1. Hepatorenal Syndrome Dr Allister J Grant Leicester Liver Unit http://hepatologist.eu

2. 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 1960s: Reversal of renal failure with kidney transplant to patients with CKD 1970s:Reversal of HRS with liver transplantation

3. 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

4. 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)

6. 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%)

7. 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

8. 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

9. 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

10. Diagnostic Criteria Major Criteria Chronic or acute liver disease with advanced liver failure or portal hypertension Low GFR (Cr > 132  mol/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

11. 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

12. 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

13. 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

14. Pathophysiology of CLD Peripheral and splanchnic arterial dilatation Reduced effective blood volume Activation of renin-angiotensin-aldosterone system Sympathetic nervous system ADH Na retention & Water retention Low urinary Na Dilutional hyponatraemia Ascites Schrier et al Hepatol 1988 Plasma volume expansion Renal vasoconstriction Reduced GFR NSAID Aminoglycosides Diuretics Sepsis NaCl Ascites and Oedema HRS Portal Hypertension

15. Treatment of HRS Vasoconstrictors – Often combined with albumin – Vasopressin analogues (Terlipressin) TIPS Liver Transplantation

16. 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

17. Pathophysiology of CLD Peripheral and splanchnic arterial dilatation Reduced effective blood volume Activation of renin-angiotensin-aldosterone system Sympathetic nervous system ADH Na retention & Water retention Low urinary Na Dilutional hyponatraemia Ascites Schrier et al Hepatol 1988 Plasma volume expansion Renal vasoconstriction Reduced GFR Ascites and Oedema HRS Portal Hypertension Vasopressin Increased blood vol

18. Meta-analysis: terlipressin therapy for the hepatorenal syndrome F. Fabrizi, V. Dixit & P. Martin APT 2006 24:935-44 Terlipressin in HRS

19. 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; I 2 = 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; I 2 = 44.3%.

20. 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

21. TIPS Reduce portal hypertension Increase effective arterial volume Reverse splanchnic vasodilatation Complications Encephalopathy Shunt stenosis Haemolysis Hyperbilirubinaemia

23. 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

24. Thank You