Hepatorenal syndrome

M.Farouk HRS

Hepatorenal Syndrome

Definition

Pathogenesis

Diagnosis

Treatment

Research points

TaKeHoMeMeSsAgEs

ByMohamed Farouk Ali

M.Sc., Specialist of Tropical medicine and Gastoenterology

[email protected]

M.Farouk HRS

M.Farouk HRS

Canwe prevent occurence of HRS?

Canwe predict it’s occurrence?

Canwe diagnose HRS early?

Dowe miss diagnosing some patients with HRS?

Should I Give up,if the patient do not respond to vasopressor therapy?

Hepatorenal SyndromeDefinition

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

Hepatorenal SyndromeDefinition

Functionalproblem

Advanced liver

diseaseAbsence of identifiable

cause

PotentialReversible

July 1956

M.Farouk HRS

The first detailed description of HRSby Hecker and Scherlock

What about the

pathogenesis

?M.Farouk HRS

Story

Advanced

livear diseas

e

Renal vasoconstrictionM.Farouk HRS

NotWell

understood

The Hallmark is

Renal vasoconstriction

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Splanchnic Steal Phenomenon

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End stage liver disease

Liver cell failure and portal hypertension

Endogenous vasoactive substances

Systemic vasodilatation and mainly splanchnicwith further pooling of blood in the splanchnic region

The thief is the splanchnic vessels&Here the game begins.…

The Body “The police” will act againstLow 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

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incr

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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

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Splanchnic Steal PhenomenonSplanchnic 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 peptidesBut not enough to correct renal vasoconstriction

More splanchnic vasodilataion….More steal of blood from renal vessels…

More renal vasoconstriction…More progress…

Splanchnic Steal PhenomenonRenal vasoconstriction

Kidney Angina

Kidney ischaemia

Impaired renal

function

M.Farouk HRS

This may explain the difference among patientsin the intensity and the course of the disease

Imbalance betweenvasoconstrictors and vasodilators

HRS

Type 2Type 1Moderate, 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

M.Farouk HRS

If you focus on problems you will have more problemsIf you focus on possibilities you will have more opportunities

Now,

How can I diagnose it

?

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1996 The International Ascites Club

Major criteria

Additional criteria

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New criteria

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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

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

M.Farouk HRS

RIFLE classification(R- renal risk, I- injury, F- failure, L- loss of kidney function, E- end- stage renal disease)

Definitionabrupt (≤48 h) reduction in kidney functionmanifested 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

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Renal Impairment

Hepatorenal syndrome

Othercauses

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Renal failure(serum creatinine >133 mol/L)

Hepatorenal syndrome

Prerenal failure

Fluid losses

Shock

Infection-induced renal failure

Nephrotoxicrenal failure

Nephrotoxic drugs

Abnormal renalultrasonography

His

tory

and

phys

ical

exa

min

ation

Bloo

d an

d ur

ine

chem

istr

ies

Rena

l ul

tras

onog

raph

yParenchymal renal disease

Signs of infection

Persistence of renal failure after

resolution of infection

Proteinuria and/orhaematuria

Acute tubular necrosis“urinary IL-18 (interleukin -18),

NGAL(neutrophil gelatinase associated lipocalin)”

M.Farouk HRS

M.Farouk HRS

Don’t miss the possibility of occurance ofthese major conditions that is

associated with acute renal failurein 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???

Incidence A multicenter retrospective study

423 patients with cirrhosis and ARFATN (35%)Prerenal failure (32%)HRS (26.6%) Type1 20% & Type2 6.6%

M.Farouk HRS

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

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 infectionsLarge-volume paracentesis without albumin infusionGastrointestinal bleedingAcute 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.

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

M.Farouk HRS

M.Farouk HRS

Treatment

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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).

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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-blockersThere 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 paracentesisThere 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 diureticsAll 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).

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Pharmacological

RRT

TIPS

Artificial liver support

liver transplantation

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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 VasodilatorsSystemic Vasoconstrictors

Pharmacological

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+

1 g/kg on day 1 followed by 40 g/dayto 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 of2 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.

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When stop?

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

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•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.

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A serum bilirubin less than 10 mg/dl before treatmentAnd

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.

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•Treatment is effective in 40–50% of patients, approximately.

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•The most frequent side effects of treatment:are cardiovascular or ischemic complications

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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.

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•Recurrence after withdrawal of therapy is uncommon and retreatment with terlipressin is generally effective.

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+

+

100 mic.g/8 hsubcutaneously,with an increase to200 mic.g/8 h

2.5 to 7.5 mg/8 hwith an increase to12.5 mg/8 h

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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.

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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+albumin

Terlipressin+albumin

Complete response75%80%

NoradrenalineTerlipressin

cost15 fold

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Comparative study :

Noradrenaline(0.1-0.7μg/kg/min+)

albumin

Midodrine (5-15mg)+octreotide (100-200 μg subcutaneously 3 times)

+albumin

Complete response73%75%

recurrence18%25%

Renal Vasodilators

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Theoretically, supposed to be successfulBut

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 himproved cortical blood flow and improved angiographic appearance of renal cortical vasculaturewithout improvement in GFR or urine flow.

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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.

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

M.Farouk HRS

M.Farouk HRS

There is no line of therapy prevent deathAll therapies for all diseases just prolong survival

Don’t worryWe still have more therapeutic lines

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

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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

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).

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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)

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Renal replacement therapy

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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.

Renal replacement therapy

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

(MARS) the molecular adsorbents recirculating systemPrometheus

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

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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)

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

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)

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 thattreatment 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).

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Prevention of HRS

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Research pointsFor 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).


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


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


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


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).


M.Farouk HRS

Role of renal biopsy to help plan the further management, including the potential need for combined liver and kidney transplantation.

"إذا وعظت فأوجز, فإنكثرة الكالم ينسي بعضه

"O بعضًاأبو بكر الصديق رضي الله عنه

M.Farouk HRS

TaKeHoMeMeSsAgEs

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

TaKeHoMeMeSsAgEs

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/8b.Terlipressin (1 mg/4–6 h intravenous bolus) in combination with albumin

M.Farouk HRS

TaKeHoMeMeSsAgEs

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

TaKeHoMeMeSsAgEs

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

M.Farouk HRS

SELF RESPECT

Education

Hepatorenal syndrome