CLINICAL RESEARCH www.jasn.

org

Change in Measured GFR Versus eGFR and CKD

Outcomes
Elaine Ku,*† Dawei Xie,‡ Michael Shlipak,§ Amanda Hyre Anderson,‡ Jing Chen,|
Alan S. Go,¶ Jiang He,** Edward J. Horwitz,†† Mahboob Rahman,††‡‡§§ Ana C. Ricardo,||
James H. Sondheimer,¶¶ Raymond R. Townsend,*** Chi-yuan Hsu,*¶ and the CRIC Study
Investigators
*Division of Nephrology, Department of Medicine, †Division of Pediatric Nephrology, Department of Pediatrics, and §Division of
General Internal Medicine, San Francisco Veterans Affair Medical Center, Departments of Medicine, Epidemiology, and
Biostatistics, University of California, San Francisco, San Francisco, California; ‡Center for Clinical Epidemiology and Biostatistics and
***Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; |Division of
Nephrology and Hypertension, Department of Medicine, Tulane University New Orleans, Louisiana; ¶Division of Research, Kaiser
Permanente Northern California, Oakland, California; **Departments of Epidemiology and Medicine, Tulane University School of
Public Health and Tropical Medicine, New Orleans, Louisiana; ††Division of Nephrology and Hypertension, Department of
Medicine, University Hospitals Case Medical Center Cleveland, Ohio; ‡‡Division of Nephrology, Department of Medicine, Louis
Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio; §§Division of Nephrology and Hypertension, Department of
Medicine, Case Western Reserve University, Cleveland, Ohio; ||Department of Medicine, Division of Nephrology, University of
Illinois, Chicago, Illinois; and ¶¶Division of Nephrology and Hypertension, Department of Internal Medicine, Wayne State University
School of Medicine, Detroit, Michigan

ABSTRACT
Measured GFR (mGFR) has long been considered the gold standard measure of kidney function, but recent studies
have shown that mGFR is not consistently superior to eGFR in explaining CKD-related comorbidities. The associations
between longitudinal changes in mGFR versus eGFR and adverse outcomes have not been examined. We analyzed a
subset of 942 participants with CKD in the Chronic Renal Insufficiency Cohort Study who had at least two mGFRs and
two eGFRs determined concurrently by iothalamate and creatinine (eGFRcr) or cystatin C, respectively. We compared
the associations between longitudinal changes in each measure of kidney function over 2 years and risks of ESRD,
nonfatal cardiovascular events, and all-cause mortality using univariate Cox proportional hazards models. The associ-
ations for all outcomes except all-cause mortality associated most strongly with longitudinal decline in eGFRcr. Every
5-ml/min per 1.73 m2 decline in eGFRcr over 2 years associated with 1.54 (95% confidence interval, 1.44 to 1.66;
P,0.001) times higher risk of ESRD and 1.23 (95% confidence interval, 1.12 to 1.34; P,0.001) times higher risk for
cardiovascular events. All-cause mortality did not associate with longitudinal decline in mGFR or eGFR. When analyzed
by tertiles of renal function decline, mGFR did not outperform eGFRcr in the association with any outcome. In conclu-
sion, compared with declines in eGFR, declines in mGFR over a 2-year period, analyzed either as a continuous variable
or in tertiles, did not consistently show enhanced association with risk of ESRD, cardiovascular events, or death.

J Am Soc Nephrol 27: 2196–2204, 2016. doi: 10.1681/ASN.2015040341

Many studies in nephrology have focused on one-

time measures of estimated or measured kidney
function and their association with the diagnosis,
complications, and prognosis of CKD.1–3 However,
in clinical practice, repeated measures of kidney
function within the same individual are typically
used to determine treatment effects and disease
prognosis. A few recent studies have shown that
changes in renal function using longitudinal
Received April 1, 2015. Accepted October 14, 2015.
Published online ahead of print. Publication date available at
www.jasn.org.
Correspondence: Dr. Elaine Ku, Division of Nephrology, Uni-
versity of California, San Francisco, 533 Parnassus Avenue, U404
Box 0532, San Francisco, CA 94143-0532. Email: elaine.ku@ucsf.
edu
Copyright © 2016 by the American Society of Nephrology

2196 ISSN : 1046-6673/2707-2196 J Am Soc Nephrol 27: 2196–2204, 2016

 www.jasn.org CLINICAL RESEARCH

measures of eGFR by either cystatin C (eGFRcys) or creatinine Table 1. Baseline demographic and laboratory
(eGFRcr) are strongly associated with risk of various CKD– characteristics of participants in the CRIC Study
related outcomes, including kidney failure, cardiovascular Mean6SD, N (%),
Characteristic (n=942)
morbidity, or death.4–8 However, a common limitation cited or Median (IQR)
in these studies is the lack of availability of measured GFR Mean age, yr 56.0 (611.8)
(mGFR) as a gold standard.4,5 Women 407 (43.2%)
More recently, there has been increased interest in the Race
association between changes in GFR over time and CKD- Non-Hispanic white 428 (45.4%)
relevant outcomes, especially in the context of potentially Non-Hispanic black 334 (35.5%)
redefining surrogate end points in clinical trials of CKD Hispanic 114 (12.1%)
Other 66 (7.0%)
interventions.9,10 Although change in eGFR over time seems
Body mass index, kg/m2 31.3 (66.6)
to be associated with risk of CKD-related outcomes,4–6,8,11 we
Diabetes 411 (43.6%)
are unaware of any studies that have compared changes in Systolic BP, mmHg 126.2 (620.3)
mGFR versus eGFR in their associations with CKD-related Diastolic BP, mmHg 72.3(612.4)
outcomes. A few studies have compared the concordance be- History of cardiovascular disease 233 (24.7%)
tween longitudinal measures of mGFR and eGFR using mGFR CHF 47 (5.0%)
as the gold standard measure of renal function,12–14 but these Peripheral vascular disease 42 (4.5%)
studies did not examine the association of change in renal Stroke 72 (7.6%)
function with outcomes of interest. Myocardial infarction 146 (15.5%)
In this study, we examined whether repeated measures of Median 24-h urine albumin, g/d 0.04 (IQR, 0.0–0.4)
measured GFR by iothalamate clearance (iGFR) are more Hemoglobin A1C, % 6.4 (61.5)
LDL, mg/dl 102.9 (635.2)
strongly associated with CKD-related outcomes, such as ESRD,
HDL, mg/dl 47.1 (615.9)
nonfatal cardiovascular disease, or death, compared with
Baseline renal function, ml/min per 1.73 m2
repeated measures of eGFR or creatinine clearance (CrCl) in iGFR 51.1 (619.5)
the Chronic Renal Insufficiency Cohort (CRIC) Study. On the eGFRcr 46.4 (613.2)
basis of prior work, we hypothesized that changes in iGFR eGFRcys 59.2 (622.4)
would not consistently outperform changes in eGFR for the CrCl 66.2 (631.7)
prediction of CKD-related outcomes.1,15–19 Mean (6SD) change in renal function
between year 2 and baseline,
ml/min per 1.73 m2 per 2 yrs
RESULTS iGFR 23.5 (613.3)
eGFRcr 23.5 (68.9)
eGFRcys 24.4 (612.1)
Baseline characteristics of 942 participants in the CRIC Study
CrCla 24.3 (627.7)
are shown in Table 1. Comparisons of baseline characteristics
Median (IQR) change in renal function
of the subcohort used in this study (n=942) versus the sub- between year 2 and baseline,
sample of participants in the CRIC Study who had at least one ml/min per 1.73 m2 per 2 yrs
GFR measurement (n=1214)16 and the entire CRIC Study co- iGFR 23.4 (210.4–3.1)
hort (n=3939) are provided in Supplemental Table 1. eGFRcr 23.0 (28.7–2.0)
The mean change in GFR was similar (23.5 ml/min per 1.73 m2 eGFRcys 24.3 (211.0–1.9)
over 2 years) by iGFR and eGFRcr (Table 1), but the mean change CrCla 24.3 (216.9–8.6)
in GFR was slightly larger using eGFRcys and eGFR by CrCl (24.4 IQR, interquartile range.
a
and 24.3 ml/min per 1.73 m2 over 2 years, respectively). The n=942 for all GFR measures except for CrCl (n=839).

widest distribution in change in kidney function was by CrCl

(SD of change =27.7 ml/min per 1.73 m2 per 2 years) followed
by iGFR (SD of change =13.3 ml/min per 1.73 m2 per 2 years),
eGFRcys (SD of change =12.1 ml/min per 1.73 m2 per 2 years), and
eGFRcr, which had the narrowest distribution of change in GFR
(SD=8.9 ml/min per 1.73 m2 per 2 years) (Table 1). The medians
and interquartile ranges for the changes in each GFR metric are
also provided in Table 1. When change in renal function was
categorized into tertiles of each metric, the means of the fastest
tertiles of decline were 16.4 ml/min per 1.73 m2 per 2 years by
iGFR, 12.9 ml/min per 1.73 m2 per 2 years by eGFRcr, 16.3 ml/min
per 1.73 m2 per 2 years by eGFRcys, and 30.4 ml/min per 1.73 m2
per 2 years by CrCl.
Figure 1 shows the correlations between iGFR and each of
the eGFR measures. Change in eGFRcr had the strongest cor-
relation with change in iGFR (r=0.44; P,0.001), whereas
change in CrCl had the weakest correlation with change in
iGFR (r=0.15; P,0.001). Overall, the Pearson correlation
was strongest between change in eGFRcr and change in eGFRcys
(r=0.51; P,0.001). Changes in CrCl showed the weakest corre-
lations with all other measures of kidney function.
After the second determination of renal function, there were
150 patients with ESRD (3.78 events per 100 person-years;
mean follow-up =6.3 years), 130 patients with nonfatal

J Am Soc Nephrol 27: 2196–2204, 2016 mGFR Versus eGFR in CKD 2197
 CLINICAL RESEARCH www.jasn.org
Figure 1. Correlation between different measures of renal function
decline. Distributions and Pearson correlation coefficients for de-
cline in each measure of GFR in a subcohort of the CRIC Study. All
comparisons of the different GFR measures had Pearson correlation
coefficients that met a threshold for statistical significance of
P,0.001. All GFR changes are provided in ml/min per 1.73 m2 per
2 years (n=942 for all GFR measures except for CrCl [n=839]).
cardiovascular events (3.33 events per 100 person-years; mean
follow-up =6.0 years), 84 patients with congestive heart failure
(CHF; 2.10 events per 100 person-years; mean follow-up =6.2
years), and 72 deaths (1.67 events per 100 person-years; mean
follow-up =6.6 years).
Results of unadjusted Cox regression models comparing
kidney function decline over a 2-year period using each of four
measures of kidney function as a continuous predictor of CKD-
related outcomes are shown in Table 2. Overall, the strengths of
association between each measure of renal function decline
and each clinical outcome varied, but iGFR did not consis-
tently outperform other measures of kidney function decline.
In terms of the magnitude of the hazard ratio, the associations
for all outcomes were strongest for longitudinal decline in
eGFRcr. In terms of discrimination, the C statistic for iGFR
was never the highest compared with the C statistic for other
metrics of renal function for any of the outcomes of interest.
For the outcome of ESRD, every 5-ml/min per 1.73 m2
decline in eGFRcr per 2-year period was associated with 1.54
(95% confidence interval, 1.44 to 1.66; P,0.001) times higher
risk of ESRD. There was a statistically significant association
between all metrics of renal function decline and ESRD in
both continuous and categorical models. Of note, change in
renal function by eGFRcr had a statistically significantly higher
C statistic than iGFR for the outcome of ESRD using both
continuous and categorical models, whereas change in renal
2198 Journal of the American Society of Nephrology
function by CrCl (continuous and categorical models) had a
statistically significantly lower C statistic than change in renal
function by iGFR (Table 2).
In the continuous models, all measures of renal function
decline, except for CrCl, were statistically significantly asso-
ciated with nonfatal cardiovascular events and CHF (Table 2).
Results were similar by categorical models, except that the
association between eGFRcys and nonfatal cardiovascular
events and CHF did not reach statistical significance. The
size of the hazard ratio was again greatest for eGFR cr in
both continuous and categorical models for nonfatal cardio-
vascular events and CHF. For the outcome of cardiovascular
events, CrCl did have a significantly lower C statistic com-
pared with iGFR. No statistically significant differences in the
C statistics were noted between any of the measures of renal
function and the outcome of CHF, although the magnitude of
the C statistic for decline in renal function by eGFRcr re-
mained the highest for CHF (c=0.60 in both continuous
and categorical models).
All four measures of decline in renal function were not
statistically significantly associated with all-cause mortality in
continuous models, and no differences in the C statistics were
noted, although confidence intervals were relatively wide
(Table 2). In categorical models, only changes in iGFR and
eGFRcr were statistically significantly associated with all-cause
mortality. Change in eGFR cr had the highest C statistic
(c=0.59) by tertile of renal function decline, although this
was not statistically significantly different from the C statistic
for iGFR (c=0.56).
Sensitivity analyses were performed using only the sub-
cohort that had at least two CrCl measures (n=839) in all pre-
vious analyses, and results were similar (not shown). We also
repeated our analyses after adjusting for demographics and
comorbidities and derived similar conclusions: change in
iGFR was not more strongly associated with future adverse
events compared with changes in estimated measures of kid-
ney function (Supplemental Table 2). Finally, we repeated our
Cox models using the 2009 creatinine–based Chronic Kidney
Disease Epidemiology Collaboration (CKD-EPI) equation
and the 2012 creatinine– and cystatin–based CKD-EPI equa-
tions (Supplemental Table 3). The CKD-EPI 2009 model had a
higher C statistic compared with the iGFR model in its asso-
ciation with risk of ESRD in the categorical model.
DISCUSSION
In this study, we showed that longitudinal changes in iGFR,
eGFRcr, or eGFRcys associated with risk of outcomes consid-
ered sequelae of worsening kidney function, such as ESRD,
nonfatal cardiovascular events, and death. However, longitu-
dinal changes in iGFR did not consistently outperform (and
are occasionally inferior to) longitudinal changes in eGFR in
the strengths of their associations with CKD-relevant out-
comes, especially ESRD.
J Am Soc Nephrol 27: 2196–2204, 2016
 Table 2. Unadjusted hazard ratios for clinical outcomes (ESRD, cardiovascular event composite, CHF, and all-cause mortality) associated with each measure of
kidney function

J Am Soc Nephrol 27: 2196–2204, 2016

Change over Time in Cox Model Using Every 5-ml/min Cox Model Comparing the Tertile of Greatest
Metric of per 1.73 m2 Decrease over 2 yrs Renal Function Decline with the Other Two Tertiles
Kidney Function iGFR eGFRcr eGFRcys CrCl iGFR eGFRcr eGFRcys CrCl
ESRD
Hazard ratio (95% CI) 1.28a (1.20 to 1.36) 1.54a (1.44 to 1.66) 1.31a (1.23 to 1.40) 1.03a (1.00 to 1.05) 3.09a (2.23 to 4.26) 4.80a (3.42 to 6.72) 2.25a (1.63 to 3.10) 1.51a (1.06 to 2.14)
C statistic 0.72 (0.68 to 0.75) 0.76 (0.71 to 0.80) 0.70 (0.66 to 0.74) 0.60 (0.55 to 0.65) 0.65 (0.61 to 0.69) 0.70 (0.67 to 0.74) 0.61 (0.57 to 0.65) 0.56 (0.52 to 0.61)
Difference between Reference 0.04 (0.001 to 0.08) 20.02 (20.06 to 0.02) 20.12c (20.18 to 20.07) Reference 0.05c (0.01 to 0.10) 20.04 (20.08 to 0.003) 20.09c (20.14 to 20.04)
C statisticsb
Cardiovascular event
composite
Hazard ratio (95% CI) 1.13a (1.05 to 1.21) 1.23a (1.12 to 1.34) 1.13a (1.04 to 1.22) 1.00 (0.97 to 1.03) 1.58a (1.11 to 2.23) 1.96a (1.39 to 2.76) 1.25 (0.87 to 1.78) 0.88 (0.59 to 1.31)
C statistic 0.59 (0.53 to 0.64) 0.60 (0.54 to 0.65) 0.57 (0.52 to 0.63) 0.50 (0.46 to 0.54) 0.56 (0.51 to 0.60) 0.59 (0.54 to 0.63) 0.54 (0.49 to 0.58) 0.51 (0.48 to 0.54)
Difference between Reference 0.01 (20.04 to 0.07) 20.01 (20.06 to 0.04) 20.09c (20.15 to 20.02) Reference 0.03 (20.01 to 0.08) 20.02 (20.07 to 0.03) 20.05 (20.10 to 0.01)
C statisticsb
CHF
Hazard ratio (95% CI) 1.13a (1.03 to 1.24) 1.27a (1.14 to 1.41) 1.15a (1.05 to 1.27) 0.99 (0.95 to 1.03) 1.60a (1.04 to 2.46) 2.17a (1.42 to 3.34) 1.11 (0.70 to 1.73) 1.02 (0.63 to 1.65)
C statistic 0.59 (0.52 to 0.65) 0.60 (0.53 to 0.68) 0.58 (0.51 to 0.65) 0.50 (0.44 to 0.56) 0.56 (0.50 to 0.62) 0.60 (0.54 to 0.65) 0.52 (0.48 to 0.57) 0.50 (0.46 to 0.54)
Difference between Reference 0.02 (20.05 to 0.08) 20.01 (20.07 to 0.05) 20.09 (20.17 to 0.003) Reference 0.04 (20.02 to 0.09) 20.04 (20.10 to 0.03) 20.06 (20.12 to 0.01)
C statisticsb
All-cause mortality
Hazard ratio (95% CI) 1.08 (0.98 to 1.19) 1.10 (0.97 to 1.24) 1.01 (0.91 to 1.12) 1.00 (0.96 to 1.04) 1.66a (1.05 to 2.65) 2.00a (1.26 to 3.18) 1.32 (0.82 to 2.12) 0.88 (0.52 to 1.50)
C statistic 0.56 (0.49 to 0.63) 0.55 (0.48 to 0.63) 0.53 (0.46 to 0.59) 0.52 (0.45 to 0.60) 0.56 (0.50 to 0.62) 0.59 (0.52 to 0.65) 0.53 (0.48 to 0.57) 0.51 (0.47 to 0.55)
Difference between Reference 20.01 (20.09 to 0.07) 20.03 (20.12 to 0.05) 20.04 (20.14 to 0.07) Reference 0.02 (20.04 to 0.08) 20.04 (20.10 to 0.03) 20.05 (20.13 to 0.02)
C statisticsb
95% CI, 95% confidence interval.
a
Hazard ratio is statistically significantly associated (P,0.05) with outcome.
b
All C statistics are compared with C statistic for iGFR.
c
C statistic is statistically significantly different (P,0.05) compared with reference C statistic (iGFR).
www.jasn.org

mGFR Versus eGFR in CKD

CLINICAL RESEARCH

2199
 CLINICAL RESEARCH www.jasn.org
Most of the literature on measuring renal function has
centered around one-time measures of GFR and their asso-
ciation with various adverse outcomes.1,16,18,19 There have
been fewer longitudinal studies of the association between
repeated measures of GFR and their association with CKD-
related outcomes. Recently, one paper reported that a 30%
decline in eGFR is associated with increased risk of ESRD
and death, although as expected, this association was stronger
for ESRD than mortality.11 A recent large meta–analysis also
showed that declines in eGFR by 30% or 40% are strongly and
incrementally associated with doubling of serum creatinine
and ESRD, which was the traditional clinical trial outcome
of CKD progression.20 In other studies, change in eGFR has
been shown to strongly associate with cardiovascular disease
and mortality risk.5,21 Our findings are, thus, largely consis-
tent with these prior studies.
Only a few studies have compared the concordance between
longitudinal changes in iGFR and longitudinal changes in
eGFR using iGFR as the gold standard measure of renal
function. For example, a secondary analysis of data from the
Modification of Diet in Renal Disease (MDRD) Study showed
that change in eGFR consistently underestimated change in
iGFR, although no variable could be found to predict a
systematic difference between the slopes.13 A recent study in
type 1 diabetes compared longitudinal measures of iGFR with
longitudinal measures of eGFRcr, eGFRcys, and eGFRcr1cys and
concluded that change in eGFRcr and eGFRcys most closely
approximated change in iGFR, although the differences be-
tween mGFR and eGFR metrics were small.12
In this study, we conducted a head to head comparison of the
performance of change in iGFR versus eGFR using clinical
sequelae of worsening kidney disease (such as ESRD or death)
as a fair umpire.22 The key finding of this study is that longi-
tudinal change in iGFR is not consistently more strongly
associated with sequelae of worsening kidney disease than
longitudinal changes in eGFR. These conclusions were robust,
even when earlier generations of estimating equations (such as
the MDRD equation as opposed to the newer CKD-EPI equa-
tion) were used.
A core finding of our analysis is the marked differences in
the SDs for the change in kidney function measures over
time within individuals (27.7 ml/min per 1.73 m2 per 2 years
for CrCl, 13.3 ml/min per 1.73 m2 per 2 years for iGFR,
12.1 ml/min per 1.73 m 2 per 2 years for eGFR cys , and
8.9 ml/min per 1.73 m2 per 2 years for eGFRcr). Because we
are comparing the same patients with themselves using four
different GFR metrics, the underlying true change in kidney
function should be the same for each person, and therefore,
the widest SD for the change in renal function (CrCl) likely
reflects greater measurement error. Thus, the metric with the
narrowest SD for change in renal function (eGFRcr ) has
greater precision.
Prior studies have shown that repeated measures of iGFR are
limited in their precision with relatively large coefficients of
variation (CVs).16,23,24 The mean intertest CVs for repeated
2200 Journal of the American Society of Nephrology
measurements of iGFR within relatively short periods of
time (days to weeks) have ranged from 8.2% to 11.9%.25,26
Potential reasons for this finding may include the fact
that direct measurement of GFR using exogenous filtration
markers is subject to considerable intraperson and diurnal
variability,27,28 including measurement error caused by poorly
timed collections and inadequate voiding, among other rea-
sons. 15,25 Fewer studies have reported the intertest CV
for eGFR, but in one study, the intertest CV was 10.7% for
eGFRcys and 6.4% for eGFRcr.29 In comparison, the reported
intertest CV for repeated 24-hour CrCl measures ranges from
11.3% to 15.7% in a few reports.29–31 The SDs of the changes
in GFR in our study are consistent with the current literature
on intertest CVs for the various mGFR and eGFR metrics. The
higher precision in GFR measurement using eGFRcr may have
led to stronger associations with the clinical outcomes of in-
terest seen here. Although eGFRcr may be more strongly asso-
ciated with ESRD, because creatinine may play a role in the
decision to initiate dialysis, the hazard ratios for change in
eGFRcr were also the largest for several other outcomes of in-
terest, including nonfatal cardiovascular events and all-cause
mortality.
We believe that, in the context of the published literature,
our results highlight a number of important issues. First, no
prior study has shown that one-time determination of iGFR
is more strongly associated with future adverse events
than eGFR.1,17–19,32 We had previously shown in the CRIC
Study that one-time measures of iGFR do not have stronger
cross–sectional associations with concurrent metabolic con-
sequences of decreased renal function (such as hyperphospha-
temia or hyperkalemia) than eGFR.16 We now show that
longitudinal measures of iGFR are also not more strongly
associated with future clinical sequelae of decreased renal
function than repeated measures of eGFR. Considering the
laborious nature of measuring GFR and the invasiveness of
such techniques, iGFR should ideally provide superior pre-
diction of clinically relevant CKD outcomes compared with
estimated measures of renal function. However, iGFR did not
outperform eGFR in this study or others.1,16–19,32
Second, outside of some very limited circumstances (as in
patients with extremes of body composition), directly mea-
suring GFR may have low utility, at least with currently
available methodology, because these measurements are no
better than eGFR for predicting CKD complications or
prognosis. Among patients with very unusual body compo-
sitions, 24-hour urine collections to quantify CrCl have been
proposed as an alternative way to assess renal function, but our
data also argue against this approach, consistent with recent
guidelines.33 Specifically, we observed that 24-hour urinary
CrCl correlated poorly with all other metrics of kidney func-
tion, and change in CrCl had the weakest associations (and
lowest C statistics) for all end points.
Third, although the current Kidney Disease Improving
Global Health 2012 guidelines suggest the use of cystatin C as a
confirmatory test for CKD when creatinine-based measures of
J Am Soc Nephrol 27: 2196–2204, 2016

renal function may be questionable,33 we did not find change
in eGFRcys to be more strongly associated with our outcomes
of interest compared with change in eGFRcr or iGFR.
Fourth, we believe that our findings support the use of eGFR
measures as a primary methodology for studying the process of
kidney function decline longitudinally.4,5,34,35
Several issues with regards to the study design should be
highlighted. We chose to use unadjusted Cox models as our
primary analysis given that our main predictor, change in GFR,
was determined as repeated measures within the same indi-
vidual, and therefore, demographics and comorbidities remain
the same, even without statistical adjustment. Strengths of this
study include its relatively large size, its diversity in terms of
demographics and inclusion of participants with and without
diabetes mellitus, and its focus on clinically meaningful hard
end points. The CRIC Study (a multicenter, national cohort)
devoted considerable effort into maintaining quality control in
the measurement of iGFR and rigorous adjudication of
cardiovascular events.
One limitation of our study is the availability of only two
measurements of renal function over a 2-year period. However,
prior studies have suggested that a 2-year period is sufficient for
observation of meaningful changes in GFR, and some studies
have shown that even changes in GFR over a 1-year period are
associated subsequently with both increased mortality and
ESRD risk.7,11 For example, in one Canadian study, a decline
in renal function by $25% over 1 year associated with a 1.89
times higher risk of all-cause mortality.8 Using more than two
measurements over 2 years would potentially have improved
the precision in quantifying renal function trajectory. How-
ever, we did not repeat our analysis in patients who had at least
three concurrent measures of iGFR and eGFR in the CRIC
Study given the potential for informative censoring of study
participants who dropped out because of poor outcomes or
were unwilling to continue in the study. We also did not have
repeated measures of renal function within short intervals in
the CRIC Study (e.g., days) and are, therefore, unable to pro-
vide intertest CVs from this specific cohort.
Our results may not be generalizable to all patients with CKD,
including those with polycystic kidney disease or rapidly pro-
gressive GN, because these were CRIC Study exclusion criteria.
Furthermore, both cystatin C and creatinine values required
calibration during the conduct of the CRIC Study, which may
have introduced additional measurement errors beyond those
already inherent in the laboratory assays themselves.23
We also acknowledge that use of eGFR to track longitudinal
changes in renal function may be limited by potential biases
from non-GFR determinants of serum creatinine (such as
interim amputation or other substantial changes in body
composition or physiology). However, it is notable that, despite
this, mGFR was not superior.
Lastly, our results may not necessarily extend to other
methods of measuring GFR using alternative exogenous
filtration markers (such as iohexol or inulin) or other clearance
methods (such as plasma disappearance).36,37
J Am Soc Nephrol 27: 2196–2204, 2016
www.jasn.org CLINICAL RESEARCH
In conclusion, we showed that, in this prospective cohort of
patients with CKD, compared with longitudinal changes in
eGFRcr or eGFRcys, changes in iGFR were not more strongly
associated with CKD-related outcomes, such as ESRD.
CONCISE METHODS
Study Population
Data used for this analysis were derived from the baseline and year 2
visits of the CRIC Study. The CRIC Study is a National Institutes of
Health–sponsored multicenter observational cohort that enrolled pa-
tients from seven clinical centers (13 recruitment sites) located
throughout the United States. 38 Participants with eGFR at a
screening visit between 20 and 70 ml/min per 1.73 m2 on the basis
of the MDRD equation were recruited for study between June of 2003
and September of 2008. The inclusion and exclusion criteria have
been previously published.38,39
A subsample (n=1214) of approximately one-third of the original
CRIC Study enrollees (n=3939) underwent direct measurements of
iGFR by urinary clearance. Exclusion criteria for this testing included
known iodine allergy, pregnancy, and impaired urinary voiding. In
this longitudinal study, 942 participants had two mGFRs and two
eGFRs and were included for analysis, of which 839 participants
also had two 24-hour urinary CrCl collections for analysis. We com-
pared the baseline characteristics of the subcohort used in this anal-
ysis (n=942) with those who underwent at least one direct GFR
measurement (n=1214) and the entire CRIC Study cohort.
Measures of Renal Function
We specified a priori that we would examine longitudinal changes
in kidney function per every 5-ml/min per 1.73 m2 decline over
2 years—which we deemed a clinically relevant change—and by ter-
tiles of decline by each method. Change in GFR was calculated as the
difference between the baseline and year 2 measures. We also speci-
fied a priori that we would conduct analyses dichotomizing changes
of each measure of renal function decline at the fastest tertile to detect
effect sizes that may be otherwise obscured by biologic variability.
Four longitudinal measures of renal function between the baseline
and year 2 visits were compared. First, we examined change in GFR
measured directly by urinary clearance of iothalamate (iGFR).
Measurement of iGFR was conducted using a protocol similar to
that in prior studies by trained GFR technologists.24,40–43 Efforts were
made in the CRIC Study to decrease variability in 125I-iothalamate
clearance results by performing all measurements after consumption
of only a low-protein (,10 g) meal, in the supine or sitting position,
and at approximately the same time of day. Nonsteroidal anti–
inflammatory agents taken on an as-needed basis, including aspirin
and ibuprofen, were withheld for at least 48 hours before each GFR
test. The patients were instructed to drink 1 L water in the evening
before and 5 ml/kg water on the morning of the test. Then, after five
drops of a saturated solution of potassium iodide (190 mg iodide)
were given, a water load of 10 ml/kg was required over the next
90 minutes. Subsequently, 125I-iothalamate (140 mg) was injected
subcutaneously at least 30 minutes after saturated solution of
mGFR Versus eGFR in CKD 2201
 CLINICAL RESEARCH www.jasn.org
potassium iodide administration.16,23 After a 60- to 90-minute waiting
period, timed collections of urine and serum were performed, with a
minimum of 30-minute waiting periods in between all voids. Urine
flow rate was maintained at an absolute minimum of .1 ml/min,
with a desirable urine flow rate of .3 ml/min, and if voids were
,250 ml per time period, longer waiting periods #120 minutes
were accepted in between timed collections. The goal was to obtain
four timed urine collection periods bracketed by blood draws to mea-
sure plasma iothalamate levels. Concurrent urine counts and urine
volumes for each period were determined. GFR was calculated as
the time-weighted average of urine count 3 urine volume/plasma
iothalamate and corrected for body surface area as performed
similarly in other prior studies.43
In the CRIC Study, 88% of subcohort enrollees had four or more
urine collection periods, 6% had three, and 5% had two or fewer. It
was noted that iGFR measures from the first period of the test were
systematically higher than the time-weighted average of all testing
periods, which could be explained by a lack of equilibrium reached
in a substantial number of iGFR tests.23 Therefore, the CRIC Study
Steering Committee decided to eliminate the first period of the iGFR
measure in all primary CRIC Study analyses involving iGFR
data.16,23 The mean intratest CV (defined as the SD across the indi-
vidual testing periods within a given iGFR measurement divided by
the average iGFR at the same visit) for the remaining timed urinary
collections for the measurement of iGFR was 13.8% after excluding
the first period. No adverse events were reported, and patients who
were only able to provide one urine sample were excluded from the
study (n=10). Measurements of iGFR were performed once at base-
line and once at year 2 visits using the same technique, and samples
were processed at the same GFR central laboratory at the Cleveland
Clinic.
Second, we examined change in eGFRcr calculated from the four–
variable MDRD equation as follows: 1753 serum creatinine21.154
3age20.203 3(0.742 if a woman) 3(1.212 if black).44,45 Serum cre-
atinine measurements were all calibrated initially to the Cleveland
Clinic Research Laboratory and subsequently, isotope dilution mass
spectrometry traceable standards.23
Third, we examined change in eGFRcys from the equation 127.73
cystatin C21.17 3age20.13 3(0.91 if a woman) 3(1.06 if black).46
Cystatin C was measured using a particle–enhanced nephelometric
immunoassay measured by a Siemens BNII Machine at the CRIC
Study Central Laboratory with an intertest CVof 4.9%. Internal stan-
dardization was implemented to correct for drift over time when
using different calibrator lots and reagent lots manufactured by Sie-
mens. Specifically, all cystatin C values were calibrated to the combi-
nation of calibrator lot 049851 and reagent lot 167840.23
Fourth, kidney function decline was examined using change in
creatinine excretion determined from a 24-hour urine collection.
Urine creatinine was determined spectrophotometrically by the Jaffe
method (Roche Diagnostics, Indianapolis, IN). Samples were rejected,
and recollection was attempted if total urine volumes were ,500 ml or
collection times were ,22 hours or .26 hours. All CrCls were cal-
culated in this paper as urine count 3 urine volume/plasma iothala-
mate standardized per 1.73 m2 body surface area using standardized
serum creatinine measurements.
2202 Journal of the American Society of Nephrology
In sensitivity analyses, we estimated change in GFR derived from
the CKD-EPI 2009 (creatinine based) and 2012 (creatinine and
cystatin C based) equations for comparison.47,48
Outcomes Evaluated
We examined three clinical outcomes: ESRD, a composite of nonfatal
cardiovascular events, and all-cause mortality. We included stroke,
myocardial infarction, CHF, and peripheral arterial disease as a
composite measure of nonfatal cardiovascular events. We also
evaluated CHF alone as a separate outcome given the stronger
association between reduced kidney function and heart failure than
other cardiovascular events.35 Ascertainment of cardiovascular out-
comes in the CRIC Study has been previously described.49 Only out-
comes after the second kidney function assessment were included for
analysis, and follow-up times for outcomes were counted after the
second kidney function assessment occurred. Analyses for cardiovas-
cular events or death were not censored after onset of ESRD.
Statistical Analyses
We determined Pearson correlations between changes in iGFR
and changes in each of the three measures of eGFR. Cox propor-
tional hazards models were used to examine the association between
5-ml/min per 1.73 m2 decrements in each measure of GFR over
2 years and the outcomes of ESRD, a composite of cardiovascular
events, CHF, and death in unadjusted models. Univariate models
were used throughout given that the primary comparisons between
renal function metrics were made within the same patients over time.
Harrell C statistic with bootstrapped confidence interval was used
to evaluate the fit of each model using four measures of GFR, and
differences between C statistics of each eGFR and the CrCl model were
compared with the C statistic of the iGFR model.
In sensitivity analyses, we repeated our Cox models with each
measure of change in GFR using only the subset of patients with at least
two CrCl measures (n=839). In addition, we also repeated our uni-
variate Cox models with adjustment for age, sex, race/ethnicity, sys-
tolic BP (as a continuous variable), total cholesterol (as a continuous
variable), presence or absence of diabetes, history of any cardiovas-
cular disease, and renal function at baseline (year 0).
ACKNOWLEDGMENTS
We thank Dr. Xuehan Zhang for literature review assistance.
E.K. was supported by American Kidney Fund Grants F32
FK098871 and KL2 TR00014. This project was also supported by
National Institute of Diabetes and Digestive and Kidney Diseases
Grants K01DK092353 (to A.H.A.) and K24 DK92291 (to C.-y.H.).
Funding for the Chronic Renal Insufficiency Cohort (CRIC) Study
was obtained under a cooperative agreement from the National
Institute of Diabetes and Digestive and Kidney Diseases Grants
U01DK060990, U01DK060984, U01DK061022, U01DK061021,
U01DK061028, U01DK060980, U01DK060963, and U01DK060902.
In addition, this work was supported, in part, by Perelman School of
Medicine at the University of Pennsylvania Clinical and Translational
Science Award (CTSA) National Institutes of Health (NIH)/National
J Am Soc Nephrol 27: 2196–2204, 2016

Center for Advancing Translational Sciences (NCATS) Grant
UL1TR000003, Johns Hopkins University Grant UL1 TR-000424,
University of Maryland Grant GCRC M01 RR-16500, the Clinical and
Translational Science Collaborative of Cleveland, NCATS/NIH Grant
UL1TR000439, the NIH Roadmap for Medical Research, Michigan
Institute for Clinical and Health Research Grant UL1TR000433,
University of Illinois at Chicago CTSA Grant UL1RR029879, Tulane
University Translational Research in Hypertension and Renal Biology
Grant P30GM103337, and Kaiser Permanente NIH/National Center
for Research Resources Grant UCSF-CTSI UL1 RR-024131.
The CRIC Study Investigators were Lawrence J. Appel (Johns
Hopkins University), Harold I. Feldman (University of Pennsylvania),
John W. Kusek (National Institute of Diabetes and Digestive and
Kidney Diseases), James P. Lash (University of Ilinois), and Akinlolu
Ojo (University of Michigan).
DISCLOSURES
None.
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org/lookup/suppl/doi:10.1681/ASN.2015040341/-/DCSupplemental.
J Am Soc Nephrol 27: 2196–2204, 2016