Hepatorenal Syndrome Dr Allister J Grant Leicester Liver Unit hepatologist.eu
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Hepatorenal SyndromeDr Allister J Grant
Leicester Liver Unit
http://hepatologist.eu
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History1863: Absence of histological changes to the kidney
in some cirrhotics with renal failure
1956: 1st detailed description of the syndrome by Hecker and Sherlock
1960s: Reversal of renal failure with kidney transplant to patients with CKD
1970s: Reversal of HRS with liver transplantation
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Definition of HRS• Functional renal failure
– Absence of Histological changes
• Occurs in patients with chronic liver disease
• Progressive liver failure and ascites
• Can occur acutely in certain settings – Spontaneous bacterial peritonitis – Large volume paracentesis without albumin
• Marked renal vasoconstriction
• Reduced GFR
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Hepatorenal Syndrome• Hepatorenal Syndrome is a severe complication of end stage
liver disease associated with an 80%-95% mortality at 2 weeks.
• The only interventions that have been shown to improve survival are liver transplantation and more recently the vasopressin analogues and TIPS
• Type 1 (Acute)
• Type 2 (Chronic)
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Clinical Types of HRS
• Type 1 • Rapid decline in renal function• Doubling of serum Cr >132 or reduction in 24h
CrCl to <40ml/min• Less than 2 weeks• Spontaneous • Associated with SBP (20%) or large volume
paracentesis w/o albumin (15%)
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• Type 2
• Slower decline in renal function • Criteria for type 1 HRS not met • Development of diuretic resistant or
refractory ascites
Clinical Types of HRS
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Epidemiology• Incidence
7-10% in hospitalized cirrhotics with ascites 20% at 1 year, 40% at 5 years
• Risk Factors Advanced ascites (diuretic resistant) Large volume paracentesis w/o albumin (15%) SBP (20%)
• Prognosis Worst prognosis of all complications of cirrhosis Type 1 median survival: <2 weeks Type 2 median survival: ~6 months
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Diagnosis• Lack of specific testing
• Diagnosis of exclusion
• Differential Diagnosis of renal failure in cirrhosis
– Hypovolaemia (GI hemorrhage, shock)– Nephrotoxins (drugs, contrast)– Glomerulonephritis (Hep B and C)– Acute Tubular Necrosis – Obstruction
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Diagnostic CriteriaMajor Criteria
• Chronic or acute liver disease with advanced liver failure or portal hypertension
• Low GFR (Cr > 132mol/L OR CrCl < 40mL/min)
• Exclusion of shock, ongoing bacterial infection, volume depletion, and use of nephrotoxic drugs
• No improvement in renal function despite stopping diuretics and volume repletion with 1.5L of saline
• No proteinuria or ultrasonographic evidence of obstruction or parenchymal renal disease
Arroyo et al; Hepatology 1996; 23: 164-76
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Diagnostic CriteriaMinor Criteria
• Urine volume < 500mL/day
• Urine sodium < 10mEq/L
• Urine osmolality > plasma osmolality
• Urine RBCs < 50 per hpf
• Serum sodium < 130mEq/LArroyo et al; Hepatology 1996; 23: 164-76
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Pathophysiology
Splanchnic arteriolar vasodilatation
– Decreased effective arterial volume (EAV)– Decreased systemic vascular resistance– Hypotension– Activation of vasoconstrictor systems
– Renin-Angiotensin Angiotensin-Aldosterone-System– Sympathetic Nervous System– Anti-Diuretic Hormone
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Pathophysiology
Hyperdynamic circulation
• Hypotension from reduced effective art vol • Low systemic vascular resistance (SVR)• Baroreceptor activation • SNS activation leading to increased
contractility • Increased cardiac output
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Pathophysiology of CLD
Peripheral and splanchnic arterial dilatation
Reduced effective blood volume
Activation of renin-angiotensin-aldosterone systemSympathetic nervous systemADH
Na retention &Water retention
Low urinary NaDilutional hyponatraemia
AscitesSchrier et al Hepatol 1988
Plasma volume expansion
Renal vasoconstrictionReduced GFR
NSAIDAminoglycosides
Diuretics Sepsis
NaCl
Ascites and OedemaHRS
Portal Hypertension
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Treatment of HRS
• Vasoconstrictors– Often combined with albumin– Vasopressin analogues (Terlipressin)
• TIPS• Liver Transplantation
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Terlipressin
• Synthetic vasopressin analogue• Most studied drug for treatment of HRS
• Mechanism: V-1 receptor agonist • Splanchnic vasoconstriction• Adverse events (arrhythmia, ischemia)
<5%• IV bolus dosing
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Pathophysiology of CLD
Peripheral and splanchnic arterial dilatation
Reduced effective blood volume
Activation of renin-angiotensin-aldosterone systemSympathetic nervous systemADH
Na retention &Water retention
Low urinary NaDilutional hyponatraemia
AscitesSchrier et al Hepatol 1988
Plasma volume expansion
Renal vasoconstrictionReduced GFR
Ascites and OedemaHRS
Portal Hypertension
Vasopressin
Increased blood vol
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Meta-analysis: terlipressin therapy for the hepatorenal syndromeF. Fabrizi, V. Dixit & P. Martin APT 2006 24:935-44
Terlipressin in HRS
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Meta-analysis: terlipressin therapy for the hepatorenal syndromeF. Fabrizi, V. Dixit & P. Martin APT 2006 24:935-44
Terlipressin in HRS
The pooled rate of patients who reversed hepatorenalsyndrome after terlipressin therapy was
0.52 (95% CI, 0.42; 0.61), P =0.0001; I2= 24.6%.
The pooled frequency of responder patients who showedhepatorenal syndrome recurrence after terlipressin withdrawal was 0.55 (95% CI, 0.40; 0.69), P =0.00001; I2= 44.3%.
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• Six randomised trials were eligible for inclusion
• 3 trials (total 51 patients) assessed terlipressin 1 mg bd for 2 to 15 days
• Co-interventions included albumin, fresh frozen plasma, and cimetidine
• Terlipressin reduced mortality rates by 34%
• The control group mortality rate was 65%
• Terlipressin improved renal function assessed by creatinine clearance, serum creatinine and urine output
2009
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TIPS
• Reduce portal hypertension • Increase effective arterial volume• Reverse splanchnic vasodilatation• Complications
Encephalopathy Shunt stenosis Haemolysis Hyperbilirubinaemia
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Liver Transplantation• Treatment of choice for HRS
• Limited by organ availability and mortality of HRS
• Higher rate of complications: – Higher post operative mortality – More days in the ICU – Increased need for post-op RRT (35% vs. 5% w/o HRS)
• Improvement in renal function – Increased GFR post-op vs. decline in non-HRS pts – Lower overall GFR compared to non HRS pts
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Thank You