PERSpECTIvES

Corrected: Author Correction

continued to be published, notably the Mayo

OPINION
Clinic Quadratic (MCQ) equation in 2004
(ref.3), the CKD Epidemiology Collaboration

Estimated GFR: time for a critical formula (CKD-​EPI) in 2009 (ref.4), and
an eGFR equation based on normalized
appraisal values of serum creatinine in 2016 (ref.14).
In 1985, cystatin C was first proposed as a
marker of renal function15. Since then,
Esteban Porrini, Piero Ruggenenti, Sergio Luis-​Lima, Fabiola Carrara, more than 15 eGFR formulae based on
Alejandro Jiménez, Aiko P.J. de Vries, Armando Torres, Flavio Gaspari cystatin C levels have been published
and Giuseppe Remuzzi (Supplementary Table 1).
In addition, several eGFR formulae have
Abstract | Since 1957 , over 70 equations based on creatinine and/or cystatin C combined creatinine and cystatin C16–20,
levels have been developed to estimate glomerular filtration rate (GFR). However, used multiple equations21,22, or included
whether these equations accurately reflect renal function is debated. In this biomarkers (such as β-​trace protein or
β2-microglobulin23) to increase the accuracy
Perspectives article, we discuss >70 studies that compared estimated GFR (eGFR) and precision of GFR estimation. The most
with measured GFR (mGFR), involving ~40,000 renal transplant recipients and recent equations available were published
patients with chronic kidney disease (CKD), type 2 diabetes mellitus or polycystic in 2018: the full age spectrum (FAS)
kidney disease. Their results show that eGFR often differed from mGFR by ±30% or formulae are based on either creatinine or
more, that eGFR values incorrectly staged CKD in 30–60% of patients, and that cystatin C levels, or both21. Finally, some
eGFR equations were developed in specific
eGFR and mGFR gave different rates of GFR decline. Errors were unpredictable,
populations, such as renal transplant
and comparable for equations based on creatinine and/or cystatin C. We argue, recipients24, patients with type 2 diabetes
therefore, that the persistence of these errors (despite intensive research) suggests mellitus (T2DM)25,26, and specific ethnic
that the problem lies with using creatinine and/or cystatin C as markers of renal groups, including African American18,27,
function, rather than with the mathematical methods used for GFR estimation. Chinese20,28–33, Japanese34 or Thai35 patients.
Most modern formulae (algorithms)
used to calculate eGFR (such as the MCQ
A reliable determination of renal function (Supplementary Table 1). These equations equation) are based on serum creatinine
is fundamental in many clinical situations, have increased in mathematical complexity and/or cystatin C levels, age, weight and sex.
including the evaluation of patients with over time, from simple ratios between a Typically, these formulae were developed
renal diseases, staging of chronic kidney constant and creatinine level2, to expressions in large populations covering the whole
disease (CKD), predicting the risk of disease involving exponentials or logarithms spectrum of renal function3,4,14,17,18,36 and,
progression, monitoring renal function combined with conditional parameters therefore, are considered more reliable
over time, determining the need for dialysis and corrective factors for sex, ethnicity or than early equations such as the MDRD,
therapy, screening living kidney donors and renal function3–6. which was derived from studies of patients
enabling dose adjustment of nephrotoxic The evolution of GFR estimation with CKD. However, the reliability of these
agents (drugs or contrast media) in patients methods can be considered from an equations remains a matter of debate.
with impaired renal function. In addition, historical perspective. The first formula Several studies performed in different
the accurate and precise evaluation based on serum levels of creatinine used clinical settings have criticized the
of glomerular filtration rate (GFR) is to calculate estimated GFR (eGFR) was performance of eGFR in reflecting real renal
particularly important in clinical studies published in 1957 and was mainly intended function37–44. Moreover, without detracting
that include renal function as a primary to facilitate dose adjustments of medications from the valuable work dedicated to
outcome measure. cleared by the kidneys, such as digitalis and developing these equations, the observation
Serum creatinine level is the most widely antineoplastic drugs7. Other equations based that new eGFR formulae continue to be
used marker of renal function in routine on serum creatinine levels followed8–11, and published implies that a definitive equation
clinical practice1. Creatinine clearance over in 1976 Cockcroft and Gault published an has not yet been developed. In fact, the
a 24 h period (24 h CrCl) is considered a eGFR formula that became very popular performance of modern eGFR formulae
surrogate marker of GFR. However, among physicians12. The eGFR formula (when assessed using appropriate statistical
measurement of 24 h CrCl is burdensome developed in the Modification of Diet in methods) has not improved substantially on
and frequently compromised by incomplete Renal Disease (MDRD) study, published that of the first equation described in 1957
data on urinary volume. To overcome in 2000, became the reference equation — even with the use of complex algorithms
these limitations, more than 70 equations for several years13. However, additional and cystatin C45,46, as we discuss in further
have been developed to estimate GFR creatinine-​based eGFR formulae have detail herein.

NAtuRe Reviews | NePhRoloGy volume 15 | MARCH 2019 | 177
Perspectives
In this Perspectives article, we critically
appraise the results of over 70 published
studies that compared the performance of
any eGFR formulae against any measured
GFR (mGFR) reference method in renal
transplant recipients and patients with
CKD, T2DM or polycystic kidney disease.
The results of studies that assessed a large
number of patients or eGFR formulae,
used appropriate statistics, or evaluated
the agreement between eGFR decline and
mGFR decline, are included in Tables 1–4.
Those that did not fulfil these criteria are
included in Supplementary Tables 2–4. We
argue that the persistence of substantial
errors in all GFR estimation formulae
developed to date suggests that the problem
lies with serum creatinine and cystatin C,
which are poor markers of real renal
function, rather than with the mathematical
approach used to develop the formulae.
Finally, we discuss the implications of eGFR
errors for clinical practice and research.
Markers for estimating GFR
An ideal marker of GFR must not be bound
to proteins and must be inert, freely filtered
by glomeruli, constantly produced, and
eliminated in the urine but not reabsorbed,
secreted or metabolized by renal cells1. The
rate of plasma clearance from the circulation
must equal that of urinary excretion1, and
the relationship between its concentrations
in serum with mGFR must be reciprocal
(Supplementary Fig. 1). Unfortunately,
neither creatinine nor cystatin C meets
these conditions47,48.
Creatinine
Serum creatinine is not bound to proteins
and is freely filtered by the glomeruli1.
However, synthesis of creatinine from
creatine is not constant, since it is affected
by the daily intake of protein and by muscle
turnover. Meat is the major dietary source
of creatine; meat intake influences the
total creatine pool and, therefore, serum
creatinine levels49. The major endogenous
source of creatinine is muscle, and changes
in muscle mass also influence the production
of creatinine. Dietary protein deficiency
leads to loss of muscle mass, which reduces
levels of creatinine50,51. In other conditions
linked to reduced muscle mass (such as
anorexia, cirrhosis or sarcopenia), reduced
production of creatinine leads to diminished
serum creatinine levels and overestimation
of GFR. By contrast, conditions associated
with increased muscle mass or high dietary
protein intakes, such as vigorous exercise52,53,
chronic glucocorticoid therapy54 and
hyperthyroidism55, can increase the levels of
178 | MARCH 2019 | volume 15 www.nature.com/nrneph
creatinine, leading to underestimation
of GFR.
Furthermore, secretion and reabsorption
of creatinine by renal tubular cells and
extrarenal clearance also influence serum
creatinine levels. Under normal conditions,
tubular secretion accounts for about 10%
of total urinary creatinine excretion, but
this percentage increases in parallel with
decreases in GFR1,47, reaching 80–100% in
patients with advanced CKD. Thus, during
the course of CKD, increased tubular
secretion of creatinine limits the increase
in serum creatinine level, which masks the
reduction in GFR. Data on the effect of
tubular reabsorption of creatinine on serum
creatinine levels are limited56–58. In addition,
extrarenal clearance of creatinine (which
includes recycling of creatinine to creatine
and degradation of creatine to products
other than creatinine) increases with the
decrease in renal function, which further
contributes to the overestimation of GFR
in patients with advanced renal disease59,60.
Similar limitations also apply to 24 h CrCl.
These factors explain why the
relationship between creatinine and mGFR
is not linear but curvilinear and why a given
value of serum creatinine can be associated
with a wide range of mGFR values (Fig. 1).
For example, a serum creatinine level of
1.5 mg/dl can be found in patients with
GFRs between 30 ml/min and 90 ml/
min (Fig. 1), illustrating the limitations of
serum creatinine levels for estimating GFR.
Interestingly, this curvilinear relationship
between serum creatinine and GFR
(and the resulting lack of accuracy and
precision of eGFR) has been known
since 1985 (ref.47) (Fig. 2).
Errors in the assays used to measure
creatinine levels might also influence the
correlation between creatinine and GFR.
The Jaffé reaction (a colorimetric method
of measuring creatinine concentration in
blood and serum) can also be induced by
organic compounds in plasma other than
creatinine, which can lead to overestimation
of creatinine levels61–63. Modern enzymatic
assays, in which creatinine levels are
standardized by calibration traceable
to isotopic dilution mass spectrometry
(IDMS) reference measurement procedures,
overcome this issue and have been proposed
as a reference method64. In addition, the
low coefficient of variation of creatinine
measurement could influence the estimation
of GFR65. However, in our opinion, the
choice of method for serum creatinine
measurement does not appreciably affect
the relationship between the two variables,
as the same curvilinear correlation between
creatinine level and GFR can be observed
irrespective of whether creatinine is
measured with the IDMS (Fig. 1) or Jaffé
(Fig. 2) methods.
Cystatin C
Cystatin C is an inhibitor of various cysteine
proteinases that is encoded by CST3, a
regulatory gene expressed in nucleated
cells66. Cystatin C has a constant rate of
production and is freely filtered across
glomeruli66,67. However, it is completely
reabsorbed and metabolized by renal tubular
cells, which prevents its use in calculations
of 24 h urinary clearance66,67. High serum
levels of cystatin C can be observed in
individuals with morbid obesity, T2DM,
hypertension and metabolic syndrome68.
Thus, changes in cystatin C levels might
reflect the patient’s clinical status, in
addition to their renal function. A possible
explanation for the association between high
cystatin C levels and conditions related to
obesity is that cystatin C is the endogenous
inhibitor of cathepsins, which have a role
in adipogenesis; thus, cystatin C might be
secreted by adipocytes in a homeostatic
response to the expansion of adipose tissue68.
As with creatinine and GFR, cystatin C
has a curvilinear relationship with GFR
such that a given value of cystatin C reflects
a range of GFR values (Fig. 1). For example,
cystatin C levels of 1.5 mg/l are associated
with GFR values of 30–90 ml/min (Fig. 1).
Finally, the low coefficient of variation of
cystatin C could influence the estimation
of GFR65. To sum up, we consider that the
extremely wide margins of error for both
creatinine-​based and cystatin C-​based
estimation of GFR make it impossible to
prove that these values can be corrected by
mathematical modelling.
Agreement between eGFR and mGFR
Agreement between mGFR and eGFR values
has been evaluated by various statistical
methods, including correlation coefficients,
mean and mean percent errors, Student’s
t-​test, linear regression, quadratic mean,
and the percentage of estimations falling
within defined margins of error (Tables 1–4;
Supplementary Tables 2–4). All these
approaches have methodological limitations.
For example, Pearson’s correlation
coefficient does not take into account any
differences in values between the groups
being compared. Thus, correlation can be
good (r > 0.9), even when eGFR values differ
from mGFR values by twofold or more
(Supplementary Fig. 2). The mean and mean
percentage errors represent the mean of the
difference between eGFR and mGFR for
 Perspectives

Table 1 | Studies that evaluated estimated GFR in patients with CKD

Study Population Gold standard Formulae Statistics and error Comments Refs
Cross-​sectional studies
Selistre 9,430 white adults Inulin Cr: CKD-​EPI, • P30 overall: CKD-​EPI 80, In 20% of patients, eGFR 81

(2016) (including 1,550 renal Schwartz Schwartz 78 error was more than ±30%
transplant recipients) • P30 CKD stage 1: CKD-​EPI of mGFR
95, Schwartz 86
• P30 CKD stage 2: CKD-​EPI
82, Schwartz 86
• P30 CKD stages 3–5: CKD-​
EPI 69, Schwartz 67
• P10 overall: CKD-​EPI 38,
Schwartz 33
Fan (2014) 1,119 white patients NS Cr: CKD-​EPI P30: Overall, 87; CKD stage • In 10–15% of patients, 82

(including 594 with 1–2, 91; CKD stage 3, 87; CKD eGFR error was more
diabetes mellitus) stage 4–5, 75 than ±30% of mGFR
• Similar error in all CKD
Cy: CKD-​EPI P30: Overall, 79; CKD stage stages
1–2, 93; CKD stage 3, 82; CKD
stage 4–5, 72
Cr+Cy: CKD-​EPI P30: Overall, 91; CKD stage
1–2, 96; CKD stage 3, 91; CKD
stage 4–5, 81
Evans (2013) 2,198 white patients Iohexol Cr: MDRD, CG, • P30: MDRD 65, CG 54, CKD-​ In 35–45% of patients, 83

with CKD stage 4 and CKD-​EPI, Rule, EPI 67 , Rule 67 , Lund-​Malmö eGFR error was more than
5 (including 729 with Lund-​Malmö 76 ±30% of mGFR
diabetes mellitus) • L A: MDRD −8 to 14, CG −6
to 18, CKD-​EPI −9 to 14,
Rule −9 to 16; Lund-​Malmö
−7 to 11
Inker (2016) 3,551 black and white Iothalamate Cr: CKD-​EPI P30: CKD-​EPI 84 • In 10–25% of patients, 23

patients (including 273 eGFR error was more

with diabetes mellitus) Cy: CKD-​EPI P30: CKD-​EPI 83 than ±30% of mGFR
Cr+Cy: CKD-​EPI, P30: CKD-​EPI 89, BTP 76, • BTP and B2M
BTP, B2M, BTP-​B2M B2M 82, BTP-​B2M 85, CKD-​ comparable to old
EPI+BTP-​B2M 90 formulae
van Deventer 100 black South Cr-​EDTA
51
Cr: MDRD, CKD-​ P30: MDRD 74, CKD-​EPI 72, In 15–30% of patients, 84

(2011) African patients EPI, van Deventer van Deventer 70 eGFR error was more than
±30% of mGFR
Cy: van Deventer P30: van Deventer 84
Stevens 1,737 black patients Iothalamate Cr: MDRD (with P30: 82 if mGFR <60 ml/min/ • In 10–20% of patients, 85

(2007) corrective factor) 1.73 m2; 88 if mGFR eGFR error was more

>60 ml/min/1.73 m2 than ±30% of mGFR
• Similar P30 in the white
population (not shown)
Feng (2013) 788 Chinese patients 99m
Tc-​DTPA Cr: CG, MDRD • P30: CG 55, MDRD 44 • In 25–55% of patients, 20

• L A: CG −52 to 47 , MDRD eGFR error was more

−60 to 52 than ±30% of mGFR
• Wide L A for all formulae
Cy: CKD-​EPI, CCG, • P30: CKD-​EPI 63, CCG 65, • In 30–50% of patients,
Feng Feng 72 eGFR led to an error in
• L A: CKD-​EPI −25 to 36, CCG the classification of CKD
−34 to 32, Feng −28 to 31
CG, CCG, Feng • P30: CKD-​EPI 63, CCG 59,
Feng 74
• L A: CKD-​EPI −33 to 39, CCG
−43 to 38, Feng −29 to 28
Murata 2,324 white patients Iothalamate Cr: MDRD, P30: MDRD 75, CKD-​EPI 75 • In 25% of patients, eGFR 86

(2011) CKD-​EPI error was more than

±30% of mGFR
• In 50–60% of patients,
eGFR led to an error in
the classification of CKD
Froissart 2,095 white patients Cr-​EDTA
51
Cr: MDRD, CG • P30 overall: MDRD 87 , CG • In 15–20% of patients, 87

(2005) 79 eGFR error was more

• P30 if mGFR >60 ml/min: than ±30% of mGFR
MDRD 92, CG 88 • In 30% of patients, eGFR
• P30 if mGFR <60 ml/min: led to an error in the
MDRD 83, CG 69 classification of CKD

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Perspectives

Table 1 (cont.) | Studies that evaluated estimated GFR in patients with CKD
Study Population Gold standard Formulae Statistics and error Comments Refs
Hojs (2011) 764 white patients Cr-​EDTA
51
• Cr: MDRD, • P30 CKD stage 3: MDRD 78, In 30–50% of patients, 88

CKD-​EPI, CG CG 59, CKD-​EPI 75, Hojs 78 eGFR error was more than
• Cy: Hojs • P30 CKD stage 4: MDRD 53, ±30% of mGFR
CG 44, CKD-​EPI 50, Hojs 70
• P30 CKD stage 5: MDRD 50,
CG 51, CKD-​EPI 44, Hojs 53
Longitudinal studies
Wang (2006) 1,094 black patients 125
I-​iothalamate Cr: AASK Poor concordance (r = 0.60) Poor agreement between 89

eGFR and mGFR

Xie (2008) 542 white patients 125
I-​iothalamate Cr: MDRD Poor correlation between eGFR decline slower than 90

eGFR and mGFR decline mGFR decline

(r = 0.60, r2 = 0.42). Between-​
patient difference between
mGFR slope and eGFR slope:
58% from −2 to +2 ml/min per
year ; 20% from −2 to −4 ml/
min per year or larger
Tent (2012) 65 white patients 125
I-​iothalamate Cr: CKD-​EPI, • Reduced r2 between mGFR • Median 9 mGFRs per 104

MDRD decline and eGFR decline: patient (range 9–16)

MDRD: 0.45, CKD-​EPI: 0.52 • Poor agreement between
• L A: from +3 to −3 eGFR and mGFR
Padala (2012) 3,531 white American 125
I-​iothalamate Cr: CKD-​EPI Mean eGFR decline 15% • All patients had 3–15 91

and African-​American (pooled data from faster in the AASK study and mGFRs
patients four studies), 18% slower in the CSG study. • Poor agreement between
AASK , DCCT, CSG, Comparable results for the eGFR decline and mGFR
MDRD DCCT study decline
Lee (2009) 146 white patients with Cr-​EDTA
51
Cr: MDRD, CG, Bias between formulae and Poor agreement between 92

stage 3–5 CKD MDRD6 mGFR ranged from +30 to eGFR decline and mGFR
99m
Tc-​DTPA
−30 ml/min at baseline, decline
12 and 24 months
AASK , The African American Study of Kidney Disease and Hypertension; BTP, β-​trace protein; B2M, β2-microglobulin; CCC, concordance correlation coefficient;
CCG, Chinese Collaborative Group formula; CG, Cockcroft–Gault; CKD, chronic kidney disease; CKD-​EPI, CKD Epidemiology Collaboration; Cr, creatinine; CrCl,
creatinine clearance; Cy , cystatin C; DTPA , pentetic acid; eGFR , estimated GFR; GFR , glomerular filtration rate; L A , limits of agreement (values in ml/min/1.73 m2
for cross-​sectional studies and in ml/min/1.73 m2 per year for longitudinal studies); mGFR , measured GFR; MDRD, Modification of Diet in Renal Disease; NS, not
specified; P, percentage of estimations included within an error of either ±30% (P30) or ±10% (P10) of measured GFR; TDI, total deviation index.

each patient. For example, in a hypothetical
group of five patients, eGFR and mGFR
values might differ by −20, −15, 20, 15 and
−5 ml/min. The mean error is −1 because
numerically identical values of opposite
signs (such as −20 and 20) cancel each other
out, blunting the deviation of eGFR from
mGFR (Supplementary Fig. 3). In the paired
t-​test, only mean values are compared, and
the differences between individual data
points are, therefore, largely underestimated.
To assess the acceptability of a formula
that estimates GFR, it is necessary to define
a priori clinically meaningful margins
of error, to determine the proportion of
estimations that fall within these margins,
and to define how much disagreement
is tolerable. The parameter used most
frequently to assess the performance of GFR
estimation equations is P30, which is defined
as the percentage of GFR estimations falling
within ±30% of mGFR values (Tables 1–4;
Supplementary Tables 2–4). Although
other parameters (usually P10 and P20,
representing the percentages of estimations
falling within ±10% and ±20% of mGFR,
respectively) have also been used, P30
deserves special consideration. Notably, P30
was defined in the absence of any clinical
or statistical rationale for considering it an
acceptable margin of error.
However, in our opinion, the limits of
±30% are extremely wide and not acceptable
for evaluating GFR estimation formulae. For
instance, in a patient with mGFR 60 ml/min/
1.73 m2, a P30 margin of error means
that eGFR values of 42–78 ml/min/
1.73 m2 (Fig. 3a) are considered acceptable.
Furthermore, for most eGFR equations, the
proportion of measurements falling within
the nominally acceptable P30 limit varies
from 50% to 90% (Tables 1–4).Thus, in
10–50% of measurements, the error in eGFR
values is >30%. A more rigorous evaluation
of eGFR than the P30 is needed.
Two issues must be considered to
establish new limits of acceptability for
eGFR: first, the reproducibility of the
reference method used to measure GFR,
which is influenced by both the variation in
measurements made by the same instrument
under similar conditions (technical
and clinical) within a short period of
time, and the biological variability of GFR;
and second, the clinical relevance of the
proposed limits in the evaluation of GFR
values and GFR decline. The reproducibility
of mGFR is 5.0–8.0% for iohexol69,70, 4.0%
for EDTA71,72 and 8.5% for iothalamate73.
Moreover, the variability of an external
quality assessment scheme for iohexol
(used by clinical laboratories to calibrate
their GFR reference measurements) is
about 8%74. Thus, the variability of all
GFR measurement methods is 4–8%. This
range includes both the intrinsic error of
the method and the biological variability
of GFR. To ensure that eGFR formulas are
reliable enough to replace mGFR, estimated
values must be comparable to measured
values. Of course, error is present in all
measurement techniques, but intrinsic
errors must be minimized. Accordingly, we
suggest that an acceptable limit of agreement
between eGFR and mGFR should not
exceed ±10% of mGFR and, importantly,
that 90% of estimations should fall within
this margin of error (Fig. 3b). Acceptance of

180 | MARCH 2019 | volume 15 www.nature.com/nrneph

 Perspectives

Table 2 | Studies that evaluated estimated GFR in patients with type 2 diabetes mellitus
Study Population Gold Formulae Statistics and error Comments Refs
standard
Cross-​sectional studies
Iliadis (2011) 448 white 51
Cr-​EDTA • Cr: MDRD, CKD-​EPI P30: MDRD 79, CKD-​EPI 81, • In 20–80% of patients, 46

patients • Cy: Rule, Perkins, Rule 53, Perkins 21, Arnal 45, eGFR error was more than
Tan, Arnal, Stevens, Stevens (Cy) 54, MacIsaac 46, ±30% of mGFR
Grubb, MacIsaac, Tan 79, Grubb 69, Tidman 40, • Similar bias between
Tidman, Flodin Flodin 43, Stevens (Cr+Cy) 70 Cr-​based and Cy-​based
• Cr+Cy: Stevens formulae
Maple-​Brown (2014) 224 indigenous Iohexol Cr: MDRD, CKD-​EPI, CG P30: MDRD 80, CKD-​EPI 87 , In 15–20% of patients, eGFR 108

Australian CG 71 error was more than ±30%

patients of mGFR
Rigalleau (2006) 200 white 51
Cr-​EDTA Cr: MDRD, CG, MCG L A: Bias NS In 30–50% of patients, 109

patients eGFR led to an error in the

classification of CKD
MacIsaac (2015) 199 white 99m
Tc-​DTPA Cr: MDRD, CKD-​EPI • P30: MDRD 86, CKD-​EPI 90 • In 10–15% of patients, 37

patients • L A: MDRD −34 to 31, eGFR error was more than
CKD-​EPI −30 to 27 ±30% of mGFR
• Wide L A
• In 10–30% of patients,
eGFR led to an error in the
classification of CKD
Inker (2012) 1,726 patientsa NS • Cr: CKD-​EPI P30: ~90 for all three In 10% of patients, eGFR 18

from a • Cy: CKD-​EPI equations error was more than ±30%

multi-​ethnic • Cr-​Cy: CKD-​EPI of mGFR
cohort
Li (2010) 91 Chinese 99m
Tc-​DTPA • Cr: MDRD P30: MDRD 69, Stevens 70, • In 60–80% of patients, 102

patients • Cy: Stevens, Ma, Rule, Ma 61, Rule 47 , MacIsaac 55, eGFR error was more than
MacIsaac, Perkins Perkins 44 ±30% of mGFR
• Similar bias between
Cr-​based and Cy-​based
formulae
Longitudinal studies
Gaspari (2013) 600 white Iohexol Cr: MDRD, CG, CKD-​ GFR at baseline: • 449 patients had multiple 45

patientsa EPI, Rule, Effersøe, Hull, mGFRs

• TDI: from Rule 32 to
Mawer, Gates, Ibrahim,
Jelliffe-2 93; CG 51, CKD-​EPI • Poor agreement between
Bjornsson, Davis-​ eGFR and mGFR
41; MDRD 52; Effersøe 55
Chandler, Jelliffe-1,
• CCC: from Jelliffe-2 0.21 • Hyperfiltration rarely
Jelliffe-2, Walser, detected
to Rule 0.52; CG 0.43,
Edwards-​Whyte
CKD-​EPI 0.43, MDRD 0.38, • Effersøe similar to CG and
Effersøe 0.31 CKD-​EPI
• eGFR decline slower than
GFR decline: mGFR decline
• CCC: from Effersøe −0.21
to Hull 0.36; CKD-​EPI 0.28,
MDRD 0.32, CG 0.35
Rossing (2006) 383 white 51
Cr-​EDTA Cr: MDRD, CG GFR at baseline: • Wide L A for eGFR and 38

patients eGFR decline

• L A µAlb: CG −58 to 31,
MDRD −66 to 20 • eGFR decline slower than
• L A proteinuria: CG −39 to mGFR decline
33; MDRD −47 to 25
GFR decline
(mean ±SD ml/min per year):
• µAlb mGFR: −4.1 ± 4.2, CG
−3.4 ± 3.2, MDRD −2.9 ± 2.8
• Proteinuria mGFR: −5.2
± 4.1, CG −4.6 ± 4.1,
MDRD −4.2 ± 3.8
Wood (2016) 152 white 99m
Tc-​DTPA Cr: CKD-​EPI GFR decline eGFR decline slower than 110

patients (ml/min per year): mGFR −2.6; mGFR decline

CKD-​EPI −1.6
µAlb, microalbuminuria; CCC, concordance correlation coefficient; CG, Cockcroft–Gault; CKD, chronic kidney disease; CKD-​EPI, CKD Epidemiology
Collaboration; Cr, creatinine; CrCl, creatinine clearance; Cy , cystatin C; DTPA , pentetic acid; eGFR , estimated GFR; GFR , glomerular filtration rate; L A , limits of
agreement (values in ml/min/1.73 m2 for cross-​sectional studies and in ml/min/1.73 m2 per year for longitudinal studies); mGFR , measured GFR; MCG, modified
Cockcroft–Gault; MDRD, Modification of Diet in Renal Disease; NS, not specified; P, percentage of estimations included within an error of either ±30% (P30) or
±10% (P10) of measured GFR; TDI, total deviation index. aOnly the patients with diabetes mellitus were considered.

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Perspectives

Table 3 | Studies that evaluated the performance of estimated GFR in patients after renal transplantation
Study Population Gold standard Formulae Statistics and error Comments Refs
Cross-​sectional studies
Luis-​Lima 193 white Iohexol Cr: 34 formulae • CCC: Rowe 0.04, Rule 0.66, CG • For all formulae, eGFR showed 79

(2015) patients 0.70, Effersøe 0.77 , CKD-​EPI 0.79, poor agreement with mGFR
MDRD 0.82, Matsuo 0.84 • In 30–60% of patients, eGFR led
• TDI: Matsuo >49%, MDRD 53%, to an error in the classification of
Effersøe and CKD-​EPI 61%, CG CKD stage
81%, Rule 101%
Cy: 14 formulae • CCC: Perkins 0.67; Rule, Tan,
Hoek 0.90
• TDI: Hoek 34%, Perkins 83%
Cr+Cy: • CCC: Ma 0.85, Stevens 0.90,
3 formulae CKD-​EPI 0.87
• TDI: Ma 49%, Stevens 37%,
CKD-​EPI 47%
Masson 825 white • Inulin Cr: MDRD, • P30: MDRD 80, CKD-​EPI 74 • In 20–25% of patients, eGFR error 115

(2013) patients • 51Cr-​EDTA CKD-​EPI • Similar errors within each CKD was more than ±30% of mGFR
stage • Wide L A for all formulae
• L A: MDRD −23 to 26, CKD-​EPI • In 30% of patients, eGFR led to
−21 to 32 an error in the classification of
CKD
Masson 670 white Inulin Cr: CKD-​EPI P30: 75 In 15–25% of patients, eGFR error 116

(2013) patients was ±30% of mGFR

Cy: CKD-​EPI P30: 81
Cr+Cy: CKD-​EPI P30: 86
Mariat 294 white Inulin Cr: MDRD, CG, • P10: MDRD 30, CG 24, Walser 28, • In 70% of patients, eGFR error 40

(2004) patients Walser, Jelliffe, Jelliffe 32, Nankivell 23, 24 h CrCl 26 was more than ±30% of mGFR
Nankivell, 24 h • L A: CG −35 to 27 , Walser −23 to • Wide L A for all formulae
CrCl 33, MDRD −29 to 28, Jelliffe −26
to 29, Nankivell −37 to 21, 24 h
CrCl −39 to 26
Mariat 284 white Inulin Cr: CG, aMDRD, P30: CG 59, aMDRD 73, MDRD-7 75 • In 25–40% of patients, eGFR 41

(2005) patients MDRD-7 error was more than ±30% of

mGFR
• Wide L A for all formulae
• In 30–40% of patients, eGFR led
to an error in the classification
of CKD
Longitudinal studies
Bosma 798 white 125
I-​iothalamate Cr: MDRD, • P30 at baseline: MDRD 88, • 478 patients had 3 mGFRs in 42

(2005) patients Jelliffe-1, Jelliffe-2, Jelliffe-1 87 , Jelliffe-2 88, Gates 5 years
Gates, Nankivell, 87 , Hull 74, Nankivell 76, CG 76; • In 10–30% of patients, eGFR
CG, Hull, Mawer, Mawer 73, Rule 72, 24 h CrCl 66; error was more than ±30% of
Rule, 24 h CrCl P10: <40% for all equations mGFR
• mGFR decline: −1.9 ± 15 • Poor agreement between eGFR
• eGFR decline: from 0.5 ± 12.0 and mGFR decline
(Jelliffe-1) to −2.3 ± 12.0 (Hull);
P30: <24% for all equations
Gaspari 81 white Iohexol Cr: CG, Nankivell, • P10 at baseline: from • All patients had 3 mGFRs 43

(2004) patients Bjornsson, Davis-Chandler 20 to Walser 46, • In 20–55% of patients, eGFR

Edwards-​White, CG 31, MDRD 44 error was more than ±10% of
Davis-​Chandler, • mGFR decline: −3.0 ml/min/ mGFR
Hull, Jelliffe-1, 1.73 m2 per year • eGFR decline was faster than
Jelliffe-2, Mawer, • eGFR decline: from Walser −5.0 mGFR decline
Walser, MDRD to Davis-Chandler −7.4 ml/
min/1.73 m2 per year
Gera (2007) 684 white 125
I-​iothalamate Cr: MDRD, CG, • mGFR decline: −3.9 ± 13 • 360 patients had >3 mGFRs in 117

patients Rule • eGFR decline:. MDRD 2.2 ± 10, 3 years

CG: −1.1 ± 11, Rule −1.5 ± 12 • eGFR decline was slower than
(% per year) mGFR decline
• Correlation (r2) between MDRD • Poor correlation between eGFR
and mGFR 0.36; between Rule and mGFR
and mGFR 0.49
Fauvel 631 white Inulin Cr: MDRD, CKD-​ L A (% of variation in GFR decline): • All patients had 2–7 mGFRs 118

(2013) patients EPI, CG, 1/Cr from −40% to 40% for all formulae • Extreme variability between
eGFR and mGFR decline

182 | MARCH 2019 | volume 15 www.nature.com/nrneph

 Perspectives

Table 3 (cont.) | Studies that evaluated the performance of estimated GFR in patients after renal transplantation
Study Population Gold standard Formulae Statistics and error Comments Refs
Hossain 99 white 99m
Tc-​DTPA Cr: MDRD, CG • mGFR decline: −6.0 eGFR decline was faster than 119

(2010) patients • eGFR decline: MDRD −6.8, CG mGFR decline

−6.2 (% per year)
Buron (2011) 1,249 white Inulin Cr: MDRD, CKD-​ • P30 at baseline: MDRD 85, CKD-​ • In 15–35% of patients, eGFR error 120

patients EPI, CG, Nankivell EPI 81, CG 77 , Nankivell 64 was more than ±30% of mGFR
• L A: MDRD −22 to 21, CKD-​EPI • Wide L A for all formulae
−21 to 29, CG −20 to 30, Nankivell • No statistical analysis of GFR
−13 to 35 decline
aMDRD, abbreviated Modification of Diet in Renal Disease; CCC: concordance correlation coefficient; CG: Cockcroft–Gault; CKD, chronic kidney disease;
CKD-​EPI, CKD Epidemiology Collaboration; Cr, creatinine; CrCl, creatinine clearance; Cy , cystatin C; DTPA , pentetic acid; eGFR , estimated GFR; GFR , glomerular
filtration rate; L A , limits of agreement (values in ml/min/1.73 m2 for cross-​sectional studies and in ml/min/1.73 m2 per year for longitudinal studies, except where
stated); mGFR , measured GFR; MCG, modified Cockcroft–Gault; MDRD, Modification of Diet in Renal Disease; P, percentage of estimations included within an
error of either ±30% (P30) or ±10% (P10) of mGFR; TDI, total deviation index.

wider limits of agreement (>10%) would
both increase the variability between eGFR
and mGFR and reduce the reliability of
GFR estimations.
Another important point to consider is
the large effect of errors in eGFR values
on the calculation of GFR decline. This factor
explains why eGFR declines can be either
faster or slower than mGFR declines in
published studies, a topic that is discussed
further in the following sections. So, eGFR
values must be comparable to mGFR values,
to avoid errors in the evaluation of renal
function and in its change over time.
Furthermore, appropriate statistics must
be used to assess the agreement between
mGFR and eGFR. Such statistics must
simultaneously consider precision and
accuracy, and must provide confidence
intervals75–77. Appropriate parameters
include the limits of agreement78, total
deviation index (TDI), concordance
correlation coefficient (CCC) and coverage
probability75–77. The limit of agreement is a
range that encompasses most differences
between two measurements (the reference
interval is defined as mean ±1.96 × 1 SD).
The narrower these limits are, the better the
agreement between the measurements.
CCC combines elements of accuracy
and precision; a score >0.90 (range 0–1)
reflects optimal concordance between
measurements. TDI is a measure that
captures a large proportion of data within
a boundary representing the allowable
difference between two measurements75.
For example, a TDI of 60% represents poor
agreement (because it means that 90% of
eGFR values fall within ±60% of mGFR,
which is a very large margin of error)75.
The ideal situation would be a TDI of <10%,
meaning that 90% of eGFR values fall within
±10% of mGFR, a much smaller margin
of error (Fig. 3b). Coverage probability
values range from 0 to 1; this statistic
estimates whether a given TDI is less than a
prespecified percentage75. All these statistics
provide confidence intervals that enable
generalization of the results. However, these
tests have rarely been used in the study of
eGFR45,79,80 (Tables 1–4).
Evidence of eGFR errors
Chronic kidney disease. Over 30 studies,
involving about 30,000 participants, have
evaluated the performance of eGFR in
patients with CKD17,20,23,28–35,81–103 (Table 1;
Supplementary Table 2). In cross-​sectional
studies, P30 ranged from 60% to 90%, and
P10 averaged 40%. Thus, most eGFR values
showed ±30% discordance with mGFR
values. Importantly, in 10–40% of patients,
the discordance with mGFR exceeded
±30%. The margin of error was comparable
for creatinine-​based and cystatin C-​based
equations, showing that cystatin C did
not improve the performance of eGFR
calculations17,20,23,82,97. For example, two
different studies observed that CKD-​EPI
equations using creatinine, cystatin C, or
both, all exhibited similar P30 values of
83–89%23,97. The limits of agreement between
eGFR and mGFR were extremely wide
(from −40 ml/min/1.73 m2 to 40 ml/min/
1.73 m2)98. The only study that used statistics
of agreement showed poor concordance
(CCC <0.75) between mGFRs and eGFRs
calculated using the MDRD, CKD-​EPI and
Cockcroft–Gault equations93.
Agreement between eGFR and mGFR
was poor for every stage of CKD81,82,88,97.
P30 values tended to be higher in CKD
stage 1–2 than in CKD stage 3–5. This error
markedly affected the classification of CKD
stage, resulting in about one in three patients
being incorrectly classified on the basis of
eGFR into a lower or higher CKD stage than
they would be by mGFR20,86,101. The MDRD
equation is considered appropriate for use in
patients with CKD, because it was developed
mostly in individuals with this condition.
However, P30 values of 92% and 88%
(obtained in patients with mGFRs above and
below 60 ml/min, respectively87), and a lower
P30 of 50% in patients with CKD stages 4–5,
have been reported with this formula88,100.
Moreover, the P30 values of formulae
developed in populations that include the
whole spectrum of GFR values (such as
CKD-​EPI, variants of which are based on
creatinine, cystatin C or both, MCQ and
Cockcroft–Gault) are similar to or even
worse than those of the MDRD equation
in patients with CKD82,83,86,88 (Table 1).
The same equation can also yield discrepant
results in similar populations; for
example, CKD-​EPI had P30s of 67%83
and 87%82 in two separate studies. Similar
variability was observed for MDRD86,87 and
cystatin C-based formulae17,82,83,97,100.
Interestingly, eGFR has shown wider
margins of error in non-​white than in
white populations. However, the use of
ethnicity-​specific corrective factors or
population-​specific equations did not
improve the accuracy or precision of eGFR
measurements. In African Americans with
CKD, eGFRs calculated using the African-​
American Study of Hypertension and
Kidney Disease (AASK) formula exhibited
great variability compared with mGFRs25,27.
In patients with eGFRs <60 ml/min/1.73 m2,
an MDRD variant adapted to African
Americans and the CKD-​EPI equation4 both
showed similar P30 values of ~82%85. In
black South Africans, the standard MDRD
exhibited a higher P30 than the adapted
formula84 (Table 1). Similarly, adapted
equations or population-​specific formulae
did not improve the accuracy of eGFRs
in Chinese or Japanese patients20,29–35,90.
Finally, equations based on β-​trace protein
or β2-microglobulin did not outperform
previous formulae23.
Few studies have compared the
performance of different eGFR formulae
in the monitoring of renal function over
time, an issue of particular relevance in
patients with progressive diseases. From a
methodological point of view, it is important
to note that GFR decline is frequently

NAtuRe Reviews | NePhRoloGy volume 15 | MARCH 2019 | 183
Perspectives
Table 4 | Studies that evaluated the performance of estimated GFR in autosomal dominant polycystic kidney disease
Study Population Gold standard Formulae
Cross-​sectional studies
Orskov 101 white Cr-​EDTA
51
(2009) patients
Longitudinal studies
Spithoven 121 white 125
I-​iothalamate Cr: MDRD,
(2013) patients
Ruggenenti 111 white Iohexol
(2012) patients
CG, Cockcroft–Gault; CKD-​EPI, Chronic Kidney Disease–Epidemiology Collaboration; Cr, creatinine; Cy , cystatin C; eGFR , estimated GFR; GFR , glomerular
filtration rate; L A , limits of agreement (values in ml/min/1.73 m2 for cross-​sectional studies and in ml/min/1.73 m2 per year for longitudinal studies); mGFR ,
measured GFR; MDRD, Modification of Diet in Renal Disease; P, percentage of estimations included within an error of either ±30% (P30) or ±10% (P10) of mGFR .
evaluated using linear regression analysis,
because the reliability of this calculation is
highly dependent on having a large number
of GFR determinations. When GFR decline
is evaluated with only 2–3 data points, as it
generally is in published studies, the result is
highly dependent on the last recorded value
of GFR. This factor has to be considered
when interpreting the results of available
studies, which have consistently shown
poor agreement between eGFR-​based and
mGFR-based rates of decline (Table 1).
Mean eGFR decline was 15% or 18%
faster than mGFR decline in two different
studies91. In another study, MDRD-​based
eGFR decline was poorly correlated
(r = 0.60, r2 = 0.42) with mGFR decline90.
Accordingly, in 58% of these patients, eGFR
decline differed from mGFR decline by
between −2 ml/min/1.73 m2 per year and
+2 ml/min/1.73 m2 per year, and another
20% of patients showed differences between
−2 ml/min/1.73 m2 per year and −4 ml/min/
1.73 m2 per year or more90. Comparable
results were observed in other studies, which
revealed either poor concordance (r = 0.60)
between eGFR decline and mGFR decline89,
or wide limits of agreement (ranging from
+3 ml/min/1.73 m2 per year to −3 ml/min/
1.73 m2 per year)104. Thus, the rate of
change in eGFR is not a reliable method
for detecting changes in renal function
over time. This factor must be taken into
consideration both in clinical practice and
184 | MARCH 2019 | volume 15 www.nature.com/nrneph
Statistics and error
Cr: CG, P30: CG 90, MDRD 83, CKD-​EPI 90;
MDRD, MDRD-​Cy 97
CKD-​EPI Cy:
MDRD-​Cy
GFR at baseline:
CKD-​EPI
• P30: MDRD 97%, CKD-​EPI 99%; P10:
MDRD 50%, CKD-​EPI 54%
• L A: MDRD −15 to 28; CKD-​EPI −15 to 22
GFR decline (ml/min per year):
• mGFR −2.8 ± 3.4; CKD-​EPI −3.2 ± 3.3;
MDRD −2.9 ± 3.2
• L A: MDRD −5 to 5; CKD-​EPI −5 to 5
Cr: MDRD, GFR at baseline:
CKD-​EPI
• L A: MDRD −30.6 to 19.5; CKD-​EPI −21.3 to 27
GFR decline (ml/min per year):
• mGFR −8 ± 10; CKD-​EPI −5 ± 9; MDRD −4.5 ± 10
• L A: MDRD −22 to 29; CKD-​EPI −21 to 28
in the design of clinical trials investigating
the prevention of renal function loss.
Very few studies have analysed the
effect of GFR decline on important clinical
outcomes such as cardiovascular disease or
end-​stage renal disease (ESRD). In one
study of patients with GFR <30 ml/min,
mGFR was a better predictor of all-​cause
mortality than CKD-​EPI-based eGFR:
an improvement in GFR of ~7 ml/min was
associated with reductions in all-​cause
mortality of 29% when mGFR was used
versus 9% when eGFR was used105. This
disparity clearly indicates that errors in
eGFR calculations affect predictions of the
consequences of CKD. Moreover, this study
used a simplified mGFR technique based on
a single measurement of plasma clearance
of iohexol, a method shown elsewhere to
be inaccurate in 25% of patients106. The
use of a more accurate GFR measurement
method might further increase the observed
difference between mGFR-​based and eGFR-​
based predictions of all-​cause mortality
in patients with CKD. In a subanalysis of
the AASK study89, the incidence of major
adverse renal events (defined as either a
50% reduction in GFR or ESRD) differed
according to whether eGFR or mGFR was
used. A total of 280 events were detected
using mGFR, of which eGFR only detected
223 (80%). Therefore, 57 of the patients
identified by mGFR as having experienced
a major adverse renal event would remain
Comments Refs
• In 10–25% of patients, eGFR 136
error was more than ±30%
of mGFR
• Similar error in eGFR
whether mGFR was above
or below 60 ml/min
• In 1–3% of patients, eGFR 137
error was more than ±30%
of mGFR
• In 46–50% of patients, eGFR
error was more than ±10%
of mGFR
• Wide L A between mGFR
and eGFR decline
• Poor agreement between 44
eGFR and mGFR decline
• mGFR decline faster than
eGFR decline
undiagnosed by eGFR. In addition, a major
adverse renal event was diagnosed in 23
patients by eGFR but not detected by mGFR.
Therefore, eGFR proved to be inaccurate in
the diagnosis of major adverse renal events.
By contrast, in a study that evaluated
the effect of GFR decline (both eGFR-​
based and mGFR-​based) on the risk of
cardiovascular events, death and ESRD107,
mGFR declines over a 2-year period did
not outperform eGFR declines for these
outcomes. Methodological limitations might
explain these intriguing and counterintuitive
results, including the determination of GFR
decline (both eGFR and mGFR) using only
two measurements in 24 months, which
as we noted above is an unreliable method
of measuring the rate of decline in renal
function. In addition, eGFR (not mGFR)
values were used to define ESRD and to
prompt the initiation of dialysis, which leads
to bias in the results favouring eGFR-​based
measurements. Finally, this study was not
designed to evaluate the non-​inferiority
of either method with regard to outcome
prediction. Therefore, the results of this
study must be interpreted cautiously.
Type 2 diabetes mellitus. Several studies,
involving about 3,500 patients with T2DM,
have evaluated the performance of eGFR
versus mGFR over a wide spectrum
of renal function: normoalbuminuria,
microalbuminuria, overt proteinuria,
 Perspectives

a 7.0 Fig. 1 | Relationship between serum levels of

6.5 creatinine or serum cystatin C and measured
6.0 glomerular filtration rate in patients with and
Serum creatinine (mg/dl)

5.5
without renal disease. The cause of renal impair-
5.0
4.5
ment in these two cohorts of patients was type 2
4.0 diabetes mellitus, renal transplantation, autoso-
3.5 mal dominant polycystic kidney disease or
3.0 chronic kidney disease. Measured glomerular fil-
2.5 tration rate (mGFR) was assessed by plasma clear-
2.0 ance of iohexol. a | The curvilinear relationship
1.5 between serum creatinine level and mGFR in
1.0 3,146 patients with renal impairment. b | In these
0.5
3,146 patients, serum creatinine 1.5 mg/dl is asso-
0.0
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180
ciated with mGFRs of 30–90 ml/min. c | The curvi-
mGFR (ml/min) linear relationship between serum cystatin C level
b 7.0 and mGFR in 597 patients with and without renal
6.5 impairment. d | In these 597 patients, serum
6.0 cystatin C 1.5 mg/l is associated with mGFRs of
Serum creatinine (mg/dl)

5.5 30–90 ml/min. Data for this figure were provided

5.0 by the Laboratory of the Aldo e Cele Daccó Center
4.5
for Rare Diseases, Mario Negri Institute, Bergamo,
4.0
3.5
Italy and the Laboratory of Renal Function,
3.0 Hospital Universitario de Canarias, University of La
2.5 Laguna, Tenerife, Spain.
2.0
1.5
In 600 patients with T2DM and
1.0
0.5 normoalbuminuria, microalbuminuria,
0.0 normal renal function or hyperfiltration45,
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 15 creatinine-​based eGFR formulae all
mGFR (ml/min) showed very poor concordance with mGFR
c 6.5
(CCC <0.52). In addition, the average TDI
6.0
5.5 was 50%, indicating that 90% of eGFRs
5.0 fell within a margin of error of ±50%
Serum cystatin C (mg/l)

4.5 compared with mGFR. In addition, 70%

4.0 of the patients with mGFR-​confirmed
3.5 hyperfiltration were not identified by any
3.0 eGFR formula. In patients with T2DM and
2.5
overt nephropathy or CKD, Cockcroft–
2.0
Gault and MDRD eGFR formulae showed
1.5
1.0
wide limits of agreement with mGFR (from
0.5
−47 ml/min to 33 ml/min)38. This error led
0.0 to the misclassification of CKD stage in
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 35% of patients, when staging was based
mGFR (ml/min) on eGFRs derived by the Cockcroft–Gault,
d 6.5
6.0
MDRD and MCQ equations109. Similar
5.5 results were observed in patients with
5.0 T2DM and CKD46,110,111. Thus, compared
Serum cystatin C (mg/l)

4.5 with mGFR, eGFR formulae have failed to

4.0 identify hyperfiltration as well as normal
3.5 kidney function or various degrees of
3.0 renal insufficiency in patients with T2DM
2.5
(reviewed elsewhere114).
2.0
Cystatin C-​based eGFR formulae have
1.5
1.0 shown no improvements in precision or
0.5 accuracy versus serum-​creatinine-based
0.0 formulae in patients with T2DM. Indeed,
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 many cystatin C-​based formulae have
mGFR (ml/min) lower P30 values than those for MDRD or
CKD-EPI formulae, although a few have P30
normal renal function, hyperfiltration from mGFRs by ±30% or more. The limits values comparable to those of creatinine-​
and CKD18,37,38,45,46,102,108–110 (Table 2; of agreement between eGFR and mGFR based formulae (Table 2). Also, the three
Supplementary Table 3). In cross-​sectional were wide and sometimes reached extreme versions of CKD-​EPI (those based on
studies, P30 was 40–90% and P10 was values; for example, from −50 ml/min to creatinine, cystatin C, or both markers) all
8–48%, indicating that most eGFRs differed 35 ml/min for the MDRD109 (Table 2). have comparable P30 values of about 90%,

NAtuRe Reviews | NePhRoloGy volume 15 | MARCH 2019 | 185
Perspectives

a 8.5 estimations fell within a margin of error of

8.0
60–70% with regard to mGFR. The error for
7.5
7.0
24 h CrCl was similar to that for eGFR42,130–132.
6.5 Furthermore, CKD staging based on eGFR
Serum creatinine (mg/dl)

6.0 values led to incorrect classification in

5.5 30–60% of patients79,132–135. The use of eGFR
5.0
values for CKD staging purposes has a major
4.5
4.0 confounding effect in this population.
3.5 Studies that compared creatinine-​based
3.0 and cystatin C-​based formulae yielded
2.5 contradictory results. One report suggested
2.0
1.5
that P30 values were comparable between
1.0 the three different CKD-​EPI formulae116.
0.5 By contrast, several cystatin C-​based
0.0 equations performed better than creatinine-​
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180
based formulae, demonstrated by a reduction
mGFR (ml/min)
b 8.5
in TDI from 70% to 40%79. However, this
8.0 numerical change, though substantial from
7.5 a mathematical point of view, is not sufficient
7.0 to indicate a clinically relevant improvement
6.5 in agreement between eGFR and mGFR.
Serum creatinine (mg/dl)

6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
0 10 20 30 40 50
Fig. 2 | Relationship between serum creatinine level and measured glomerular filtration rate.
Measured glomerular filtration rate (mGFR) was assessed by plasma clearance of 99Tc-​labelled pentetic
acid (DTPA). a | The curvilinear relationship between serum creatinine level and mGFR in 171 patients
with renal disease. b | In these 171 patients, serum creatinine 1.5 mg/dl is associated with mGFRs of
20–70 ml/min. Adapted with permission from ref.47, Elsevier.
and similar results have also been observed
in other studies111 (Table 2). So, as observed
for patients with CKD, the use of cystatin C
did not improve the accuracy of eGFR
formulae in patients with T2DM.
Decline in renal function was slower
when determined by eGFR than by mGFR.
For example, in one longitudinal study
in patients with T2DM, the mean mGFR
decline was −3.37 ml/min/1.73 m2 per year,
whereas the mean eGFR decline was 50–60%
slower (from −1 ml/min/1.73 m2 per year to
−1.50 ml/min/1.73 m2 per year) with various
creatinine-​based formulae45. Similar results
were observed for the CKD-​EPI110, MDRD38
and Cockcroft–Gault38 equations, in patients
with normoalbuminuria, microalbuminuria
or overt proteinuria38,45. The fact that eGFR
decline is slower than mGFR decline limits
the use of eGFR formulae in clinical practice.
Moreover, clinical trials that use eGFR to
measure renal function decline will have a
60 70 80 90 100 110 120 130 140 150 160 170 180
mGFR (ml/min)
reduced statistical power to detect potential
benefits of treatments designed to prevent
renal function loss in patients with T2DM.
Renal transplantation. The performance of
eGFR formulae in renal transplant recipients
has been evaluated in more than 30 studies,
including ~6,000 patients40–43,79,115–135 (Table 3;
Supplementary Table 4). In cross-​sectional
studies, P30 was 30–90% and P10 was
8–48%. Thus, most eGFR formulae erred
by ±30% compared to mGFR, and errors
were frequently even greater. The limits
of agreement between eGFR and mGFR
were wide, from −30 ml/min to 30 ml/min
on average40,115,122,131. This error was similar
for creatinine-​based and cystatin C-​based
equations116,127,131–135. In 193 patients evaluated
using 51 eGFR formulae, all equations
showed poor concordance with mGFR
(CCC 0.04–0.90)79. The average TDI was
about 60–70%, indicating that 90% of
A TDI of 40% still represents a very wide
margin of error that cannot be accepted in
day-​to-day clinical practice or research.
Longitudinal studies have shown opposite
results: in some publications, eGFR decline
was faster, and in others it was slower, than
mGFR decline. One study reported an mGFR
decline of ~2 ml/min per year, but most
eGFR equations showed slower declines42.
Another report showed that eGFR decline
was 30–50% slower than mGFR decline117.
Finally, eGFR decline measured using
creatinine-​based eGFR formulae was twofold
faster than the mGFR decline43. Thus, eGFR
has poor reliability for monitoring kidney
function over time in this population.
Autosomal dominant polycystic kidney
disease. Few studies have tested the
performance of eGFR formulae in patients
with autosomal dominant polycystic
kidney disease (ADPKD)44,136,137 (Table 4).
Two reports showed that most eGFRs
(calculated using MDRD, Cockcroft–Gault
and CKD-EPI equations) fell within a
margin of error of ±30%136,137. In longitudinal
studies, eGFR decline showed wide limits of
agreement with mGFR decline137. Moreover,
eGFR decline was 50% slower than mGFR
decline: −8 ml/min per year versus −4 ml/min
per year44. This difference indicates that eGFR
formulae fail to detect patients who progress
rapidly towards CKD in this population.
Flaws of eGFR in clinical trials
In clinical trials of interventions designed
to slow the rate of decline in renal function
over time, the use of a reliable tool to
determine GFR is imperative. The fact
that chronic nephropathies are slowly
progressive must be taken into account.

186 | MARCH 2019 | volume 15 www.nature.com/nrneph


a b
mGFR mGFR
ml/min 30 36 42 60 78 84 90 ml/min 42 48 54 60 66 72 78
90%
P30 (%) –50 –40 –30 30 40 50 P10 (%) –30 –20 –10 10 20 30
Fig. 3 | The clinical relevance of margins of error in parameters used to assess agreement
between estimated and measured glomerular filtration rates. a | P30 is defined as the percentage
of estimated glomerular filtration rates (eGFRs) that lie within ±30% of the measured glomerular fil-
tration rate (mGFR). In a patient with mGFR 60 ml/min, eGFRs of 42–78 ml/min are within the P30
limit and are therefore considered to be in good agreement with mGFR . b | P10 is defined as the per-
centage of eGFR values that lie within ±10% of mGFR . In a patient with mGFR 60 ml/min, eGFRs of
54–66 ml/min fall within the P10 limit and are considered to be in good agreement with mGFR . To be
clinically meaningful, 90% of eGFRs should fall within this range.
The 2012 Kidney Disease: Improving Agency recommended that mGFR should be
Global Outcomes (KDIGO) clinical practice prioritized over eGFR whenever the precise
guideline on CKD defined rapid progression determination of GFR is considered essential
to CKD as a GFR decline faster than (that is, in prospective studies) to avoid the
−5 ml/min per year138. Clinical interventions great variability in eGFR140.
that achieve a 40–50% reduction in GFR
decline (for example, from −5.0 ml/min mGFR in clinical practice
per year to −2.0 or −2.5 ml/min per year) A new approach to the evaluation of renal
are considered to have proven efficacy in function in day-​to-day clinical practice
preventing renal function loss in high- is needed. According to the evidence we
risk patients. Although this difference discuss here, the development of further
in the rate of decline is clinically important, eGFR equations similar to those already
the change is numerically small, so very published might not be the correct strategy.
precise and accurate tools are needed However, the incorporation of biomarkers of
to detect it. The margin of error of all renal damage into existing equations might
eGFR formulae is wide, and errors are improve the precision and accuracy of eGFR.
unpredictable and occur randomly. Thus, Another possibility could be that mGFR
in serial eGFR values, variations of ±30% could be used in circumstances in which a
from mGFR severely affect the calculation reliable determination of renal function is
of GFR decline, especially when only a few needed. No international recommendations
measurements are obtained. in this field are available. We speculate —
Several studies in renal transplant based on the available literature — that
recipients and patients with CKD, T2DM or mGFR could be implemented to evaluate
ADPKD showed important discrepancies in renal function, its evolution over time and
renal function decline as assessed by eGFR CKD staging in patients with established
and mGFR. In fact, the rate of change in renal disease, and to prevent or avoid the
renal function using eGFR formulae proved toxic effects of drugs or procedures involving
to be 50–100% faster or slower than with contrast media. These circumstances might
mGFR38,42–45,90,91,110,117. This variability can include, for example: the evaluation of living
mask the effects of interventions that slow kidney donors before nephrectomy141,142;
GFR decline. For example, data from the evaluation of the progression of renal
ALADIN study139 showed a 50% reduction function over time in patients with
in GFR decline versus placebo in patients established CKD20,79,86,101,109,132–135; dose
with ADPKD receiving somatostatin adjustment of potentially nephrotoxic drugs
(−2 ml/min per year versus −4 ml/min per (such as chemotherapeutic agents) according
year; P = 0.03). However, recalculation of to renal function; evaluation of patients
GFR decline using the abbreviated MDRD with CKD scheduled to undergo procedures
equation led to slower rates of decline in that require the use of contrast media; to
both groups, particularly in the patients guide therapeutic decisions based on renal
receiving somatostatin, which masked the function, such as the initiation of dialysis
difference between groups (−3.0 ml/min per in patients with advanced (stage 4–5) CKD;
year versus −2.8 ml/min; P not significant) to investigate the possibility of performing
for somatostatin versus placebo nephron-​sparing surgery in patients with
(P.R., unpublished observations). CKD scheduled to undergo nephrectomy;
In the light of the evidence from and evaluation of patients with CKD in
published studies, the European Medicines whom urine collection is not possible.
NAtuRe Reviews | NePhRoloGy
Perspectives
Several different methods have been used
for measuring GFR: the clearance of inulin,
51
Cr-​EDTA,99Tc-​pentetic acid (DTPA), iohexol
or iothalamate143. All these methods have been
criticized as impractical, difficult, burdensome
and time-consuming, which has limited and
even discouraged their use in clinics and
research. However, these limitations mostly
relate to measuring the clearance of inulin,
which requires continuous marker infusion
and urine collection. In a review of studies
that compared clearance of 51Cr-​EDTA,
99
Tc-​DTPA, iohexol or iothalamate with
inulin clearance, the authors concluded that
the evidence suggests that renal clearance
of iothalamate, renal or plasma clearance of
EDTA, and plasma clearance of iohexol are
reliable alternatives to inulin clearance in the
measurement of GFR144. This conclusion is
especially important because inulin is now
very expensive. Additionally, 51Cr-​EDTA
and 99Tc-​DTPA have the disadvantage of
requiring administration of a radiolabelled
substance. However, iothalamate and iohexol
are non-​radioactive markers and clearance
of these agents is simple and practical to
measure in the clinic69,70. In fact, measuring
the plasma clearance of iohexol is safe145 and
only requires a single intravenous injection
of the marker (5 ml in 2 min) with minimal
blood sampling over the subsequent 4–8 h
depending on the patient’s renal function69,70.
Glossary
Accuracy
The degree of closeness of the determined value (in this
case, estimated glomerular filtration rate) to the true
value (measured glomerular filtration rate) under
prescribed conditions. Accuracy is also sometimes
termed trueness.
Bias
The difference between an estimated value (such as
estimated glomerular filtration rate) and a true value
(measured glomerular filtration rate), which is also
termed error. A statistic is biased if it is calculated in
such a way that it is systematically different from the
parameter being estimated.
Coefficient of variation
The variation obtained when measurements are
repeated under the same conditions. A low value
indicates that the technique is both accurate and
precise.
Precision
The closeness of agreement (that is, the degree of
scatter) in a series of determinations (that is, estimated
glomerular filtration rate values) obtained from multiple
sampling of the same homogenous sample under the
prescribed conditions.
Reproducibility
The precision of results compared between two
laboratories. Reproducibility also refers to the precision
of a particular method when used under the same
operating conditions over a short period of time.
volume 15 | MARCH 2019 | 187
Perspectives
Importantly, plasma clearance of inulin and
iohexol result in comparable mGFR values
when multiple blood samples are taken146.
Moreover, iohexol-based GFR measurement
is not a particularly expensive procedure; it
costs about €100–200 (refs69,70).
If methodological complexity is claimed
as an argument against the clinical use of
mGFR, the most appropriate approach must
be to simplify the reference method without
losing its accuracy and precision. One group
simplified the measurement of plasma
clearance of iohexol by replacing venous
blood samples with dried capillary blood
samples deposited on filter paper147. The
dried blood sampling approach is simple and
safe, and increases patient comfort owing to
the use of a painless finger prick to collect
capillary blood. This sampling method also
reduces the number of venipunctures as well
as the cost of iohexol clearance measurement
(since tubes, syringes and sample
centrifugation are not needed). Moreover,
dried blood on filter paper is stable at room
temperature and does not need to be stored
in the freezer. Agreement between the dried
blood sampling approach and the standard
method for measuring plasma clearance of
iohexol was excellent (TDI 9%), suggesting
that the two methods are interchangeable147.
Thus, the dried blood sampling approach
represents a valuable simplification of a
reference method for measuring GFR that
could help to promote the use of mGFR in
clinical practice and research.
Finally, we consider that the suggestion
that GFR measurement is time-​consuming
cannot defend the continued use of
suboptimal and unreliable measures of
kidney function. No one would today
challenge the role of morphological and
functional evaluations in the diagnosis
and monitoring of cardiovascular and
gastroenterological diseases that require
time-​consuming and costly procedures,
such as angiography, colonoscopy,
magnetic resonance neurography or
histological evaluations.
Conclusions
Our review of comparative studies reveals
that the margin of error for all eGFR
formulae is unexpectedly and unacceptably
wide across the whole spectrum of kidney
function, from hyperfiltration and normal
renal function to moderate and advanced
CKD. The performance of eGFR formulae
(in terms of recognized metrics such as
P30 values) has not improved over the
past 60 years, and no improvements can
be attributed to the use of cystatin C-​based
formulae. Thus, eGFR is an unreliable tool to
188 | MARCH 2019 | volume 15 www.nature.com/nrneph
assess renal function in health and disease, as
well as in clinical practice and research.
Whenever feasible, we recommend the
direct measurement of GFR in situations
where careful monitoring of kidney function
and/or its changes over time are required at
the individual level. In the era of precision
medicine, the ongoing use of unreliable
eGFRs rather than mGFR, a key marker of
kidney function, remains a paradox.
Esteban Porrini1,2*, Piero Ruggenenti3,4,
Sergio Luis-Lima1,2, Fabiola Carrara4,
Alejandro Jiménez1, Aiko P. J. de Vries5,
Armando Torres1,2, Flavio Gaspari4 and
Giuseppe Remuzzi3,4,6
1
Hospital Universitario de Canarias, Tenerife, Spain.
2
University of La Laguna, ITB: Instituto de Tecnologías
Biomédicas, Tenerife, Spain.
3
Nephrology and Dialysis Unit, Azienda Socio Sanitaria
Territoriale Papa Giovanni XXIII, Bergamo, Italy.
4
Istituto di Ricerche Farmacologiche Mario Negri
IRCCS, Centro di Ricerche Cliniche per le Malattie Rare
“Aldo e Cele Daccò”, Ranica, Bergamo, Italy.
5
Leiden University Medical Centre, Department of
Medicine, Division of Nephrology, Leiden, Netherlands.
6
Department of Biochemical and Clinical Sciences ‘
L. Sacco’, University of Milan, Milan, Italy.
*e-​mail: esteban.l.porrini@gmail.com
https://doi.org/10.1038/s41581-018-0080-9
Published online 5 December 2018
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Acknowledgements
The authors acknowledge research support from the
DIABESITY working group of the ERA-​EDTA, the IMBRAIN
(CIBICAN) project (FP7-RE6-POT-2012-CT2012-31637-
IMBRAIN) funded under the 7th Framework Programme
(capacities); Instituto de Salud Carlos III (ISCIII) grants
PI13/00342 and PI16/01814 to E.P. and A.T., REDINREN
RD16/0009 and PI10/02428 grants to E.P. and A.T.; and
funding from the IRSIN (Instituto Reina Sofia de Investigacion)
and FEDER (both to A.T.). S.L.L. is a research fellow
supported by ISCIII grant CM15/00214 for Río Hortega spe-
cialized health-​c are post-​t raining contracts. E.P. is a
researcher supported by the ISCIII Ramón y Cajal Programme
and Fundación Caja Canarias grant DIAB05. The authors
thank F. G. Rinne for preparation of the figures, N. N. Mena
for performing the iohexol method in the Laboratory of Renal
Function, and M. L. McLean for technical assistance.
Author contributions
E.P., F.C. and F.G. researched data for the article, made sub-
stantial contributions to discussions of its content, wrote the
manuscript and reviewed or edited the manuscript before
submission. P.R., A.d.V. and G.R. made substantial contri­
butions to discussions of the article content, wrote the
manuscript and reviewed or edited the manuscript before sub-
mission. S.L.-L. researched data for the article, contributed
substantially to discussions of its content, and reviewed or
edited the manuscript before submission. A.J. researched data
for the article and contributed substantially to discussions of
its content. A.T. substantially contributed to discussions of the
article content.
Competing interests
The authors declare no competing interests.
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Reviewer information
Nature Reviews Nephrology thanks E. Cavalier, L. Dubourg
and the other anonymous reviewer(s) for their contribution to
the peer review of this work.
Supplementary information
Supplementary information is available for this paper at
https://doi.org/10.1038/s41581-018-0080-9.