Hepatorenal syndrome

Samir MohindraManav Wadhawan

• Progressive weakness for 5 months• Productive cough , low grade fever X 20 days • Progressive ascites with decreasing urine output x 15 daysAltered sensorium x 2 days

No GI Bleed/Jaundice

• H/o Treatment with multiple i.v. antimicrobials prior to admission for LRTI• No H/O:• Prior surgery• Skin rash• Blood transfusion• Unknown drugs

O/E : afebrile, BMI- 24 Pallor +, Icterus + Edema Tense ascites

April 2016

78/F, HTN X 17ycontrolled

Dec 2015

5 months

Parameters ValuesHbsAg/Anti HCV Negative

ANA,ASMA,ALKM1 Negative

S. Ferritin/B12 Normal

Anti Tissue Tranglutaminase Antibody

<3.0 au/ml

S . ceruloplasmin 20 mg/dl(N<20-40)

Ascitic fluid analysis High SAAG ascites, no SBP

Chest X ray Resolving right side pneumonia

Parameters Values

Hemoglobin 9.8 g/dl

TLC 8.4 x 1000/ul

Platelets 80 x 1000/ul

Total bilirubin 1.2 mg/dl

AST/ALT 74/60

ALP 128

Total s. protein 5.7 g/dl

Albumin 2.7 g/dl

INR 19.2/12.9 (1.6)

Na/K/Cr 108/3.8/2.1

Ig G 1630 mg/dl (N)

TSH 1.84 miu/ ml (N)

HbA1C 5.4 %

Investigations

UGIE – NormalUSG- CLD , PHT, Gross ascites

Diagnosis

• Cryptogenic cirrhosis (CTP C , MELD- 20) • Tense ascites • HE II (possible precipitants : LRTI, constipation,

hyponatremia)• AKI with oliguria ? Cause of Renal failure ? AKI ? Underlying CKD (Hypertension related)

How commonly AKI seen in decompensated cirrhosis ?

Audience poll

1. Less than 10%2. 10-30%3. 30-50%4. More than 50%

Incidence of AKI (at presentation)

• 15-20% cirrhosis

• 40-50% cirrhosis with ascites

• 2-6 fold increased mortality

Types of AKI

What percent of AKI in cirrhosis are due to HRS?

1. <25%2. 25-50%3. 50-75%4. >75%

Causes of AKI in pts with cirrhosis

Martín-LlahíM et al, Gastroenterology. 2011;140(2):488.

Diagnostic criteia of renal dysfunction in cirrhosis

• Acute renal failure : Rise in s.creatinine ≥ 50% from baseline or rise by ≥ 0.3 mg/dL in < 48h

• Chronic kidney disease :GFR < 60ml/min for >3mo

• Acute on chronic renal dysfunction: Rise in s.creatinine ≥ 50% from baseline or rise by ≥0.3 mg/dl in < 48h in cirrhosis whose GFR < 60ml/min for >3mo

Actuarial probability to survive in cirrhotic patients with different renal impairments

Adapted from Alessandria et al

How to investigate AKI ?

• Urine r/m• Urine spot sodium• 24 hour urine protein• USG abdomen

Forms of kidney injury in chronic liver disease

Patient’s Reports

S. Na 109

S. Potassium 3.6

S. Creatinine 2.1

24 Hr Na 5.7

24 Hr K 8.6

24 Hr Cr 2.1

24 Hr Albumin 360 mg

Fe Na < 1%

URINE r/m WNL, No casts, RBC- 0-2/hpf, protein - trace

Urine C/S sterile

Central venous pressure 14 cm

Chest X RAY Right sided pneumonia (RESOLVING)

USG Abdomen/KUB CLD, PHT, Gross ascites, Kidneys- Normal

Final diagnosis

• Cryptogenic cirrhosis , CTP B , MELD- 20 • Tense ascites, HRS 2, AKI cause HRS • No SBP/HE/Bleed• Hypertension, Concentric LVH, NYHA II

HRS

• Volume-unresponsive, refractory prerenal azotemia in

patients with chronic liver disease, characterized by

systemic and splanchnic vasodilatation but profound

renal vasoconstriction, without parenchymal kidney

injury

How to diagnose HRS?

Diagnostic criteria of HRS

Minor criteria are supportive but not required for the diagnosis

Salerno F et al. Gut 2007;56:1310

International club of ascites acute kidney injury (ICA-AKI)

Issues with s.creatinine

• Affected by age, gender, race, body weight• Malnutrition,muscle wasting,advanced liver disease• High bilirubin values.• Increased secretion of creatinine by tubules• Expanded volume of distribution

Risk of overestimating renal function

Types of HRS

HRS type1 vs type2

Course Precipitating event

H/o diuretic resistant ascites

Prognosis

HRS type1 Doubling of s.creatinine <2 weeks

>50% cases ± 90d survival<10%

HRS type2 Gradually progressive

Usually absent Usually present Median suvival 6 mo

Actuarial probability to survive in cirrhotic patients with different renal impairments

Adapted from Alessandria et al

Pathophysiology of HRS

Potential Role of Bacterial Translocation and Cytokine

Overproduction on Splanchnic Arterial

Vasodilatation.

How to monitor and treat our patient ?

Treatment goals

• Control infection• Anti hepatic encephalopathy measures• Treatment for HRS

Ideal Treatment of HRS Improvement of liver function

• Recovery of alcoholic hepatitis1

• Treatment of decompensated hepatitis B with

effective antiviral therapy2

• Recovery from acute hepatic failure

• Liver transplantation

1. Amini M et al. Alcoholic hepatitis 2010: a clinician's guide to diagnosis and therapy. World J Gastroenterol 2010; 16:49052, Garg H et al Tenofovir improves the outcome in patients with spontaneous reactivation of hepatitis B presenting as acute on chronic liver failure. Hepatology 2011; 53:774

Treatment strategies

• Improve renal perfusion – volume • Improve renal perfusion – splanchnic

vasoconstriction• Reverse portal hypertension

– TIPSS– Liver Transplant

Improve intravascular volume

• Albumin • 1 g/kg per day [100 g maximum] followed by

25 to 50 grams per day until therapy continued

Vasoconstrictor drugs

Drug Dose Noradrenaline Continuous infusion (0.5 to 3 mg/hr)

Vasopressin Starting at 0.01 units/min and titrating upward

Terlipressin Intravenous bolus (1 to 2 mg every four to six hours)

Midodrine + Octreotide

Orally (starting at 7.5 mg and increasing the dose at eight hour intervals up to a maximum of 15 mg by mouth three times daily)

Response to Terlipressin

1. Less than 10%2. 10-25%3. 25-50%4. More than 50%

Terlipressin in HRS

• Multicenter double blinded RCT• HRS type 1 diagnosed by

ICA criteria (1996)• Treatment discontinued if

– Treatment failure– Liver transplantation– Adverse effects

• If treatment success achieved, discontinue or continue drug at investigator discretion till max. of 14 days

Placebo

Albumin 25g/dN =56

180 d0 14 d3 d

Terlipressin 1mg q6h

Albumin 25g/dN =56

Dose increased to 2mg q6h if Cr decrease <30%

Albumin 100g on day 1

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

Terlipressin in HRS

Terlipressin in HRS – Survival benefit

No difference in survival at 180 d

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

Noradrenaline vs Terlipressin

Equally efficacious Adverse events (mostly abdominal pain, chest pain,

or arrhythmia) were significantly more common with Terlipressin (28 versus 8%)

Cost of Terlipressin 3X of NE

NE in ICU

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 groupn=60

Control groupn=21

P value

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

How to manage our patient?

What treatment is most appropriate for her ?

• Terlipressin • Effective but high risk- old age, concentric LVH• Noradrenaline • Equally effective, similar safety profile• TIPS • H/O HE II +, invasive, require expertise • Liver transplant • Curative but MELD 20, old age, low patient

acceptability

Albumin 20 gm/day, Terlipressin 2 mg/day in infusion

Discharged in June 2016

• Lasix – 40 mg OD• Aldactone – 50 mg OD• Remained well till September 2016• Readmitted 2 days back with ascites & creatinine of

4.2 mg%

Case 2

• 52/M, HCV cirrhosis• HRS-2, Creatinine – 3.2 mg%• No response to Terlipressin & albumin

Treatment options

• TIPSS• Liver transplant

TIPSS in HRS

1. Is it useful?2. Does it improve survival?3. Problems?

Transjugular intrahepatic portosystemic shuntTIPS

• Used in the treatment of refractory ascites• Provide short-term benefit• Considered only as a last resort in selected patients

TIPSS and HRS

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

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 Transplant in HRS – Our data

p=o.13, Log rank test

Prevention of HRS

1. Salerno F et al. Clin Gastroenterol Hepatol. 2013;11(2):123

2. Fernández J et al. Gastroenterology. 2007;133(3):818.

Take home messages…..

• HRS is second most common form of AKI in cirrhosis• HRS has a very poor prognosis and high resource

utilization• Vasoconstrictors & albumin are effective in less than

50% of HRS patients• TIPSS can be used as a stop gap treatment in

selected group of patients• Liver transplantation is the only effective treatment• Prevention of HRS possible in few cases

Thank You