Acute Renal Failure and Cirhosis By Syed Rizwan, MD

Differential Diagnosis- not always straightforward. Mainly invlove, ATN Volume Depletion Hepatoprenal Syndrome

CIRHOSIS Involves complex Pathophysiologic changes in body. Ascites-most common complication Hydraulic and Oncotic pressures determine net capillary pressure and Ascites formation Portal Pressure > 12 mmHg required for Ascites formation

CIRHOSIS Ascites results from Anatomic Pathophysiologic Biochemical Changes Theory involving the Areterial Vasodilatation Hypothesis best explains Development of Ascites

CIRHOSIS Redution in Systemic Vascular Resistance Lower mean arterial pressure Increased cardiac output Hyperdynamic Circulation Reduced SVR is more prominent in the Splanchnic circulation- Ascites formation

Mechanisms of Vasodilation in CIRHOSIS Increased circulation of vasodilators Vasoactive intestinal peptide Substance P Platelet Activating factor Glucagon Praotagladins Nitric Oxide – most important

NITRIC OXIDE(NO) NO synthase activity higher in cirhotic rat with ascites. Nitrite and Nitrate higher in Patients with cirhosis. Inhibition of NO increase SVR, BP in cirhotic rats.

NITRIC OXIDE(NO) Increased NO synthesis is possibly because of, Increased endotoxin absorption from GI tract. Decreased clearance by liver because of Portasystemic shunts. Decreased Reticuloenthelial Cell Function

NITRIC OXIDE(NO) NO concetration higher in Portal vein than peripheral veins Correlation between serum nitrite and nitrate and endotaxin levels Oral antiboiotic colistin reduce endotoxin level and nitrite and nitrate. Bacterial DNA in cirhotic Patients blood.

Activation of Vasoconstrictors Low MAP/SVR – reduced pressure in carotid and Renal baroreceptors, to activate Sympathetic nervous System Renin-angiotensin system Antidiueretic Harmone

Consequences of Vasodilation Increased endogenous Vasoconstrictors. Sodium retention Water retention Renal vasoconstrition

Sodium Retention Vasodilation leads to third spacing and reduce central blood volume “Effective Volume Depletion” leads to impaired Sodium excretion. Low Sodium excretion could predict poor prognosis

Water Retention Increased ADH because of Low Effective Volume. More rention with Ascites and Progression of liver disease. Water renetion leads to Hyponatremia. Poor prognostic indicator

Renal Vasoconstriction Vasodilation leads to activation of Vasoconstrictor System, Reduce renal blood flow Renal vasoconstrction Renal Nitric oxide and Prostracylin production try to maintain renal blood flow initially

Renal Vasoconstriction Protective mechanism (Nitric oxide and Prostracycline ) production are overcome with Progresive liver diseae. Gradual Decline in GFR could lead to Hepatorenal syndrome.

Estimation of Renal Function in Cirhosis Serum Creatinine not reliable, Low muscle mass Low protein intake Blood Urea could be low or high Low Protein intake Lower Urea production GI Bleed

Estimation of Renal Function in Cirhosis GFR estimation may be better with creatinine clearance than serum creatinine.

Differential Diagnosis- not always straightforward. Mainly invlove, ATN Volume Depletion Hepatoprenal Syndrome

ARF and Cirhosis Hepatorenal Syndrome is a diagnosis of exclusion

ARF and Cirhosis Diagnosis is difficult because, Low urine in all settings Low urine sodium even with ATN Hyperbilirubinemia can induce Granular and Epithelial cast in urine even in Volume depleted Patient. Diuretics may interfere Urine Sodium

ARF and Cirhosis Differential diagnosis is important because of variable prognosis and management

Hepatorenal Syndrome Classically charaterised by Oligouria Benign Urine sediments Low Urine Sodium Rise in creatinie

Hepatorenal Syndrome “Dianostic Criteria” Advance Hepatic failure Plasma creatinine > 1.5 Exclude other causes of ARF Low Urine Sodium(<10 meg/L) Low Urine Protein(<500mg/Day) Lack of imparovement with Voluma Exapnsion

Hepatorenal Syndrome Incidence increased with duration of Liver disease. Higher risk with, Hyponatremia High renin activity Precipated by acute insult, Spontaneous Bacterial peritonitis, GL bleed, Infections Diuretics are blamed but may not cause

Hepatorenal Syndrome TYPES Type 1 Hepatorenal Syndrome More serious Rapid onset- with 2weeks Type 2 Hepatorenal syndrome Less severe Resistant to diuretics Better prognosis

ARF and Cirhosis Treatment Hold Diuretics Volume Expansion Rx any cause for ARF Rx of Liver disease/Liver Transplant Midodrine and Octreotid Hemodialysis /CVVHD TIPS/ Portasystemic shunts Peritoneovenous Shunt Prevention

ARF and Cirhosis Treatment If volume contracted, Hold Diuretic Volume Expansion- Normal Saline at least 1-2 liters

ARF and Cirhosis Treatment Prevent/Rx ARF, Stop ACEI Stop NSAID Maintain BP Rx of infection Avoid IV contrast Albumin after large volume Paracentesis

ARF and Cirhosis Treatment Rx of Liver Disease, - Hepatitis B Liver Transplantation

ARF and Cirhosis Treatment Midodrine and Octreotide Midodrine – selctive Alpha-1 adrenergic agonist causes systemic vasoconstriction. Octreotoide- a somatostatin analog inhibits endogenous vasodilators release. Combined therapy effective

ARF and Cirhosis Treatment Midodrine and Octreotide Reversal of Type 1 Hepatorenal Syndrome with Midodrine and Octreotide (Angeli, P, Volpin, R, Gerunda, G et al. Hepatology : 1690)

ARF and Cirhosis Treatment Midodrine and Octreotide - 13 Patients - Group A- 8 - Group B-5(Midodrine and Octreotide) - Both received IV Albumin - Dopamine to maintain BP - Similar characteristics Reversal of Type 1 Hepatorenal Syndrome with Midodrine and Octreotide (Angeli, P, Volpin, R, Gerunda, G et al. Hepatology : 1690)

ARF and Cirhosis Treatment Midodrine and Octreotide Group B: 2 liver Tx, 1 lived > 472 days 1 died of Pneumonia(ARF resolved) 1 stoped Rx – died 15 days after dicharge Group A: 7 died with in 12 days 1 transplanted Reversal of Type 1 Hepatorenal Syndrome with Midodrine and Octreotide (Angeli, P, Volpin, R, Gerunda, G et al. Hepatology : 1690)

ARF and Cirhosis Treatment Midodrine and Octreotide Group B vs Group A Lower creatinine 1.8 vs 5.0 mg/dl Better GFR 46vs 10 ml/min. Urine volume 1540 vs 680 cc Reversal of Type 1 Hepatorenal Syndrome with Midodrine and Octreotide (Angeli, P, Volpin, R, Gerunda, G et al. Hepatology : 1690)

ARF and Cirhosis Treatment Midodrine and Octreotide Midodrine /Octreotide therapy improves survival in Type-1 Hepatorenal Syndrome(abstract) (analysis of 53 treated and 21 controls Gastroenterlogy 2003; 124:A718. Esrailian,E, et al)

ARF and Cirhosis Treatment Midodrine and Octretide Retrospective study 53 Rx with Midodrine and Octretide 21 control(non-randomized) All had IV Albumin Mortality Reduction(49 vs 67%) and lower creatinine (30 vs 14 %) in treated group vs controls Midodrine /Octreotide therapy improves survival in Type-1 Hepatorenal Syndrome (analysis of 53 treated and 21 controls Gastroenterlogy 2003; 124:A718. Esrailian,E, et al)

ARF and Cirhosis Treatment Drugs with variable Benefits Ornipressin(Vasopressin analog) Reduce splanchnic vasidilation Induce ischemia Misoprostol(Prostaglandin Analog) Used with IV Albumin Conflicting data Norepinephrine with Albumin Risk of Myocardial ischemia N-acetylcysteine- Reduce splanchnic vasodialtion Need to be furhter studied

ARF and Cirhosis Treatment Hemodialysis/CVVHD Usually difficult b/o low BP but can be done. Consider in Pt waiting for liver Tranlplant or has chance for any recovery from liver injury. Consider CVVHD(Continous Venovenous Heomdialysis) in Patients with lower BP.

ARF and Cirhosis Treatment Peritoneovenous Shunts Improves hemodynamics Reduce serum creatinie Survival not improved Unstable Patients with higher complications

ARF and Cirhosis Treatment TIPS (Transjugular intrahepatic portosystemic Shunt) In refractory Ascites can improve renal function. In Hepatorenal Syndrome- much less information.

ARF and Cirhosis Treatment TIPS (Transjugular intrahepatic portosystemic Shunt) TIPS in Hepatorenal syndrome. Lancet 1997; 349:697 Brensing, KA, Textor, J, Strunk, H, et al

ARF and Cirhosis Treatment TIPS (Transjugular intrahepatic portosystemic Shunt) 16 Patients 6 with severe Hepatorenal Syndrome(S.Cr>2.5) 13 out of 16 had Deceased S.Creatinine Improved creatinine clearance Increased urine out put Renal functions improved with in 2 weeks. Further improvement in ensuing 6-8 weeks. TIPS in Hepatorenal syndrome. Lancet 1997; 349:697 Brensing, KA, Textor, J, Strunk, H, et al

ARF and Cirhosis Treatment TIPS (Transjugular intrahepatic portosystemic Shunt) TIPS in Hepatorenal Syndrome Hepatology 1998; 28:416 Guevera, M Gines, P, Bandi, JC et al

ARF and Cirhosis Treatment TIPS (Transjugular intrahepatic portosystemic Shunt) 7 Patients with Hepatorenal Syndrome. Increased creatinine even with Volume expansion. With TIPS GFR increased 9 to 27 TIPS in Hepatorenal Syndrome.Hepatology 1998; 28:416 Guevera, M Gines, P, Bandi, JC et al

ARF and Cirhosis Treatment TIPS (Transjugular intrahepatic portosystemic Shunt) Pts. Too ill to undergo TIPS Scoring System suggested by Malinchoc ( A model to predict poor survival in Patients undergoing TIPS. Hepatology 2000 ; 31:864) MELD risk score > 18 not candidate for TIPS High risk of encephalopathy Consider as a last resort or for Pt. Waiting for Liver Transplant.

ARF and Cirhosis Treatment Prevention IV Albumin shown to prevent Hepatorenal syndrome in SBP(Spontenous Bacterial Peritonitis) NEJM 1999; 341:403(Sort, P, Navasa, M, Arroyo, V et al Albumin 1.5g/kg at the time of diagnosis and another dose 1.0g/kg on third day of Antibiotic Rx Reduce incidence of ARF Did not reduce mortality or Hospitalization.

ARF and Cirhosis Summary Hold Diuretics IV Fluid Challenge/ IV Albumin/FFP Pressors to Support BP(Dopamine) Midiodrine/Octreotide. Hemodialysis/CVVHD in Selected Pts. TIPS in selected Pts. Liver Transplant Prevent by Rx of infections / iv Albumin