and re-
porting kidney function. Although
many experts agree that we should
396
Downloaded from nejm.org on February 3, 2021. For personal use only. No other uses without permission.
Copyright © 2021 Massachusetts Medical Society. All rights reserved.
Vaccine Innovations — Past and Future
gens, but providing affordable ac-
system and of host–pathogen in-
teractions. For new experimental
HIV and respiratory syncytial vi-
rus (RSV) vaccines, a detailed
structural understanding of anti-
body interactions with the HIV
envelope or the RSV prefusion
form of the fusion (F) protein is
needed.
Vaccines remain the most ef-
fective tool for preventing infec-
tious diseases and improving
global health. Remarkable prog-
ress has been made with the use
of vaccines, including the eradi-
cation of smallpox and the con-
trol of childhood diseases such
as measles, mumps, rubella,
and polio. New insights into the
functioning of the immune sys-
tem on a cellular and molecular
level have made possible the rap-
id development of new vaccines.
Difficulties facing vaccinologists
include predicting the type and
timing of the next pandemic; de-
veloping vaccines to combat rap-
idly changing pathogens such as
HIV-1, influenza, and multidrug-
resistant bacteria; and establish-
ing rapid-response strategies to
control emerging and reemerging
infectious diseases. The future
holds great promise for vaccine-
mediated control of global patho-
reconsider the use of race in
equations for estimated glomer-
ular filtration rate (eGFR) and in
medicine more generally,1,2 pre-
cisely how eGFR equations should
remove race remains unclear. In
August 2020, the National Kid-
n engl j med 384;5  nejm.org  February 4, 2021
The New England Journal of Medicine
cess to effective vaccines for
everyone who could benefit from
them remains an important chal-
lenge.
The series editors are Victor J. Dzau, M.D.,
Harvey V. Fineberg, M.D., Ph.D., Kenneth I.
Shine, M.D., Samuel O. Thier, M.D., Debra
Malina, Ph.D., and Stephen Morrissey, Ph.D.
Disclosure forms provided by the authors
are available at NEJM.org.
From Merck, Kenilworth, NJ (J.L.G.); and
the Duke Human Vaccine Institute, Duke
University School of Medicine, Durham,
NC (B.F.H.).
This article was published on January 30,
2021, at NEJM.org.
1. Plotkin SA, Orenstein WA, Offit P. A short
history of vaccination. In:​Plotkin SA, Oren-
stein WA, Offit P, Edwards KM, eds. Plot-
kin’s vaccines. 7th ed. Philadelphia:​Elsevier
Press, 2017:​1-15.
2. Lee LA, Franzel L, Atwell J, et al. The
estimated mortality impact of vaccinations
forecast to be administered during 2011-
2020 in 73 countries supported by the GAVI
Alliance. Vaccine 2013;​31:​Suppl 2:​B61-B72.
3. Greene SA, Ahmed J, Datta SD, et al.
Progress toward polio eradication — world-
wide, January 2017–March 2019. MMWR
Morb Mortal Wkly Rep 2019;​68:​458-62.
4. Carroll D, Daszak P, Wolfe ND, et al. The
Global Virome Project. Science 2018;​ 359:​
872-4.
5. Usdin S. WHO mapping out Covid-19
vaccines. Redwood City, CA:​Biocentury,
February 14, 2020 (https://www​.­biocentury​
.­com/​­article/​­304456/​­who​-­is​-­creating​-­a​
-­roadmap​-­to​-­develop​-­covid​-­19​-­vaccines).
DOI: 10.1056/NEJMp2029466
Copyright © 2021 Massachusetts Medical Society.
Vaccine Innovations — Past and Future
ney Foundation (NKF) and the
American Society of Nephrology
(ASN) formed a joint task force
to provide recommendations. Var-
ious changes to eGFR reporting
have already materialized, with
diverse implications for Black pa-
PE R S PE C T IV E
tients, including new diagnoses
and reclassifications of chronic
kidney disease (CKD), contrain-
dications and dose reductions for
prescription drugs, increased eli-
gibility for specialist care and
kidney transplantation, and de-
creased eligibility for kidney do-
nation and clinical trials.2 Some
observers argue that applying
clinical judgment while bearing
in mind the imprecision of the
eGFR may lessen these effects.
Still, the magnitude of changes
generated by using current coef-
ficients (16 to 21%) suggests that
removing race may substantively
affect care.2
Earlier equations for kidney
function were derived exclusively
from White people and did not
consider race. The finding of de-
creased accuracy in Black Ameri-
cans later prompted researchers
to introduce race-based factors
statistically derived from diverse
populations. For example, the fac-
tor of 15.9% in the eGFR equa-
tion developed by the CKD Epide-
miology Collaboration (CKD-EPI)
was derived from the observation
that measured GFR (mGFR) for
Black Americans was, on average,
15.9% higher than that for non-
Black persons with the same se-
rum creatinine level, sex, and age.3
Adjusting for this difference made
statistically unbiased GFR esti-
mates possible in both groups.
Observed differences are attrib-
utable to non-GFR determinants,
including tubular secretion and
creatinine generation. Although
it was initially hypothesized that
differences in body size or mus-
cle mass were explanatory fac-
tors, they have not been shown
to explain observed differences.
Researchers should continue to
investigate underlying causes and
replace race with factors measur-
able by clinicians.
n engl j med 384;5  nejm.org  February 4, 2021
The New England Journal of Medicine
Downloaded from nejm.org on February 3, 2021. For personal use only. No other uses without permission.
Copyright © 2021 Massachusetts Medical Society. All rights reserved.
Today, nearly all laboratories
estimate GFR using race, but mul-
tiple academic medical centers
have recently removed the race
coefficient for Black patients out
of concern about differential ac-
cess to kidney transplantation and
specialist care, as well as broad
misuses of race as a biologic cate-
gory.1,2 However, no reports have
systematically evaluated all op-
tions for computing and report-
ing eGFR. We documented race-
free alternatives with respect to
validation, overall and within-
group accuracy, availability of
assays and equation parameters,
representation of Black patients
in development data, and use of
race (see table). The potential im-
plications for millions of patients
necessitate a thorough considera­
tion of these factors in the search
for a better equation.
Alternatives are typically pro-
posed as modifications of the
CKD-EPI equations. These equa-
tions — eGFR computed from se-
rum creatinine (eGFRcr), cystatin C
(eGFRcys), and both (eGFRcr-cys)
— are recommended by authori-
tative guidelines such as “Kidney
Disease: Improving Global Out-
comes” (KDIGO). Validation of the
equations revealed no substantial
bias (defined as eGFR minus
mGFR) in either Black Ameri-
cans or the general population.
The 2009 eGFRcr and 2012
eGFRcys and eGFRcr-cys equa-
­ White patients while concentrating
tions were derived from popula-
tions containing approximately
three times the proportion of
Black people as in the overall U.S.
adult population (31.5% and
40.0%, respectively, vs. 11.7%). The
eGFRcr and eGFRcr-cys require
race, whereas eGFRcys does not.
eGFRcys is a validated race-
free equation with minimal bias.
Although assays for cystatin C
are now standardized, some argue
In Search of a Better Equation
that eGFRcys and eGFRcr-cys pre­
sent problems of limited assay
availability, longer turnaround
times, and imprecisely under-
stood associations with smoking,
fat mass, and inflammation. These
challenges are surmountable with
efforts to increase assay avail-
ability and further investigate
non-GFR determinants of serum
cystatin C concentrations.
Among the first alternatives
implemented for removing race
from the eGFRcr involved rela-
beling its two outputs (“if Black”
and “if White/Other”). One ap-
proach relabels race-specific out-
puts as the high and low ends
for a range of plausible eGFR val-
ues (“Black” becomes “high esti-
mate” and “White/Other” becomes
“low estimate”). These ranges
misrepresent the true variability
of GFR estimates and would be
biased downward for Black pa-
tients and upward for non-Black
patients. Another approach rela-
bels race-specific outputs as dif-
ferences in muscle mass (“Black”
becomes “high muscle mass” and
“White/Other” becomes “low mus-
cle mass”). This approach lacks
evidentiary support.
Subsequent proposals have in-
cluded, first, simply using eGFRcr
with the race coefficient removed
— effectively using the White/
Other output for all patients; this
approach preserves accuracy for
errors in Black patients. A second
proposal was refitting eGFRcr
without race — a more statisti-
cally valid approach that distrib-
utes errors more evenly, although
Black patients remain dispropor-
tionately affected. A third was
refitting eGFRcr with height and
weight replacing race, based on
the now-unsupported hypothesis
that body measurements may ac-
count for observed racial GFR
397
 Alternatives for Computing or Reporting eGFR from Serum Markers.*

398
Coefficient for Overall
KDIGO External Black Race Development Data Accuracy Availability
Method Input Variables Recommended Validation (value) Representation vs. eGFRcr Median Bias (Reason)
PERS PE C T IV E

no. of persons
(% Black) ml/min/1.73 m2
eGFRcr Creatinine, age, sex, race Yes Yes Yes (1.159) 8254 (31.5) (Baseline) Black: 0.0; White/ Yes (implemented in
Other: −0.5 nearly all hospitals)
eGFRcr-cys Creatinine, cystatin, age, Yes Yes Yes (1.080) 5352 (40.0) Higher Black: −0.3; White/ Yes; limited (cystatin C
sex, race Other: 0.0 assay currently not
widely accessible)
eGFRcys Cystatin, age, sex Yes Yes No 5352 (40.0) Equal Black: 0.0; White/ Yes; limited (cystatin C
Other: −0.5 assay currently not
widely accessible)
eGFRcr with “Black” and Creatinine, age, sex No No No Not fitted from Unknown, Unknown Yes (implemented in
“White/Other” relabeled data most likely some hospitals)
as the high and low ends (NA) lower
of an eGFR range
eGFRcr with “Black” rela- Creatinine, age, sex No No No Not fitted from Unknown, Unknown Yes (implemented in
beled as “high muscle data most likely some hospitals)
mass” and “White/Other” (NA) lower
as “low muscle mass”
eGFRcr with race coefficient Creatinine, age, sex No No No 8254 (31.5) Lower Black: −6.1; White/ Yes (implemented in
removed Other: −0.5 some hospitals)
eGFRcr refitted without race Creatinine, age, sex No No No 8254 (31.5) Lower Black: −4.0; White/ No (equation parame-
variable Other: 1.4 ters not available)
eGFRcr refitted with height Creatinine, age, sex, No No No 8254 (31.5) Lower Black: −3.7; White/ No (equation parame-
and weight replacing race height, weight Other: 1.3 ters not available)

The New England Journal of Medicine

Blended eGFRcr (weighted Creatinine, age, sex No No No 8254 (31.5) Unknown, Unknown likely Yes (multiple options
combination of race-­ most likely negative for for weighting)

n engl j med 384;5  nejm.org  February 4, 2021

specific outputs) lower Black and
positive for
White

Copyright © 2021 Massachusetts Medical Society. All rights reserved.

eGFRmet Acetylthreonine, phenyl- No No No 2424 (51.8) Higher Black: −1.4; White/ No (assays not avail-
acetylglutamine, tryp- Other: 1.3 able)
tophan, pseudouridine
eGFR-LMWPs Creatinine, cystatin C, No Yes No 5017 (38.5) Higher Black: −1.1; No (assays not widely
B2M, BTP, age, sex White/Other: available)
0.4

Downloaded from nejm.org on February 3, 2021. For personal use only. No other uses without permission.
* Accuracy is defined relative to the baseline of eGFRcr on the basis of a statistically significant difference (P<0.05) in either the root mean squared error of eGFR relative to mGFR (log-log scale) or 1 mi-
nus P30% (defined as <30% difference from mGFR). All data sets had a mean mGFR of 68 ml/min/1.73 m2, except eGFRmet (55 ml per minute per 1.73 m2 of body-surface area) and eGFR-LMWP
(58 ml per minute per 1.73 m2). The median bias is the median difference between eGFR and mGFR in the development data. Some previous CKD-EPI studies reported bias differently, as mGFR mi-
nus eGFR. The mean bias is expected to be zero in development data sets overall and in race subgroups if there is a race coefficient. B2M denotes beta-2-microglobulin, BTP beta-trace protein, eGFR
estimated glomerular filtration rate, KDIGO Kidney Disease: Improving Global Outcomes, LMWPs low-molecular-weight proteins, mGFR measured glomerular filtration rate, and NA not applicable.
In Search of a Better Equation
PE R S PE C T IV E
differences. Evaluation of these al-
ternatives using the CKD-EPI de-
velopment data showed decreased
accuracy and increased bias rela-
tive to race-based eGFRcr and
race-free eGFRcys, especially in
Black patients (see table). None
of these alternatives requires race
input, but only the first one has
been implemented.
Other race-free approaches
include blended equations and
equations based on filtration
markers other than creatinine or
cystatin. Blending combines race-
specific outputs using weights
based on population proportions
(e.g., 11.7% for Black and 88.3%
for White/Other) and can be ap-
plied to either eGFRcr or eGFRcr-
cys. Blended equations would not
require refitting or additional as-
says and would distribute errors
more evenly than direct removal.
In theory, each institution could
assign weights according to its
patient demographics or those of
the U.S. population; however, non-
uniform weights may confuse pa-
tients, clinicians, and trainees who
travel among organizations. Final-
ly, multiple-filtration-marker pan-
els such as eGFRmet (metabolite)
and eGFR-LMWP (low-molecular-
weight proteins) have been shown
to have accuracy and bias equiva-
lent to those of KDIGO-recom-
mended equations even without
using race. Though they are prom-
ising, their feasibility for wide-
spread adoption is unclear.
Race is a social construct that
has been used to divide people in
ways that harm human health;
removal of race from clinical al-
gorithms is therefore needed. It is
not appropriate, however, to ignore
race or the pervasive effects of
structural racism. Race-blind ap-
proaches can benefit minorities
by increasing access to specialist
care and kidney transplantation,2
n engl j med 384;5  nejm.org  February 4, 2021
The New England Journal of Medicine
Downloaded from nejm.org on February 3, 2021. For personal use only. No other uses without permission.
Copyright © 2021 Massachusetts Medical Society. All rights reserved.
but can also result in biases.4 For
example, observational retrospec-
tive data suggest that transition-
ing from thresholds based on
race-blind serum creatinine mea-
sures to those based on race-
adjusted eGFR reduced disparities
in metformin access by account-
ing for higher serum creatinine
levels in Black patients.5 As hospi-
tals move from race-based equa-
tions, we must remain vigilant in
reassessing data and algorithms
for bias.
The national conversation has
rightly focused on equity con-
cerns for Black people, who are
the most affected by disparities
in kidney outcomes and are the
only group for whom race adjust-
ment is recommended in the
United States. Non-Black minority
populations are also affected. Al-
though non-Hispanic Black and
White patients were well-repre-
sented in the data used to devel-
op the eGFRcr (31.3% and 61.7%,
respectively), neither Hispanic
(1.5%) nor Asian (1.2%) patients
were. Increased representation of
non-White and non-Black persons
is desirable.
Furthermore, there are con-
cerns that race may be assigned
by investigators or clinicians in
developing or using eGFR equa-
tions. In clinical and research set-
tings where race or other identity
characteristics will be considered,
patients should define their own
identity. Further discussion with
patients is especially important
when their identity is not well
described by existing inputs to
eGFR equations or when patient
values affect the risk–benefit bal-
ance. It is thus vital to maintain
transparency and shared decision
making.
While we await guidance from
the NKF-ASN task force in the
next several months, the search
In Search of a Better Equation
for a better equation remains a
highly complex process with no
universally accepted outcome.
Broad consensus is important; a
uniform method for computing
and reporting the eGFR would
facilitate communication and de-
velopment of best practices. The
ideal race-free solution will priori-
tize accuracy to avoid generating,
maintaining, or worsening dis-
parities. Future kidney-function
estimation should be shaped by
evidence from clinical research-
ers, social context from activists
and historians, and ultimately,
consideration of patient care and
preferences.
Disclosure forms provided by the authors
are available at NEJM.org.
From the Computational Health Informat-
ics Program, Boston Children’s Hospital
(J.A.D., A.K.M.), the Department of Bio-
medical Informatics (J.A.D., A.K.M.) and
the Program in Health Sciences and Tech-
nology (J.A.D.), Harvard Medical School,
and the Division of Nephrology (L.A.I.,
A.S.L.) and the Institute for Clinical Re-
search and Health Policy Studies (H.T.),
Tufts Medical Center — all in Boston; and
the Department of Medicine, University of
California, San Francisco, and Priscilla
Chan and Mark Zuckerberg San Francisco
General Hospital — both in San Francisco
(N.R.P.).
This article was published on January 6,
2021, at NEJM.org.
1. Eneanya ND, Yang W, Reese PP. Recon-
sidering the consequences of using race to
estimate kidney function. JAMA 2019;​322:​
113-4.
2. Diao JA, Wu GJ, Taylor HA, et al. Clinical
Implications of Removing Race From Esti-
mates of Kidney Function. JAMA 2020 De-
cember 2 (Epub ahead of print).
3. Levey AS, Stevens LA, Schmid CH, et al.
A new equation to estimate glomerular fil-
tration rate. Ann Intern Med 2009;​150:​604-
12.
4. Obermeyer Z, Powers B, Vogeli C, Mul-
lainathan S. Dissecting racial bias in an al-
gorithm used to manage the health of popu-
lations. Science 2019;​366:​447-53.
5. Shin J-I, Sang Y, Chang AR, et al. The
FDA metformin label change and racial and
sex disparities in metformin prescription
among patients with CKD. J Am Soc Nephrol
2020;​31:​1847-58.
DOI: 10.1056/NEJMp2028243
Copyright © 2021 Massachusetts Medical Society.
In Search of a Better Equation
399