Tolvaptan Can Improve Clinical Course in Responders

Imamura, Teruhiko; Kinugawa, Koichiro; Minatsuki, Shun; Muraoka, Hironori; Kato, Naoko; Inaba, Toshiro; Maki, Hisataka; Hatano, Masaru; Yao, Atsushi; Komuro, Issei

doi:10.1536/ihj.54.377

Cited by 25 publications

(32 citation statements)

References 18 publications

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“…5) Despite the increase in the P-AVP level at day-7, the U-AQP2 level did not return to the baseline level after 7 days of TLV administration (75% compared with that at baseline) in the TLV-responders, indicating that the AQP2 excretion in urine was considerably suppressed after 24 hours of TLV administration. Since the antagonistic effect of TLV is transient (personal communication from Otsuka Pharmaceuticals), we hypothesize that TLV at its measured trough concentration at day-7 can inhibit the V2R in the presence of AVP.…”

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confidence: 84%

“…[1][2][3][4][5][6][7][8][9][10] In contrast, we sometimes experience TLV-non-responders in our daily clinical practice. 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.…”

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

2016

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“…AQP2-GUIDED TLV TREATMENT tages of TLV only in responders defined by urine osmolality. 11,12) We also reported in a propensity-matched retrospective study that the survival advantage of long-term TLV treatment was observed only in the responders defined by U-AQP2. 8) A prospective study to analyze the long-term efficacy of TLV, such as improved survival, reduced readmission rate, or freedom from renal replacement therapy in responders would be of value.…”

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confidence: 87%

Aquaporin-2-Guided Tolvaptan Therapy in Patients With Congestive Heart Failure Accompanied by Chronic Kidney Disease

Imamura

2014

Int. Heart J.

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R ecently, there has been increasing evidence supporting the efficacy and safety of the arginine vasopressin (AVP) type 2 (V 2 ) antagonist tolvaptan (TLV) in the improvement of hyponatremia or amelioration of congestion sparing renal function in acute/chronic heart failure (HF) patients refractory to considerable amounts of loop diuretics. 1)However, such a clinical benefit of TLV-incorporated diuretic therapy is not necessarily observed in all HF patients. In other words, we sometimes experience non-responders to TLV, whose clinical course worsens regardless of the initiation of TLV. 2)Although the precise mechanism of resistance to TLV is unknown, we previously speculated that aging and chronic kidney disease (CKD) were major risk factors of non-responders.3) In fact, concentrating and diluting ability in the collecting ducts is essential for the efficacy of TLV, but is often impaired in elderly or those with advanced CKD. However, according to our clinical experience, there were several responders to TLV even though they were complicated with stage G4 CKD. Article p.533The efficacy of TLV treatment in patients with CKD is controversial. Sato, et al demonstrated in a recent study that some responders with diabetes mellitus nephropathy received a clinical benefit from TLV treatment even though their renal dysfunction was approximately equivalent to stage G4 CKD (22.1 ± 18.1 mL/minute/1.73m 2 of estimated glomerular filtration ratio). 4) Among the 8 patients from whom renal specimens were obtained, 7 were responders and simultaneously had explicit expression of aquaporin-2 (AQP2) in the collecting ducts. The remaining patient was a non-responder showing no expression of AQP2 with histological evidence of tubulointerstitial damage. Although the sample number was very small, they speculated that some, albeit not all, patients with advanced CKD did respond to TLV, and that the responses to TLV might be dependent on residual expression of AQP2 in the collecting ducts.AQP2 is the recently characterized AVP-regulated water channel expressed in the collecting ducts in the kidney.5,6) Secreted AVP from the pituitary gland binds to V 2 receptors located in the basolateral membrane of principal cells in the collecting ducts, and then the activated V 2 receptors trigger the transport of AQP2 from intracellular storage vesicles into the apical membrane. The amount of AQP2 activated determines the water permeability in the apical membrane and then dominates urinary concentrating ability. 7) Expression of AQP2 in the apical membrane is considered as an index of the V2-receptor dependent activity of the collecting ducts, which may be essential for the response to TLV because TLV cannot block water-reabsorption there without baseline expression or activation of AQP2 protein.Considering the above mechanism, AQP2 can be a good marker for predicting responses to TLV especially in patients with CKD. However, how can we measure the expression of AQP2 in the human kidney? Sato, et al obtained renal biopsy specimens and demonstrated ...

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“…Propensity score matching analyses: The clinical use of TLV has increased recently, and many authors have showed that TLV is beneficial in ameliorating symptomatic congestion and in normalizing hyponatremia, thus improving renal function in patients with decompensated HF. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Therefore, prospective recruitment of a control group has thus far been ethically difficult considering the obvious clinical advantage of TLV treatment.…”

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confidence: 99%

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14] Although the long-term efficacy of TLV remains controversial, 6) we recently demonstrated the benefits of long-term administration of TLV on survival and re-admission, especially in responders to TLV. 15) Despite its clinical advantage, TLV is expensive compared with other conventional diuretics, which is an important limitation considering current increases in total medical expenses.…”

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Tolvaptan Reduces Long-Term Total Medical Expenses and Length of Stay in Aquaporin-Defined Responders

et al. 2016

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SummaryThe vasopressin type-2 antagonist tolvaptan (TLV) has clinical advantages including amelioration of congestion and normalization of hyponatremia in patients with decompensated heart failure (HF). However, there have been no studies on the cost-effectiveness of TLV therapy. We enrolled 60 consecutive hospitalized patients with stage D HF who received TLV [TLV (+) group], and 60 propensity score-matched HF patients without TLV treatment [TLV (-) group]. We excluded 54 patients who died or received cardiac replacement therapy within 1 year, and finally enrolled 32 patients who received TLV and 34 who did not, who were followed for > 1 year. Among 45 aquaporin-defined responders, whose urine aquaporin-2 relative to plasma arginine vasopressin level was > 1.4 × 10 3 L/g Cre, the TLV (+) group required significantly lower total medical expenses and shorter lengths of stay (LOS) In contrast, among the remaining 21 aquaporin-defined non-responders, medical expenses and LOS were comparable irrespective of TLV administration (P = 0.087 and P = 0.407). In conclusion, TLV therapy may reduce total medical expenses in aquaporin-defined responders with stage D HF. (Int Heart J 2016; 57: 593-599)

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Tolvaptan Can Improve Clinical Course in Responders

Cited by 25 publications

References 18 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

Aquaporin-2-Guided Tolvaptan Therapy in Patients With Congestive Heart Failure Accompanied by Chronic Kidney Disease

Tolvaptan Reduces Long-Term Total Medical Expenses and Length of Stay in Aquaporin-Defined Responders

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