hepatorenal syndrome , simplified and detailed...

1. M.Farouk HRS
Hepatorenal
Syndrome
Definition
Pathogenesis
Diagnosis
Treatment
Research points
TaKeHoMeMeSsAgEs
By
Mohamed Farouk Ali
M.Sc., Specialist of Tropical medicine and
Gastoenterology
Dr.mfarouk.git@hotmail.com

2. M.Farouk HRS

3. M.Farouk HRS
Can
we prevent occurence of HRS?
Can
we predict it’s occurrence?
Can
we diagnose HRS early?
Do
we miss diagnosing some patients with HRS?
Should I Give up,
if the patient do not respond to vasopressor therapy?

4. Hepatorenal Syndrome
Definition
The occurrence of renal failure
in a patient with advanced liver disease
in the absence of an identifiable cause of renal failure.
Thus, the diagnosis is essentially by exclusion of other causes of
renal failure

5. Hepatorenal Syndrome
Definition
Functional
problem
Advanced
liver
diseaseAbsence of
identifiable
cause
Potential
Reversible

6. July 1956
M.Farouk HRS
The first detailed description of HRS
by Hecker and Scherlock

7. What about the
pathogenesis
?
M.Farouk HRS

8. Story
Advance
d livear
disease
Renal
vasoconstric
tionM.Farouk HRS
Not
Well
understo
od

9. The Hallmark is
Renal
vasoconstricti
on
M.Farouk HRS

10. Splanchnic Steal Phenomenon
M.Farouk HRS

11. 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
M.Farouk HRS

12. increasingCOP
Splanchnic Steal Phenomenon
ADH
ActivationofSympatheticnervoussystem
Activationof
Reninangiotensinaldosteronsystem
Body’s defence will act against that vasodilatation
not enough to
correct the
haemodynamic
instabilty
Failed trial
Sometimes,
Decreased COP
caused by cirrhotic
cardiomyopathy
Endothelin
M.Farouk HRS

13. Splanchnic Steal Phenomenon
Splanchnic region,
Unfortunatelly,
will respond poorly to vasoconstrictive mechanisms
Vasoconstriction elsewhere will occur
Renal vasoconstriction
Decreased activity of renal vasodilatory factors:
PGs, NO
M.Farouk HRS
Increased release of natreuretic peptides
But not enough to correct renal vasoconstriction
More splanchnic vasodilataion….
More steal of blood from renal vessels…
More renal vasoconstriction…
More progress…

14. Splanchnic Steal Phenomenon
Renal vasoconstriction
Kidney
Angina
Kidney
ischaemia
Impaired
renal
function
M.Farouk HRS
This may explain the difference among patients
in the intensity and the course of the disease
Imbalance between
vasoconstrictors and vasodilators

15. HRS
Type 2Type 1
Moderate, steady renal failure with
a serum creatinine of >1.5 mg/dl.
arises spontaneously and is the main
underlying mechanism of refractory
ascites.
Rapidly progressive renal failure that
is defined by
doubling of initial serum creatinine
to a level >2.5 mg/dl
or by 50% reduction in creatinine
clearance to a level <20 ml/min
in <2 wk
a precipitating factor frequently is
identified
M.Farouk HRS

16. M.Farouk HRS
If you focus on problems you will have more problems
If you focus on possibilities you will have more opportunities

17. Now,
How can I
diagnose it
?
M.Farouk HRS

18. 1996 The International Ascites Club
Major criteria
Additional criteria
M.Farouk HRS

19. 2005 The International Ascites Club
New criteria
M.Farouk HRS

20. 2005 The International Ascites Club
1.Cirrhosis with ascites
2.Serum creatinine >133 μmol/l (1.5 mg/dl)
3.No improvement of serum creatinine (decrease to a level of ≤133 μmol/l) after at least
two days of diuretic withdrawal and volume expansion with albumin. The recommended
dose of albumin is 1 g/kg body weight per day up to a maximum of 100 g/day
4.Absence of shock
5.No current or recent treatment with nephrotoxic drugs
6.Absence of parenchymal kidney disease as indicated by proteinuria >500 mg/ day,
microhematuria (>50 red blood cells per high power field) and/or abnormal renal
ultrasonography
New criteria
M.Farouk HRS

21. Serum creatinine
• loss of muscle mass
• reduced dietary protein intake
• excerise less than normal
• impaired liver function
• ethnic
• sex
Therefore, false negative diagnosis of HRS is relatively
common
M.Farouk HRS

22. M.Farouk HRS
RIFLE classification
(R- renal risk, I- injury, F- failure, L- loss of kidney function, E- end- stage renal disease)
Definition
abrupt (≤48 h) reduction in kidney function
manifested by an absolute increase in serum creatinine of ≥26 μmol/l (0.3 mg/dl),
equivalent to a ≥50% increase in serum creatinine (1.5- fold from baseline)
or a urine output of <0.5 ml/kg/h for more than 6h.
The application of these AKI criteria to patients with cirrhosis could lead to the
identification of many patients with acute renal dysfunction, normal serum creatinine
levels but low GFR.
However, the real usefulness of the AKI criteria must be tested appropriately in the
cirrhotic population before recommending these criteria for clinicians to use in clinical
practice.
AKI

23. M.Farouk HRS

24. Renal
Impairment
Hepatorenal
syndrome
Other
causes
M.Farouk HRS

25. Renal failure
)serum creatinine >133 mol/L(
Hepatorenal syndrome
Prerenal failure
Fluid losses
Shock
Infection-induced renal failure
Nephrotoxic
renal failure
Nephrotoxic drugs
Abnormal renal
ultrasonography
Historyand
physicalexamination
Bloodandurine
chemistries
Renal
ultrasonography
Parenchymal renal disease
Signs of infection
Persistence of renal
failure after
resolution of infection
Proteinuria and/or
haematuria
Acute tubular necrosis
“urinary IL-18 (interleukin -18),
NGAL(neutrophil gelatinase
associated lipocalin)”
M.Farouk HRS

26. M.Farouk HRS
Don’t miss the possibility of occurance of
these major conditions that is
associated with acute renal failure
in patients with cirrhosis
•Pancreatitis
•Decreased effective intravascular volume
congestive heart failure or other causes of myocardial failure
•Anaphylaxis
•Renal artery or renal vein occlusion by thrombosis; atheroembolism
•Effect of increased intra abdominal pressure on renal perfusion and renal
function???

27. Incidence
A multicenter retrospective study
423 patients with cirrhosis and ARF
ATN (35%)
Prerenal failure (32%)
HRS (26.6%) Type1 20% & Type2 6.6%
M.Farouk HRS

28. M.Farouk HRS
1. Doppler ultrasound Early detection of renal vasoconstriction
2. dilutional hyponatremia
3. low urinary sodium
4. reduced plasma osmolality
5. low arterial BP
6. high plasma renin activity
Olivera-Martinez et al., 2012
suggested that:
early treatmen might
increase survival

29. 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
Large-volume paracentesis without albumin infusion
Gastrointestinal bleeding
Acute alcoholic hepatitis
•large-volume paracentesis without albumin expansion precipitates type 1 HRS
in 15%
•25% of patients who present with acute alcoholic hepatitis eventually develop
HRS
•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.
M.Farouk HRS
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)

30. In type 2 HRS and in some patients with type 1 HRS,
no precipitating factor can be identified.
M.Farouk HRS

31. M.Farouk HRS

32. Treatment
M.Farouk HRS

33. General Measures
Once diagnosed, treatment should be started early in order to prevent the progression
of renal failure.
An excessive administration of fluids should be avoided to prevent fluid overload and
development/progression of dilutional hyponatremia.
Potassium-sparing diuretics should not be given because of the risk of severe
hyperkalemia.
Careful Monitoring:
•urine output,
•and arterial pressure, as well as other standard vital signs.
•Ideally central venous pressure should be monitored to help with the management of
fluid balance and prevent volume overload.
•Patients are generally better managed in an intensive care or semi-intensive care unit
(Level A1).
M.Farouk HRS

34. Use of antibiotics
•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
•There are no data on the use of antibiotics as empirical treatment for unproven infection in
patients presenting with type 1 HRS (Level C1).
Use of beta-blockers
There are no data on whether it is better to stop or continue with beta-blockers in patients
with type 1 HRS who are taking these drugs for prophylaxis against variceal bleeding (Level
C1).
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 is useful in relieving
patients’ discomfort (Level B1).
Use of diuretics
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
hyperkalemia (Level A1).
M.Farouk HRS

35. Pharmacological
RRT
TIPS
Artificial liver support
liver transplantation
M.Farouk HRS

36. 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
M.Farouk HRS

37. +
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.
M.Farouk HRS

38. When stop?
on maximum dose:
If no response …………. stop after 4days
If partial response (<50% reduction in serum creatinine)………… stop after 7days
If response ………… stop on reversal, with maximum 14 days
M.Farouk HRS

39. •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.
M.Farouk HRS

40. 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.
M.Farouk HRS

41. •Treatment is effective in 40–50% of patients, approximately.
M.Farouk HRS

42. •The most frequent side effects of treatment:
are cardiovascular or ischemic complications
M.Farouk HRS

43. 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.
M.Farouk HRS

44. •Recurrence after withdrawal of
therapy is uncommon and
retreatment with terlipressin is
generally effective.
M.Farouk HRS

45. +
+
100 mic.g/8 h
subcutaneously,
with an increase to
200 mic.g/8 h
2.5 to 7.5 mg/8 h
with an increase to
12.5 mg/8 h
M.Farouk HRS

46. 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.
M.Farouk HRS
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).
Noradrenaline+albumi
n
Terlipressin+albumin
Complete response 75% 80%
Noradrenaline Terlipressin
cost 15fold

47. M.Farouk HRS
Comparative study :
Noradrenaline
)0.1-0.7μg/kg/min(+
albumin
Midodrine (5-15mg(+
octreotide (100-200 μg
subcutaneously 3 times(
+albumin
Complete response 73% 75%
recurrence 18% 25%

48. Renal
Vasodilators
M.Farouk HRS
Theoretically, supposed to be successful
But
Unfortunately,
None of the studies that used renal vasodilators showed improvement in renal
perfusion or GFR
By direct renal vasodilators
(dopamine and prostaglandins)
By antagonizing the endogenous effect of renal vasoconstrictors
(saralasin, angiotensin-converting enzyme inhibitors, and endothelin
antagonist).
Barnardo et al. and Bennett et al.,
low-dose dopamine infused for up to 24 h
improved cortical blood flow and improved angiographic appearance of renal
cortical vasculature
without improvement in GFR or urine flow.

49. M.Farouk HRS
Attempts to use dopamine in combination with vasoconstrictors
conferred a better success rate, but this could be attributed to
vasoconstrictor therapy.
Similarly, the oral prostaglandin-E1 analog misoprostol or intravenous
prostaglandin infusion did not induce significant changes in GFR or sodium
excretion. Improvement in renal function occurred in one report but could
be explained by volume expansion.
The endothelin-A antagonist BQ-123 demonstrated a dose-dependent
renal improvement in three treated patients, but there still is controversy
over the role of endothelin blockers in HRS because subsequent studies
showed a paradoxic vasodilating effect of endothelin in patients with
cirrhosis.

50. Because of adverse effects and lack of benefit, the use of renal
vasodilators in HRS largely has been abandoned
M.Farouk HRS

51. M.Farouk HRS
There is no line of therapy prevent death
All therapies for all diseases just prolong survival
Don’t worry
We still have more therapeutic lines

52. 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.
31 patients :
•type 1 and type 2 HRS
•not candidates for liver transplantation
After TIPS, survival was:
3 months ………… 81%
6 months ………… 71%
12 months ……..… 48%
18 months ……..… 35%
 7 dialysis-dependent patients …………. 4 discontinued dialysis
Moreover, liver transplantation was performed in two patients 7 mo and 2 yr after
TIPS, when the medical condition that precluded transplantation has abated.
Transjugular intrahepatic portosystemic shunts
M.Farouk HRS

53. unanswered observations
First, the clinical and biochemical parameters, although improved, still do not normalize
after TIPS, suggesting that TIPS does not correct all of the underlying mechanisms of HRS.
Second, the maximum renal recovery is delayed to 2 to 4 wk after TIPS insertion, and the
renal capacity to excrete sodium still is impaired. The cause of this delay and the inability
to normalize salt excretion are not clear.
Third, patients with advanced cirrhosis are at risk for worsening liver failure and/or
hepatic encephalopathy and are not candidates for TIPS.
Fourth, TIPS has the potential for worsening the existing hyperdynamic circulation or
precipitating an underlying acute heart failure; therefore, careful attention to the cardiac
status is required.
M.Farouk HRS

54. 14 patients:
•cirrhosis and type 1 HRS
•oral midodrine and intravenous octreotide with albumin infusion
•followed by TIPS insertion in selected patients with preserved liver function (5 patients)
The exciting finding was:
persistent improvement in serum creatinine, RPF, GFR, and natriuresis after TIPS
insertion, reduction in plasma renin and aldosterone levels 1 mo after TIPS.
All five patients who received combined therapy:
were alive 6 to 30 mo after TIPS,
with only one patient requiring liver transplantation 13 mo afterward.
patients who responded to vasoconstrictors and did not receive TIPS:
either died (three patients) or required a liver transplant (two patients).
M.Farouk HRS

55. There is a group of patients whom TIPS insertion might prolong survival enough either:
to receive a liver transplant or,
if they are not candidates, to stay off dialysis
(Wadei et al., 2006)
Combination therapy may preclude the need for future liver transplantation and
improve survival compared with vasoconstrictor therapy alone
(Wadei et al., 2006)
TIPS is currently considered an experimental therapy for HRS,
that can be considered in a Childs-Pugh class A or B patient,
who meets the criteria for TIPS insertion
(i.e, serum bilirubin <5 mg/dL, INR <2, and Childs-Pugh score <12),
and who fails to respond to vasoconstrictor therapy and plasma volume expansion
(Munoz SJ, Med Clin N Am 92 (2008) 813–837)
TIPS is a valuable option in patients with severe Acute alcoholic hepatitis complicated
by HRS and are waiting for liver transplantation.
(Testino et al., 2012)
M.Farouk HRS

56. Renal replacement therapy
M.Farouk HRS
Precautions that should be taken in consideration:
Dose of anticoagulants
Dose of Sodium citrate that is metabolized by the liver and the body clearance of
this compound has been shown to be significantly reduced in critically ill cirrhotic
patients.
Monitor serum ionized calcium level and blood pH.
Both hemodialysis or continuous venous hemofiltration, have been used to treat
patients with type 1 HRS.
However, published information is very scant.
immediate treatment with renal replacement therapy:
severe hyperkalemia,
metabolic acidosis,
and volume overload
Peritoneal dialysis may be
better tolerated by cirrhotic
patients than hemodialysis.
•enables removal of the
ascites fluid
•does not expose patients to
anticoagulants.

57. Renal replacement therapy
M.Farouk HRS
Renal replacement therapy may be useful in patients
who do not respond to vasoconstrictor therapy, and who
fulfill criteria for renal support.

58. (MARS) the molecular adsorbents recirculating system
Prometheus
may have beneficial effects in patients with type 1 HRS.
more data are needed.
With more encouraging data, this may become a new therapeutic tool in treatment of
HRS, serving as a possible bridge to transplantation.
Artificial liver support systems
M.Farouk HRS
In patients with cirrhosis, refractory ascites and type 1 HRS not responding to
vasoconstrictor treatment:
MARS is ineffective in improving systemic haemodynamics and renal function despite
reduction in NO levels.
(Wong et al.,2010)

59. Liver transplantation is the treatment of choice for both type 1 and type 2 HRS.
in type 1 HRS 3year Survival rates: 65%.
The lower survival rate compared to patients with cirrhosis without HRS:
is due to the fact that renal failure is a major predictor of poor outcome after
transplantation.
Moreover, patients with type 1 HRS have a high mortality whilst on the waiting list and
ideally should be given priority for transplantation.
patients who have been under prolonged renal support therapy (8-12 weeks):
Need combined liver–kidney transplantation
Treatment of HRS before transplantation (i.e., with vasoconstrictors) may improve
outcome after transplantation.
The improvement in serum creatinine and MELD score after treatment:
should not change the decision to perform liver transplantation since the prognosis after
recovering from type 1 HRS is still poor.
Liver Transplantation
M.Farouk HRS

60. M.Farouk HRS

61. 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)
Patients who present with SBP should be treated with intravenous
albumin since this has been shown to decrease the incidence of
HRS and improve survival (Level A1).
There are some data to suggest that
treatment with pentoxifylline decreases the incidence of HRS in
patients with severe alcoholic hepatitis and advanced cirrhosis &
treatment with norfloxacin decreases the incidence of HRS in
advanced cirrhosis.
But further studies are needed (Level B2).
M.Farouk HRS
Prevention of HRS

62. M.Farouk HRS

63. Research points
For our department
Role of RIFLE staging system for AKI in cirrhotic patients in
diagnosis of hepatorenal syndrome especially in cases with
normal creatinin values.
M.Farouk HRS
Repeated measurement of serum
creatinine over time, particularly in
hospitalized patients, is helpful in the
early identification of HRS (Level B1).

64. Research points
For our department
Use of beta-blockers: There are no
data on whether it is better to stop
or continue with beta-blockers in
patients with type 1 HRS who are
taking these drugs for prophylaxis
against variceal bleeding (Level C1).
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 is useful in relieving patients’ discomfort
(Level B1).
M.Farouk HRS

65. Research points
For our department
There is very limited information with respect to the use of
norepinephrine or midodrine plus octreotide, both in association
with albumin in patients with type 1 HRS (Level B1).
There are no data on the use of antibiotics
as empirical treatment for unproven
infection in patients presenting with type 1
HRS (Level C1).
M.Farouk HRS

66. Research points
For our department
TIPS: more studies are needed in
type 1 HRS and there is no
comaparative studies with
standard medical therapy in type 2
HRS.
There are insufficient data on the impact of Terlipressin plus
albumin on clinical outcomes in patients with type 2 HRS (Level B1).
M.Farouk HRS

67. Research points
For our department
M.Farouk HRS
There are very limited data on artificial liver support systems, and
further studies are needed before its use in clinical practice can be
recommended (Level B1).

68. Research points
For our department
M.Farouk HRS
Role of renal biopsy to help plan
the further management,
including the potential need for
combined liver and kidney
transplantation.

69. ‫فإن‬ ,‫فأوجز‬ ‫وعظت‬ ‫"إذا‬
"‫بعضا‬ ‫بعضه‬ ‫ينسي‬ ‫الكل م‬ ‫كثرة‬
‫عنه‬ ‫ا‬ ‫رضي‬ ‫الصديق‬ ‫بكر‬ ‫أبو‬
M.Farouk HRS

70. TaKeHoMeMeSsAgE
s
We must identify precipitating factors and
prevent it, and if occurred it must be
treated early and appropriately
We have to predict occurance of HRS and
treat it early
Put in consideration overestimation (other
causes of renal imparement difficult to
be differentiated from HRS) and
underestimation of HRS (patients with
renal impairment despite S.creatinine
less than 1.5mg/dl and urine out put
that seems to be within normal)
M.Farouk HRS

71. TaKeHoMeMeSsAgE
s
the first line therapeutic agent for type 1
HRS is?
a.Midodrine 2.5 to 7.5 mg/8 h and
octreotide 100 mic.g/8 h subcutaneously,
with an increase to 12.5 mg/8 h and 200
mic.g/8
b.Terlipressin (1 mg/4–6 h intravenous
bolus) in combination with albumin
M.Farouk HRS

72. TaKeHoMeMeSsAgE
s
Recurrence of type 1 HRS after
discontinuation of terlipressin therapy is
relatively uncommon?(Level A1).
a.Treatment with terlipressin should be
repeated and is frequently successful.
b. Don’t try to repeat terlipressin as it will
have no role then.
Contraindications to terlipressin therapy
include ischemic cardiovascular diseases.
Patients on terlipressin should be carefully
monitored for development of cardiac
arrhythmias or signs of splanchnic or digital
ischemia, and fluid overload, and treatment
modified or stopped accordingly.
M.Farouk HRS

73. TaKeHoMeMeSsAgE
s
Terlipressin plus albumin is effective in 60–
70% of patients with type 2 HRS. There are
insufficient data on the impact of this
treatment on clinical outcomes (Level B1).
Liver transplantation is the best treatment
for both type 1 and type 2 HRS. HRS should
be treated before liver transplantation,
since this may improve post-liver
transplant outcome (Level A1).
M.Farouk HRS

74. M.Farouk HRS
SELF RESPECT