Hepatorenal syndrome

hepatorenal syndrome is a one of the complication of cirrhosis of liver. It causes hepatic decompensation of liver. It has high risk of mortality. HRS has two types and type 1 usually present as a acute kidney injury. so, at first HRS should exclude from AKI. HRS type 2 present as a refractory ascites. As this has worst prognosis, only valuable management is liver transplantation.

1. Hepatorenal Syndrome Dr. Md. Ashiqur Rahman . Phase-B Resident, Dept. of Gastroenterology, BSMMU .

2. Case A 38 year-old man with cirrhosis due to HCV infection is admitted to the hospital with spontaneous bacterial peritonitis. He is hemodynamically stable and is not on any diuretics. He is treated with broad-spectrum iv antibiotics and iv albumin on admission. At the time of admission, his serum creatinine is 1.2mg/dl On day 3 of his hospitalization, His serum creatinine is 2.8mg/dl , and he is anuric . His urinalysis and renal us is normal.

3. What is the Likely Diagnosis ?

4. Introduction Renal dysfunction is a severe complication of advanced cirrhosis. Traditionally, defined as a serum creatinine ≥1.5 mg/dl Pre-renal, renal, post-renal. Patients with cirrhosis may develop a specific type of renal dysfunction called hepatorenal syndrome ( HRS )

5. HRS first used in 1939 to describe AKI HRS is one of the potential causes of AKI in patients with acute or chronic liver disease. HRS functional type of RF occurs Haemodynamic alterations Reduced renal perfusion Overactivity of the vasoconstrictor

6. HRS-1 involves a rapid reduction in renal function, defined as Doubling of the serum creatinine to a level greater than 2.5 mg/dl Or, 50% reduction of the 24 h creatinine clearance to a level lower than 20 ml/min in less than 2 weeks. HRS-2 is characterised by renal dysfunction which does not progress rapidly, mainly associated with refractory ascites

7. HRS occurs in 20% at 1 year and 40% at 5 years in patients with decompensated cirrhosis. HRS occurs in 25 to 30% in patients with acute liver disease. HRS occurs in 30% patients with SBP or other infection, 25% with severe alcoholic hepatitis, and 10% who require serial LVP

8. Pathophysiology Portal HTN Splanchnic vasodilation Effective arterial blood volume Reduced cardiac output Reduced renal perfusion Overactivity of vasoconstrictor( RAS,SNS) Renal vasoconstriction

9. What’s New in pathophysiology Systemic inflammation- Bacterial translocation Bacterial infection Inflammatory cytokines( IL-6, TNF-a, IL-b1) Microvascular dysfunction Triggers activation of RAS Lowers the GFR.

10. Cholemic nephropathy (bile-salt induced) Bile salt-related direct tubular damage Bile-salt cast 18-75%. Intra-abdominal HTN, > 12mmhg Hepato -adrenal syndrome.

11. RISK factors Refractory ascites Dilutional hyponatremia Low MABP( <80mmhg) High plasma renin activity Decrease cardiac index Precipitating factors Extra-hepatic Bacterial infection (mainly) Gastrointestinal haemorrhage , LVP without albumin administration, Excessive response to diuretics Hepatic Alcohol, Drugs, Flare of viral hepatitis.

12. Recent concept First, absolute increase in scr of ≥0.3 mg/dl from baseline or increase of ≥50% from baseline. Second, systemic inflammation induced by PAMP or by DAMP plays a key role. Finally, Patients with cirrhosis may have CKD Cirrhosis secondary to NAFLD, with metabolic syndrome (DM, HTN).

13. Definition and Diagnostic Criteria Diagnostic criteria of HRS have been revised many times. First definition came from ICA in 1996, was based on major and minor criteria. Subsequently criteria revised in 2007, where Minor criteria Ongoing bacterial infection without septic shock Creatinine clearance criteria was removed, and A lbumin used for plasma volume expansion

14. In 2015 ICA diagnostic criteria Abandoned fixed sCr value KDIGO UO criteria to define AKI.

15. Scr in cirrhosis is affected (1) decreased formation of creatinine secondary to muscle wasting (2) increased renal tubular secretion of creatinine (3) the increased volume of distribution in cirrhosis that may dilute sCr (4) interference with assays for sCr by elevated bilirubin UO is affected (a) frequently oliguric with avid sodium retention, despite a relatively normal GFR (B) they may have an increased UO because of diuretics (C) on a regular ward, urine collection is often inaccurate

16. 2015 ICA Diagnostic Criteria for HRS Cirrhosis with ascites Diagnosis of AKI according to international club of ascites-aki criteria No or insufficient response in 48 hr after diuretic withdrawal and adequate volume expansion with iv albumin Absence of shock No evidence of recent use of Nephrotoxic agents Absence of intrinsic renal disease

17. ICA New Definitions of AKI in Patients with Cirrhosis

18. Baseline sCr level Value obtained in the previous 3 months can be used as baseline Patients with multiple values in previous 3 months the value closest to the admission can be used Patients without a previous sCr determination, the admission value should be used Importance Approx. 20-30% AKI cases develop prior to hospital admission, which can be Dx by using baseline sCr. This will avoid diagnostic delay of at least 2days.

19. AKI Increase in sCr ≥50% from the last available baseline value of outpatient sCr within 3 months Or Absolute increase in sCr ≥0.3 mg/dl within 48 h

20. Staging of AKI

21. Progression of AKI Progression Progress to a higher stage Need for RRT Regression Regress to a lower stage

22. Response to treatment

23. New diagnostic criteria for HRS-AKI 2019 Cirrhosis; acute liver failure; acute-on-chronic liver failure Increase in scr ≥0.3 mg/dl within 48 h or ≥50% from baseline value according to ICA consensus And/or Uo ≤0.5 ml/kg B.W. ≥6 h* No full or partial response, according to the ica consensus document, after at least 2 days of diuretic withdrawal and volume expansion with albumin. The recommended dose of albumin is 1 g/kg of body weight per day to a max. Of 100 g/day

24. Absence of shock No current or recent treatment with nephrotoxic drugs Absence of parenchymal disease as indicated by proteinuria >500 mg/day, microhaematuria (>50 rbc / hpf ), urinary injury biomarkers (if available) and/or abnormal renal us**. Suggestion of renal vasoconstriction with FENA of <0.2% (with levels <0.1% being highly predictive)

25. What’s new in diagnostic criteria New diagnostic criteria by angeli et al change the nomenclature from HRS-1 to HRS-AKI and HRS-2 to HRS-NAKI . It include cirrhosis; acute liver failure; acute-on-chronic liver failure. Included UO criteria for assessment of critical ill patient and urine biomarkers (if available).

26. HRS‑2 is poorly defined and assumed more chronic abnormalities without a definite timeline. Angeli et al. Proposed that the diagnosis of HRS‑NAKI can be made In the context of CKD, GFR <60 ml/min/1.73 m2 for >3 months (HRS‑CKD) in whom other causes have been excluded, or In the context of AKD, defined as a renal dysfunction that does not meet criteria for AKI and lasts for <3 months (hrs- akd )

27. Differential Diagnosis In cirrhotic patients with ascites , the most common causes of acute renal failure are: Pre-renal (37%), Acute tubular necrosis(42%) HRS is around (20%) Post-renal failure (0.3%)

28. Approach Step- 1 : Diagnosis Of AKI Step- 2 : Cause ( Pre-renal, Renal, Post-renal) Step- 3 : Stage Of AKI Step- 4 : Monitor Course ( Progress/Regress) Step- 5 : Response To Volume Expansion (No/Partial/Complete) Step- 6 : Treatment Of HRS/Non-HRS

29. Differentiate Between HRS Vs ATN is Challenging HRS ATN Recent Shock No Likely Response to volume change NO NO U. Na+ < 20 40 FENa < 1 1 Urine osmolarity < 500 350 Granular cast No Yes

30. Role of Biomarker Most promising are urinary biomarkers are NGAL, IL-18, KIM-1, L-FABP, and albumin There value significantly higher in patients with ATN than in those without ATN. NGAL is maker of renal injury, NGAL has been most investigated biomarker, consistent in differentiating functional from structural AKI (HRS vs ATN) Disadvantage: Not available No difference in ngal level in treatment responder/non-responder .

31. Management of HRS

32. Prevention of HRS Avoidance of intravascular volume depletion Overuse of diuretics, Diarrhoea by lactulose , GI bleeding, LVP without albumin Judicious management of Nephrotoxic agents ACEI ARBs, NSAIDs, Antibiotics

33. Prompt diagnosis and treatment of infections SBP, Sepsis SBP prophylaxis Measures to prevent variceal bleeding ( e.G. , NSBB, band ligation) Pentoxifylline for severe alcohol-associated hepatitis

34. TREATMENT OF HRS General Medical therapy TIPS LT RRT MARS Emerging therapy

35. General Discontinuation of all nephrotoxic agents ACEIs, ARBs, NSAIDs, Diuretics Antibiotics for infections

36. Medical therapy IV albumin Bolus :1 g/kg/day on presentation (max.100 g daily). Continue : 20-60 g daily as required Target : maintain CVP 10-15 cm H2O Role of albumin Maintain cardiac output. Improve effecive circulatory volume Improve cardiac contractility. If co decrease terlipressin worsen systemic vasoconstriction.

37. Vasoconstrictor( in addition to albumin) Terlipressin Dose : I/V bolus – 0.5-1mg/4-6h to max. 2mg/4h I/V continuous – 2mg/day to max. 12mg/day Response : Scr decrease 25% after 3days, if not increase the dose. Hrs-1 complete response 55% , recurrence <20% . Hrs-2 response rate higher but, recurrence common. That’s why HRS-NAKI not consider indication for terlipressin even in patient on waiting list for LT. ( Rodriguez E, et al, LT 2015)

38. Duration : Until scr reach within 0.3mg/dl of pt baseline scr. If no/partial response discontinue within 2weeks. Side effects : Persistent diarrhea Abdominal ischemia Peripheral ischemia Angina pectoris, Circulatory overload

39. Conclusion : terlipressin given by continuous I/V infusion is better tolerated than I/V boluses in the treatment of type 1 HRS. It is effective at doses lower than those required for I/V bolus administration

40. Midodrine and octreotide —initialy 2.5-5 mg orally 3 times daily to a max. Dose of 15 mg 3 times daily + octreotide at 100 μg s/c 3 times daily to max. 200 μg s/c 3 times daily, Target : MAP 15 mm hg Norepinephrine —0.1-0.7 μg /kg/min as an IV infusion.

41. TIPS Effective for treatment of diuretic- resistent ascites , precursor for HRS-2. Use of vasoconstrictor followed by tips effective for hrs-1 in small cohort study.

42. Advantage: Improve sCr Improve Na+ excretion Improve Neurohormonal response Bridge to LT Disadvantage: No impact on survival May worsen hepatic function in DCLD

43. Liver Transplant (LT) LT is the only therapeutic modality that potentially reverse both liver dysfunction and HRS. Rates of postoperative complications and in-hospital mortality are higher in patients transplanted with HRS than in those transplanted without HRS

44. Predictors of survival Duration, degree, and cause of renal dysfunction (HRS or ATN) Patients who require hemodialysis Pre-existing comorbidity 3-year survival rate is approximately 60% in patients transplanted with HRS 80% in patients transplanted without HRS.

45. Renal replacement therapy (RRT) RRT does not improve survival in Hepatorenal syndrome. Indication Unresponsive to drug treatment Volume overload Uremia Electrolyte imbalance Bridge to transplantation Short term mortality and ineligible for transplantation.

46. Others Extracorporeal albumin dialysis with MARS Remove water-soluble, albumin binding toxin Improve sCr Improve survivality in patient who respond to vasoconstrictor.

47. Serelaxin ( recombinent human relaxin-2 ) Novel agents acts on renal vasculature. Increase RBF, decrease vascular resistance, reversal of endothelial function pentoxyphyllin Anti-TNF Anti-inflammatory effect Treatment targeting systemic inflammation ( pamp,damp )

48. Prognosis The prognosis for people with liver failure is much worse if they develop HRS. In fact, 50% of people die within 2 weeks of diagnosis and 80% of people die within 3 months of diagnosis A liver transplant improves the survival rate for individuals with either type of HRS

49. Take Home Message Use diagnostic criteria Must rule out other cause of AKI Record baseline sCr to detect HRS at admission Mostly precipitated by systemic inflammation (SBP, other infection) Standard medical therapy is vasoconstrictor plus albumin Only curative therapy is LT

50. THANK YOU

51. REFERRENCES News in pathophysiology , definition and classification of hepatorenal syndrome: A step beyond the international club of ascites , journal of hepatology 2019 vol. 71 j 811–822 Hepatorenal syndrome: a review into changing definition, diagnostic criteria, pathophysiology , and management 2020 chrismed journal of health and research Sleisenger and fordtran’s gastrointestinal and liver disease ( pathophysiology • diagnosis • management ) 11 edition Sherlock’s diseases of the liver and biliary system 13 edition Internet