hepatorenal syndrome

Moderator- Prof. J. Mokta
Hepatorenal
Syndrome

• A 32 year-old man with cirrhosis due to alcohol is
admitted to the hospital with spontaneous bacterial
peritonitis.
• He is hemodynamically stable and is not on any
diuretics.
• He is treated with broad-spectrum IV antibiotics and IV
albumin on admission. At the time of admission, his
serum creatinine is 1.2.
• On day 5 of his hospitalization, his serum creatinine is
4.1, and he is anuric. His urinalysis is normal.
 WHAT IS THE LIKELY DIAGNOSIS ?
 WHAT IS THE PROGNOSIS FOR THIS
YOUNG MAN ?
 WHAT TREATMENT SHOULD HE BE
Case Vignette

Introduction
• Freriches and Flint first reported that oliguria in the
absence of renal histological changes in patients with
advanced cirrhosis and ascites in 1861
• The term ‘hepatorenal syndrome’ was used in 1939 to
describe the occurrence of renal failure after biliary
surgery in patients showing a pathological pattern of
acute tubular necrosis or tubular interstitial nephritis
• Koppel et al in 1960s also showed that kidneys from
patients who succumbed from Hepato- Renal
Syndrome (HRS) were functioned normally when
transplanted into patients with chronic uremia

• Renal failure is one of the most severe
complications of cirrhosis
• More than 50% of patients with renal failure and
cirrhosis die within 1 month after the diagnosis
• Twenty percent of hospitalized patients with
cirrhosis and ascites develop acute kidney injury.
Twenty percent of these patients have
hepatorenal syndrome (HRS), a condition that
occurs mainly in patients with cirrhosis and
ascites.

Clinical features
• HRS occurs almost exclusively in patients with ascites
• The cumulative probability of HRS in patients with cirrhosis
and ascites is equal to 18% after 1 year, rising to 39% at 5
years
• The hepatorenal syndrome is characterized by the following
features in a patient who has established or clinically
evident acute or chronic liver disease :
 A progressive rise in serum creatinine
 An often normal urine sediment
 No or minimal proteinuria (less than 500 mg per day)
 A very low rate of sodium excretion (ie, urine sodium
concentration less than 10 meq/L)
 Oliguria

• HRS has two distinct types of clinical presentations.
• Type 1 HRS is an acute form of HRS and characterized
by rapidly progressive renal failure.
It is defined as at least a twofold increase in serum
creatinine to a level greater than 2.5 mg/dL during a
period of less than two weeks
Type 1 HRS usually develops after a precipitating event
such as gastrointestinal bleeding, large volume
paracentesis, acute alcoholic hepatitis and
spontaneous bacterial peritonitis.
Type 1 HRS is commonly associated with rapid
deterioration of extra-renal organ function including
the heart, brain, liver, and adrenal glands.

• Type 2 HRS is a chronic form of HRS and characterized
with moderate and slow progressive renal failure
It is defined as a slowly progressive rise in serum
creatinine to more than 1.5 mg/dl
It is usually associated with diuretics resistant ascites.
• Although there is a clear distinction of two different
types of HRS, renal impairment is often progressive
and can be regarded as “continuum” instead of two
different entities, such as most patients initially
represents type 2 HRS and turn into type 1 HRS after
several episodes of precipitating events

In 50% cases, the development of HRS is
spontaneous,
whereas in other half 1 or more identifiable
triggers may be found which include—
• Bacterial infections–Ascitic fluid, respiratory
system, urinary tract, GI tract infections and
infections of the biliary tract
Precipitating Factors for HRS

 Approximately one-third of patients with
spontaneous bacterial peritonitis develop HRS
at the time of infection or immediately
thereafter, in the absence of septic shock.
 Patients who develop type 1 HRS as a result
of spontaneous bacterial peritonitis have a
dismal outcome, with almost 100% hospital
mortality if not treated appropriately

• Diarrhoea and vomiting
• Diuretics
• Gastrointestinal bleeding-variceal bleeding
• Large volume paracentesis (LVP)–more than 5
litres without adequate blood volume
expansion

Risk factors for developing HRS
• Three important and easily recognized risk
factors are low mean arterial blood pressure
(< 80 mm Hg), dilutional hyponatremia, and
severe urinary sodium retention (urine sodium
< 5 mEq/L)
• Interestingly, patients with advanced liver
disease, defined by a high Child-Pugh score or
worsening parameters of liver function, such
as albumin, bilirubin, and prothrombin levels,
are NOT at higher risk of developing HRS

• Other risk factors
 High plasma renin activity
 Increased plasma norepinephrine
 Low plasma osmolality
 High urine osmolality
 High serum potassium
 Previous episodes of ascites
 Absence of hepatomegaly
 Presence of esophageal varices
 Poor nutritional status

 Moderately increased serum urea (>30 mg/dL)
 Moderately increased serum creatinine (>1.5
mg/dL)
 Moderately reduced GFR (< 50 mL/min)

Definition and diagnosis
• Although hepatorenal syndrome (HRS) is the
most often cited diagnosis whenever renal
dysfunction is diagnosed in patients with
cirrhosis, HRS is actually a diagnosis of
exclusion with a defined set of diagnostic
criteria; it is diagnosed when all other causes
of renal failure have been ruled out.

The International Ascites Club initially defined
HRS in 1996 and then revised in 2007

RIFLE and AKIN criteria for AKI

the latest is----------ICA 2015

• The role of biomarkers
• The most frequently studied biomarker of renal
dysfunction in cirrhosis is urinary neutrophil
gelatinase-associated lipocalin (NGAL), which is a
marker of renal tubular damage. In several
studies, urinary NGAL levels, could differentiate
between functional and structural causes of renal
dysfunction in patients with cirrhosis.
• In the future, biomarkers might become
specialized for identifying AKI susceptibility,
establishing mechanisms of injury, tracking
progression of AKI, so that the clinician’s task of
initial diagnosis, staging, differential diagnosis
and prognosis will be made easier.

• In cirrhotic patients with ascites, the most
common causes of acute renal failure are:
pre-renal (around 37%), acute tubular necrosis
(around 42%), and post-renal failure (0.3%);
HRS is around 20%
Differential Diagnosis

• Martin-Llahi et al. prospectively evaluated 562
patients with cirrhosis and AKI and adjudicated
patients into the somewhat unconventional
diagnoses of “renal failure because of
parenchymal nephropathy”, “hypovolemia
related renal failure”, and “hepatorenal
syndrome”
• Outcomes differed significantly by etiology with
three month mortality for patients with AKI due
to parenchymal injury, hypovolemia, and HRS of
27%, 54%, and 85%, respectively, and etiology
was independently associated with mortality
Martin-Llahi M, Guevara M, Torre A, et al. Prognostic importance of the cause
of renal failure in patients with cirrhosis. Gastroenterology. 2010; [PubMed:
20682324]

Diagnostic Approach to AKI in Cirrhotics
AKI in a pt with cirrhosis
ECF fluid losses;rapid/excessive diuretics
Vomiting,diarrhoea,hemorrhage,recent
LVP /hemodynamic changes due to use of
NSAIDS (or)ACEI
NO
YES
hold diuretics/offending
medications
Trial of intravascular volume
expander (albumin)
if renal function ↑ses with trial,
Diagnosis of prerenal failure is
made
Recent use of nephrotoxic medications
Hypotension(sepsis,hemorrhage)
Glomerular proteinuria&hematuria
i.e.,dysmorphic RBCs and RBC cast
Toxic or ischemic renal injury
YES
Glomerular disease
Depending upon clinical scenario
Further workup may include
Cryoglobulins C3,C4 and renal
biopsy
YES
NO
NO
Imaging (USG,CT scan)shows
Hydronephrosis,urinary retention
SuggestObstructive uropathy
Unless long standiing relief of obstruction
Should lead to improvement in
renalfunction
YES
Patient has evidence of Portal
Hypertension & fulfills HRS-AKI
diagnostic criteria
Diagnosis of HRS can be
made
NO
YES
YES
YES
YES
YES
NO
NO
NO
NO

Management of HRS
• General Measures
 The general management of patients with cirrhosis and HRS
depends on the severity of kidney failure and associated
complications
 Patients with type 1 HRS who are waiting for a liver
transplant are managed appropriately in an intensive care
setting
Considering the high mortality rate of type 1 HRS, decisions
about the management of patients who are not candidates
for transplant or who have important comorbid conditions
should be made on an individual basis
 Patients with type 2 HRS without associated complications
are managed as outpatients

• Monitoring
 Patients with type 1 HRS should be monitored
carefully
 Parameters to be monitored include urine output,
fluid balance, and arterial pressure and standard vital
signs
 Ideally central venous pressure should be monitored
to help with the management of fluid balance and
prevent volume overload

• Volume Resuscitation
 Excessive administration of fluids should be avoided to
prevent volume overload
 All diuretics should be stopped in patients at the initial
evaluation and diagnosis of HRS
 There are no data to support the use of furosemide in
patients with ongoing type 1 HRS. Nevertheless
furosemide may be useful to maintain urine output and
treat central volume overload if present
Spironolactone is contraindicated because of high risk
of life-threatening hyperkalaemia
 Patients with HRS should be optimally resuscitated,
with intravenous administration of albumin (initially 1 g
of albumin/kg of body weight for 2 days up to a
maximum of 100 g, followed by 20-40 g/day) in
combination with vasopressor therapy, for up to 14
days

• Screening for Sepsis
 Bacterial infection should be identified early, by blood,
urine and ascitic fluid cultures, and treated with
antibiotics.
 Patients who do not have signs of infection should
continue taking prophylactic antibiotics, if previously
prescribed.
• Use of Paracentesis
 There are few data on the use of paracentesis in patients
with type 1 HRS.
 Nevertheless, if patients have tense ascites, large volume
paracentesis with albumin may be useful.
<<Administration of albumin 8 g/litre of fluid aspirated
(specially if the aspiration is more than or equal to 5
litres)>>

Pharmacologic therapy
• Administration of vasoconstrictor drugs currently is
considered the best therapy for managing type 1 HRS
• Vasopressin analogues, such as terlipressin which has a
preferential effect on V1 receptors, which are densely
located in the splanchnic bed. The improvement in
renal perfusion is attributed to splanchnic
vasoconstriction, rise in the effective circulating
volume, mean arterial pressure, and decrease in the
plasma renin and aldosterone and overall
improvement in renal perfusion pressure.
Terlipressin is not yet approved by the Food and Drug
Administration (FDA) in the USA for use in HRS, though
it is commonly used in Europe and Asia.

 Results from randomized controlled studies
and systematic reviews show that treatment
with the combination of terlipressin and
albumin is associated with reversal of HRS in
40%-50% of patients, making this approach
the preferred initial therapy
 The ADQI recommends that patients with
Type 1 HRS should be optimally resuscitated
with albumin in combination with a
vasoconstrictor, preferentially terlipressin

 The terlipressin treatment protocol comprises an
initial dose of 0.5-1 mg terlipressin intravenous
injection every 4-6 h
 The therapy is aimed to improve renal function
and to decrease serum creatinine to less than 1.5
mg/dl (complete response)
 If serum creatinine does not decrease at least
25% of its base value after 3 days, the dose of
terlipressin should be increased in a stepwise
manner up to a maximum of 2 mg/4 hour

• Therapy should be discontinued after 14 days
in non-responders and only continued
thereafter in partial responders while awaiting
the outcome of salvage techniques
• After withdrawal of therapy, HRS recurs in 15%
of patients, and in these cases, a second
treatment with terlipressin usually is effective.

• The incidence of side effects (usually ischemic)
that mandate discontinuation of treatment is
12%
• Contraindications to terlipressin therapy include a
history of coronary artery disease,
cardiomyopathies, cardiac arrhythmias, and
obliterative arterial disease of the lower limbs
• Patients on terlipressin should be carefully
monitored for development of cardiac
arrhythmias or signs of splanchnic or digital
ischaemia, and treatment modified or stopped
accordingly.

• Predictors of response include
pretreatment bilirubin < 10 mg/dL and
increase of MAP ≥ 5mmHg at day three of therapy
• It is unlikely that vasoconstrictor drugs improve
survival beyond the short term
• A multicentre randomised controlled trial comparing
terlipressin and albumin to albumin alone in 46
patients with HRS showed improved renal function in
the former group (43.5% versus 8.7%, 𝑃 = 0.017), but
no survival advantage in either group at three months
(27% versus 19%, 𝑃 = 0.7).

• Norepinephrine is less expensive than
terlipressin; it increases the mean arterial
pressure by its α1 –mediated effect on systemic
vascular resistance and its β1-mediated inotropic
activity.
• Initial dose: 0.1 mg/kg/min intravenous infusion
• If no increase in mean arterial pressure by
10 mm Hg: increase dose by 0.05 mg/kg/min
every 4 h up to a maximum dose of 0.7
mg/kg/min
It is recommended by ADQI as an alternative to
terlipressin along with albumin for the treatment
of HRS.

• Midodrine, an α-1 agonist causes vascular
smooth muscle constriction
The availability of an oral preparation makes
administration of this drug on an outpatient basis
feasible.
Studies have shown that it is the combination of
thrice daily midodrine (7.5- 12.5 mg) with
octreotide (100- 200 µg subcutaneously) and
albumin, which improves renal plasma flow, GFR,
urinary sodium excretion along with a reduction
in renin, vasopressin and glucagon after 3 weeks
of treatment.

• Low-dose dopamine (2-5 mcg/kg/min) is frequently
prescribed to patients with renal failure in the hope
that its vasodilatory properties may improve renal
blood flow. Little evidence exists to support this
practice.
Five studies have evaluated the role of dopamine in
HRS, and none have reported significant changes in
RPF, GFR, or urine output.
• Misoprostol is a synthetic analogue of PG E1, whose
use in HRS was based on the observation that these
patients had low urinary levels of vasodilatory PGs.
None of the studies demonstrated an improvement in
the GFR, sodium excretion, or renal function in patients
with HRS.

Transjugular Intrahepatic
Portosystemic Shunt (TIPS)
• TIPS involves the insertion of an intrahepatic stent that
connects the portal vein to the hepatic vein. This shunts
portal blood into the systemic circulation, which reduces
the portal pressure and increases the systemic venous
return. In turn, this treats the arterial underfilling and the
overactivity of the RAAS and SNS.
• Unfortunately, most patients with HRS are ineligible for
TIPS due to contraindications (e.g., INR > 2, serum bilirubin
> 5mg/dL, CP score > 11, and cardiopulmonary disease).
• Furthermore, TIPS can aggravate the liver failure and
precipitate encephalopathy.
• The ADQI work group recommends that (i) TIPS should not
be used as the first line treatment for type 1 HRS due to
insufficient data and (ii) TIPS may be used in patients with
type 2 HRS and refractory ascites

• RRT may be used to treat specific complications of
renal impairment such as metabolic acidosis,
hyperkalaemia, volume overload, and uraemic
symptoms
• The ADQI work group recommends that RRT should
be avoided in type 1 HRS patients unless there is an
acute reversible component or an intention to
pursue liver transplantation
Renal replacement therapy

• Molecular adsorbent recirculating system (MARS) is a
modified dialysis technique for extracting albumin
bound and water-soluble substances from the blood.
This removes vasodilator substances such as nitric
oxide, tumour necrosis factor, and cytokines, which are
implicated in the pathogenesis of HRS.
Recently, a large randomised controlled trial (RELIEF)
involving 19 European centres comparing MARS with
standard therapy in patients with acute-on-chronic
liver failure reported that while MARS provided
temporary organ benefit (liver, kidney, and brain), it did
not improve overall survival
Artificial Liver Support Systems

• Prometheus is an extracorporeal technique
involving fractional plasma separation and
adsorption with haemodialysis for removing
water-soluble and albumin bound substances.
• Given the lack of a definitive survival benefit
and high costs, the ADQI work group suggests
that extracorporeal support systems should be
limited to research protocols

• Liver transplantation is the definitive treatment
for HRS
• The five-year survival for HRS is 60% for patients
that underwent liver transplantation compared
with 0% for patients that did not undergo liver
transplantation
• Patients with HRS have worse post transplant
outcomes than patients without HRS. This
includes reduced short- and long-term survival,
increased risk of bleeding and infection, and
longer hospital stay .
Liver Transplantation

• Restuccia et al suggested that reversal of the
renal dysfunction prior to transplantation
improves posttransplant outcomes
The study found that HRS patients treated with
vasopressin analogues before transplantation had
similar outcomes to controls with normal renal
function. Both groups had comparable survival
(three-year survival 100% in HRS-treated group
versus 83%in controls, 𝑃 = 0.15), frequency of
posttransplant renal dysfunction, and length of
hospital stay.

• Between 58 and 94% of patients with HRS
demonstrate recovery of renal function after
liver transplantation .
• Factors associated with a failure of renal
recovery include the time interval between
onset of HRS and transplantation (≥ 4–6
weeks),
dialysis for ≥ 8 weeks, and
a serum creatinine of ≥ 2mg/dL .
Such patients may benefit from simultaneous
liver and kidney transplantation.

• The median survival of patients with type 1 HRS is only
10% at 90 days, whereas for type 2 HRS it is 6 months
without treatment
Prognosis is however improved with treatment with
the 3 month survival of 20 and 40% respectively for
type 1 and 2 HRS
• The survival in these groups of patients is dictated by
the deterioration in liver function, and the response to
pharmacological treatment.
If there is no improvement with treatment of
vasoconstrictors for 10-14 days, it indicates a poor
prognosis.
Prognosis

Prevention of HRS
• With better understanding of the
pathophysiology of HRS, certain specific
strategies have been identified to prevent HRS
in specific clinical situations
• A systematic literature review was conducted
by acute dialysis quality initiative (ADQI) in
2010, where the experts developed a
consensus recommendation for standardised
care of cirrhotics with HRS.

 Careful assessment, close monitoring and
prevention of precipitating factors in cirrhotics
with ascites
 Drugs which reduce renal perfusion and those
causing nephrotoxicity have been reported to
precipitate HRS, should be avoided
 Antibiotic prophylaxis has shown to reduce
spontaneous bacterial peritonitis (SBP). Studies
using norfloxacin have reported not only a
reduction in SBP (7 versus 61%) but also a
reduction in the incidence of HRS (28 versus 41%)
 Albumin infusions have been reported to
decrease the incidence of HRS in patients with
SBP

 Prophylactic pentoxifylline, a tumour necrosis
factor-α antagonist, reduces complications in
patients with advanced cirrhosis including renal
dysfunction
 Large volume paracentesis (LVP) may induce
paracentesis induced circulatory dysfunction
(PICD) leading to development or exacerbation of
AKI and HRS. Administration of albumin 8 g/litre
of fluid aspirated (specially if the aspiration is
more than or equal to 5 litres) leads to the
prevention of PICD

• A 54-year-old male was hospitalized 3 days ago following a self-
limited episode of hematemesis. He is now being evaluated for 24
hours of oliguria. He is a K/C/O cirrhosis due to chronic hepatitis C
infection.
The patient’s temperature is 36.9 C, BP is 110/65 mmHg,
PR is 75/min, and respiratory rate is 18 /min.
Physical examination reveals severe ascites and abdominal
tenderness to palpation. He has 2+ pitting edema in both lower
extremities. Serum creatinine is 5.14 mg/dL.
Urine sodium is 6mEq/L. Urine analysis is normal.
A challenge with 60gm of albumin over several hours fails to
improve urine output.
• Which of the following is the most likely diagnosis?
a. Acute tubular necrosis
b. HRS
d. Prerenal azotemia

• A 55-year old man with decompensated cirrhosis admitted
with SBP is noted to have a low urine output and increasing
creatinine after resolution of the infection.
He has jaundice, tense ascites and peripheral edema.
Laboratory data reveal a serum creatinine 3.1 mg/dL (4
weeks prior: 0.8 mg/dL, at time of SBP 2.0 mg/dL), BUN 52
mg/dL, serum sodium 123 mEq/L
• All of the following management options is
are appropriate at the present time EXCEPT?
A. Obtain urinalysis, urine sodium measurement, and urine
sediment
B. Obtain renal ultrasound
C. Expand intravascular volume with
albumin
D. Start IV furosemide

• A 32 year-old man with cirrhosis due to alcohol is admitted to the
hospital with spontaneous bacterial peritonitis. He is
hemodynamically stable and is not on any diuretics.
He is treated with broad-spectrum IV antibiotics, and IV albumin on
admission.
At the time of admission, his serum creatinine is 1.2. On day 5 of his
hospitalization, his serum creatinine is 4.1, and he is anuric.
He is diagnosed with hepatorenal syndrome.
• Which of the following is TRUE?
A. He has type II hepatorenal syndrome and should be
evaluated for a combined liver/kidney transplant.
B. He has type I hepatorenal syndrome, and should be treated with daily IV
albumin and terlipressin, as a bridge to a liver transplant.
C. After a liver transplant, his renal function is unlikely to fully recover.
D. Pharmaceutical management involves vasodilator therapy, with the goal of
improving renal perfusion.

A new algorithm for
the management of AKI in cirrhosis
• According to the new ICA-AKI diagnostic
criteria for AKI, a new algorithm for the
management of AKI in patients with cirrhosis
is proposed.
• The algorithm is based on the new staging of
AKI.

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