Hepatorenal Syndrome one of the Major Complication of Liver Cirrhosis ( Early detection & Treatment ) .......26/6/2016.....Kafrelshiek University ( Resident Lectures).

1. Dr/ Mohammed Hussien
Assistant Lecturer of Gastroentrology & Hepatology
Kafrelsheik University
Hepatorenal Syndrome

2. 2016 By Dr Mohammed Hussien
 Historical Background
 Definition
 Pathogenesis
 Diagnosis
 Pervention
 Treatment
Hepatorenal Syndrome

3. Historical Background
1863: Absence of histological changes to the kidney in some
cirrhotics with renal failure
1956: 1st detailed description of the syndrome by Sherlock
and Hecker.
1970s: Reversal of HRS with liver transplantation

4. Hepatorenal Syndrome
Definition
• HRS is a functional renal failure that develops in patients with
advanced cirrhosis as a consequence of a severe reduction in renal
perfusion.
• There is good Evidence suggesting the functional nature of this syndrome.
First, renal histology is normal or present lesions that do not justify the reduction
in glomerular filtration rate (GFR).
Second, the kidneys of cirrhotic patients with HRS function normally when
transplanted to patients with chronic renal failure.
Finally, HRS may reverse following treatment with vasoconstrictors and albumin.

5. Mohammed Hussien 2016
Pathogenesis

6. Types of HRS
HRS TYPE 1 HRS TYPE 2
Characterized by a rapidly progressive
reduction of renal function, defined as either
doubling (100% increase) of the initial serum
creatinine to > 2.5 mg/dL or a 50% reduction
in GFR to < 20 mL/min over a 2-wk period.
Characterized by a more benign steady course,
with a stable reduction in GFR over weeks to
months, accompanying diuretic-resistant
ascites and avid sodium retention.
Average s. creatinine is 4 mg/dl Average s. creatinine is 2 mg/dl
Mean survival after the onset is 2-3 weeks Mean survival after the onset is 6-8 months

7. Part of the acute on chronic liver failure
syndrome (ACLF), With acute impairment in
hepatic, cerebral, cardiovascular & adrenal
functions. (ACLF Is severe inflammatory
systemic immune response due to excess
circulatory endotoxins & bact products DNA)
Clinical feature mainly is refractory ascites due
to poor or no response to diuretics with non-
progressive hepatic and circulatory functions.
Usually occurs in relation to a precipitating
factors mainly:
- Infections mainly SBP
- GI Haemorrhage
- Major surgery
- HRS Type 2 + hyponatremia or
hypovolaemia
- Viral, toxic, alcoholic, ischemic hepatitis on
top of LC, e.g. Ischemia after TIPS.
- No cause mostly bacterial products ,
endotoxins translocation .
May be the same but with non progressive
deterioration of hepatic and circulatory
functions
HRS TYPE 1 HRS TYPE 2

8. 2016
 Type 3: cirrhosis with types 1 or 2 HRS
superimposed on chronic kidney disease or acute
renal injury
 Type 4: fulminant liver failure with HRS

9. 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

10. Causes of kidney involvement in liver diseases
Intrinsic kidney involvement in liver diseases
Tubulo-interstitial involvement:
1. Drugs (paracetamol, aspirin, carbon tetrachloride, halogenated
hydrocarbons, immunosupressent agents)
1. Toxins (Galerina family of mushrooms, hemoglobin, myoglobin,
bilirubin, contrast agents)
1. Infections (leptospirosis, malaria, hepatitis)
2. Hypersensitivity reactions (sulphonamides, salicylates, etc.)
Glomerular involvement
1. Drugs (carbon tetrachloride)
2. Infections: Hepatitis A, B, C
3. Type II mixed cryoglobulinemia
4. IgA nephropathy (alcoholic cirrhosis, HCV cirrhosis)
5. Others (sickle cell disease, hemochromatosis, acute fatty liver and toxemia of pregnancy)
Vascular
1. Vasculitis
2. Toxemia of pregnancy and HELLP syndrome

11. Differential diagnosis of ARF in advanced liver disease
Pre-renal failure Intrinsic
renal failure
HRS
History of disease &
clinical findings.
Profound
Volume contraction
Volume Contraction
Nephrotoxic agent
Sepsis
Advanced liver
disease
Tence ascites
Fluid challenge + - -
Urinary sodium <10 >30 <10
Urinary /plasma
Creat
>30:1 <20:1 >30:1
Urinary / plasma
Osmo.
UO>PO UO=PO UO>PO
Urine sediment Normal Casts & cellular debris Unremarkable

12. 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
How to suspect HRS
( Tense Ascites + Deep Jaundice+ Hypotension)

13. 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)

14. 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.
Large-volume paracentesis without albumin infusion
Gastrointestinal bleeding
Acute alcoholic hepatitis
Bacterial infections
•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
Precipitating Factors
Identifiable precipitating
factors include:

15. 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).

16. 2016

17. 2016

18. 2016 DR Mohammed Hussien
Management of Hepatorenal
syndrome
Pharmacological
RRT
Artificial liver support
TIPS
liver transplantation

19. General measures
2004
 Stop diuretics, and nephrotoxic agents. potassium-sparing diuretics (such as
spironolactone) are contraindicated because of the risk of hyperkalemia,
and loop diuretics (such as furosemide) may be ineffective.
Therefore, large-volume ascites should be treated with repeated large-
volume paracenteses and the intravenous administration of albumin (8 g
of albumin per liter of ascites removed)
 CVP measurement "preclude volume related ARF"
 Fluid challenge : Expansion of intravascular volume with
Albumin: 1gm/kg up to 100 gm IV repeated after 12 hours provided that CVP is
<10mmhg during the first day then 20-40gm in the second day with follow up of S .
Creat.
Saline or volume expanders
 Search for sepsis: tapping of ascites for WBC, GM stain & culture. Culture of blood
, urine, cannula tips. Start Broad spectrum antibiotic promptly.

20. Specific treatment lines
1. Pharmacologic treatment (Bridging therapy)
 Vasoconstrictors
 Albumin
1. Liver transplantation (the only definitive therapy)
2. TIPS (HRS 2)
3. Renal replacement therapy
 Arterio-venous Hemofiltration
 Veno-venous Hemofiltration
1. MARS (HRS 1)

21. Pharmacologic ttt:
Vasoconstrictors plus albumin:
- Include IV terlipressin, IV norepinephrine, SC octeriotide + oral
Midodrine.
- TTT should be continued until creatinin normalization. Median
Duration of treatment is 7 days.
- Induce reversal (decreased s. creat to <1.5mg/dl) in 40-60% of
patients.

22. - Terlipressin + albumin (best evidence) prolong short term survival as recently
confirmed by meta-analysis.
Dose and duration . It should be started at a dose 0.5 – 1 mg i.v. (slow
push) every 4 – 6 h. If there is no early response (>25 % decrease in
creatinine levels a% er 2 days), the dose can be doubled every 2 days up
to a maximum of 12 mg / day (i.e., 2 mg i.v. every 4 h). Treatment can be
stopped if serum creatinine does not decrease by at least 50 % after 7
days at the highest dose. In patients with early response, treatment
should be extended until reversal of HRS (decrease in creatinine below 1.5
mg / dl) or for a maximum of 14 days .
A more rational method for adjusting the dose of vasoconstrictors is by
monitoring mean arterial blood pressure (an indirect indicator of
vasodilatation). This method has been used for adjusting the dose of
midodrine plus octreotide. Doses of octreotide and midodrine are titrated
to obtain an increase in the mean arterial pressure of at least 15 mm Hg.
- One small randomized trial showed that noradrenalin infusion may be equivalent
to terlipressin.

23. 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

24. 100 mic.g/8 h subcutaneously,with
an increase to 200 mic.g/8 h
1 g/kg on day 1 followed by 40 g/day
to improve the efficacy of treatment on
circulatory function.
2.5 to 7.5 mg/8 h
with an increase to
12.5 mg/8 h
1 mg/4–6 h and increased to a
maximum of
2 mg/4–6 h if there is no
reduction in creatinine

25. Terlipressin - Cardiac: angina MI & arrhythmia
- GI: cramps, vomiting, diarrhea,
intestinal ischemia.
- Periph: finger ischemia, skin and
scrotal necrosis.
- Others: HTN, bronchospasm, dyspnea
Noradrenaline Chest pain and ventilatory
hypokinesia
Octeriotide (glucagon release
inhibitor)
Diarrhea , tingling
Midodrine (alfa adrenergic agonist) HTN
•Vasodilators as dopamine at renal doses has no effect in HRS.
•Side effects:

27. Liver transplantation:
 The only (definitive) treatment associated with improved survival
for both HRS1 & 2.
 Pretreatment is important and improves LTX outcome (morbidity
& mortality).
 After LTX calcinurine inhibitors (cyclosporine & tacrolimus) should
be avoided, azathioprine , steroids and IL2 receptor blockers
should be used instead until diuresis is started.
 The main problem of LTX in HRS1 is its applicability owing to their
extremely short survival. HRS should be allocated to the first
places of the waiting list.

28. TIPS:
TIPS, is an alternative treatment of type 1 HRS in patients without response to
terlipressin plus albumin.
o TIPS is effective in reversing type 2 HRS, The introduction of covered stents in
management of refractory ascites and type 2 HRS, mainly in those patients with
relatively good liver function.
o 2 pilot studies have recently evaluated transjugular intrahepatic portacaval shunt
(TIPS) in type 2 HRS: one showed marked reduction of s. creatinin in 8 out of 9
patients with long-term survival in 2 pts. The second showed significant
improvement in all patients as regard s. creatinin and ascites with 70% 1 year
survival probability. (Guevara & Arroyo, 2011).
o TIPS may improve renal perfusion and decrease RAAS activity.
o It can be considered also if HRS recurs after successful vasoconstrictor ttt
specially if liver transplantation is not likely in the near future.

29. Renal replacement therapy :
Renal-replacement therapy in the form of hemodialysis or continuous venovenous
hemofiltration has been used in the management of the hepatorenal syndrome,
particularly in patients awaiting transplantation or in those with acute, potentially
reversible conditions (e.g., alcoholic hepatitis).
Complications during hemodialysis, particularly hypotension, bleeding, and infections, are
common. Unfortunately, the optimal renal-replacement method for patients with the
hepatorenal syndrome is not clear, nor is it clear whether renal replacement therapy will
improve the prognosis for patients who are not candidates for a liver transplant.
Moreover, there are no data from studies comparing renal-replacement therapy with
vasoconstrictor administration. Until such data are available, it seems reasonable to start
therapy with vasoconstrictors and albumin alone unless there is an urgent need for
hemodialysis (i.e., because of severe hyperkalemia, metabolic acidosis, or volume
overload), and to reserve hemodialysis for patients who do not have a response to
vasoconstrictor therapy.

30. Extracorporial albumin dialysis:
In a small, randomized study, the molecular adsorbent
recirculating system (MARS), a modi$ed dialysis method
using an albumin-containing dialysate, was shown to improve
the 30 -day survival in 8 patients with HRS-1 compared with
5 patients treated with intermittent venovenous hemo$
ltration alone . However, clear beneficial effects on systemic
hemodynamics and on HE were observed. MARS is still
considered to be an experimental therapy and its use in
patients with type-1 HRS cannot be recommended outside
prospective pathophysiological or therapeutic investigations.

31. Prevention
1. Careful use and monitoring of diuretics therapy.
2. Early recognition of electrolyte imbalance, haemorrhage and infections
3. Avoid nephrotoxic agents
4. In large volume paracentesis, use salt-poor albumin (8g/L removed ascites)
5. Treatment of SBP properly (IV albumin & antibiotics)
1.5g/kg body wt IV at diagnosis of infection
1g/kg IV for 48 h (10% develop HRS Vs 33% without albumin)
1. Primary prophylaxis of SBP using longterm norfloxacin (400mg/day) or Ciprofloxacin (250-500 mg daily) in patients
with:
- CTP >9
- S.Bilirubin >4 mg/dl
- S. Creatinin >1.2 mg/dl
- S.sodium <130 meq/l
- Low ascetic fluid protein <1.5 mg/dl.