Irazabal Et Al. - 2011 - Short-Term Effects of Tolvaptan on Renal Function

8/3/2019 Irazabal Et Al. - 2011 - Short-Term Effects of Tolvaptan on Renal Function

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Short-term effects of tolvaptan on renal function andvolume in patients with Autosomal Dominant

Polycystic Kidney DiseaseMaria V. Irazabal1, Vicente E. Torres1, Marie C. Hogan1, James Glockner2, Bernard F. King2, Troy G. Ofstie1,Holly B. Krasa3, John Ouyang3 and Frank S. Czerwiec3

1Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA; 2Department of

Radiology, Mayo Clinic, Rochester, Minnesota, USA and 3Otsuka Pharmaceutical Development & Commercialization, Inc.,

Rockville, Maryland, USA

Tolvaptan and related V2-specific vasopressin receptor

antagonists have been shown to delay disease progression in

animal models of polycystic kidney disease. Slight elevationsin serum creatinine, rapidly reversible after drug cessation,

have been found in clinical trials involving tolvaptan. Here,

we sought to clarify the potential renal mechanisms to see

whether the antagonist effects were dependent on

underlying renal function in 20 patients with Autosomal

Dominant Polycystic Kidney Disease (ADPKD) before and

after 1 week of daily split-dose treatment. Tolvaptan induced

aquaresis (excretion of solute-free water) and a significant

reduction in glomerular filtration rate (GFR). The serum uric

acid increased because of a decreased uric acid clearance, and

the serum potassium fell, but there was no significant change

in renal blood flow as measured by para-aminohippurateclearance or magnetic resonance imaging (MRI). No

correlation was found between baseline GFR, measured by

iothalmate clearance, and percent change in GFR induced by

tolvaptan. Blinded post hocanalysis of renal MRIs showed that

tolvaptan significantly reduced total kidney volume by 3.1%

and individual cyst volume by 1.6%. Preliminary analysis of

this small cohort suggested that these effects were more

noticeable in patients with preserved renal function and with

larger cysts. No correlation was found between changes of

total kidney volume and body weight or estimated body

water. Thus, functional and structural effects of tolvaptan on

patients with ADPKD are likely due to inhibition of V2-driven

adenosine cyclic 30,50-monophosphate generation and itsaquaretic, hemodynamic, and anti-secretory actions.

Kidney International advance online publication, 4 May 2011;

doi:10.1038/ki.2011.119

KEYWORDS: ADPKD; kidney volume; polycystic kidney disease;

renal function; vasopressin

Tolvaptan is an orally effective, non-peptide arginine

vasopressin (AVP) V2 receptor antagonist currently approved

in the United States and EU for the treatment ofhyponatremia associated in euvolemic and hypervolemic

states and SIADH, respectively, and in Japan for the treatment

of cardiac edema resistant to diuretics. Tolvaptan is also being

studied as an adjunct therapy for volume overload in patients

with heart failure and as a primary therapy to delay

progression of Autosomal Dominant Polycystic Kidney

Disease (ADPKD). Both tolvaptan and a related V2-specific

AVP receptor antagonist have been shown to delay disease

progression in animal models of human polycystic kidney

disease.13 The mechanism of these effects is proposed to

involve inhibition of the AVP V2 receptor and the subsequent

decrease in adenosine cyclic 3

0

,5

0

-monophosphate concentra-tions in the kidney. Elevated adenosine cyclic 30,50-mono-

phosphate in the kidney is thought to promote cyst fluid

accumulation and the epithelial cell growth, thereby displa-

cing normal kidney and accelerating renal failure.4,5

Transient decreases in blood urea nitrogen and increases in

serum creatinine and uric acid have been observed during

tolvaptans evaluation for indications involving patients with

hyponatremia and heart failure.6,7 In these studies, the incidence

of adverse events related to acute or chronic renal failure have

been similar, but consistently numerically lower in those treated

with tolvaptan than with placebo. Similar changes have been

seen in ADPKD patients who have been given twice-daily

tolvaptan (to consistently inhibit AVP action at the kidneysAVP V2 receptors) over the last 4 years in an open-label study.

8

Because renal function is critically important to those

diagnosed with ADPKD, we sought to clarify the possible

mechanisms of these changes in serum creatinine by studying

renal hemodynamics and function in ADPKD patients given

daily, split-dose tolvaptan administration over 1 week. We

also sought to determine whether the level of residual renal

function impacts the effect of tolvaptan on glomerular

filtration rate (GFR) and creatinine clearance. Analysis of

renal structure, along with correlations to hemodynamics

and function were added post hoc.

http://www.kidney-international.org o r i g i n a l a r t i c l e

& 2011 International Society of Nephrology

Received 5 August 2010; revised 14 February 2011; accepted 8 March

2011

Correspondence: Vicente E. Torres, Division of Nephrology and Hyperten-

sion, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota

55901, USA. E-mail: [email protected]

Kidney International 1
http://dx.doi.org/10.1038/ki.2011.119http://www.kidney-international.org/mailto:[email protected]:[email protected]://www.kidney-international.org/http://dx.doi.org/10.1038/ki.2011.119


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RESULTSBaseline clinical and laboratory parameters and kidneyvolumes

The baseline (day 0) clinical and laboratory parameters are

shown in Table 1. Baseline total kidney volume (TKV) was

inversely correlated with baseline para-aminohippurate

(PAH)-renal blood flow (RBF) (and, not shown, magnetic

resonance (MR)-RBF) and GFR, and directly correlated withurine albumin excretion (Figure 1ac). PAH- and MR-RBFs

were highly correlated (r 0.958, Po0.001), but the ratio of

PAH-RBF to MR-RBF was lower in the patients with a GFR

o60ml/min per 1.73 m2 possibly because the 90% renal

extraction of PAH used to estimate RBF-PAH is too high

when renal function is low (results not shown).

Short-term effects of tolvaptan on clinical and laboratoryparameters and kidney volumes

As expected the administration of tolvaptan induced

aquaresis, which was accompanied by reductions in body

weight of 1.6% and increases in plasma sodium concentra-tion of 1.1% (Table 1). Estimated total body water decreased

by 1.1% (not shown). No significant changes were observed

in blood pressure, hematocrit or serum protein, and albumin

concentrations (Table 1).

Serum creatinine, cystatin C, and uric acid increased by

8.9, 8.9, and 13.0% (Table 1), respectively. The percent

increase in serum uric acid was numerically greater than

creatinine or cystatin C but not significantly so (P 0.16 and

0.30). Serum blood urea nitrogen and plasma renin activity

and aldosterone did not change significantly (not shown).

The administration of tolvaptan increased urine flow and

free water clearance, and induced an 8.6% reduction in GFR,

without a consistent or significant change in RBF-PAH or

RBF-magnetic resonance imaging (MRI; Table 1). There was

no correlation between percent changes in GFR and GFR

values at baseline (P 0.398). Consistent with its effect on

GFR, tolvaptan significantly reduced the osmolar and uric

acid clearances, but only the reduction in uric acid clearance

remained significant when these clearances were adjusted for

the reduction in GFR (Table 1). Moreover, the percent

reduction in uric acid clearance was significantly larger than

the reduction in GFR, indicating that a change in the rates of

uric acid reabsorption and/or secretion contributes to the

reduction in uric acid clearance in addition to the reduction

in GFR.

Changes in TKV were not an initial focus for this study, as

it had been believed that it would take months to detect theeffects due to inhibition of cell proliferation or fluid

secretion. Unexpectedly, however, a post hoc-blinded analysis

of the renal MRI obtained for measurement of renal blood

flow and to document disease progression showed a 3.1%

reduction in TKV from baseline after 1 week of tolvaptan

therapy (Po0.001; Table 1, Figure 2). The percent change in

right and left kidney volumes were significantly correlated

Table 1 | Short-term effects of tolvaptan on clinical and laboratory parameters and on TKVs

All study participants

Pre Post %W P-value

Age (years) 47.88.7Weight (kg) 84.022.0 82.721.7 1.61.3 o0.001MAP (mm Hg) 92.010.1 90.010.8 1.710.1 0.390RKV (ml) 12361538 12111533 4.04.1 o0.001LKV (ml) 10811211 10641201 2.52.9 0.003TKV (ml) 23162715 22742700 3.13.0 o0.001Hb (g/dl) 13.01.1 13.01.0 0.15.4 0.925Protein (g/dl) 7.00.6 7.10.4 2.87.8 0.153Albumin (mg/l) 4.40.2 4.40.3 0.94.1 0.323GFR (ml/min per 1.73 m2) 69.334.8 62.428.7 8.613.9 0.018PAH (ml/min per 1.73 m2) 345.7184.4 320.5156.7 5.713.1 0.071RBF-PAH (ml/min per 1.73 m2) 619338 570286 5.915.6 0.109RBF-MRI (ml/min per 1.73 m2) 536266 514221 1.018.9 0.459SCr (mg/dl) 1.40.8 1.50.8 8.910.5 0.004Cystatin C (mg/l) 1.20.6 1.30.6 8.910.4 0.011

BUN (mg/dl) 21.710.7 21.110.0 1.316.4 0.564Uric acid (mg/dl) 5.62.1 6.22.2 13.014.1 0.002Sodium (mmol/l) 137.92.3 139.52.7 1.11.2 o0.001Potassium (mmol/l) 4.60.5 4.40.6 4.85.5 0.001Urine flow (ml/min) 7.33.2 8.53.1 23.843.9 0.012CH2O (ml/min) 4.12.7 6.02.8 91.7160.7 o0.001(CH2O/GFR)100 5.62.7 9.12.2 107131 o0.001Cosm (ml/min) 3.30.8 2.70.8 16.016.9 0.001(Cosm/GFR)100 5.12.2 4.82.2 6.616.7 0.121Curi (ml/min) 9.64.9 6.83.0 26.814.8 o0.001(Curi/GFR)100 12.83.6 10.64.5 18.717.2 o0.001

Abbreviations: BUN, blood urea nitrogen; CH2O, free water clearance; Cosm, osmolar clearance; Curi, uric acid clearance; GFR, glomerular filtration rate determined byiothalamate clearance; Hb, serum hemoglobin; LKV, left kidney volume; MAP, mean arterial pressure; PAH, para-aminohippurate clearance; RKV, right kidney volume; RBF-PAH, renal blood flow determined by para-aminohippurate clearance; RBF-MRI, renal blood flow determined by magnetic resonance imaging; SCr, serum creatinine; TKV,total kidney volume.Bold denotes statistical significance.

2 Kidney International

o r i g i n a l a r t i c l e MV Irazabal et al.: Acute effects of tolvaptan in ADPKD


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(r

0.526, P

0.017). No significant correlation was detectedbetween the changes in TKV and body weight (r 0.054, NS)

or estimated body water (r 0.184, NS; not shown). The

percent reduction in TKV was higher in patients with a GFR

X60 ml/min per 1.73 m2 than in those with a GFRo60 ml/

min per 1.73 m2, without reaching statistical significance

(P 0.057).

To determine whether the reduction in kidney volume was

due to changes in cyst volume, we measured individual cyst

volumes in nine patients (six with a GFR X60 ml/min per

1.73 m2 and three with a GFRo60 ml/min per 1.73 m2). A

total of 1120 cysts per patient were measured before and

after the administration of tolvaptan. To protect against bias

the two MRIs for each patient were de-identified and dates ofexaminations removed, so that the examiner was blinded to

the dates and patient data. The two MRI studies for each

patient, however, were examined at the same time. Excellent

image quality in both studies was used as the criterion to

otherwise randomly select 1120 cysts from each patient

between 10 and 100 mm in diameter to measure individual

cyst volumes. In eight of the nine patients, the mean cyst

volume was lower following the administration of tolvaptan

and in three of them the change was statistically significant.

The overall percent reduction in individual cyst volume was

1.64% (P 0.0004). The percent reduction of individual cyst

volumes was more marked in patients with a GFRX60 ml/

min per 1.73 m2 than in those with a GFRo60 ml/min per

1.73 m2 (Figure 3a). The percent reduction in cyst volume

associated with the administration of tolvaptan was sig-nificant in cysts X10 ml, but not in those o10ml (Figure

3a). Percent changes in individual cyst volumes were

correlated with natural log transformed cyst volumes at

baseline (P 0.002; Figure 3b).

Safety of short-term administration of tolvaptan

The administration of tolvaptan was well tolerated and all the

patients completed the study without discontinuation of the

medication. Common adverse events included polyuria

(100%), polydipsia (100%), nocturia (85%), and dry mouth

(45%). There were no serious adverse events.

DISCUSSION

The main observations of this study are that the adminis-

tration of tolvaptan over 1 week reduces GFR and

significantly reduces kidney and cyst volume to a greater

extent than it reduces body weight and body water.

The reduction in GFR induced by tolvaptan occurred

without a significant change in RBF measured indirectly by

the PAH clearance or directly using MRI. Nevertheless,

reductions in PAH clearance and PAH-RBF approached

statistical significance, and an effect of tolvaptan on PAH

clearance and RBF cannot be excluded because of the small

sample size. We cannot exclude either that a reduction in

filtered PAH or an interference of tolvaptan or one of itsmetabolites with the tubular secretion of PAH could account

for these trends. The MR results suggest that the adminis-

tration of tolvaptan does not have an effect on RBF or

that this effect is small and not likely to explain the reduction

in GFR.

As previously observed in patients with ADPKD, admin-

istration of this drug acutely results in a small increase in

serum creatinine concentration, which is paralleled by a

similar reduction in GFR. The percent reduction in GFR is

similar in patients with chronic kidney disease stage 1 or 2

and in those with chronic kidney disease stage 3. It is unlikely

1400r=0.696P-0.001

r=0.788

P-0.001r=0.693P-0.001

140 7

6

5

4

3

2

PreLNUAlbE(g/min)

1

0

120

100

80

60

40

20

5.5

1200

1000

800

600

400

RBF-PAHpre(ml/minper1.7

3m

2)

GFRpre(ml/minper1.7

3m

2)

200

0

5.5 6 6.5 7 7.5 8 8.5 9 9.5

LN TKV pre

6 6.5 7 7.5 8 8.5 9 9.5

LN TKV pre

5.5 6 6.5 7 7.5 8 8.5 9 9.5

LN TKV pre

Figure 1 | Correlation between total kidney volume (TKV) and renal blood flow (RBF), glomerular filtration rate (GFR), and urinealbumin excretion (UAlbE) at baseline. Natural logarithmic transformation (LN) of TKV at baseline (LN TKV pre) inversely correlates withrenal blood flow calculated by para-aminohippurate clearance at baseline (RBF-PAH pre) Po0.001 (a) and with GFR at baseline (GFR pre)Po0.001 (b), and directly correlates with the LN of UAlbE at baseline (pre LN UAlbE) Po0.001 (c).

20

0

20

40

60

80Changefrom

baselineTKV(ml)

1000 500 1000 1500 2000 2500

Baseline TKV (ml)

4000 6000 8000 10,000

Figure 2 | The change in total kidney volume (TKV) frombaseline observed in each patient plotted against eachindividual TKV at baseline.


MV Irazabal et al.: Acute effects of tolvaptan in ADPKD o r i g i n a l a r t i c l e


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that the observed 1.1% reduction in total body water

accounts for the 8.9% increase in serum creatinine. More-

over, an increase in serum creatinine by this mechanism

should be self-limiting, as it would result in an increase in

filtered creatinine and creatinine clearance. It is also unlikely

that relative contraction of plasma volume accounts for the

8.6% reduction in GFR, as no significant change in blood

hemoglobin or serum protein or albumin concentration was

detected and GFR is usually maintained in the presence of

moderate volume contraction by efferent arteriolar constric-

tion and an increase in glomerular pressure.9

As the administration of tolvaptan results in an increase in

vasopressin release, the possibility that a higher level of

circulating vasopressin accounts for the reduction in GFR has

to be considered.10 Direct hemodynamic effects of vasopres-

sin on V1a receptors in the renal vasculature are not likely to

account for the observed change. Under physiological

conditions, elevations of circulating vasopressin within the

physiological range induced by water restriction or exogen-

ous administration have no effect on RBF or GFR.1113 A

renal vasoconstrictor response to vasopressin is observed only

with very high concentrations of vasopressin.14 Increased

levels of circulating vasopressin are more likely to have

an effect on the efferent arterioles and medullary circula-

tion,1520 but this would increase rather than decrease GFR.

Although direct effects of vasopressin on the renal

vasculature are unlikely explanations for the observed

changes, a direct effect of circulating vasopressin on

glomerular function may contribute to the reduction in

GFR. Administration of vasopressin to rats undergoing water

diuresis induces a marked decline in hydraulic pressure

within the Bowmans space, but GFR remains unchanged

because the increase in pressure gradient is offset by a

reduction in the glomerular ultrafiltration coefficient,

possibly due to a direct effect on mesangial V1a receptors

and mesangial cell contraction.21,22

Tolvaptan may also lower GFR by inhibiting the

vasopressin V2-mediated urine concentrating activity

and indirectly affecting renal hemodynamics.23,24 Urine

osmolality and GFR were found to be directly correlated in

conscious rats when urine concentrating activity was

increased by a constant infusion of 1-deamino-8-D-argininevasopressin or reduced by increasing water intake. Reducing

AVP V2R activity may reduce GFR through reduction of urea

recycling and/or sodium chloride reabsorption in the thick

ascending Henles limb, lowering the sodium concentration at

the macula densa and suppressing tubuloglomerular feedback.

Urine concentrating activity and GFR are also correlated in

healthy human volunteers during low and high hydration.25

AVP administration to water loaded healthy volunteers induces

parallel increases in creatinine clearance and urine osmolality.26

Conversely, administration of V2R antagonists after dehydration

induces a fall in creatinine clearance.

The other main observation of this study is thatadministration of tolvaptan for 1 week is sufficient to induce

a significant reduction in TKV and volume of individual

cysts. It seems unlikely that the 1.1% reduction in total body

water entirely accounts for the 3.1% reduction in TKV. The

lack of correlation between the percent changes in total body

water (or body weight) and in total kidney weight supports

this interpretation. A plausible explanation for the tolvaptan

induced reduction in kidney and cyst volumes in this study is

consistent with its proposed mechanism of action in

polycystic kidneys, that is, inhibition of adenosine cyclic

30,50-monophosphate production and chloride-driven fluid

secretion.15 Indeed, renal cysts excised from patients with

ADPKD secrete as well as absorb fluid in vitro and the rate ofnet fluid secretion is augmented by forskolin, which activates

adenylate cyclase.27 Moreover, tolvaptan inhibits AVP-in-

duced chloride currents in ADPKD cell polarized monolayers

and AVP-induced growth of ADPKD cell-derived microcysts

in collagen gels.28 Therefore, inhibition of fluid secretion by

tolvaptan may alter the balance between secretion and

absorption, and induce net fluid reabsorption and reduction

in cyst volume. The greater effects of tolvaptan on kidney and

cyst volumes in patients with a GFRX60 ml/min per 1.73 m2

suggest that tolvaptan may be more effective in early than in

late stages of the disease. Given the small sample size,

50

n= 86% = 1.94P-0.001

n= 52% = 1.14

GFR. 60 ml/min

per 1.73 m2

.10 mlGFR < 60 ml/min

per 1.73 m2


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however, these comparisons should be regarded as explora-

tory and hypothesis generating. Confirmation of these

specific hypotheses will necessitate a replicate study in which

the proposed hypothesis is stated as primary or secondary

with appropriate adjustment to exclude type I error.

A few other observations merit comment. Administration

of tolvaptan resulted in a reduction in uric acid clearance and

an increase in serum uric acid levels that were more marked

than changes in GFR and levels of serum creatinine and

cystatin C. An elevation in serum uric acid is a cha racteristic

of both central and nephrogenic diabetes insipidus.29,30 It has

been suggested that the degree of the elevation may be more

marked in central than in nephrogenic diabetes insipidus

because stimulation of V1a receptors may have a uricosuric

effect.29 Changes in uric acid clearance often closely correlate

with changes in RBF. In our study, however, the reduction in

uric acid clearance occurred in the absence of a significant

change in RBF, particularly when we consider the RBF-MRI,

which likely is more reliable than RBF-PAH in patients

with impaired renal function. The reduced renal clearanceof uric acid associated with the administration of tolvaptan

may be linked to increased proximal reabsorption of

sodium to compensate for reduced V2 receptor-mediated

sodium reabsorption in the distal nephron and collecting

duct.3134 An additional finding associated with the admin-

istration of tolvaptan is a small but significant reduction in

the level of serum potassium. This may be due to the

increased rate of sodium and fluid delivery to the cortical

collecting duct.35

In summary, the results of this study suggest that, very

early after initiation of treatment with tolvaptan, there is an

increase in serum creatinine because of a reduction in GFRlikely due to its effects on tubuloglomerular feedback and/or

glomerular ultrafiltration, a reduction in TKV and cyst

volume accounted at least in part by its effects on fluid

secretion, and a serum uric acid increase and potassium

decrease likely explained by its effects on sodium reabsorp-

tion in the distal nephron and collecting duct.

MATERIALS AND METHODSStudy subjectsStudy participants were previously diagnosed ADPKD patients

based on Ravines criteria,36,37 1860 years of age, and selected to

represent a wide range of disease severity with estimated creatinine

clearances by the CockcroftGault equation X30 ml/min. A total of20 participants (10 caucasian males and 10 caucasian females) were

enrolled in the study, in which 12 had eCrCl X60 ml/min (6 without

hypertension and 6 hypertensive) and 8 had eCrCl 3059ml/min (all

hypertensive). Exclusion criteria included concurrent diseases that

could interfere with the conduct of the study or the interpretation of

the results (for example, diabetes mellitus), uncontrolled hyperten-

sion, use of diuretics, administration of an investigative drug or

donation of blood within 30 days before dosing, allergy to iodine

or benzazepines, and contraindications to MR studies. The

antihypertensive regimen for the study participants with hyperten-

sion included an angiotensin I converting enzyme inhibitor or an

angiotensin II receptor blocker. The protocol was approved by the

Mayo Institutional Review Board. Written informed consent was

obtained from all patients.

Study designThis is a single center, sequential, multiple-dose study of the effect of

a split-dose regimen of tolvaptan tablets on renal function in

patients with ADPKD. Subjects checked into the outpatient clinic on

day

1 and underwent physical examination and measurements ofserum chemistry and hematology parameters, urinalysis, and if

applicable exclusion of pregnancy. On study day 0, all subjects

underwent baseline renal function testing. Subjects were given

enough study medication for 7 days and were instructed to

administer tolvaptan in a split-dose regimen, 45 mg (3 15mg,

oral tablets) on awakening followed by 15mg (1 15mg, oral

tablet) 8 h later on study days 16. On day 7, subjects administered

tolvaptan 45 mg (3 15mg) on awaking at home and the 15mg

dose was administered in the study facilityB8 h after the morning

dose. On study day 8, subjects were given the 45 mg dose at 0700

hours in the study facility and underwent measurements of renal

clearances, followed by measurements of RBF by MRI, and

chemistry and hematology parameters.

Laboratory measurements of renal clearances, RBF, and totalbody waterOn days 0 and 8, subjects were instructed to wake up at 0600 hours,

remain upright for 2 h. They reported to the Renal Function

Laboratory at 0645 hours at which time height and weight were

obtained and an intravenous needle for blood collection was placed

in the dominant arm. At 0700 hours, they drank 240 ml of water

(day 0) or took 45 mg of tolvaptan with 240 ml of water (day 8).

Between 0700 and 0800 hours they drank 7201200 ml of water. At

0800 hours, blood and urine samples were collected for plasma

aldosterone, serum cystatin C, standing plasma renin activity, and

predose iothalamate and PAH. An intravenous catheter was inserted

into the non-dominant arm to administer the priming andsustaining solutions of iothalamate and PAH. Blood and urine

samples were collected within 5 min of each other every 30 min

between 0900 and 1030 hours for measurements of iothalamate,

PAH, urea, creatinine, uric acid, osmolality, urinary protein, and

albumin. Bladder emptying was monitored by ultrasound. GFR

and renal plasma flow (RPF) were determined by iothalamate

and PAH clearances, respectively. Clearances were calculated as

UiV/Pi and UPAHV/PPAH 1.1 and the average of the three

collection intervals were considered the final value of the renal

function test. RBF was estimated from RPF values obtained from

clearance of PAH using the measured hematocrit values as

RBFRPF/(1hematocrit).

Race- and sex-specific total body water (TBW) prediction

equations38 were used to estimate TBW at baseline. TBW on day 8was estimated as the baseline TBW minus free water deficit,

calculated as baseline TBW ((Na post/Na pre)1).

MR measurements of kidney volume, cyst volumes, and RBFMR images were obtained on 1.5-T scanners (Signa; GE Medical

Systems, Milwaukee, WI) at 1100 hours on study day 0 and 8.

After an initial scout to localize the kidneys, coronal T2-weighted

images (single-shot fast spin-echo/fast imaging employing

steady-state acquisition) with 3 and 9 mm fixed slice thickness

and three-dimensional volume-interpolated spoiled-gradient

echo coronal T1-weighted images were obtained (5-mm slice

thickness).




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For kidney volume measurements, image data were transferred

digitally to a workstation. The two MRIs for each patient were

examined at the same time, but they were de-identified and the

examiner was blinded to the dates and patient data. Coronal

T2-weighted images were used to outline both kidneys and TKV was

calculated using the ANALYZE bioimaging software system (Mayo

Foundation, Biomedical Imaging Resource, Rochester, MN). On five

arbitrarily selected patients, measurements were carried out on twoseparate occasions for later assessment of intraobserver variability.

The interval between the consecutive sets of measurements was at

least 30 days. The average intraobserver variability (or percentage

measurement error) was 0.70%.

For measurements of individual cyst volumes, 1120 cysts

measuring 1697 mm in diameter, with good quality images on

both, pre- and post-tolvaptan studies were selected. Coronal T2-

weighted images (3 mm sections) were used to outline each cyst and

cyst volumes were calculated using the ANALYZE bioimaging

software system. As for TKV, all measurements were blinded to

study dates.

For RBF measurements, thick-section, oblique-axial, two-dimen-

sional, phase-contrast, breath-hold MR angiograms were obtained

along the course of each renal artery and acted as reference images.

The MR flow measurements were obtained perpendicular to the

oblique-axial, two-dimensional reference images of the renal arteries

using a cardiac-gated, two-dimensional, fast gradient-echo, phase-

contrast pulse sequence. MR blood flow pulse sequence parameters

were repetition time 810ms, echo time 35 ms, field of

view 1420 cm, flip angle 201, 5-mm slice thickness, 224256

phase encodings, one excitation. The velocity encoding value was

100 cm/s, and flow acquisition was obtained in the slice direction.

Flow analysis was performed using FLOW software version 4

(Medis, Leiden, The Netherlands). Semiautomated or manual

techniques were used for definition of the vessel borders in the

flow images depending on image quality. Vessel area estimations

were made in images at all phases of the cardiac cycle. All RBFmeasurements were performed by the same radiologist (JG).

Validation of the technique used in regards to accuracy and

reproducibility have been reported.3941

Data handling and statistical considerationsNo formal sample size calculation was performed. The number of

subjects tested was based on experience from other previous clinical

studies. Only key exploratory analyses are reported in this paper,

pharmacokinetic analyses will be reported elsewhere.

The primary outcome variables were the changes in GFR and

RBF determined by PAH and MR from study day 0 to 8. Secondary

outcomes were changes in urine volume, uric acid, osmolar and free

water clearances, urine protein/creatinine ratio, urine albumin/

creatinine ratio, serum cystatin C concentrations, plasma reninactivity, plasma aldosterone concentrations, and the assessment of

the safety of tolvaptan determined by the presence of adverse event,

vital signs, laboratory tests, and electrocardiograms. Exploratory

assessments included markers of volume status, for example, serum

sodium, serum protein, blood hemoglobin, fluid intake, and thirst

ratings. Changes in TKV and individual cyst volume were assessed

post hocby raters blinded to image sequence.

The changes in the primary and secondary renal hemodynamic

parameters at study day 8 were tested against study day 0 using

paired t-test. Comparisons between patients with GFRX60 ml/min

per 1.73 m2 and o60ml/min per 1.73m2 were performed

using unpaired t-test. All tests were two-sided with alpha level

0.05. Pearsons correlations were performed to determine linear

correlation.

Measurement error was calculated as the absolute value of the

difference between the measured volumes of the same patient at the

two readings. Intraobserver variability, as the percentage measure-

ment error, was determined by dividing the measurement error by

the average of the two measurements for each MR study.

An adverse event was defined as any new medical problem, orexacerbation of an existing problem, experienced by a subject while

enrolled in the study, whether or not it was considered drug related

by the investigator.

Data are presented as means (s.d.) or medians (range) when

appropriated. All statistics were performed at Mayo using JMP

software, version 8.0 (SAS Institute, Cary, NC).

DISCLOSUREFSC, JO, and HBK are employees of Otsuka. VET and the Mayo Clinichave received materials and funding for pre-clinical research and VETis an investigator and Chair of the Steering Committee for severalOtsuka studies involving ADPKD. All the other authors declared nocompeting interests.

ACKNOWLEDGMENTSWe thank the patients for taking part in the study. Funding for thisstudy was provided by Otsuka Pharmaceutical Development &Commercialization, Inc.

REFERENCES1. Gattone VH, Wang X, Harris PC et al. Inhibition of renal cystic disease

development and progression by a vasopressin V2 receptor antagonist.Nat Med 2003; 9: 13231326.

2. Torres VE, Wang X, Qian Q et al. Effective treatment of an orthologousmodel of autosomal dominant polycystic kidney disease. Nat Med 2004;10: 363364.

3. Wang X, Gattone II V, Harris PC et al. Effectiveness of vasopressin V2receptor antagonists OPC-31260 and OPC-41061 on polycystic kidneydisease development in the PCK rat. J Am Soc Nephrol2005; 16: 846851.

4. Belibi FA, Reif G, Wallace DP et al. Cyclic AMP promotes growth andsecretion in human polycystic kidney epithelial cells. Kidney Int 2004; 66:964973.

5. Yamaguchi T, Pelling J, Ramaswamy N et al. cAMP stimulates the in vitroproliferation of renal cyst epithelial cells by activating the extracellularsignal-regulated kinase pathway. Kidney Int 2000; 57: 14601471.

6. Konstam MA, Gheorghiade M, Burnett Jr JC et al. Effects of oral tolvaptanin patients hospitalized for worsening heart failure: the EVERESTOutcome Trial. JAMA 2007; 297: 13191331.

7. Schrier RW, Gross P, Gheorghiade M et al. Tolvaptan, a selective oralvasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med2006;355: 20992112.

8. Torres VE, Winklhofer F, Chapman AB et al. Phase 2 open-label study todetermine long-term safety, tolerability and efficiacy of split-doseTolvaptan in ADPKD. J Am Soc Nephrol 2009; 20: 746A.

9. Schor N, Ichikawa I, Brenner BM. Glomerular adaptations to chronicdietary salt restriction or excess. Am J Physiol 1980; 238: F428F436.

10. Grantham JJ, Chapman AB, Torres VE et al. Acute and chronic osmostasisafter vassopressin V2 receptor inhibiton with Tolvaptan in ADPKD. J AmSoc Nephrol 2005; 16: 361A.

11. Gellai M, Silverstein JH, Hwang JC et al. Influence of vasopressin on renalhemodynamics in conscious Brattleboro rats. Am J Physiol 1984; 246:F819F827.

12. Harrison-Bernard LM, Brizzee BL, Clifton GG et al. Renal versushindquarter hemodynamic responses to vasopressin in conscious rats.

J Cardiovasc Pharmacol1990; 16: 719726.13. Liard JF, Deriaz O, Schelling P et al. Cardiac output distribution during

vasopressin infusion or dehydration in conscious dogs. Am J Physiol1982;243: H663H669.

14. Roald AB, Tenstad O, Aukland K. The effect of AVP-V1 receptor stimulationon local GFR in the rat kidney. Acta Physiol Scand 2004; 182: 197204.

15. Cowley Jr AW. Control of the renal medullary circulation by vasopressinV1 and V2 eceptors in the rat. Exp Physiol 2000; 85 Spec No: 223S231S.

6 Kidney International

o r i g i n a l a r t i c l e MV Irazabal et al.: Acute effects of tolvaptan in ADPKD


7/7

16. Davis JM, Schnermann J. The effect of antidiuretic hormone on thedistribution of nephron filtration rates in rats with hereditary diabetesinsipidus. Pflugers Arch 1971; 330: 323334.

17. Edwards RM, Trizna W, Kinter LB. Renal microvascular effects ofvasopressin and vasopressin antagonists. Am J Physiol 1989; 256:F274F278.

18. Fisher RD, Grunfeld JP, Barger AC. Intrarenal distribution of blood flow indiabetes insipidus: role of ADH. Am J Physiol 1970; 219: 13481358.

19. Yamada K, Nakano H, Nishimura M et al. Effect of AVP.V1-receptor

antagonist on urinary albumin excretion and renal hemodynamics inNIDDM nephropathy: role of AVP.V1-receptor. J Diabetes Complications1995; 9: 326329.

20. Zimmerhackl B, Robertson CR, Jamison RL. Effect of arginine vasopressinon renal medullary blood flow. A videomicroscopic study in the rat. J ClinInvest 1985; 76: 770778.

21. Jard S, Lombard C, Marie J et al. Vasopressin receptors from culturedmesangial cells resemble V1a type. Am J Physiol 1987; 253: F41F49.

22. Schor N, Ichikawa I, Brenner BM. Mechanisms of action of varioushormones and vasoactive substances on glomerular ultrafiltration in therat. Kidney Int 1981; 20: 442451.

23. Bankir L. Antidiuretic action of vasopressin: quantitative aspects andinteraction between V1a and V2 receptor-mediated effects. CardiovascRes 2001; 51: 372390.

24. Bouby N, Ahloulay M, Nsegbe E et al. Vasopressin increases glomerularfiltration rate in conscious rats through its antidiuretic action. J Am SocNephrol 1996; 7: 842851.

25. Anastasio P, Cirillo M, Spitali L et al. Level of hydration and renal functionin healthy humans. Kidney Int 2001; 60: 748756.26. Andersen LJ, Andersen JL, Schutten HJ et al. Antidiuretic effect of

subnormal levels of arginine vasopressin in normal humans. Am J Physiol1990; 259: R53R60.

27. Ye M, Grantham J. The secretion of fluid by renal cysts from patients withautosomal dominant polycystic kidney disease. New Eng J Med1993; 329:310313.

28. Reif GA, Nivens E, Pinto CS et al. Tolvaptan inhibits AVP-inducedCl- secretion and in vitro cyst growth of human ADPKD cyst epithelialcells. J Am Soc Nephrol 2008; 19: 365A.

29. Decaux G, Prospert F, Namias B et al. Hyperuricemia as a clue for centraldiabetes insipidus (lack of V1 effect) in the differential diagnosis ofpolydipsia. Am J Med 1997; 103: 376382.

30. Gorden P, Robertson GL, Seegmiller JE. Hyperuricemia, a concomitant ofcongenital vasopressin-resistant diabetes insipidus in the adult. N Engl JMed 1971; 284: 10571060.

31. Bankir L, Fernandes S, Bardoux P et al. Vasopressin-V2 receptorstimulation reduces sodium excretion in healthy humans. J Am SocNephrol 2005; 16: 19201928.

32. Perucca J, Bichet DG, Bardoux P et al. Sodium excretion in response tovasopressin and selective vasopressin receptor antagonists. J Am SocNephrol 2008; 19: 17211731.

33. Sauter D, Fernandes S, Goncalves-Mendes N et al. Long-term effects ofvasopressin on the subcellular localization of ENaC in the renal collectingsystem. Kidney Int 2006; 69: 10241032.

34. Mutig K, Saritas T, Uchida S et al. Short-term stimulation of the thiazide-sensitive Na+-Cl- cotransporter by vasopressin involves phosphorylationand membrane translocation. Am J Physiol Renal Physiol 2010; 298:F502F509.

35. Muto S. Potassium transport in the mammalian collecting duct. PhysiolRev 2001; 81: 85116.

36. Ravine D, Gibson RN, Walker RG et al. Evaluation of ultrasonographicdiagnostic criteria for autosomal dominant polycystic kidney disease 1.Lancet 1994; 343: 824827.

37. Pei Y, Obaji J, Dupuis A et al. Unified criteria for ultrasonographicdiagnosis of ADPKD. J Am Soc Nephrol 2009; 20: 205212.

38. Chumlea WC, Guo SS, Zeller CM et al. Total body water reference valuesand prediction equations for adults. Kidney Int 2001; 59: 22502258.39. Torres VE, King BF, Chapman AB et al. Magnetic resonance measurements

of renal blood flow and disease progression in autosomal dominantpolycystic kidney disease. Clin J Am Soc Nephrol 2007; 2: 112120.

40. King BF, Torres VE, Brummer ME et al. Magnetic resonance measurementsof renal blood flow as a marker of disease severity in autosomal-dominant polycystic kidney disease. Kidney Int 2003; 64: 22142221.

41. Dambreville S, Chapman AB, Torres VE et al. Renal arterial blood flowmeasurement by breath-held MRI: accuracy in phantom scans andreproducibility in healthy subjects. Magn Reson Med 2010; 63: 940950.



Irazabal Et Al. - 2011 - Short-Term Effects of Tolvaptan on Renal Function

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