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Acute Kidney Injury in Liver Disease: Incidence, Outcome, and Evolution in Pediatric and Adult Patients

This study explores the incidence, risk factors, and outcome of acute kidney injury (AKI) in liver disease, including acute liver failure, chronic liver disease, and post-liver transplantation. It examines the impact of AKI on liver transplantation and mortality rates.

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Acute Kidney Injury in Liver Disease: Incidence, Outcome, and Evolution in Pediatric and Adult Patients

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  1. 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 0

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

  3. 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

  4. AKI in liver disease • ALF • Chronic liver disease – ACLF • Post liver transplantation

  5. 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

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

  7. 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

  8. 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

  9. 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 ?

  10. AKI vs etiological classification of ALF

  11. 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

  12. HE STAGE vs AKI AKI No AKI

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

  14. 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

  15. Urine output in 1st week

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

  17. 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

  18. AKI in chronic liver disease/ Hepatorenal Syndrome (HRS)

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

  20. Rajiv Jalan, UCL

  21. 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

  22. 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

  23. 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

  24. 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)

  25. 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.

  26. King’s College Hospital Data 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] 36 survived (66%) 9 died post-LT (5%) 9 died post-LT (17%) Tassos, Dhawan, etal 224 patients with BA Listed for LT(1990-2009)

  27. Results-Risk factors associated with mortality

  28. 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

  29. Problems with Serum Creatinine and Urine Output • Serum Creatinine : • 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

  30. 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.

  31. 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

  32. 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

  33. 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

  34. 73% Creatinine >1 .5 mg/dl 463 patients over 6 years Single centre 46% 31% 15% 562 cirrhotics with AKI 3 month mortality

  35. 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)

  36. 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.

  37. 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 RRT, TIPS, OLT Ascites Schrier et al Hepatol 1988

  38. 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 • alpha-agonist, systemic vasoconstrictor • Octreotide • analogue of somatostatin, inhibitor of vasodilation.

  39. 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

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

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

  42. 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

  43. Sanyal A Gatroenterology 2008 :134:1360

  44. 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 The REVERSE Study : Change from Baseline in SCr Correlates with Survival at Day 90 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) 2 23 27 25 22 47 21 13 4 0.0 -80-<-60 -60-<-40 -40-<-20 -20-<0 0-<20 20-<40 40-<60 60-<80 80-<100 SCr decreasing SCr increasing Percent change from baseline to last SCr on the day of the last dose

  45. The REVERSE Trial: Overall Survival Up to Day 90 Probability Terlipressin Placebo 1.0 0.9 0.8 0.7 0.6 • 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, 0.5 0.4 Log-rank p=0.644 0.3 0.2 0.1 0 0 14 30 60 90 Days

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