Hepato-renal
Syndrome
– What is it?
Akash Deep, Director - PICU
King’s College Hospital
London
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Questions to be answered
• How common is renal dysfunction in children with
liver disease ?
• Is every renal dysfunction in liver disease
Hepatorenal Syndrome (HRS) ?
• What is the impact of kidney dysfunction in
children with existing liver disease? – Prognosis
• What is HRS – Definition, pathogenesis,
diagnosis
• Impact of HRS on transplant candidacy?
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Hepatorenal Syndrome
• No data exists in paediatric literature
• Adult data extrapolated.
2
Progress of cirrhosis
3
Braveno IV status classification of cirrhosis
STAGE 1.
NO VARICES
NO ASCITES
STAGE 2.
VARICES
NO ASCITES
1-year Outcome Probabilities
1%
3.4%
DEATH
STAGE 3.
ASCITES
VARICES
20 %
STAGE 4.
BLEEDING +/ASCITES
57%
J Hepatology 2006;44:217-231
Natural History Chronic Liver Disease
J Hepatology 2006;44:217-231
Christensen et al
Scand J Gastro 1989;24:999-1006
Mortality Prediction Scores in Cirrhosis
• Extra-hepatic organ dysfunction progresses
• Common ITU Scores – PIM2, Child Pugh
Score, MELD, SOFA, APACHE
• Renal Dysfunction omitted or only based on
SCr
• How important is the contribution of renal
dysfunction to the mortality of patients with liver
disease?
• Inclusion of SCr in Model for End-Stage Liver
Disease (MELD)
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AKI in Liver disease
• Is every AKI in liver disease HRS ?
• What are the different causes of AKI in
liver disease?
• Can we reliably differentiate between the
various causes of AKI?
• If HRS exists, what is it, clinical
manifestations and diagnosis and how do
we treat it?
• Impact of AKI on transplant candidacy?
9
Frequent causes of AKI in CLD
• Pre-renal : Hypovolaemia: GI bleeding – (don’t forget
the ulcer ) GI fluid losses (Lactulose, Terlipressin, PPI)
Diuretics abuse/over use
• Acute Tubular necrosis
• Parenchymal disease: GN, Cryoglobulinaemia, IgA
nephropathy – Biopsy? ATN/HRS
• Drugs: CIN, NSAIDS, Abx, CNI post Tx
• Intra Abdominal Hypertension
• Hepato-renal Syndrome
Kidney dysfunction in cirrhosis
Natural Progression of disease
complications
Renal dysfunction
HRS
V/s
Stable patient with cirrhosis, PHT
precipitating event
HRS
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HRS, does it exist?
Epidemiology
• 50% of patients with cirrhosis with ascites will develop
AKI
• HRS constitutes a very small proportion of AKI in cirrhosis
• ONLY 7.6% of all 129 cirrhotics with AKI had HRS as the
cause of deterioration
(Montoliu S, Ballesté B, Planas R, et al )
• Multicentre trial – 423 patients with cirrhosis and AKI
(ATN -35%, Pre-renal failure-32%, HRS-1- 20%, HRS-2 6.6%
(Moreau R, Durand F, Poynard T, et al)
Adult vs Paediatric HRS
•
•
•
•
Biliary atresia most common cause of OLT
Fewer numbers and split liver transplant
Waiting lists smaller – transplant – no HRS
Adults – more in number, varied
aetiologies, longer waiting lists and
develop all complications including HRS
• HRS in Paediatrics VERY RARE.
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What is HRS ?
Hepatorenal syndrome (HRS) is defined as
the occurrence of renal failure in a patient
with advanced liver disease in the absence
of an identifiable cause of renal failure
DIAGNOSIS OF EXCLUSION
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Issues :
Not even eGFR
Creatinine is produced in the liver
Woman vs men
Ethnic diversity
Decreased muscle mass in cirrhosis
Consider acute renal dysfunction in cirrhosis : RIFLE
Problems with Serum Creatinine
• Bilirubin interferes with assays, with hyperbilirubinaemia
masking increase in SCr
• Ethnic and Sex predilection
• Liver synthetic function -production of creatinine is reduced
by 50%
• Muscle mass and protein malnutrition
• Lower baseline range for creatinine in advanced liver
disease
• Cirrhotic patients for a given change in GFR have smaller
and delayed changes in SCr
• Delay access to timely HRS treatment and may adversely
affect these patients’ prognosis.
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Characteristics of Type 1 and Type 2 Hepatorenal Syndrome
Course
Precipitating
Event
History of
DiureticResistant
Ascites
Type -1
HRS
Acute, MOF,
Precipitous
doubling of
serum creatinine
in < 2 weeks
Present in >
May or may
50% of cases, not be
overlaps with
present
other causes of
AKI
Without
therapy- 90day
survival of
10%
Type -2
HRS
Gradually
progressive
Absent
Median
survival6 months
Always
Present
Prognosis
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Mediators of Splanchnic Vasodilatation
• Nitric Oxide (shear-stress-induced upregulation
of endothelial NO synthase (eNOS) activity and
endotoxin-mediated eNOS)
• Calcitonin gene-related peptide (CGRP)
• Substance P
• Carbon monoxide
• Endocannabinoids
Overproduction of TNF-α may be a major
mechanism leading to HRS
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Portal Hypertension
Pathophysiology of CLD
Peripheral and splanchnic arterial dilatation
Reduced effective blood volume
NSAID
Aminoglycosides
Diuretics
Sepsis
Activation of renin-angiotensin-aldosterone system
Sympathetic nervous system
ADH
NaCl
Na retention
&
Water retention
Renal vasoconstriction
Reduced GFR
Ascites and Oedema
Low urinary Na
Dilutional hyponatraemia
HRS
Plasma volume expansion
Ascites
Schrier et al Hepatol 1988
Bacterial DNA
LPS binding protein
Norfloxacin effect
TNF
IL6
NO
Effects of SBP
Gut 2008
40
40
30
30
20
20
Compliance 
IAP
10
IAP
CVP
PcwP
10
IAP
Intra-abdominal pressure
Sugrue et al Arch Surg 1999 134:1082
Malbrain CCM 2005;33:315
263 patients 40.7% increased IAP
Renal dysfunction:
32% with IAP elevated
14% with normal IAP
32% IAP > 12
40% IAP > 20
0
0
0
0
IVCP
SVCP
10
10
20
20
30
30
40
40
Renal autoregulation in HRS
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Renal Blood Flow in cirrhotics
Splannchnic vasodilation
Decreased ITBV
Intra-hepatic resistance
Porto-renal reflex
Ring-Larsen et al.
Precipitating Factors
Lead to rapid deterioration of the systemic
circulation and to the development of the
HRS
• Gastrointestinal bleeding
• Spontaneous bacterial peritonitis
• Sepsis
• Aggressive diuresis
• Large volume Paracentesis
• Cholestasis
• NSAIDs
ATN
AKI
What is what?
HRS - Diagnosis of exclusion
• Hepatorenal syndrome (HRS) is defined as the
occurrence of renal failure in a patient with
advanced liver disease in the absence of an
identifiable cause of renal failure
• The diagnosis of HRS is one of exclusion,
so investigations should be performed to
rule out other common causes of AKI.
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Differentiating one from the other
• HRS and ATN difficult to differentiate
• Granular casts observed in the urinary
sediment in both conditions
• Presence of renal tubular epithelial cells
favours ATN
• FeNa < 1.0% - tubular reabsorptive integrity
favours HRS
• Hpovolemic or septic shock immediately before
renal failure - ATN
• Prolonged HRS ----- ATN ????
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Prognosis
• Depends on etiology
• HRS carries the worst survival among all causes of AKI in
cirrhotic patients
• 562 cirrhotic patients with AKI
• 3-month survival :
 HRS patients -15%
 Infection induced AKI - 31%
 Hypovolemia-induced AKI -46%
 AKI associated with evidence of parenchymal renal
disease - 73%
Determining the etiology of AKI in cirrhotic patients does not only
determine the treatment plan but also foretells the prognosis.
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Creatinine >1 .5 mg/dl
463 patients over 6 years
Single centre
3 month
mortality
Implications of AKI on transplantation
• Patients with cirrhosis and renal failure are at
high risk for death while awaiting transplantation
• HRS is a strong predictor of mortality
• In patients listed for transplantation, the
development of HRS – Untransplantable or who
receive a transplant associated with increased
morbidity and mortality after transplantation
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Why is HRS considered functional?
• Initially histological abnormalities are minimal
and inconsistent
• Tubular function and sodium absorption
remains intact
• Kidneys transplanted from patients with HRS
can resume normal function in the recipient
• Renal function can return in patients with HRS
who receive liver transplant
• Only 2/3rds recover kidney function after
transplantation.
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Prognosis
50% at 2, 20% at 6 months
1 vs 6 months respectively
Prognosis of HRS -1 and 2
• Gines et al – 134 HRS patients
o 2-week mortality rate 80% in untreated type 1
HRS patients with only 10% of patients
surviving for 3 months
• Salerno et al - 116 HRS patients
o Some of them did receive vasoconstrictor
therapy
o 3-month survival was 20% and 40% for type 1
and type 2 HRS, respectively.
Conclusion
•
•
•
•
•
AKI common in decompensated cirrhotics
Not every AKI in cirrhosis is HRS
Extremely rare in paediatrics
AKI predicts increased mortality in liver disease
HRS drastic complication and carries a very bad
prognosis
• Splanchnic vasodilatation and renal vasoconstriction
– main causes
• Need to know what caused AKI – is it HRS ????
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