2. Overview
• Definition of Hepatorenal syndrome(HRS)
• Epidemiology and Types of HRS
• Diagnosis
• Pathogenesis
• Prevention
• Management
• Conclusion
2
3. Hepatorenal Syndrome
Definition
International ascites club defined HRS as a syndrome
that occurs in patients with cirrhosis, portal hypertension
and advanced liver failure, characterized by impaired
renal function with marked abnormalities in the arterial
circulation and activity of endogenous vasoactive
systems
Is a functional disorder
Kidneys - histologically normal
Arroyo V et al, Hepatology 1996;23:164e76
3
5. Incidence of HRS in patients with chronic liver disease is not
well studied.
In a study of 234 non azotemic patients with liver disease who
had ascites and cirrhosis,18% developed HRS at 1year and
39% developed by 5 years.
Retrospective studies indicate HRS is present in 17% of
pts admitted to hospital with ascites,and in > 50% of
cirrhotics dying from liver failure
A multicenter retrospective study
423 patients with cirrhosis and ARF
ATN (35%)
Prerenal failure (32%)
HRS (26.6%) Type1 20% & Type2 6.6%
Some patients without ascites devolped the condition in the
setting of acute fulminant hepatic failure.
EPIDEMIOLOG
Y
6. CLASSIFICATION OF HRS
Classified based on TIME COURSE and PRECIPITATING
FACTORS
Four types-
HRS type-1: Cirrhosis with rapidly progressive acute renal
failure
HRS type-2:Cirrhosis with sub acute renal failure
HRS type-3:Cirrhosis with type-1 or type-2 HRS
superimposed on chronic kidney disease/acute renal
injury
HRS type-4:fulminant liver failure with HRS
Clinics of North America,2006
7. Type-1 HRS
Rapidly progressive reduction of renal function as defined
by doubling of the initial S.cr to a level >2.5 mg/dL in < 2
wk
Clinical pattern: acute renal failure
Salerno et al, Gut 2007
7
Types of HRS
8. Type 2 of HRS
Moderate renal failure (S.cr ranging from 1.5 to 2.5 mg/dL) with
a steady or slowly progressive course
Clinical pattern: refractory ascites
10. Type 3 HRS
Recently defined type
Cirrhosis with type 1 or type 2 HRS superimposed
on chronic kidney disease or acute renal injury
85% of end-stage cirrhotics - intrinsic renal disease
on Kidney Bx
Allessandria C. Hepatology 2005
Renal histology may be required to accurately
diagnose cause of renal failure
Diagnostic markers of HRS are absent
May require liver-kid transplant.
Never studied in therapeutic trials.
10
11. Type 4 HRS
> 50 % of ALF develop HRS.
Rarely refractory ascites and PHT
Very poor prognosis esp. if ALF
acetaminophen-related.
Pathophysiology ? similar. Lack of studies.
Moore K; Eur J Gastroentrol Hepatol.1999
11
14. • All major criteria must be present for diagnosis
of hepatorenal syndrome.
• Minor criteria are not necessary for diagnosis
but provide supportive evidence
Diagnostic criteria for hepatorenal
syndrome 1996
1-Major criteria.
2-Minor criteria
28. In type 1 HRS, a precipitating event is identified in 70 to 100% of
patients with HRS, and more than one event can occur in a single
patient.
Identifiable precipitating factors include:
Bacterial infections esp. SBP (25-30%)
Large-volume paracentesis
without albumin infusion(15%)
Gastrointestinal bleeding
Acute alcoholic hepatitis (25%)
NB.Intravascular volume depletion by overdose diuretic use or
lactulose induced diarrhea have been considered triggering factors
for HRS; however, evidence to support this is lacking.
Early identification of a
precipitating event of HRS
is clinically important
because it is frequently
preventable or treatable
with specific medical
therapy.
(Munoz SJ, 2008)
29. In type 2 HRS and in some patients with type 1
HRS,
no precipitating factor can be identified.
30. 1. Doppler ultrasound Early detection of
renal vasoconstriction
2. dilutional hyponatremia
3. low arterial BP
4. high plasma renin activity
5. low urinary sodium
6. reduced plasma osmolality
Olivera-Martinez et al., 2012
suggested that:
early treatmen might
increase survival
33. Pathogenisis
Four interrelated pathways have been
implicated in the pathophysiology ..
“Possible impact of each one of
these pathways on renal
vasoconstrcition and development of
HRS varies from one patient to
other .”
1.PERIPHERAL ARTERIAL VASODILATION
2.STIMULATION OF RENAL SNS
3.CARDIAC DYSFUNCTION
4.CYTOKINES ,VASOACTIVE MEDIATORS.
34. Pathogensis of HRS
CIRRHOSIS
splanchnic arterial vasodilation
arterial underfilling
stimulation of systemic vasoconstrictors
renal vasoconstriction
late stage of cirrhosis early stages of cirrhosis
local vasodilators , local vasoconstrictors systemic and local
vasodilators
HEPATORENAL SYNDROME PRESERVED RENAL PERFUSION
36. Splanchnic Steal Phenomenon
End stage liver disease
Liver cell failure and portal hypertension
Endogenous vasoactive substances
Systemic vasodilatation and mainly splanchnic
with further pooling of blood in the splanchnic
region
The thief is the splanchnic vessels
&Here the game begins….
The Body “The police” will act against
Low arterial pressure, reduced effective bl. Vol.
and pooling of blood in the Splanchnic region
Low arterial blood pressure resulting in:
Reduced effective arterial blood volume
38. Splanchnic Steal Phenomenon
Renal vasoconstriction
Kidney
Angina
Kidney
ischaemia
Impaired
renal
function
This may explain the difference among patients
in the intensity and the course of the disease
Imbalance between
vasoconstrictors and vasodilators
42. The goal
is to reverse renal failure and prolong survival until
candidates undergo liver transplantation.
Pharmacologic agents can be grouped into two
broad categories:
Renal Vasodilators
Systemic Vasoconstrictors
Pharmacological
43. I.RENAL VASODILATORS:
A. DIRECT renal vasodilators
DOPAMINE
Low dose dopamine(2-5µgm/kg /min) is prescribed in the hope
that its vasodilatory properties may improve renal blood flow
MISOPROSTOL
A synthetic analogue of PG E1, its use was based on the
observation of low urinary levels of vasodilatory PGs.
The use of both the above drugs was not substantiated by any
studies
44. B. RENAL VASOCONSTRICTOR ANTAGONIST
Sarlasin: Angitensin II receptor antagonist used in attempt
to reverse renal vasoconstriction.This inhibits the hemostatic
response to hypotension and led to further worsening of renal
function, abandoned .
Endothelin antagonists: Non specific tezosentan
endothelin A receptor antagonist(BQ123)
N-ACETYLCYSTEINE: Mechanism of action is unknown but
studies encourage optimism for medical management where
option for liver transplant is not present
45. None of the studies that used renal vasodilators showed
imrpovement in renal perfusion or GFR. -- Barnado et al ,
Benette et al .
Because of adverse effects
,lack of benefit the use of
renal vasodilators has been
abandoned.
46. II. Systemic vasoconstrictors
Most promising agents.
Interruption of splanchnic vasodilation will relieve the
intense renal vasoconstriction.
A. VASOPRESSIN ANALOGUES -ORNIPRESSIN ,TERLIPRESSIN
B. SOMATOSTATIN ANALOGUE -OCTREOTIDE.
C. ADRENERGIC AGONISTS - MIDODRINE,
NOREPINEPHRINE.
47. A. VASOPRESSIN ANALOGUES:
Ornipressin -- ischemic adverse effects. (30% )
Terlipressin – most common used drug now.
Marked vasoconstrictor effect.
V1receptors on smooth muscle of arterial wall .
Better response in type 2 HRS than in type 1 HRS.
48. +
1 g/kg on day 1 followed by 40
g/day
to improve the efficacy of
treatment on circulatory function.
•There is no standardized dose
schedule for terlipressin
administration because of the lack of
dose-finding studies.
•Terlipressin is generally started at a
dose of:
1 mg/4–6 h and increased to a
maximum of
2 mg/4–6 h if there is no reduction in
serum creatinine of at least 25%
compared to the baseline value at
day 3 of therapy.
49. •Response to therapy is generally characterized by:
a slowly progressive reduction in serum creatinine (to below 1.5 mg/dl)
increase in arterial pressure,
increase urine volume,
increase serum sodium concentration.
50. A serum bilirubin less than 10 mg/dl before treatment
And
an increase in mean arterial pressure of >5 mm Hg at
day 3 of treatment
are associated with a high probability of response to
therapy.
51. Treatment with terlipressin is associated with an improved
short-term survival.
Treatment with terlipressin has been shown to improve
survival in some studies but not in others.
•Treatment is effective in 40–50% of patients,
approximately.
52. B. SOMATOSTATIN ANALOGUE (Octreotide):
An inhibitor of glucagon.
Ineffective in type 2 HRS
C. Alpha ADRENERGIC AGONISTS (Midodrine,
Norepinephrine)
Both are ineffective in type 2 HRS .
Better response in type I HRS.
Noradrenaline (0.5–3 mg/h) (0.1-0.7mic.g/kg/min) is
administered as a continuous infusion.
Need further studies to evaluate its efficacy.
54. Comparative study : (mean base line serum creatinine 2.4 mg/dl)
83% of the patients responding to noradrenaline were successfully bridged
to liver transplantation, with improved survival.
No significant ischemic complications occurred in either group. HRS
recurred after discontinuation of therapy in about 50% of patients.
But it is still unknown, whether these favorable results apply to patients
with severe or advanced HRS (creatinine >4 mg/dL, or severe hepatic
decompensation with bilirubin >10 mg/dL, and INR >3).
Terlipressin+albuminNoradrenaline+albu
min
80%75%Complete response
TerlipressinNoradrenaline
15 foldcost
55. A-
Is theoretically attractive maneuver
• improve renal function in type 1 HRS, but more studies are needed.
• improve renal function and control ascites in patients with type 2 HRS.
• However, TIPS has not been compared with standard medical therapy
in type2 patients.
Few studies available (case series)
NON PHARMACOLOGICAL
57. C-Artificial hepatic support
Detoxification treatment ~ form of artificial extracorporeal liver support.
Considered to be a bridge to liver transplantation
Currently three systems are available for albumin
dialysis
1. Molecular Adsorbents Recirculation System (MARS)
2. Prometheus system
3. Single Pass Albumin Dialysis (SPAD)
57
58. 1-Molecular adsorbent recirculating
system (MARS)
Most frequently used albumin dialysis system
Dialysate recirculated and perfused online through charcoal and anion
exchanger columns
Improve systemic hemodynamics and renal perfusion.
Better than HD for sodium,creatinine, bilirubin and PT
Substance ≥ 50 KDa are not removed .
58
59. • Albumin permeable
membrane ,size of 250kDa.
• Albumin passes through the
membrane and adsorbers
that remove toxins.
Reduction of both urea ,
bilirubin more <MARS
2-Prometheus
60. 3-SINGLE PASS ALBUMIN DIALYSIS(SPAD)
Dialyses blood/plasma against a 4.4% solution
of albumin,disposed after a sinlge pass.
A standard renal replacement machine is
used with out any additional perfusion pump
system
With regard to bilirubin,ammonia it is greater
than MARS in its detoxifying capacity.
In vivo useful in fulminant hepatic failure.
Further experience required for routine use.
63. SUMMARY OF SPECIFIC
THERAPY OF HRS
TYPE OF HRS TREATMENT
TYPE I HRS
Vasoconstrictors,albumin,TIPS,li
ver Trx
TYPE 2 HRS Vasoconstrictors
,LVP,TIPS(ref),Liver Trx
TYPE 3 HRS CRRT, LKT
TYPE 4 HRS idealy LTx
Editor's Notes
Original –
Hepatorenal syndrome may be classified on a clinical basis into two different clinical types: (1) type I hepatorenal syndrome, characterized by rapidly progressive reduction of renal function as defined by a doubling of the initial serum creatinine to a level greater than 2.5 mg/dL or a 50% reduction of the initial 24-hour creatinine clearance to a level lower than 20 mL/min in less than 2 weeks; and (2) type II hepatorenal syndrome, in which the renal failure does not have a rapidly progressive course.
In type 1 HRS the serum creatinine level doubles to greater than 2.5 mg/dL within 2 weeks. The key features of type 1 HRS are its rapid progression and high mortality, with a median survival of only 1 to 2 weeks. Common precipitating events in type 1 HRS include bacterial infections, particularly spontaneous bacterial peritonitis; variceal hemorrhage; major surgery; and acute alcoholic hepatitis. Sometimes acute hepatic injury, superimposed on cirrhosis, may lead to liver failure and HRS. The hepatic injury can occur from acute viral hepatitis; drug-induced liver injury (acetaminophen; idiopathic drug-induced hepatitis); hepatic ischemia; flare of chronic hepatitis B virus infection caused by an emergent resistant viral strain or withdrawal of antiviral therapy; or superimposed acute delta virus hepatitis. Early identification of a precipitating event is clinically important because it is frequently preventable or treatable with specific medical therapy.
In type 2 HRS, the serum creatinine increases slowly and gradually during several weeks or months with a reciprocal gradual reduction in glomerular infiltration rate (GFR). This generally occurs without a precipitating factor. The median survival of type 2 HRS is about 6 months, significantly longer than for type 1. Nonetheless, type 2 HRS still has an extremely poor prognosis. Unless liver transplantation is performed, or a dramatic response to therapy of the underlying liver disease occurs (such as HBV related cirrhosis responding to antiviral therapy), many patients with type 2 HRS eventually progress to type 1 HRS because of a precipitating factor.
The clinician should distinguish between type 1 and type 2 HRS. The former is associated with a rapidly fatal prognosis. Type 1 HRS must be urgently managed, with elimination of precipitating factors and evaluation for liver transplantation. In contrast, type 2 HRS permits less frantic evaluation and therapy. Both types are part of a spectrum of renal dysfunction in the setting of severe liver disease. Patients may progress from type 2 to type 1 HRS without an obvious precipitating factor other than worsening liver failure. The mechanisms of this progression are unknown.
Clinical data suggest that type-1 and type-2 HRS are different syndromes and not different expressions of a common underlying disorder. Renal failure in type-1 HRS is severe and progressive whereas in type-2 it is moderate and steady. As expected, circulatory function is also stable in type-2 HRS whereas a rapidly progressive impairment in circulatory function occurs in type-1 HRS. Type-1 HRS is frequently associated to a precipitant event, mainly SBP. In contrast, type-2 HRS develops spontaneously in most cases. Finally, the main clinical consequence of type 1 HRS is severe hepatorenal failure and death whereas it is refractory ascites in type-2 HRS. Type-2 HRS probably represents the genuine functional renal failure of cirrhosis. It would be the extreme expression of the impairment in circulatory function that spontaneously develops during the course of the disease. In contrast, type-1 HRS mimics the acute renal failure associated with other conditions such as sepsis or severe pancreatitis, with features of multiorgan failure including acute impairment in cardiovascular, renal, hepatic and cerebral function and relative adrenal insufficiency
Many disease states in which there are clinical indications of renal and hepatic disease but there is no relationship between the two, e.g. a systemic disease in which the agent causes both hepatic and renal damage.
