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A Practical Guide for Treatment of Rapidly Progressive

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ADPKD with Tolvaptan

Fouad T. Chebib,1 Ronald D. Perrone,2 Arlene B. Chapman,3 Neera K. Dahl,4
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Peter C. Harris ,1 Michal Mrug,5 Reem A. Mustafa,6 Anjay Rastogi,7 Terry Watnick,8
Alan S.L. Yu,6 and Vicente E. Torres1
1
Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota; 2Division of
Nephrology, Department of Medicine, Tufts Medical Center, Boston, Massachusetts; 3Section of Nephrology, University
of Chicago School of Medicine, Chicago, Illinois; 4Section of Nephrology, Yale University School of Medicine, New
Haven, Connecticut; 5Division of Nephrology, Department of Veterans Affairs Medical Center and University of Alabama,
Birmingham, Alabama; 6Division of Nephrology and Hypertension and the Kidney Institute, University of Kansas Medical
Center, Kansas City, Kansas; 7Division of Nephrology, Department of Medicine, University of California, Los Angeles, Los
Angeles, California; and 8Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland

ABSTRACT
In the past, the treatment of autosomal dominant polycystic kidney disease (ADPKD) has guidelines, but does not address practical
been limited to the management of its symptoms and complications. Recently, the US questions raised by nephrologists, inter-
Food and Drug Administration (FDA) approved tolvaptan as the first drug treatment to nists, general practitioners, and patients.
slow kidney function decline in adults at risk of rapidly progressing ADPKD. Full prescribing The purpose of this manuscript is to
information approved by the FDA provides helpful guidelines but does not address prac- provide practical guidance and discuss
tical questions that are being raised by nephrologists, internists, and general practitioners steps to consider before and after pre-
taking care of patients with ADPKD, and by the patients themselves. In this review, we scribing tolvaptan (Figure 1). These
provide practical guidance and discuss steps that require consideration before and after are determined on the basis of published
prescribing tolvaptan to patients with ADPKD to ensure that this treatment is implemen- evidence and the authors’ collective expe-
ted safely and effectively. These steps include confirmation of diagnosis; identification of riences during the clinical trials and open-
rapidly progressive disease; implementation of basic renal protective measures; counsel- label extension studies of tolvaptan in
ing of patients on potential benefits and harms; exclusions to use; education of patients on ADPKD. 1–4 Comprehensive descrip-
aquaresis and its expected consequences; initiation, titration, and optimization of tolvap- tions of advances in the understanding of
tan treatment; prevention of aquaresis-related complications; evaluation and management ADPKD genetics and pathophysiology can
of liver enzyme elevations; and monitoring of treatment efficacy. Our recommendations be found in excellent recent reviews.5–7
are made on the basis of published evidence and our collective experiences during the
randomized, clinical trials and open-label extension studies of tolvaptan in ADPKD.
STEP 1. CONFIRM THE DIAGNOSIS
J Am Soc Nephrol 29: 2458–2470, 2018. doi: https://doi.org/10.1681/ASN.2018060590
OF ADPKD

The diagnosis of ADPKD is not always

The treatment for autosomal dominant
polycystic kidney disease (ADPKD) has
been limited to the management of
symptoms and complications. Two large,
randomized, clinical trials recently
showed that tolvaptan reduced kidney
growth by 45% and eGFR decline
by 26% in early ADPKD (creatinine
clearance .60 ml/min) over 3 years
(Tolvaptan Efficacy and Safety in Man-
agement of Autosomal Dominant Poly-
cystic Kidney Disease and Its Outcomes
3:4 Trial [TEMPO 3:4])1 and eGFR de-
cline by 35% in advanced ADPKD (eGFR
25–65 ml/min per 1.73 m2) over 1 year
(Replicating Evidence of Preserved
Renal Function: an Investigation of Tol-
vaptan Safety and Efficacy in ADPKD
[REPRISE]).2 On the basis of these stud-
ies, the US Food and Drug Administration
(FDA) approved tolvaptan to slow kidney
function decline in adults at risk of rapidly
progressing ADPKD. Full FDA-approved
prescribing information provides helpful
obvious. When there is a family history of
ADPKD, diagnosis relies primarily on
Published online ahead of print. Publication date
available at www.jasn.org.
Correspondence: Prof. Vicente E. Torres or Dr.
Fouad T. Chebib, Division of Nephrology and Hy-
pertension, Mayo Clinic, 200 First Street Southwest,
Rochester, MN 55901. E-mail: torres.vicente@
mayo.edu or chebib.fouad@mayo.edu
Copyright © 2018 by the American Society of
Nephrology

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Figure 1. A stepwise approach should be followed to evaluate patients with ADPKD for
treatment eligibility and management of potential side effects.
imaging.8 With improving technology, ul-
trasound criteria to confirm or exclude
the diagnosis in individuals from affected
families have evolved. A recent study sug-
gested that a total of more than ten kidney
cysts by magnetic resonance imaging
(MRI) in individuals younger than 30 years
has 100% sensitivity and specificity, and
that high-resolution ultrasonography
has the potential to rival MRI.9 These
criteria apply to ADPKD caused by
PKD1 or PKD2 mutations, but not to
polycystic disease associated with muta-
tions in other genes.
When there is no clear family history
or when the appearance and function of
the kidneys are not congruent or consis-
tent with ADPKD, genetic testing is help-
ful to detect rare forms of ADPKD and
other cystic diseases.7,10–13 For example,
three patients in the Consortium for Ra-
diologic Imaging Studies of Polycystic
Kidney Disease (CRISP) and two patients
in the Halt Progression of Polycystic Kid-
ney Disease clinical trials were later found
to have mutations in GANAB (which
causes a mild form of cystic disease
that does not progress to ESRD) or in
J Am Soc Nephrol 29: 2458–2470, 2018
DNAJB11 (which causes a type of cystic
disease in which ESRD may develop with-
out marked kidney enlargement).10,14 Pa-
tients with various forms of autosomal
dominant tubulointerstitial disease often
progress to ESRD without kidney enlarge-
ment and may be misdiagnosed as
ADPKD (Figure 2). This underscores the
importance of consistency between ap-
pearance and function of the kidneys in
ADPKD.
In the consensus report of the Kidney
Disease: Improving Global Outcomes
Controversies Conference, the potential
benefits of presymptomatic diagnosis for
at-risk adults were deemed to usually out-
weigh the risks, provided that the implica-
tions of a positive diagnosis, which vary
from country to country, are discussed be-
forehand with the patient.5 With the ap-
proval of tolvaptan, the potential benefit
of screening has increased. Because of per-
sisting concerns with respect to health and
a patient’s ability to obtain life insurance,
we continue to recommend a discussion
of the pros and cons of presymptomatic
diagnosis along with obtaining appropri-
ate insurance coverage before screening.
Treating Rapidly Progressive ADPKD with Tolvaptan
www.jasn.org REVIEW
STEP 2. CONFIRM THE DIAGNOSIS
OF RAPIDLY PROGRESSIVE
DISEASE
The FDA-approved indication for tolvap-
tan in ADPKD is to “slow kidney function
decline in adults at risk of rapidly pro-
gressing ADPKD.”15 How to identify rapid
progression has not been delineated by
regulatory agencies and varies among
countries.16,17 We propose the following
recommendations to guide practitioners,
particularly those in the United States.
The CRISP trial, a longitudinal study
(now in its 18th year) of patients aged
15–46 years with creatinine clearance
$70 ml/min, characterized the relation-
ship between total kidney volume (TKV)
and measured GFR. 18–20 The study
showed that kidney growth precedes
change in GFR; that the rate of growth is
quasiexponential, unique to, and variable
among patients; and that height-adjusted
total kidney volume (htTKV) predicts fu-
ture GFR decline. The predictive value of
TKV, together with age and eGFR, was
confirmed by the PKD Outcomes
Consortium, a collaborative effort includ-
ing the PKD Foundation, the FDA, the
Critical Path Institute, academic centers,
and pharma.21,22 This work led to the
FDA and European Medicines Agency
qualification of TKV, together with age
and eGFR, as a prognostic biomarker.
Therefore, physicians prescribing tol-
vaptan should consider the patient’s age,
htTKV, and eGFR to identify individuals
at the highest risk of rapid progression.
In young patients at early ADPKD stages,
eGFR will likely be preserved despite sig-
nificant cystic burden. In patients with
more advanced disease, reduced eGFR
(,60 ml/min per 1.73 m2) alone is likely
to be informative. Nevertheless, imaging
remains valuable and important in this
setting to rule out other contributing
factors. Patient’s age and cyst burden
should match the level of renal function.
If not, other diagnoses or contributing
factors should be considered (Figure 2).
The Mayo imaging classification is a
simple tool that uses htTKV and age to
identify patients at the highest risk for
progression independent of renal func-
tion.23,24 Most patients with ADPKD
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Figure 2. These cases illustrate the importance of an accurate diagnosis of the renal cystic disease, particularly when the renal cystic
burden is not congruent with the renal function. Five cases (A–E) could have qualified as ADPKD per ultrasound/MRI imaging criteria but
renal phenotype and function were inconsistent in four of them. Genetic testing revealed the presence of mutations in genes other than
PKD1 or PKD2. (A) A 41 year old (y.o) man with seven and ten cysts in the right and left kidney, respectively. His htTKV was 274 ml/m. His
eGFR was 48 ml/min per 1.73 m2. He had a strong family history of renal cystic disease reaching ESRD (early fifth decade). Genetic studies
revealed a mutation in the MUC1 gene. (B) A 29 y.o woman with bilateral renal cysts (more than ten cysts in each kidney) with htTKV of 186
ml/m. Her eGFR was 70 ml/min per 1.73 m2. Her 66 y.o mother had 13 cysts on her CT scan. She was found to have a mutation in the HNF1B
gene. (C) A 40 y.o woman with more than ten cysts in each kidney and htTKV of 210 ml/m and eGFR 92 ml/min per 1.73 m2. She was found
to have a mutation in DNAJB11. (D) A 48 y.o woman with negative family history of renal disease was found to have bilateral renal cysts
incidentally on her MRI scan. Her htTKV was 179 ml/m. Her eGFR was 67 ml/min per 1.73 m2. She had gout at age 44 years. She was found
to have a mutation in the UMOD gene. (E) A 50 y.o woman with numerous small bilateral small cysts on ultrasound and family history of
renal cystic disease and intracranial aneurysm. Her eGFR was 39 ml/min per 1.73 m2. She was enrolled in Halt Progression of Polycystic
Kidney Disease study B and was later found to have a mutation in DNAJB11.

(approximately 95%) have typical dis-
ease with diffuse cystic involvement
(class 1). They are stratified into five clas-
ses (A–E) on the basis of growth rates
(,1.5%, 1.5%–3%, 3%–4.5%, 4.5%–6%,
or .6% per year) estimated from pa-
tient age and a theoretical starting
htTKV (150 ml/m) (Figure 3). A model
that uses this classification plus eGFR
predicts future eGFR decline with rea-
sonable accuracy (http://www.mayo.
edu/research/documents/pkd-center-
adpkd-classification/doc-20094754). In
the approximately 5% of patients dis-
playing atypical renal imaging (class 2),
htTKV does not predict eGFR decline.
Most patients with htTKV class 2 have
focal cystic disease and a few are older
individuals with atrophic kidneys with
cysts (Supplemental Figure 1). The
Mayo imaging classification has been
validated by an independent study 25
and shown to be informative in post hoc
analyses of several clinical trials.24,26
In most patients, the ellipsoid equa-
tion using coronal, sagittal, and trans-
verse diameters (obtained by various
imaging modalities) provides a fairly ac-
curate estimation of TKV, image class,
and eligibility for treatment. We
prefer a computed tomography (CT)
scan (including contrast enhancement
in patients with eGFR.60 ml/min per
1.73 m2) or MRI scan without contrast
(in patients with reduced eGFR).27 These
images allow the physician to directly con-
firm the typical classification and to mea-
sure TKV by the ellipsoid equation using
a web-based calculator (http://www.
mayo.edu/research/documents/pkd-
center-adpkd-classification/doc-20094754).
The cost of imaging is justified when long-
term treatment with tolvaptan is consid-
ered. Although ultrasound measurements
of kidney length have been found to be
good predictors of GFR decline in cohorts
of patients in a research setting,28 the im-
precision of these measurements in rou-
tine clinical practice limits their utility
for making treatment decisions in indi-
vidual patients. More accurate and time-
consuming methods, such as planimetry or
stereology, have been utilized when using
TKV as an end point in clinical trials. They
may also be more reliable for prognosti-
cation in young individuals (,25 years)
where small differences in htTKV may

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 www.jasn.org REVIEW

patients with rapid progression who start

treatment at early CKD stages (3A or ear-
lier) (Figure 5, Table 1). In the REPRISE
trial, patients aged .55 years did not ben-
efit from tolvaptan.2 This might have been
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because of slow disease progression, as

suggested by their lower rate of eGFR de-
cline on placebo (22.34 ml/min per
1.73 m 2 ) compared with those aged
#55 years (24.60 ml/min per 1.73 m2).
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Therefore, we recommend confirming the

diagnosis of rapid progression by the Mayo
classification if patients aged .55 years
are considered for treatment, even in the
presence of a reduced eGFR.
Although our preferred method to
identify rapid progression uses the
Mayo classification, the European Renal
Association–European Dialysis and
Transplant Association Working Groups
on Inherited Kidney Disorders and Euro-
pean Renal Best Practice puts emphasis
first on eGFR indexed for age.17 This
group proposed a hierarchical decision al-
gorithm encompassing a sequence of risk-
factor assessments. It uses the premise
that in the majority of patients, eGFR
indexed for age will distinguish rapid
from slowly progressive disease. Pa-
tients aged 40–50 years with eGFR.60
ml/min per 1.73 m2 (CKD stages 1 and
2) or patients 30–40 years with eGFR.90
Figure 3. The Mayo imaging classification provides a simple tool for the identification of ml/min per 1.73 m2 (CKD stage 1) are
patients with rapidly progressive ADPKD. This imaging classification predicts the change in considered slow progressors and not ap-
eGFR over time in patients with typical, bilateral, and diffuse distribution of cysts. (A) The A–E propriate for treatment. In the remain-
classification is on the basis of htTKV and age at the time of imaging, assuming kidney ing patients, at least one of the following
growth rates of ,1.5%, 1.5%–3%, 3%–3.5%, 4.5%–6%, or .6% per year and a theoretical additional criteria is required to diag-
initial htTKV of 150 ml/m; the dots correspond to the patients in (B). (B) MRI studies cor- nose rapid progression and thus indica-
responding to three 41-year-old patients in classes A (bottom), C (middle), and E (top). tion for treatment: (1) a confirmed eGFR
(C) eGFR slopes in cohort of 376 patients stratified by imaging class (20.23, 21.33, 22.63, decline of $5 ml/min per 1.73 m2 in 1 year
23.48, and 24.78 ml/min per 1.73 m2 per year for classes A–E, respectively). Average eGFR at
or $2.5 ml/min per 1.73 m2 per year over a
baseline (75 ml/min per 1.73 m2) and average age at baseline (44 years) for all patients were
period of 5 years; (2) a TKV increase of
used for the model; values for normal slope were obtained from a population of healthy kidney
donors; eGFR slopes were significantly different among the classes, and all but class A were
.5% per year by repeated measurements
significantly different from the control population of healthy kidney donors. The table shows (preferably three or more, each at least 6
the estimated eGFR slopes for each class by sex. Reprinted from reference 22, with months apart and by MRI); (3) Mayo im-
permission. age class 1C, 1D, or 1E; (4) kidney length
assessed by ultrasound of .16.5 cm in
affect the image classification (Figure 3). Var- class 1A progress slowly and should not patients aged ,45 years; and/or (5)
iants of these methods have been automated be treated. Patients in class 1B should be having a truncating PKD1 mutation in
and validated and we expect that they will reassessed and their TKV measured after conjunction with early onset of clinical
become increasingly accessible and available 2–3 years to confirm a slow rate of pro- symptoms consistent with a Predicting
for disease prognostication.29,30 gression. Patients in class 1C, 1D or 1E Renal Outcome in Polycystic Kidney Dis-
Once a patient is determined to have have rapidly progressing disease and are ease (PROPKD) score .6.
typical ADPKD, the Mayo class should the most likely to benefit from treatment. In our opinion, the European Renal
be ascertained (Figure 4). Patients in Predicted benefit is greater for young Association–European Dialysis and

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Figure 4. The algorithm depicted in the Figure summarizes a practical approach to identify the patients more likely to benefit from
treatment with tolvaptan and optimize their overall management. After confirming ADPKD diagnosis, the patients are classified into typical
and atypical ADPKD on the basis of their kidney imaging features. This is followed by measurement of htTKV, which allows the stratification
of the typical patients into slowly (Mayo class 1A or 1B) or rapidly progressing (Mayo class 1C, 1D, and 1E). Treatment with tolvaptan to slow
down the disease progression should be considered for 18- to 55-year-old patients at risk for rapid progression (Mayo class 1C, 1D, or 1E)
with eGFR.25 ml/min per 1.73 m2. The reduced benefit of treatment in the patients with advanced CKD should be pondered in the
decision. The Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD trial did not
show benefit from tolvaptan in patients older than 55 years probably because many of them had slowly progressive disease. General
measures that may improve the outcome of ADPKD should be implemented in all patients. BMI, body mass index.

Transplant Association algorithm is
complicated and not entirely justified
by available evidence (Table 2). The pre-
mise that eGFR indexed for age can dis-
tinguish rapidly from slowly progressive
disease in the majority of patients with
ADPKD is not accurate, nor is it helpful
in patients aged 18–30 years, and those
with rapid progression in this age group
are likely to benefit the most from
tolvaptan. We do not agree that most pa-
tients aged 30–40 years with an eGFR
.90 ml/min per 1.73 m2 and most pa-
tients aged 40–50 years with an eGFR
.60 ml/min per 1.73 m2 have slow pro-
gression; many have rapidly progressive
disease. For example, in the CRISP
study, 30 patients aged 30–39 years
had a baseline eGFR .90 ml/min per
1.73 m2; 15 had class 1A or 1B and 15
had class 1C–E ADPKD. After a median
follow-up of 13.5 years, eGFR had de-
clined 26.7621.9 in class 1A and 1B pa-
tients, 34.9615.4 ml/min per 1.73 m2 in
class 1C–E patients, and one patient (class
1D) had reached ESRD. Forty-five CRISP
patients aged 40–50 years had a baseline
eGFR .60 ml/min per 1.73 m2; 26 had
class 1A, 1B, or 2A and 19 had class 1C
or 1D. After a median follow-up of
13.5 years, eGFR had declined 16.66
23.1 ml/min per 1.73 m2 in class 1A, 1B,
and 2A patients, 37.2618.3 ml/min per
1.73 m2 in class 1C and 1D patients, and
six patients (one class B, three class C,
and two class D) had reached ESRD
(V.E. Torres, C. Shen, D.P. Landsittel,
A.S.L. Yu, A.B. Chapman, K.T. Bae,
M. Mrug, P.C. Harris, F.F. Rahbari-Oskoui,
W.M. Bennett, unpublished results).
Historical evidence of eGFR decline16,17 is
unreliable in many cases because of the high
variability of eGFR values .60 ml/min per
1.73 m2 and because information on a mul-
titude of factors affecting the values is often
unavailable.
In addition, very few patients will have
three or more CTor MRI scans for historical
determinations of TKV growth17 unless
repeated scans were obtained for indica-
tions that often might have affected TKV.
For measurements of TKV growth to be
reliably predictive, atypical cases must be
excluded and laborious planimetry or ste-
reology with intraobserver variabilities of
0.8%–1.8% are required.30 Furthermore,
these errors become magnified when the
change in TKV between measurements
over an interval of only a few months is
extrapolated to 1 year.31 Additionally

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Figure 5. Extrapolations from the results of the TEMPO 3:4 and REPRISE trials allow estimations of the potential benefit of tolvaptan treatment in
delaying the need of renal replacement therapy depending on the eGFR at the initiation of treatment. The effect of tolvaptan is predicted to be
sustained and cumulative on the basis of tolvaptan trial extension and single-center experiences.4 (A) According to baseline GFR at time of treatment
initiation, tolvaptan might delay reaching stage 5 CKD by 7.3, 4.4, 2.9, or 1.5 years if baseline eGFR was 90, 60, 45, or 30 ml/min, respectively. These
extrapolations are made using the average decline in eGFR between placebo (23.7 ml/min per year) and tolvaptan (22.72 ml/min per year)
groups in the TEMPO3:4 trial. (B) According to baseline GFR at time of treatment initiation, tolvaptan might delay reaching stage 5 CKD
by 6.8, 4.5, or 2.3 years if baseline eGFR was 60, 45, or 30 ml/min, respectively. These extrapolations are made using the average decline
in eGFR between placebo (23.61 ml/min per year) and tolvaptan (22.34 ml/min per year) groups in the REPRISE trial. Although this pre-
diction model is simplistic as it assumes that all patients progress at the same slope to ESRD, it allows for visualizing of the benefit gained by
patients if treated with tolvaptan early in their disease state. Predictions in (A) may underestimate the long-term benefit because the treatment
effect observed in the TEMPO 3:4 trial in patients with earlier disease was less than that observed in the REPRISE trial in patients with more
advanced disease. REPRISE, Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD;
TEMPO 3:4, Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes.

ultrasound measurements are operator disease, and atypical patients with slow score incorporates genetics, early onset
dependent, young patients with lengths progression may have lengths .16.5 cm of urological complications and hyper-
,16.5 cm may have rapidly progressive because of large cysts. The PROPKD tension, and sex into a model predicting

Table 1. Potential long-term benefit on kidney function on the basis of the rates of eGFR decline in tolvaptan-treated patients
and controls observed in the TEMPO 3:4 and REPRISE clinical trials
eGFR Decline, ml/min per 1.73 m2 (No. of Patients) Estimated Delay to CKD 5 in Years
Study Difference From From From From
Placebo Tolvaptan P Value
(Treatment Effect, %) eGFR 90 eGFR 60 eGFR 45 eGFR 30
TEMPO 3:4 (randomized, parallel-arm, controlled trial, eCrCl.60 ml/min)
All 23.70 22.72 20.98 ,0.001 7.3 4.4 2.9 1.5
CKD stage 2 23.90 (216) 22.76 (411) 21.14 (29.2) ,0.001 7.9 4.8 — —
CKD stage 3 25.36 (84) 23.70 (151) 21.66 (30.9) ,0.001 — 3.8 2.5 —
REPRISE (Randomized, withdrawal, controlled trial, eGFR 25–65 ml/min per 1.73 m2)
All 23.61 (663) 22.34 (668) 21.27 (35.1) ,0.001 — 6.8 4.5 2.3
Age #55 yr 24.60 (569) 23.07 (572) 21.53 (33.2) ,0.001 — 4.9 3.3 1.6
Age .55 yr 22.34 (94) 22.54 (96) 0.2 (-8.5) 0.65 — 21.5 21.0 20.5
CKD stage 2 24.65 (38) 22.81 (31) 21.84 (39.5) 0.14 10.6 6.3 — —
CKD stage 3a 24.49 (196) 22.13 (206) 22.36 (52.5) ,0.001 — 11.1 7.4 —
CKD stage 3b 23.99 (304) 23.20 (194) 20.79 (19.7) 0.008 — — 1.9 —
CKD stage 4 24.60 (125) 23.80 (137) 20.8 (17.3) 0.02 — — — 0.7
Average eGFR decline is listed in placebo and tolvaptan columns. Number of patients in each group is listed in parentheses. Estimated delay to CKD stage 5 in years
was calculated using the following formula: delay 5([initial eGFR215]/rate of yearly eGFR decline of tolvaptan-treated patients)2([initial eGFR215]/rate of yearly
eGFR decline of placebo patients), e.g., from eGFR 90: delay5([90215]/2.72)2([90215]/3.7)527.57–20.2757.3 year delay. TEMO 3:4, Tolvaptan Efficacy and
Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes; REPRISE, Replicating Evidence of Preserved Renal Function: an In-
vestigation of Tolvaptan Safety and Efficacy in ADPKD; eCrCl, estimated Creatinine Clearance; —, eGFR unit is ml/min per 1.73 m2.

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Table 2. European Renal Association–European Dialysis and Transplant Association algorithm to identify rapidly progressive
ADPKD
Steps Criteria Limitations
1 Exclusion of slow progressors by eGFR indexed for age above Not helpful in 18- to 30-yr-old patients. Incorrect in
high cut-off values many 30- to 40-yr-old patients with CKD stage 1 and
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40- to 50-yr-old patients with CKD stage 1 or 2

1 Inclusion of patients with eGFR indexed for age compatible
with rapid progression
2 eGFR decline $5 ml/min per 1.73 m2 in 1 yr or $2.5 ml/min per
1.73 m2 per yr over 5 yr
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Does not exclude factors other than rapid ADPKD
progression contributing to the reduced eGFR
High variability of eGFR values .60 ml/min per 1.73 m2;
historical factors affecting historical values often

3 TKV increase .5% per year by repeated measurements
(preferably three or more, each at least 6 mo apart)
4 Mayo image class 1C, 1D, or 1E
4 Kidney length by ultrasound .16.5 cm in patients aged ,45 yr
4 PROPKD score .6
unavailable
Very few patients will have three or more MRIs or CTs;
does not exclude atypical cases; requires precise
measurements (planimetry or stereology); rates of
TKV increase in patients with PKD1 and PKD2
mutations are similar
Cost, but this is minor compared with the cost of
tolvaptan and safety laboratory testing
Operator-dependent measurements; young patients
with lengths ,16.5 cm may have rapidly progressive
disease; atypical patients with slow progression may
have lengths .16.5 cm because of large cysts
Not helpful in patients aged ,35 yr unless already
hypertensive and have experienced urologic
complications

disease progression.32 This scoring system
cannot be used in patients aged ,35 years
unless they were hypertensive or experi-
enced urologic complications. In patients
aged ,35 years without complications or
in patients with missing clinical informa-
tion, genetic information alone could be
used for prognosis because truncating
PKD1 mutations, nontruncating PKD1
mutations, and PKD2 mutations are asso-
ciated with most severe, intermediate, and
least severe disease, respectively.32,33 Nev-
ertheless, imaging is still desirable in
these cases because ADPKD progres-
sion is highly variable for individuals
within these three mutation classes,20
even among affected individuals with
the same mutation or of the same fam-
ily. 34,35 Given these limitations, the
Mayo ADPKD classification, in our
opinion, is simpler and easier to imple-
ment in clinical practice (Table 3).
STEP 3. ENSURE THAT BASIC
RENAL PROTECTIVE MEASURES
ARE IMPLEMENTED
Physicians prescribing tolvaptan should
not overlook other simpler interventions
that, in combination, can have a substan- STEP 4. PROVIDE BALANCED
tial effect on the long-term outcome of INFORMATION OF BENEFITS AND
ADPKD (Figure 4). These are discussed POTENTIAL HARMS
in a recent review36 and consist of specific
BP target goals, treatment with pre- The potential benefits and harms of tol-
ferred antihypertensive agents (i.e., an- vaptan treatment (Table 4) should be
giotensin-converting enzyme inhibitors discussed in an individualized manner,
or angiotensin II receptor blockers), and on the basis of the patient’s age, current
lifestyle modifications. Their inclusion eGFR, and ability to tolerate the
in the tolvaptan protocol presents an medication.
opportunity to optimize the manage- Tolvaptan slows the rate of cyst
ment of ADPKD. growth and the rate of eGFR decline.
Table 3. Mayo imaging classification to identify rapidly progressive ADPKD:
advantages and limitations
Criteria Advantages Limitations
Class 1C, 1D, or 1E One-time measurement of htTKV Lack of validation in nonwhite
ethnic or racial populations
Most helpful in patients with If MRI is contraindicated or not
eGFR.60 ml/min per 1.73 m2 tolerated, it can be substituted
by CT
Confirmatory in patients with Cost, but this is minor compared
eGFR,60 ml/min per 1.73 m2 with the cost of tolvaptan and
(if discordant, consider other safety laboratory testing
disease process contributing to
reduced eGFR)
Most commonly in patients with a
truncating PKD1 mutations (if
discordant, it may be a clue to
other factors contributing to
disease severity)

2464 Journal of the American Society of Nephrology J Am Soc Nephrol 29: 2458–2470, 2018

The major expected but still unproven
benefit is delaying the need for RRT.
The TEMPO 3:4 and REPRISE trials
showed its effectiveness over a broad
range of disease stages (Figure 5, Table
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1).1,2,4 An open-label study (TEMPO
4:4) and a small single-center retro-
spective analysis suggest that tolvap-
tan’s slowing of the rate of eGFR
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decline is sustained and cumulative
(approximately 1 ml/min per 1.73 m 2
per year of treatment) over time (Fig-
ure 5, Table 1).3,4 Other benefits of tol-
vaptan treatment include a reduction
in the frequency of events of kidney
pain, nephrolithiasis, hematuria, and
urinary tract infection,1 and a slight re-
duction in mean arterial pressure and
systolic BP.37
The most common side effects asso-
ciated with tolvaptan are related to its
aquaretic effect (polyuria, increased
urinary frequency, nocturia, thirst,
and in some cases, fatigue). 1,2 These
are more disruptive during the initial
weeks of treatment. The aquaretic ef-
fect is less marked in patients with re-
duced GFR versus those with normal
GFR. 38 In the TEMPO 3:4 trial, re-
searchers found that moderate eleva-
tions in serum uric acid are common
(change from baseline, 0.861.0 mg/dl
in tolvaptan-treated patients com-
pared with 0.26 0.86 mg/dl in pla-
cebo-treated patients at month 12),
but gout occurred rarely (in 2.9% of
tolvaptan-treated patients versus
1.4% of placebo-treated patients,
respectively).
An important adverse event associ-
ated with tolvaptan is idiosyncratic he-
patocellular injury.39 Alterations in bile
acid disposition and inhibition of
Table 4. Potential benefits and harms from tolvaptan treatment in ADPKD
Benefits
Slows kidney growth
Slows eGFR decline
May delay need for renal replacement
Reduces pain, hematuria, stone, and
urinary tract infection events
Slight reduction in BP
J Am Soc Nephrol 29: 2458–2470, 2018
mitochondrial respiration have been
identified in in vitro assays as potential
mechanisms.40 In the TEMPO 3:4 and
TEMPO 4:4 studies, monitoring every
3–4 months revealed transaminase ele-
vations more than three times the upper
limit of normal (ULN) occurred at least
once in 4.4% of patients receiving tol-
vaptan compared with 1% of patients
receiving placebo.1,3 Three of 1271 tol-
vaptan-treated patients in these studies
met the Hy law criteria, i.e., serum ala-
nine aminotransferase (ALT) more than
three times the ULN and bilirubin more
than two times the ULN, which denote a
10% risk of progression to acute and ir-
reversible hepatic failure. The elevations
of hepatic transaminases occurred
mostly during the first 18 months,
suggesting a window of susceptibility,
and resolved within 1–4 months after
discontinuation of tolvaptan.39 In the
REPRISE trial, monthly monitoring re-
vealed the occurrence of transaminase
elevations more than three times the
ULN in 5.6% of tolvaptan-treated
patients and 1.2% of placebo-treated pa-
tients; no cases met the Hy law criteria,
likely because of more frequent moni-
toring and earlier discontinuation of
tolvaptan.2 Acute liver failure requiring
liver transplantation has occurred in
one patient in the postmarketing
ADPKD experience. Because of the po-
tential hepatocellular toxicity, a risk
evaluation and mitigation strategy
(REMS) program, including liver func-
tion testing before initiation and at spe-
cific intervals (after 2 and 4 weeks, then
monthly for 18 months, and every 3
months thereafter), is a required com-
ponent of tolvaptan treatment in all pa-
tients with ADPKD.
Harms
Polyuria, pollakiuria, and nocturia
Thirst and fatigue
Uric acid elevations (rarely gout)
Transaminase elevations and risk of severe
hepatocellular toxicity
Need for frequent monitoring of liver function
Possible drug interaction (CYP3A inhibitors)
Financial burden
Treating Rapidly Progressive ADPKD with Tolvaptan
www.jasn.org REVIEW
STEP 5. EXCLUSIONS TO
TREATMENT
Pregnancy, lactation, uncorrected hy-
pernatremia, history of significant liver
injury not due to polycystic liver disease,
hypovolemia, inability to sense or re-
spond to thirst, and urinary tract ob-
struction are contraindications. As
there are insufficient data to determine
tolvaptan’s risk to fetal development,
females of reproductive potential
should be educated to discontinue the
medication before a planned pregnancy
and to inform their prescriber of a
known or suspected pregnancy. Breast-
feeding during treatment with tolvap-
tan is not advised.
Drug interactions should be consid-
ered. Concomitant use of strong CYP3A
inhibitors (e.g., ketoconazole, itracona-
zole, clarithromycin, lopinavir, ritona-
vir, and indinavir) is contraindicated.
Moderate CYP3A inhibitors (e.g., amio-
darone, erythromycin, fluconazole, diltia-
zem, verapamil, grapefruit, imatinib, and
fosamprenavir) can increase tolvaptan ex-
posure and lowering tolvaptan dosing
may be necessary. Tolvaptan could raise
the levels of OATP1B1/3 and OAT3 trans-
porter substrates (e.g., statins, furosemide,
glyburide, repaglinide, and methotrexate)
and BCRP transporter substrates (e.g.,
rosuvastatin), so concomitant use of tol-
vaptan with such drugs generally should
be avoided. When the need for treatment
with such agents outweighs potential
risks, monitoring of drug-related adverse
effects and dose adjustment may be
needed. Approximately 14% of the pa-
tients randomized to tolvaptan in the
TEMPO 3:4 trial were treated with statins;
no association with liver toxicity was de-
tected.41 We recommend using statins
with caution and only when clearly
indicated.
Concomitant use of diuretics and tol-
vaptan is likely to further decrease eGFR,
elevate circulating vasopressin, and in-
crease the risk for gout. Nevertheless, a
case report suggested that a thiazide may
increase the tolerability to tolvaptan by
reducing the polyuria.42 At present, we
recommend avoiding the concomitant
use of these drugs.
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STEP 6. PATIENT EDUCATION ON
AQUARESIS AND ITS EXPECTED
CONSEQUENCES
Tolvaptan blocks the actions of vasopres-
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sin on V2 receptors in the distal nephron
and collecting duct, including urinary
concentration, inhibition of tubuloglo-
merular feedback, and promotion of so-
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dium reabsorption. As a result, tolvaptan
promotes aquaresis and stimulates tubu-
loglomerular feedback, increasing affer-
ent arteriolar constriction and lowering
intraglomerular pressure and GFR.38,43
It also reduces sodium reabsorption in
the distal nephron and collecting
duct.43,44 Patients should understand
that the administration of tolvaptan
will result in significant polyuria, a slight
reduction in GFR that is less noticeable
in advanced CKD and that is reversible
after discontinuation of the drug,38,45
and a moderate increase in serum uric
acid.1 BP should be monitored and anti-
hypertensive medications adjusted if
necessary. An eGFR reduction of
5%–10% can be expected with initiation
of tolvaptan and no action is needed
Figure 6. The algorithm depicted in the Figure summarizes the recommended steps for the initiation, titration and optimization of tol-
vaptan treatment and the schedule of laboratory tests to monitor its safety. LFT, liver function tests; Na1, sodium; Q1Mo, every 1 month;
Q3Mo, every 3 months.
2466 Journal of the American Society of Nephrology
other than ensuring adequate hydration.
If the drop in eGFR approaches 20%, a
reduction of the dose or holding the
medication to restart later at a lower
dose is appropriate. After initiation of
tolvaptan, we recommend monitoring
eGFR at 2 and 4 weeks, then monthly for
18 months, and every 3 months thereafter.
STEP 7. INITIATION, TITRATION,
AND OPTIMIZATION OF
TOLVAPTAN TREATMENT
The goal of treatment with tolvaptan is a
sustained suppression of the action of va-
sopressin on the kidney 24 hours a day,
every day.46,47 To achieve this effect while
curtailing nocturia, daily split doses of tol-
vaptan are necessary, with the first dose
taken early in the morning and the second
taken 8 hours later, in the afternoon (Fig-
ure 6). In clinical trials of tolvaptan, 45 mg
in the morning and 15 mg in the after-
noon were given initially, and then titrated
to 60/30 and 90/30 mg, as tolerated.1,2
With the current packaging of the drug
dispensed by the approved pharmacies,
titration in clinical practice is intended
to proceed as in the clinical trials. How-
ever, starting titration at lower doses (i.e.,
15/15 and 30/15) could reduce early dis-
continuation, make the titration process
more tolerable, and allow for the treat-
ment of patients who are highly sensitive
to tolvaptan and otherwise could not be
treated. Supplemental Figure 2, A and B
illustrate how titration can be performed
within the context of monthly pharmacy
dispensations, with starting doses of 45/15
and 15/15 mg, respectively.
It can also be argued that tolvaptan
needs to be titrated only to the dose re-
quired to achieve persistent suppression
of the vasopressin effect on the kidney
(i.e., urine hypotonicity relative to
plasma, a urine osmolality [Uosm] of
#280 mOsm/kg in a first-void morning
sample before the morning dose). In the
early dose-finding studies of tolvaptan
for ADPKD, efficacy was defined by the
capacity to achieve a sustained Uosm of
,300 mOsm/kg.48,49 In these studies,
approximately 30% of the patients re-
ceiving 90/30 mg of tolvaptan were not
able to achieve a sustained Uosm of
J Am Soc Nephrol 29: 2458–2470, 2018

,300 mOsm/kg. For those able to attain
this target with lower doses, there is no
evidence that further lowering of Uosm
is beneficial. On the contrary, it may re-
duce quality of life and could possibly
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have detrimental effects due to chronic
dehydration. In the TEMPO 3:4 trial, the
dose was increased to 90/30 mg if toler-
ated, but it is possible that the degree of
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vasopressin V2 receptor suppression
achieved by a patient tolerating this
dose might also have been attainable
by a patient who tolerated only 45/15
mg or even by a patient able to tolerate
only 15/15 mg (who would have drop-
ped from the study). Establishing the op-
timal dose of tolvaptan in ADPKD will
require further studies.
Frequent monitoring of plasma so-
dium and/or plasma osmolality to ensure
that a patient taking tolvaptan is drinking
enough water to prevent thirst and main-
tain adequate hydration is essential for
safety and efficacy. Plasma sodium opti-
mally should be maintained between 135
and 143 mEq/L. We recommend moni-
toring plasma sodium 2 and 4 weeks after
initiation of treatment, then monthly
for 18 months, and every 3 months there-
after, at the same time that liver function
is assessed. Maintaining adequate hydra-
tion is important to prevent marked
elevations of circulating vasopressin,
which can activate V1 receptors and po-
tentially result in unintended effects,
such as vasoconstriction. Whether mea-
surements of plasma copeptin can pre-
dict or help to monitor the response to
tolvaptan deserves study.50 Levels of se-
rum uric acid should be monitored; a
uric acid–lowering agent should be con-
sidered to reduce the risk of gout if uric
acid level exceeds 10 mg/dl or to treat the
condition if it develops.51 At present,
there is insufficient evidence to recom-
mend treatment of asymptomatic hyper-
uricemia with the purpose of delaying
the progression of CKD.52,53
STEP 8. PREVENT AQUARESIS-
RELATED COMPLICATIONS
Tolvaptan should preferably be started on a
day when patients are not at work, to help
J Am Soc Nephrol 29: 2458–2470, 2018
them adjust to the immediate aquaretic
response. They should be instructed to in-
gest fluids in anticipation of or at the first
sign of thirst to avoid thirst or dehydration;
to ingest at least 2–3 L of fluid during the
day and one to two cups of additional wa-
ter before bedtime, regardless of perceived
thirst; and to replenish fluids after each
episode of nocturia. They should also be
instructed to monitor their body weight
daily and report changes of .3% in a
week. The aquaretic effect becomes
more tolerable after the first few days or
weeks of treatment. Adjustment may also
include adapting the schedule, timing,
and doses of tolvaptan to the particulars
of the patient’s daily activities. Dietary
changes that reduce daily osmolar loads,
such as moderate reductions in the inges-
tion of protein and sodium, help to reduce
the aquaretic effect.54
Tolvaptan should be held and hydra-
tion increased during intercurrent
illnesses that lead to dehydration or in-
terfere with adequate hydration, such as
food poisoning and gastroenteritis;
when conditions such as outdoor activi-
ties in warm weather increase insensible
water loss; and when water access is re-
stricted, such as during travel and social
events. Tolvaptan should also be held
24–48 hours before elective surgeries
and not be restarted until the patients
are able to maintain adequate hydration.
Fluids with high sugar or fat content
such as soft drinks, juices, and whole
milk should be avoided to prevent exces-
sive caloric intake. The safe and clean
quality of the ingested water should be en-
sured. Tolvaptan can be continued until the
decision to start RRT is made. Discontin-
uation at that time may result in a small
increase in eGFR.
STEP 9. EVALUATION AND
MANAGEMENT OF LIVER
ENZYME ELEVATIONS
Frequent monitoring with liver function
tests is mandated by the FDA as part of the
REMS program for prescribing tolvaptan
(Figure 6). All physicians prescribing
tolvaptan for ADPKD must be trained
and certified in its safe use (see the
Treating Rapidly Progressive ADPKD with Tolvaptan
www.jasn.org REVIEW
REMS website for details: https://www.
jynarquehcp.com/rems-program). Fail-
ure to comply with this testing prohibits
the specialty pharmacy from dispensing
the medication to the patient. Patients
and their treating team should be vigi-
lant for any signs or symptoms of hepatic
injury, which include fatigue, nausea,
vomiting, right upper quadrant pain or
tenderness, jaundice, fever, and rash.
Tolvaptan should be immediately held
at the onset of signs or symptoms con-
sistent with hepatic injury or if ALT or
aspartate aminotransferase (AST) levels
increase to more than two times the ULN
or more than two times the baseline levels
even if the latter is less than two times the
ULN. Tests for ALT, AST, alkaline phos-
phatase, and total bilirubin should be re-
peated as soon as possible (within 48–72
hours) for confirmation and to determine
if levels of these biomarkers are increasing
or decreasing (Figure 7).
In the setting of elevated hepatic
enzymes, a detailed medical history
should be obtained regarding prior or
concurrent diseases, concomitant drug
use (including nonprescription medica-
tions and herbal and dietary supplement
preparations), alcohol use, recreational
drug use, special diets or change in
diet, exposure to environmental chemi-
cal agents, or excessive exercise. Other
potential explanations should be ruled
out, including acute viral hepatitis types
A–E, autoimmune or alcoholic hepatitis,
nonalcoholic steatohepatitis, hypoxic/
ischemic hepatopathy, and biliary tract
disease. Gastroenterology or hepatology
consultations should be obtained if liver
function test abnormalities persist after
tolvaptan has been discontinued.
If laboratory abnormalities resolve,
tolvaptan may be reinitiated with in-
creased frequency of monitoring (weekly
for the first month) as long as ALT and
AST have remained below three times
ULN. Tolvaptan should not be restarted
in patients who experience signs or
symptoms consistent with hepatic injury
or who have ALT or AST levels that have
ever exceeded three times ULN during
treatment with tolvaptan, unless there
is another explanation for liver injury
and the injury had resolved.
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 REVIEW www.jasn.org
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Figure 7. The algorithm depicted in the figure summarizes the recommendations for evaluation and management of potential drug-
induced liver injury. LFT, liver function tests.
All patients with evidence of possible
drug-induced liver injury should be fol-
lowed until all abnormalities return to
normal or to the baseline state.
STEP 10. MONITOR TREATMENT
EFFICACY
There is no foolproof way to monitor the
efficacy of treatment with tolvaptan in in-
dividual patients. We do not recommend
yearly TKV volume measurements to
monitor the drug’s efficacy. Because of
the variability of the measurements and
the inability to know how much TKV
would have increased without treatment,
the rate of TKV increase is not likely to be
informative, particularly over a short pe-
riod of observation. However, it may be
instructive to obtain an MRI or CTscan to
measure TKV volume every 3–5 years to
assess whether the rate of TKV growth
compares with that anticipated from the
initial imaging class assigned to the pa-
tient. Monitoring the rate of eGFR decline
during tolvaptan treatment can be used
for reassurance that the rate of decline is
less than anticipated according to the
Mayo imaging class and the derived
2468 Journal of the American Society of Nephrology
predictive equation.4 Using quality-of-
life and ADPKD-specific questionnaires
(the ADPKD Impact Scale)55 at baseline
and post-treatment could provide addi-
tional measures of treatment efficacy and
patient satisfaction.
ACCESS AND COST OF
TOLVAPTAN
Tolvaptan has been approved for the treat-
ment of adult patients with ADPKD in the
United States, Japan, the European Union,
Canada, South Korea, Switzerland, Hong
Kong, Australia, Turkey, and Taiwan. It is
reimbursed according to varying patient
criteria, including in countries with cen-
tralized drug coverages such as Japan, the
United Kingdom, and France.56–58 In
other countries, such as Canada, public
payers are not currently covering the tol-
vaptan cost, although private insurance
coverage is available. The Canadian Drug
Expert Committee of the Canadian
Agency for Drugs and Technology in
Health reviewed a pharmacoeconomic
evaluation prepared by the manufac-
turer.59 With the current price of tolvaptan
(CAN$34,000 per year), the incremental
cost-to-utility ratio per quality-adjusted
life year when compared with standard of
care was higher than the willingness-to-
pay threshold per quality-adjusted life
year. The price for tolvaptan used in the
evaluation did not account for patent ex-
piration, generic availability, and possible
introduction of other vaptans into the
market.
No studies have been published looking
at the cost effect of the treatment of
ADPKD with tolvaptan on the United
States health care system. The current
wholesale acquisition cost of tolvaptan is
$170,000 per year. Likely out-of-pocket
costs for patients are not yet known, as
United States insurance providers (public
and private) are still conducting their ini-
tial reviews of the product. Out-of-pocket
costs can range from $0 to the full cost of
drug, depending on coverage by insurance
and through other programs, including a
copay program of the manufacturer.
ACKNOWLEDGMENTS
This study has been supported in part by
the Mayo Clinic Robert M. and Billie Kelley
Pirnie Translational Polycystic Kidney Disease
J Am Soc Nephrol 29: 2458–2470, 2018

Center and the National Institute of Di-
abetes and Digestive and Kidney Diseases
(grant DK090728).
DISCLOSURES
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R.D.P. is a member of the steering committee for
the Tolvaptan Efficacy and Safety in Management of
Autosomal Dominant Polycystic Kidney Disease
and Its Outcomes (TEMPO) and Replicating Evi-
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 07/19/2023
dence of Preserved Renal Function: an Investiga-
tion of Tolvaptan Safety and Efficacy in ADPKD
(REPRISE) clinical trials, has received research/
clinical trial support from Otsuka, Kadmon, and
Sanofi-Genzyme, and has consulted for Vertex and
Palladio. A.B.C. is a member of the steering commit-
tee for the TEMPO and REPRISE clinical trials and
has received research/clinical trial support from Ot-
suka. N.K.D. has received research/clinical trial sup-
port from Otsuka and Kadmon and has consulted for
Otsuka. P.C.H. has received research support from
Otsuka and consulted for Vertex. M.M. has received
research/clinical trial support from and has consulted
for Otsuka and Sanofi-Genzyme. A.R. has received
research/clinical trial support from Sanofi-
Genzyme, Kadmon, Amgen, Astra Zeneca, Bayer, Ot-
suka, Quesctor, Sandoz, and Reata. T.W. has received
research/clinical trial support from Otsuka and Kad-
mon. A.S.L.Y. has consulted for Regulus Therapeutics
and Sanofi-Genzyme. V.E.T. is a member of the steer-
ing committees for the TEMPO and REPRISE clini-
cal trials, has received research support from Otsuka,
and consulted for Vertex, Sanofi-Genzyme, and
Palladio. F.T.C. and R.A.M. have no conflicts of
interest.
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1681/ASN.2018060590/-/DCSupplemental.
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