HEPATORENAL SYNDROME.

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HEPATORENAL SYNDROME

Acute Kidney Injury in Cirrhosis Nearly 50% of patients with cirrhosis develop AKI Causes Pre-renal Renal Post-renal

Assessment of Kidney Function in Cirrhotics In patients with cirrhosis, serum CR is unreliable due to low production rate of creatine by liver with reduced muscle mass CR-based equations also unreliable (MDRD, CKD-EPI) 24-hour CR clearance more accurate but cumbersome Gold standard: Iohexol or iothalamate clearance study

Hospitalized patients with cirrhosis Chronic renal failure 1% Acute Kidney Injury 19% (293/1544) Post-renal (obstructive) (<1%) Pre-renal 68% (437/639) Intra-renal (ATN, GMN) 32% (224/712) Figure 1. Prevalence and types of acute renal failure (ARF)/acute kidney injury (AKI) in hospitalized patients with cirrhosis. Percentages and numbers were obtained by adding up patients in the references cited. ATN= acute tubular necrosis; GMN=glomerulonephritis; HRS=hepatorenal syndrome. *Pre-renal azotemia Volume-responsive* 66% (288/437) Infection Hypovolemia Vasodilators Other Not volume-responsive HRS type 1 25% (108/437) HRS type 2 9% (41/437) Garcia-Tsao G et al. Hepatology 2008

Hepatorenal Syndrome A functional form of acute kidney injury (AKI) that results in severe renal vasoconstriction without evidence of structural kidney disease Arroyo V. J Hepatol ’13

Hepatorenal Syndrome A functional form of AKI that results in severe renal vasoconstriction without evidence of structural kidney disease Type 2: Extreme expression of the spontaneous deterioration of circulatory function in cirrhosis, associated with refractory ascites & poor survival (months) Arroyo V. J Hepatol ’13

Hepatorenal Syndrome A functional form of AKI that results in severe renal vasoconstriction without evidence of structural kidney disease Type 2: Extreme expression of the spontaneous deterioration of circulatory function in cirrhosis, associated with refractory ascites & poor survival (months) Type 1: A form of acute renal failure that occurs secondary to a rapid deterioration of cardiocirculatory function closely associated in time with a precipitant & having an extremely poor survival (days or weeks) Arroyo V. J Hepatol ’13

Diagnosis of Exclusion Hepatorenal Syndrome A functional form of AKI that results in severe renal vasoconstriction without evidence of structural kidney disease Type 2: Extreme expression of the spontaneous deterioration of circulatory function in cirrhosis, associated with refractory ascites & poor survival (months) Type 1: A form of acute renal failure that occurs secondary to a rapid deterioration of cardiocirculatory function closely associated in time with a precipitant & having an extremely poor survival (days or weeks) Diagnosis of Exclusion Arroyo V. J Hepatol ’13

Pathophysiology of HRS

Intrahepatic resistance Cirrhosis Intrahepatic resistance Portal (sinusoidal) hypertension Splanchnic/systemic vasodilatation Effective arterial blood volume Activation of neurohumoral systems Renal vasoconstriction HEPATORENAL SYNDROME

Wong F. Nat Rev. Gastoenterol 2012

Mechanisms Leading to Circulatory & Renal Dysfunction in Cirrhosis

Precipitants of Type 1 HRS Infection Spontaneous bacterial peritonitis (SBP) Urinary tract infection Cellulitis Gastrointestinal hemorrhage NSAID use Large volume paracentesis without albumin Adrenal insufficiency

HRS Diagnostic Criteria Cirrhosis with ascites Serum creatinine > 133 μmol/L (1.5 mg/dL) No sustained improvement of serum creatinine (decrease to a level of 133 μmol/L or less) after at least 2 d of diuretic withdrawal and volume expansion with albumin; the recommended dose of albumin is 1 g/kg of body weight per day up to a maximum of 100 g/d Absence of shock No current or recent treatment with nephrotoxic drugs Absence of parenchymal disease as indicated by proteinuria >500 mg/d , microhematuria (> 50 red blood cells per high-power field) and/or abnormal renal ultrasonography

Clinical Characteristics of HRS Ascites Advanced liver disease Low mean arterial pressure (median 74 mmHg) Low serum Na (median 127 mEq/L) Low urinary output Do not rely on urine Na or urine sediment to differentiate HRS from ATN

Cumulative Survival of Patients with HRS Type 1 & HRS Type 2 Salerno et al, J Hepatol 2011

Prevention of AKI in Patients with Cirrhosis Careful use of diuretics & lactulose Albumin after large volume paracentesis Avoid NSAIDs & aminoglycosides Albumin & antibiotics for treatment of SBP Primary prophylaxis of SBP with antibiotics Antibiotics for 7 days at time of GI bleed Pentoxifylline for severe alcoholic hepatitis ?Target mean arterial BP >60 mmHg

Patient with cirrhosis & acute renal failure (abrupt rise in creatinine from baseline) STOP diuretics, lactulose, vasodilators, potential nephrotoxins Investigate & initiate Rx (if present) for infection, blood or fluid losses Albumin IV (1 g/Kg of body weight QD or BID) History of shock (septic or hypovolemic), nephrotoxins, contrast Treat as ATN Granular or epithelial casts in urine? Urine biomarkers of ATN? Improvement in creatinine No improvement in creatinine Figure 4. Approach to the patient with cirrhosis and acute renal failure. IV=intravenously; QD=every day; BID= twice a day; ATN=acute tubular necrosis; HRS=hepatorenal syndrome * if compatible clinical characteristics, i.e. ascites, low mean arterial pressure and hyponatremia (see text for approach to patient with suspected HRS). Continue therapy No granular or epithelial casts in urine? Central venous pressure >10 cmH2O Treat as HRS

Treatment of Hepatorenal Syndrome

Intrahepatic resistance Cirrhosis Intrahepatic resistance Portal (sinusoidal) hypertension Splanchnic/systemic vasodilatation Effective arterial blood volume Activation of neurohumoral systems Figure 8. Site of action of different therapies for hepatorenal syndrome. *ECAD stands for extracorporeal albumin dialysis, an experimental therapy that seems to improve HRS that probably acts by decreasing the amount of circulating vasodilators. Renal vasoconstriction HEPATORENAL SYNDROME

Intrahepatic resistance Cirrhosis Intrahepatic resistance Portal (sinusoidal) hypertension Splanchnic/systemic vasodilatation Albumin Effective arterial blood volume Activation of neurohumoral systems Renal vasoconstriction HEPATORENAL SYNDROME

Intrahepatic resistance Cirrhosis Intrahepatic resistance Portal (sinusoidal) hypertension Splanchnic/systemic vasodilatation Vasoconstrictors Albumin Effective arterial blood volume Activation of neurohumoral systems Renal vasoconstriction HEPATORENAL SYNDROME

Vasoconstrictors in HRS Midodrine Terlipressin† Norepinephrine Rationale ++ +++ Route Oral + octreotide* IV slow bolus IV infusion Clinical Effectiveness Uncontrolled Phase III RCT Phase II RCTs Level of monitoring No special needs Monitored bed ICU bed Safety GI, piloerection GI, ischemia Ischemia, GI, ARDS Cost + ? *Octreotide alone is ineffective; †Not FDA-approved

Overall Survival Following Terlipressin or Placebo Treatment Sanyal AJ, et al. Gastroenterology. 2008

Survival Following Terlipressin or Placebo Treatment – HRS Reversal Sanyal AJ, et al. Gastroenterology. 2008

Patient Survival Probability Based on Response to Treatment with Terlipressin or Terlipressin/Albumin Martin-Llahi M, et al. Gastroenterology. 2008

Predictors of HRS Reversal with Terlipressin Treatment effect most dominant in patients with baseline CR 3-5 mg/dl No patient with baseline CR >5.6 mg/dl responded to terlipressin Sustained rise in mean arterial pressure required for HRS reversal Boyer et al, J Hepatology 2011

Management of HRS Midodrine 7.5 mg PO TID, up to 12.5 mg PO TID Octreotide 100 μg SC TID, up to 200 μg SC TID Titrate to obtain increase in MAP ≥15 mmHg Albumin (maintenance) 25-50 g/day Discontinue if serum albumin >4.0 g/dL Stop treatment if no reduction in serum CR after 3 days or not <50% by day 7 of highest dose ?Norepinephrine infusion If response, continue until Cr <1.5 mg/dL or 14 days

Terlipressin + Albumin versus Midodrine + Octreotide + Albumin 42 patients: 37 HRS type 1, 5 HRS type 2 + CR >2.5 Group A: IV infusion of terlipressin (3 mg/24 hr*) Group B: Midodrine (7.5 mgs PO TID*) + octreotide (100 μg S/C TID*) All patients albumin 1 g/Kg day 1, then 20-40 g/day *initial dose Group A (terlipressin) B (Midodrine + Octroetide) Improved renal function 75% 35.3% ↓ Serum CR to <1.5 mg/dl 13/24 (54%) 2/17 (11.8%) %Responders among survivors 91.6% 54.5% Cavallin M., et al. Hepatology 2011; LB#2

Intrahepatic resistance Cirrhosis Intrahepatic resistance TIPS Portal (sinusoidal) hypertension Splanchnic/systemic vasodilatation Effective arterial blood volume Activation of neurohumoral systems Renal vasoconstriction HEPATORENAL SYNDROME

TIPS in HRS Reversal of HRS can occur Recovery of kidney function can take weeks Concerns Uncontrolled hepatic encephalopathy Worsening liver function Heart failure Caution with: Ejection fraction <60% High MELD

Renal Replacement Therapy in Patients with Cirrhosis and Acute Renal Failure Published information scarce In most studies, type 1 HRS not differentiated from ATN Continuous hemofiltration >> intermittent hemodialysis Pilot studies suggest albumin dialysis [Prometheus system or Molecular Adsorbents Recirculation System (MARS)] might be beneficial in type 1 HRS Significant beneficial effect of MARS albumin dialysis on HE, no beneficial effect on survival More studies needed Arroyo, V. & Fernández, J. Nat. Rev. Nephrol. 2011

Intrahepatic resistance Liver Transplant Cirrhosis Intrahepatic resistance Portal (sinusoidal) hypertension Splanchnic/systemic vasodilatation Effective arterial blood volume Activation of neurohumoral systems Renal vasoconstriction HEPATORENAL SYNDROME

Liver Transplant in Patients with HRS Type 1 In the terlipressin/albumin vs. albumin alone study (Sanyal et al, Gastroenterology 2008) 99 patients randomized to terlipressin (TRL) or placebo 35 patients (35%) underwent liver transplantation (LT) Six-month Survival (%) Boyer T, et al. Liver Transplantation 2011

Liver Transplant in Patients with HRS Type 1 Survival significantly better in those not transplanted who achieved HRS reversal vs. those who did not achieve reversal (47% vs. 4%) vs. survival of 97% in those undergoing LT Six-month Survival (%) Boyer T, et al. Liver Transplantation 2011