Cre

atin

ine

(mg/

dL)

6

4

3

2

1

0

5

Months Weeks

-4-6 -2 0 1 2 3

Therapeuticparacentesis

Cefotaxime

Type-2 HRS Type-1 HRS

EncephalopathyJaundice

CLINICAL TYPES OFHEPATORENAL SYNDROME (HRS)

DIFFERENCES BETWEEN TYPE-1 AND TYPE-2 HRS

Setting

Renal failure

Type-2 Type-1

Consequence

Survival

Non-azotemic cirrhosis

Moderate and steady

Refractory ascites

Months

Type-2 HRS

Severe and progressive

Terminal hepatorenal failure

Days

Onset Spontaneous Precipitated

HRS. SURVIVAL

600500400300200100

1.0

0.8

0.6

0.4

0.2

0.0

Type-1

Type-2

p<0.0001

Median survival

Type-1

Type-2

15 days

150 days

Days

Pro

babi

lity

0

TIME-COURSE OF THE CIRCULATORY, NEUROHORMONALAND RENAL FUNCTION ABNORMALITIES IN CIRRHOSIS

TIME-COURSE OF THE CIRCULATORY, NEUROHORMONALAND RENAL FUNCTION ABNORMALITIES IN CIRRHOSIS

No Ascites

Time

Deg

ree

o f s

pla

nchn

icar

ter ia

l va s

o dil a

ti on

Ascites

Hyperdinamic circulation

RAAS, SNS and sodium retention

ADH and hyponatremia

HRS

Ruiz del Arbol et al., Hepatology 2002

CARDIOVASCULAR HEMODYNAMICS IN 8 PATIENTS DEVELOPING TYPE-1 HRS AFTER SBP

CARDIOVASCULAR HEMODYNAMICS IN 8 PATIENTS DEVELOPING TYPE-1 HRS AFTER SBP

At SBP diagnosis SBP-HRS

83±7MAP (mmHg) 73±8*

* p<0.02

PRA (ng/mL.h)

SVR (dyn.s/cm-5)

CO (L/min) 5.7±0.9

1137±220

18±11

1268±320

28±12*

4.6±0.7*

Ruiz del Arbol et al., Hepatology 2005

* baseline measurements: 9±1 months prior HRS

SVR (dyn.s/cm-5) 1099±81 1211±97 NS

CO (L/min) 5.8±0.2 4.6±0.3 <0.01

PRA (ng/mL.h) 12.9±2.6 25.8±3.4 <0.01

NE (pg/mL) 735±69 1385±99 <0.001

HR (bpm) 86±5 84±4 NS

PCP (mmHg) 8.7±1 6.5±1 <0.01

RAP (mmHg) 7±0.8 5±0.5 <0.01

CARDIOVASCULAR HEMODYNAMICSIN 12 PATIENTS DEVELOPING TYPE-1 HRS*

Baseline Type-1 HRS p

MAP (mmHg) 84±2.6 70±2.3 <0.001

Healthy subjects (H), cirrhotic patients without ascites (NA),with ascites (A) and with hepatorenal syndrome (HRS)

REGIONAL CIRCULATORY CHANGES IN CIRRHOSIS

*

H NA A HRS

* p<0.05

Bra

chia

l blo

od fl

ow

(m

L/m

in) 80

60

40

20

0

*

Re

sist

ive

inde

x m

idd

le

cere

bra

l art

ery

0.8

0.7

0.6

0.4

0.9

0.5

H NA A

p<0.001

Maroto et al., Hepatology 1993 Guevara et al., Hepatology 1998

CHANGES IN HEPATIC HEMODYNAMICSASSOCIATED WITH TYPE-1 HRS

CHANGES IN HEPATIC HEMODYNAMICSASSOCIATED WITH TYPE-1 HRS

Ruiz del Arbol et al., Hepatology 2005

HVPG IN PATIENTS DEVELOPINGTYPE-1 HRS AFTER SBP

HVPG IN PATIENTS DEVELOPINGTYPE-1 HRS AFTER SBP

HV

PG

(m

mH

g)

15

20

25

30p<0.05

At SBPdiagnosis

After SBPresolution

Ruiz del Arbol et al., Hepatology 2002

HBF IN PATIENTS DEVELOPINGTYPE-1 HRS

HBF IN PATIENTS DEVELOPINGTYPE-1 HRS

Hep

atic

blo

od f

low

(m

L/m

in)

Type-1HRS

400

600

1000

800

Baseline measurements:9±1 months prior HRS

Baseline

Fernández et al. (unpublished)

INCIDENCE OF RELATIVE ADRENAL INSUFFICIENCY*IN CIRRHOTIC PATIENTS (n=20) WITH SEPTIC SHOCK

Cirrhotics Child B 25%

Non-cirrhotic patients 10-40%

Cirrhotics Child C 75%

* Diagnostic criteria:- baseline cortisol <9 g/dL- increase in cortisol after ACTH <9 g/dL- peak cortisol <20 g/dL

TYPE-I HRS AS A PART OF A MULTIORGAN FAILURE

Spontaneous bacterial peritonitisor other precipitating event

Increase in arterial vasodilationDecrease in cardiac output

Adrenaldysfunction

A-II, NE, ADH

resistance toportal venous flow

Regional arterialvasoconstriction

Aggravation ofportal hypertension

Kidneys

Liver

Brain

Liver failure

Encephalopathy

HRS

MAP (mmHg)

PRA (ng/mL.h)

NE (pg/mL)

Creatinine (mg/dL)

Baseline(n=15)

15±15

1257±938

3±1

70±8

Day 7(n=9)

2±3

550±410

2±1

77±9

Day 14(n=7)

1±1

316±161

1±1

79±12

EFFECT OF VASOCONSTRICTORS(Ornipressin and Terlipressin)

PLUS I.V. ALBUMIN IN TYPE-1 HRS

GFR (mL/min) 9±1 25±2.5 41±1.5

Guevara et al., Hepatology 1998; Uriz et al., J Hepatol 2000

SERUM CREATININE BEFORE AND AFTERTREATMENT OF TYPE-1 HRS (11 cases)

WITH TERLIPRESSIN PLUS ALBUMIN

3

5

4

0Baseline 1 day 1 month

Ser

um c

reat

inin

e (m

g/dL

)

2

1

After treatment

Ortega et al., Hepatology 2002

Group 1(n=154)

Group 2(n=137)

* Multicenter French Study

Liver transplantation 12.3% - 13%

HRS recurrence 20% - -

Reversal of HRS 61.7% 2.9% 58%

Survival 1 month 3%41.6% 40%

MCFS*(n=99)

Survival 3 months 0%30% 22%

TREATMENT OF HRS WITH VASOCONSTRICTORSAND ALBUMIN (Group 1) AND STANDARD MEDICAL

THERAPY (Group 2). REVIEW OF 18 STUDIES

TREATMENT OF TYPE-1 HRSWITH TERLIPRESSIN PLUS

I.V. ALBUMIN vs TERLIPRESSIN

Complete response

Survival >1 month

OLT

Terlipressin +albumin (n=13)

Terlipressin(n=8)

12

5

2

0

10 2

Ortega et al., Hepatology 2002

Guevara et al., Hepatology 1998

TIPS IMPROVES CIRCULATORY AND RENALFUNCTION IN TYPE-1 HRS (7 patients)

Renin (ng/mL/h)

NE (pg/mL)

Creatinine (mg/dL)

GFR (mL/min)

Baseline

1257±187

5.0±0.8

9±4

18±5

Day 7

853±102

3.7±1.0

11±5

6±2

Day 30

612±197

1.8±0.4

27±7

3±1

After treatment

CIRCULATORY SUPPORT WITH I.V. ALBUMIN IN PATIENTSWITH SBP. EFFECT ON ARTERIAL BLOOD VOLUME

Cefotaxime + albumin Cefotaxime

* p<0.05

9

8

1

PR

A (

ng/m

L.h)

7

6

5

03 6 9 Days

3

4

2

1

* *

*

Sort et al., N Engl J Med 1999

CIRCULATORY SUPPORT WITH I.V. ALBUMININ PATIENTS WITH SBP. EFFECT ON HRS

DEVELOPMENT AND HOSPITAL MORTALITY

Cefotaxime(n=63)

Resolution of infection

HRS

Hospital mortality

Cefotaxime +albumin (n=63)

20 (32%)

17 (27%)

6 (10%)*

6 (10%)*

57 (93%) 59 (98%)

* p<0.001

Sort et al., N Engl J Med 1999

Fernandez et al., Hepatology 2005

EFFECTS OF HYDROXYETHYL STARCH (HES) ANDALBUMIN (ALB) ON EFFECTIVE BLOOD VOLUME IN SBP

MAP (mmHg)

PRA (ng.mL/h)

76±9

80±15

5.7±4.7

8.5±7.3

Baseline

85±13

81±8

3.1±3.4

16.8±24.6

At resolution

0.01

NS

0.04

NS

p

HES

HES

ALB

ALB

Fernandez et al., Hepatology 2005

EFFECTS OF HYDROXYETHYL STARCH (HES)AND ALBUMIN (ALB) ON PERIPHERAL ARTERIAL

CIRCULATION IN SBP

SVR (dyn/cm5)

NO (nmol/mL)

vWF:Ag (U/dL)*

* vWF:Ag Von Willebrand-related antigen factor

668±134

777±239

61±30

39±13

297±44

331±35

Baseline

803±197

778±290

78±55

63±32

278±47

257±65

At resolution

0.03

NS

NS

0.03

NS

0.01

p

HES

HES

HES

ALB

ALB

ALB

EFFECT OF I.V. ALBUMIN ONSYSTEMIC HEMODYNAMICS IN CIRRHOSIS

Albumin infusion

IMPROVEMENTOF CIRCULATORY

DYSFUNCTION

Increased systemicvascular resistance

DecreasedNO synthesis

Inhibition ofendothelial activation

Intravascularvolume expansion

Increasedcardiac preload

Improvement in leftventricular function