Hepato-renal Syndrome

1. Hepato-renal Syndrome – What is it? Akash Deep, Director - PICU King’s College Hospital London 0

2. 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?

3. Hepatorenal Syndrome • No data exists in paediatric literature • Adult data extrapolated.

4. Progress of cirrhosis

5. Braveno IV status classification of cirrhosis 1-year Outcome Probabilities STAGE 1. NO VARICES NO ASCITES 1% STAGE 2. VARICES NO ASCITES 3.4% DEATH STAGE 3. ASCITES VARICES 20 % STAGE 4. BLEEDING +/- ASCITES 57% J Hepatology 2006;44:217-231

6. Natural History Chronic Liver Disease Christensen et al Scand J Gastro 1989;24:999-1006 J Hepatology 2006;44:217-231

8. 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)

10. 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?

11. 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

12. Kidney dysfunction in cirrhosis Natural Progression of disease complications Renal dysfunction HRS V/s Stable patient with cirrhosis, PHT precipitating event HRS

13. HRS, does it exist?

14. 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)

15. 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.

16. 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

17. 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

18. 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.

19. Characteristics of Type 1 and Type 2 Hepatorenal Syndrome

22. 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

23. NSAID Aminoglycosides Diuretics Sepsis Renal vasoconstriction Reduced GFR NaCl HRS Pathophysiology of CLD Portal Hypertension Peripheral and splanchnic arterial dilatation Reduced effective blood volume Activation of renin-angiotensin-aldosterone system Sympathetic nervous system ADH Na retention & Water retention Ascites and Oedema Low urinary Na Dilutional hyponatraemia Plasma volume expansion Ascites Schrier et al Hepatol 1988

24. Bacterial DNA LPS binding protein Norfloxacin effect TNF IL6 NO Effects of SBP

27. Gut 2008

28. Compliance  CVP PcwP 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

29. Renal autoregulation in HRS

31. Renal Blood Flow in cirrhotics Splannchnic vasodilation Decreased ITBV Intra-hepatic resistance Porto-renal reflex

33. 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

34. ATNAKIWhat is what?

35. 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.

36. 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 ????

37. 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.

38. Creatinine >1 .5 mg/dl 463 patients over 6 years Single centre 3 month mortality

39. 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

40. 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.

41. Prognosis 50% at 2, 20% at 6 months 1 vs 6 months respectively

42. 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.

43. 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 ????