Hepatorenal Syndrome HRS HRS secrets

1. Hepatorenal Syndrome (HRS) & HRS secrets

3. HRS - the Classical Era Treatment of ascites known since ancient times (description of paracentesis by Hippokrates) 300 B.C.: Erasitratus of Cappadocia postulates connection of ascites with liver disease 100 B.C.: Celsus recognizes the role of renal function in the pathogenesis of ascites: Urine volume exceeds drinking volume: hope for recovery Urine volume declines: no hope

7. Hepatorenal syndrome is a circulatory disorder

8. Milestones in HRS Pathophysiology19th century Friedrich Theodor von Frerichs [Clinics of Liver disease] Berlin 1858-1861: Increased congestion of portal vein causes arterial underfilling Arterial underfilling: responsible for decrease in urinary output Austin Flint (1863) Clinical report on hydro-peritoneum, based on analysis of forty-six cases. Am J Med Sci 45,306 Renal histology described as normal in all patients [!] Patients died rapidly No specific treatment available

9. With current treatment, renal histology is abnormal in most patients

10. Renal comorbidities Acute tubular necrosis Causes Prolonged hypoperfusion vasoconstriction Low serum albumin Molecular dysfunction of albumin Hypoxia, mitochondrial damage Radiographic contrast agents Sepsis Diuretic therapy Drugs - NSAIDs, antibiotics IgA- nephritis

11. Heyd CG (1924): The liver and its relation to chronic abdominal infection. Ann Surg 79:55-77 Helwig & Schutz (1932): A liver-kidney syndrome. Surg Gynecol Obstet 55:570-80 1950/60: landmark studies Isolation of aldosterone 1953 Kowalski, Cardiac output in Laennec's cirrhosis, J Clin Invest 1953 Papper et al., Renal failure in Laennec‘s cirrhosis, Ann Int Med 1959 Hecker & Sherlock, Electrolyte and circulatory changes in terminal liver failure. Lancet 1956 Milestones in HRS Pathophysiology20th century

14. Epstein M, et al. Renal failure in the patient with cirrhosis. The role of active vasoconstriction. Am J Med 49:175-185, 1970 intravital post mortem Liver transplantation Milestones in Pathophysiology20th century

15. HRS is a potentially reversible syndrome that occurs in patients with cirrhosis, ascites and liver failure, as well as in patients with acute liver failure or alcoholic hepatitis. It is characterised by impaired renal function, marked alterations in cardiovascular function and overactivity of the sympathetic nervous and renin–angiotensin systems. Portal hypertension is required to develop HRS Severe renal vasoconstriction leads to a decrease of GFR.

16. Doppler ultrasound in HRS: high RI predicts HRS 2 yrs in advance

17. Type-2 HRS is characterised by moderate renal failure (serum creatinine from 1.5 to 2.5 mg/dl), with a steady or slowly progressive course. It appears spontaneously, but can also follow a precipitating event. Type-2 HRS is typically associated with refractory ascites. Survival of patients with type-2 HRS is shorter than that of non-azotaemic cirrhotic patients with ascites but better than that of patients with type-1 HRS

19. Type-1 HRS is characterised by rapid progressive renal failure defined by doubling of the initial serum creatinine concentrations to >2.5 mg/dl in <2 weeks. It may appear spontaneously, but often develops after a precipitating event, particularly SBP. Type-1 HRS usually occurs within the setting of an acute deterioration of circulatory function characterised by arterial hypotension and activation of endogenous vasoconstrictor systems, and may be associated with impaired cardiac and liver functions as well as encephalopathy. Prognosis is poor

20. What is the incidence of HRS? Prospective study - Ginés et al, n=234 Cirrhotic patients with normal renal function Incidence of HRS at 1 yr follow up 18% Incidence of HRS at 5 yrs 39% Greates risk for HRS and death: Low serum osmolality Low urinary sodium (<5mVal/L) Independent risk factors: Absence of hepatomegaly Plasma renin activity >3.5 ng/ml/h MAP < 85 mm Hg

21. gut barrier dysfunctionplays a key role in the development of renal dysfunction

25. Correlation of exhaled NO and hyperdynamic ciculation in cirrhosis

26. HRS secret #4 „Hyperdynamic“ circulation is restricted to splanchnic vessels, shifting blood away from kidneys and brain. The concept of “splanchnic steal“ appears more adequate.

30. Current treatment of HRS depends on pathophysiology Treat central hypovolemia Albumin 20% solution (initial dose 1 g/kg, then 20-40 g/day until improvement) Remove nephrotoxic drugs Diuretics, NSAIDs, Antihypertensives, ACE-Inhib. Aminoglycosides and other nephrotoxic ABs Treat infection UTI SBP Pneumonia Sepsis, endocarditis

31. Vasodilators in HRS:usually catastrophic results !!! No chance in afferent renal Vasoconstriction systemic hypotension -> INCREASE of renal vasokonstriktion

32. Vasodilators in HRS: No success AT-II Antagonists ACE - Inhibitors alpha1-Antagonists Ca - Antagonists Prostaglandine analogues (PgE1, PgI2, Misoprostol) Questionable N-Acetylcysteine (n=6) Endothelin-A-Antagonists (n=3) Dopamine

33. Vasoconstrictors in HRScaution in CAD, arterial stenosis, intestinal vasculopathy, NOMI Vasopressin No studies, Thrombozytopenia, DIC, liver toxicity Ornipressin Infusion 1-4 U/h Too cheap - killed by industry Noradrenaline Infusion 0.03-0.5 µg/kg/min Midodrin Oral drug available: outcome not improved Terlipressin Pro-drug (Triglycyl-Lysin-Vasopressin) Bolus 0.5-2 in 4-8 hours interval Larger experience

34. Terlipressin: effects on HRS resolution

37. HRS secret #5 Prophylaxis is best therapy of HRS