1. 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

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. 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

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 : (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
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

11. 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

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
AKI – 32%
NO AKI – 62.5%

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

24. 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

25. 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 %
(Moreau R, Durand F, Poynard T, et al)

26. 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.

27. King’s College Hospital Data
224 patients with BA Listed for LT( )
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

28. 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

29. 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

31. 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

33. 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.

34. 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

35. 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

36. 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

37. 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

38. 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)

41. 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.

42. 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

43. 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.

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

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

46. 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

47. 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

48. Sanyal A Gatroenterology 2008 :134:1360

49. 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

50. The REVERSE Trial: Overall Survival Up to Day 9014 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

51. 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 : )
If not, can we identify those who will not respond ?
Side effect profile, implications for transplantation and development of new therapies.

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

53. terlipressin
Hepatology 2011
placebo

54. 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

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

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

58. 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)

59. 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

60. 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

61. 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

62. 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

63. 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)

64. 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?

65. Children’s Critical Care Centre @ Kings
Teams make things work
Children’s Critical Care Kings 64 64