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Hepatorenal syndrome

Hepatorenal syndrome

• Pathophysiology
• Diagnosis
• Natural history
• Management
Pathophysiology
Pathophysiology

Pathogenesis of HRS is complex


1. Macrovascular dysfunction (systemic vasodilatation, inadequate
cardiac output)
2. Microvascular dysfunction
3. Danger/inflammation signals from either pathogen- (PAMPs) or
tissue-associated (DAMPs) molecular patterns and
4. Direct tubular damage.
Pathophysiology

Pathology Mediators

Arterial vasodilatation in splanchnic Nitric oxide, carbon monoxide, &


circulation endogenous cannabinoids

Bacterial translocation &


pro-inflammatory cytokines
Peripheral & renal vasoconstriction, Renin–angiotensin system, sympathetic
sodium & water retention nervous system activation & arginine
vasopressin hypersecretion
Precipitating/triggering events Hypovolemia (excessive diuretic use,
diarrhea), GI bleed, SBP, LVP without
plasma expansion

Gines P et al. N Engl J Med 2009;361:1279


Wiest R et al. Hepatology 2005;41:422
Pathophysiology
Diagnosis
Diagnostic criteria of HRS
ICA criteria (1996)
• Major criteria
• Minor criteria

• HRS type 1
– Rapid progressive renal failure defined by doubling of the initial
serum creatinine concentrations to a level greater than
2.5 mg/dl in less than 2 weeks
– Often develops after a precipitating event
• HRS type 2
– Moderate renal impairment with a steady progressive course
evolving over weeks to months
– Develops de novo in patients with refractory ascites
Arroyo V et al. Hepatology 1996;23:164
Fixed value of creatinine in criteria - fallacies

• Under diagnosis of AKI/HRS


• Fixed threshold does not take into account the dynamic changes in
serum Cr that occur in the preceding days or weeks
• Severity of AKI/HRS could not be assessed
International Club of Ascites (ICA-AKI)
AKI in cirrhosis (2015)

Angeli P. J Hepatol (2015)


New diagnostic criteria for HRS-AKI
New classification of HRS subtypes

Angeli P et al, journal of hepatology 2019. vol 71


Criteria for AKI
Criteria for diagnosis of HRS-NAKI
Role of urinary biomarkers in AKI differential diagnosis

Fagundes C et al. J. Hepatol. 2012 ; 57 : 267–273


Belcher J M et al. Hepatol. 2014;60:622
Natural history & prognosis
Prognostic factors & outcome in HRS
• 105 cirrhosis with HRS
• Data collected from 1992 to 2001
• HRS diagnosed based on ICA criteria (1996)

• Most common etiology of cirrhosis Alcoholic 45 (43%)


• HRS type 1 & type 2 41 (39%) & 64 (61%)
• Median follow up 2.7 mo (0.1-68 mo)
• Outcome at end of follow up
– Death 78 (74%)
– Liver transplantation 15 (14%)
– Lost to follow up 7 (7%)
– Alive 5 (5%)
• Only HRS type & MELD score associated with independent
prognostic value
Alessandria C et al. Hepatol 2005;41:1282
Prognostic factors & outcome in HRS
Median survival
Type 1 = 1 mo
Type 2 = 6.7 mo

HRS type 1 had higher MELD, CTP scores, lower MAP,


higher norepinephrine, vasopressin, ANP & endothelin compared to HRS type 2

Alessandria C et al. Hepatol 2005;41:1282


Prognostic factors & outcome in HRS

Median survival
MELD >20 = 1 mo
MELD <20 = 8 mo

Alessandria C et al. Hepatol 2005;41:1282


Treatment

• Vasoconstrictor Therapy
• Transjugular Intrahepatic Portosystemic Shunt
• Extracorporeal Support Systems
• Liver Transplantation
Terlipressin in HRS

Dose increased to 2mg q6h if


Cr decrease <30%
• Multicenter double blinded RCT
• HRS type 1 diagnosed by
Terlipressin 1mg q6h ICA criteria (1996)
N =56
Albumin 25g/d • Treatment discontinued if
Albumin 100g on day 1 – Treatment failure
– Liver transplantation
Placebo – Adverse effects
N =56
Albumin 25g/d • If treatment success achieved,
discontinue or continue drug at
investigator discretion till
max. of 14 days

0 3d 14 d 180 d

Sanyal A J et al. Gastroenterology 2008; 134(5): 1360


Terlipressin in HRS
Study end points definition
Treatment success At day 14, Cr ≤ 1.5 mg/dl on 2 occasions 48h apart
No dialysis
No death
No recurrence of HRS before day 14
HRS reversal Cr ≤ 1.5 mg/dl during treatment
No dialysis
Partial response Cr decrease by 50% from baseline but >1.5 mg/dl
No dialysis
No recurrence of HRS
Treatment failure At day 14, Cr ≥ baseline after 7 days
Dialysis
Death

Sanyal A J et al. Gastroenterology 2008; 134(5): 1360


Terlipressin in HRS
Response
Terlipressin Placebo P value
n=56 n=56
Median treatment 6.3 d 5.8 d
duration
Treatment success 14 (25%) 7 (12.5%) 0.093
HRS reversal 19 (34%) 7 (12.5%) 0.008
Partial response & 16 (29%) 10 (18%) 0.181
treatment success
Treatment failure 31 (55%) 37 (56%) 0.247
One patient in each group had recurrence of HRS that reversed after retreatment
HRS reversal maintained in 19 at 30 days & in 12 at 60 days of follow up

Sanyal A J et al. Gastroenterology 2008; 134(5): 1360


Terlipressin in HRS
Survival benefit

No difference in survival No difference in survival at 180 d

Sanyal A J et al. Gastroenterology 2008; 134(5): 1360


Predictors of response (HRS reversal) to terlipressin

Sanyal A J et al. Gastroenterology 2008; 134(5): 1360


T.D. Boyer et al. J. Hepatol. 2011 ; 55 ; 315
Terlipressin in HRS

Dose increased to 2mg q4h if


Cr decrease <25%
• Multicenter randomized
non placebo non blinded
Terlipressin 1mg q4h • HRS type 1 & 2 diagnosed by
N =23
Albumin 40g/d adj. to CVP
ICA criteria (1996)
Albumin 1g/kg on day 1
• Treatment response =
reduction of Cr to <1.5 mg/dl
• Terlipressin continued till
response achieved or up to
N =23 Albumin 40g/d adj. to CVP
maximum of 15 days

0 3d 15 d 90 d

Martin-Llah´I M et al. Gastroenterology 2008;134:1352


Terlipressin in HRS
Response
Terlipressin + Albumin P value
albumin n=23
n=23
Mean treatment duration 7±5d 8±5d 0.741
Treatment response
Overall 10/23 (43.5%) 2/23 (8.7%) 0.017
HRS type 1 6/17 (35%) 2/18 (11%)
HRS type 2 4/6 (67%) 0/5
Survival at 3 mo 6/23 (27%) 4/23 (19%) 0.7
Recurrence of HRS seen in one patient in terlipressin group

Martin-Llah´I M et al. Gastroenterology 2008;134:1352


Terlipressin in HRS

Terlipressin 1mg q12h • Randomized placebo controlled


N =12
Albumin & FFP adj. to CVP
single blinded
• HRS type 1 diagnosed by
ICA criteria (1996)
• Reversal of HRS =
reduction of Cr to <1.5 mg/dl
Placebo
N =12 • Reversal of HRS in 5/12 (42%) in
Albumin & FFP adj. to CVP
terlipressin & none in placebo
• Survival at day 15 =
– 5/12 (42%) in terlipressin who
0 15 d
had HRS reversal survived
– None survived in placebo

Solanki P et al. Journal of Gastroenterology and Hepatology 2003;18,152


Terlipressin & noradrenaline in HRS

Dose increased to 2mg q6h if


Cr decrease < 1mg/dl
• Randomized non blinded
• HRS type 1 diagnosed by
Terlipressin 0.5mg q6h ICA criteria (1996)
N =23
Albumin 20g/d adj. to CVP • Reversal of HRS =
reduction of Cr to <1.5 mg/dl
• Survival assessed at day 15 & 30
Norad 0.5mg/h increased upto
3mg/h till MAP increase of
10mmHg
N =23 Albumin 20g/d adj. to CVP

0 3d 15 d 30 d

Singh V et al . J Hepatol 2012;56:1293


Terlipressin & noradrenaline in HRS
Terlipressin Noradrenaline P
n=23 n=23 value
Mean treatment duration 7.82 ± 3.12 d 9.3 ± 4.0 d
HRS reversal 9 (39%) 10 (43%) 0.764
Survival at Day 15 9 (39%) 11 (48%) 0.461

Singh V et al . J Hepatol 2012;56:1293


Terlipressin & noradrenaline in HRS
Dose increased to 2mg q6h if
Cr decrease < 1mg/dl
• Randomized non blinded
Terlipressin 0.5mg q6h • HRS type 2 diagnosed by
N =23
Albumin 20g/d adj. to CVP ICA criteria (2007)
• All patients had creatinine
Norad 0.5mg/h increased upto
3mg/h till MAP increase of between 1.5 to 2.5 mg/dl
N =23 10mmHg
Albumin 20g/d adj. to CVP • Reversal of HRS =
reduction of Cr to <1.5 mg/dl
0 3d 15 d 90 d

Terlipressin Noradrenaline P
n=23 n=23 value
Mean treatment duration 8.6 ± 3.2 d 8.7 ± 3.8 d
HRS reversal 17 (74%) 17 (74%) 1.0
Survival at Day 90 15 (65%) 14 (61%) 0.461
Ghosh S et al. Liver Int. 2013: 33: 1187
Midodrine, octreotide in HRS

• Retrospective study of 60 patients with type 1 HRS treated with


midodrine/octreotide compared with 21 untreated controls
• Dose of drugs titrated to achieve MAP increase of 15 mmHg
– Octreotide 100 to 200 µg TID subcutaneous
– Midodrine 5, 7.5, 10, 12.5 & 15 mg TID oral
• Outcome measured - HRS reversal & survival at 30 days

Treatment group Control group P value


n=60 n=21
Sustained reduction of Cr 24 (40%) 2 (10%) 0.01
Death at 30 days 26 (43%) 15 (71%) 0.03

Esrailian E et al. Dig Dis Sci (2007) 52:742


Midodrine, octreotide, TIPS in HRS
14 patients of HRS type 1
Oral midodrine 2.5mg/d +
octreotide 25µg/h infusion + albumin 50g/d

10 4
Responded to treatment No response at 7 days
(Cr <1.5 mg/dl for 3 d) Discontinued treatment

5
5
Did not undergo TIPS due to All died
Underwent TIPS
contraindications (0.5-2.3 mo)
(INR >2, bili >5, CTP >12, PVT,
active infection)

4 alive 3 underwent OLT & 3 died


(6-30 mo) alive
(6-27 mo)
Wong F et al. Hepatology 2004; 40: 55
Midodrine, octreotide, TIPS in HRS

Wong F et al. Hepatology 2004; 40: 55


TIPS in HRS
41 non transplant candidates with HRS

10 excluded
Bili >15, CTP >12, severe encephalopathy

31 eligible candidates for TIPS

14 of HRS type 1 underwent TIPS 17 of HRS type 2 underwent TIPS

• Median interval between first detection of renal failure to TIPS


– Type 1 HRS 2.2 (0.3-6) weeks
– Type 2 HRS 4 (1.5-5) weeks
• Type 1 HRS patients had more advanced degree of liver dysfunction, higher Cr &
lower GFR
• Post TIPS
– Ascites improved in 14 & completely resolved in 10
– Encephalopathy worsened in 8 & occurred de novo in 3
Brensing K A et al. Gut 2000;47:288
Post TIPS response

Brensing K A et al. Gut 2000;47:288


TIPS in refractory ascites & HRS type 2
• 70 patients with refractory ascites (excluding Type 1 HRS) randomized to
either TIPS (35) or LVP + albumin (35)
• Type 2 HRS
– TIPS 11 patients
– LVP + alb 15 patients

Survival probability among Probability of development of


HRS type 2 patients de novo HRS or progression from
type 2 to type 1 HRS

Gines P et al. Gastroenterology 2002;123:1839


MARS
(Molecular adsorbent recirculating system)
• Randomized multicenter study
• 13 HRS type 1 patients
• MARS 8 patients
• HDF 5 patients

• MARS treatment
• 6 to 8h session/day
• Max 10 sessions
• Stopped if bilirubin elevation
<1mg/dl between sessions
• HDF done if indicated

Mitzner S R et al. LiverTransplant 2000;6:277


MARS
(Molecular adsorbent recirculating system)
• Mean treatment sessions per patient
• MARS 5.25 ± 3.62
• HDF 3.2 ± 1.48

Mitzner S R et al. LiverTransplant 2000;6:277


MARS
RELIEF study
• 189 ACLF patients randomized to either MARS + SMT (95) or SMT alone (94)
• MARS therapy
– 8h per session
– Initial 1-4 sessions in first 4 days
– Later 3 sessions per week upto max of 10 sessions
– MARS stopped if Cr<1.5, HE gd <1, & stable bilirubin for 2 consecutive days

MARS+SMT

SMT alone

28 day survival probability


Benares R et al. Hepatology 2013;57:1153
Prometheus
(Fractionated Plasma Separation and Adsorption)
HELIOS study
• 145 ACLF patients randomized to FPSA (77) or
SMT (68)
• Treatment protocol
– Week 1 & 2 = 5 & 3 sessions
– Week 3 = add. 3 sessions if no improvement

FPSA SMT p
(n=77) (n=68) value
HRS type 1 27 (35%) 18 (26%)
HRS type 2 12 (16%) 13 (19%)
Change in Cr -0.2±1.7 -0.1±1.7 0.60
from baseline

Kribben A et al. Gastroenterology 2012;142:782


Liver transplantation

• Retrospective analysis of 726 LT patients


• 71 patients fulfilled HRS criteria (ICA 1996) pre transplant
Survival at 1 y Survival at 3 y
With HRS 80.3% 76.6%
Without HRS 90.7% 85.3%

Improvement in renal
function over first month

Lee J P et al. Liver Transplant 2012;18:1237


Liver transplantation
Predictors of survival

Lee J P et al. Liver Transplant 2012;18:1237


Combined liver-kidney transplantation

Charlton MR et al. Liver Transpl 2009;15:S1


Prevention of HRS
Role of pentoxifylline
• 70 patients with cirrhosis & ascites, creatinine clearance 40-80 ml/min,
Cr <1.5 mg/dl & absence of renal parenchymal disease
• Randomized to pentoxifylline or placebo for 6 months

• ITT analysis – 7 in pentoxifylline &


14 in placebo developed HRS (p 0.05)
Placebo • No difference in hospitalization rates
or mortality between 2 groups at
Pentoxifylline 6 months

Tyagi P et al. Eur J Gastroenterol Hepatol 23:210


Prevention of HRS
Role of pentoxifylline
• 101 patients of severe alcoholic hepatitis randomized to pentoxifylline
or placebo for 4 weeks
Pentoxifylline Placebo P
n=49 n=52 value
Deaths 12 (24.5%) 24 (46.1%) 0.037
Mean days to 29 ± 15.7 33.1 ± 27.3 0.63
death after
randomization
New onset HRS 4 (8.2%) 18 (34.6%) 0.0015

Pentoxifylline

Placebo

Akriviadis E et al. Gastroenterology 2000; 119:1637


Prevention of HRS
Primary prophylaxis of SBP
• 68 patients with cirrhosis & ascites with the following randomized
to norfloxacin (400mg OD) or placebo for 1 year:
– Ascitic fluid protein <1.5 g/dl
– Creatinine >1.2 mg/dl, serum sodium <130 mEq/L
– CTP >9, bilirubin >3 mg/dl

Fernandez J et al. Gastroenterology 2007;133:818


Prevention of HRS
Role of albumin in SBP
• 126 patients with ascites & SBP randomized to cefotaxime alone or
cefotaxime + albumin (1.5 g/kg on day 1 & 1 g/kg on day 3)

Sort P et al. N Engl J Med 1999;5:403


SUMMARY
Algorithm for workup and management of AKI
Claire Francoz et al Clin J Am Soc Nephrol 14, May, 2019
Summary

• HRS is not a purely ‘‘functional” entity


• Haemodynamic derangements, systemic inflammation, oxidative
stress and bile salt-related tubular damage may contribute
significantly
• Vasoconstrictors & albumin effective in less than 50% of HRS
patients
• Response to vasoconstrictors decrease with increasing severity of
renal dysfunction
• TIPS/ECAD – not better than vasoconstrictors
• Liver transplantation is the only effective treatment
• Prevention of HRS possible in few cases