Clinical characteristics of patients with or without tolvaptan
Cohort creation were summarized in the patient flow (supplementary Figure 1). In this study, we divided the 113 LC patients into 3 groups : without ascites group, with ascites non-treatment group or with ascites treatment group. Table 1 shows the comparison of baseline clinical characteristics and laboratory variables between non-treatment group and treatment group. In the treatment group, AST, total bilirubin, CRP, the Child-Pugh score, ALBI score and FIB4-index were significantly increased, while serum albumin and sodium levels were reduced, suggesting that patients treated with tolvaptan demonstrated more advanced liver diseases. In the treatment group, the dose of diuretics drugs (Furosemide and/or Spironolactone) was significantly higher. In contrast, there were no obvious differences in age, gender, bodyweight, BMI, PMI, prevalence of HCC, ALT, prothrombin time, MELD score, MELD-Na score, creatinine, BUN, eGFR (Cockcroft and MDRD-6), copeptin, ZAG, NGAL, L-FABP and cystatin C between the two groups (Table 1).
Correlation of copeptin, ZAG, cystatin C, NGAL and L-FABP to clinical parameters in all patients
The correlations between copeptin, ZAG, cystatin C, NGAL or L-FABP and clinical parameters in LC patients were shown in Table 2. Copeptin was strongly correlated with mainly hepatic function including albumin (p=0.0007; Figure 1-D), Child-Pugh score (p<0.0001), ALBI score (p=0.0003) and CRP (p=0.0047; Figure 1-C). In contrast, ZAG was more strongly correlated with renal function including creatinine (p<0.0001), BUN (p<0.0001) and GFR (MDRD-6) (p<0.0001) (Table 2; Figure 1-K and L). In addition, ZAG was correlated with bodyweight (p=0.0092; Figure 1-G), BMI (p=0.0001; Figure 1-H) and CRP (p<0.0001; Figure 1-I). Cystatin C was signiﬁcantly correlated with age (p=0.0191), renal parameters (creatinine, BUN and eGFR: p<0.0001), copeptin (p=0.0008), NGAL (p<0.0001) and L-FABP (p<0.0001) (Table 2). NGAL and L-FABP were signiﬁcantly correlated with indicators of both renal function and hepatic function (Table 2). MELD-Na score significantly correlated with all, copeptin (p=0.0008), ZAG (p=0.001), cystatin C (p<0.0001), NGAL (p<0.0001) and L-FABP (p=0.0003).
Background comparison between Responders and Non-responders to tolvaptan
In this study, we excluded 7 from 45 cases for which tolvaptan efficacy could not be determined because of transferring hospitals, lack of weight data or with other treatment such as albumin transfusion, large volume paracentesis, and cell-free and concentrated ascites reinfusion therapy (Supplementary Figure 1). We enrolled 38 decompensated LC patients with ascites (24 males and 14 females) with a median age of 66.0 (59.5-73.0) years. We divided the 38 patients into two tolvaptan treatment groups: Responders and Non-responders. There were no obvious differences in age, gender, bodyweight, BMI, PMI, presence of HCC, AFP, DCP, dose of diuretic drugs, albumin, total bilirubin, Child-Pugh score, ALBI score, FIB4-index, MELD score/MELD-Na score, creatinine, eGFR, serum sodium, cystatin C, NGAL and L-FABP between the two groups (Table 3; Figure 2-D, E and F). In contrast, BUN, copeptin and ZAG levels were significantly higher in Non-responders when compared to the Responders group (respectively, p=0.0014, p=0.0265, p=0.0142) (Table 3; Figure 2-A, B and C). We further examined except for HCC, because HCC have pro-inflammatory condition. BUN (p=0.015) was significantly higher in Non-responders (n=7) when compared to the Responders (n=8) in patients without HCC. In contrast, copeptin and ZAG levels were not higher in Non-responders in patients without HCC.
Predictors contributing to the effect of tolvaptan in treatment for ascites
We calculated the cutoff values, area under the ROC curve, sensitivity and speciﬁcity of BUN, copeptin and ZAG using ROC analysis. The cutoff values ascertained from our analyses of BUN, copeptin and ZAG were 18.3mg/dL, 10.1pmol/L and 32.4 μg/mL, respectively (Table 4). The contribution of HCC, BUN, copeptin and ZAG were evaluated using multivariate logistic regression analysis. We found serum BUN (odds ratio 7.43, p=0.0306), copeptin (odds ratio 9.12, p=0.0136) and ZAG (odds ratio 7.43, p=0.0306) levels to be the signiﬁcant predictors contributing to the efficacy of tolvaptan in the treatment for ascites; however, presence of HCC was not selected (Table 4).