CLINICAL EPIDEMIOLOGY www.jasn.

org

Intimal Hyperplasia, Stenosis, and Arteriovenous

Fistula Maturation Failure in the Hemodialysis Fistula
Maturation Study
Alfred K. Cheung,*†‡ Peter B. Imrey,§| Charles E. Alpers,¶ Michelle L. Robbin,**
Milena Radeva,| Brett Larive,| Yan-Ting Shiu,* Michael Allon,†† Laura M. Dember,‡‡§§||
Tom Greene,¶¶ Jonathan Himmelfarb,*** Prabir Roy-Chaudhury,†††‡‡‡ Christi M. Terry,*
Miguel A. Vazquez,§§§ John W. Kusek,||| and Harold I. Feldman,‡‡§§||¶¶¶
and Hemodialysis Fistula Maturation Study Group
*Division of Nephrology and Hypertension, University of Utah, Salt Lake City, Utah; †Medical Service, Veterans Affairs Salt Lake City
Healthcare System, Salt Lake City, Utah; ‡Department of Nephrology, The Second Xiangya Hospital, Central South University,
Changsha, Hunan, People’s Republic of China; §Department of Medicine, Cleveland Clinic Lerner College of Medicine of Case
Western Reserve University, Cleveland, Ohio; |Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio;
¶
Department of Pathology, University of Washington Medical Center, Seattle, Washington; **Department of Radiology and ††Division
of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama; ‡‡Renal-Electrolyte and Hypertension Division,
Department of Medicine, §§Center for Clinical Epidemiology and Biostatistics, and Departments of ||Biostatistics and Epidemiology
and ¶¶¶Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; ¶¶Department of
Population Health Sciences, University of Utah School of Medicine, Salt Lake City, Utah; ***Department of Medicine, Kidney Research
Institute, University of Washington, Seattle, Washington; †††Division of Nephrology, University of Arizona Health Sciences and Banner
University Medical Center, Tucson, Arizona; ‡‡‡Medical Service, Southern Arizona Veterans Affairs Healthcare System, Tucson, Arizona;
§§§
Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas; and |||Division of Kidney, Urologic and
Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland

ABSTRACT
Intimal hyperplasia and stenosis are often cited as causes of arteriovenous fistula maturation failure, but definitive
evidence is lacking. We examined the associations among preexisting venous intimal hyperplasia, fistula venous
stenosis after creation, and clinical maturation failure. The Hemodialysis Fistula Maturation Study prospectively
observed 602 men and women through arteriovenous fistula creation surgery and their postoperative course. A
segment of the vein used to create the fistula was collected intraoperatively for histomorphometric examination.
On ultrasounds performed 1 day and 2 and 6 weeks after fistula creation, we assessed fistula venous stenosis using
pre-specified criteria on the basis of ratios of luminal diameters and peak blood flow velocities at certain locations
along the vessel. We determined fistula clinical maturation using criteria for usability during dialysis. Preexisting
venous intimal hyperplasia, expressed per 10% increase in a hyperplasia index (range of 0%–100%), modestly
associated with lower fistula blood flow rate (relative change, 22.5%; 95% confidence interval [95% CI], 24.6%
to 20.4%; P=0.02) at 6 weeks but did not significantly associate with stenosis (odds ratio [OR], 1.07; 95% CI, 1.00
to 1.16; P=0.07) at 6 weeks or failure to mature clinically without procedural assistance (OR, 1.07; 95% CI, 0.99 to
1.15; P=0.07). Fistula venous stenosis at 6 weeks associated with maturation failure (OR, 1.98; 95% CI, 1.25 to 3.12;
P=0.004) after controlling for case mix factors, dialysis status, and fistula location. These findings suggest that
postoperative fistula venous stenosis associates with fistula maturation failure. Preoperative venous hyperplasia
may associate with maturation failure but if so, only modestly.

J Am Soc Nephrol 28: ccc–ccc, 2017. doi: https://doi.org/10.1681/ASN.2016121355

Received December 22, 2016. Accepted May 13, 2017. Correspondence: Dr. Alfred K. Cheung, University of Utah, Di-
vision of Nephrology and Hypertension, University of Utah, 295
Published online ahead of print. Publication date available at Chipeta Way, Suite 4000, Salt Lake City, UT 84108. Email: alfred.
www.jasn.org. cheung@hsc.utah.edu

Copyright © 2017 by the American Society of Nephrology

J Am Soc Nephrol 28: ccc–ccc, 2017 ISSN : 1046-6673/2810-ccc 1

 CLINICAL EPIDEMIOLOGY www.jasn.org
Although the arteriovenous fistula (AVF) is the preferred type
of vascular access for maintenance hemodialysis, many AVFs
fail to mature.1–4 The pathogenic processes leading to matu-
ration failure have not been clearly delineated. Although de
novo outflow venous stenosis is recognized as an important
cause of failure of synthetic arteriovenous grafts,5–7 the roles of
preexisting and newly occurring venous stenosis in AVF mat-
uration failure remain unclear. Vascular access stenosis is pre-
dominantly caused by intimal hyperplasia, and preexisting
venous intimal hyperplasia before AVF creation has been fre-
quently observed.8–10 In the Hemodialysis Fistula Maturation
(HFM) Study, a prospective, multicenter cohort study of 602
men and women with newly placed AVFs, we previously found
that intimal hyperplasia occupied .20% of the luminal cross-
sectional area in most (57%) vein samples for which this could
be quantified.11
We extend our HFM Study findings by examining (1) the
association of preexisting venous intimal hyperplasia with
subsequent AVF stenosis identified from serial ultrasound
measurements after AVF creation surgery and (2) the associ-
ations of both preexisting venous intimal hyperplasia and
postoperative AVF vein stenosis with clinical AVF maturation
failure. Our hypotheses are that preexisting intimal hyperpla-
sia in the vein used for AVF creation promotes postoperative
AVF stenosis and subsequent maturation failure and that ste-
nosis developing after AVF creation by any mechanism also
contributes to maturation failure.
RESULTS
The HFM Study
Detailed baseline characteristics of the HFM Study cohort have
been previously published.12 Six hundred and two participants
were enrolled from March of 2010 to September of 2013 and
followed prospectively. At baseline, the mean age was 55.16
13.4 (SD) years old, 70% were men, 44% were blacks, 59%
self-reported diabetes, and 64% were receiving maintenance
hemodialysis. Forty-eight percent were taking an antiplatelet
agent, 7% were taking an anticoagulant, 50% were taking a
renin-angiotensin system blocker, 28% were taking a statin,
and 25% were taking an active vitamin analog. Four hundred
fifty-seven (76%) of 602 participants had their AVFs created in
the upper arm.
Vein samples were obtained from 554 (92.0%) participants.
A complete circumferential vein section unobscured by valves
was observed histologically in 365 (65.9%) of these samples.
The numbers of postoperative AVF ultrasound measurements
available for evaluation at 1 day, 2 weeks, and 6 weeks after
surgery were 550 (91.4%), 537 (89.2%), and 517 (85.9%),
respectively.
Less than one half (263 of 602; 43.7%) of the participants
had AVFs that achieved unassisted maturation; approximately
one quarter (166 or 27.6%) had AVFs that matured with as-
sistance, and approximately one quarter (133 or 22.1%) had
2 Journal of the American Society of Nephrology
AVFs that failed to mature. Unassisted and overall maturation
status could not be determined for 4.3% and 6.6% participants,
respectively, primarily because follow-up was terminated ad-
ministratively before dialysis was required or the maturation
status could be resolved or the participant received a kidney
transplant before the resolution of maturation status. Matu-
ration status stratified by sex and arm location is presented in
Supplemental Table 1. Patients with indeterminate AVF mat-
uration status, missing ultrasound measurements, and/or in-
complete vein samples from which the hyperplasia index
could not be adequately assessed were retained in the analysis
by multiple imputation of such missing data from ultrasounds
at other time points and additional patient attributes as pre-
viously described.13
Frequency, Characteristics, and Time Course of
Stenosis on Postoperative Ultrasounds
Postoperative ultrasound measurements were analyzed for the
presence or absence of venous stenosis and other features.
Stenoses meeting the criteria described in Concise Methods
were classified as either juxta anastomotic (juxta-anastomotic
stenosis) or AVF draining vein (distal stenosis) on the basis
of whether the distance from the anastomosis in the AVF drain-
ing vein was #2 or .2 cm, respectively. As shown in Figure 1,
the prevalence of stenosis detected on ultrasound was 14% at
Figure 1. Prevalence and transitions of ultrasound-detected
stenoses at three different time points after AVF creation. Black
boxes represent participants in whose AVFs one or more stenoses
were detected, and white boxes represent those without detected
stenosis. Numbers in black boxes are percentages with stenosis
(prevalence) among all participants who underwent the ultrasound
examination at the time point indicated on the left. Those in white
boxes are the percentages of stenosis-free participants. Numbers
adjacent to arrows are percentages of participants in the higher
box who transitioned to the lower box on the next ultrasound from
data on all participants who underwent both examinations. Black
arrows indicate stenosis development or persistence, whereas white
arrows indicate continued absence or resolution of stenosis.
J Am Soc Nephrol 28: ccc–ccc, 2017
 www.jasn.org CLINICAL EPIDEMIOLOGY

1 day, doubled to 28% at 2 weeks, and increased slightly to
30% from 2 to 6 weeks. Juxta-anastomotic stenosis was ob-
served more frequently than distal stenosis at 1 day (61
[11.1%] versus 23 [4.2%] participants, including three with
both types) and 2 weeks (92 [17.1%] versus 60 [11.2%],
including four with both types), but these were similar in
frequency (75 [14.5%] versus 80 [15.5%], including six with
both types) at 6 weeks. Supplemental Table 2 shows, sepa-
rately, the prevalence of juxta-anastomotic stenosis and distal
stenosis for forearm and upper arm AVFs. The increase in
prevalence of stenosis was not cumulative, because 37% of
study participants who exhibited stenosis on the 1-day ultra-
sound did not exhibit stenosis on the 2-week ultrasound, and
virtually the same fraction (36%) of those who exhibited ste-
nosis on the 2-week ultrasound did not exhibit stenosis on the
6-week ultrasound. Conversely, among participants with ul-
trasounds that did not reveal stenosis at 1 day, a new stenosis
was identified in 21% at 2 weeks; for those with no stenosis at
2 weeks, a new stenosis was identified in 16% at 6 weeks
(Figure 1).
The mean AVF vein inner diameter was lower in participants
with a stenosis than those without a stenosis detected by ul-
trasound at 1 day (4.48 versus 4.84 mm; P=0.02), 2 weeks (5.44
versus 5.88 mm; P,0.001), and 6 weeks (5.86 versus 6.57 mm;
P,0.001). The mean blood flow rate was also lower in partic-
ipants with a stenosis (495 versus 726 ml/min at 1 day; 714
versus 962 ml/min at 2 weeks; and 764 versus 1124 ml/min at
6 weeks; P,0.001 for each).
Association of Preexisting Venous Intimal Hyperplasia
with Stenosis on Postoperative Ultrasounds
As previously reported, 88% of the 365 complete vein samples
examined showed some degree of intimal hyperplasia. How-
ever, 42.7% of these samples showed intimal hyperplasia in-
dices #20%, and only 24.1% showed indices .50%.11 Table 1
summarizes associations of the preexisting venous intimal hy-
perplasia with the presence of stenosis identified on each
postoperative ultrasound examination expressed as odds ra-
tios (ORs) comparing samples differing in their intimal hy-
perplasia indices by 10% of maximal luminal area (Concise
Methods). The OR for the 6-week ultrasound, designated a
priori as the primary ultrasound examination for this report,
was 1.07 (95% confidence interval [95% CI], 1.00 to 1.16),
which approached but did not achieve statistical significance
(P=0.07). The associations of the intimal hyperplasia index
with stenosis at 1 day and 2 weeks were weaker and also
statistically nonsignificant. The associations of the intimal hy-
perplasia index with juxta-anastomotic stenosis and distal ste-
nosis are reported separately in Supplemental Table 3, where
the associations with juxta-anastomotic stenosis seem weaker
than those with distal stenosis.
Associations of Preexisting Venous Intimal Hyperplasia
with Postoperative Vein Diameter and Blood Flow Rate
Greater preexisting venous intimal hyperplasia was signifi-
cantly associated with lower AVF blood flow rates assessed
by ultrasound at 6 weeks (2.5% reduction per 10% increase
in intimal hyperplasia index; P=0.02) (Table 1) but was not
significantly associated with the 2-week or 1-day measure-
ments. Associations between preexisting venous intimal hy-
perplasia and vein diameters were not statistically significant
at any postoperative time point examined.
Associations of Preexisting Venous Intimal Hyperplasia
with Clinical Maturation Failure
The association of increasing venous preexisting hyperplasia
with clinical AVF maturation failure that occurred in the ab-
sence of assistance did not achieve statistical significance (OR,
1.07 per 10% increase in hyperplasia index; 95% CI, 0.99 to
1.15; P=0.07). Results were similar for overall maturation fail-
ure (i.e., failure that occurred regardless of whether interven-
tional procedures were used to assist maturation; OR, 1.08;
95% CI, 0.98 to 1.19; P=0.11). If the association of intimal
hyperplasia with postoperative variables was mediated by

Table 1. Associations of preexisting venous intimal hyperplasia index with AVF stenosis, venous blood flow rate, and mean
venous diameter on three postoperative ultrasounds
Postoperative Ultrasound Stenosis Prevalence Venous Blood Flow Rate Mean Venous Diameter
Time Point ORa 95% CI P Valueb Relative D, %c,d 95% CI P Valueb D, mmc,e 95% CI P Valueb
6 wkf 1.07 1.00 to 1.16 0.07 22.5 24.6 to 20.4 0.02 20.018 20.07 to 0.03 0.46
2 wk 1.00 0.93 to 1.09 0.91 21.5 23.3 to 0.5 0.14 20.002 20.04 to 0.04 0.92
1d 1.04 0.94 to 1.16 0.49 20.2 21.9 to 1.5 0.81 20.001 20.03 to 0.03 0.94
All analyses involve multiply imputed data.
a
OR of developing stenosis per 10% increase in intimal hyperplasia index adjusted for age, sex, black race, chronic dialysis status at time of AVF creation, and AVF
location (upper arm versus forearm) as well as inflow artery diameter, mean vein diameter, and brachial artery blood flow rate on preoperative ultrasound, with
clinical center modeled as a random variable.
b
P#0.05 is nominally considered to be statistically significant.
c
Adjusted for age, sex, black race, chronic dialysis status at time of AVF creation, and AVF location (upper arm versus forearm), with clinical center modeled as
a random variable.
d
Percent relative change in AVF blood flow rate per 10% increase in intimal hyperplasia index.
e
Change in mean AVF vein diameter (millimeters) per 10% increase in intimal hyperplasia index.
f
Week 6 results were identified a priori as the primary ultrasound outcomes among the three time points. Hence, these P values were not corrected for testing
at multiple time points.

J Am Soc Nephrol 28: ccc–ccc, 2017 Intimal Hyperplasia, Stenosis, and AVF Maturation 3
 CLINICAL EPIDEMIOLOGY www.jasn.org

reduced preoperative venous diameter and/or blood flow rate,
adjustment for these two latter variables might obscure this
association. In sensitivity analyses, we removed adjustments
for preoperative venous diameter and blood flow rate on ul-
trasound from the statistical models relating the intimal hy-
perplasia index to postoperative venous diameter, blood flow
rate, and both types of clinical maturation outcomes. This
modification did not meaningfully change the results (OR, 1.07;
95% CI, 1.00 to 1.16; P=0.05 for unassisted maturation failure;
OR, 1.09; 95% CI, 0.99 to 1.20; P=0.09 for overall maturation
failure). Note that effects of such magnitudes of hyperplasia are
modest. Eighty-one percent of patients with full cross-section
samples had hyperplasia indices #60%. With an OR of 1.07, in-
creasing hyperplasia from 0% to 60% of lumen area or maximally,
to 100% would increase the maturation failure risk from 40% risk
to 50% and 57%, respectively.
Association of Stenosis Determined by Postoperative
Ultrasound Measurements with Clinical Maturation
Failure
Stenosis identified on ultrasound at each postoperative time
point was directly associated with failure to achieve unassisted
maturation and failure to achieve overall maturation after adjust-
ment for case mix and preoperative ultrasound measures. The ORs
of unassisted maturation failures for stenosis identified by the 1-
day, 2-week, and 6-week ultrasounds were 1.86 (95% CI, 1.09
to 3.18; P=0.02), 1.47 (95% CI, 0.96 to 2.25; P=0.08), and 1.98
(95% CI, 1.25 to 3.12; P=0.004), respectively. The correspond-
ing ORs of overall maturation failures were 2.24 (95% CI, 1.27
to 3.93; P=0.005), 1.66 (95% CI, 1.04 to 2.65; P=0.04), and 1.98
(95% CI, 1.26 to 3.13; P=0.004), respectively (Table 2).
We investigated whether the association of stenosis with
AVF clinical maturation failure varied depending on the loca-
tion of the stenosis by comparing juxta-anastomotic stenosis
with distal stenosis. For ultrasounds at each time point, the
associations of unassisted maturation with distal stenosis were
stronger than those with juxta-anastomotic stenosis, al-
though the difference was statistically significant only at 2
weeks (Supplemental Table 4).
Previously, we have shown in the HFM Study that the com-
bination of AVF vein diameter, blood flow rate, and depth on
ultrasound predicted both AVF unassisted maturation and
overall maturation failure moderately strongly.14 Because
these measures are conceptually related to, albeit not directly
used in, the criteria for defining stenosis, we investigated
whether the associations of stenosis with maturation failure
remained detectable after adjustment for concurrent ultra-
sound measures of vein diameter, blood flow rate, and depth.
Accordingly, alternative analyses were performed with adjust-
ments for concurrent mean AVF vein diameter, blood flow
rate, and depth instead of adjustment for preoperative vein
diameter and blood flow rate. In these alternative analyses,
associations of stenosis with maturation failure were greatly
attenuated and no longer statistically significant (Table 2). In
contrast, the associations of maturation failure with lower
concurrent vein diameter and blood flow rate and higher
depth remained largely statistically significant (i.e., in five of
six [equals two types of maturation outcomes 3 three ultra-
sound examination time points] analyses for vein diameter,
five of six analyses for blood flow rate, and six of six analyses
for vein depth; data not shown). Results of sensitivity analyses
replacing mean vein diameter with minimum vein diameter
were similar (Supplemental Table 5).
DISCUSSION
Although stenosis is established as a common cause of failure
of synthetic arteriovenous grafts, its role in AVF maturation
failure is unclear. In the absence of external compression,
which is probably rare, stenosis is likely to be caused by intimal
hyperplasia. In this study, we examined the associations of

Table 2. Associations of stenosis on ultrasound at three postoperative time points with clinical maturation failure outcomes
Postoperative Ultrasound Time Point Unassisted Maturation Failure Overall Maturation Failure
and Ultrasound Adjustmenta OR 95% CI P Value OR 95% CI P Value
Week 6b
Preoperative ultrasound measures 1.98 1.25 to 3.12 0.004 1.98 1.26 to 3.13 0.004
Concurrent ultrasound measures 1.19 0.67 to 2.08 0.55 1.24 0.73 to 2.11 0.42
Week 2
Preoperative ultrasound measures 1.47 0.96 to 2.25 0.08 1.66 1.04 to 2.65 0.04
Concurrent ultrasound measures 0.89 0.54 to 1.45 0.64 1.12 0.67 to 1.88 0.66
Day 1
Preoperative ultrasound measures 1.86 1.09 to 3.18 0.02 2.24 1.27 to 3.93 0.005
Concurrent ultrasound measures 1.14 0.65 to 2.00 0.66 1.43 0.78 to 2.61 0.25
All analyses involved multiply imputed data.
a
Models adjusting for preoperative ultrasound measures included inflow artery diameter, mean vein diameter, and brachial artery blood flow rate. Models adjusting
for concurrent ultrasound measures instead included mean AVF venous diameter, blood flow rate, and depth obtained from the same ultrasound as the stenosis
assessment. All models included additive adjustments for age, sex, black race, chronic dialysis status at time of AVF creation, AVF location (upper arm versus
forearm), and Gaussian clinical center random effects.
b
Week 6 results were identified a priori as the primary ultrasound outcomes among the three time points.

4 Journal of the American Society of Nephrology J Am Soc Nephrol 28: ccc–ccc, 2017

preexisting intimal hyperplasia in vein samples obtained at the
time of AVF creation surgery and postoperative AVF venous
stenosis detected by serial ultrasounds with each other and
AVF clinical maturation failure.
We recently reported that preexisting intimal hyperplasia
was highly prevalent (88%) in veins used for AVF creation in the
HFM Study.11 One might expect that such preexisting hyper-
plasia would be manifested as stenosis on ultrasound soon
after AVF creation surgery. However, there was no significant
association between the presence of preexisting hyperplasia
assessed by histomorphometry and the presence of AVF ve-
nous stenosis on postoperative ultrasounds (Table 1). In fact,
in the complete case (nonimputed) data, nine of 33 (27.3%)
AVFs created using veins with preexisting hyperplasia index
.80% achieved unassisted clinical maturation. A plausible
explanation for this lack of significant association is that the
degree of the postoperative stenosis, even if present, was too
modest to satisfy the diameter and peak flow velocity ratio
criteria (Concise Methods). Moreover, if the degree of preex-
isting venous hyperplasia varies substantially along the vessel,
our single-vein sample might have inadequately represented
the overall level of hyperplasia along the entire length of the
vein. Other available data also suggest that preexisting venous
hyperplasia does not progress significantly after AVF creation.
For example, proliferative activity, as indicated by the paucity
of Ki67-positive cells, was low in the hyperplastic lesions in the
samples of vein used for the anastomosis in the HFM Study.11
In a single-site study of 113 participants, Allon et al.15 found
no difference in the frequency of stenosis on ultrasounds per-
formed 4–6 weeks after AVF creation in veins with preexisting
maximal intimal thickness above the median of 22.3 mm com-
pared with those with preexisting maximal intimal thickness
below. A recent single-center study of 56 patients by Tabbara
et al.10 also showed that preexisting venous intimal hyperpla-
sia did not correlate with increases in the hyperplasia observed
in vein samples collected at the second-stage AVF transposi-
tion surgery.
Our study does not show statistically significant associations
of preexisting venous intimal hyperplasia with unassisted or
overall AVF maturation failure. This does not, however,
definitively exclude a role of preexisting hyperplasia in AVF
maturation failure, because the HFM Study was insufficiently
powered to detect modest relationships in the multifactorial
setting of AVF development. Nonetheless, these results are gen-
erally consistent with the results from the study by Allon et al.,15
in which preexisting venous hyperplasia did not correlate with
AVF clinical maturation failure, and that by Tabbara et al.,10 in
which preexisting venous hyperplasia was not associated with
AVF anatomic maturation failure. Together, these data suggest
that the clinical significance of any relationship of preexisting
hyperplasia to clinical maturation failure is not great.
Five of six associations relating stenosis detected on post-
operative ultrasounds to unassisted maturation failure or over-
all maturation failure were statistically significant, with ORs
from 1.47 to 2.24, even after adjustment for preoperative ar-
J Am Soc Nephrol 28: ccc–ccc, 2017
www.jasn.org CLINICAL EPIDEMIOLOGY
terial and venous ultrasound features and various potential
confounders (Table 2). This observation is also in general
agreement with the study of Allon et al.,15 in which maturation
failure was approximately four times (30% versus 7%;
P=0.001) more common in participants with juxta-anastomotic
stenosis than those without stenosis on ultrasound at 4–6
postoperative weeks. It is, however, in apparent contrast to
the results of Allon et al.15 on more distant stenosis, in which
no association with maturation failure was found, and the
study of Tabbara et al.,10 in which postoperative AVF venous
hyperplasia was not associated with AVF anatomic matura-
tion failure. There are a number of differences between the
HFM Study and the studies by Allon et al.15 and Tabbara
et al.,10 including sample size, single center versus multicen-
ter, the methods used to determine intimal hyperplasia, the
numbers of postoperative ultrasound examinations, and the
criteria for AVF maturation.
The associations of stenosis with maturation failure were
attenuated and no longer statistically significant after adjusting
for concurrent mean AVF venous diameter, blood flow rate,
and depth (Table 2), which collectively predict maturation
failure more accurately than stenosis per se. Thus, from a prog-
nostic perspective, the maturation prospects of an AVF that
satisfies the definition of stenosis seem no worse than those of
any AVF with similar mean diameter, depth, and AVF flow. It
should be noted that the stenosis definition reflects a localized
variation as assessed by ratios in diameter and flow (through
peak systolic velocity) along the length of the vessel, whereas
the parameters used for adjustments in the statistical model
were blood flow rate, mean diameter, and depth of the AVF
vein, which numerically need not reflect such localized var-
iation. Hence, this empirical result cannot be presumed a
priori. Our results are consistent with stenosis as an impor-
tant cause of clinical maturation failure mediated by effects
on venous diameter, blood flow rate, and less likely, depth of
the AVF. Our results do not support a contribution of steno-
sis to maturation failure via other pathways. It is also possible
that stenosis is not a cause of maturation failure but is
simply a consequence or correlate of small AVF vein diameter
and low blood flow rate.
The apparent changes in the prevalence of stenosis on post-
operative AVF ultrasounds over time are interesting observa-
tions. Overall stenosis prevalence increased over time (14%,
28%, and 30% in the 1-day, 2-week, and 6-week ultrasounds,
respectively). As discussed above, it seemed unlikely that pre-
existing venous hyperplasia progressed significantly after AVF
creation. Alternatively, the new lesions detected by postoper-
ative ultrasounds could have resulted from de novo intimal
hyperplasia formation induced by various factors, such as
highly aberrant mechanical forces on the venous wall after
AVF creation. Perhaps more intriguing was that some stenotic
lesions detected in an earlier ultrasound were no longer pre-
sent in subsequent ultrasounds (Figure 1). There are sev-
eral potential explanations for this loss of detectable stenotic
lesions over time: (1) technical variability in ultrasound
Intimal Hyperplasia, Stenosis, and AVF Maturation 5
 CLINICAL EPIDEMIOLOGY www.jasn.org
measurements resulting in reclassification of patients across
the dichotomization criteria for stenosis; (2) expansion of the
lumen and consequently, decrease in peak systolic blood flow
velocity ratio, such that these parameters no longer satisfied
the criteria of stenosis on ultrasound defined a priori; and (3)
actual regression of intimal hyperplasia.
This study has a number of strengths. The HFM Study is the
largest multicenter prospective study of AVF, including detailed
information on a broad range of measures, such as histology,
vascular functions, ultrasound, and clinical attributes. Stan-
dardized protocols were used for vein sample collection and
centralized morphometric analysis of the vein histologic sec-
tions by the Histology Core.11 We used standardized training
for data collection and ultrasound measurements, a central
facility for the reading of ultrasound images, and uniform
criteria for defining stenosis.14 Serial postoperative research
ultrasounds at prespecified time points were performed to
examine the evolution of AVF development. Clinical data
were concealed from the pathology personnel analyzing the
venous histologic sections and radiologists reading the ultra-
sound images. Clinical AVF maturation was assessed using
rigorous, standardized criteria.16 Statistical treatment in-
cluded a comprehensive multiple imputation process for
missing data, adjustment for a suite of potential confounding
variables using generalized linear mixed models (GLMMs),
and investigation of the incremental contribution of stenosis
to clinical maturation prediction over prediction by AVF vein
diameter, blood flow rate, and depth.13
Our study also has the following limitations. (1) The sample
size, although considerable, was too low for adequate statisti-
cal power against modest rather than strong associations with
binary outcomes, such as clinical maturation. (2) A single-vein
sample may not adequately reflect the degree of hyperplasia
along the entire length of the vein. (3) Although clinical us-
ability as an outcome has the advantage of clinical relevance,
the many factors that may affect it, such as processes of care in
the dialysis unit and variability in decisions to intervene sur-
gically, can partially obscure its association with AVF proper-
ties. (4) Our results pertain only to preexisting hyperplasia
that was mostly mild and may not be applicable to more severe
hyperplasia that would likely preclude use of the vein for AVF
creation. (5) There are no consensus criteria for stenosis on
ultrasound in the literature, and other criteria may yield dif-
ferent results. (6) The HFM Study did not include regularly
scheduled ultrasound examination after 6 weeks postopera-
tively; therefore, stenotic lesions occurring later were not in-
cluded in this analysis. (7) The lack of repeated vein tissue
sampling and histologic examination precludes tracking of
the postoperative evolution of intimal hyperplasia and further
understanding of its role in AVF development. (8) Intimal
hyperplasia or postoperative stenosis of the feeding artery,
not included in our analyses, may also be important for AVF
development.8 (9) The observational study design precludes
the establishment of causality. (10) Many other factors, such as
medications, precise AVF configuration, aberrant shear stress
6 Journal of the American Society of Nephrology
along the vascular wall, and other abnormal mechanical
forces, potentially modulate AVF development. Some of these
factors will be topics of other analyses.
In summary, our data are consistent with but insufficient
to confirm a modest association of preexisting venous intimal
hyperplasia with subsequent AVF maturation failure. Steno-
sis after detected AVF creation was clearly associated with
clinical maturation failure, but its implications for matura-
tion were not distinguishable from those of other ultrasound
measures, such as mean diameter, blood flow rate, and depth
of the AVF vein.
CONCISE METHODS
Participant Cohort
The design of the HFM Study has been previously reported.16 Briefly,
the HFM Study is a prospective cohort study sponsored by the
National Institute of Diabetes and Digestive and Kidney Diseases
conducted at seven clinical sites located in United States academic
institutions, designed to identify predictors and elucidate underlying
mechanisms of AVF maturation failure. The study enrolled 602 par-
ticipants who were scheduled to undergo a single-stage AVF creation
surgery in an upper extremity as recommended by their respective
own surgeons. All clinical decisions regarding the AVF, including
timing of the creation surgery, location and configuration, potential
remedial intervention, and timing of cannulation for dialysis, were
determined by the clinical team and were not determined by the
investigators. The participants were followed for a median of 2.1 years
(range of 0.2–4.1 years) until abandonment of the AVF, kidney
transplant, death, or administrative end of the HFM Study. The
institutional review boards of each clinical institution and the Data
Coordinating Center approved the study. Informed consent was
obtained from each participant before enrollment.
AVF Creation Surgery
Only one-stage AVF creation surgeries in the arm were eligible for
inclusion in the HFM Study.16 Of these upper arm AVFs, 62% and
38% had brachial-cephalic and brachial-basilic configurations, re-
spectively. A 5- to 10-mm segment of the vein used for the anasto-
mosis was excised for research purposes immediately before the
anastomosis creation as previously described.11
AVF Ultrasonography
Figure 2 depicts the study schedule for vein sample collection and
ultrasounds. Before AVF creation surgery, all participants underwent
detailed ultrasound examination of the arteries and veins in the ex-
tremity to be used for AVF creation.17 The HFM Study protocol also
mandated ultrasound examination of the AVF within 3 days and
preferably, at 1 day, 2 weeks, and 6 weeks after AVF creation. For
individual logistical reasons, 32%, 48%, 13%, and 2% of the 1-day ul-
trasounds were actually performed on postoperative days 0, 1, 2, and 3,
respectively, with 4% missing from this 3-day window.
Preoperative vascular mapping and postoperative AVF ultraso-
nography were performed by clinical site personnel trained by the
J Am Soc Nephrol 28: ccc–ccc, 2017

Figure 2. Timeline of study procedures. Preoperative ultrasound
for mapping of the arteries and veins was performed preferably
within 45 days of the AVF creation surgery and needed to be
within 90 days of the surgery. Postoperative ultrasounds of the
AVF were performed at 1 day, 2 weeks, and 6 weeks.
HFM Study Ultrasound Core using standardized protocols, and all
images were read centrally by one of three core radiologists special-
izing in hemodialysis vascular access ultrasound as described.17 For
the postoperative AVF ultrasounds, the internal diameter of the
brachial or radial artery (depending on the AVF configuration)
was measured 2 cm upstream from the anastomosis. The internal
diameter of the AVF draining vein was measured at 2, 5, 10, and 15
cm, and the blood flow rate through the AVF was measured in
triplicate 10 cm downstream from the anastomosis in a straight
section of the vein.17 In reporting results, diameter refers to the
mean of the diameters at these four locations along the length of
the vein, and blood flow rate refers to the mean of the triplicate
blood flow rate measurements.
The algorithm for defining an AVF venous stenosis on ultrasound
in the HFM Study has been previously described.17 Stenosis detection
was initially triggered by gross visualization or elevation of peak sys-
tolic velocity. The stenosis was confirmed if the suspicious location
satisfied both of the following criteria: (1) the vein diameter was
,50% of the measured diameter upstream of the narrowing and
(2) the ratio of the peak systolic blood flow velocity at this location
to the peak systolic velocity measured 2 cm upstream exceeded 3.0
when the location was within 2 cm of the anastomosis or exceeded 2.0
when the location was farther from the anastomosis. The stenosis was
described as juxta anastomotic in the former case and distal in the
latter case.
Results of the 1-day and 2-week postoperative ultrasounds were
not available to clinicians or the HFM Study investigators unless
there was a finding that threatened the participant’s immediate
health (e.g., impending rupture of a pseudoaneurysm) as
determined by the Central Core radiologist. Results of the 6-
week postoperative ultrasounds were available to local clinicians
only if a 6-week AVF ultrasound was part of routine clinical prac-
tice at that clinical center.
Vein Morphometry
A segment of the vein used for the anastomosis harvested during the
AVF creation surgery was processed by the HFM Histology Core as
previously described.11 Morphometric analysis of intimal hyperplasia
was performed on a slide in all 365 patients in whom a complete
circumferential histologic section of the vein was present and was
not obscured by valves. Cross-sectional open luminal area and max-
imal luminal area were measured using the ImagePro Plus software.
Maximal luminal area was defined as the entire area within the internal
elastic lamina (i.e., the open luminal area plus the intimal hyperplasia
J Am Soc Nephrol 28: ccc–ccc, 2017
www.jasn.org CLINICAL EPIDEMIOLOGY
area). The intimal hyperplasia index was defined as the ratio of open
area to maximal area, subtracted from 1.0, and valued between
0 and 1.0.
Definitions of AVF Clinical Maturation
The primary HFM Study outcome was unassisted clinical matura-
tion16 defined as use of the AVF with two needles for $75% of dialysis
sessions over a continuous 4-week period, including either four con-
secutive sessions during the 4-week period in which two needles were
used with mean dialysis machine blood pump speed $300 ml/min,
or any session with a single-pool urea Kt/V $1.4 or urea reduction
ratio .70%. Unassisted maturation was considered to have been
achieved on the date of the first of the consecutive sessions with
pump speed $300 ml/min, or the date of the first qualifying Kt/V
or urea reduction ratio, provided that this date was within 9 months
of AVF creation or 4 weeks of hemodialysis initiation without any
preceding endovascular or surgical interventions on the AVF. Over-
all maturation was fulfillment of these same criteria, regardless of
whether it was preceded by such interventions. Treating clinicians,
not HFM Study personnel, made all decisions regarding the initia-
tion of chronic dialysis, whether and when the AVF would be used,
and the need for diagnostic and interventional procedures to assist
maturation.
Statistical Analyses
GLMMs, with random Gaussian clinical center effects, were used to
assess (1) the associations of the preexisting venous intimal hyper-
plasia index with the diameter, blood flow rate, and stenosis in the
AVF vein on each postoperative ultrasound and with both unas-
sisted and overall clinical maturation; (2) the associations of ste-
nosis on each ultrasound with both types of clinical maturation;
and (3) whether associations of stenosis with clinical maturation
varied with the location of the stenosis. The intimal hyperplasia
index was treated as a predictor of each outcome in 1, whereas
stenosis was treated as a predictor for each outcome in 2 and 3.
Additive linear models were used for vein diameters and analogous
logistic regression models were used for stenosis and each matu-
ration outcome. We modeled blood flow rates using a gGLMM
with log link function due to their skew.
The 6-week ultrasound outcomes were a priori considered pri-
mary among the three postoperative ultrasounds. This was the latest
regularly scheduled ultrasound mandated by the HFM Study pro-
tocol and, therefore, closest to clinical utilization, and it was only
rarely preceded by procedural interventions on the AVF, which were
discouraged in the protocol before 6 weeks after surgery. Unless
otherwise noted, all models included adjustment for a set of case
mix variables: sex, age, black race, whether the patient was on main-
tenance dialysis at the time of AVF creation surgery, AVF location
(forearm versus upper arm) as well as preoperative ultrasound mea-
sures of inflow artery diameter, vein diameter, and brachial artery
blood flow rate.
The above models were fit by maximum likelihood, using numer-
ical integration, to a dataset consisting of ten imputations of (1)
missing values of the venous intimal hyperplasia index; (2) miss-
ing ultrasound measures before AVF thrombosis or death of the
Intimal Hyperplasia, Stenosis, and AVF Maturation 7
 CLINICAL EPIDEMIOLOGY www.jasn.org
participant; (3) the few ultrasound measures that were observed after
a procedural intervention on the AVF and treated as missing and
replaced, because they no longer reflected the natural history of AVF
development; and (4) sporadically missing values of other variables,
including the clinical maturation outcomes. We did not impute ultra-
sound measurements subsequent to AVF thrombosis or participant’s
death. A comprehensive set of potential predictors of physiologic mat-
uration parameters (diameter, blood flow rate, and depth of the AVF
vein), clinical maturation, and/or missingness was used for imputing
(supplemental table 2 in the work by Allon et al.13). Results thus apply
to patients alive without prior AVF thrombosis at the time of the
stenosis measurement under analysis and are valid under the standard
missing at random assumption that missingness may depend on these
predictors but not, once they are taken into account, on the unob-
served values themselves. Because (1) the absence or partial circum-
ferentiality of the intraoperative vein sample was almost certainly due
to idiosyncratic surgical issues, (2) missing ultrasounds were largely
due to logistical issues in scheduling the ultrasounds, and (3) these two
factors produced the great majority of missing values, the missing at
random assumption is a highly plausible approximation to reality for
these data.
The multiple Imputation by Chained Equations R package18,19
was used to impute by sequentially modeling each variable condi-
tional on the others and iterating, with clinical centers treated as
fixed rather than random effects, predictive mean matching used
to impute continuous variables and multiple logistic and propor-
tional odds models used for categorical variables. The GLMMs
were then fit to each imputation using PROC GLIMMIX, and results
were combined in a standard manner20 using PROC MIANALYZE in
SAS V.9.4.21 Additional details of the multiple imputation process
and the specific variables used for imputing the HFM Study data have
been published.13
ACKNOWLEDGMENTS
We thank the patients for their participation in the Hemodialysis
Fistula Maturation (HFM) Study. We acknowledge Lin Belt, Carl Abts,
and Lauren Alexander for their invaluable expertise at the HFM
Ultrasound Core.
The HFM Study is funded by National Institute of Diabetes, Digestive
and Kidney Disease (NIDDK) grants U01DK082179, U01DK082189,
U01DK082218, U01DK082222, U01DK082232, U01DK082236, and
U01DK082240.
The members of the HFM Study Group are as follows: Chair,
Steering Committee, University of Pennsylvania: H.I.F.; Clinical
Centers, Boston University: L.M.D. (principal investigator [PI]),
A. Farber, J. Kaufman, L. Stern, P. LeSage, C. Kivork, D. Soares,
M. Malikova; University of Alabama: M.A. (PI), C. Young, M. Taylor, L.
Woodard, K. Mangadi; University of Cincinnati: P.R.-C. (PI),
R. Munda, T. Lee, R. Alloway, M. El-Khatib, T. Canaan, A. Pflum,
L. Thieken, B. Campos-Naciff; University of Florida: T. Huber (PI),
S. Berceli, M. Jansen, G. McCaslin, Y. Trahan; University of Texas
Southwestern: M.A.V. (PI), W. Vongpatanasin, I. Davidson, C. Hwang,
T. Lightfoot, C. Livingston, A. Valencia, B. Dolmatch, A. Fenves, N.
8 Journal of the American Society of Nephrology
Hawkins; University of Utah: A.K.C. (PI), L. Kraiss, D. Kinikini, G.
Treiman, D. Ihnat, M. Sarfati, Y.-T.S., C.M.T., I. Lavasani, M. Maloney,
L. Schlotfeldt; University of Washington: J.H. (PI), C. Buchanan, C.
Clark, C. Crawford, J. Hamlett, J. Kundzins, L. Manahan, J. Wise;
Data Coordinating Center, Cleveland Clinic: G. Beck (PI), J. Gassman,
T.G., P.B.I., L. Li, J. Alster, M. Li, J. MacKrell, M.R., B. Weiss, K.
Wiggins; Histology Core Facility, University of Washington: C.E.A.
(PI), K. Hudkins, T. Wietecha; US Core Facility, University of
Alabama at Birmingham: M.L.R. (PI), H. Umphrey, L. Alexander,
C. Abts, L. Belt; Vascular Function Core Facility, Boston University:
J. Vita (PI; deceased), N. Hamburg (PI), M. Duess, A. Levit; NIDDK
Biosample Repository, Fisher BioServices: H. Higgins, S. Ke, O.
Mandaci, C. Snell; NIDDK DNA Repository, Fred Hutchinson
Cancer Research Center: J. Gravley, S. Behnken, R. Mortensen;
External Expert Panel: G. Chertow (Chair), A. Besarab, K. Brayman,
M. Diener-West, D. Harrison, L. Inker, T. Louis, W. McClellan,
J. Rubin; NIDDK: J.W.K., R. Star.
DISCLOSURES
A.K.C. was a member of the Data and Safety Monitoring Board for a trial on
vascular graft cosponsored by Humacyte, Inc. and the National Heart, Lung,
and Blood Institute as well as a member of the Clinical Events Committee and
Data Safety and Monitoring Board for the Novel Endovascular Access Trial
sponsored by TVA Medical, Inc. M.A. is a consultant for CorMedix, Inc. L.M.D.
is a member of the Data Monitoring Committee for vascular access trials
sponsored by Proteon Therapeutics. P.R.-C. is a consultant or advisory board
member for Bard Peripheral Vascular; CorMedix, Inc.; W.L. Gore and Asso-
ciates, Inc.; Humacyte, Inc.; Medtronic; and TVA Medical, Inc. M.A.V. is a
member of the Managing Committee for the University of Texas Southwestern
Health Systems-DVA Dialysis Joint Venture. P.B.I., C.E.A., M.L.R., M.R., B.L.,
Y.-T.S., T.G., J.H., C.M.T., J.W.K., and H.I.F. have no disclosures.
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This article contains supplemental material online at http://jasn.asnjournals.
org/lookup/suppl/doi:10.1681/ASN.2016121355/-/DCSupplemental.
Intimal Hyperplasia, Stenosis, and AVF Maturation 9