2. Case Presentation
• 56 Yr old AA Female with PMH of cirrhosis
• C/o Diarrhea since April 2011.
• Abdominal distention
• Abdominal pain for 1 day, dull, aching, diffuse,
4/10 in intensity
• Associated with Nausea and Vomiting
• Hemetemesis , day of presentation.
• Denies fever, Chills
4. • Family history- HTN in mother
• Social history: Denies alcohol or drug abuse.
• ROS: b/l lower Extremity edema.
UGIB, Blood Transfusion.
• Paracentesis- September 15, 2011, 4.6 L
removed; August 1, 2011-6 L
5. Physical Exam
• Temp: 98.7 Pulse: 97 RR:20 Pulse Ox: 98% on
RA, BP: 134/70
• HEENT: Scleral Icterus, Conjunctival Pallor
• RS: Clear to auscultation, no respiratory distress
• CVS: Normal S1/S2
• Abdomen: Distended, Tense, no tenderness on
palpation
• Extremities: 3+ pitting edema B/l lower Extremities.
6. Diagnostic Tests and Studies
• WBC: 5.2, Hb: 7.5<- 8.6, Plt: 236
• Na:137, K+:3.4, BUN: 46, Creatinine: 8.0<-2.6
• Albumin: 2.5, T.bil: 1.5, Alk Phos: 155, U.Na+-10,
U.creat-520, FENa-0.1%
• AST: 195 ALT: 65 Complement levels - normal
• Colonoscopy(9/6/11): normal
• CT scan abdomen(7/11/11)-hepatic Cirrhosis, right
renal calculi, Findings of portal hypertension,
including moderate abdominopelvic ascites and
splenomegaly,Mild right renal atrophy and
compensatory hypertrophy of the left kidney
• USG abdomen: enlarged liver, portal hypertension,
moderate ascites, normal sized kidneys.
7. Hospital Course
• Admitted to ICU for UGIB and received blood
transfusion.
• Parcentesis done: no organisms.
• Underwent EGD, showed esophageal varices and got
banding for same.
• During stay in ICU had very poor UO, 8-10 ml/hr
• Medications in hospital: Protonix Gtt, Ceftriaxone.
• Her creatinine elevated at 7.9, GU c/s for foley
catheter, after foley placed Cr.8.1, Uo-20 ml/hr even
after receiving multiple fluid boluses.
• Patient was stable hemodynamically and her creatinine
improved to 7.7, the patient was advised to be
transferred to UPEN for further evaluation and possible
liver transplant.
8. • But she was denied for liver transplant secondary to
high BMI.
• She was transferred to floor and her creatinine was
not improving and she was C/o shortness of breath
and underwent paracentesis and felt better.
• She was also started on midodrine and octreotide
without much improvement
• She developed uremic symptoms and thus started
on dialysis.
9. HepatoRenal Syndrome
(International Ascites Club Definition)
• HepatoRenal syndrome is the clinical condition that
develops in patients with Chronic liver disease and
advanced hepatic failure and portal HTN
characterized by impaired renal function and marked
abnormalities in arterial circulation and activity of
endogenous vasoactive systems. In the kidney,
there is marked renal vasoconstriction that results in
low GFR. There is also vasoconstriction in other
vascular territories such as muscle, spleen and
brain. In the splanchnic circulation, there is an
intense arteriolar vasodilatation that results in
reduction of total systemic vascular resistance and
arterial hypotension. A similar syndrome can also
develop in the setting of acute liver failure.
10. HepatoRenal Syndrome
• The development of acute renal failure in a
patient who usually has advanced liver disease
due to cirrhosis, severe alcoholic hepatitis, or
(less often) metastatic tumor
• The HepatoRenal syndrome usually represents
the end-stage of a sequence of reductions in
renal perfusion induced by increasingly severe
hepatic injury.
11. Pathogenesis
• Arterial vasodilatation in the splanchnic circulation,
which is triggered by portal hypertension, appears
to play a central role in the hemodynamic changes
and the decline in renal function in cirrhosis
• The presumed mechanism is increased production
or activity of vasodilators, mainly in the splanchnic
circulation, with nitric oxide thought to be most
important
• Splanchnic arterial vasodilatation triggers intense
homeostatic neurohumoral response causing
sodium retention and solute-free water retention
and finally, severe renal vasoconstriction due to
increase in plasma renin activity and
norepinephrines.
12. • Most accepted theory considers that renal
vasoconstriction is consequence of the extreme
under filling of systemic arterial circulation, which
activates homeostatic vasoconstrictive systems,
whose effect on kidney cannot be
counterbalanced by either renal or systemic
vasodilators.
13. Pathophysiology
• Incidence of HRS in patients with cirrhosis
hospitalized for Ascites is approx 10%.
• Probability of developing HRS in patients with
cirrhosis and Ascites is 18% at 1 yr and increase
to 39% at 5 yrs.
• Renal failure is associated with oliguria, marked
Na+ retention, and spontaneous dilutional
hyponatremia.
14. Types Of HepatoRenal
Syndromes
Type 1
• Rapid and progressive impairment of renal
function as defined by doubling of initial S.
Creatinine to level higher than 2.5 mg/dl
or 50% reduction of initial 24-h creatinine
clearance to a level lower than 20 ml/min < 2
wks.
• Rapid and aggressive course ( very ill in days or
weeks)
• Develops spontaneously
• large volume paracentesis (>5 L) without I.V.
albumin may precipitate in 20% cases.
15. • Bacterial infection, particularly SBP recognized
as precipitating cause( 1/3 rd cases with SBP)
• Without treatment median survival rate is 1
month.
• MELD score with type of HRS have an
independent prognostic value in survival.
• Most patients with Type 1 HRS have MELD
score of >20.
16. Type 2
• Impairment in renal function with serum creatinine
>1.5 mg/dl that does not meet criteria for type 1.
• Less severe and stable reduction in GFR
• Serum creatinine levels are usually less than 2.0
mg/dl.
• Main clinical consequence is diuretic-resistant
ascites due to combination of intense sodium
retention and reduced GFR.
• Expected survival is longer
• If MELD score >20 in type 2 HRS associtaed with
worse prognosis.
17. Parameters associated with a higher risk for
HRS development in non-azotemic patients
with cirrhosis and Ascites.
• Previous episodes of Ascites
• Poor nutritional status
• Moderately increased BUN( 30 mg/dl)
• Moderately increased creatinine( 1.5 mg/dl)
• Low serum Na+(<130 Meq/L)
• Low urinary Na+ excretion(<10 Meq/l)
• High plasma renin activity
• Low MAP(<85mm Hg)
• Reduced solute-free water excretion after water
load(<3 ml/min)
• Increased plasma norepinephrines
19. Diagnostic Criteria
Major:
• Low GFR, as indicated by S. creat >1.5 Mg/Dl or
24-h Creatinine Clearance < 40 Ml/min
• Absence of shock, on- going bacterial infection,
fluid losses, and current treatment with
neprotoxic drugs
• No sustained improvement in renal
function( decrease in S. creatinine to < 1.5 mg/dl
or increase in Creatinine clearance to >40
ml/min) following diuretic withdrawal and
expansion of plasma volume with 1.5 L of
plasma expander.
• Proteinuria <500 Mg/d and no USG evidence of
obstructive uropathy or parenchymal renal
21. Prevention
• HRS can be prevented in 2 clinical settings:
• SBP- administration of albumin( 1.5 g/kg body
weight at diagnosis of infection and 1 g/kg body
weight 48 hrs later), prevents circulatory
dysfunction.
• Incidence of HRS in SBP patients receiving albumin
together with antibiotics is 10% compared to 33%
not receiving albumin.
• Hospital mortality lower(10% in patients receiving
albumin Vs not receiving same(29%)
• Acute Alcoholic Hepatitis: administration of
pantoxifylline, an inhibitor of TNF-Alpha( 400 mg TID
orally for 28 d) reduces incidence of HRS from 35%
to 8% and mortality from 46% to 24%.
22. Treatment
• Diuretics should be held
• Saline infusions should not be administered, as it
leads to increase in edema and Ascites. because of
dilutional hyponatremia in these patients, water
restriction (1000 ml/d) should be instituted.
• Early identification of bacterial infections and
treatment with the broad spectrum antibiotics
should be started.
• Patient should be evaluated for liver transplant and
if already in the list, the status should be updated.
specific treatment with vasoconstrictors and
albumin should be initiated as soon as the
diagnosis is suspected.
23. Treatment
• Pharmacologic therapy:
• While considering pharmacologic therapy, patients
should be evaluated for Liver transplant.
• Renal vasodilators:
• Dopamine: in suppressor doses, but studies shown
no or minimal effect on the GFR, thus no data to
support use in clinical practice.
• Prostaglandins and PG analog: rationale in use is
renal vasoconstriction in HRS is partially secondary
to reduced intrarenal synthesis of PGs.
• No consistent beneficial effect on renal function
were observed after IV or intra-arterial
administration of PGA1 or PGE2.
24. • Oral administration of misoprostol(PGE1 analog)
was found to improve renal function in 1 study
but was not confirmed in subsequent
investigation.
• Side effect of PGs- Diarrhea.
• Other approaches such as endothelin
blockers(BQ123) and N-acetyl cysteine are
promising but larger trails needed for
confirmation.
25. • Systemic vasoconstriction with plasma
expansion seem to be best therapy, particularly
in HRS type 1.
• Vasoconstrictors- vassopressin
analogs( terlipressin) vasoconstictor effect by
action on V1 receptors with low V2 receptor
agonist activity
• Somatostatin analog( octreotide) acts as
glucagon inhibitors and alpha adrenergic
agonists( midodrine and noradrenaline), cause
vasoconstriction by acting on alpha receptors.
• Ischemic side effects of terlipressin is less as
compared to vassopressin and ornipressin( only
5-10% compared to 30-40%)
26. • Administration of terlipressin and albumin
is associated with significant improvement
in GFR and reduction of S. creatinine <1.5
mg/dl in patients with Type 1 HRS.
• Patient with child-pugh score >13 and
those not receiving albumin do not
respond well.
• Chance of recurrence after stopping the
treatment
• Treatment with terlipressin can be
stopped, if S. creatinine does not
decrease by 50% after 7 days of
maximum dose or if no reduction in S.
creatinine after first 3 days.
27. • If early response present treatment, treatment
should be extended until reversal of HRS or
maximum of 14 days.
• Administration of midodrine with octreotide and
albumin improves renal function.
• Treatment titrated based on MAP, optimum
increase is by at least 15mm Hg.
• Therapeutic approach limited to only 2 studies,
with total of less than 20 patients.
• In all cases there was marked improvement in
the GFR and renal perfusion and suppression of
renin, aldosterone, norepinephrine and AVP to
normal or near normal levels.
• Octreotide is ineffective when administered
alone.
28. • Administration of noradrenaline ( 0.5-3 mg/h)
with albumin for minimum of 5 days resulted in
increase in MAP, improvement of renal function,
marked reduction in renin and aldosterone.
• Titration of Noradrenaline based on increase in
MAP of atleast 10 mm Hg or increase in 4-h
urine output to more than 200 ml.
• Single episode of reversible myocardial
hypokinesia., no ischemic events.
• Limited validity secondary to lack of large
randomized studies.
29. Recommendations
• These drugs should be used for at least 7-10
days, as renal improvement occurs slowly.
• Therapy should be aimed at reducing S.
creatinine level below 1.5 mg/dl.
• Concomitant administration of albumin(1g/Kg on
first day, followed by 20-40 g/d) as plasma
expander.
• Because of limited information and possibility of
side effects, treatment of vasoconstrictors
should be restricted to patients with Type 1
HRS.
30. Recommended Dosages
• Midodrine: 7.5 mg orally TID with an increase to
12.5 mg TID if needed and octreotide: 100 mcg
Sc TID with increase to 200 Mcg TID, if needed.
• Noradrenaline: Titration of 0.5 to 3 mg/hr
continuous IV infusion.
• Terlipressin: 0.5 mg IV every 4 hrs, can increase
dose in stepwise manner (i.e. every 2 days) to 1
mg/4 hrs and than up to 2 g/4 hrs in cases
where there is no reduction in S. creatinine.
32. Therapeutic Response to Vasoconstrictors in Hepatorenal
Syndrome Parallels Increase in Mean Arterial Pressure: A
Pooled Analysis of Clinical Trials.
Velez JC, Nietert PJ.
• AIM: To explore across all tested
vasoconstrictors whether achievement of a
substantial increase in arterial blood pressure is
associated with recovery of kidney function in
HRS.
• RESULT: An increase in MAP is associated
strongly with a decrease in serum creatinine
level, but is not associated with an increase in
urinary output. Most studies tested terlipressin
as vasoconstrictor, whereas fewer studies tested
33. ornipressin, midodrine, octreotide, or
norepinephrine. Furthermore, a decrease in PRA
correlated with improvement in kidney function.
• CONCLUSIONS: An increase in MAP during
vasoconstrictor therapy in patients with HRS is
associated with improvement in kidney function
across the spectrum of drugs tested to date.
These results support consideration for a goal-
directed approach to the treatment of HRS.
34. Hepatorenal syndrome: do the vasoconstrictors work?
Leung W, Wong F.
Gastroenterol Clin North Am. 2011 Sep;40(3):581-98.
• Abstarct: The development of hepatorenal
syndrome (HRS) is related to many changes
associated with advanced cirrhosis. Because
vasoconstrictors correct systemic and
splanchnic hemodynamic abnormalities, they
are effective treatments for HRS, although only
in approximately 40% of HRS patients.
Emerging data show that combination treatment
with vasoconstrictors and TIPS may yield better
outcomes than either alone. All HRS patients
should be assessed for liver transplantation.
Reversing HRS before transplantation is
associated with better long-term survival.
35. Transjugular intrahepatic
Portosystemic shunt (TIPS)
• Rationale is by reducing the portal pressure may
improve circulatory function and suppress RAAS
and SNS activities.
• TIPS may improve Renal function and GFR as
well as reduce activities of RAAS and SNS in
patients with Type 1 HRS.
• Studies with assessing TIPS for type 1 HRS
have included patients with relatively preserved
liver function.
• An approach combining TIPS with
vasoconstrictive therapy had excellent outcomes
with improvement in renal function.
36. • In Type 2 HRS, TIPS reduce ascites and
improve renal function.
• One report, however, suggested that the
reduction in intrahepatic pressure induced by
this modality may prevent the development of
the hepatorenal syndrome. This retrospective
study evaluated 204 patients with variceal
bleeding who were treated with either a
portasystemic shunt or sclerotherapy (or other
nonshunt modality) . Shunting was associated
with a lower incidence of ascites (15 versus 73
percent) and hepatorenal syndrome (4 versus
21 percent), a higher incidence of
encephalopathy, and no difference in overall
patient survival.
37. Dialysis
• HD and PD- sporadic cases of improvement of renal
function.
• HD not routinely recommended for HRS but can be
option for liver transplant candidates as bridge to
transplantation
• Especially inpatients who failed vasoconstrictive and
TIPS therapy or develop severe volume overload,
metabolic acidosis, or refractory hyperkalemia.
• Data on extracorporeal albumin dialysis system, that
is molecular adsorbent recirculating system (MARS)
seems beneficial but only 1 study available.
• Albumin dialysis is associated with increased BP
secondary to ability of the albumin to bind
vasodilators.
38. Liver Transplantation
• Best treatment option
• Long term outcomes are good, survival 85% at 1
yr and 73% at 3 yrs.
• Presence of HRS before the transplantation
increase the morbidity and mortality.
• Patients with HRS type 1 have poor prognosis,
thus should be given immediate priority for liver
transplantation.
• Patients with HRS type 2 but MELD score >20,
should be given priority too.
• If patients treated successfully with
pharmacological therapy, outcomes after liver
transplant are similar to those without HRS.
39. Combined liver– kidney transplantation is
indicated for those with irreversible kidney injury.
Otherwise, there is some merit in performing a
liver transplant first and only considering a
kidney transplant later.
40. References
• Schiff’s disease of the liver, tenth edition, Authers: Eugene R. Schiff et al
• Text book of Gastroenterology, fifth edition, Authers: Tadataka Yamada et al
• Hepatorenal Syndrome, Charles KF Ng, Michael HM Chan, Morris HL Tai,
and Christopher WK Lam*
• Levinsky NG: Nephrology Forum: Refractory ascites in cirrhosis. Kidney Int
14:93–102, 1978
• DiBona GF: Nephrology Forum: Renal neural activity in hepatorenal
syndrome. Kidney Int 25:841–853, 1984
• Fullen WD: Hepatorenal syndrome: reversal by peritoneovenous shunt.
Surgery 82:337–341, 1977
• Pladson TR, Parrish RM: Hepatorenal syndrome: recovery after
peritoneovenous shunt. Arch Intern Med 137:1248–1249, 1977
• Levy M: Hepatorenal syndrome, in The Kidney: Physiology and
Pathophysiology (2nd ed), edited by Seldin DW, Giebisch G, New York,
Raven, 1992, pp 3305–3326
• Epstein M: Hepatorenal syndrome, in The Kidney in Liver Disease (3rd ed)
edited by Epstein M, Baltimore, Williams & Wilkins, 1988, pp 89–118
