Increased Urine Aquaporin-2 Relative to Plasma Arginine Vasopressin Is a Novel Marker of Response to Tolvaptan in Patients With Decompensated Heart Failure

Imamura, Teruhiko; Kinugawa, Koichiro; Fujino, Takeo; Inaba, Toshiro; Maki, Hisataka; Hatano, Masaru; Yao, Atsushi; Komuro, Issei

doi:10.1253/circj.cj-14-0244

Cited by 86 publications

(109 citation statements)

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“…The U-AQP2 level was measured using a sandwich enzyme-linked immunosorbent assay (human aquaporin-2 ELISA kit, LSI Medience) and was corrected for the urine creatinine (U-Cre) concentration to allow for a quantitative comparison as previously described. 12,17) The urine volume (UV) collected during 24 hours after the initiation of the TLV treatment (day-1) was compared with that of the previous 24 hours (day-0). The patients, whose 24-hour UV at day-1 increased compared with that at day-0, were defined as TLV-responders (UV-defined responders).…”

Section: Methodsmentioning

confidence: 99%

“…12) However, few reports exist on the concentration-time profile of U-AQP2 after the initiation of TLV therapy. Martin, et al previously reported that the U-AQP2 level decreased significantly after the administration of TLV, 14) however, the potential relationship between the changes in the U-AQP2 level and the responsiveness to TLV remains unknown.…”

Section: 23)mentioning

confidence: 99%

“…This result supports our hypothesis that the unresponsiveness to TLV was not attributable to the low blood concentration of TLV due to malabsorption, but rather to the dysfunction of the renal collecting duct. 11,12) Accordingly, the up-titration of TLV may not be effective in the TLV-non-responders. We previously proposed the criterion to predict responsiveness to TLV: the U-AQP2 level relative to the P-AVP level, which can be obtained before the initiation of TLV therapy.…”

Section: )mentioning

confidence: 99%

“…11) We previously proposed a novel predictor of responsiveness to TLV, ie, the baseline urine aquaporin-2 (U-AQP2) level relative to the plasma AVP (P-AVP) level, which may indicate a preserved vasopressin type 2 receptor (V2R)-related signaling pathway in the principal cells of the renal collecting duct. 12,13) However, little is known about the concentration-time profile of U-AQP2 after the initiation of TLV treatment. Although Martin, et al observed the changes of U-AQP2 after the initiation of V2R antagonist, the responsiveness to TLV was not discussed.…”

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Tolvaptan Prolongs Blockage of the Vasopressin Type II Receptor Over 24 Hours in Responders With Stage D Heart Failure

2016

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SummaryThe urine aquaporin-2 (U-AQP2) level relative to the plasma arginine vasopressin (P-AVP) level is a novel predictor of the responsiveness to the vasopressin type 2 receptor (V2R) antagonist tolvaptan (TLV). However, little has been reported about the concentration-time profile of U-AQP2 after TLV treatment. We evaluated 24 patients with decompensated stage D heart failure (HF) who had received 3.75 mg/day of TLV on a de novo basis for > 7 days to treat congestion refractory to conventional diuretics. Seventeen patients were TLV-responders, whose 24-hour urine volume (UV) increased after TLV initiation; the other 7 patients were TLV-non-responders. The U-AQP2 of the TLV-responders, corrected for the urine creatinine concentration, decreased significantly at 4 hours after TLV administration without returning to the day-1 morning level on the morning of day-7. The TLV-non-responder U-AQP2 levels remained low even before the TLV treatment. On the morning of day-7, the TLV-responder U-AQP2/P-AVP ratio was comparable to that of the TLV-non-responders. Among 18 patients (11 responders and 7 non-responders), the day-7 TLV trough concentration was 64 ± 62 ng/mL and was negatively correlated with the estimated glomerular filtration rate (eGFR). TLV has antagonistic effects on the V2R over 24 hours in TLV-responders with advanced heart failure and chronic kidney disease, probably due to persistently elevated blood TLV concentration. The unresponsiveness to TLV in the TLV-non-responders is not attributable to malabsorption. (Int Heart J 2016; 57: 41-46)

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confidence: 99%

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confidence: 99%

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Tolvaptan Prolongs Blockage of the Vasopressin Type II Receptor Over 24 Hours in Responders With Stage D Heart Failure

2016

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“…[10][11][12][13][14][15][16][17] TLV has a specific feature of excreting only water without increasing electrolyte excretion because it functions as an antagonist to the vasopressin V2 receptor in renal collecting tubules. 18) In addition, it has been shown that TLV treatment resulted in favorable but modest changes in filling pressures (ie, pulmonary capillary wedge pressure, right atrial pressure, and pulmonary artery pressure) associated with a significant increase in urine output.…”

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Successful Treatment of Congestive Heart Failure Due to Severe Aortic Valve Stenosis With Low Dose Tolvaptan in Elderly Patients

et al. 2017

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SummaryMedical therapy for severe aortic valve stenosis (AS) is necessary for inoperable patients due to comorbid conditions. Tolvaptan (TLV), unlike other diuretics, resulted in modest changes in filling pressures associated with an increase in urine output, suggesting that TLV improves congestive heart failure (CHF) due to severe AS without hemodynamic instability.We retrospectively investigated 14 consecutive patients ≥ 80 years of age admitted due to decompensated CHF with severe AS at Juntendo University Hospital from April 2014 to November 2015. Seven of the 14 patients were treated with TLV. We examined the safety and efficacy of TLV treatment for severe AS.Mean age was 90.0 ± 6.3 years and mean aortic valve area was 0.57 ± 0.22 cm 2. Urine volume at day 1 of TLV treatment was increased and urine osmolality significantly decreased at day 1 of TLV treatment (all P < 0.05). New York Heart Association classification and brain natriuretic peptide levels significantly improved 1 week after treatment and at discharge (all P < 0.05) whereas brain natriuretic peptide levels did not improve in the patients without TLV. Severe adverse events did not occur during TLV treatment. During the first 3 days, blood pressure and heart rate were relatively stable. TLV treatment did not affect serum creatinine, blood urea nitrogen, or the estimated glomerular filtration rate.In elderly patients with severe AS, TLV treatment improved CHF without hemodynamic instability. Further prospective studies are needed to assess the safety and efficacy of TLV in decompensated heart failure due to severe AS. (Int Heart J 2017; 58: 378-384)

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Impact of chronic kidney disease on the diuretic response of tolvaptan in acute decompensated heart failure

et al. 2017

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AimThis study investigated the relationship between the initial diuretic response to tolvaptan and clinical predictors for tolvaptan responders in patients with acute decompensated heart failure (ADHF).Methods and resultsPatients (153) with ADHF (clinical scenario 2 or 3 with signs of fluid retention) who were administered tolvaptan were enrolled. Tolvaptan (15 or 7.5 mg) was administered for at least 7 days to those patients in whom fluid retention was observed even after standard treatment. The maximum urine volume immediately after tolvaptan administration showed good correlations with the ejection fraction and estimated glomerular filtration rate that were independent predictors of the urine volume (UV) responders (≥1500 mL increase in urine volume). The diuretic response (in terms of maximum diuresis) diminished with advancing chronic kidney disease (CKD) stage and concomitant deterioration of the renal function. Furthermore, advanced CKD was a significant negative predictor for the body weight (BW) responders (2.0% decrease in the body weight within 1 week after starting tolvaptan). As compared with non‐CKD, the presence of advanced CKD predicts poor diuretic response for both UV and BW responders.ConclusionsThe diuretic response following tolvaptan administration gradually diminished with progressive deterioration of the CKD stage. Worsening renal function was not observed. Tolvaptan is effective in treating CS2 or CS3 ADHF patients who present fluid retention and congestion, suggesting its potential efficacy for fluid management in the ADHF patients with CKD without worsening the renal function.

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Increased Urine Aquaporin-2 Relative to Plasma Arginine Vasopressin Is a Novel Marker of Response to Tolvaptan in Patients With Decompensated Heart Failure

Cited by 86 publications

References 35 publications

Tolvaptan Prolongs Blockage of the Vasopressin Type II Receptor Over 24 Hours in Responders With Stage D Heart Failure

Tolvaptan Prolongs Blockage of the Vasopressin Type II Receptor Over 24 Hours in Responders With Stage D Heart Failure

Successful Treatment of Congestive Heart Failure Due to Severe Aortic Valve Stenosis With Low Dose Tolvaptan in Elderly Patients

Impact of chronic kidney disease on the diuretic response of tolvaptan in acute decompensated heart failure

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