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

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

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

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

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

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

The CLIF Organ Failure score for diagnosis of ACLF Organ System Score = 1 Score = 2 Score = 3 Liver (mg/dl) Bilirubin < 6 6 ≤ Bilirubin ≤ 12 Bilirubin >12 Kidney (mg/dl) Creatinine <2 Creatinine ≥2 <3.5 Creatinine ≥3.5 or renal replacement Brain (West-Haven) Grade 0 Grade 1-2 Grade 3-4 Coagulation INR < 2.0 2.0 ≤ INR < 2.5 INR ≥ 2.5 Circulation MAP ≥70 mm/Hg MAP <70 mm/Hg Vasopressors Respiratory: PaO2/FiO2 or SpO2/FiO2 >300 >357 ≤300 - > 200 >214- ≤357 ≤200 ≤214 Values at Study Enrolment. Highlighted area reflects the definition of each organ failure. Jalan, Pavesi et al. AASLD 2012

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

Epidemiology (Montoliu S, Ballesté B, Planas R, et al ) 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.

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

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

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.

Consider acute renal dysfunction in cirrhosis : RIFLE 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

Characteristics of Type 1 and Type 2 Hepatorenal Syndrome Course Precipitating Event History of Diuretic- Resistant Ascites Prognosis Type -1 HRS Precipitous doubling of serum creatinine > 2.5 mg/dl in < 2 weeks Present in > 50% of cases May or may not be present Without therapy- 90-day survival of 10% Type -2 HRS Gradually progressive to S Ccreat > 1.5 mg/dl Absent Always Present Median survival- 6 months

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

Compliance  IAP CVP PcwP 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 auto-regulation in HRS

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 ????

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

Urinary TLR4 is markedly increased in ACLF with renal failure

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.

Pathophysiology of CLD Portal Hypertension Vasopressin/ Terlipressin + albumin Peripheral and splanchnic arterial dilatation Reduced effective blood volume Increased blood volume Activation of renin-angiotensin-aldosterone system Sympathetic nervous system ADH Renal vasoconstriction Reduced GFR HRS Na retention & Water retention Ascites and Oedema Low urinary Na Dilutional hyponatraemia Plasma volume expansion Ascites Schrier et al Hepatol 1988

RCT Terlipressin in Type I HRS Sanyal 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

Sanyal A Gatroenterology 2008 :134:1360

Do all patients treated with terlipressin respond 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.

Will there be a response in advanced disease ????? 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 ?????

terlipressin Hepatology 2011 placebo

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!!!

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

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

RRT, TIPS, OLT HRS at KCH Noradrenaline (Max 0.5 mcg/kg/min) Add Terlipressin (1mg 6 hourly or infusion) (Monitor ischaemic side effects) Double Terlipressin 2mg Stop Terlipressin RRT, TIPS, OLT

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

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

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?

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