SINDROME HEPATORRENAL

IV CURSO PARA RESIDENTES DE LA AEEH

DIAGNÓSTICO Y TRATAMIENTO DE LAS
ENFERMEDADES HEPÁTICAS

Barcelona, 18-19 de Octubre de 2013

ASCITIS Y SINDROME
HEPATORRENAL

Pere Ginès
Servei d’Hepatologia
Hospital Clínic
Universitat de Barcelona
 ASCITES
Pathogenesis and established therapies

CIRRHOSIS

TIPS Portal hypertension

Splanchnic arterial vasodilation

Reduced effective arterial blood volume

Activation of vasoconstrictor
/antinatriuretic systems

Aldosterone Renin-aldosterone Sympathetic nervous

antagonists system system

Other diuretics Sodium retention

Large-volume
ASCITES/EDEMA
paracentesis + albumin
 DIURETICS IN THE MANAGEMENT OF ASCITES
Tips for clinical use

1. Treat the first episode of ascites with low doses of

spironolactone. Don’t push weight loss above 0.5 Kg/day
(1Kg/day in patients with leg edema)

2. Full antagonism of aldosterone by spironolactone takes

approx 5 days. Don’t expect immediate natriuresis

3. Visit or call patients weekly when ascites is decreasing or

the dose of diuretics has been increased. Educate patients
on the effects of diuretics

4. Monitor the effect of diuretics with body weight. Measure

urine sodium in patients with poor or no response
 DIURETICS IN THE MANAGEMENT OF ASCITES
Tips for clinical use

5. Use spironolactone with caution in patients with increased

serum creatinine levels because of risk of hyperkalemia

6. Old patients or patients with chronic kidney disease have

an impaired response to diuretics

7. Patients with pleural effusion respond poorly to diuretics

and frequently develop side effects. Doses should be
adjusted very carefully

8. USE DIURETICS WISELY. IMPORTANT SIDE EFFECTS

CAUSED BY DIURETICS ARE VERY COMMON
 HYPOVOLEMIC HYPONATREMIA IN A PATIENT
WITH CIRRHOSIS AND ASCITES DUE TO OVERDIURESIS

132 1.50

Serum creatinine (mg/dL) (

Furosemide (40 mg/day) + Spironolactone (200 mg/day)
)

130
Serum sodium (mEq/L) (

1.25

128
1.00
126

0.75
124

)
Hepatic
encephalopathy
122 0.50
1 2 3 4 5 6 7 8 9 10 11
Days
BW (kg) 74 72 70.5 68.3 67.2 64.8 61.5 59.2 59.5 60.3 61.1
ALBUMIN IN LARGE-VOLUME PARACENTESIS
Comparison albumin vs other expanders
Effects on survival

Odds Ratio (CI)

Bernardi et al, Hepatology 2012

 REFRACTORY ASCITES
Pathogenesis and established therapies

CIRRHOSIS

TIPS Portal hypertension

Intense splanchnic arterial vasodilation

Severely reduced effective arterial blood volume

Marked activation of vasoconstrictor

/antinatriuretic systems

Aldosterone Renin-aldosterone Sympathetic nervous

antagonists system system

Other diuretics Intense sodium retention

Large-volume
REFRACTORY ASCITES
paracentesis + albumin
 TIPS vs. PARACENTESIS FOR REFRACTORY ASCITES
Summary of studies

Control Hepatorenal Hepatic

Cost Survival
of ascites syndrome encephalopathy

Lebrec et al., Better with No Worse

- -
J Hepatol 1997 TIPS difference with TIPS

Rossle et al., Better with No Better with

- -
N Engl J Med 2000 TIPS difference TIPS?

Ginès et al., Better with Less frequent Worse Greater No

Gastroenterology 2002 TIPS with TIPS with TIPS with TIPS difference

Sanyal et al., Better with Worse No

- -
Gastroenterology 2003 TIPS with TIPS difference

Salerno et al., Better with Less frequent Worse Better with

-
Hepatology 2005 TIPS with TIPS with TIPS TIPS
 EASL GUIDELINES ON ASCITES IN CIRRHOSIS 2010
Management of Refractory Ascites

- Repeated large volume paracentesis plus albumin

(8 g/L of ascites removed) is the first line of treatment
for refractory ascites
- The use of TIPS should be considered in patients with
very frequent requirement of paracentesis or in those
in whom paracentesis is ineffective (e.g. due to the
presence of loculated ascites)

EASL Guidelines on Ascites, J Hepatol 2010

HEPATORENAL SYNDROME

Epstein et al., Am J Med 1970

 HEPATORENAL SYNDROME
Clinical types

Type 1
- Rapidly progressive renal failure: doubling of
the initial serum creatinine concentration to a
level greater than 2.5 mg/dL in less than 2 weeks
- Clinical presentation::acute renal failure
- Median survival: 2 weeks, if untreated

Type 2
- Stable renal failure
- Clinical presentation: refractory ascites
- Median survival: 6 months

International Ascites Club, Hepatology 1996

 TYPE 1 HEPATORENAL SYNDROME
EASL Guidelines 2010

1. Consider liver transplantation; give priority to candidates

2. Terlipressin and albumin is the first-line treatment
3. Alternative therapies include norepinephrine and midodrine
and octreotide plus albumin but information is limited
4. Consider TIPS if no response to vasoconstrictors
in patients without contraindications (low applicability)
5. Use renal replacement therapy if no response
to vasoconstrictors
6. Liver transplantation alone. No combined liver-kidney tx
except for patients requiring prolonged renal support
 CIRCULATORY AND KIDNEY FUNCTION IN
HEPATORENAL SYNDROME AND EFFECTS OF
TERLIPRESSIN AND ALBUMIN

CIRRHOSIS
Portal hypertension

Terlipressin Splanchnic arterial vasodilation

Albumin Decreased effective arterial blood volume

Vasoconstrictor systems

Cerebral Renal Brachial/femoral

vasoconstriction vasoconstriction vasoconstriction

Maintenance of effective
arterial blood volume

HEPATORENAL SYNDROME
 CIRCULATORY AND KIDNEY FUNCTION IN
HEPATORENAL SYNDROME AND EFFECTS OF
TERLIPRESSIN AND ALBUMIN

CIRRHOSIS
Portal hypertension

Splanchnic arterial vasoconstriction

Increase in effective arterial blood volume

Suppressed vasoconstrictor systems

Cerebral Kidney Brachial/femoral

Vasodilation?? vasodilation Vasodilation??

Maintenance of effective
arterial blood volume

IMPROVED KIDNEY FUNCTION

 HEPATORENAL SYNDROME
Effects of terlipressin and albumin on circulatory
and kidney function

Pretreatment End of treatment p

Serum creatinine (mg/dL) 3.9±0.7 1.5±0.2 <0.001

Serum sodium (mEq/L) 122±1 131±2 <0.01
Mean arterial pressure (mmHg) 68±2 80±4 <0.05
Plasma renin activity (ng/mL.h) 23±12 3±2 <0.01
Plasma aldosterone (ng/dL) 342±73 89±29 <0.01
Plasma norepinephrine (pg/mL) 1,549±373 373±98 <0.01

Uriz et al., J Hepatol 2000

PHARMACOLOGICAL TREATMENT OF TYPE-1
HEPATORENAL SYNDROME
Changes in arterial pressure in responders
and non-responders

Boyer T et al. JHepatol 2011

 SPECIFIC ISSUES IN THE MANAGEMENT
OF PATIENTS WITH HEPATORENAL SYNDROME

• Differential diagnosis between type-1 HRS and other

causes of kidney failure

• Evaluation and management of type-1 HRS associated

with infections

• Treatment of patients with type-2 HRS

 SPECIFIC ISSUES IN THE MANAGEMENT
OF PATIENTS WITH HEPATORENAL SYNDROME

• Differential diagnosis between type-1 HRS and other

causes of kidney failure

• Evaluation and management of type-1 HRS associated

with infections

• Treatment of patients with type-2 HRS

 CAUSES OF KIDNEY FAILURE IN CIRRHOSIS
Prospective series of 265 hospitalized patients

% 50

40 36%

30 25% 24%

20 15%

10

0
HEPATORENAL PRE-RENAL INTRINSIC OTHER
SYNDROME AKI AKI*

PRE-RENAL AKI: KIDNEY FAILURE DUE TO HYPOVOLEMIA

INTRINSIC AKI: KIDNEY FAILURE DUE TO ACUTE TUBULAR NECROSIS
AKI, ACUTE KIDNEY INJURY
Barreto et al., unpublished
 BIOMARKERS FOR THE DIAGNOSIS
OF ACUTE KIDNEY INJURY

Constituent biomarkers
NAG
• N-acetylglucoseaminidase (NAG)
α-GST
• α-glutation-S-transferase (α-GST)
KIM-1
• π-glutation-S-transferase (π-GST)
MCP-1 π-GST
β2-microglobuline NGAL
Inducible biomarkers
• Neutrophil gelatinase-associated
lipocalin (NGAL)
• Kidney injury molecule-1 (KIM-1)
• Monocyte chemoattractant
protein-1 (MCP-1)
NGAL
Low molecular
weight proteins
• β2-microglobuline
 URINE NGAL AND CAUSE OF KIDNEY
FAILURE IN HOSPITALIZED CIRRHOTICS

327 SENS 0.67

SPECIF 0.86

p<0.001

Median 32 33 67 98 417

* p<0.001
** p<0.05
∞ Miscellaneous: Chronic Kidney Disease, Nephrotoxicity … Barreto et al, unpublished
 SPECIFIC ISSUES IN THE MANAGEMENT
OF PATIENTS WITH HEPATORENAL SYNDROME

• Differential diagnosis between type-1 HRS and other

causes of kidney failure

• Evaluation and management of type-1 HRS associated

with infections

• Treatment of patients with type-2 HRS

 TYPE-1 HEPATORENAL SYNDROME ASSOCIATED
WITH SEPSIS
Lack of reversibility with antibiotic therapy

No Reversibility

% 100
Age < 60 years 100%
100
Age ≥ 60 years 100%
86%
80%
75 75 67%
64%
60%

50 50

25 25

0%
0 0
Bilirubin <8mg/dL Bilirubin ≥8mg/dL Bilirubin <8mg/dL Bilirubin ≥8mg/dL

No Nosocomial infection
Nosocomial infection

Barreto et al. Hepatology 2013

TYPE-1 HEPATORENAL SYNDROME ASSOCIATED
WITH SEPSIS
Effects of terlipressin and albumin

a
0
Responders
Non Responders

Efficacy 65%

Responders

Rodriguez E et al. unpublished

 SPECIFIC ISSUES IN THE MANAGEMENT
OF PATIENTS WITH HEPATORENAL SYNDROME

• Differential diagnosis between type-1 HRS and other

causes of kidney failure

• Evaluation and management of type-1 HRS associated

with infections

• Treatment of patients with type-2 HRS

 TREATMENT OF TYPE-2 HEPATORENAL SYNDROME

• Information on treatment of type-2 HRS is limited

• Terlipressin and albumin is effective in improving kidney
function in approximately 60% of patients, but recurrence
after treatment withdrawal is almost constant
• The effect of pharmacological treatment on survival has not
been evaluated in large studies
• TIPS may improve renal function but an improvement in
survival has not been demonstrated
 CONCLUSIONS

• The use of kidney biomarkers, such as NGAL, may be useful

in the differential diagnosis of HRS from other causes of
acute kidney dysfunction, but more studies are needed
before the use of biomarkers can be applied to clinical
practice.

• Terlipressin and albumin is the treatment of choice for

type-1 HRS. Response to treatment is dependent on
improvement of systemic hemodynamics. Early treatment
may improve the response rate.
• Type-1 HRS associated with sepsis is seldom reversible only
with antibiotic treatment. Terlipressin and albumin
appears effective in these patients
BARCELONA LIVER CIRRHOSIS STUDY GROUP