hrs

2.  Hepato Renal Syndrome (HRS) is a functional and reversible
form of renal failure , in patients with advanced chronic liver
disease.
 Interactions between systemic and portal hemodynamics
causes intense renal vasoconstriction .
 May develop spontaneously without known precipitating
factors but there are known triggers.
 To be diagnosed based on criteria.
 Worst prognosis of all the complications of cirrhosis.
 Terlipressin is the drug of choice in treatment.
 Liver transplantation is the definitive cure for patients.
 Recently liver dialysis by means of albumin bound membranes is
providing a means of extracorporeal liver support.

3.  Frerichs ,Flint - first report of renal failure in the
absence of significant renal histologic changes,in
chronic liver diseases.
 Hecker, Sherlock (1956) – Pathogenesis of
hepatorenal syndrome.
 Epstein et al - splanchnic ,systemic vasodilation
together with intense renal vasoconstriction is
the pathophyisological hallmark of HRS.
 1970 s -TERMINAL FUNCTIONAL RENAL FAILURE
 2007 -Molecular Adsorbent Recirculating System.

4.  Heyd's syndrome
 Flint's syndrome
 Frerichs' syndrome
 Bile nephrosis,
 Cholemic nephrosis,
 Hepatonephrite,
 Hepatonephritis serosa acuta,
 Leber-Nieren-Syndrom (German),
 Nephrite fonctionelle (French).

5.  Large volume paracentesis
 Shock
 Sepsis
 Nephrotoxic Medications
 Intrinsic renal diseases
 Volume depletion secondary
to diuresis.
H
Y
P
O
T
E
N
S
I
O
N
Renal failure

6. Renal failure 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 h
hold diuretics,offending medications
Trial of ntravascularvolumeexpander
(albumin)if renal function ↑ses ,
Diagnosis of prerenal failure is
made
Recent use of nephrotoxicmedications
Hypotension(sepsis,hemorrhage)
Glomerular proteinuria&hematuria
i.e.,dysmorphic RBCs and RBC cast
Toxic or ischemic renal failureYES
Suspected glomerular diseaseYES
NO
NO
Imaging (USG,CT scan)shows
Hydronephrosis,urinary retention
Suggestive of obstructive uropathy
YES
Patient has evidence of Portal
Hypertension & serum
creatinine>1.5mg/dl
Diagnosis of HRS can be
made
NO
YES

7.  First systemic attempt to define HRS was made by
International Ascites Club(1994)
 HEPATORENAL SYNDROME is a distinct form
of fucntional acute/sub acute renal failure
charecterised by severe renal vasoconstriction
which develops in decompensated Cirrhosis or
Acute liver failure,in the absence of uderlying
renal pathology.
 Recently updated to include Albumin as volume
expander.
DEFINITION

8.  Incidence of HRS in patients with chronic liver disease is not
well studied.
 4% of patients admitted with decompensated cirrhosis.
 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
 Some patients without ascites devolped the condition in the
setting of acute fulminant hepatic failure.
EPIDEMIOLOG
Y

9.  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.

10.  1.PERIPHERAL ARTERIAL VASODILATION :
 Rational and simple explanation to the hemodynamic
changes that takes place in cirrhosis ,HRS.
 Degree of hepatic decompensation  degree
of hyperdynamic circulation ,
 Degree of hepatic decompensation  1/
arterial BP.
 Reversal of HRS ,improvement of hemodynamics by
systemic vasoconstriction gives support to this
hypothesis.

11. 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

12.  2.stimulation of renal SNS :
  sympathetic tone in pts with cirrhosis.
 vena caval ligation -- increased intrahepatic
pressure -- renal sympathomimetic activity --wears
after anterior hepatic nerves are cut.
 Severing renal ,hepatic,spinal nerves abolishes the
response of decreased GFR ,RPF seen after
hepatocyte swelling.

13.  3.cardiac dysfunction :
 Myocardial contractility impaired.(  cirrhosis )
 Diastolic dysfunction  cirrhosis progression
 Hyperdynamic state being present
 Cause is diseased liver ,reversible after TRx
 BNP  , CVP  child pugh score ,ventricular wall
thickness.
 Neurohormonal activity - growth ,fibrosis – disturbed
relaxation .
 Inhibitory effect of TNF  ,NO on ventricular function.

14.  4.cytokines ,vasoactive mediators:
 Not a sole player.
 NO,TNF  ,endothelin , endotoxin,glucagon,increased PG s .
 Upregulation of e NOS activity,endotoxin ,inducible.
 Reduces pressor effect of vasoconstrictors.
 More in cirrhotics ,ascites.
 Renal vasoconstriction due to dimethylarginine - a
natural NO inhibitor.
 Reduced cyclooxygenase activity in renal medullary
tissue.

16.  In type I HRS ppting event identified in 70-100 % pts.
 More than one event in a patient.
 Bacterial infections
 Large volume paracentesis without albumin infusion.
(15%)
 GI bleeding
 Acute alcoholic hepatitis. (25%)
 SBP - 20-30% develop HRS.

17.  Diagnosis of HRS is made on certain predefined criteria
in the appropriate clinical setting
 Increasing s.creatinine in patients with cirrhosis and
acute fulminant liver failure itself is enough to
investigate for Hepatorenal syndrome
 All the major criteria are to be met
for the diagnosis of HRS and minor
criteria are just supportive and are not
essential to make the diagnosis

18. 1)Chronic/Acute liver disease with advanced hepatic failure or
portal hypertension
2)Serum creatinine >1.5mg/dl(reflecting decreased GFR),<40
ml/min
3)Absence of shock,bacterial infection,current or recent
treatment with nephrotoxic drugs,absence of renal or g.i.t
losses
4)No increase in renal function after diuretic withdrawal and
plasma volume expansion and intravenous albumin(1g/kg
bdy wt upto a maximum of 100g)
5)Proteinuria <500mg/dl, no USG evidence of renal
parenchymal damage (urine analysis) , no obstructive
uropathy.

19. Urine volume <500ml/24 hr
Urine sodium <10 meq/L
Urine plasma osmolality greater than plasma osmolality
Urine blood cells<50 per HPF
Serum sodium <130 meq/L

21. 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

22. It is the cirrhosis with rapidly progressive acute renal failure
Characterized by-
Rapid elevation of BUN and creatinine:100% increase with a level
reaching 2.5mg/dl in 2 weeks or a 50% reduction in initial 24 hr
clearance to < 20 ml/min
Rapidly progressive
Mortality reaching 80% with 2 weeks
Commonly has precipitating factors-SBP(20%)
-variceal hemorrhage
-acute alcoholic hepatitis
-drug induced(acetaminophen)
-acute hepatic injury from viral hepatitis
Deeply jaundiced ,coagulopathy
Death by hepatic plus renal failure,variceal bleeding.

23. Cirrhosis with sub acute renal failure
Characterized by-
Slowly increasing serum creatinine levels and slow
reduction of GFR(Takes weeks to months)
No precipitating factor
It has poorer prognosis and eventually progresses to type -
1 due to precipitating factors

24. Cirrhosis with type 1 or type 2 HRS superimposed on
chronic kidney disease or acute renal injury
85% of end stage cirrhotics have intrinsic renal disease
on renal biopsy
Diagnostic markers of HRS are absent

25. Fulminant liver failure with HRS
More than 50% of acute fulminant liver failure develop
HRS
Prognosis of HRS is superimposed on already poor
prognosis of acute fulminant liver failure.

26.  SYMPTOMS-
-distension of the abdomen
-change in mental status(confusion,delirium and
dementia)
-coarse muscle movements or muscle jerks
-dark coloured urine
-yellow skin
-↓sed urine output
-nausea and vomiting
-weight gain

27.  SIGNS
-Confusion
- icterus
- ascites
- abnormal reflexes
- decreased testicle size
- gynaecomastia
- sores on the skin

28.  Pre renal causes--- hemorrhage ,diarrhea,hypovolemia
 Intra Renal causes --- acute tubular necrosis,interstitial
nephritis.
 Post renal causes -- uropathy
 Diagnosis by exclusion.
 it is extreme example of prerenal failure.(Una <20 ,Fna <1,
Ucr/Pcr >40 ,Uosm/Posm >1.5 )

29.  Diagnosis depends mainly on s . creatinine levels as no
specific tests establish the diagnosis of HRS. (>1.5mg/dl)
 Though serum creatinine level is a poor marker of renal
function in cirrhosis (low muscle mass)
no other validated and reliable non invasive markers exist
for monitoring renal function in these patients.
 Inulin clearance is cumbersome and is not used clinically.
 Low GFR is defined by s cr >1.5 mg/dl without diuretic
therapy for at least 5 days.
 overestimates GFR by upto 50% .

30. CBP ,WBC : infection such as SBP if leucocytosis or bands are
present,a condition known to present with reversible
impairment in renal function
Serum electrolytes and renal function
Liver function test with PT (although the degree of liver failure
doesn’t correlate with the development of HRS,these are
essential for Child-Pugh scoring)
Blood cultures- for bacteremia particularly if no precipitant is
identified,is prudent( 20% SBP are culture -ve)
Cryoglobulins- in patients with hepatitis B and or C who can
develop renal failure from cryoglobulinemia.

31.  GENERAL MANAGEMENT:
 Type I HRS - hospitalization, type 2 - outpatient.
 CVP for assessing fluid status.
 Stop diuretics
 Tense ascites -paracentesis
 If > 5l of fluid removed ,then albumin is good as
volume expander.
 low salt diet,free water restriction -hyponatremia cases.
 HRS type-1 & 4 need intensive management

32.  Pharmacological treatment
 Surgical
 TIPS
 Artificial liver support
 RRT
 Liver transplantation.
 LKT

33.  Goal : reverse renal function
 Prolong survival until liver TRx.
 1.RENAL VASODILATORS
 2.SYSTEMIC VASOCONSTRICTORS.
 1.RENAL VASODILATORS:
 DIRECT renal vasodilators - DOPAMINE,FENOLDOPAM,PGs
 Antagonizing endogenous effect of renal vasocontrictors-
Sarlasin,ACEI ,endothelin antagonists.

34. 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, use was based on the observation of
low urinary levels of vasodilatory PGs.
The use of both the above drugs was not substanciated by any studies
RENAL VASOCONSTRICTOR ANTAGONIST
Sarlasin used in attempt to reverse renal vasoconstriction.
This inhibits the hemostatic response to hypotension and led to further
worsening of renal function .
N-ACETYLCYSTEINE
Mechanism of action is unknown but studies encourage optimism for
medical management where option for liver transplant is not
present

35.  None of the studies that used renal vasodilators
showed imrpovement in renal perfusion or GFR.
 Because of adverse effects
,lack of benefit the use of
renal vasodilators has been
abandoned.

36.  Most promising agents.
 Interruption of splanchnic vasodilation will relieve the
intense renal vasoconstriction.
 VASOPRESSIN ANALOGUES -ORNIPRESSIN ,TERLIPRESSIN
 SOMATOSTATIN ANALOGUE -OCTREOTIDE.
  ADRENERGIC AGONISTS - MIDODRINE,
NOREPINEPHRINE.

37.  VASOPRESSIN ANALOGUES:
 Marked vasoconstrictor effect.
 V1receptors on smooth muscle of arterial wall .
 Rx of acute variceal hemorrhage.
 Ornipressin -- ischemic adverse effects. (30% )
 Terlipressin – most common used drug now.
 Better response in type 2 HRS than in type 1 HRS.
 17-50% recurrence rate of HRS. – reversible.
 Duration of therapy is unclear.
 60-80% improvement in type IHRS
 To be given until s creatinine< 1.5 mg/dl ,or 15days.
 Liver disease occurs in 3 months of therapy if not TRx.

38.  OCTREOTIDE:
 An inhibitor of glucagon.
 Ineffective in type 2 HRS
 Alpha ADRENERGIC AGONISTS - MIDODRINE,NE
 Both are ineffective in type 2 HRS .
 Better response in type I HRS.
DRUG DOSE DURATION SIDE EFFECTS
TERLIPRESSIN 0.5-2mg every 4 hrs as
IV bolus
15 days Peripheral,cardiac,splanchnic
ishemia
NOREPINEPHRINE 0.5-3.0 mg/hr IV
infusion
15 days same
MIDODRINE 7.5-12.5 mg every 8 hrs
oral
?? Not reported

39. TREATMENT PROTOCOL
OF NORADRENALINE/TERLIPRESSIN PLUS
AIBUMIN FOR HRS:
 NA –Initial dose 0.139µg/kg/min iv infusion,if no increase in
MAP by 10mm Hg,  dose by 0.05µg/kg/min every 4thhrly up
to dose of 0.7µg/kg/min
 Terlipressin- 1mg iv bolus every 4th hrly.At day 3 if baseline
s. creatinine not reduced ≥25% , the dose up to 2mg every
4thhrly

40. Midodrine(alpha adrenergic blocker) and octreotide
(somatostatin analogue)
Rx protocol of midodrine plus octreotide therapy
Octreotide
initial dose:100µgm t.i.d SC
goal to increase upto 200µgm t.i.d SC
Midodrine
Initial dose:5mg,7.5mg,10mg t.i.d orally
goal to ↑dose upto 12.5mg to 15mg t.i.d if necessary
Because of oral and subcutaneous route of the drug
suitable for use in outpatient deparment

41. CONTRAINDICATIONS OF
VASOCONSRICTOR THERAPY:
 CAD
 Cardiomyopathies,
 Cardiac arrythmias,
 Cardiac/respiratory failure,
 Arterial HTN,
 Cerebrovascular disease,
 Peripheral vascular disease,
 Bronchospasm,asthma,
 Terminal liver disease,
 Advanced hepatocellular carcinoma,
 Age >70yrs

42.  Insertion causes reduction of portal pressure.
 Beneficial in patients with cirhhosis and refractory
ascites.
 M.O.A- suppression of putative hepatorenal reflex,
improvement in circulatory volume,ameiloration of
cardiac function.
 Unanswered observations
 1 . Parameters improve,but not normalize. After TIPS.
 2.maximum renal recovery is 2-4 wks.
 3.advanced cirrhotic patients are not benefited.
 4.pts underlying acute heart failure.

43. Is theoretically attractive therapy
It dramatically lowers portal pressure leading to ↓ pooling of
blood in splanchnic bed
But ↑venous return is inappropriately handled
And many patients do not meet the criteria for TIPS
insertion(i.e serum bilirubin <5mg/dl,INR <2 and Child-Pugh
score <12)
When these conditions are not met TIPS insertion may lead to
liver failure or intractable hepatic encephalopathy
Done only in patients with Child-Pughs A/B with criteria and
who do not respond to vasoconstrictor therapy
Patients with refractory ascites often proceed to the
development of HRS type -2 and TIPS in these patients may
lead better survival.

44. PERITONEOVENOUS SHUNTING
theoretically seems attractive because it leads to plasma
volume expansion and improvement of circulatory
function
Has no role in type-1 HRS
Important for patients type-2HRS who have refractory
ascites and are not candidates for orthotopic liver
transplant and do not tolerate frequent LVPs

45. Eliminates circulating mediators of splanchnic
vasodilatation & renal vasoconstriction
Provides hemodynamic benefit and decreases s. creatinine
Continous venovenous hemofilteration is better.
In Acute liver failure patients treated with porcine
hepatocyte based bioartificial liver reported renal
failure
no details provided
Currently these are being used in HRS but are not
advocated for its treatment.

46.  Currently three systems are available for albumin
dialysis.
 1.MARS
 2.PROMETHEUS
 3.SINGLE PASS ALBUMIN DIALYSIS (SPAD)

47.  Designed by Stange and Mitzner from Germany in 1993.
 Cell free ,modified dialysis technique.
 Three circuits - blood,albumin,renal.
 600 ml of 20% albumin acts as dialysate
 Removes both albumin bound,water soluble substances
by using a combination of albumin enriched
dialysate,CRRT.
 Removal of albumin bound bile acids (detrimental to
hepatocytes) ,kidney –stabilizes liver function.
 Removes water soluble TNF A , IL6 and NO.
 Substance . 50 KDa are not removed .

48.  First described in 1999 .
 Principle of fractioned plasma seperation and adsorption.
 Albumin permeable membrane ,size of 250kDa.
 Albumin passes through the membrane and adsorbers
that remove toxins.
 Reduction of both bilirubin,urea more > MARS.

49.  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.

50.  Controversial role in pts with type I HRS ,not undergoing
liver TRx.
 To be individualized.
 Indications:
 1.waiting for liver TRx
 2.developed volume overload
 3.intractable metabolic acidosis.
 4.hyperkalemia.
 Bridge to liver TRx.
 CRRT > HD - removes inflammatory cytokines - TNF A,IL-
6
 FUTILE IN pts on mechanical ventilator.

51.  Best treatment for suitable patients with HRS.
 RENAL SODIUM excretion,hemodynamic abnormalities
normalize in 1 month.
 Renal resistance index normalize in 1 year post
transplantation.
 Allocation is by MELD score.
 MELD score not beneficial for HRS pts.
 Prolonged hospitalizations required
 Renal failure persists for weeks post TRx.
 Post TRx reversal of HRS is 58%.

52. Long term survival following liver transplant is good
Mortality of individuals with HRS was as high as 25% within the
first month after transplantation(HRS patients with grater
hepatic dysfunction MELD score >36 are at greater risk of
early mortality)
high priority is given to type-1
But these patients are not transplanted because of the
precipitating event which initiated HRS and are extremely ill
with multiorgan failure and rapid course of the disease
providing insufficient time

53. In patients with HRS type -2 liver transplant is more
practical because of the absence of precipitating
factors,longer clinical course & less severe renal failure
In type-3 HRS both liver and kidney transplant in these
extremely ill patients is a dilemma.
only liver transplant may be beneficial given the
prospect of post op RRT
Patients with low MELD score and successful
vasoconstrictor therapy have lower post op
complications.
Further deterioration of renal function after liver
transplantation is transient and is thought to be due to
use of immunosuppressants that are
nephrotoxic(tacrolimus, cyclosporin)

54.  Younger recipients
 Nonalcoholic liver disease
 Low posttransplantation bilirubin
 Age of the donor

55.  Prolonged duration of RRT pretransplantation.
 h/o previous renal failure
 CKD on biopsy.

56. TYPE OF HRS TREATMENT
TYPE I HRS
Vasoconstrictors,albumin,TIP
S,liver Trx
TYPE 2 HRS Vasoconstrictors
,LVP,TIPS(ref),Liver Trx
TYPE 3 HRS CRRT, LKT
TYPE 4 HRS idealy LTx

57. Prompt treatment of precipitating factors of type-1
HRS like sepsis, shock, variceal hemorrhage,acute
alcoholic hepatitis and nephrotoxic drugs according
to standard guidelines
A trial has shown norfloxacin as prophylaxis for SBP
decreases HRS to 28% compared to 41%
Albumin administration at diagnosis and day 3 in
patients with SBP decreases HRS. (10%)
Pentoxyphylline 400mg tid for 28 days in alcoholic
hepatitis decreases HRS.( 24%)
However these are not proved in recent studies

58.  Worst prognosis of all complications of cirrhosis.
 Type 1 HRS without Rx < 2 weeks
 All pts in 8-10 weeks after onset of RF.
 Type 2 HRS - 6 months .

59.  1.best modality of therapy
 2.predictability of LKT versus a liver only transplant.
 3.how are vasoconstrictors compare with TIPS,MARS
 4.best to use vasoconstrictor?
 5.whether there is an independent beneficial effect of
albumin in HRS?
 6.why renal recovery rate is variable between centers.

60.  1.HRS is a functional reversible renal
failure in cirrhotic, fulminant liver failure
patients.
 2. patients with SBP ,who underwent LVP ,
had GI hemorrhage should be carefully
followed up as they are more prone for HRS.
 3 .diagnosis by exclusion ,based on major
criteria.
 4.type I HRS has high mortality ,HRS 2
prolonged survival ,type3 in CKD ,type 4
HRS - fulminant hepatic failure.
 5.ppting factors identified in type I HRS
,refractory ascites assosciated with type 2
HRS.
 6.TERLIPRESSIN is effective drug in
phramacological therapy..

61.  7.MARS is an upcoming procedure.
 8.Liver TRx is treatment of choice .
 9.MELD score does not work out for
HRS patients
 10.recovery depends on age,s
bilirubin,non alcoholic liver disease.
 11.role of LKT in patients with HRS to
be checked out.
 12.albumin infusion in patients with SBP
at 1.5 g/kg at admission,1 g/kg 48 hrs
later prevents HRS,pentoxyfilline in
alcoholic hepatitis.