HEPATORENAL SYNDROME

Dr. Suman Adhikari.

2nd Year Resident,Internal medicine.
NAMS, BIR HOSPITAL

DEFINITION

Renal failure (serum creatinine >1.5 mg/dL),

in a patient with advanced liver disease and
portal hypertension with:
marked decrease in glomerular filtration rate
(GFR) and renal plasma flow (RPF) in the
absence of other identifiable causes of renal
failure
marked abnormalities in systemic
hemodynamics
activation of endogenous vasoactive systems.

Acute renal dysfunction occurs in 15% to 25% of

hospitalized patients with cirrhosis.

HRS- 10% to 30%

Annual frequency of HRS in cirrhotic patients

with ascites- 8%

HRS develops in 30% (with SBP or other infection),

25% (with severe alcoholic hepatitis), and 10%
(require serial large-volume paracenteses)

Not all concomitant hepatic and renal

impairment is due to HRS.

Alternative diagnoses may imply a better

prognosis.

PATHOPHYSIOLOGY

Most widely accepted theory: Vasodilatation

theory

Disturbance in systemic hemodynamics

Increased activity of vasoconstrictor system

Reduced or insufficiently increased activity

of vasodilator factors

FIG: PATHOPHYSIOLOGY

PATHOPHYSIOLOGY

CLINICAL PRESENTATION

Asymptomatic

Decreased urine output

May present in HE

Recognition can be difficult-as cirrhotic

patients are malnourished with significantly
decreased muscle mass-sCR overestimates
GFR.
Signs of advanced liver diseaseascites,stigmata of
CLD,PHTN,jaundice,coagulopathy.
CVS-edema,hypotension
Electrolytes-dilutional hyponatremia

Poor nutrtional status

Urine output-oligo-anuria the norm in type 1
HRS,anuria is an ominous sign.
U/A-bland,no proteinuria and hematuria
Normal USG/imaging
However renal doppler may detect increased
vascular resistance.

CLASSIFICATION
Type

1 HRS:
Characterized by a severe and rapidly
progressive renal failure defined as doubling
of the serum creatinine to a level greater
than 2.5 mg/dL in less than 2 weeks
Patients usually have severe liver failure
(jaundice, encephalopathy, and
coagulopathy)

Frequently occurs following a precipitating

factor (severe bacterial infection,
gastrointestinal hemorrhage, therapeutic
paracentesis without plasma expansion)

the complication with the poorest prognosis

in cirrhosis

Median survival time is only 2 weeks

 Type

2 HRS:
Moderate and stable renal failure

Associated with relatively preserved liver

failure

Often associated with refractory ascites

characterized by serum creatinine levels

lower than 2.5 mg/dL.

Median survival time is approximately 6

months

Type 1 HRS may develop in patients with

type 2 HRS following a triggering event

DIFFERENCE BETWEEN TYPES OF HRS:

DIAGNOSIS

International Ascites Club Consensus Workshop in 2007

cirrhosis with ascites

serum creatinine level higher than 1.5 mg/dL (133

mol/L)

lack of improvement in the serum creatinine level to

1.5 mg/dL (133 mol/L) or less after at least 2 days of
diuretic withdrawal and volume expansion with
albumin (1 g/kg of body weight/day, to a maximum of
100 g/day)

absence of shock

lack of current or recent treatment with

nephrotoxic drugs

absence of parenchymal kidney disease as indicated

by proteinuria of more than 500 mg/day,
microhematuria (50 red blood cells/highpower
field), or abnormal renal US findings

The revised criteria incorporate several new

iterations which include
1. Removal of creatinine clearance
2. Recognition that ongoing bacterial
infection,in the absence of septic shock,no
longer excludes a diagnosis of HRS
3. Preference for the choice of albumin rather
than saline for plasma expansion
4. Removal of the minor diagnostic criteria.

The IAC criteria have several shortcomings.

The serum creatinine should be interpreted

with caution in patients with cirrhosis.

These patients have lower baseline serum

creatinine than normal.

Causes of low serum creatinine in cirrhotic

patients
1. Reduced endogenous creatinine production
related to decreased hepatic synthesis and
decreased muscle mass from malnutrition
2. Medications related to increased to tubular
secretion of creatinine
3. Fluctuations in serum creatinine in patients
with cirrhosis and large volume
ascites(e.g,following diuretic therapy or
paracentesis with volume expansion)

Other causes
Lab based underestimations of serum
creatinine due to interactions with
bilirubin.

As such creatinine based measurements run

the risk of overestimating renal function and
underestimates the severity of renal
impairment.
This raises 2 issues Need to develop more accurate laboratory
and imaging biomarkers of renal function.
Whether to put cut off value of SCR
threshold of 1.5mg% for HRS as to lower it
down to allow patients to be diagnosed and
treated while being at an earlier stage.

Current IAC criteria do not consider clinical

scenario of HRS developing in patients with
underlying chronic kidney disease.

Munoz et al proposes that patients with HRS

superimposed on CKD be categorized as having
type3 HRS.

Some argue that some patients that do not

fulfill the full IAC criteria may be treated as
having presumed HRS based on the clinical
index of suspicion.

DIFFERENTIAL DIAGNOSIS
ATN:

H/o nephrotoxic drugs, radiocontrast, bleeding with

decrease BP

Rapid rise in serum creatinine

high urine sodium concentration

abnormal urine sediment

urinary levels of neutrophil gelatinaseassociated lipocalin (NGAL), interleukin 18

(IL-18), kidney injury molecule-1 and liver
fatty acid-binding protein are elevated in
liver disease patients with acute tubular
necrosis.

 Glomerular

patients with more severe glomerular abnormalities

mainly develop proteinuria and/or hematuria

Pre

disease:

renal azotemia:

causes of intravascular volume depletion include

vomiting, diarrhea, and diuretic overuse, bleeding

PROPOSED CRITERIA FOR DIAGNOSIS OF KIDNEY DYSFUNCTION IN

PATIENT WITH CIRRHOSIS

TREATMENT
Medical
TIPS

therapy

placement

Liver

transplantation

MEDICAL THERAPY

Medical therapies for HRS are directed

toward:

Reversing the underlying splanchnic and

systemic vasodilatation with vasoconstrictors

Increasing effective circulatory volume with

the use of colloid

ALBUMIN

Bolus of 1 g/kg/day on presentation

(maximum dose, 100 g daily) for 2 days

Continue at dose of 20-60 g daily as needed

to maintain central venous pressure between
10 and 15 cm H2O

TERLIPRESSIN

Vasoconstrictor analogue of ADH

Mechanism: vasoconstriction of splanchnic

circulation

Approximately 40% of patients with HRS

respond to treatment with terlipressin and
albumin

Start at 1 mg IV every 4 hr and increase up to

2 mg IV every 4 hr if baseline serum
creatinine level does not improve by 25% at
day 3 of therapy

Side effects: cardiac arrhythmia, angina, MI,

HTN, bronchospasm, diarrhea, nausea,
vomiting, intestinal ischemia, finger ischemia

J URIZ ET AL. TERLIPRESSIN PLUS ALBUMIN INFUSION: AN EFFECTIVE AND SAFE THERAPY OF HEPATORENAL
SYNDROME: J HEP. 2000 JULY; 33(1):43-48

S SAGI ET AL. TERLIPRESSIN THERAPY FOR REVERSAL OF TYPE 1 HEPATORENAL SYNDROME: A META ANALYSIS OF
RANDOMIZED CONTROLLED TRIALS. J GAS. 2010 MAY; 25(5):880-885.

NOR EPINEPHRINE

Alpha1 adrenergic agonist

0.1-0.7 g/kg/min as an IV infusion.

Increase by 0.05 g/kg/min every 4 hr and

titrate to an MAP increase of at least 10 mm
Hg

C. ALESSANDRIA, ET AL. NORADRENALINE VS TERLIPRESSIN IN PATIENTS WITH HEPATORENAL SYNDROME: A

PROSPECTIVE, NON RANDOMIZED, UNBLINDED, PILOT STUDY. J HEP 2007 OCT: 47(4):499-505;

MIDODRINE AND OCTREOTIDE

Midodrine, an orally administered 1adrenergic agonist

begin midodrine at 2.5-5 mg orally 3 times

daily and increase to a maximum dose of 15
mg 3 times daily. Titrate to an MAP increase
of at least 15 mm Hg;

Octreotide, a somatostatin analog that inhibits

endogenous vasodilators

begin octreotide at 100 g subcutaneously 3 times

daily and increase to a maximum dose of 200 g
subcutaneously 3 times daily, or begin octreotide at
a 25-g IV bolus and continue at a rate of 25 g/hr

Side effects: diarrhea, tingling sensation,

goosebumps

RENAL REPLACEMENT THERAPY

RRT is among the so-called bridging therapies

designed to support patients awaiting liver
transplant

Continuous renal replacement therapy

(CRRT) is usually preferred to intermittent
dialysis due to its greater hemodynamic
stability ensuring fewer fluctuations in
intracranial pressure

MOLECULAR ADSORBENT
RECIRCULATING SYSTEM-MARS.

Uses conventional CRRT monitor or a standard HD

machine with albumin dialysate circuit

Based on the removal of albumin-bound toxins (bile

acids and nitric oxide) and water-soluble cytokines
(IL-6 and TNF-) to stabilize liver function and
improve organ damage

EXTRACORPOREAL ARTIFICIAL
LIVER SUPPORT THERAPY

Liver support systems are designed to

enhance and optimize livers detoxifying
system increasing the removal of water
soluble toxins and those linked to albumin.

FRACTIONATED PLASMA SEPARATION

AND ABSORPTION (PROMETHEUS)

The Prometheus system consists of a primary circuit

(plasma filter and dialyzer) and a secondary circuit
(adsorbent filters to remove bilirubin) for the
combined removal of toxin albumin-bound and
water-soluble molecules using a fractionated
plasma separation and adsorption (FPSA) system

TIPS

Effective for the treatment of diureticresistant ascites, a precursor to type 2 HRS

Complication:
Increase in HE
Worsening of liver function
Bleeding complication during procedure
Risk of contrast induced renal injury

LIVER TRANSPLANTATION

The only therapeutic modality that has the

potential to reverse both liver dysfunction
and HRS

Rates of postoperative complications and inhospital mortality are higher in patients

transplanted with HRS than in those
transplanted without HRS and up to 35% of
patients with HRS require long-term renal
replacement therapy

PREVENTION

Therapeutic paracentesis: use plasma volume

expander (albumin) while performing large volume
paracentesis

SBP: albumin (1.5g/kg) at the diagnosis of infection

and 1g/kg after 48 hours along with antibiotics

Primary prophylaxis of SBP: oral norfloxacin

400mg/day in patient with ascitic protein
<1.5mg/dL and bilirubin > 4mg/dL with CTP
>9 or creatinine >1.2mg/dL

Administration of Pentoxifylline 400mg TDS

to patient with severe acute alcoholic
hepatitis reduced the occurrence of HRS

TAKE HOME MESSAGE

The diagnosis of HRS depends on exclusion of

other causes of AKI.
AKI is common in cirrhosis.
Current diagnostic guidelines are still
incomplete as controversies do exist.
There is a strong urge to look for some
biomarkers that may differentiate HRS and AKI.
At present,terlipressin along with albumin is
the medical treatment of choice for
HRS,though liver transplantation is always the
final and the best modality.

REFERENCES

Handbook of liver disease, 3rd edition

Sleisenger and Fordtrans gastrointestinal
and liver disease, 10th edition
Sherlocks diseases of the liver and biliary
system, 12th edition
Hepatorenal syndrome Update on diagnosis
and treatment-World journal of nephrology.
Oxford nephrology,2nd edition.

THANK YOU