Hepato-renal Syndrome
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Hepato-renal Syndrome – What is it? Akash Deep, Director - PICU King ’ s College Hospital London. 0. Questions to be answered. How common is renal dysfunction in children with liver disease ? Is every renal dysfunction in liver disease Hepatorenal Syndrome (HRS) ?

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Hepato renal syndrome

Hepato-renal Syndrome

– What is it? Akash Deep, Director - PICU King’s College Hospital London


Questions to be answered

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?

Hepatorenal syndrome

Hepatorenal Syndrome

  • No data exists in paediatric literature

  • Adult data extrapolated.

Progress of cirrhosis

Progress of cirrhosis

Braveno iv status classification of cirrhosis

Braveno IV status classification of cirrhosis

1-year Outcome Probabilities













20 %





J Hepatology 2006;44:217-231

Natural history chronic liver disease

Natural History Chronic Liver Disease

Christensen et al

Scand J Gastro 1989;24:999-1006

J Hepatology 2006;44:217-231

Mortality prediction scores in cirrhosis

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)

Aki in liver disease

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?

Frequent causes of aki in cld

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

Kidney dysfunction in cirrhosis

Natural Progression of disease complications Renal dysfunction HRS


Stable patient with cirrhosis, PHT precipitating event HRS

Hepato renal syndrome

HRS, does it exist?



  • 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

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.

What is hrs

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


Hepato renal syndrome

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

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.

Characteristics of type 1 and type 2 hepatorenal syndrome

Characteristics of Type 1 and Type 2 Hepatorenal Syndrome

Mediators of splanchnic vasodilatation

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

Pathophysiology of cld





Renal vasoconstriction

Reduced GFR



Pathophysiology of CLD

Portal Hypertension

Peripheral and splanchnic arterial dilatation

Reduced effective blood volume

Activation of renin-angiotensin-aldosterone system

Sympathetic nervous system


Na retention


Water retention

Ascites and Oedema

Low urinary Na

Dilutional hyponatraemia

Plasma volume expansion


Schrier et al Hepatol 1988

Hepato renal syndrome

Bacterial DNA

LPS binding protein

Norfloxacin effect




Effects of SBP

Hepato renal syndrome

Gut 2008

Hepato renal syndrome

Compliance 




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

Renal autoregulation in hrs

Renal autoregulation in HRS

Renal blood flow in cirrhotics

Renal Blood Flow in cirrhotics

Splannchnic vasodilation

Decreased ITBV

Intra-hepatic resistance

Porto-renal reflex

Precipitating factors

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

ATNAKIWhat is what?

Hrs diagnosis of exclusion

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.

Differentiating one from the other

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 ????



  • 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.

Hepato renal syndrome

Creatinine >1 .5 mg/dl

463 patients over 6 years

Single centre

3 month


Implications of aki on transplantation

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

Why is hrs considered functional

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.



50% at 2, 20% at 6 months

1 vs 6 months respectively

Prognosis of hrs 1 and 2

Prognosis of HRS -1 and 2

  • Gines et al – 134 HRS patients

  • 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

  • Some of them did receive vasoconstrictor therapy

  • 3-month survival was 20% and 40% for type 1 and type 2 HRS, respectively.



  • 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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