Learning objectives To understand the pathophysiologic basis for vasoactive therapies for HRS To become familiar with the diagnostic criteria for HRS.

Learning objectives

• To understand the pathophysiologic basis for vasoactive therapies for HRS

• To become familiar with the diagnostic criteria for HRS

• To learn about therapeutic options for patients with HRS

1. Sinusoidal portal hypertension, in the presence of severe hepatic decompensation

2. Leads to splanchnic and systemic vasodilatation-role of NO

3. Decreased effective arterial blood volume

4. Activation of systemic vasoactive factors, such as the renin-angiotensin system, the sympathetic nervous system, and vasopressin aimed at restoring arterial filling pressure.

5. Renal vasoconstriction increases concomitantly (leukotrienes and endothelins), counterbalanced by the intrarenal hyperproduction of vasodilating prostaglandins. When this balance is lost renal hemodynamics worsens, and hepatorenal syndrome develops

39-year-old man with a history of heavy alcohol abuse and cirrhosis but no other significant past medical problems was admitted for treatment of increasing ascites.

He had no known history of kidney disease

He had jaundice, tense ascites, severe leg edema, and mild to moderate encephalopathy.

He had no signs of fluid loss, such as bleeding or diarrhea.

The patient was not taking any nephrotoxic medications.

His AST and ALT were 202 U/L and 68 U/L, respectively, and his initial serum creatinine level was 62 micromoles/L and Na 123.

Results of serologic testing for antibody to hepatitis C virus, hepatitis B surface antigen, IgM antibody to hepatitis A virus, antinuclear antibodies, and antibody to Sm nuclear antigen were negative.

The patient had no detectable paracetamol level, and his ceruloplasmin level was normal.

Between day 5 and day 14 of the patient's hospitalization, his serum creatinine level increased from 230 micromoles/L.

No improvement in renal function after volume expansion with 1.5L isotonic saline solution

Microscopic examination of his urine revealed fewer than 50 red blood cells per high-power field. Urine and serum osmolality values were 354 mOsm/kg H2O and 246 mOsm/kg H2O

Urine protein excretion was 246 mg/24 hr, and spot urine sodium level was 7 mmol/L.

Renal ultrasound was normal.

Serum-ascites albumin gradient was 2.1 g/dL, and PMN count 2

International Ascites Club diagnostic criteria for HRSInternational Ascites Club diagnostic criteria for HRS

Major criteria 1. Chronic or acute hepatic disease and liver failure with portal

hypertension 2. Serum creatinine level >133 micromoles/L or 24-hr creatinine clearance

<40 mL/min3. Absence of shock, ongoing bacterial infection, recent use of nephrotoxic

drugs, excessive fluid or blood loss 4. No sustained improvement in renal function after volume expansion with

1.5 L isotonic saline solution 5. Proteinuria <500 mg/day and no ultrasonographic evidence of renal tract

or parenchymal disease

Minor criteria 1. Urine volume <500 mL/day 2. Urine sodium <10 mEq/L 3. Urine osmolality greater than plasma osmolality 4. Urine red blood cell count <50 per high-power field 5. Serum sodium <130 mEq/L

Types of HRSTypes of HRS• Type I HRS is the more serious type defined by a rise in creatinine level to over 221

micromoles/L in less than 2 weeks (or at least a 50 percent lowering of the creatinine clearance to a value below 20 mL/min) median survival of 2 weeks

• Type II HRS is defined as less severe renal insufficiency than that observed with type I disease; it is principally characterized by ascites that is resistant to diuretics. median survival of 3-6 months.

Other Problems to be Excluded: Other Problems to be Excluded:

• Prerenal azotemia from volume depletion(diuretic/GI bleed/LVP)

• Systemic infection/SBP(HRS type 1 develops in 15% )

• Drug-induced nephrotoxicity: aminoglycosides, diuretics, iodine-containing contrast agents, and nonsteroidals. ACE inhibitors, demeclocycline, and dipyridamole.

• Postrenal azotemia from outflow obstruction

• Renal vascular disease

• Glomerulonephritis, nonstreptococcal postinfectious

PRERENAL HRS ATN

SPOT Na <10 <10 >30

Urine sediment

Nil Nil Positive

Fluid challenge

Responds Nil Nil

HEPATORENAL SYNDROME

IncidenceIncidence

• HRS occurs in approximately 4% of patients with cirrhosis who are decompensated,

• With a cumulative probability of 8% per year, which increases to 39% at 5 years.

• In hospitalized patients with ascites, the incidence rate is 7-15%.

Assessing renal perfusionAssessing renal perfusion

• Creatinine production may be substantially reduced in this setting, due to the liver disease and to decreased muscle mass and protein and meat intake.

• Creatinine clearance value obtained in patients with renal insufficiency will tend to overestimate the true GFR due to increased creatinine secretion

• Noninvasive techniques to assess the degree of renal vasoconstriction duplex Doppler ultrasonography.A high resistive index ( 0.70) is indicative of renal vasoconstriction.

Treatment optionsTreatment options

• OLT• Haemodialysis• TIPSS• Vasoactive Medical treatment

OLTOLT• Liver transplantation carries the best

chance for long-term survival, but the rapid deterioration associated with type 1 HRS means that many patients die before an organ becomes available.

• The systemic and neurohumoral abnormalities associated with HRS also resolve in the first postoperative month.

• The hepatorenal syndrome is a prerenal disease, as the kidneys are normal histologically

Dialysis Dialysis • This is used most commonly in patients who are awaiting

liver transplantation, as dialysis improves the priority score for the transplant.

• Acute and potentially reversible hepatic insult may benefit from dialysis, since renal function will recover in parallel with improving hepatic function.

• Hemodialysis is frequently difficult to perform in patients with hepatorenal syndrome since decompensated hepatic function is associated with hemodynamic instability.

TIPSSTIPSS• The transjugular intrahepatic portosystemic shunt (TIPS) has been

used in the treatment of refractory ascites. When used in this setting, there may also be a delayed improvement in renal function

• There is much less information on the use of TIPS in patients who fulfill criteria for the hepatorenal syndrome

• Overall, these results suggest that, in selected patients with hepatorenal syndrome, TIPSS may provide short-term benefit. Given the risks associated with this procedure (particularly the high incidence of encephalopathy), it should be considered only as a last resort in patients who are not a candidate for or are awaiting liver transplantation.

Medical treatmentMedical treatment• Hepatorenal syndrome was recalcitrant to

medical therapy for so many years that it is still perceived by many physicians as untreatable.

• Clearly, new therapies have significantly brightened the short-term outlook for patients with type 1 hepatorenal syndrome, and improvement in short-term survival rates may lead to increased opportunity for definitive therapy (ie, liver transplantation).

Vasoactive therapyVasoactive therapy

• Midodrine- octreotide- albumin regime

• Terlipressin plus albumin

• Midodrine and octreotide – Growing data suggest that combination therapy with midodrine (a selective alpha-1 adrenergic agonist) and octreotide (a somatostatin analog) may be highly effective and safe.

• The rationale is midodrine (systemic vasoconstrictor) and octreotide (inhibitor of endogenous vasodilator release)will reverse the pathophysiology

Angelie et al Hepatology 1999Pomier-Layrargues et al Hepatology 2003

1. Sinusoidal portal hypertension, in the presence of severe hepatic decompensation

2. Leads to splanchnic and systemic vasodilatation-role of NO

3. Decreased effective arterial blood volume

4. Activation of systemic vasoactive factors, such as the renin-angiotensin system, the sympathetic nervous system, and vasopressin aimed at restoring arterial filling pressure.

5. Renal vasoconstriction increases concomitantly (leukotrienes and endothelins), counterbalanced by the intrarenal hyperproduction of vasodilating prostaglandins. When this balance is lost renal hemodynamics worsens, and hepatorenal syndrome develops

Midodrine- octreotide- albumin Midodrine- octreotide- albumin regimeregime

• Midodrine (7.5 mg by mouth every 8 hours)

• Octreotide (100 mg subcutaneously every 8 hours)

• Albumin (25 mg intravenously per day)

Terlipressin plus albuminTerlipressin plus albuminregimeregime

• Terlipressin bolus(0.5mg/4h)-increase every 3 days if no response to 1-2mg/4h

• Given until creatinine normalizes or for 15 days

• Albumin 1g/kg on day1,20-60g/d thereafter

Uriz et al Uriz et al J HepatolJ Hepatol 2000 2000

• In one prospective, nonrandomized study 21 patients were treated with terlipressin plus albumin compared with terlipressin alone.

• The group treated with terlipressin and albumin had a 3-month survival rate of 50%, compared to 10% for the terlipressin-only group.

Ortega et al hepatology 2002

• A small cohort of nine patients with cirrhosis and HRS were given Terlipressin and albumin until the reversal of hepatorenal syndrome or for a maximum of 15 days

• Seven of the nine patients showed a reversal of hepatorenal syndrome. There was also a marked improvement in MAP. Plasma renin activity and plasma norepinephrine decreased

Uriz et al Uriz et al J HepatolJ Hepatol 2000 2000

PREVENTION PREVENTION • In patients with spontaneous bacterial peritonitis, the

administration of intravenous albumin (1.5 g/kg) at the time of diagnosis of infection and another dose of albumin (1.0 g/kg) on day three of antibiotic treatment may reduce the incidence of both renal impairment and mortality during hospitalization and at three months

• Pentoxifylline (400 mg PO TID) may be preventive in patients with severe alcoholic hepatitis

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