Endourology and Stones

Pharmacological Dilutional Therapy

Using the Vasopressin Antagonist
Tolvaptan for Young Patients With
Cystinuria: A Pilot Investigation
Caleb P. Nelson, Michael P. Kurtz, Alyssia Venna, Bartley G. Cilento, Jr., and Michelle A. Baum
OBJECTIVE To perform a pilot study of short-term safety, tolerability, and impact on urinary stone risk parameters
of the vasopressin V2-receptor antagonist tolvaptan (which increases urinary excretion of free water)
among adolescents and young adults with cystinuria.
MATERIALS AND We enrolled cystinuria patients age 12-25 years. Subjects were treated for 4 days at low-dose tolvap-
METHODS tan (0.3 mg/kg/day, maximum 30 mg) and 4 days at high dose (0.6 mg/kg/day, maximum 60 mg).
Twenty-four-hour urine collections were done at baseline, day 3-4 of the dosing period, day 7-8 of
the dosing period, and 3-6 days after washout. Primary outcome was cystine capacity (mg/L, target
capacity > 0). Secondary outcomes included other urinary/serum parameters, tolerability, and thirst
response.
RESULTS Two females (17, 23 years) and 2 males (13, 24 years) were enrolled. Cystine capacity respectively
went from baseline of 312, 82, 353, and 628 mg/L to 97, 111, 75, and 3 mg/L on high
dose (Figure 1). Twenty-four-hour volume went from 1.96, 3.0, 2.1, and 0.91 L to 11.74, 6.5, 9.9,
and 2.8 L on high dose (Figure 2). There were no abnormalities in serum electrolytes or liver
enzymes. Subjects did experience extreme thirst (9/10 on visual scale), but none discontinued
treatment or reduced dose.
CONCLUSION Dilutional therapy with tolvaptan increased both cystine capacity and urinary volumes. This treat-
ment approach has the potential to reduce recurrence of stones in this population. Further investi-
gation should study longer term effects and safety, and determine optimal dosing to improve
tolerability. UROLOGY 144: 65−70, 2020. © 2020 Elsevier Inc.

C
ystinuria is a disorder of amino acid metabolism
that leads to high levels of cystine in the urine.
Patients with cystinuria form stones because the
urinary cystine concentration exceeds the maximum solu-
bility, resulting in the amino acid precipitating out of solu-
tion to form crystals and then stones, with most patients
presenting before age 20 years.1 Urolithiasis in patients
with cystinuria is a difficult problem to manage, with
large, recurrent stones, and high rates of surgery as well as
chronic kidney disease.1-3 Strategies for preventing cystine
stones focus on increasing solubility of cystine in the urine
Funding Source: Study drug for this project was provided at no cost by Otsuka Pharma-
ceuticals, through a grant. Otsuka was otherwise not involved in the research design, exe-
cution, analysis, or writing of the manuscript.
Financial Disclosure: The authors declare that they have no relevant financial interests.
Conflicts of Interest: Dr. Baum has the following to report: Medical Advisory for Retro-
phin, provider of tiopronin (Thiola).
From the Department of Urology, Boston Children’s Hospital and Harvard Medical
School, Boston, MA; and the Division of Nephrology, Boston Children’s Hospital and
Harvard Medical School, Boston, MA
Address correspondence to: Caleb P. Nelson, M.D., M.P.H., Harvard Medical
School, Department of Urology, Boston Children's Hospital, 300 Longwood Ave,
Boston, MA 02115. E-mail: caleb.nelson@childrens.harvard.edu
Submitted: April 28, 2020, accepted (with revisions): July 5, 2020
through dilution, alkalization, or cystine-binding thiol
drugs (CBTD). Dilutional therapy with aggressive hydra-
tion can reduce stone recurrence,4 but many patients
struggle to maintain adequate fluid intake, and new strate-
gies are needed to reduce the substantial burden of this
condition.
The selective arginine vasopressin V2-receptor antago-
nist tolvaptan is approved for treatment of hypervolemic
and euvolemic hyponatremia (eg, heart failure and Syn-
drome of Inappropriate Antidiuretic Hormone (SIADH)),
and to slow progression of autosomal dominant polycystic
kidney disease (ADPKD). Tolvaptan increases urinary
excretion of water by blocking vasopressin-mediated water
reabsorption in the collecting duct. Thus, tolvaptan ther-
apy has the potential to improve stone outcomes through
augmented dilution and the resultant stimulation of the
thirst response, significantly increasing urine output and
increasing cystine solubility. Although there have been
case reports of use of tolvaptan in urolithiasis, it has not
been investigated rigorously and systematically.
In this study we sought to characterize the short-term
safety profile, and the effect on urinary risk factors for

© 2020 Elsevier Inc. https://doi.org/10.1016/j.urology.2020.07.002 65

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urolithiasis, of tolvaptan therapy in adolescent patients
with cystinuria. We hypothesized that tolvaptan would be
well tolerated with low adverse effects, and would result
in >25% increased urine output and increase in urinary
cystine capacity of >25%.
MATERIALS AND METHODS
This study was a single-arm, unblinded, short-term pilot evalua-
tion of tolvaptan in adolescent and young adult patients with
cystinuria. The treatment period was 8 days, and the study time-
line is shown in Figure 1. Subjects spent two 24-hour periods
under inpatient observation, with the remainder under outpa-
tient observation, with daily visits. The day prior to the treat-
ment period (Day 0) was used to obtain baseline clinical and
laboratory data. Study drug was administered starting on Day 1
to Day 8, with a 2-day washout period on days 9 and 10. Patients
were monitored during the period with 24-hour urine collection
on day 3-4 and day 7-8, daily weights, vital signs, blood draws,
fluid intake and output, and assessment of subjective outcomes.
Inclusion criteria were ages 12-25 years with confirmed cys-
tinuria (documented cystine stones (stone >75% cystine on
chemical analysis) or crystals in urine, or urinary cystine levels
greater than 250 mg/L). Subjects were recruited from our
existing database of cystinuria patients, from new patients pre-
senting during the research period, and via advertising
through the International Cystinuria Foundation, Rare Kid-
ney Stone Consortium, and social media. Of 41 screened
patients, 12 were ineligible due to age (n = 12), no cystinuria
(n = 1), or deceased (n = 2)); of the 29 eligible patients, 19
could not be contacted, and of the 10 who were contacted, 4
declined, 1 enrolled but withdrew due to travel limitations, 1
was found to be ineligible due to renal disease, and 4 com-
pleted the study.
Potential subjects were excluded if they had estimated glomeru-
lar filtration rate less than 80 mL/min/1.73 m2 (measured within 6
months of enrollment), concurrent nonrenal disease that might
increase risk of complications due to aquaresis, chronic or acute
liver or biliary disease, malabsorption syndrome or other gastroin-
testinal condition that could interfere with response to therapy,
noncutaneous malignancy within last 5 years, or history of adverse
Figure 1. Timeline of the study intervention, starting with baseline 24-hour urine evaluation 3-6 days prior to start of tolvap-
tan therapy.
66
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reaction or allergy to Tolvaptan or other arginine vasopressin V2-
receptor antagonist. Informed consent was obtained from all
patients and guardians, and the study was reviewed and approved
by the Institutional Review Board.
Drug Administration. Starting at noon on Day 1, tolvaptan
was administered orally at an initial dose of 0.3 mg/kg, up to a
maximum dose of 30 mg (these doses were based on typical dos-
ing in prior literature). This once-daily dose continued for a total
of 4 doses, through Day 4. On Day 5, the dose was increased to
0.6 mg/kg once daily, up to a maximum dose of 60 mg. If toler-
ated, the higher dose was continued for a total of 4 doses to Day
8; if not tolerated, dose was returned to the initial dose. No
wash-out period was used between the low-dose and high-dose
periods, due to practical concerns about the length of study time
frame. No drug was given on day 9 or 10. The half-life of tolvap-
tan is 3-12 hours depending on dose; urinary output returns to
baseline within 24 hours at maximum dose.5 Tolvaptan is pro-
duced commercially as 15 mg triangular tablets and 30 mg round
tablets. For subjects whose calculated dose was within 10% of
the value of a whole tablet (15 or 30 mg), half-tablet (7.5 mg),
or combination of whole and half tablet, tablets were given. For
those whose calculated dose is outside of this window, tablets
were crushed and dissolved in water and the appropriate dose
given.6 All doses were administered by the research team during
late morning each day. Patients currently on CBTD or alkaliza-
tion therapy at the time of enrollment did not discontinue these
medications during the study period.
Outcome measures. The primary outcome was urinary cystine
supersaturation as measured by “cystine capacity”. This proprie-
tary test (Litholink Corp., Chicago IL) is reported as a value in
mg/L above or below zero, with positive values indicating urine
undersaturated with cystine, while negative values indicate that
the urine is supersaturated with cystine.7,8 Cystine capacity
allows for assessment of urinary cystine supersaturation in the
presence of CBTD’s. While conventional cystine supersaturation
is the ratio of the measured urinary cystine concentration to the
empirically determined saturation concentration of the patient’s
urine, thiol-containing drugs commonly used to treat cystinuria
(eg, tiopronin) can interfere with calculation of supersaturation.
Many assays cannot distinguish cystine from soluble cysteine-thiol
drug complex. Therefore, the cystine capacity test was developed
to permit calculation of urinary cystine supersaturation in the
UROLOGY 144, 2020
presence of such drugs.9,10 Cystine capacity measurements were
based on four 24-hour urine samples obtained during the study: 1
at baseline 3-6 days prior to Day 0, 1 on day 3-4 of the dosing
period, 1 on day 7-8 of the dosing period, and one 3-6 days after
the washout period. Each 24-hour urine sample was sent for analy-
sis by Litholink Corp. Other 24-hour parameters measured
included urine volume, cystine concentration, and cystine super-
saturation. Secondary outcomes included serum sodium and other
electrolyte levels, tolerability related to thirst and voiding symp-
toms, and measurement of liver function tests. Tolerability related
to thirst was assessed with a visual analog scale.11-13 Nocturia
symptoms were assessed using the AUA Symptom Score item.
Adverse event monitoring and safety. Patients were
observed in the inpatient setting for 24 hours after the initial
dose (Day 1) and also for 24 hours after the increased dose
(Day 5). During each of these 24-hour periods, subjects under-
went around-the-clock monitoring of vital signs and daily
input and outputs. On Day 2-4 and Day 6-8, subjects were
monitored as outpatients, with daily vital signs. Serum elec-
trolytes were checked every 2 days while on treatment. Liver
function tests were obtained at baseline, Day 4, and Day 8,
and Day 10. Criteria for cessation of treatment included
abnormal electrolytes, include unstable vital signs, intolerable
subjective thirst or voiding symptoms, or other symptoms
subjectively attributed to the medication.
RESULTS
Two females (17, 23 years) and 2 males (13, 24 years) were
enrolled. All had a history of proven cystinuria and urolithia-
sis, and all were medically managed at other centers. All 4
subjects completed the entire protocol and none had to dis-
continue study medication during the trial. One subject (sub-
ject 3) failed to properly collect the 24-hour urine sample for
the low-dose measurement and so had missing data for that
time point. 24-hour creatinine values were generally within
expected ranges (variation <20% of mean for each subject)
suggesting appropriate collection, with the following excep-
tions: the post-treatment samples for Subjects 2 and 3 were
likely over-collected, and the high-dose sample for Subject 3
was likely under-collected (Supplemental Table 1). Among
the group, only 1 patient was on active medical therapy for
cystinuria at the time of study enrollment (subject 4 was on
captopril and potassium citrate). None of the other 3 subjects
were on CBTD therapy or alkalization.
Cystine stone risk parameters improved from baseline in all
subjects, and with slightly greater improvement on high dose
versus low dose in most (Fig. 2). Cystine capacity increased with
tolvaptan treatment in all study subjects (Fig. 2a), reaching posi-
tive range on low-dose tolvaptan in 2 of the 3 subjects who com-
pleted the low-dose 24-hour urine. The third of these subjects
approached zero with capacity at low-dose of 6. Three of the

Figure 2. Changes in urinary cystine parameters during pilot study.

(a). Urinary cystine capacity for 4 study subjects at baseline, on lower-dose tolvaptan, on higher dose tolvaptan, and after
washout. Target range is positive (>0). (Subject 3 did not have a low-dose value due to error in collection.)
(b). Urinary cystine supersaturation for 4 study subjects at baseline, on lower dose tolvaptan, on higher dose tolvaptan,
and after washout. Target supersaturation is <0.6. (Subject 3 did not have a low-dose value due to error in collection. Patient
4 was on captopril during the study, so cystine supersaturation may not be reliable for this subject.)
(c). Urinary cystine concentration for 4 study subjects at baseline, on lower dose tolvaptan, on higher dose tolvaptan, and
after washout. Target concentration is commonly <250 mg/L. (Subject 3 did not have a low-dose value.) (Color version avail-
able online.)

UROLOGY 144, 2020 67

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Figure 3. 24-hour urine volume for 4 study subjects at baseline, on lower dose tolvaptan, on higher dose tolvaptan, and
after washout. (Color version available online.)

4 subjects reached the positive range capacity on the high-dose
24-hour urine, and the fourth approached zero with a capacity
at high-dose of 3. Cystine capacity increased from baseline
to high-dose from 312 to 97, 82 to 111, 353 to 75,
and 628 to 3 mg/L for the 4 subjects, respectively (Fig. 2a).
Cystine supersaturation decreased dramatically with tolvaptan
therapy, with 3 of 4 subjects achieving conventional cystine
supersaturation < 0.6 (Fig. 2b). Cystine concentration
decreased consistently with all 4 subjects at <250 mg/L on
high-dose tolvaptan (Fig. 2c).
Urinary volume also increased dramatically with tolvaptan
therapy. Some patients produced extraordinary volumes of urine
during treatment. Respectively, 24-hour volume change from
baseline to high-dose increased from 1.96 L to 11.74 L, 3.0 L to
6.5 L, 0.91 L to 2.8 L, and 2.1 L to 9.9 L for the 4 subjects,
respectively (Fig. 3). Of note, the patient with the lowest (least
favorable) capacity also had the lowest 24-hour volume. Fluid
intake increased correspondingly: self-reported 24-hour fluid
intake for the 4 subjects during the low-dose period averaged 9.1
L (Patient 1) 8.6 L (patient 2), 3.1 L (Patient 3), and 7.2 L
(Patient 4), respectively, and during the high-dose period aver-
aged 10.9 L (Patient 1), 9.7 L (Patient 2), 4.1 L (Patient 3), and
9.1 L (Patient 4), respectively.
There were no abnormalities in serum electrolytes during the
study period (Table 1). Despite the large urine output and fluid
intake, subject sodium, potassium, chloride, and other electro-
lytes all remained in the normal range during and after the treat-
ment period. No subject stopped or modified the protocol due to
concerns about serum chemistry perturbations. Liver function
tests (aspartate aminotransferase, alanine aminotransferase, alka-
line phosphatase) were measured at baseline, on low-dose treat-
ment, on high-dose treatment, and after treatment, and no
elevation of liver enzymes was noted in any subject during or
after the treatment period.
Subjects did experience severe thirst, with thirst averaging 8.8
of 10 on a visual analog scale at the low dose (range: 8.8-9.0)
and 8.6 of 10 at the high dose (range: 6.8-9.5;
Supplementary Figure 1), but all completed treatment and none
terminated or reduced dose due to thirst. All subjects reported
some nocturia, but 3 of 4 reported less than 2 voids per night,
even at higher dose (Supplementary Table 1).
COMMENT
In this pilot study, we have shown that dilutional therapy
using the selective arginine vasopressin V2-receptor
antagonist tolvaptan increases urine output dramatically
and favorably alters cystine saturation in the urine, such
that most subjects on treatment reached a positive cystine
capacity. As expected, response returned to baseline after
cessation of tolvaptan, suggesting the effects are only seen
during treatment, and are not cumulative.
Dilutional therapy is the underlying foundation of cys-
tinuria treatment, based on the principle that adequate
hydration will result in dilution of the fixed cystine load
to a concentration below that at which crystallization typ-
ically occurs (<250 mg/L). While there is longstanding
recognition that hyper-hydration can be effective in
reducing stone recurrence,4 in practice adequate oral
hydration is difficult to achieve for many patients and
compliance rates are low,14,15 and there are many barriers
to successful compliance.16 Similarly, medical therapy

Table 1. Serum electrolytes for each subject before, during, and after tolvaptan treatment (Sodium/Potassium/Chloride in
mmol/L)
Day 2 Day 4 Day 6 Day 8 Day 10
Pretreatment (Low Dose) (Low Dose) (High Dose) (High Dose) (Washout)
Subject 1 (24 yo male) 138/4.2/101 141/4.1/101 141/3.9/102 140/4.1/102 141/4.3/103 137/4.0/101
Subject 2 (17 yo female) 141/3.9/103 142/3.6/102 141/3.8/101 140/4.0/102 142/3.7/102 140/4.0/103
Subject 3 (24 yo female) 140/3.7/102 144/4.0/104 140/3.6/102 143/4.1/104 142/3.8/ 102 140/3.8/101
Subject 4 (13 yo male) 140/4.3/104 140/4.1/101 139/4.2/102 140/3.9/101 139/4.4/101 138/4.8/102

68 UROLOGY 144, 2020

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through dietary modification, alkalization, and CBTD’s
have had limited effectiveness. Therapy discontinuation
rates for the common CBTD’s (penicillamine and tiopro-
nin) are between 30% and 70% due to side effects.17,18
The combination of oral hydration, alkalization, and
CBTD represents a multifaceted approach to stone pre-
vention in cystinuria, but few patients achieve adequate
results with current medical therapy. In one study, only
15% of medically managed patients durably maintained
adequate urinary cystine concentrations.14 Clearly, new
therapies are urgently needed for this devastating illness.
The selective arginine vasopressin V2-receptor antago-
nist tolvaptan has been used clinically for treatment of
hyponatremia,19 congestive heart failure,6 SIADH20 and
ADPKD.21 It is currently FDA-approved for short-term
use (less than 30 days) for clinically significant hyponatre-
mia, primarily in patients with heart failure and SIADH,
and for long-term use to slow kidney function decline in
adults at risk of rapidly progressing ADPKD. Tolvaptan
blocks V2-receptors, preventing insertion of aquaporin
channels in the apical membrane of collecting duct cells,
resulting in decreased water absorption from the tubular
lumen into the interstitium, and increased urinary excre-
tion of water, with minimal changes in electrolyte excre-
tion. The most common tolvaptan-associated side effects
have long been recognized to be thirst and dry mouth,22
which tend to stimulate drinking. Since creation of dilute
urine is a primary objective of hydration in urolithiasis
patients, vasopressin antagonist therapy has the potential
to improve stone outcomes through its dilutional effect on
the urine as well as stimulation of the thirst response, with
resulting increases in fluid intake. This concept has been
implemented in limited reports in adults with cystinuria23
and calcium stone formers,24 but these papers provided
very limited in detail of outcome and tolerability metrics.
Further work would be needed to determine whether
dilutional therapy with vasopressin antagonists would be a
viable long-term treatment for cystinuria. This would
include determination of optimal dosing25 to achieve the
desired effect on cystine saturation, while maximizing tol-
erability (taking into account that the thirst-inducing
property of tolvaptan is, in part, what makes it effective).
In prior studies of chronic tolvaptan use in ADPKD
patients, 8.3% discontinued the trial drug because of aqua-
resis-related symptoms (thirst and urinary symptoms),21
although a majority of ADPKD patients are able tolerate
the aquaresis symptoms of tolvaptan.26 Furthermore,
given the side effects associated with current treatments
available for cystinuria,18 as well as the profound health
and quality-of-life consequences of recurrent cystine uro-
lithiasis,3 one must consider that some risk and/or discom-
fort associated with tolvaptan-based dilutional therapy
may be acceptable if this treatment were to also result in
substantial decreases in stone-associated pain, need for
surgery, infection, and risks of chronic kidney disease.27 It
is also possible that other agents in the selective V2-recep-
tor antagonist class (Lixivaptan, Mozavaptan, and Sata-
vaptan)28 may prove to be more suitable for this purpose.
UROLOGY 144, 2020
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The return of all parameters to baseline after washout sug-
gests that, as expected, V2-receptor antagonist therapy
would need to be continuous and ongoing to be effective.
Long-term use of tolvaptan has demonstrated that
liver injury is a potential side effect in a small minority of
patients. In a 3-year trial of tolvaptan versus placebo
among patients with ADPKD, the tolvaptan group had a
significantly higher incidence of elevated liver function
enzymes; elevated alanine aminotransferase was seen
in 4.9% of tolvaptan patient versus 1.2% of placebo
patients.21 Abnormal liver tests returned to normal in all
cases in this trial, either before or after discontinuation
of study drug, and there were no persistent sequelae
reported. However, post-marketing experience has docu-
mented rare occurrences of severe, permanent liver injury
requiring liver transplant. As a result, FDA has restricted
long-term tolvaptan use to ADPKD patients under a Risk
Evaluation and Mitigation Strategy, requiring monthly
liver function testing and careful monitoring of outcomes.5
This study should be interpreted in light of its limita-
tions. This was a short-term pilot study in a small number
of patients with cystinuria; longer-term treatment might
demonstrate less dramatic impacts on stone parameters,
and effects on clinical stone formation may be less pro-
nounced. This study was also likely not long enough to
demonstrate more severe adverse reactions such as liver
injury; no subjects demonstrated evidence of liver injury.
Subjects were also not in their usual home environment for
the study period, with disruption of typical routines and 2
overnight inpatient stays required. Therefore, the results we
observed in this highly-structured study environment may
not reflect those that would be seen in “real-world” use of
the agent as part of routine care. We were unable to track
fluid intake precisely during the outpatient periods of the
study, making it challenging to determine how much of the
effect on urine output was due to the diuretic action of the
drug versus thirst stimulation as a side effect (or a combina-
tion of these). The urine collections were completed inde-
pendently by the subjects themselves and 3 samples were
likely under- or over-collected; however most of the sam-
ples were acceptable. Importantly, cystine capacity and
other measures of cystine saturation are concentration-
based, and are not influenced by urine volume variability
related to under- or over-collection. Only 1 patient in this
study was taking captopril and potassium citrate at the time
of the study, and none were taking tiopronin or penicilla-
mine, so this study was limited in its ability to assess tolvap-
tan’s effect under the more complex pharmacological
conditions common in cystinuria patients; vasopressin V2-
receptor antagonist therapy may prove to be most effective
in combination with other agents. For reasons of feasibility,
no mid-study wash-out period or cross-over was used; it is
possible that the greater response at the higher dose resulted
from cumulative effect of several days at the lower dose.
However, the rapid return of parameters to baseline after
completing the treatment period suggests that the response
was dose-dependent and immediately reversible upon drug
cessation.
69
CONCLUSION
Dilutional therapy with tolvaptan increased both cystine
capacity and urinary volumes. This treatment approach
has the potential to reduce recurrence of stones in this
population. Further investigation should study longer
term effects and safety, and determine optimal dosing to
improve tolerability.
Acknowledgment. The authors acknowledge the support of
John R. Asplin, MD in helping to develop this protocol, direct-
ing the laboratory measurements, and reviewing the findings.
SUPPLEMENTARY MATERIALS
Supplementary material associated with this article can
be found in the online version at https://doi.org/10.1016/
j.urology.2020.07.002.
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