Dr/ Mohammed Hussien

Assistant Lecturer of Gastroentrology & Hepatology

Kafrelsheik University

Hepatorenal Syndrome

2016 By Dr Mohammed Hussien

Historical Background

Definition

Pathogenesis

Diagnosis

Pervention

Treatment

Hepatorenal Syndrome

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

Hepatorenal SyndromeDefinition

• 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.

Mohammed Hussien 2016

Pathogenesis

Types of HRSHRS TYPE 1

HRS TYPE 2

Characterized by a rapidly progressivereduction 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

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

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

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 renalultrasonography

Causes of kidney involvement in liver diseasesIntrinsic kidney involvement in liver diseases

Tubulo-interstitial involvement:1. Drugs (paracetamol, aspirin, carbon tetrachloride, halogenated

hydrocarbons, immunosupressent agents)2. Toxins (Galerina family of mushrooms, hemoglobin, myoglobin,

bilirubin, contrast agents)3. Infections (leptospirosis, malaria, hepatitis)4. Hypersensitivity reactions (sulphonamides, salicylates, etc.)

Glomerular involvement1. Drugs (carbon tetrachloride)2. Infections: Hepatitis A, B, C3. Type II mixed cryoglobulinemia4. IgA nephropathy (alcoholic cirrhosis, HCV cirrhosis)5. Others (sickle cell disease, hemochromatosis, acute fatty liver and toxemia of pregnancy)

Vascular1. Vasculitis2. Toxemia of pregnancy and HELLP syndrome

Differential diagnosis of ARF in advanced liver disease

Pre-renal failure Intrinsicrenal failure

HRS

History of disease & clinical findings.

ProfoundVolume contraction

Volume ContractionNephrotoxic agent Sepsis

Advanced liver diseaseTence 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

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)

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)

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 infusionGastrointestinal bleedingAcute alcoholic hepatitisBacterial 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:

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).

2016

2016

2016 DR Mohammed Hussien

Management of Hepatorenal syndrome

Pharmacological

RRT Artificial liver support

TIPS

liver transplantation

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 withAlbumin: 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.

Specific treatment lines1. Pharmacologic treatment (Bridging therapy) Vasoconstrictors Albumin1. Liver transplantation (the only definitive therapy)2. TIPS (HRS 2)3. Renal replacement therapy Arterio-venous Hemofiltration Veno-venous Hemofiltration1. MARS (HRS 1)

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.

- 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.

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

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/dayto improve the efficacy of treatment on

circulatory function.

2.5 to 7.5 mg/8 hwith 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

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:

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.

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.

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.

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.

Prevention1. 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)

6. 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.