Patient characteristics
During this period, 755 ACLF with HRS-AKI patients were reviewed; 221 met inclusion criteria either at admission or during the course of hospitalization (Fig. 1). HBV infection and alcohol consumption were the most common acute and chronic insults. 113 patients were included in terlipressin plus albumin (TA) group and 108 in albumin alone (AA) group. Baseline demographic and clinical characteristics of patients were presented in Table 1.
Table 1
Demographics and baseline clinical characteristics of all eligible included patients.
Variables | Terlipressin plus albumin (TA) group (n = 113) | Albumin alone (AA) group (n = 108) | P value |
---|
Demographic | | | |
Age, years | 52.43 ± 11.93 | 52.91 ± 11.68 | .77 |
Sex, M/F | 93/20 | 88/20 | .87 |
Hypertension, No. | 22 | 21 | .50 |
Diabetes mellitus, No. | 21 | 15 | .35 |
Etiology, No. | | | |
Alcohol | 47 | 40 | .49 |
HBV | 51 | 58 | .20 |
HCV | 3 | 2 | 1.00 |
PBC | 7 | 3 | .33 |
Others | 5 | 5 | 1.00 |
Infection, No. | | | |
SBP | 54 | 61 | .19 |
Pneumonia | 13 | 11 | .75 |
Others | 7 | 0 | - |
None | 39 | 36 | .85 |
WBC (×109/L) | 8.77 (6.33, 12.80) | 9.59 (6.21, 14.05) | .59 |
HB (g/dL) | 9.2 (7.2, 11.3) | 9.5 (7.6, 11.2) | .53 |
PLT (×109/L) | 68.00(43.5, 107.50) | 73.00(48.25, 100.75) | .71 |
TBil (mg/dL) | 24.00 ± 12.86 | 25.21 ± 10.55 | .44 |
DBil (mg/dL) | 12.79 (6.81, 17.04) | 12.52 (7.98, 16.25) | .98 |
ALT (IU/L) | 41.50 (22.40, 84.75) | 44.80 (22.45, 108,23) | .51 |
AST (IU/L) | 82.70 (55.75, 143.40) | 95.70 (57.30, 165.95) | .43 |
Albumin (g/dL) | 2.88 ± 0.52 | 2.81 ± 0.44 | .35 |
BUN (mg/dL) | 13.40 (9.96, 20.04) | 12.75 (8.40, 17.33) | .09 |
sCr (mg/dL) | 1.60 (1.32, 2.10) | 1.54 (1.22, 2.31) | .49 |
sCr < 1.5 mg/dL, No. | 47 | 51 | .42 |
Na (mmol/L) | 130.11 ± 6.30 | 129.92 ± 5.57 | .81 |
K (mmol/L) | 4.15 ± 0.81 | 4.19 ± 0.89 | .68 |
INR | 2.09 (1.81, 2.50) | 2.16 (1.83, 2.71) | .51 |
MAP (mmHg) | 83.00 (78.00, 92.00) | 83.00 (75.50, 92.75) | .79 |
MELD | 29.24 ± 7.53 | 30.12 ± 6.42 | .35 |
CLIF-C ACLFs | 46.28 ± 7.09 | 47.39 ± 7.08 | .24 |
Datas are presented as geometric mean ± SD or median (interquartile range; IQR) or number. |
P value was obtained by Mann–Whitney U test, independent t test or Pearson chi-square tests when appropriate. |
PBC = Primary biliary cholangitis; SBP = Spontaneous bacterial peritonitis; WBC = White blood cell count; HB = Hemoglobin concentration; PLT = Platelet count; TBil = Total bilirubin; DBil = Direct bilirubin; ALT = Alanine transaminase; AST = Aspartate transaminases; BUN = Blood urea nitrogen; sCr = Serum creatinine concentration; Na = Serum sodium concentration; K = Serum potassium concentration; INR = International normalized ratio; MAP = Mean arterial pressure; MELD = Model for End-stage Liver Disease score; CLIF-C ACLFs = Chronic liver failure consortium acute-on-chronic liver failure score. |
The use of terlipressin and/or albumin in TA group and AA group
In TA group, 85 patients were treated with terlipressin by continuous intravenous infusion. The initial dose of 76 patients was 2 mg/d; 4 patients were adjusted to 3 mg/d whereas 2 patients to 4 mg/d on day 3. The initial dose of 9 patients were 4 mg/d, and 3 were adjusted to 2 mg/d on day 3. 28 patients were administered by regular intravenous bolus injection at a dose of 2–4 mg/d, and 4 patients reduced dosage on day 3. The administration time of terlipressin was 7.18 ± 3.91 days. Total dosage of albumin in TA group vs. AA group was 132.79 ± 57.51 g vs. 140.72 ± 63.39 g (P = .331), respectively. The average dosage was 14.56 ± 3.69 g/d and 14.66 ± 3.91 g/d (P = .839), respectively. The dynamic measurements of albumin between two groups were significant different from those on day 3 (Fig. 2).
Efficiency of terlipressin plus albumin for HRS-AKI in ACLF
The sCr in TA group was significantly lower than AA group in about 7 days (P = .032) (Fig. 3). In TA group, rate of HRS-AKI reversal was 35.39% (40 of 113), compared to 23.15% (25 of 108) in AA group (P = .046). In patients with sCr <1.5 mg/dL at initial treatment, 41.46% (17 of 47) were reversed in TA group, whereas 19.61% (10 of 51) in AA group (P = .067). Among patients with sCr ≥1.5mg/dL, 34.84% (23 of 66) were reversed in TA group whereas 26.31% (15 of 57) in AA group (P = .307). There was no statistical difference within each group (TA group: P = .884, AA group: P = .409) (Fig. 4).
The reversal time in TA Group was 8.18 ± 4.39 days, compared to 11.29 ± 3.67 days in AA group (P = .005). For patients with sCr <1.5 mg/dL at initial treatment, reversal time was 8.12 ± 5.75 days in TA group, compared to 9.40 ± 2.67 days in AA group (P = .117). Among patients with sCr ≥1.5 mg/dL, reversal time was 8.22 ± 3.18 days in TA group whereas 12.64 ± 3.75 days in AA group (P = .001). There was no statistical difference within TA group (P = .884), whereas a significant difference within AA group (P = .036) (Fig. 5).
In TA group, 5 cases relapsed, 1 case was reversed after terlipressin therapy, 1 case was reversed after terlipressin combined with norepinephrine therapy, 2 cases were treated with CRRT, and 1 case was not re-intervened. Two patients in AA group relapsed and received CRRT.
Adverse events
In TA group, 20 patients had diarrhea, 11 patients improved after treatment with loperamide and/or montmorillonite powder, 6 patients were stable, and 3 patients improved after reducing the dose of terlipressin. 6 patients presented abdominal pain, with mild symptoms. 4 patients with abdominal pain and diarrhea and given a lower drug dose. One patient had abdominal distension, and recovered spontaneously. 2 patients presented with acrocyanosis (at the end of hands and feet), receiving no special treatment. One patient had palpitations and discomfort, and one patient had right knee joint pain. The symptoms relieved spontaneously.
Predictive Factors For The Reverse Of Hrs-aki In Aclf
In multivariate binary logistic regression models, the absence of SBP (odds ratio [OR]: 2.11; 95% CI: 1.127–3.949; P = .02 ), TBil (OR; .997; 95% CI: .996 − .999; P = .001) and CLIF-C ACLFs (OR: .955; 95% CI: 0.912–1.000; P = .049) were predictors for reverse in HRS-AKI (Table 2).
Table 2
Univariate and multivariate analysis of Pretreatment predictive factors for reverse of HRS-AKI in ACLF.
Variables | reverse (n = 65) | non-reverse (n = 156) | P value | P, Regression (OR, 95%CI) |
---|
Age, years | 52.38 ± 10.19 | 52.78 ± 12.41 | .82 | |
Sex, M/F | 49/16 | 132/24 | .13 | |
Hypertension, No. | 9 | 34 | .20 | |
Diabetes mellitus, No. | 10 | 26 | 1.00 | |
Etiology, No. | | | | |
Alcohol | 28 | 59 | .55 | |
HBV | 29 | 80 | .38 | |
HCV | 2 | 3 | .63 | |
PBC | 3 | 7 | 1.00 | |
Others | 3 | 7 | 1.00 | |
Infection, No. | | | | |
SBP | 25 | 90 | .01 | .02 (2.11, 1.127–3.949) |
Pneumonia | 7 | 17 | 1.00 | |
Others | 3 | 4 | .42 | |
None | 30 | 45 | .02 | |
WBC (×109/L) | 9.38 (5.85, 10.76) | 9.02 (6.69, 14.08) | .06 | |
HB (g/dL) | 9.40 (7.30, 112.00) | 9.40 (7.40, 112.00) | .67 | |
PLT (×109/L) | 74.00(47.50, 108.00) | 70.00(47.00, 101.00) | .72 | |
Tbil (mg/dL) | 20.10 ± 10.22 | 26.46 ± 11.91 | < .001 | .001 (.997, .996 − .999) |
Dbil (mg/dL) | 9.70 (5.13, 14.94) | 13.44 (8.77, 16.87) | .004 | |
ALT (IU/L) | 45.40 (23.20, 67.05) | 40.85 (22.33, 109.88) | .47 | |
(IU/L) | 83.60 (56.80, 127.45) | 92.35 (54.80, 167.68) | .30 | |
Albumin (g/dL) | 2.83 ± 5.02 | 2.85 ± 4.78 | .81 | |
BUN (mg/dL) | 11.63 (9.24, 18.33) | 13.22 (9.52, 17.85) | .46 | |
sCr (mg/dL) | 1.61 (1.28, 2.06) | 1.55 (1.26, 2.27) | .77 | |
Na (mmol/L) | 130.67 ± 5.90 | 129.74 ± 5.95 | .29 | |
K (mmol/L) | 4.18 ± 0.85 | 4.16 ± 0.85 | .88 | |
INR | 2.06 (1.82, 2.49) | 2.18 (1.81, 2.79) | .27 | |
MAP (mmHg) | 83.00 (73.50, 90.00) | 83.50 (78.00, 93.00) | .06 | |
MELD | 27.56 ± 5.59 | 30.55 ± 7.36 | .004 | |
CLIF-C ACLFs | 44.55 ± 6.51 | 47.77 ± 7.12 | .002 | .05 ( .955, .912 -1.000) |
CI = confidence interval. |
Predictive Factors For 28-day Overall And Transplantation-free Survival
Liver transplantation was operated in 11 patients, 10 survived and 1 died. Of 221 patients, 24 patients discharged from hospital lost follow-up, while 133 patients died within 28 days. The 28-day overall survival rate was 46.08% (47 of 102) in TA group, significantly better than in AA group (17.89%, 17 of 95; P < .001) (Fig. 6A). Among non-liver transplant patients, 28-day survival rate in TA group was 41.94% (39 of 93), significantly higher than in AA group (16.13%, 15 of 93; P = .001) (Fig. 6B). In multivariate Cox regression models, TBil (Hazard ratio [HR], 1.001; 95% CI: 1.000-1.002; P = .003), INR (HR,1.151; 95% CI: 1.037–1.277; P = .008) and CLIF-C ACLFs (HR, 1.048; 95% CI: 1.022–1.075; P < .001) were independent predictors of 28-day overall survival (Table 3). After excluding cases with liver-transplantation, in multivariate Cox regression models, TBil (HR, 1.001; 95% CI: 1.000-1.002; P = .002), INR (HR,1.175; 95% CI: 1.071–1.290; P = .001) and CLIF-C ACLFs (HR, 1.050; 95% CI: 1.024–1.077; P < .001) were independent predictors of 28-day transplantation-free survival (Table 3).
Table 3
Predictor of 28-day overall survival and transplantation-free survival of patients with HRS-AKI in ACLF.
Variables | | Univariate | | | Multivariate | |
---|
HR (95% CI) | PValue | HR (95% CI) | PValue |
---|
28-day overall survival |
ALT (IU/L) | 1.001 (1.000–1.002) | .004 | | |
AST (IU/L) | 1.001 (1.000–1.002) | .013 | | |
TBil (mg/dL) | 1.001 (1.001–1.002) | < .001 | 1.001 (1.000–1.002) | .003 |
DBil (mg/dL) | 1.002 (1.000–1.003) | .004 | | |
INR | 1.198 (1.102–1.302) | < .001 | 1.151 (1.037–1.277) | .008 |
MELD | 1.044 (1.019–1.069) | .001 | | |
CLIF-C ACLFs | 1.060 (1.035–1.085) | < .001 | 1.048 (1.022–1.075) | < .001 |
28-day transplantation-free survival |
ALT (IU/L) | 1.002 (1.001–1.002) | < .001 | | |
AST (IU/L) | 1.002 (1.001–1.003) | .002 | | |
TBil (mg/dL) | 1.002 (1.001–1.002) | < .001 | 1.001 (1.000–1.002) | .002 |
DBil (mg/dL) | 1.002 (1.000–1.003) | .005 | | |
INR | 1.211 (1.120–1.310) | < .001 | 1.175 (1.071–1.290) | .001 |
MELD | 1.055 (1.029–1.082) | .001 | | |
CLIF-C ACLFs | 1.062 (1.037–1.087) | < .001 | 1.050 (1.024–1.077) | < .001 |