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ascites is a major complication associated with portal hypertension in decompensated cirrhotic patients ( 1,2 ) and is commonly treated with aldosterone antagonists and loop diuretics ( 3 ) .
however , patients with cirrhosis have decreased serum sodium and hypoalbuminemia ( 4 ) , which reduce the effects of diuretics ( 4 ) .
this requires an dosage adjustment , resulting in limitations in treatment ( 5,6 ) due to concerns of exacerbating hyponatremia and nephropathy by high - dose diuretics ( 7,8 ) .
tolvaptan is an oral vasopressin v2 receptor antagonist that was approved for the indications of fluid retention associated with cirrhosis in september 2013 .
tolvaptan has a mechanism of action that differs completely from other diuretics ( 9 ) and eliminates excess water without increased electrolyte excretion .
therefore , tolvaptan may be an innovative therapy for ascites that is resistant to treatment with existing diuretics in patients with hepatic edema .
tolvaptan is a diuretic drug that functions independently of liver functions , particularly the level of serum albumin .
clinical trial data in japan showed that tolvaptan is effective for ascites complicated with decompensated cirrhosis with decreased albumin synthesis ( 10 - 12 ) .
the efficacy of tolvaptan has been found to be about 60% ( 13 ) , but in clinical practice some patients with cirrhosis experienced earlier relief and improved quality of life ( qol ) , whereas other patients have a delayed response or are nonresponsive to tolvaptan and require other treatment .
therefore , in the current study we compared patients with cirrhosis who did and did not show an early response to tolvaptan , with the goal of identifying predictors of the effect of tolvaptan that would allow another therapeutic intervention to be used as soon as possible in non - responders .
the subjects included 26 patients with cirrhosis who were treated with tolvaptan in our hospital from september 2013 to april 2015 .
tolvaptan was administered to liver cirrhosis patients who had ascites despite treatment with combination therapy of a loop diuretic and an anti - aldosterone agent .
tolvaptan was initially administered at a dose of 3.75 mg and increased to 7.5 mg if the effect was insufficient on administration day 3 .
height , body weight , urine volume , blood test and urinalysis data were collected and are presented as the mean  standard deviation ( sd ) .
statistical analyses were conducted using the jmp9 software program ( sas institute , cary , usa ) . a chi - square test or fisher 's exact test was used to evaluate differences between two groups .
changes from baseline in the sample data from the same group were evaluated by the t - test .
cut - off values were determined by receiver operating characteristic ( roc ) analyses to build categorical valuables from consecutive data .
the study was performed according to the declaration of helsinki and the clinical research guidelines in japan and approved by the institutional review board at yamaguchi university hospital ( no .
data are shown as median ( range ) , number ( % ) or mean  sd
tolvaptan was initially administered to all patients at a dose of 3.75 mg and increased to 7.5 mg if the effect was insufficient on administration day 3 .
body weight decreased significantly from 55.511.8 kg before treatment to 52.110.5 kg after 1 week of treatment .
urine osmolality significantly decreased from 488170.4 to 355.5138.6 mosm / kg after 1 week of treatment ; however , serum albumin , creatinine and sodium concentrations were not significantly changed after 1 week ( table 2 ) .
body weight decreased by approximately 2.4 and 3.5 kg after 1 and 2 weeks of treatment , respectively , with respective reductions of 6.2% and 8.0% from baseline ( fig .
data are shown as mean  sd changes in body weight after the administration of tolvaptan .
body weight significantly decreased from 55.5  11.8 kg before treatment to 52.1  10.5 and 5.1  11.7 kg after 1 and 2 weeks of treatment ( p<0.001 ) .
the respective body weight decreases of approximately 2.4  3.3 and 3.5  4.7 kg after 1 and 2 weeks represented reductions of 6.2% and 8.0% , respectively , from baseline .
data were compared between patients with weight loss 2 kg ( early responders , group r ) and < 2 kg ( early non - responders , group n ) after 1 week of treatment with tolvaptan ( fig .
2 ) . four patients in group n subsequently had a decrease in body weight of 2 kg after reduction of loop diuretics ( 2 patients ) , fluid replacement ( 1 patient ) and ascites removal ( 1 patient ) , leading to remission and hospital discharge .
there were no significant differences in age , height , body weight , sex , child - pugh score , hepatic function including albumin , model for end - stage liver disease ( meld ) score , meld - na score , rate of complication with hepatocellular carcinoma ( hcc ) , or dose of diuretics between groups r and n. however , blood urea nitrogen ( bun ) and serum creatinine were significantly lower and the renal function was better maintained in group r , suggesting that these conditions were requirements for an early effect of tolvaptan ( table 3 ) .
data are shown as mean  sd after initiating treatment with tolvaptan , urine osmolality 4 h after oral administration was significantly lower ( 23696 vs. 364122 mosm / kg , p<0.05 ) and the % decrease in osmolality from baseline was significantly higher ( 48.023.3% vs. 15.417.3% , p<0.01 ) in group r. the patients in group r also had higher serum sodium and lower brain natriuretic peptide ( bnp ) levels , however , the levels were not significantly difference from that of group n ( table 3 ) .
treatment outcomes for hcc were compared between the two groups using the response evaluation criteria in solid tumors ( recist ) .
there were no significant differences in the rate of complication with hcc , clinical stage , or cancer treatment between groups r and n ( table 3 ) .
3 ) , and the complete response ( cr ) + partial response ( pr ) rate did not differ significantly between groups r and n ( 40.0% vs. 14.3% , p=0.28 ) ( fig .
4 ) . the prognosis in group r was better due to a significant increase in the kaplan - meier survival curve ( p<0.05 ) ( fig .
kaplan - meier curves for patients with hcc ( solid line ) and without hcc ( dotted line ) .
significant differences were analyzed by the log - rank test ( cochran - mantel - haenszel ) . 
 
association between therapeutic effects of tolvaptan on ascites and the response evaluation criteria in hepatocellular carcinoma .
the results were evaluated using the response evaluation criteria in solid tumors solid tumors ( recist ) .
the y - axis indicates the complete response ( cr)+partial response ( pr ) rates ( % ) for hcc .
kaplan - meier curves for early responders ( solid line ) and early non - responders ( dotted line ) to tolvaptan .
significant differences were analyzed by the log - rank test ( cochran - mantel - haenszel ) .
the treatment of 26 patients in our hospital with tolvaptan at a dose of 3.75 mg for 1 week resulted in an overall response rate of 61.5% . within 1 week , 16 of these patients had achieved a weight loss 2 kg .
therefore , the results of this study were similar to or better than those in a previous clinical trial that showed an efficacy of 55% at a dose of 7.5 mg ( 13 ) .
there was no significant difference in the hepatic reserve between responders and non - responders in the current study ; however , the renal function in early responders was better than that in early non - responders .
diuretics cause renal impairment ( 14 - 16 ) and the effect of tolvaptan is poor in patients with heart failure , an increased bun / cre ratio and decreased estimated glomerular filtration rate ( egfr ) ( 15 - 18 ) . because the renal function is involved in the prognosis of hepatic cirrhosis , it is important to maintain the renal function and control diuretics ( 19 - 22 ) .
however , the non - responder group may have included many patients with potential renal insufficiency .
therefore , further prospective studies are needed to evaluate whether the efficacy of tolvaptan improves by early administration . in the current study , non - responders were likely to have higher bnp levels , however , none had clinical heart failure .
non - responders were found to have significantly poorer renal functions and there was a correlation between the renal function and bnp level ( 18,19 ) .
therefore , the bnp level in non - responders may be increased by renal impairment . in responders ,
urine osmolality 4 h after tolvaptan administration was significantly lower and the rate of reduction of urine osmolality was high .
the cut - off values determined by the roc analysis to achieve a weight loss 2 kg were bun 29 mg / dl , serum creatinine 1.35 mg / dl , and decreased urine osmolality 4 h after administration 34.7% .
a clinical study showed that tolvaptan was effective in patients with urine osmolality > 352 osm / l before administration and decreased urine osmolality of > 26% at 4 to 6 h after administration ( 19,20 ) . for patients with hepatic cirrhosis , the change in urine osmolality after administration is an indicator of efficacy in early administration .
determination of urine osmolality 4 h after the administration of tolvaptan can predict the subsequent efficacy and appropriate dosage of tolvaptan .
if tolvaptan is effective , the qol is improved due to reduced ascites and edema ; however , such a prognosis has not been shown in patients with hepatic cirrhosis .
some cardiovascular studies have shown an improved prognosis in responders , whereas others have indicated that the prognosis is not improved ( 21 - 24 ) . in this study , there was no significant difference in the treatment outcome of hcc between responders and non - responders and no significant difference in the prognosis between patients with and without hcc .
however , the prognosis of responders was significantly improved in comparison with that of non - responders .
this result suggests that tolvaptan can improve the prognosis in patients with hepatic cirrhosis ; however , the responder group included many subjects with good renal functions .
consequently , it is possible that their prognosis was already good before the administration of tolvaptan .
because of the small numbers of patients in the multivariate analysis , there were no significant differences ; however , the prognosis tended to improve in the effective group ( data not shown ) . a potential limitation associated with this study
therefore , prospective randomized comparative trial ( rct ) studies are needed in more subjects without complication of hcc and in those with relatively well - maintained hepatic functions .
tolvaptan is effective for diuretics - resistant ascites regardless of the hepatic function and albumin level and may improve the prognosis .
an accumulation of cases for prospective rct studies including multivariate analyses is needed to evaluate the long - term safety and efficacy of tolvaptan , the effect on prognosis , and the appropriate administration period .
objective tolvaptan was first approved for use for cirrhosis in japan in september 2013 . 
 the aim of the study was to examine the effect of tolvaptan , a vasopressin v2 receptor antagonist , on the prognosis of cirrhosis . 
 
 methods the effect of tolvaptan was evaluated in 26 patients with cirrhosis treated at our hospital from september 2013 to april 2015 . 
 
 results the primary disease was hepatitis c in 20 patients , hepatitis b in 2 , nonalcoholic steatohepatitis in 2 and others in 2 ; and 12 had hepatocellular carcinoma . 
 the child - pugh score was 9.71.6 and the serum albumin level was 2.530.44 g / dl . 
 body weight decreased from 55.511.8 kg before administration to 52.114.7 kg after 7 days of tolvaptan treatment . 
 after 7 days , patients with weight loss 2 kg ( n=16 , mean decrease of 4.32.3 kg ) had significantly lower blood urea nitrogen ( 24.214.4 vs. 36.111.4 mg / dl ) and serum creatinine ( 1.10.5 vs. 1.50.7 mg / dl ) levels and decreased urine osmolality 4 h after the administration of tolvaptan ( 23696 vs. 364122 mosm / kg ) compared with patients with weight loss < 2 kg ( n=10 , mean increase of + 0.72.1 kg ) ( all p<0.05 ) . 
 the prognosis was significantly better in the group with weight loss 2 kg . 
 
 conclusion the effect of tolvaptan on the renal function is likely to improve the prognosis of patients with cirrhosis if the drug is started at a stage in which the renal function is maintained .