Synt
hesis
Regu
lation
Deto
xification
Liver
cells
Adso
rber
Dialysis
• ammonia • bilirubin • endotoxins • aromatic amino acids • toxins
• albumin • amino acids • glucose, lipids • coagulation factors • unknown substances
• acid-base-status • electrolytes • amino acids • CNS energy supply • CNS transmitter precursors
Liver support
Renal support
Dialysis therapies
Peritoneal dialysis
Intermittent HD/HF/HDF
Hybrid techniques
CAVHF
CVVHF
CVVHF high volume plasma exchange
Peritoneal dialysis
Acute or AonCLD
advantage no anticoagulation
glucose based
disadvantages clearance
fluid balance
hyponatraemic
changes in cardiac filling
0
20
40
60
80
0 4 8 12 16 time (hrs)
MAP
mmHg
colloid
cardiac arrest & death
norepinephrine
CCPD 2 l cycles
fixed dilated pupils
GTN epinephrine
Cerebral perfusion during PD
Peritoneal dialysis
CLD
awaiting transplantation risk of peritonitis ?
splenic vein thrombosis
not for transplantation no increased infection risk
no increased protein losses
capillary CSF
brain Start of
hemodialysis
During hemodialysis
End of hemodialysis
urea urea urea
urea urea urea
urea urea urea
osmolality osmolality
osmolality
idiogenic osmoles
H20 H20
uremic slow fast urea high Na controls hemodialysis
0
1
2
3
4
5
Measu
red b
rain w
ate
r L/k
g dry
wt
dogs 2 hrs
hemodialysis plasma urea
72 24 mmol/l * p < 0.05
Arieff et al KI 1973
Brain water post hemodialysis *
*
white matter
gray matter
0 4 8 12 16 20 24 28 32 36 40 44 48 52 Time h
Art
erial NH
3 u
g/l
0
50
100
150
200
250
300
SJUH 45 yr pt Acet-aminophen CVVHF 1.5 /h
65 yr pt 4 hr HD
CLD
Ammonia clearance
CVHHF
HPL
C e
lution
pro
file
0
50
100
150
200
250
300
Tohoku Univ Sendai,
Japan ALF CVVH
Polysulfone 0.6m2
500-600 ml/min
Nafamostat 30-40 mg/h
CVVH for acute liver failure
Matsubara et al CritCareMed 1990
plasma
filtrate
30 45 60 75 90 Time min
0 20 40 60 80 100 120 Duration of haemodialysis (min)
0
10
20
30
40
Cum
ulative
no
of a
pnoe
as
> 1
0 s
DeBacker et al AmRevRespirDis 1987
Apnoeas during haemodialysis
CP-Bic
PAN-Bic
CP-Ac
PAN-Ac
capillary cerebrospinal fluid brain
start of dialysis
end of dialysis
HCO3
-
during dialysis
HCO3-
pH pH
Idiogenic osmoles
pH
H+
H2O + CO2
H2O
HCO3
-
HCO3-
HCO3
-
pH
Idiogenic osmoles
H+ CO2
Univ Frankfurt Univ Erlangen
Nürnberg 30 pts septic
shock AKI PS /heparin
QB 250 ml/min mean (SD)
* p < 0.05
John et al NephrolDialTransplant 2001
CVVH vs intermittent HD
CVVHF 2l/h lac
4 h HD bic UF 0.25-0.5 l/h
baseline 0.5 2 4 24 time hr
-30
-20
-10
0
10
20
30
Chang
e in
Syst
olic B
P mmHg
* *
Warm and Cold HD and HF
10
0
-10
-20
-30
-40
0 12060 180 240
MAP Changes [mmHg]
time [min]
standard (cold) HF
cold hemodialysis
warm HF
standard (warm) hemodialysis
Maggiore Q, Pizzarelli F, Sisca S, Zoccali C, Parlongo S, Nicolò F, Creazzo G. Blood temperatureand vascular stability during hemodialysis and hemofiltration. ASAIO Trans 1982;28:523-7
0 4 8 12 16 20 24 28 32 36 40 44 48 52 Time h
Mea
n IC
P m
mH
g
0
5
10
15
20
25
30
24 yr old pt acetaminophen CVVHF 1.5 /h
CRRT for acute liver failure
CVHHF
treatment time ( mins)
RBV change % UF rate l/h
0 50 100 150 200 250
0
- 6
-12
-18
-24
3
2
1
BIOFEEDBACK DEVICE
Biofeedback controlled HD-Hemocontrol
-25%
-20%
-15%
-10%
-5%
0%
0 30 60 90 120 150 180 210
time (min) BV (%)
Upper
tolerance
Lower
tolerance
Objective
Ideal trajectory
Actual value 0
1
2
3
0 60 120 180 240
WLR
13
14
15
16
0 60
17
120 180 240
DC
pre 2 4 6 8 10 12 duration of treatment min
20
30
40
50
60
70
80
MAP
mmHg
SJUH 10 pts sham CVVH
PAN 69 mean
Sudden catastrophic hypotension
Diluted Blood - Membrane
interaction
Hypersensitivity reaction
Blood – membrane interaction
Patient acidosis Rinsing solution
(pH, buffer, dilution)
heparins
Dialysate Composition
(acetic acid …)
Bacterial contamination exotoxins
Water treatment system
?
XII
XIIa XI
XIa
Heparin reactions
Contact coagulation
pathway
plasma prekallikrein
plasma kallikrein
-vely charged membrane
C3 C3a
C5 C5a
HMWt kininogen
bradykinin
0
2
4
6
8
10L/min/m2
0
400
800
1200
1600
SVRI
HRSAscitesPre-AsciticNormal
dyn s cm5 m2
Cirrhotic cardiomyopathy
Helmy et al. Gastro 2000;118:565-572; Jalan et al. Gut 1997;40:664-70; Jalan, Unpublished
SVRI
Card
iac
outp
ut
CRRT
homeostasis electrolytes
acid –base
fluid balance
cardiovascular stability
Extracorporeal liver support
Albumin Infusion prevents Renal Failure in
patients with Spontaneous Bacterial Peritonitis
Sort et al. NEJM, 1999, 126 patients with SBP
Antibiotics vs Albumin+Antibiotics in SBP
MORTALITY (In hospital)
Cefotaxime alone: 18 (28%)
Albumin + Cefotaxime: 6 (10%) p<0.01
RENAL IMPAIRMENT
Cefotaxime alone: 21 (33%)
Albumin + Cefotaxime: 6 (10%) p<0.002
Why albumin ?
albumin binds
nitric oxide
hormones
• Liver Failure – aromatic amino acids
– biliriubin
– bile acids
– copper
– free fatty acids
– indoles
– mercaptans
– phenols
filtrate
Thermodynamic limitation
Non selective losses
Costs
Plasma exchange
SPAD
Equilibrium limitations
Effective perfusion time
MARS
Prometheus
fresh
dialysate
effluent
dialysate
dialysate
blood flow blood flow
blood flow blood flow
Open loop circuit Closed loop circuit
dialysate
Albumin “Dialysis”
Single pass techniques
SPAD no trial data
PE+HD
abstract (Heidelberg - Paed Nephrol 2009)
9 children
3 Rx MARS all died
4 Rx PE & HD 75% survived
anionic resin
60 kD
cut off
blood flow
MARS
Prometheus
albumin dialysate
300 kD
cut off
fresh
dialysate
+ glucose
spent
dialysate
activated
charcoal
anionic
resin
high flux
dialyzer
high flux
dialyzer fresh
dialysate
+ glucose
spent
dialysate
SC
albumin
0.6
neutral resin
0 1 2 3 4 5 6 time h
Chang
e in
MAP
mmHg
-5
0
5
10
15
20
MARS in hyperacute liver failure
Schmidt et al Liver Transplant 2003 Rigshospitalet Copenhagen 13 pts ALF
8 MARS single Rx 5 cooled controls
(ice packs) mean
* p < 0.05
*
Prometheus vs MARS
Rigshospitalet 24 patients cirrhosis
MAP mmHg Pre Rx Post Rx
HD 75.2 ±7 76.6 ±5
MARS 68.9 ±4 78.1 ±5*
Prometheus 74.0 ±4 74.4 ±5
Dethloff et al WorldJGastroenterol 2008
MARS in acute liver failure
Kamala et al Liver Int 2008
survival MARS Standard
Medical Rx
p value
with OLTx 94% 77% p=0.06
No OLTx 66% 40% p=0.03
Death due to cerebral herniation
4% 18% p=0.014
Non randomised
deaths 1-5 days 6-10 days 11-180 days
SMT 5 (16%) 2 (8%) 10 (42%)
MARS+SMT 5 (13%) 4 (12%) 10 (33%)
MARS trial vs SMT
Hassanein et al Hepatol 2007
FULMAR study – French multicentre
mortality MARS Medical Rx
Supportive
p value
All patients 8/53 12/49 > 0.05
POD 3/20 6/10 > 0.05
RELIEF trial (MARS AonCLF)
Bannares et al JHepatol 2010
0
10
20
30
40
50
60
%
MARS + SMT
SMT
fall in bilirubin
fall in creatinine
grade 0/1 hepatic
encephalopathy
28 day mortality
189 patients randomised to MARS (95) vs SMT (94) Bilirubin > 5 mg/dl AND hepatic encephalopathy II-IV or HRS or bilirubin > 20 mg/dl Early drop out
19 MARS 4 SMT Precipitant of AonCLF
SBP 16.4% MARS vs 7.1% SMT (p=0.05)
HELIOS trial (Prometheus AonCLF)
• 145 patients randomised to Prometheus (77) vs SMT (68)
• 8-11 Prometheus 4 hour treatments
• 56% EtOH 20% viral hepatitis
JHepatol 2010
0
10
20
30
40
50
60
70
% s
urvi
val
28 day 90 day
Prometheus + SMT
SMT
Sub group Analysis
possible benefit HRS type 1 MELD >30
p=0.04
The UCL Liver Dialysis Device Incorporates Endotoxin removal + Albumin Exchange
Subject
In Vitro plasma
Pig
Patient
ENSO membrane
P2SX
Albumin
Rich
Dialysis
Soln.
Dialysate
Plasma Flow
Additional
Albumin
Infusion
Albumin
Dialysis
Waste
Subject
In Vitro plasma
Pig
Patient
ENSO membrane
P2SX
Albumin
Rich
Dialysis
Soln.
Dialysate
Plasma Flow
Additional
Albumin
Infusion
Albumin
Dialysis
Waste
Liver synthesis
natural anticoagulants Antithrombin
Proteins S & C
Heparin CoF-II
Pro-coagulant vs Anticoagulant
Liver synthesis
clotting factors
complement
fibrinogen
PAI-1
CRRT circuit life
groups
liver ALF
AonCLD
post LTx
controls systemic sepsis
haematological malignancy
TEG ALF Sepsis
R time min 12.1 (9-28) 14 (10.8-20)
K time min 5.2 (3.0-22.5) 5.6 (4.9-13.1)
angle 40 (13-56) 35.7 (24.2-42.6)
Max Ampl mm 41.2
3.6 51.6
4.6
G dyne/s 4.2
0.6 6.2
0.9
EPL % 0(0-0.15) 0 (0-0.05)
Thrombin
generation
ALF Sepsis
ETP 1033
111 1355
86*
peak 154
16 239
25 **
Time to peak 5.0
0.4 5.4
0.3
slope 68.4
8 110
16*
ETP (MP) 949
121 1267
85*
Anticoagulants for ALF and AonCLD Options depend upon institution
Japan nafamostat maleate
Europe prostanoids
citrate
heparin
USA heparin
citrate