Hepatorenal Disorders/ AKI in Liver disease Akash Deep Director-PICU King’s College Hospital, London Chair Renal/CRRT section European Society of Paediatric and Neonatal Intensive Care (ESPNIC) Hepatorenal Disorders/ AKI in Liver disease Akash Deep Director-PICU King’s College Hospital London

DISCLOSURE Research grant from Mallinckrodt Pharmaceuticals  – Terlipressin in paediatric HRS Taskforce member for ESPNIC/SCCM joint septic shock guidelines – Adjunctive therapies in septic shock

Overview Is AKI in liver disease = AKI in non-liver disease patients ? AKI in liver disease – ALF, ACLF, post-liver transplantation Is every renal dysfunction in liver disease Hepato-renal Syndrome (HRS) ? New Nomenclature for AKI /HRS in cirrhosis HRS – pathogenesis, diagnosis, prevention and treatment strategies

AKI in liver disease ALF Chronic liver disease – ACLF Post liver transplantation

Mechanisms of AKI in ALF Multifactorial Pre-renal AKI Acute tubular necrosis due to profound hypovolemia and hypotension Direct drug nephrotoxicity (paracetamol, NSAIDs) Hepatorenal syndrome Intra-abdominal hypertension (IAH) and development of abdominal compartment syndrome

Pathogenesis of AKI in ALF Arterial vasodilatation (‘’VASOPLEGIA’’) Decreased SVR High Cardiac Output Renal Auto-regulation becomes Pressure Dependent - Intra-renal Vasoconstriction

Akash Deep, Romit Saxena Hepatorenal Disorders/ AKI in Liver disease Acute Kidney Injury (AKI) in Acute Liver failure – results from King’s prospective pALF registry Akash Deep, Romit Saxena King’s College Hospital, London Hepatorenal Disorders/ AKI in Liver disease Akash Deep Director-PICU King’s College Hospital London 6 6

Aim : Incidence, aetiology, risk factors, outcome and evolution of acute kidney injury (AKI) in PALF Definition of pALF: US paediatric acute liver failure group Time period : 2002-2016 (125 children) Prospective paediatric Acute liver failure registry maintained at King’s College Hospital, London. Demographic, clinical, biochemical details and ICU course for the first 7 days of stay AKI defined by KDIGO classification

ALF specific questions related to AKI How many children with ALF with same severity of illness and same supportive measures survive without transplant when they had an AKI vs when they did not have an AKI – rate of spontaneous regeneration ( avoidance of transplant) How many of those with AKI successfully proceed to transplant vs those without AKI? How many of those with pre-transplant AKI continue to have AKI post- transplant ?

AKI vs etiological classification of ALF   AKI in 1st week Total no AKI AKI (KDIGO) ETIOLOGY Infection 10 8 18 Sepsis 1 Metabolic 13 12 25 Hematological 4 3 7 Ischemic hepatitis Paracetamol overdose Autoimmune 2 Wilsons Cryptogenic 28 20 48 66 57 123

Any stage AKI developed in 45.5% of pALF patients vs 26.9% in AWARE HIGHEST KDIGO   Frequency Percent Valid Percent Cumulative Percent Valid 74 32.9 59.7 1 17 7.6 13.7 73.4 2 13 5.8 10.5 83.9 3 20 8.9 16.1 100.0 Total 124 55.1 Missing System 101 44.9 225 Severe AKI – 26.6% 13.7% Severe AKI -26.6% Severe AKI in AWARE – 11.6% Any stage AKI developed in 45.5% of pALF patients vs 26.9% in AWARE

HE STAGE vs AKI AKI No AKI

Mortality in pALF group – 23.1% Mortality in pALF with AKI – 37.3% Mortality in pALF with no AKI – 21.1%

Evolution of AKI in pALF over 7 days AKI (at arrival to PICU : 40/56 (71.4%) 16 patients ( 8 patients on Day-2 and another 4 on day 3) developed new onset AKI in the first week of admission , which also subsequently resolved Max AKI (86%) developed within 48 hours of admission to PICU ( need for pre-PICU resuscitation) None required RRT post- discharge

Urine output in 1st week

Impact of AKI on requirement of liver transplant Patients listed for transplant… delisted as improved --- spontaneous regeneration AKI – 32% NO AKI – 62.5%

Preliminary Conclusions (from the data analysed so far) Significant number of children with pALF develop AKI – 45% Maximum AKI in 1st 48 hours – AKI present pre-admission and need for pre-PICU resuscitation Presence of AKI is dependent on the aetiology of ALF- cryptogenic disease, paracetamol overdose and underlying metabolic liver disease AKI seems to affect spontaneous regeneration of hepatocytes trending more towards liver transplantation and increases mortality Prediction model needs to be generated and tested

AKI in chronic liver disease/ Hepatorenal Syndrome (HRS)

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

Rajiv Jalan, UCL

Mortality Prediction Scores in Cirrhosis Common ITU and liver disease severity scores – PIM2, Child Pugh Score, MELD, SOFA, APACHE(Deep A, Mathews C. Crit Care 2015) CLIF-C : Chronic liver failure Consortium CLIF-C ACLF CLIF-C ADs

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.

King’s College Hospital Data 224 patients with BA Listed for LT(1990-2009) 54 developed ACLF (24%) PELD 8.11[1.6 to 10.6] 170 had gradual deterioration (76%) PELD 6[0.4 to 8.6] 12 recovered (22%) PELD 5.8[3.5 to 8.5] 10 died pre-LT (19%) PELD 6.4[3.5 to 9.5] 11 died pre-LT (6%) PELD 6[0.6 to 9.5] 44 LT (81%) PELD 6.4[-0.8 to 9.3] 159 LT(94%) PELD 5.2[-2.5 to 9.6] 9 died post-LT (5%) 9 died post-LT (17%) 36 survived (66%) Tassos, Dhawan, etal

Results-Risk factors associated with mortality ACLF Sepsis 47% p=0.997 GI bleeding 43% p=0.307 HRS 11% p=0.000 CVVH Exchange Tx 5% p=0.0046 HE 30% p=0.214 Ascites 33% p=0.070 PICU 61% p=0.012 Ventilation

Results Predictors of mortality Survival analysis In a logistic regression model predictors of mortality were: -serum albumin (p=0.01) -INR (p=0.01) - HRS (p=0.07) ACLF in children with BA has -high mortality -affects mostly <1yr olds Sepsis & GI bleeding are the main precipitating events Renal decompensation has a poor prognosis Prevention of precipitating factors and early identification of ACLF may improve outcome

Problems with Serum Creatinine and Urine Output Serum creatinine – liver synthetic function / muscle mass Liver synthetic function- creatinine production reduced by 50% Muscle mass- decreased formation of creatinine from creatine Increased tubular secretion of creatinine Increased volume of distribution in cirrhosis might dilute SCr Urine Output : 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

2013 Criteria Pre-2013 Type -1 HRS – doubling of serum creatinine to > 2.5 mg/dL in < 2 weeks Type-2 HRS – gradual rise in serum creatinine > 1.5 mg/dL

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

Creatinine >1 .5 mg/dl 463 patients over 6 years Single centre 73% Creatinine >1 .5 mg/dl 463 patients over 6 years Single centre 46% 31% 15% 562 cirrhotics with AKI 3 month mortality

Differentiating the spectrum of AKI Specific aetiology of AKI important for both prognostic and therapeutic purposes Various biochemical and clinical criteria used historically HRS and ATN difficult to differentiate However, these criteria do not rule out the possibility of renal parenchymal damage Role of biomarkers proposed (NGAL, KIM-1, L-FABP)

Treatment - General Prevention of Complications/precipitating event 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 RRT, TIPS, OLT Ascites Schrier et al Hepatol 1988

Treatment Vasoconstrictors to improve circulatory function: Vasopressin analogues Ornipressin- improvement of renal function but limited by ischemic complications Terlipressin - lesser incidence of ischemia Midodrine alpha-agonist, systemic vasoconstrictor Noradrenaline Octreotide analogue of somatostatin, inhibitor of vasodilation.

Terlipressin in Children for HRS Dose in children – Bolus - 20 mcg/kg - 4-6 hourly Infusion – Up to 10 -20mcg/kg/hour Long acting synthetic vasopressin analogue Half life – 6 hours Max serum concentration – 120 minutes Release over sustained period – bolus/infusion

Diarrhoea – gut ischaemia Blue fingers and toes Myocardial events Diarrhoea – gut ischaemia

CT abdomen in a child with ACLF and HRS on Terlipressin Intramural air and gangrenous bowel CT abdomen in a child with ACLF and HRS on Terlipressin

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

The REVERSE Study : Change from Baseline in SCr Correlates with Survival at Day 90 Change from baseline in SCr strongly correlates with survival, Survival correlates with decrease in SCr even in the absence of CHRSR 60% of subjects with a significant decrease in SCr did not achieve CHRSR but still had a higher survival rate compared to those subjects without a decrease in SCr 90.0 80.0 70.0 60.0 r2=0.938 p<0.0001 50.0 % Alive 40.0 30.0 20.0 TOTAL(n) 10.0 20 10 2 CHRSR(n) 23 27 25 22 47 21 13 4 2 0.0 -80-<-60 -60-<-40 -40-<-20 -20-<0 0-<20 20-<40 40-<60 60-<80 80-<100 SCr decreasing SCr increasing Change from baseline in SCr strongly correlates with survival Survival correlates with SCr even in the absence of confirmed HRS reversal Subjects with a significant decrease in SCr, even in the absence of achieving confirmed HRS reversal, have improved survival compared to those subjects without a decrease in SCr 60% of subjects with a significant decrease in SCr did not achieve CHRSR but still had a higher survival rate compared to those subjects without a decrease in SCr Percent change from baseline to last SCr on the day of the last dose

The REVERSE Trial: Overall Survival Up to Day 90 14 30 60 90 Days Log-rank p=0.644 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Terlipressin Placebo Probability 90 day overall survival > 50%, Approximately 30% of subjects received liver transplant – terlipressin as a bridge Transplant free survival up to 90 days was 25-30% for both treatment arms, 90 day overall survival, over 50%, higher than generally previously reported Approx 30% of subjects received liver transplant, the majority within 30 days (mean time to transplant 17 days) The majority of enrolling study sites were experienced centers specializing in liver disease, associated with liver transplant programs Improved care of ESLD overall Transplant free survival up to 90 days was approx 25-30% for both treatment arms, similar to that previously reported

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 Therefore start treatment early and consider stopping in case of no response by day-4/5 !!! Sustained rise in MAP rather than only initial rise required for response

Maximum daily and mean daily doses of terlipressin were lower in the infusion group

Terlipressin given by continuous infusion is better tolerated than boluses AND is more effective at lower doses

Comparative costs Drug Strength Presentation Cost Cost/unit Terlipressin 1mg 1 x 5 vial £69.95 £13.99/ 1mg vial Vasopressin 20units/ml (2ml) 1 x 10 (2ml amps) £320.50 £32.50/ vial (40units/2ml) 20units/ml (1ml) 1 x 25 (1ml amps) £133 £5.32/ vial (20units/ml) Noradrenaline 1:1000 (2ml) 1 x 5 (2ml amp) £9.50 £1.90/vial (2ml) 1:1000 (4ml) 1 x 10( 4ml amp) £19 £1.90/vial (4ml) 1:1000 (8ml) 1 x 10 (8ml amp) £45 £4.50/vial (8ml)

Role of vaptans (Vasopressin receptor antagonists) Portal Hypertension Tolvaptan, Lixivaptan, Conivaptan, Satavaptan Peripheral and splanchnic arterial dilatation Reduced effective blood volume Activation of renin-angiotensin-aldosterone system Sympathetic nervous system Non-osmotic release of Vasopressin Renal vasoconstriction Reduced GFR HRS Na retention & Water retention Ascites and Oedema Low urinary Na Dilutional hyponatraemia Vasopressin receptor antagonists Blocks V2 receptors Solute free diuresis Plasma volume expansion Antagonism of V2 – increased AVP levels- unopposed vasoconstrictor activity of V1 receptors – splanchnic vasoconstriction Ascites

Other treatments TIPS – Transjugular Intrahepatic porto-systemic shunts Renal Replacement therapy – Volume overload, intractable metabolic acidosis, and hyperkalemia - CRRT/MARS – Delay in RRT - > 90% mortality Liver Transplantation ( Not all recover kidney function) – Poor prognosis with HRS post-transplantation Combined Liver-kidney Transplantation if RRT > 8 weeks

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 HRS-2 Early use of appropriate antibiotics Fluid resuscitation Treat raised IAP (Drain and replace with albumin) Recognise and treat precipitating factors Once in ICU – Cardiac output monitoring, fluids, full organ support, prioritise transplant listing Early vasoconstrictors and albumin

RRT, TIPS, OLT HRS at KCH Noradrenaline (Max 0.5 mcg/kg/min) Add Terlipressin infusion 10 mcg/kg/hour (Monitor ischaemic side effects) Double Terlipressin if no response in 48 hours Stop Terlipressin if no response RRT, TIPS, OLT

Future Are there new therapies on the horizon? What can be done to improve the prognosis of these patients before new therapies are available ? Biomarkers to differentiate HRS from ATN – NGAL, IL-18 Experimental drugs – Partial vasopressin(V1a)receptor agonists Serelaxin-recombinant form of the human peptide relaxin-2 Reduce Inflammation and organ failure in ACLF/HRS Plasmapheresis: remove inflammatory and vasoactive mediators; decrease SIRS and mortality Mesenchymal stem cell transplantation: reducing systemic inflammation and improving organ function Granulocyte colony-stimulating factors – stimulation of innate immunity- improves liver function, improves survival Paediatric specific criteria for AKI in ACLF - ESPNIC study on ACLF in the pipeline ( King’s, France and Netherlands)

Conclusion AKI can occur in ALF, ACLF and post-liver transplant ACLF is a/w MSOF including AKI/HRS Criteria to diagnose AKI in cirrhosis not the same as for non-liver AKI – none in paediatrics Not every AKI in cirrhosis is HRS – Role of biomarkers HRS is extremely rare in paediatrics and carries a very bad prognosis Prevent precipitating factors Vasoconstrictors seem to have a role Unanswered question - At what point should one be denied transplant ? Can prolonged vasoconstrictors work as bridge to transplant?

Children’s Critical Care Centre @ Kings Teams make things work akash.deep@nhs.net Children’s Critical Care Centre @ Kings 64 64