1. HEPATORENAL SYNDROME

2. Acute Kidney Injury in Cirrhosis
Nearly 50% of patients with cirrhosis develop AKI
Causes
Pre-renal
Renal
Post-renal

3. Assessment of Kidney Function in Cirrhotics
In patients with cirrhosis, serum CR is unreliable due to low production rate of creatine by liver with reduced muscle mass
CR-based equations also unreliable (MDRD, CKD-EPI)
24-hour CR clearance more accurate but cumbersome
Gold standard: Iohexol or iothalamate clearance study

4. Hospitalized patients with cirrhosis
Chronic renal failure 1%
Acute Kidney Injury
19% (293/1544)
Post-renal
(obstructive)
(<1%)
Pre-renal
68% (437/639)
Intra-renal (ATN, GMN) 32% (224/712)
Figure 1. Prevalence and types of acute renal failure (ARF)/acute kidney injury (AKI) in hospitalized patients with cirrhosis. Percentages and numbers were obtained by adding up patients in the references cited. ATN= acute tubular necrosis; GMN=glomerulonephritis; HRS=hepatorenal syndrome. *Pre-renal azotemia
Volume-responsive*
66% (288/437)
Infection
Hypovolemia
Vasodilators
Other
Not volume-responsive
HRS type 1
25% (108/437)
HRS type 2
9% (41/437)
Garcia-Tsao G et al. Hepatology 2008

5. Hepatorenal Syndrome
A functional form of acute kidney injury (AKI) that results in severe renal vasoconstriction without evidence of structural kidney disease
Arroyo V. J Hepatol ’13

6. Hepatorenal Syndrome
A functional form of AKI that results in severe renal vasoconstriction without evidence of structural kidney disease
Type 2: Extreme expression of the spontaneous deterioration of circulatory function in cirrhosis, associated with refractory ascites & poor survival (months)
Arroyo V. J Hepatol ’13

7. Hepatorenal Syndrome
A functional form of AKI that results in severe renal vasoconstriction without evidence of structural kidney disease
Type 2: Extreme expression of the spontaneous deterioration of circulatory function in cirrhosis, associated with refractory ascites & poor survival (months)
Type 1: A form of acute renal failure that occurs secondary to a rapid deterioration of cardiocirculatory function closely associated in time with a precipitant & having an extremely poor survival (days or weeks)
Arroyo V. J Hepatol ’13

8. Diagnosis of Exclusion
Hepatorenal Syndrome
A functional form of AKI that results in severe renal vasoconstriction without evidence of structural kidney disease
Type 2: Extreme expression of the spontaneous deterioration of circulatory function in cirrhosis, associated with refractory ascites & poor survival (months)
Type 1: A form of acute renal failure that occurs secondary to a rapid deterioration of cardiocirculatory function closely associated in time with a precipitant & having an extremely poor survival (days or weeks)
Diagnosis of Exclusion
Arroyo V. J Hepatol ’13

9. Pathophysiology of HRS

10. Intrahepatic resistance
Cirrhosis
Intrahepatic resistance
Portal (sinusoidal) hypertension
Splanchnic/systemic vasodilatation
Effective arterial blood volume
Activation of neurohumoral systems
Renal vasoconstriction
HEPATORENAL SYNDROME

11. Wong F. Nat Rev. Gastoenterol 2012

12. Mechanisms Leading to Circulatory & Renal Dysfunction in Cirrhosis

13. Precipitants of Type 1 HRS
Infection
Spontaneous bacterial peritonitis (SBP)
Urinary tract infection
Cellulitis
Gastrointestinal hemorrhage
NSAID use
Large volume paracentesis without albumin
Adrenal insufficiency

14. HRS Diagnostic Criteria
Cirrhosis with ascites
Serum creatinine > 133 μmol/L (1.5 mg/dL)
No sustained improvement of serum creatinine (decrease to a level of 133 μmol/L or less) after at least 2 d of diuretic withdrawal and volume expansion with albumin; the recommended dose of albumin is 1 g/kg of body weight per day up to a maximum of 100 g/d
Absence of shock
No current or recent treatment with nephrotoxic drugs
Absence of parenchymal disease as indicated by proteinuria >500 mg/d , microhematuria (> 50 red blood cells per high-power field) and/or abnormal renal ultrasonography

15. Clinical Characteristics of HRS
Ascites Advanced liver disease Low mean arterial pressure (median 74 mmHg) Low serum Na (median 127 mEq/L) Low urinary output Do not rely on urine Na or urine sediment to differentiate HRS from ATN

16. Cumulative Survival of Patients with HRS Type 1 & HRS Type 2
Salerno et al, J Hepatol 2011

17. Prevention of AKI in Patients with Cirrhosis
Careful use of diuretics & lactulose
Albumin after large volume paracentesis
Avoid NSAIDs & aminoglycosides
Albumin & antibiotics for treatment of SBP
Primary prophylaxis of SBP with antibiotics
Antibiotics for 7 days at time of GI bleed
Pentoxifylline for severe alcoholic hepatitis
?Target mean arterial BP >60 mmHg

18. Patient with cirrhosis & acute renal failure
(abrupt rise in creatinine from baseline)
STOP diuretics, lactulose, vasodilators,
potential nephrotoxins
Investigate & initiate Rx (if present)
for infection, blood or fluid losses
Albumin IV (1 g/Kg of body weight QD or BID)
History of shock
(septic or hypovolemic), nephrotoxins, contrast
Treat as ATN
Granular or epithelial
casts in urine?
Urine biomarkers of
ATN?
Improvement in creatinine
No improvement in creatinine
Figure 4. Approach to the patient with cirrhosis and acute renal failure.
IV=intravenously; QD=every day; BID= twice a day; ATN=acute tubular necrosis; HRS=hepatorenal syndrome
* if compatible clinical characteristics, i.e. ascites, low mean arterial pressure and hyponatremia (see text for approach to patient with suspected HRS).
Continue therapy
No granular or epithelial
casts in urine?
Central venous pressure
>10 cmH2O
Treat as HRS

19. Treatment of Hepatorenal Syndrome

20. Intrahepatic resistance
Cirrhosis
Intrahepatic resistance
Portal (sinusoidal) hypertension
Splanchnic/systemic vasodilatation
Effective arterial blood volume
Activation of neurohumoral systems
Figure 8. Site of action of different therapies for hepatorenal syndrome. *ECAD stands for extracorporeal albumin dialysis, an experimental therapy that seems to improve HRS that probably acts by decreasing the amount of circulating vasodilators.
Renal vasoconstriction
HEPATORENAL SYNDROME

21. Intrahepatic resistance
Cirrhosis
Intrahepatic resistance
Portal (sinusoidal) hypertension
Splanchnic/systemic vasodilatation
Albumin
Effective arterial blood volume
Activation of neurohumoral systems
Renal vasoconstriction
HEPATORENAL SYNDROME

22. Intrahepatic resistance
Cirrhosis
Intrahepatic resistance
Portal (sinusoidal) hypertension
Splanchnic/systemic vasodilatation
Vasoconstrictors
Albumin
Effective arterial blood volume
Activation of neurohumoral systems
Renal vasoconstriction
HEPATORENAL SYNDROME

23. Vasoconstrictors in HRS
Midodrine
Terlipressin†
Norepinephrine
Rationale ++
+++
Route
Oral + octreotide*
IV slow bolus
IV infusion
Clinical Effectiveness
Uncontrolled
Phase III RCT
Phase II RCTs
Level of monitoring
No special needs
Monitored bed
ICU bed
Safety
GI, piloerection
GI, ischemia
Ischemia, GI, ARDS
Cost + ?
*Octreotide alone is ineffective; †Not FDA-approved

24. Overall Survival Following Terlipressin
or Placebo Treatment
Sanyal AJ, et al. Gastroenterology. 2008

25. Survival Following Terlipressin or Placebo Treatment – HRS Reversal
Sanyal AJ, et al. Gastroenterology. 2008

26. Patient Survival Probability Based on Response to Treatment with Terlipressin or Terlipressin/Albumin
Martin-Llahi M, et al. Gastroenterology. 2008

27. Predictors of HRS Reversal with Terlipressin
Treatment effect most dominant in patients with baseline CR 3-5 mg/dl
No patient with baseline CR >5.6 mg/dl responded to terlipressin
Sustained rise in mean arterial pressure required for HRS reversal
Boyer et al, J Hepatology 2011

28. Management of HRS Midodrine 7.5 mg PO TID, up to 12.5 mg PO TID
Octreotide 100 μg SC TID, up to 200 μg SC TID
Titrate to obtain increase in MAP ≥15 mmHg
Albumin (maintenance) g/day
Discontinue if serum albumin >4.0 g/dL
Stop treatment if no reduction in serum CR after 3 days or not <50% by day 7 of highest dose
?Norepinephrine infusion
If response, continue until Cr <1.5 mg/dL or 14 days

29. Terlipressin + Albumin versus Midodrine + Octreotide + Albumin
42 patients: 37 HRS type 1, 5 HRS type 2 + CR >2.5
Group A: IV infusion of terlipressin (3 mg/24 hr*)
Group B: Midodrine (7.5 mgs PO TID*) + octreotide (100 μg S/C TID*)
All patients albumin 1 g/Kg day 1, then g/day
*initial dose
Group A
(terlipressin) B
(Midodrine + Octroetide)
Improved renal function
75%
35.3%
↓ Serum CR to <1.5 mg/dl
13/24
(54%)
2/17
(11.8%)
%Responders among survivors
91.6%
54.5%
Cavallin M., et al. Hepatology 2011; LB#2

30. Intrahepatic resistance
Cirrhosis
Intrahepatic resistance
TIPS
Portal (sinusoidal) hypertension
Splanchnic/systemic vasodilatation
Effective arterial blood volume
Activation of neurohumoral systems
Renal vasoconstriction
HEPATORENAL SYNDROME

31. TIPS in HRS Reversal of HRS can occur
Recovery of kidney function can take weeks
Concerns
Uncontrolled hepatic encephalopathy
Worsening liver function
Heart failure
Caution with:
Ejection fraction <60%
High MELD

32. Renal Replacement Therapy in Patients with Cirrhosis and Acute Renal Failure
Published information scarce
In most studies, type 1 HRS not differentiated from ATN
Continuous hemofiltration >> intermittent hemodialysis
Pilot studies suggest albumin dialysis [Prometheus system or Molecular Adsorbents Recirculation System (MARS)] might be beneficial in type 1 HRS
Significant beneficial effect of MARS albumin dialysis on HE, no beneficial effect on survival
More studies needed
Arroyo, V. & Fernández, J. Nat. Rev. Nephrol. 2011

33. Intrahepatic resistance
Liver Transplant
Cirrhosis
Intrahepatic resistance
Portal (sinusoidal) hypertension
Splanchnic/systemic vasodilatation
Effective arterial blood volume
Activation of neurohumoral systems
Renal vasoconstriction
HEPATORENAL SYNDROME

34. Liver Transplant in Patients with HRS Type 1
In the terlipressin/albumin vs. albumin alone study (Sanyal et al, Gastroenterology 2008)
99 patients randomized to terlipressin (TRL) or placebo
35 patients (35%) underwent liver transplantation (LT)
Six-month
Survival
(%)
Boyer T, et al. Liver Transplantation 2011

35. Liver Transplant in Patients with HRS Type 1
Survival significantly better in those not transplanted who achieved HRS reversal vs. those who did not achieve reversal (47% vs. 4%) vs. survival of 97% in those undergoing LT
Six-month
Survival
(%)
Boyer T, et al. Liver Transplantation 2011