Positive Response to Tolvaptan Treatment Would Be a Good Prognostic Factor for Cirrhotic Patients with Ascites

Aims: Ascites is one of the major complications in advanced cirrhotic patients. Tolvaptan is a non-peptide orally available arginine vasopressin V2 receptor antagonist. We investigated and found that tolvaptan therapy improved the prognosis and predictive factor of cirrhotic patients with ascites. Methods: Overall, 99 patients with newly diagnosed ascites with cirrhosis were enrolled. No patients had intrahepatic malignancy. The patients were divided into 2 groups based on tolvaptan therapy: 86 patients treated with tolvaptan (tolvaptan-group) and 13 patients treated without tolvaptan (non-tolvaptan-group). Tolvaptan-responder was defined as body weight loss of ≥1.5 kg/week after administering tolvaptan. Results: Tolvaptan therapy was effective in 61.6% of cirrhotic patients. There was a significant difference in the overall survival (OS) between the tolvaptan-responder-group and the other groups (p < 0.001). Male (HR 5.05; p = 0.01), tolvaptan responder (HR 0.21; p = 0.02), and dosage of furosemide < 40 mg/day (HR 0.17; p = 0.01) were factors that were independently associated with the OS. The multivariate analysis revealed that C-reactive protein < 0.9 mg/dL (HR 0.07; p = 0.001), and furosemide dosage < 40 mg/day (HR 0.09; p = 0.003) were independently associated with the tolvaptan response. Conclusion: Therapeutic response to tolvaptan was associated with longer survival in cirrhosis patients complicated with ascites. These preliminary findings warrant validation and further exploration.

Dose-Titrated Vasopressin V2 Receptor Antagonist Improves Renoprotection in a Mouse Model for Autosomal Dominant Polycystic Kidney Disease

Background: In autosomal dominant polycystic kidney disease, renoprotective treatment with a vasopressin V2 receptor antagonist (V2RA) is given in a fixed dose (FD). Disease progression and drug habituation could diminish treatment efficacy. We investigated whether the renoprotective effect of the V2RA can be improved by dose titration of the V2RA aiming to maintain aquaresis at a high level. Methods: The V2RA OPC-31260 was administered to Pkd1-deletion mice in an FD (0.1%) or in a titrated dose (TD, up to 0.8% when drinking volume dropped). Total kidney weight (TKW) and cyst ratio were investigated and compared to non-treated Pkd1-deletion mice. Treatment was started early or late (21 or 42 days postnatal). Results: Water intake was significantly higher throughout the experiment in the TD compared to the FD group. FD treatment that was initiated early reduced TKW and cyst ratio but lost its renoprotective effect later during the experiment. In contrast, TD treatment was able to maintain the renoprotective effect. TD treatment, however, was also associated with a higher early termination rate in comparison with FD treatment. Late start of treatment (FD or TD) did not show a renoprotective effect. Conclusions: Titration of a V2RA aimed to maintain aquaresis at a high level showed a better renoprotective effect compared to FD administration. However, this treatment regimen was poorly tolerated and did not overcome treatment unresponsiveness when started later in the disease.