Hepatorenal Disorders/ AKI in Liver disease Akash Deep Director-PICU King ’ s College Hospital

1. Hepatorenal Disorders/ AKI in Liver disease Akash Deep Director-PICU King’s College Hospital London Hepatorenal Syndrome Akash Deep Director-PICU King’s College Hospital London 0

2. Questions to be answered • Is every renal dysfunction in liver disease Hepato-renal Syndrome (HRS) • How common is renal dysfunction in children with liver disease ? • New Nomenclature for AKI /HRS in cirrhosis • HRS – pathogenesis, diagnosis • Prevention and Treatment strategies • What is the impact of kidney dysfunction in children with existing liver disease? – Prognosis

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

5. Kidney dysfunction in Cirrhosis Stable patient with cirrhosis PHT precipitating event HRS Natural Progression of Liver disease Complications(PHT) Renal dysfunction HRS

6. 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

7. 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) Deep A, Mathews C. Crit Care 2015

8. The CLIF Organ Failure score for diagnosis of ACLF Values at Study Enrolment. Highlighted area reflects the definition of each organ failure. Jalan, Pavesi et al. AASLD 2012

9. Frequent causes of AKI in CLD • Hypovolaemia: GI bleeding – (don’t forget the ulcer ) GI fluid losses (Lactulose, Terlipressin, PPI) Diuretics abuse/over use • Parenchymal disease: GN, Cryoglobulinaemia, IgA nephropathy – Biopsy? ATN/HRS • Drugs: CIN, NSAIDS, Abx, CNI post Tx • Intra Abdominal Hypertension • Hepato-renal Syndrome

10. 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)

11. 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.

13. Problems with Serum Creatinine • Muscle mass – decreased formation of creatinine from creatine • Increased tubular secretion of creatinine • Increased volume of distribution in cirrhosis that might dilute SCr • Bilirubin interferes with assays, with hyperbilirubinaemia masking increase in SCr • Age, Ethnic and Sex predilection • Liver synthetic function -production of creatinine is reduced by 50% • Cirrhotic patients for a given change in GFR have smaller and delayed changes in SCr

14. Urine output in Cirrhosis • Frequently oliguric with avid sodium retention yet a NORMAL GFR • Patients on diuretics – increased urine output

16. HRS-Diagnosis • 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.

17. Issues : Not even eGFR Creatine is produced in the liver Woman vs men Ethnic diversity Decreased muscle mass in cirrhosis Consider acute renal dysfunction in cirrhosis : RIFLE

18. Characteristics of Type 1 and Type 2 Hepatorenal Syndrome

20. 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

21. 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. 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

25. Renal auto-regulation in HRS

27. Differentiating the spectrum of AKI • 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 ????

31. Evidence of Tubular damage, TLR4 staining and Cellular infiltration in ACLF Shah et al. Liver International 2013

32. Urinary TLR4 is markedly increased in ACLF with renal failure

33. Treatment - General Prevention of Complications is Key Treat associated conditions • GI bleeding / hypovolaemia ( Surviving Sepsis guidelines, measurement of haemodynamics, problems associated with IAP ) • Infection • Diuretics / nephrotoxic drugs • Large volume ascites - TIPS / paracentesis • Adrenal insufficiency.

34. Vasopressin/ Terlipressin + albumin Increased blood volume Renal vasoconstriction Reduced GFR 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

35. RCT Terlipressin in Type I HRSSanyal A Gatroenterology 2008 :134:1360 1 mg 6 hrly vs placebo Albumin in both groups If no response (30% decrease in creat) at day 4- dose doubled to 2mg 6 hrly 14 days Rx : 56 in each grp Success defined as creatinine < 1.5 mg/dl for 48 hrs by Day 14 Rx success : 34 vs 12.5 % Best Predictor – Low baseline Serum creatinine Similar survival between grps HRS reversal improved 180 day outcome

36. Sanyal A Gatroenterology 2008 :134:1360

37. Do all patients treated with terlipressin respond ? 52% HRS respond to terlipressin (Meta-analysis: terlipressin therapy for the hepatorenal syndrome F. Fabrizi, V. Dixit & P. Martin APT 2006 24:935-44 ) • If not, can we identify those who will not respond ? • Side effect profile, implications for transplantation and development of new therapies.

38. Best response - SCr <3.0 mg/dl Highest baseline serum creatinine in a terlipressin responder - 5.6 mg/dl. No response – SCr > 7mg/dl Will there be a response in advanced disease ?????

39. terlipressin Hepatology 2011 placebo

40. Response to Terlipressin • Best response - SCr < 3 mg/dl or 3-5 mg/dl • Poor response - SCr > 7 Mg/dl • If no response by Day 4 - NO response thereafter • Sustained rise in MAP rather than only initial rise required for response • Therefore start treatment early!!!

41. Management of AKI in Cirrhosis patients Stage 1 AKI # Stage 2 and 3 AKI # Withdrawal of diuretics and volume expansion with albumin Close monitoring Remove risk factors, plasma volume expansion in case of hypovolemia Response YES NO Resolution Stable Progression Meets criteria of HRS Close follow up Further treatment of AKI decided case by case§ NO YES Specific treatment for other AKI phenotypes Vasocontrictors and albumin Angeli et al. J Hepatology 2015

42. What is my management strategy for HRS? • Differentiate between natural progression of liver disease with its complications versus acute deterioration of kidney function – HRS-1 or AKI • Fluid resuscitation • Treat raised IAP(Drain and replace with albumin) • Aggressive antibiotics (cephalosporins) • Recognise and treat precipitating factors • Once in ICU – Cardiac output monitoring, fluids, full organ support, prioritise transplant listing • Early vasoconstrictors

43. HRS at KCH RRT, TIPS, OLT

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

45. 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

46. Conclusion • Prevent infections, raised IAP(paracentesis) and iatrogenic factors • Vasoconstrictors seem to have a role • Unanswered questions –Relapse after stopping terlipressin, at what point should one be denied transplant ? • Can prolonged vasoconstrictors be used as bridge to transplant?

47. Children’s Critical Care Centre @ Kings Teams make things work akash.deep@nhs.net 46