OLD and NEW definition of Hepatorenal syndrome , EASL 2018 +AASLD 2012 guidelines , pathophysiology mechanisms , Precipitants of HRS , prevention and treatment of HRS , new drugs for HRS on lane , few evidences .

1. HEPATORENAL SYNDROME
- Dr.Gowthaman DM CCM
AIIMS BHOPAL

2. OVERVIEW
DEFINITION
CAUSES
PATHOPHYSIOLOGY
HOW TO PREVENT
HOW TO TREAT
ANYTHING NEW ???

3. 2012
2018

4. 2020 september

5. DEFINITION
Chronic or Active Liver disease with Failure + portal hypertension .
AKI – Increase in creat of 0.3 mg / dl in 48 hrs OR 50 % rise in 7 days
OR rise > 1.5 mg / dl
With, 1. No Shock
2. No Nephrotoxic drug usage
3. Normal kidney size
4. No other Renal parenchymal disease
5. No improvement , despite stopping diuretics & volume
expansion with ALBUMIN 1g / kg/ day upto 100 g/ day for atleast 2 days .
6. Urine RBC < 50 / hpf + Protein < 500 mg / day .

6. 1. Less severe
2. associated with
REFRACTORY
ASCITES .
1. Very Severe
2. 2 fold increase in Creat
( 2.5 mg/dl )
3. in < 2 weeks
4. 50 % drop in Cr.
Clearance
TYPES
TYPE 1 TYPE 2

7. Fulminant Liver failure
with HRS
Cirrhosis + HRS 1 or 2
superimposed on CKD /
AKI
TYPE 3 TYPE 4

8. TYPE 1 : HRS-AKD
Egfr< 60 , for < 3 mnths +
absence of other causes of AKI .
Increase in creat <50 % of last
value within 3 months .
TYPE 2 : HRS-CKD
egfr < 60 for > 3 months +
absence of other causes .
Increase in creat > 0.3 mg/
dl in 48 hrs OR >= 1.5 mg/dl
from baseline within 3
months
AND
Other criteria as per old
definition .
TYPE 1a : < 1.5 mg/dl
TYPE 1b : > 1.5 mg/dl
NEW DEFINITION OF HRS BY ICA
HRS – AKI HRS-NAKI

9. CAUSES
 Cirrhosis Liver
 Alcoholic Hepatitis
 Metastasis of Liver
 Acute Liver Failure
 Fulminant Liver failure of ANY CAUSE

10. MAJOR PATHOPHYSIOLOGICAL
MECHANISM OF HRS ? ? ? ? ? ? ? ? ? ?
HYPOVOLEMIA + SPLANCHNIC
VASODILATION + RENAL
VASOCONSTRICTION

11. HRS DOESNOT OCCUR IN ? ? ? ? ?
Primary Biliary Cholangitis
Reason ? ? ? ? ?
Natriuresis RENAL Vasodilator
BILE SALTS retention
GFR maintained

12. OTHER MECHANISMS:
CIRRHOTIC Cardiomyopathy
Systemic INFLAMMATION
Hepato – Adrenal Syndrome
Cholemic Nephropathy
Intraabdominal HYPERTENSION
Hepatorenal reflex Hypothesis

13. PATHOPHYSIOLOGY
LIVER FAILURE
Vasodilators ( NO, PG , CO )
Splanchnic Vasodilation
Total Vasc Resistance
EABV RAAS, SNS , AVP
AMMONIA Arginine metabolism Nitric oxide
Renal Hypoperfusion

14. RENAL
HYPOPERFUSION
2. Systemic inflammation
IL-6, IL-8,TNF-A,
PAMP, DAMP
Vasodilators ( NO)
Renal
VASOCONSTRICTION
RENAL HYPOPERFUSION
3.Hepato adrenal syndrome
RAI in cirrhosis
Low MAP, High renin+Norad
Cortisol productn , HPA axis dysfuntion

15. OTHER MECHANISMS:
4. Cholemic Nephropathy
Bile acids toxic to
tubules + obstructing
tubules
AKI  HRS
5. Raised IAP
Renal hypoperfusion

16. VASODILATORS

17. PRECIPITANTS OF HRS
TRIGGERS HRS
1. Bacterial infection
2. SBP
3. Acute GI BLEEDING
4. Diuretic induced
azotemia .
HYPOVOLEMIA – Culprit

18. CAN I PREDICT SEVERITY OF HRS ? ? ?
Difficult  But Why ? ? ?
Urea , Creat  Poor indicators .
Liver disease  Less urea ,
creatinine production
Falsely low Creat :
1. Restricted protein , meat intake
.
2. Low muscle mass
Even creatinine of 1 -
1.3 can have GFR as
low as 20 -30 ml /min .
BUN/ Creat ratio is
unreliable .

19. HOW CAN I DIAGNOSE HRS ? ? ? ? ?
Clinically only  Diagnosis of exclusion.
No specific tests available
It should follow HRS DEFINITION criteria

20. DD OF HRS IN LIVER DISEASE PATIENT ? ? ? ?
Sepsis  ATN 
GI Bleed  Hypotension  ATN
Antibiotics in CLD patient  Aminoglycoside  ATN
Analgesics in CLD patient  NSAIDS  ATN
CT scan in CLD patient  CONTRAST  ATN
HRS VS ATN
PSEUDO HRS

21. HRS VS PRE RENAL AZOTEMIA
1. GI Fluid Loss/ Large Vol Paracentesis
2. GI Bleeding ( varices )
3. Diuretics  hypovolemia .
4. Blirubin induced vomiting  Hypovolemia
5. Anti HTN drugs, Beta blockers in a
worsening cirrhosis patient  Hypotension
DD OF HRS IN LIVER DISEASE PATIENT ? ? ? ?
HYPOTENSION

PRERENAL

22. PREVENTION
PRECIPITANTS :
1.Infection .
2.Large Volume paracentesis without
albumin replacement ( >4-5 L) .
3.SBP ( 30 % ) .
HOW TO PREVENT :
1. Prophylactic Antibiotics ( SBP,sepsis)
2. Albumin infusion + paracentesis .
3. Avoid nephrotoxins/ Diuretics .
ALBUMIN : Volume expansion , endothelium funtion stabilise ,
anti oxidant , anti inflammatory .

23. MANAGEMENT
• Medical drugs .
• TIPS
• MARS
• RRT
• Liver transplant
• LK transplant

24. TREATMENT
VASOCONSTRICTORS + ALBUMIN + Reversing
precipitant factors .
Measures to prevent variceal bleeding .
Volume resuscitation + Withdraw DIURETICS .
20 % ALBUMIN 1g / kg / day for 2 days .
Stop all nephrotoxins
Hold Beta blockers temporarily ( to maintain cardiac
output , if low C.O ) .

25. Acute increase in creat > 0.3 mg / dl
Increase < 2 fold Increase > 2 fold
AKI – 1 A AKI – 1 B AKI 2 -3
Risk factor management
+ Monitor 48 hrs
Resolution
Monitor
NO
YES
ALBUMIN 1 g /kg - 2 days
Resolution
NO

26. Urine biomarkers
Consistent with
ATN
Consistent with
HRS
Not available /
Non -diagnostic
RRT
Vasoconstrictor
+ Albumin

27. ALBUMIN IN HRS
DOSE :
1 g / kg /day for 2 days .
MAXIMUM DOSE : 100 g / day
Daily maintanence : 20 – 60 g / day
When should I stop ???
Continue till Terlipressin is stopped / kidney function
improves .
ALBUMIN: Anti oxidant+ Anti inflamm + Volume expand + inotropic

28. VASOCONSTRICTORS
1.TERLIPRESSIN
2.Noradrenaline
3.Octreotide + Midodrine
4.Vasopressin + Albumin
GUIDELINES :
AASLD  Norad ( 2012 )
EASL  Terlipressin ( 2018 )

29. FACTS ABOUT TERLIPRESSIN
DOSE :
1 mg 4 - 6 hrly  upto 2 mg 4 – 6 hrly .
MAXIMUM DOSE : 12 mg / day
When should I increase the dose ??
 If creat doesnot drops by 25 % at day 3 of
therapy .
Max : 14 days .

30. CONTD…..
Should I give BOLUS / INFUSION ???
 BOLUS : in ward settings ( More side effects )
 INFUSION : in ICU settings ( less side effects )
SIDE EFFECTS :
 Ischemia,Gangrene ( peripheries / mesentric / Cardio )
When should I stop Terlipressin :
 Till creat drops < 1.5 mg/ dl , Urine increases, Sodium rises,

31. OTHER VASOCONSTRICTORS
NORADRENALINE :
DOSE : 0.1 – 0.7 mics/ kg /min . ( Target MAP  Atleast 10 mm Hg increase )
OCTREOTIDE + MIDODRINE :
OCTREOTIDE  Somatostatin analogue : Splanchnic constrictor
MIDODRINE  Alpha 1 agonist .
DOSE : ( Max : Give for 14 days )
1. OCTREOTIDE : 100 mics s/c TDS MAX DOSE : 200 mics s/c TDS ( WARD
setting) .
25 – 50 mics / hour infusion ( ICU setting )
2. MIDODRINE : 2.5 – 5 mg P/O TDS MAX DOSE: 15 mg TDS
S.E : Bradyarryhtmia, diarrhea , hyperglycemia .
DURATION : Max 2 weeks ( Till HRS reversal / Liver transplant )

32. EVIDENCES
which vasoconstrictor has strong evidence ? ? ? ? ?? ? ?
Should we give Albumin + Norad ???
What about other vasoconstrictors results ? ? ?

33. 2003 - 2020

34. AASLD -2012 – ON ALBUMIN + OTHER
VASOPRESSORS

35. EASL – 2018 – ON VASOCONSTRICTORS

36. OTHER MODALITIES . . . . . . .
MARS :
Molecular absorbent Recirculatory systems
Removes ALBUMIN-BOUND toxins .
TIPS :
Transjugular intrahepatic porto systemic shunt
RRT :
As a bridge to transplant .

37. ULTIMATE TREATMENT
LIVER TRANSPLANT
+/- Kidney Transplant

38. ANYTHING NEW ? ? ? ?
SERELAXIN :  RHR-2  Phase 3 trial .
 Renal vasodilator + RVR  Increase perfusion .
 Anti TNF-alpha , anti inflam.
 in Alcoholic hepatitis .

SERELAXIN :
PENTOXYPHYLLINE :
ANG-2

39. REFERENCES:
AASLD GUIDELINES 2012
EASL GUIDELINES 2018
UPTODATE
BRITISH MEDICAL JOURNAL
PUBMED
JOURNAL OF HEPATOLOGY

40. THANK YOU
for patient listening………