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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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