This retrospective study evaluated tolvaptan's efficacy, safety, and predictive indicators in managing volume overload in chronic kidney disease (CKD) patients.

CKD patients with volume overload, treated with loop diuretics alone or with tolvaptan at Zhongda Hospital, Southeast University, from 1 March 2022 to 31 December 2023, were included. Patients were divided into loop diuretic (Group C) and loop diuretic combined with tolvaptan (Group T) cohorts. Primary outcomes included volume control, changes in weight, urine output, and laboratory parameters within 1 week post-medication. Adverse events such as hypernatremia and hyperkalemia, etc., were recorded. We further conducted immunohistochemical staining of renal biopsy tissues to investigate the roles of aquaporin-2 (AQP2) in the collecting duct and plasma albumin in predicting the efficacy of tolvaptan.

Of 174 CKD patients with volume overload, 108 (67.07%) were male. Group C and Group T each comprised 87 patients. At baseline, no significant differences in urine output and weight were noted. By day 3, Group T exhibited a greater increase in urine output (P < .001) and weight reduction (P < .001). At day 7, Group T maintained more significant diuretic effects (P < .001). More Group C patients required ultrafiltration therapy (P = .040). Adverse event rates did not significantly differ. Notably, AQP2 expression in the collecting duct may predict tolvaptan responsiveness, while plasma albumin did not affect efficacy.

Tolvaptan showed efficacy and safety in managing volume overload in CKD patients. The expression of AQP2 in the collecting duct could predict tolvaptan's efficacy.This study protocol was approved by the Ethics Committee of Zhongda Hospital Affiliated to Southeast University (Approval No. 2023ZDSYLL180-P01, Clinical Trial Registration No. ChiCTR2300075274, Trial Registration Link: https://www.chictr.org.cn/guide.html).

In 2023, Chinese Society of Hepatology of Chinese Medical Association convened a panel of experts to update the Chinese guidelines on the management of ascites and associated complications in cirrhosis which was launched in 2017 and renamed this guidelines as "Guidelines on the Management of Ascites in Cirrhosis." This comprehensive resource offers essential recommendations for the diagnosis and treatment of cirrhotic ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome.

Acute kidney injury (AKI) is associated with liver cirrhosis (LC), water retention, diuretics to treat water retention, and a poor prognosis. Urinary neutrophil gelatinase-associated lipocalin (uNGAL) reportedly predicts a poor prognosis in decompensated LC. This study investigated the usefulness of uNGAL in predicting the short- and long-term effects of tolvaptan (TVP) and the incidence of AKI post-TVP administration.

Of the LC cases with water retention, 86 with available pre-treatment uNGAL were analyzed. A short-term response was defined as weight loss of ≥ 1.5 kg within the first week; a long-term response was defined as a short-term response without early recurrence. The uNGAL usefulness in predicting the short- and long-term effects of TVP and AKI incidence post-TVP administration was investigated.

Short-term effects of TVP were observed in 52 patients. Of these, 15 patients had an early recurrence. In multivariate analysis, significant short-term predictive factors were C-reactive protein (CRP) < 1.4 mg/dl, uNa/K ratio ≥ 3.51, and uNGAL < 50.2 ng/ml. Patients were classified according to these three cut-off values, with short-term response rates of 92.9%, 68.8%, 26.7%, and 0% for 0, 1, 2, and 3 points, respectively. CRP < 0.94 mg/dl and uNGAL < 50.2 ng/ml were significant factors for predicting the long-term response of TVP. The AKI incidence post-TVP was 8.1% (n = 7) and was significantly higher among those with uNGAL ≥ 38.1 ng/mL.

uNGAL is a useful predictor of the short- and long-term efficacy of TVP and can be useful in predicting AKI incidence post-TVP administration.

Tolvaptan (TVP) is an effective treatment for patients with cirrhotic ascites; however, studies have indicated that a sufficient effect is difficult to obtain in patients with hepatocellular carcinoma (HCC). This study evaluates the efficacy of TVP in patients with HCC with refractory ascites.

We retrospectively enrolled 32 patients with liver cirrhosis and refractory ascites [mean age: 74 years (range, 47-86 years), men: 78.1% (25/32)]. All patients had HCC and were treated with TVP at our hospital. A TVP responder was defined as a patient who experienced decrease in body weight by ≥1.5 kg within 1 week of treatment. Univariate and multivariate analyses were performed to evaluate clinical and laboratory predictive factors of TVP response.

The TVP response rate was 46.9% (15/32 patients) after 1 week of treatment. HCC treatment (transcatheter arterial chemoembolization and/or radiofrequency ablation) was administered to 11/15 (73.3%) responders. In the multivariate analysis, the reduction of urine osmolality was higher in responders than nonresponders (202 mOsm/l vs. 65 mOsm/l, P = 0.040), and the tumor stage (P = 0.043) was worse in nonresponders. Multivariate Cox proportional hazards regression analysis indicated a significantly better prognosis among responders than among nonresponders (P < 0.01).

The HCC tumor stage and the reduction in urine osmolality can predict the efficacy of TVP in patients with refractory ascites complicated with HCC. TVP may allow therapeutic intervention for HCC and improve prognosis, even in patients with Child-Pugh class C.

The aim of this retrospective study was to determine whether tolvaptan treatment reduces the amount of albumin administered, volume of ascites removed, and frequency of paracentesis procedures in patients with decompensated cirrhosis with uncontrolled ascites with conventional diuretics.

The control (C) group included patients treated with conventional diuretics. The tolvaptan (T) group included patients treated with both tolvaptan and conventional diuretics. Both groups were matched according to baseline parameters. The amount of albumin administered, volume of ascites removed, and frequency of paracentesis within 30 days of onset of uncontrolled ascites were compared between the two groups.

After matching, 74 patients (C=37, T=37) were included. Baseline parameters (C vs. T group) were as follows: age, 69.5 ± 9.3 vs. 70.4 ± 11.0 years (p = 0.702) ; males, 24 (64.9%) vs. 25 (67.6%) (p = 0.999) ; patients with hepatocellular carcinoma, 17 (45.9%) vs. 18 (48.6%) (p = 0.999) ; serum albumin levels at treatment initiation, 2.76 ± 0.48 vs. 2.73 ± 0.49 g/dL (p = 0.773), and serum creatinine levels at treatment initiation, 1.18 ± 1.23 vs. 1.09 ± 0.48 g/dL (p = 0.679). In the C vs. T groups, respectively, mean amount of albumin administered was 51.0 ± 31.4 vs. 33.4 ± 29.8 g/month (p = 0.016) ; mean volume of ascites removed was 2,905 ± 4,921 vs. 1,824 ± 3,185 mL/month (p = 0.266) ; and mean frequency of paracentesis was 0.92 ± 1.46 vs. 0.89 ± 1.45 procedures (p = 0.937).

Tolvaptan reduced the use of albumin infusion in patients with decompensated cirrhosis and was effective and acceptable for uncontrolled ascites.

Wisteria floribunda agglutinin (WFA) is a lectin that binds to the sugar chain of Mac-2 binding protein (M2BP), and WFA-positive M2BP (WFA+-M2BP) has been reported as a useful marker for assessing liver fibrosis in chronic liver disease. Tolvaptan (TLV), a selective vasopressin V2 receptor antagonist, is used for cirrhotic ascites in Japan, but good predictors of treatment efficacy remain to be established. Our aim was to investigate whether WFA+-M2BP monitoring before and after TLV administration can predict treatment efficacy in patients with cirrhotic ascites. Twenty patients (10 men), with a median age of 72 years, were enrolled. Cirrhosis was caused by hepatitis B virus (n = 3), hepatitis C virus (n = 4), alcohol (n = 8), and others (n = 5). Responders were defined as having a body weight loss of ≥ 1.5 kg/week after TLV administration. Serum WFA+-M2BP levels were measured at baseline and days 1, 3, and 7 after TLV treatment. Twelve patients (60%) were responders. Baseline WFA+-M2BP levels were correlated with serum albumin levels (r = -0.544, P = 0.013). The baseline furosemide dose was lower and platelet count was higher in responders than in non-responders (P < 0.05). The ratio of WFA+-M2BP levels on day 1 after TLV administration to baseline was lower in responders than in non-responders (P < 0.05). The decrease in the ratio discriminated responders from non-responders (AUC = 0.844, P < 0.05). In conclusion, monitoring serum WFA+-M2BP is helpful for predicting the efficacy of TLV treatment in patients with cirrhotic ascites.

Tolvaptan is a newly available diuretic that has a specific function in water reabsorption inhibition. Given that spironolactone or furosemide induces the aggravation of cirrhotic hyponatremia and dehydration, tolvaptan affects the management strategy of liver cirrhosis. Representative predictive markers of its response include renal function-related markers such as urea nitrogen or creatinine. However, vascular function-related markers have not been well investigated. We investigated the effect of the vascular function-related marker asymmetric dimethylarginine (ADMA) and the effective arterial blood volume (EABV) marker, fractional excretion of sodium (FENa), on the early tolvaptan response and survival in liver cirrhosis.

We prospectively recruited 49 patients who required add-on tolvaptan for refractory ascites or edema. Laboratory data were obtained immediately before and 1 day after tolvaptan administration. Patients exhibiting >1.5 kg weight loss after 1 week were categorized as early responders to tolvaptan. Patients were followed for a median of 200 days and were assessed for survival.

Early responders showed lower creatinine levels (<1.0 mg/dL), and higher ADMA levels (≥0.61 nmol/mL) than others in a multivariate analysis. Patients with a shorter survival were positive for hepatocellular carcinoma and had a low FENa (<0.35%).

Early responders showed higher ADMA levels reflecting vascular stricture, suggesting that higher vascular tonus is required for a tolvaptan early response. Patients with a shorter survival showed a lower FENa, reflecting a lower EABV and suggesting that adequate EABV is required for the prolonged survival after tolvaptan administration.

Decompensated liver cirrhosis patients with refractory ascites or pleural effusion have a poor prognosis. Tolvaptan has been used for treating water retention associated with cirrhosis. However, despite the short-term response, water retention recurrence is still observed in some cases. This study aimed to clarify the water retention recurrence rate and the relationship between long-term response without recurrence and prognosis.

Altogether, 100 patients with decompensated cirrhosis treated with tolvaptan were retrospectively analyzed. Recurrence was evaluated according to the criteria of the EASL clinical practice guideline. The recurrence rate and prognosis of non-responders, patients with recurrence, and long-term responders were analyzed. The baseline factors related to short-term response, recurrence, and long-term response were also evaluated.

Approximately 31.0% of the short-term responders had recurrence. Although there was no significant difference in the prognosis by short-term response (p = 0.07), the long-term responders had a significantly better prognosis than those with recurrence and non-responders (p < 0.01). Low CRP levels and high urinary Na/K ratios were significant factors related to short-term response, and the presence of acute kidney injury was also a factor related to non-response. The low CRP level (relapse: < 1.10 mg/dl, long-term response: < 0.94 mg/dl) was identified as a factor related to recurrence and long-term response.

The long-term responders without recurrence had a significantly better prognosis. CRP was a useful predictor for long-term response, whereas renal function parameters were useful predictors for short-term response. Inflammation control may be important for long-term response and prognosis in cirrhosis patients with water retention.

To determine the safety and efficacy of different doses of tolvaptan for treating Chinese cirrhotic patients with or without hyponatraemia who still had ascites after routine therapy with diuretics.

In the present placebo-controlled, randomized, double-blinded, multicentre clinical trial, patients with cirrhotic ascites who failed to adequately respond to a combination of an aldosterone antagonist plus an orally administered loop diuretic were randomly placed at a 4:2:1 ratio into 3 groups [the 15 mg/day tolvaptan group (N = 301), 7.5 mg/day tolvaptan group (N = 153) and placebo group (N = 76)] for 7 days of treatment. The effects and safety were evaluated on days 4 and 7. A change in body weight from baseline on day 7 of treatment was the primary endpoint.

The administration of 7.5 or 15 mg/day tolvaptan significantly decreased body weight from baseline on day 7 of treatment compared to that with placebo treatment (P = 0.026; P = 0.001). For the secondary endpoints, changes in abdominal circumference from baseline and improvements in ascites were markedly different in the treatment groups and the placebo group on day 7 (P7.5 = 0.05, P15.0 = 0.002 and P7.5 = 0.037, P15.0 = 0.003), but there was no difference between the 7.5 mg/day and 15 mg/day dosage groups. The 24-h cumulative urine volume was higher in the 7.5 mg/day and 15 mg/day tolvaptan groups than the placebo group (P = 0.002, P < 0.001) and was greater in the 15 mg/day tolvaptan group than the 7.5 mg/day tolvaptan group (P = 0.004). Sodium serum concentrations were higher in patients with hyponatraemia after tolvaptan treatment, with no significant difference between the two dosage groups. The incidence of serious adverse drug reactions was not different between the groups (P = 0.543).

Tolvaptan treatment at 7.5 mg per day might be a good therapeutic choice for Chinese cirrhotic patients with ascites who did not achieve satisfactory clinical responses to previous treatment regimens with combination therapy with an aldosterone antagonist and an orally administered loop diuretic.

NCT01349348. Retrospectively registered May 2011.

The prognosis of cirrhotic patients with hepatic edema is poor. Although several short-term predictors of tolvaptan (novel diuretic agent) treatment for such patients have been reported, the factors related to long-term survival are still unclear.

Among 459 patients with hepatic edema enrolled in a retrospective, multicenter collaborative study, we analyzed 407 patients who received tolvaptan.

Patients consisted of 266 men and 141 women, with the median age of 68 years (range, 28-93 years). The frequency of short-term responders to tolvaptan was 59.7% (243/407). In the Cox regression analysis, short-term response to tolvaptan, low average dosages of furosemide and spironolactone during tolvaptan treatment, Child-Pugh classification A and B, and absence of hepatocellular carcinoma were independent factors contributed to 1-year survival. The 1-year and long-term cumulative survival rates in short-term responders were significantly higher than those in non-responders (P = 0.011 and 0.010, respectively). Using a receiver operating characteristic curve analysis, the optimal cut-off values of average daily dosages of furosemide and spironolactone for predicting 1-year survival were 19 and 23 mg/day, respectively. The long-term cumulative survival rates in patients who received a mean dosage of spironolactone < 23 mg/day during tolvaptan treatment were significantly higher than those receiving a mean dosage of ≥ 23 mg/day (P = 0.001).

The present study suggests that the short-term response to tolvaptan and low dosages of conventional diuretics during tolvaptan treatment might improve the 1-year and long-term survival rates in cirrhotic patients with hepatic edema.

Tolvaptan represents an oral V₂ -receptor antagonist, which has been suggested as a promising add-on diuretic treatment for refractory ascites. The present meta-analysis aims to accumulate current evidence and identify which clinical and laboratory factors are linked to short-term response to tolvaptan therapy.

Medline, Scopus, Cochrane Central Register of Controlled Trials, Clinicaltrials.gov, and Google Scholar databases were searched from inception. All observational studies reporting the correlation of patients' characteristics with tolvaptan response were selected.

Tolvaptan response was associated with significantly higher baseline body weight (mean difference: 4.59 kg, 95% confidence interval [CI]: [3.58, 5.61]), presence of hepatitis C (odds ratio: 1.59 95% CI: [1.18, 2.14]), lower blood urea nitrogen (BUN) (mean difference: -6.88 mg/dL, 95% CI: [-8.13, -5.63]), lower serum creatinine (mean difference: -0.17 mg/dL, 95% CI: [-0.30, -0.05]), lower C-reactive protein (mean difference: -1.43 mg/dL, 95% CI: [-2.52, -0.35]), and higher sodium levels (mean difference: 1.00 mEq/L, 95% CI: [0.45, 1.55]). The outcomes of bodyweight, hepatitis C, BUN, and C-reactive protein remain significant independently of response definition and risk of bias.

The present findings suggest bodyweight, BUN, C-reactive protein, and hepatitis C as potential predictive factors of tolvaptan short-term response in patients with refractory ascites. Future studies are needed to introduce cut-off values and construct an optimal combined screening model.

The goals of the study were to identify an effective treatment for ascites and to examine the influence of tolvaptan on outcomes by investigating non-responders to tolvaptan and comparing outcomes of hepatic cirrhosis in patients treated with and without tolvaptan.

In Study 1, of 145 patients with hepatic cirrhosis who were treated with tolvaptan between September 2013 and March 2018, 45 who did not achieve weight loss of ≥1.5 kg within one week were investigated. In Study 2, 83 patients who received tolvaptan for ascites between September 2013 and March 2017 were compared with 131 patients who were treated for ascites without use of tolvaptan between January 2006 and January 2012.

In Study 1, the 45 patients were divided into three groups based on changes in dosing of diuretics. Renal function was retained in the dose reduction group compared with that in the other groups, and the rate of discharge with remission and the outcomes were also favorable in patients with dose reduction. In Study 2, survival was significantly more favorable in patients treated with tolvaptan.

Dose reduction of diuretics may be effective for patients with reduced renal function for whom tolvaptan is ineffective or the effect is insufficient and may also improve outcomes of patients with hepatic cirrhosis by preventing a decline in renal function caused by an increased dose of diuretics.

Tolvaptan exerts an aquaretic effect by blocking vasopressin V2 receptor. Although tolvaptan ameliorates body fluid retention even in patients with chronic kidney disease (CKD), predictors of body fluid reduction induced by tolvaptan remain unclear. We, therefore, examined the clinical parameters associated with the effect of tolvaptan on fluid volume in CKD patients.

Twelve CKD patients (stage 3-5) with fluid retention were treated with tolvaptan in addition to conventional diuretic treatment. Patients were divided into low and high responders by the median change in total body water (TBW) for 1 week measured by a bioimpedance analysis (BIA) device, and clinical parameters were compared between the groups.

The body weight significantly decreased by 2.0 ± 2.3 kg (p = 0.005), but the estimated glomerular filtration rate (eGFR) was not significantly changed (16.9 ± 11.9 vs. 17.4 ± 12.4 mL/min/1.73 m², p = 0.139) after 1 week. The BIA showed that the intracellular water (ICW) decreased by 6.0% ± 4.7% (p < 0.001), the extracellular water (ECW) decreased by 6.7% ± 5.4% (p = 0.001), and the TBW decreased by 6.3% ± 4.9% (median value - 6.02%, p < 0.001). The serum albumin level in the high responders was significantly lower than in the low responders (2.3 ± 0.5 vs. 3.3 ± 0.8 g/dL, p = 0.013). Significant partial correlations adjusted for the eGFR were observed between the baseline serum albumin level and changes in the ICW (r = 0.440, p = 0.048), ECW (r = 0.593, p = 0.009) and TBW (r = 0.520, p = 0.020).

Serum albumin levels predict the body fluid response to tolvaptan in CKD patients. Tolvaptan may be a promising therapeutic option for ameliorating body fluid retention, especially in patients with hypoalbuminemia.

The Chinese Society of Hepatology developed the current guidelines for the Management of Ascites and Its Related Complications in Cirrhosis based on the published evidences and the panelists' consensus. The guidelines provided recommendations for the diagnosis and management of cirrhotic ascites emphasizing a step-wise approach with the first-, second-, and third-line therapy. For refractory ascites, vasoconstrictors and albumin are recommended for splanchnic vasodilation and selective vasopressin (V2) receptor antagonists for moderate-to-severe hyponatremia. For spontaneous bacterial peritonitis, empirical anti-infection treatment was recommended based on the local microbiological examination of community- or hospital-acquired infections. For hepatorenal syndrome, the administration of vasopressor terlipressin and albumin is recommended.

Tolvaptan, an oral vasopressin V2 receptor antagonist, has been widely used for the treatment of patients with cirrhosis and ascites. However, its efficacy in patients with renal dysfunction remains unknown. The objective of this study was to investigate the efficacy and safety of tolvaptan in patients with decompensated cirrhosis and severe chronic kidney disease (s-CKD).

We studied 43 patients with liver cirrhosis who received tolvaptan (7.5 mg/day) for refractory ascites. s-CKD was defined as an estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2. Response to tolvaptan was defined as weight loss ≥ 1.5 kg in 7 days of treatment.

Eighteen patients (42%) had s-CKD (s-CKD group), while the other 25 patients (58%) did not have s-CKD (n-CKD group). Rates of response to tolvaptan were similar: 68% in the n-CKD group and 56% in the s-CKD group. Urine volumes increased significantly from baseline to day 7 in both groups. Incidences of adverse events were also similar (P = 0.93). Mean eGFR did not decline even in the s-CKD group (27.3 ± 2.2 mL/min/1.73 m2 at baseline vs. 26.6 ± 2.3 mL/min/1.73 m2 on day 7; P = 0.9). The cumulative survival rate did not differ significantly between the n-CKD and s-CKD groups. In the s-CKD group, responders obtained a better prognosis than non-responders.

Tolvaptan significantly increased urine volumes similarly in patients with s-CKD and n-CKD without affecting renal function. As responders achieved a better prognosis, tolvaptan could be a good option to treat ascites in patients with cirrhosis and s-CKD.

Objective Hyponatremia is closely associated with the pathophysiology of cirrhosis. However, the association between the serum sodium level and the response to tolvaptan is unclear. This study evaluated the factors related to the tolvaptan response and the prognosis in cirrhosis patients with ascites and hyponatremia. Methods We retrospectively reviewed the clinical records of cirrhosis patients hospitalized for treatment with tolvaptan. The associations of patient baseline characteristics with the tolvaptan response after one week and of the characteristics after one-month tolvaptan treatment with the prognosis were analyzed. Results We analyzed 83 cirrhosis patients with ascites, including 34 patients with hyponatremia. The response rates to tolvaptan in patients with serum sodium <130 mEq/L, 130-135 mEq/L, and >135 mEq/L were 20%, 66%, and 58%, respectively (p=0.22). The serum sodium level was associated with the response to tolvaptan [odds ratio=1.18; 95% confidence interval (CI) =1.02-1.37; p=0.029]. In patients with hyponatremia, the serum sodium level after 1-month tolvaptan treatment was increased compared to baseline (132 mEq/L vs. 136 mEq/L, p=0.006), and an increasing serum sodium level was associated with a lower risk of mortality (hazard ratio=0.85; 95% CI=0.75-0.97; p=0.016). The survival rate was higher in patients with an increase in the serum sodium level after 1 month than in patients with a decreased serum sodium level (p=0.023). Conclusion Tolvaptan treatment was effective in cirrhosis patients with ascites and hyponatremia, but a low serum sodium level was associated with non-responsiveness to tolvaptan. An increased serum sodium level after one-month tolvaptan treatment may positively influence the mortality risk in cirrhosis patients with hyponatremia.

This study aimed to clarify the factors predictive of treatment response to tolvaptan (V2-receptor antagonist) for cirrhotic patients with hepatic edema in a real-world setting.

In this retrospective, multicenter study, tolvaptan was orally administered at a dose of 7.5 mg once a day. Patients with a decrease in body weight of 1.5 kg or greater from baseline were characterized as responders at day 7.

Of 229 patients, 210 were subjected to this analysis. Patients consisted of 133 men and 77 women, with the median age of 67 years (range, 40-89 years). According to the Child-Pugh classification, five patients were classified as class A, 90 as class B, and 115 as class C. The frequencies of responders and nonresponders were 55.2% and 44.8%, respectively. Blood urea nitrogen (BUN) level was significantly lower in responders compared with nonresponders (P = 3.77 × 10^-3 ). Using the receiver operating characteristic curve, the cutoff value of 28.2 mg/dL was the most useful in discriminating responders from nonresponders. Among 154 patients with BUN level of less than 28.2 mg/dL, 95 (61.7%) were responders. By contrast, among 56 patients with BUN level of 28.2 mg/dL or more, 21 (37.5%) were nonresponders (P = 2.70 × 10^-3 ). On multivariate analysis, BUN level of <28.2 mg/dL and urine sodium >51 mEq/day were found to be independent factors associated with the response to tolvaptan.

This study suggests that BUN level and urinary sodium excretion are closely associated with the response to tolvaptan in cirrhotic patients with hepatic edema.

The study aimed to evaluate the effects of tolvaptan treatment on survival of patients with decompensated liver cirrhosis with refractory ascites.

This multicenter, retrospective, observational study included patients with cirrhosis who were treated with tolvaptan for hepatic ascites refractory to conventional diuretics. Patients who could and could not decrease accompanying diuretics within 1 month after tolvaptan administration were defined as the "Decreased" and "Not-decreased" groups, respectively.

Median body weight change 1 week after tolvaptan treatment was -1.95 kg, with the 50% of patients experiencing a 2 kg/week reduction. Spot urinary sodium was found to be a better predictor of tolvaptan response than liver function and liver fibrosis markers. Median survival was significantly longer (not reached versus 116 days, p = 0.005) and serum creatinine concentrations 12 weeks after tolvaptan administration significantly lower (0.99 vs. 1.55 mg/dL, p < 0.05) in the Decreased than in the Not-decreased group. Multivariate analysis showed that the presence of viable hepatocellular carcinoma (hazards ratio [HR] 2.14, p = 0.02) and a decrease in diuretics were independently prognostic of survival (HR 0.36, p < 0.01).

The maintenance of renal function is essential in enhancing survival of patients with cirrhosis. Doses of diuretics should be adjusted appropriately during tolvaptan treatment.

Although tolvaptan is an effective treatment for hepatic edema, there are no established criteria for assessment of the therapeutic effect. The present study evaluates the association between body weight change and clinical symptoms to identify an effective indicator of tolvaptan response.

The study comprised 460 patients. The first data set contained 147 patients with hepatic edema who received tolvaptan in Kagoshima Kouseiren Hospital, a representative institution of this study. From these data, an optimal cutoff value of body weight change, which accurately indicated symptom reduction, was identified. The response rates obtained based on the cutoff value were evaluated by receiver-operating characteristic (ROC) analysis and kappa coefficients. The kappa coefficient was then validated internally using the bootstrap method and externally using the validation data set of 313 patients from four other hospitals.

A cutoff value for body weight loss of 1.5 kg/week produced the largest area under the ROC curve (0.961; sensitivity, 89.8%; specificity, 92.0%) and a high kappa coefficient (0.831). The correlation between symptom reduction and body weight loss of 1.5 kg/week was evaluated internally and externally, and the cutoff value was validated.

The cutoff value of body weight change that most accurately reflected symptom reduction was 1.5 kg/week; this value is expected to be an effective indicator of response to tolvaptan in clinical practice.

Water retention, hepatic ascites, and peripheral edema are significant problems in patients with liver cirrhosis (LC). Although furosemide and spironolactone are commonly used as treatment, they are often insufficient to treat hyponatremia and renal insufficiency in patients with LC. Tolvaptan (TVP) could provide an effective treatment alternative. However, predictive factors of a therapeutic response to TVP are unclear. Our aim was to examine clinical predictors of the response to TVP in patients with LC and water retention.

Fifty-two patients were treated with TVP, with therapeutic effects judged by a decrease in body weight (≥2 kg) and increase in urinary volume (≥500 mL) within 7 days. Blood biochemical tests were carried out at baseline and post-treatment, including serum soluble CD14 (sCD14) and urinary aquaporin 2 (AQP2) levels. Clinical and laboratory predictive factors of a TVP response were evaluated by univariate and multivariate analyses.

The overall response to TVP was 55.8%. On univariate analyses, serum C-reactive protein (CRP) level, the neutrophil-to-lymphocyte ratio, urinary blood urea nitrogen, and urinary AQP2 were predictors of the TVP response, with only serum CRP retained on multivariate analysis. A higher serum sCD14 level was strongly associated with a non-response to TVP. A decrease in urinary AQP2 to undetectable level was associated with a response.

Tolvaptan provides a rapid and strong effect to improve water retention in patients with LC. Baseline serum sCD14 and CRP levels are useful predictors of a response to TVP, with a decrease in urinary AQP2 during treatment indicating an early response.

To assess the effects of a combination therapy with natriuretic and aquaretic drugs in cirrhotic ascites patients.

A two-center, randomized, open-label, prospective study was conducted. Japanese patients who met the criteria were randomized to trial group and the combination diuretic group (received 7.5 mg of tolvaptan) or the conventional diuretic group (received 40 mg of furosemide) for 7 d in addition to the natriuretic drug which was used prior to enrolment in this study. The primary endpoint was the change in body weight from the baseline. Vital signs, fluid intake, and laboratory and urinary data were assessed to determine the pharmacological effects after administration of aquaretic and natriuretic drugs.

A total of 56 patients were randomized to receive either tolvaptan (n = 28) or furosemide (n = 28). In the combination and conventional diuretic groups, the average decrease in body weight from the baseline was 3.21 ± 3.17 kg (P < 0.0001) and 1.75 ± 2.36 kg (P = 0.0006), respectively, when measured on the final dosing day. Following 1 wk of treatment, a significantly greater reduction in body weight was observed in the combination diuretic group compared to that in the conventional diuretic group (P = 0.0412).

Compared to a conventional diuretic therapy with only a natriuretic drug, a combination diuretic therapy with natriuretic and aquaretic drugs is more effective for patients with cirrhotic ascites.

The vasopressin V2 receptor antagonist tolvaptan has been used for the treatment of cirrhotic patients with ascites; however, no predictor of efficacy and prognosis has been developed. We evaluated candidate predictors of response to tolvaptan treatment.

This was a single-center retrospective study. Overall, 97 Japanese cirrhotic patients (60 men, median age 63 years), who were hospitalized for ascites treatment including oral tolvaptan coupled with conventional diuretics, were enrolled. The efficacy of tolvaptan was defined as a urination increase of ≥500 mL or a urine volume ≥2000 mL/day on the day following treatment. The prognosis of tolvaptan treatment was evaluated by the post-treatment survival time by Kaplan-Meier analysis.

Tolvaptan therapy was effective in 67% of cirrhotic patients. Patients showed -1.5 (-17.2 to +6.2) kg change in body weight and 40% achieved ≥2.0 kg reduction in body weight after 1 week of treatment. Platelet counts, urine sodium (Na) level, and urine Na/potassium (Na/K) ratio were higher, and the blood urea nitrogen (BUN)/creatinine (Cr) ratio was lower, in cases showing a response to tolvaptan. The combination of a BUN/Cr ratio ≥17.5 and urine Na/K ratio <3.09 was predictive of being non-responsive to tolvaptan, and the response rate in these patients was only 39% (P < 0.01). The mean post-treatment survival duration was significantly longer in patients who responded to tolvaptan therapy.

Urinary BUN and Na excretion were predictive of a response to tolvaptan, and tolvaptan treatment may improve the prognosis of cirrhotic patients.