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Hepato-renal Syndrome
– What is it? Akash Deep, Director -
PICU King’s College Hospital
London
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?2
Hepatorenal Syndrome
• No data exists in paediatric literature
• Adult data extrapolated.
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Progress of cirrhosis
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Braveno IV status classification of cirrhosis
STAGE 1.NO VARICESNO ASCITES
STAGE 2.VARICES
NO ASCITES
STAGE 3.ASCITESVARICES
STAGE 4.BLEEDING +/-
ASCITES
1-year Outcome Probabilities
DEATH
1%
3.4%
20 %
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?10
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 menEthnic 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 Diuretic-Resistant Ascites
Prognosis
Type -1 HRS
Acute, MOF, Precipitous doubling ofserum creatinine in < 2 weeks
Present in > 50% of cases, overlaps with other causes of AKI
May or may not bepresent
Without therapy- 90-daysurvival of 10%
Type -2 HRS
Gradually progressive
Absent Always Present
Median survival-6 months
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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 HRS22
Pathophysiology of CLDPeripheral and splanchnic arterial dilatation
Reduced effective blood volume
Activation of renin-angiotensin-aldosterone systemSympathetic nervous system
ADH
Na retention &
Water retentionLow urinary Na
Dilutional hyponatraemia
Ascites Schrier et al Hepatol 1988
Plasma volume expansion
Renal vasoconstrictionReduced GFR
NSAIDAminoglycosides
Diuretics Sepsis
NaCl
Ascites and Oedema HRS
Portal Hypertension
TNFIL6NO
Bacterial DNALPS binding proteinNorfloxacin effect
Effects of SBP
Gut 2008
Intra-abdominal pressureSugrue et al Arch Surg 1999 134:1082
Malbrain CCM 2005;33:315
263 patients 40.7% increased IAPRenal dysfunction:
32% with IAP elevated14% with normal IAP
32% IAP > 12 40% IAP > 20
CVPPcwP
Compliance
IAPIVCP
403020100
IAP
40
30
20
10
0
SVCP
403020100
IAP
40
30
20
10
0
Renal autoregulation in HRS
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Renal Blood Flow in cirrhotics
Ring-Larsen et al.
Splannchnic vasodilationDecreased ITBV
Intra-hepatic resistancePorto-renal reflex
Precipitating Factors Lead to rapid deterioration of the
systemic circulation and to the development of the HRS
• Gastrointestinal bleedingGastrointestinal bleeding• Spontaneous bacterial peritonitisSpontaneous bacterial peritonitis• SepsisSepsis• Aggressive diuresisAggressive diuresis• Large volume ParacentesisLarge volume Paracentesis• CholestasisCholestasis• NSAIDsNSAIDs
ATNAKI
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 ????36
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. 37
Creatinine >1 .5 mg/dl463 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 months1 vs 6 months respectively
Prognosis of HRS -1 and 2
• Gines et al – 134 HRS patientso 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 patientso Some of them did receive vasoconstrictor
therapyo 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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