IV CURSO PARA RESIDENTES DE LA AEEHDIAGNÓSTICO Y TRATAMIENTO DE LAS

ENFERMEDADES HEPÁTICAS

Barcelona, 18-19 de Octubre de 2013

ASCITIS Y SINDROME ASCITIS Y SINDROME HEPATORRENALHEPATORRENAL

Pere Ginès

Servei d’HepatologiaHospital Clínic

Universitat de Barcelona

SINDROME HEPATORRENAL

TIPS

Aldosteroneantagonists

Large-volumeparacentesis + albumin

CIRRHOSIS

Portal hypertension

Splanchnic arterial vasodilation

Reduced effective arterial blood volume

Activation of vasoconstrictor/antinatriuretic systems

Renin-aldosteronesystem

Sodium retention

ASCITES/EDEMA

Sympathetic nervoussystem

Other diuretics

ASCITES Pathogenesis and established therapies

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 ASCITESTips 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

DIURETICS IN THE MANAGEMENT OF ASCITESTips for clinical use

HYPOVOLEMIC HYPONATREMIA IN A PATIENT WITH CIRRHOSIS AND ASCITES DUE TO OVERDIURESIS

132

124

122

128

BW (kg) 74 72 70.5 68.3 67.2 64.8 61.5 59.2 59.5 60.3 61.1

1

130

126

3 7 8 115 64

1.50

1.00

1.25

0.50

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

Ser

um s

odiu

m (

mE

q/L)

(

)

Serum

creatinine (mg/dL) ( )

Hepaticencephalopathy

9 10

0.75

2Days

Bernardi et al, Hepatology 2012

Odds Ratio (CI)

ALBUMIN IN LARGE-VOLUME PARACENTESIS Comparison albumin vs other expanders

Effects on survival

TIPS

Aldosteroneantagonists

Large-volumeparacentesis + albumin

CIRRHOSIS

Portal hypertension

Intense splanchnic arterial vasodilation

Severely reduced effective arterial blood volume

Marked activation of vasoconstrictor/antinatriuretic systems

Renin-aldosteronesystem

Intense sodium retention

REFRACTORY ASCITES

Sympathetic nervoussystem

Other diuretics

REFRACTORY ASCITES Pathogenesis and established therapies

Cost

-

-

-

-

Greaterwith TIPS

Hepatorenalsyndrome

-

-

-

Less frequentwith TIPS

Less frequentwith TIPS

Rossle et al.,N Engl J Med 2000

Ginès et al.,Gastroenterology 2002

Sanyal et al.,Gastroenterology 2003

Salerno et al.,Hepatology 2005

Lebrec et al.,J Hepatol 1997

Controlof ascites

Better withTIPS

Better withTIPS

Better withTIPS

Better withTIPS

Better withTIPS

Hepatic encephalopathy

No difference

Worsewith TIPS

Worsewith TIPS

Worsewith TIPS

No difference

Survival

Better withTIPS?

No difference

No difference

Better withTIPS

Worsewith TIPS

TIPS vs. PARACENTESIS FOR REFRACTORY ASCITES

Summary of studies

- 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

EASL GUIDELINES ON ASCITES IN CIRRHOSIS 2010Management of Refractory Ascites

Epstein et al., Am J Med 1970

HEPATORENAL SYNDROME

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

HEPATORENAL SYNDROMEClinical types

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

TYPE 1 HEPATORENAL SYNDROMEEASL Guidelines 2010

HEPATORENAL SYNDROME

CIRRHOSIS

Splanchnic arterial vasodilation

Decreased effective arterial blood volume

Cerebralvasoconstriction

Maintenance of effectivearterial blood volume

Renalvasoconstriction

Brachial/femoralvasoconstriction

Vasoconstrictor systems

Portal hypertension

Terlipressin

Albumin

CIRCULATORY AND KIDNEY FUNCTION IN HEPATORENAL SYNDROME AND EFFECTS OF

TERLIPRESSIN AND ALBUMIN

IMPROVED KIDNEY FUNCTION

CIRRHOSIS

Splanchnic arterial vasoconstriction

Increase in effective arterial blood volume

CerebralVasodilation??

Maintenance of effectivearterial blood volume

Kidneyvasodilation

Brachial/femoralVasodilation??

Suppressed vasoconstrictor systems

Portal hypertension

CIRCULATORY AND KIDNEY FUNCTION IN HEPATORENAL SYNDROME AND EFFECTS OF

TERLIPRESSIN AND ALBUMIN

Uriz et al., J Hepatol 2000

Serum creatinine (mg/dL)

Serum sodium (mEq/L)

Mean arterial pressure (mmHg)

Plasma renin activity (ng/mL.h)

Plasma aldosterone (ng/dL)

Plasma norepinephrine (pg/mL)

342±73

Pretreatment

3.9±0.7

122±1

68±2

23±12

1,549±373

89±29

End of treatment

1.5±0.2

131±2

80±4

3±2

373±98

<0.01

p

<0.001

<0.01

<0.05

<0.01

<0.01

HEPATORENAL SYNDROMEEffects of terlipressin and albumin on circulatory

and kidney function

Boyer T et al. JHepatol 2011

PHARMACOLOGICAL TREATMENT OF TYPE-1 HEPATORENAL SYNDROME

Changes in arterial pressure in respondersand non-responders

• 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 MANAGEMENTOF 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 MANAGEMENTOF PATIENTS WITH HEPATORENAL SYNDROME

Barreto et al., unpublished

0

10

20

30

40

50

HEPATORENALSYNDROME

PRE-RENALAKI

INTRINSICAKI*

OTHER

36%

25%

15%

24%

%

PRE-RENAL AKI: KIDNEY FAILURE DUE TO HYPOVOLEMIAINTRINSIC AKI: KIDNEY FAILURE DUE TO ACUTE TUBULAR NECROSISAKI, ACUTE KIDNEY INJURY

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

Inducible biomarkers

NGAL

• Neutrophil gelatinase-associated lipocalin (NGAL)• Kidney injury molecule-1 (KIM-1)• Monocyte chemoattractant protein-1 (MCP-1)

NGAL

KIM-1MCP-1

• β2-microglobuline

Low molecularweight proteins

β2-microglobuline

• N-acetylglucoseaminidase (NAG)• α-glutation-S-transferase (α-GST)• π-glutation-S-transferase (π-GST)

Constituent biomarkers

π-GST

NAGα-GST

NGAL

• Neutrophil gelatinase-associated lipocalin (NGAL)

NGAL

BIOMARKERS FOR THE DIAGNOSIS OF ACUTE KIDNEY INJURY

Barreto et al, unpublished

p<0.001

* p<0.001** p<0.05∞ Miscellaneous: Chronic Kidney Disease, Nephrotoxicity …

Median 32 33 67 98 417

327 SENS 0.67SPECIF 0.86

∞

URINE NGAL AND CAUSE OF KIDNEYFAILURE IN HOSPITALIZED CIRRHOTICS

• 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 MANAGEMENTOF PATIENTS WITH HEPATORENAL SYNDROME

TYPE-1 HEPATORENAL SYNDROME ASSOCIATED WITH SEPSIS

Lack of reversibility with antibiotic therapy

Barreto et al. Hepatology 2013

No Nosocomial infection Nosocomial infection

0%

64%60%

100%

0

25

50

75

100

Bilirubin <8mg/dL Bilirubin ≥8mg/dL

86%

67%

100%

80%

0

25

50

75

100

Bilirubin <8mg/dL Bilirubin ≥8mg/dL

Age < 60 years Age ≥ 60 years

No Reversibility

%

TYPE-1 HEPATORENAL SYNDROME ASSOCIATED WITH SEPSIS

Effects of terlipressin and albumin

a0

Responders

Non Responders

Responders

Efficacy 65%

Rodriguez E et al. unpublished

• 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 MANAGEMENTOF PATIENTS WITH 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

TREATMENT OF TYPE-2 HEPATORENAL SYNDROME

• 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

CONCLUSIONS

BARCELONA LIVER CIRRHOSIS STUDY GROUP