CLINICAL EPIDEMIOLOGY www.jasn.

org

Overweight and Obesity Are Predictors of Progression

in Early Autosomal Dominant Polycystic Kidney Disease
Kristen L. Nowak ,* Zhiying You,* Berenice Gitomer,* Godela Brosnahan,*
Vincente E. Torres,† Arlene B. Chapman,‡ Ronald D. Perrone,§ Theodore I. Steinman,|
Kaleab Z. Abebe,¶ Frederic F. Rahbari-Oskoui,** Alan S.L. Yu,†† Peter C. Harris ,†
Kyongtae T. Bae,‡‡ Marie Hogan,† Dana Miskulin,§ and Michel Chonchol*
*Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado;
†
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota; ‡Section of Nephrology, University
of Chicago, Chicago, Illinois; §Division of Nephrology, Tufts University Medical Center, Boston, Massachusetts;
|
Department of Medicine and Renal Division, Beth Israel Deaconess Medical Center, Boston, Massachusetts; ¶Center for
Clinical Trials & Data Coordination, Division of General Internal Medicine, and ‡‡Department of Radiology, University of
Pittsburgh, Pittsburgh, Pennsylvania; **Division of Renal Medicine, Emory University School of Medicine, Atlanta,
Georgia; and ††Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, Kansas

ABSTRACT
The association of overweight/obesity with disease progression in patients with autosomal dominant polycystic
kidney disease (ADPKD) remains untested. We hypothesized that overweight/obesity associates with faster
progression in early-stage ADPKD. Overall, 441 nondiabetic participants with ADPKD and an eGFR.60 ml/min
per 1.73 m2 who participated in the Halt Progression of Polycystic Kidney Disease Study A were categorized on
the basis of body mass index (BMI; calculated using nonkidney and nonliver weight) as normal weight (18.5–
24.9 kg/m2; reference; n=192), overweight (25.0–29.9 kg/m2; n=168), or obese ($30 kg/m2; n=81). We eval-
uated the longitudinal (5-year) association of overweight/obesity with change in total kidney volume (TKV) by
magnetic resonance imaging using linear regression and multinomial logistic regression models. Among
participants, mean6SD age was 3768 years, annual percent change in TKV was 7.4%65.1%, and BMI was
26.364.9 kg/m2. The annual percent change in TKV increased with increasing BMI category (normal weight:
6.1%64.7%, overweight: 7.9%64.8%, obese: 9.4%66.2%; P,0.001). In the fully adjusted model, higher BMI
associated with greater annual percent change in TKV (b=0.79; 95% confidence interval [95% CI], 0.18 to 1.39,
per 5-unit increase in BMI). Overweight and obesity associated with increased odds of annual percent change
in TKV $7% compared with ,5% (overweight: odds ratio, 2.02; 95% CI, 1.15 to 3.56; obese: odds ratio, 3.76;
95% CI, 1.81 to 7.80). Obesity also independently associated with greater eGFR decline (slope) versus normal
weight (fully adjusted b =20.08; 95% CI, 20.15 to 20.02). In conclusion, overweight and, particularly, obesity
are strongly and independently associated with rate of progression in early-stage ADPKD.

J Am Soc Nephrol 29: ccc–ccc, 2017. doi: https://doi.org/10.1681/ASN.2017070819

Autosomal dominant polycystic kidney disease
(ADPKD) is the most common inherited renal dis-
ease, affecting approximately 1:500–1:1000 live
births.1,2 It is characterized by the growth of nu-
merous fluid-filled cysts which progressively de-
surprisingly, the association of overweight and obesity
with progression in patients with ADPKD has never
been evaluated. Studies in mouse models of ADPKD
Received July 31, 2017. Accepted October 8, 2017.

stroy the adjacent renal parenchyma and massively
enlarge the kidneys.3 Similar to the general popu-
lation, body mass index (BMI) in individuals with
ADPKD has been increasing over recent decades.4,5
Obesity is an established risk factor for the devel-
opment and progression of CKD.6–9 However,
Published online ahead of print. Publication date available at
www.jasn.org.
Correspondence: Dr. Kristen L. Nowak, Division of Renal Dis-
eases and Hypertension, 12700 E 19th Avenue C281, Aurora, CO
80045. Email: Kristen.Nowak@ucdenver.edu
Copyright © 2017 by the American Society of Nephrology

J Am Soc Nephrol 29: ccc–ccc, 2017 ISSN : 1046-6673/2902-ccc 1

 CLINICAL EPIDEMIOLOGY www.jasn.org
have suggested that ADPKD is a state of defective glucose metab-
olism and metabolic reprogramming.10,11 Furthermore, mild-to-
moderate food restriction slows disease progression in multiple
mouse models of ADPKD,12,13 suggesting that changes in energy
status may have a profound effect on ADPKD progression.
The Halt Progression of Polycystic Kidney Disease (HALT)
Study A was a randomized, double-blind, placebo-controlled
study in nondiabetic patients with early-stage ADPKD and is
among the largest trials ever conducted in patients with
ADPKD.14 In order to evaluate the association of overweight
and obesity with ADPKD progression, we examined the lon-
gitudinal association of baseline BMI categories with the pri-
mary outcome in Study A (percent change in total kidney
volume [TKV]). We hypothesized that categorization as over-
weight or obese would be independently associated with a
greater rate of progression in early-stage ADPKD, as indicated
by greater annual change in TKV. We also evaluated whether
overweight and obesity were associated with decline in eGFR.
RESULTS
Participant Characteristics at Baseline
Four hundred forty-one participants with early ADPKD who
participated in HALT Study A14 were included in the analysis
of the association of overweight and obesity with change in
TKV. Among these participants, the mean6SD age was 3768
years, 93.9% (n=426) were white, and the mean6SD annual
percent change in TKV was 7.4%65.1%. Participants were
categorized by baseline BMI (calculated from an adjusted
weight removing the contribution of weight of the kidney
and liver) as normal weight (18.5–24.9 kg/m2), overweight
(25.0–29.9 kg/m2), or obese ($30 kg/m2). The median BMI
at baseline was 26.364.9 kg/m2. The median (interquartile
range) baseline TKV was 1040 (808, 1552) ml. Individuals
with a higher BMI were more likely to be men, had a higher
systolic BP (SBP) and fasting serum glucose, and had a larger
liver volume at baseline (Table 1).
Relation between Overweight and Obesity and
Change in TKV
We first considered the initial and final TKV values from each
participant in HALT Study A and calculated annual percent
change in TKV. Using this approach, the annual percent
change in TKV was greater with increasing BMI category
(normal weight: 6.1%64.7%, overweight: 7.9%64.8%,
obese: 9.4%66.2%; P,0.001; Figure 1), with a mean6SD
follow-up period of 4.760.8 years. In both unadjusted and
adjusted analyses, obesity was associated with increased rate
of change in TKV as compared with the normal weight group
(Table 2). When BMI was considered as a continuous vari-
able, higher BMI was also associated with greater annual
percent change in TKV in the fully adjusted model (model
5: b=0.79; 95% confidence interval, 0.18 to 1.39, per 5-unit
increase in BMI).
2 Journal of the American Society of Nephrology
Significance Statement
Autosomal dominant polycystic kidney disease (ADPKD) is the most
common inherited renal disease, characterized by the development
and growth of numerous fluid-filled cysts that ultimately result in
renal failure. The association of overweight and obesity with pro-
gression in patients with ADPKD has not been examined. This study
provides the first evidence that overweight, and particularly obesity,
are strongly associated with rate of progression in early-stage
ADPKD, as measured by kidney growth and decline in renal func-
tion. These results pose the interesting and clinically relevant question
of whether weight loss may be an effective strategy to slow progression
in patients with ADPKD.
Because of a significant interaction term of BMI 3 sex in
the linear regression model with an outcome of annual per-
cent change TKV (P value for interaction=0.03) and previous
analysis of baseline HALT Study A data which showed effect
modification by sex,15 additional analyses were performed
stratified by sex. In the final adjusted models, the association
between BMI as a continuous variable and annual percent
change in TKV was significant in both men and women, but
quantitatively larger in men (men: b=1.71; 0.92 to 2.50;
women: b=0.87; 0.34 to 1.39, per 5-unit increase in BMI).
Next, we considered three categories of annual percent
change in TKV using the initial and final TKV measurements
from each participant (,5% growth, 5%–7% growth, and
$7% growth). In the fully adjusted model, compared with
the normal weight group, the obese group had a 3.76 (1.81
to 7.80) greater odds of progressing at a rate of $7% compared
with ,5% TKV growth (Table 3). The odds of progressing at a
rate $7% compared with ,5% were also significantly greater
in the overweight compared with normal weight group (odds
ratio [OR], 2.02; 1.15 to 3.56). For every 5-unit increase in
BMI, the odds of progressing at $7% was 1.89 (1.42 to 2.52) in
the fully adjusted model.
As a sensitivity analysis, we also considered a clinically
meaningful final TKV end point of .1500 ml. In the fully
adjusted model, the odds of reaching the .1500 ml end
point were significantly greater in the overweight (OR,
3.33; 1.12 to 9.97) and obese (OR, 3.52; 1.06 to 11.69) com-
pared with normal weight group. For every 5-unit increase
in BMI, the odds of reaching a final TKV.1500 ml were 1.89
(1.41 to 4.04) in the fully adjusted model.
Last, in a sensitivity analysis utilizing a linear mixed model
approach incorporating all available time points where TKV
was measured, there was a significant BMI 3 time interaction
in the fully adjusted model (P,0.01), consistent with the results
of the primary analysis. For every 5-unit increase in BMI, TKV
increased by 32.0 (12.2, 51.8) ml at month 24, 71.6 (33.3, 109.9)
ml at month 48, and 101.8 (50.5, 153.0) ml at month 60.
Relation between Overweight and Obesity and
eGFR Slope
Four hundred forty-eight participants with early ADPKD who
participated in HALT Study A were included in the analysis of
J Am Soc Nephrol 29: ccc–ccc, 2017
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Table 1. Baseline characteristics of study participants from HALT Study A according to BMI category
Normal Weight Overweight Obese
Variable P Value
(BMI 18.5–24.9 kg/m2) (n=192) (BMI 25–29.9 kg/m2) (n=168) (BMI‡30 kg/m2) (n=81)
Age, yr 3769 3867 3669 0.10
Men, % 40.6 66.1 51.9 ,0.001
White race, % 93.2 94.0 95.1 0.84
Study BP Target Randomization 49.0 50.0 51.9 0.91
Group (low, %)
Study BP Medication Randomization 46.9 50.0 53.1 0.63
Group (ACEi + ARB, %)
CKD-EPI eGFR, ml/min per 1.73 m2 92.6616.9 88.6617.3 89.9618.1 0.09
SBP, mm Hg 124614 129613 129615 ,0.001
BMI, kg/m2 22.061.7 27.461.4 34.163.7 ,0.001
Urinary albumin, mg/24 h 18.1 (11.8–34.9) 17.5 (12.2–27.4) 19.8 (11.0–33.3) 0.61
Fasting serum glucose, mg/dl 88610 94610 92610 ,0.001
TKV, ml 985 (641–1561) 1051 (763, 1689) 1103 (762, 1394) 0.33
Liver volume, ml 18696911 19746873 21696511 0.03
Mutation class, %
PKD1 truncating 52.2 45.1 41.2 0.13
PKD1 nontruncating 20.1 32.3 30.1
PKD2 18.5 17.1 16.0
No mutation detected 9.2 5.5 11.1
Data are mean6SD, %, or median (IQR). BMI is calculated from body weight adjusted to remove the contribution of the liver and kidneys to total weight. Mutation
class is unavailable in n=12. ARB, angiotensin receptor blocker; CKD-EPI, CKD-EPI equation.

the association of overweight and obesity with slope of eGFR
over the study duration. Baseline characteristics were very sim-
ilar to the cohort included in the analysis of the TKVend point
(Supplemental Table 1). The mean6SD annual decline in
eGFR (long-term phase) was 23.263.1 ml/min per 1.73 m2
per year. In the fully adjusted linear regression model incor-
porating all available measurements .4 months (to eliminate
short-term hemodynamic effects), obesity was associated with
greater decline in eGFR as compared with the normal weight
group (Table 4). Results were similar when BMI was consid-
ered as a continuous variable (model 4: b=20.03; 20.05 to
0.00, per 5-unit increase in BMI).
In a sensitivity analysis utilizing a linear mixed model ap-
proach incorporating all available time points after month 4
where eGFR was measured, there was a significant BMI 3 time
interaction in the fully adjusted model (P=0.03), consistent
with the results of the eGFR slope analysis. For every 5-unit
increase in BMI, eGFR declined by 20.01 (20.96, 0.93) ml/min
per 1.73 m2 at month 24, 21.60 (23.02, 20.19) ml/min per
1.73 m2 at month 48, and 21.71 (23.17, 20.24) ml/min per
1.73 m2 at month 60.
DISCUSSION

We have demonstrated for the first time that overweight, and

Figure 1. Annual percent change in TKV is greater with increasing
BMI category. Annual percent change in TKV according to clas-
sification as normal weight, overweight, and obese. *P,0.001.
particularly obesity, are strongly associated with rate of pro-
gression of early-stage ADPKD, as measured by annual percent
change in TKV and eGFR slope. In early-stage patients in HALT
Study A, compared with normal weight individuals, obesity was
associated with nearly four times greater adjusted odds of pro-
gressing at an annual rate of change in TKV of $7% compared
with ,5%. The annual percent increase in TKV in obese indi-
viduals was .50% greater than in normal weight individuals.
These findings cannot be accounted for by baseline kidney and
liver size, because BMI was calculated after removing the contri-
bution of weight from these organs. Furthermore, baseline TKV
and liver volume were included in all final adjusted models. In
sensitivity analyses, overweight and obesity were also associated
with achieving a clinically meaningful final TKV.1500 ml, a
volume at which risk of subsequent decline in eGFR is increased.16
Importantly, obesity was also associated with greater decline in
eGFR as compared with the normal weight group.

J Am Soc Nephrol 29: ccc–ccc, 2017 Overweight and Obesity in ADPKD 3

 CLINICAL EPIDEMIOLOGY www.jasn.org

Table 2. Associations (b-estimates [95% confidence intervals]) of BMI categories with annual percent change in TKV
Normal Weight Overweight Obese
Model
(BMI 18.5–24.9 kg/m2) (n=192) (BMI 25–29.9 kg/m2) (n=168) (BMI>30 kg/m2) (n=81)
Unadjusted Ref 1.84 (0.79 to 2.88) 3.39 (2.08 to 4.71)
Model 1 Ref 1.36 (0.34 to 2.38) 3.05 (1.80 to 4.29)
Model 2 Ref 1.33 (0.30 to 2.35) 3.05 (1.81 to 4.29)
Model 3 Ref 0.93 (20.11 to 1.96) 2.71 (1.46 to 3.95)
Model 4 Ref 1.05 (0.02 to 2.07) 2.84 (1.59 to 4.08)
Model 5 Ref 0.82 (20.22 to 1.87) 2.70 (1.45 to 3.95)
Model 1: adjusted for age, sex, and race/ethnicity. Model 2: adjusted for model 1+randomization group and SBP Model 3: model 2+eGFR (CKD-EPI equation),
urinary albumin excretion, and serum glucose. Model 4: model 3+baseline TKV and liver volume. Model 5: model 4+mutation class. Mutation class is unavailable in
n=12.

In a previous cross-sectional analysis of the baseline data
from HALT, body surface area but not BMI was independently
associated with baseline height-adjusted TKV and eGFR.15
Body surface area was thought to reflect genetic and environ-
mental factors influencing both birth weight and postnatal
growth velocities in a manner associated with, but distinct
from, body size. In unadjusted analyses only, BMI was signif-
icantly associated with height-adjusted TKV and eGFR in men
but not women. Similarly, in the current analysis, the associ-
ation of BMI with annual percent change in TKV was slightly
stronger in men than women. Notably, these associations
were significant after adjustment for potential confounders,
unlike in the analysis of baseline HALT Study A data. It is not
unusual for longitudinal data to differ from cross-sectional
data because the latter considers only a single time point.
The current results suggest that overweight and obesity may
indeed be important contributors to rate of progression in
ADPKD.
It is biologically plausible that common pathways may be
implicated in both ADPKD and obesity. Obesity can increase
the mechanistic target of rapamycin (mTOR) activity via ac-
tivation by PI3K/Akt and reduced AMP-activated protein
kinase (AMPK) activity.17–19 Overnutrition and obesity acti-
vate mTOR complex 1 and its downstream target S6 kinase
(S6K) via elevated cellular amino acid, glucose, and ATP con-
centrations,20 whereas caloric restriction represses mTOR
via AMPK activation in the presence of low glucose, high
AMP/ATP ratios, and decreased amino acids.21,22 Overacti-
vation of mTOR/S6K is also central to the progression of
ADPKD, playing a major role in mediating hyperproliferation
of the cystic epithelium.23,24 Additionally, AMPK negatively
regulates both the cystic fibrosis transmembrane conductance
regulator (CFTR), which promotes secretion of cyst fluid,25,26
as well as mTOR signaling.27,28 Metformin, a pharmacologic
activator of AMPK, has been shown to slow cyst growth
in vitro and ex vivo in models of cystogenesis via inhibition
of the mTOR pathway and CFTR.29
It has been proposed that obesity in the setting of a positive
energy balance may increase cancer risk, in part due to inhi-
bition of AMPK and activation of mTOR and downstream
proliferative pathways. 20 Additionally, mTOR inhibitors
have been shown to block tumor-promoting effects of obesity
in mouse models.18,30,31 Inflammation and oxidative stress are
also increased in obesity, which may additionally promote

Table 3. Associations (OR [95% confidence interval]) of BMI categories with categories of annual percent change in TKV
End Point Normal Weight Overweight Obese
Model
(Annual %Δ in htTKV) (BMI 18.5–24.9 kg/m2) (n=192) (BMI 25–29.9 kg/m2) (n=168) (BMI ‡30 kg/m2) (n=81)
5%–7% versus ,5% Unadjusted Ref 2.10 (1.12 to 3.93) 2.22 (0.95 to 5.20)
Model 1 Ref 1.92 (1.00 to 3.67) 2.16 (0.92 to 5.12)
Model 2 Ref 2.00 (1.03 to 3.89) 2.26 (0.94 to 5.44)
Model 3 Ref 1.55 (0.79 to 3.07) 1.97 (0.81 to 4.81)
Model 4 Ref 1.62 (0.81 to 3.21) 2.16 (0.87 to 5.38)
Model 5 Ref 1.66 (0.82 to 3.38) 2.32 (0.91 to 5.91)
$7% versus ,5% Unadjusted Ref 2.39 (1.50 to 3.83) 3.54 (1.89 to 6.64)
Model 1 Ref 2.20 (1.33 to 3.64) 3.45 (1.80 to 6.63)
Model 2 Ref 2.31 (1.38 to 3.85) 3.72 (1.91 to 7.23)
Model 3 Ref 1.92 (1.11 to 3.07) 3.29 (1.67 to 6.51)
Model 4 Ref 2.03 (1.19 to 3.48) 3.70 (1.84 to 7.45)
Model 5 Ref 2.02 (1.15 to 3.56) 3.76 (1.81 to 7.80)
Model 1: adjusted for age, sex, and race/ethnicity. Model 2: adjusted for model 1+randomization group and SBP. Model 3: model 2+eGFR (CKD-EPI equation),
urinary albumin excretion, and serum glucose. Model 4: model 3+baseline TKV and liver volume. Model 5: model 4+mutation class. Mutation class is unavailable in
n=12.

4 Journal of the American Society of Nephrology J Am Soc Nephrol 29: ccc–ccc, 2017

Table 4. Associations (b [95% confidence interval]) of BMI categories with eGFR slope
Normal Weight
Variable
(BMI 18.5–24.9 kg/m2) (n=206)
Unadjusted Ref
Model 1 Ref
Model 2 Ref
Model 3 Ref
Model 4 Ref
Model 1: adjusted for age, sex, race/ethnicity, and randomization group. Model 2: adjusted for model 1+randomization group and SBP. Model 3: Model 2+eGFR
(CKD-EPI equation), urinary albumin excretion, and serum glucose. Model 4: model 3+mutation class. Mutation class is unavailable in n=11.
tumorigenesis.20,32 Because ADPKD is characterized by many
features that align with the hallmarks of cancer,33 it is tempting
to speculate that obesity may contribute to cystogenesis. Con-
sistent with this hypothesis, mild-to-moderate food restriction
was recently shown to slow progression in multiple mouse mod-
els of ADPKD, concomitant with suppressed mTOR signaling
and AMPK activation.12,13
Obesity is a well established independent risk factor
for incident CKD,6,34,35 ESRD,7,8 and decline in eGFR in the
general population.36 In individuals with prevalent CKD, obe-
sity is associated with a decline in eGFR in some8,37 but not in
other studies.38–40 The association of obesity with decline in
renal function in an ADPKD cohort has not been evaluated
previously. We found an independent association between
categorization as obese, but not overweight, and decline in
eGFR in early-stage ADPKD. This finding is notable, be-
cause in the Consortium for Radiologic Imaging Studies
of Polycystic Kidney Disease study, an observational study
of early-stage ADPKD, the decline in eGFR over a 3-year
period was significant only in individuals with baseline
TKV.1500 ml. 16 Additionally, in HALT Study A, the low
BP group had a significantly lower annual percent increase
in TKV compared with the standard BP group with no dif-
ferences in rate of change in eGFR,14 highlighting that HALT
Study A participants were indeed in an early stage of a slowly
progressing disease. Thus, a greater rate of decline in eGFR
in patients with early-stage ADPKD with obesity is clinically
significant.
There are several limitations to this study. We are only able to
demonstrate an association of overweight and obesity with
ADPKD progression, rather than causation, and there may
be residual confounding. Although BMI is commonly used
to classify overweight and obesity, it is unable to distinguish
between fat and muscle mass. Additionally, only baseline BMI
and covariates were used in the statistical models. The major
strength of this study is that we demonstrated a strong asso-
ciation of overweight and obesity with ADPKD progression,
which is a novel and clinically relevant finding. Our results were
consistent across various statistical approaches and accounted
for any contribution of baseline kidney and liver weight to BMI
classification. Last, progression was evaluated longitudinally
with approximately 5 years of follow-up, and covariates were
well characterized in the setting of a clinical trial.
J Am Soc Nephrol 29: ccc–ccc, 2017
www.jasn.org CLINICAL EPIDEMIOLOGY
Overweight Obese
(BMI 25–29.9 kg/m2) (n=168) (BMI‡30 kg/m2) (n=81)
20.03 (20.08 to 0.03) 20.08 (20.15 to 20.02)
20.03 (20.08 to 0.02) 20.09 (20.15 to 20.02)
20.02 (20.07 to 0.03) 20.08 (20.14 to 20.01)
20.03 (20.08 to 0.03) 20.08 (20.14 to 20.02)
20.02 (20.08 to 0.03) 20.08 (20.15 to 20.02)
These results pose an interesting and clinically relevant
question of whether weight loss may be an effective strategy
to slow progression in patients with ADPKD. The prevalence of
overweight and obesity in the HALT study was over half of
participants, thus an effective intervention could affect a large
number of individuals. Given well known difficulties with
weight loss adherence and the life-long nature of ADPKD,
targeting prevention of the development of overweight and
obesity early in life could potentially be a novel approach.
Future research should evaluate the association of overweight
and obesity with ADPKD progression in other cohorts, includ-
ing late-stage patients, and whether weight loss or prevention
of weight gain may slow disease progression.
CONCISE METHODS
Study Design
The design of the HALT PKD Study A has been described in detail
previously.14,15,41 Briefly, the study was a prospective, randomized,
double-blind, placebo-controlled, multicenter trial. Eligible partici-
pants were enrolled across seven clinical sites between February of
2006 and June of 2009. All participants provided written informed
consent and the study adhered to the Declaration of Helsinki. Study
A employed a 232 factorial design and evaluated the effect of (1)
multilevel renin angiotensin aldosterone system blockade with an
angiotensin converting enzyme inhibitor (ACEi) + angiotensin re-
ceptor blocker (ARB) compared with ACEi + placebo, and (2) low
(95–110/60–75 mm Hg) compared with standard (120–130/70–
80 mm Hg) BP control.
All participants had a known diagnosis of ADPKD and either
hypertension or high-normal BP. All participants were free from di-
abetes. Participants in HALT Study A were 15–49 years of age with an
eGFR.60 ml/min per 1.73 m2 using the four-variable Modification
of Diet in Renal Disease equation. The primary outcome in HALT
Study A was percent change in TKV assessed by magnetic resonance
imaging. TKV was assessed at baseline, 24, 48, and 60 months.
Of the 558 participants randomized in Study A, 487 had at least
two measurements of TKV. One was missing data for BMI, 14 were
excluded due to classification of BMI as underweight (see below), and
an additional 31 were missing covariates (described below), leaving
441 participants for the current analysis. Twenty-four months data
were used as baseline for n=2 participants who were missing baseline
Overweight and Obesity in ADPKD 5
 CLINICAL EPIDEMIOLOGY www.jasn.org
TKV data. Of the 558 participants in HALT Study A, 529 also had
at least two measurements of eGFR, 14 were excluded due to classifi-
cation of BMI as underweight, and an additional 67 were missing
covariates or TKV/liver volume for calculation of adjusted BMI, leaving
448 participants for the analysis of change in eGFR.
Study Variables
An adjusted body weight was calculated by subtracting out kidney and
liver weight, assuming a tissue density equal to that of water (1 g/cm3),42
thus removing the contribution of kidney and liver size to BMI classi-
fication. BMI was then calculated using baseline adjusted body weight in
kilograms divided by baseline height in meters squared (measured at
clinical research clinics) and rounded to the nearest tenth. Participants
were categorized on the basis of BMI as normal weight (18.5–24.9 kg/m2),
overweight (25.0–29.9 kg/m2), or obese ($30 kg/m2) using the National
Heart, Lung, and Blood Institute’s criteria.43 Fourteen participants had an
adjusted BMI,18.5 kg/m2 (i.e., underweight) and were thus excluded
from analyses, because underweight individuals may differ physiologi-
cally from those of normal weight. Magnetic resonance imaging was
performed at each study site using a protocol developed by the HALT
PKD Imaging Subcommittee to determine TKV (as well as total liver
volume).15,41 Following acquisition, images were reviewed locally and
transferred electronically to the Image Analysis Center at the University
of Pittsburgh for analysis.
Baseline and follow-up eGFR were calculated using the Chronic
Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.14
Two blood samples were drawn a minimum of 1 hour apart and sent
to the central laboratory (Cleveland Clinic Foundation Reference
Laboratory) for measurement of serum creatinine.41 Consistency
(,20% variation) was required, with a second set of samples drawn
for repeat analysis if this requirement was not met.
Confounders related to BMI and the primary outcomes were
selected a priori as potential covariates, and all were measured at
baseline. Race was categorized as white or nonwhite, as determined
by self-report. SBP was measured in the clinical research clinics with
the participant seated quietly in a chair for at least 5 minutes, feet on
the floor, and arm supported at heart level. Three measurements were
taken with at least 30 seconds between each measurement and the last
two readings were repeated if there was a .10 mm Hg difference. The
last two readings were averaged and reported.41 Urinary albumin
excretion was determined from 24-hour urine collections.41 Glucose
level was measured in fasted serum samples during screening using
standard methodology. Liver volume was measured as described
above. Mutation analysis was performed previously, with mutation
class categorized as PKD1 truncating mutations, PKD1 nontruncat-
ing mutations, PKD2 mutations, and no mutation detected.44
Statistical Analyses
The association of overweight and obesity with change in TKV was
assessed using linear regression and multinomial logistic regression
models. Participants were classified into three categories according to
BMI as described above (normal weight, overweight, and obese),
with the normal weight category serving as the reference group in
all analyses. In the linear regression models, the dependent variable
was annual percent change in TKV calculated from the first and last
6 Journal of the American Society of Nephrology
available measurements. On the basis of analyses of baseline associ-
ations in HALT Study A,15 we tested for a statistical interaction be-
tween BMI and sex as a predictor of annual percent change in TKV.
We performed stratified analyses on the basis of a significant inter-
action term (P,0.05) with BMI as a continuous variable only. There
was no significant interaction with study randomization group
(ACEi/ angiotensin receptor blocker versus ACEi/placebo or low
versus standard BP target).
In the multinomial logistic regression models, the outcome was
three categories of annual TKV growth (,5%, 5%–7%, and $7%),
again calculated from the first and last available measurements. ORs
were calculated with the ,5% annual TKV growth, normal weight
group serving at the reference. There were no significant interaction
terms between BMI/BMI category and either sex or randomization
group, thus stratified analyses were not performed.
In both approaches, the initial model was unadjusted, then mul-
tivariable adjusted models were performed to include age, sex, and
race/ethnicity (model 1), model 1 plus randomization group and SBP
(model 2), model 2 plus eGFR (CKD-EPI) and urinary albumin ex-
cretion (model 3), and model 3 plus baseline TKV, baseline liver
volume, and serum glucose (model 4). Mutation class was added to
model 4 (model 5) for those with the information available (n=429).
We additionally considered BMI as a continuous predictor variable.
The interaction term was included in model 2 for the linear regression
model, considering BMI as a continuous variable. As a sensitivity
analysis, we also evaluated achieving a final TKV.1500 ml as a clin-
ically meaningful end point.16 The same covariates were included in
these models as described previously.
Linear regression models were also used to evaluate the association
of BMI categories with eGFR slope, which was obtained by fitting a
linear regression model to all eGFR measurements from an individual
participant obtained at .4 months (i.e., long-term phase14). The
initial model was unadjusted, then multivariable adjusted models
were performed to include age, sex, race/ethnicity, and randomi-
zation group (model 1), model 1 plus SBP (model 2), and model 2
plus eGFR (CKD-EPI) and urinary albumin excretion (model 3).
Mutation class was added to model 3 (model 4) for those with the
information available (n=437). Annual change in eGFR was calcu-
lated using the final and month 5 eGFR values. There were
no significant interaction terms between BMI/BMI category and
either sex or randomization group, thus stratified analyses were not
performed.
Last, as sensitivity analyses, we performed linear mixed model
analysis incorporating all available measurements (with the exception
of month 90 and 96 eGFR, which caused model failure due to a
low number of measurements), with BMI as a continuous predictor
variable and (1) TKV and (2) eGFR as continuous end points. Results
were similar when the variable TKV was log-transformed. The same
covariates were used as described above.
In all analyses, baseline characteristics were summarized by BMI
categories and presented as mean6SD or median (interquartile
range) for continuous variables and n (%) for categoric variables.
Comparisons across BMI categories were made using a chi-squared
or Wilcoxon score test for categoric data and ANOVA for continuous
variables.
J Am Soc Nephrol 29: ccc–ccc, 2017

Two-tailed values of P,0.05 were considered statistically signifi-
cant for all analyses. All statistical analyses were performed using SAS
version 9.4.
ACKNOWLEDGMENTS
K.L.N. is supported by the National Institute of Diabetes and Digestive
and Kidney Diseases (NIDDK), K01 DK103678. The Halt Progression
of Polycystic Kidney Disease studies were supported by the NIDDK
grants U01 DK062402, U01 DK062410, U01 CK082230, U01
DK062408, and U01 DK062401; the National Center for Research
Resources General Clinical Research Centers (RR000039 to Emory
University, RR000585 to the Mayo Clinic, RR000054 to Tufts Med-
ical Center, RR000051 to the University of Colorado, RR023940 to
the University of Kansas Medical Center, and RR001032 to Beth
Israel Deaconess Medical Center); the National Center for Advanc-
ing Translational Sciences Clinical and Translational Science Awards
(RR025008 and TR000454 to Emory University, RR024150 and
TR00135 to the Mayo Clinic, RR025752 and TR001064 to Tufts
University, RR025780 and TR001082 to the University of Colorado,
RR025758 and TR001102 to Beth Israel Deaconess Medical Center,
RR033179 and TR000001 to the University of Kansas Medical
Center, and RR024989 and TR000439 to Cleveland Clinic); by
funding from the Zell Family Foundation (to the University of
Colorado); and by a grant from the Polycystic Kidney Disease
Foundation.
The funding agencies had no direct role in the conduct of the study;
the collection, management, analyses, and interpretation of the data;
or preparation or approval of the manuscript.
DISCLOSURE
None.
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This article contains supplemental material online at http://jasn.asnjournals.
org/lookup/suppl/doi:10.1681/ASN.2017070819/-/DCSupplemental.
J Am Soc Nephrol 29: ccc–ccc, 2017