0. 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

1. 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

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

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

5. 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:

6. 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

7. 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

8. 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

9. 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)

10. 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.

12. 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

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

15. 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.

16. 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

17. 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

19. 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

20. 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

23. Compliance  IAP CVP PcwP Intra-abdominal pressure
Sugrue et al Arch Surg :1082
Malbrain CCM 2005;33:315
263 patients % increased IAP
Renal dysfunction:
32% with IAP elevated
14% with normal IAP
32% IAP > 12
40% IAP > 20

24. Renal auto-regulation in HRS

26. 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 ????

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

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

32. 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.

33. 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

34. 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

35. Sanyal A Gatroenterology 2008 :134:1360

36. 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.

37. 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 ?????

38. terlipressin
Hepatology 2011
placebo

39. 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!!!

40. 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

41. 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

42. 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

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

44. 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

45. 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?

46. Children’s Critical Care Centre @ Kings
Teams make things work
Children’s Critical Care Kings 46 46