Molecular Adsorbent Recirculating SystemCan Reduce Short-term Mortality amongPatients with Acute-on-chronic Liver Failure
MARS in ACLF patients
Hans U. Gerth*, Michele Pohlen*, Gerold Thölking, Hermann Pavenstädt, Marcus Brand, Anna Hüsing-Kabar, Christian Wilms, Miriam Maschmeier, Iyad Kabar, Marco Pavesi, Vicente Arroyo, Rafael Banares*, Hartmut H. J. Schmidt*
Table of contents
Supplementary Methods……………………………………………………………..2
Supplementary Fig. 1…………………………………………………………………4
Supplementary Fig. 2…………………………………………………………………5
Supplementary Table 1……………………………………………………………….6
Supplementary Table 2……………………………………………………………….7
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Supplementary Methods
CLIF-COrgan Failure and ACLF criteria
Classification of organ failure (OF) subscore and acute-on-chronic liver failure (ACLF) grade was made according to the definition of the current CLIF-C-criteria (Jalan R, Saliba F, Pavesi M, et al: Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure. J Hepatol 2014;61:1038-1047).
The CLIF-C-organ failure score system has a 3-point range per organ system and includes five different organ systems: liver, kidney, brain, coagulation, circulation and respiratory system.
A subscore of 3 is the definition of organ failure for each system, except for the kidney, for which a subscore of 2 or more is the definition.
For example, a kidney failure (subscore 2 or more) is defined by serum creatinine levels of 2.0 mg/dL or more, or the use of renal-replacement therapy. A coagulation failure (subscore 3) was defined by an INR of more than 2.5.
The diagnosis of ACLF was based on the presence of at least renal failure or any other single organ failure if associated with renal dysfunction (serum creatinine 1.5–1.9 mg/dL) and/or grade I–II HE (ACLF grade 1). Patients with two organ failures were graded as ACLF grade 2 and those with three or more organ failures as ACLF grade 3.
SMT
SMT used for patient management and complications of cirrhosis in both treatment groups was based on institutional guidelines:
In detail, routinely screening for HBV, HCV and HIV was performed at time of hospital admission. Care for chronic liver disease and the complications of cirrhosis was performed completely within hospital care. Other causes of jaundice than chronic liver disease / cirrhosis were excluded by abdominal ultrasound. In patients with alcoholic cirrhosis abstinence from alcohol was intended.
A systematic screening for bacterial infections included blood, ascites and urine analysis and culture. In addition ascites, hepatic encephalopathy (HE), portal hypertension and/or variceal bleeding were monitored closely and treated if necessary. Prophylaxis of variceal bleeding was performed with the use of beta-blockers and/or variceal band ligation. Diagnostic abdominal paracentesis was performed with clinically apparent new-onset ascites. Treatment for patients with cirrhosis and ascites included sodium restricted diet, diuretics (usually spironolactone and furosemide) and large-volume paracentesis combined with albumin administration. Spontaneous bacterial peritonitis was usually treated with third-generation cephalosporins.
H2 antagonist or proton pump inhibitors, antibiotics (prophylactic and empirical) and antifungal regimes followed local guidelines with microbiological input. HE was treated with standard therapy, including lactulose.
Clinical relevant hemorrhage was treated with coagulation factor replacement if indicated, although coagulation support was not routinely offered in both groups.
Renal function parameters including electrolytes were monitored closely to screen of renal failure and start early treatment of hepatorenal syndrome (HRS). Hemodialysis was initiated for clinical reasons according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria.
MARS
The albumin circuit contained 500 mL 20% human albumin. Blood access was established through a conventional double lumen hemodialysis catheter via the patient’s jugular or femoral veins.
Blood flow rates were 250-350 mL/min, and the flow rates in the albumin circuit were approximately 250 mL/min. If not contraindicated, standard heparin was used as an anticoagulant in most treatments. In case of coagulopathy, little or no heparin was administered.
Ultrafiltration was adjusted to control volume balance when necessary. For safety, blood pressure and heart rate were continuously monitored during the MARS sessions, and laboratory measurements were taken at least once per day.
Supplementary Fig. 1
Corresponding cumulative probability of 28-day transplant-free survival rate in the RELIEF cohort
PP population subdivided by ACLF grade.
(A) ACLF grade < 2 and(B) ACLF grade ≥2.
Green line: MARS therapy plus SMT. Blue line: SMT alone. In addition, the estimated probability of 14-day survival is depicted.
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Supplementary Fig. 2
Corresponding 14-day mortality rate prediction via recursive partitioning analysis in the RELIEF cohort
ACLF grade (< 2vs. ≥ 2) and treatment mode (MARS vs. SMT) served as split variables (p 0.05)
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Supplementary Table 1. Baseline patient characteristics: Comparison of Muenster and RELIEF PP cohorts
Parameter / Muenster Cohort(n=101) / RELIEF PP Cohort
(n=156) / p-value
Age (years) / 53.40 (12.8) / 50.85 (10.7) / 0.040
Male sex, n (%) / 64 (63.4) / 107 (68.5) / 0.386
Body weight (kg) / 82.29 (18.8) / 79.18 (17.8) / 0.187
HRS, n (%) / 41 (40.6) / 82 (52.6) / 0.061
Hepatic encephalopathy, n (%)
grade 1
grade 2
grade 3
grade 4 / 47 (46.5)
15 (14.9)
7 (6.9)
0 (0) / 27 (17.3)
35 (22.4)
23 (14.7)
8 (5.1) / < 0.001
Ascites, n (%)
None
Moderate
Severe / 22 (22.0)
28 (28.0)
50 (50.0) / 36 (23.1)
64 (41.0)
56 (36.9) / 0.054
Laboratory data
Bilirubin (mg/dL)
Serum sodium (mmol/L)
Serum potassium (mmol/L)
Creatinine (mg/dL)
White blood count (103 cells/µL)
Hemoglobin (g/dL)
Platelets (103 cells/µL)
Albumin (g/dL)
INR / 21.96 (8.0)
134.26 (5.8)
4.07 (0.6)
1.82 (1.3)
11.40 (6.6)
10.73 (1.8)
125.93 (70)
3.02 (0.5)
1.91 (0.7) / 26.89 (12.0)
132.52 (8.3)
3.91 (0.9)
2.32 (2.1)
15.8 (10.3)
10.12 (1.8)
125.12 (73.6)
2.77 (0.8)
1.75 (0.3) / < 0.001
0.026
0.025
0.343
< 0.001
0.010
0.610
0.017
0.763
CLIF-organ failure subscore
Liver, n (%)
Subscore1
2
3
Kidney, n (%)
Subscore1
2
3
Brain, n (%)
Subscore1
2
3
Coagulation, n (%)
Subscore1
2
3
Circulation, n (%)
Subscore1
2
3
Respiration, n (%)
Subscore1
2
3
CLIF ACLF grade, n (%)
1
2
3
4
5
CLIF-C ACLF score / 0 (0)
0 (0)
101 (100.0)
70 (69.3)
21 (20.8)
10 (9.9)
32 (31.7)
62 (61.4)
7 (6.9)
66 (65.3)
18 (17.8)
17 (16.8)
94 (93.1)
7 (6.9)
0 (0.0)
99 (98.0)
2 (2.0)
0 (0.0)
58 (57.4)
31 (30.7)
12 (11.9)
0 (0)
0 (0)
47.81 (8.6) / 6 (3.8)
16 (10.3)
134 (85.9)
98 (62.8)
22 (14.1)
36 (23.1)
61 (39.1)
63 (40.4)
31 (19.9)
112 (71.8)
42 (26.9)
2 (1.3)
141 (90.4)
11 (7.1)
4 (2.6)
129 (82.7)
13 (8.3)
14 (9.0)
81 (51.9)
46 (29.5)
15 (9.6)
5 (3.2)
1 (0.6)
49.8 (8.7)* / < 0.001
0.018
0.003
< 0.001
0.267
0.001
0.083
0.158
* Calculated based on patients with ACLF grade ≥1 (148 patients). 8 patients had no ACLF.
Abbreviations: HRS, hepatorenal syndrome; ACLF, acute-on-chronic liver failure; CLIF, chronic liver failure
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Supplementary Table 2. Survival analysis according to predetermined subgroups (14-day mortality) in the PP population of the RELIEF trial
Parameter / MARS(n=71) / SMT
(n=85) / p-value
HRS / 11/37 (29.7) / 13/45 (28.9) / 0.934
HE grade ≥ 2 / 5/28 (17.9) / 13/38 (34.2) / 0.140
MELD score > 20 / 15/69 (21.7) / 18/80 (22.5) / 0.911
CLIF-C ACLF score > 47.5* / 12/42 (28.6) / 15/42 (35.7) / 0.641
CLIF-organ failure subscore
Liver, subscore ≥ 2
Kidney, subscore ≥ 2
Brain, subscore ≥ 2
Coagulation, subscore ≥ 2
Circulatory, subscore ≥ 2
Respiratory, subscore ≥ 2
ACLF grade ≥ 2 / 15/70 (21.4)
9/26 (34.6)
11/42 (26.2)
4/19 (21.1)
5/9 (55.6)
3/15 (20.0)
7/31 (22.6) / 18/80 (22.5)
12/32 (37.5)
14/52 (26.9)
8/25 (32.0)
4/6 (66.7)
4/12 (33.3)
14/36 (38.9) / 0.756
0.820
0.936
0.419
0.667
0.432
0.151
* Calculated based on patients with ACLF grade ≥ 1 (148 patients)
Abbreviations: HRS, hepatorenal syndrome; HE, hepatic encephalopathy; MELD, model of end-stage liver disease; CLIF, chronic liver failure; ACLF, acute-on-chronic liver failure
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