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Hepatorenal Syndrome Dr Allister J Grant Leicester Liver Unit http://hepatologist.eu. History. 1863: Absence of histological changes to the kidney in some cirrhotics with renal failure 1956: 1 st detailed description of the syndrome by Hecker and Sherlock
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Hepatorenal Syndrome Dr Allister J Grant Leicester Liver Unit http://hepatologist.eu
History 1863: 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
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
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)
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%)
Clinical Types of HRS • Type 2 • Slower decline in renal function • Criteria for type 1 HRS not met • Development of diuretic resistant or refractory ascites
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
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
Diagnostic Criteria Major 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
Diagnostic Criteria Minor Criteria • Urine volume < 500mL/day • Urine sodium < 10mEq/L • Urine osmolality > plasma osmolality • Urine RBCs < 50 per hpf • Serum sodium < 130mEq/L Arroyo et al; Hepatology 1996; 23: 164-76
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
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
NSAID Aminoglycosides Diuretics Sepsis Renal vasoconstriction Reduced GFR NaCl HRS Pathophysiology of CLD Portal Hypertension Peripheral and splanchnic arterial dilatation Reduced effective blood volume Activation of renin-angiotensin-aldosterone system Sympathetic nervous system ADH Na retention & Water retention Ascites and Oedema Low urinary Na Dilutional hyponatraemia Plasma volume expansion Ascites Schrier et al Hepatol 1988
Treatment of HRS • Vasoconstrictors • Often combined with albumin • Vasopressin analogues (Terlipressin) • TIPS • Liver Transplantation
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
Vasopressin Increased blood vol Renal vasoconstriction Reduced GFR HRS Pathophysiology of CLD Portal Hypertension Peripheral and splanchnic arterial dilatation Reduced effective blood volume Activation of renin-angiotensin-aldosterone system Sympathetic nervous system ADH Na retention & Water retention Ascites and Oedema Low urinary Na Dilutional hyponatraemia Plasma volume expansion Ascites Schrier et al Hepatol 1988
Terlipressin in HRS Meta-analysis: terlipressin therapy for the hepatorenal syndrome F. Fabrizi, V. Dixit & P. Martin APT 2006 24:935-44
Terlipressin in HRS The pooled rate of patients who reversed hepatorenal syndrome 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 showed hepatorenal syndrome recurrence after terlipressin withdrawal was 0.55 (95% CI, 0.40; 0.69), P =0.00001; I2= 44.3%. Meta-analysis: terlipressin therapy for the hepatorenal syndrome F. Fabrizi, V. Dixit & P. Martin APT 2006 24:935-44
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
TIPS • Reduce portal hypertension • Increase effective arterial volume • Reverse splanchnic vasodilatation • Complications Encephalopathy Shunt stenosis Haemolysis Hyperbilirubinaemia
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