The hepatorenal syndrome Assessing kidney function in pts with cirrhosis

The hepatorenal syndrome

Assessing kidney function in pts with cirrhosis

• Cr assays are subject to interference by chromogens, bilirubin being the major one

• There is decreased hepatic production of creatine

• The edematous state that complicates end-stage liver disease leads to large distribution of Cr in the body and lower serum Cr concentration

• Complications such as variceal bleeding, spontaneous bacterial peritonitis or sepsis lead to increased Cr tubular excretion

• HRS is a form of acute or subacute renal failure characterized by severe renal vasoconstriction, which develops in decompensated cirrhosis or ALF

• Nearly half of patients die within 2 weeks of this diagnosis

• The annual incidence of HRS ranges between 8% and 40% in cirrhosis depending on the MELD score

• The frequency of HRS in severe acute alcoholic hepatitis and in fulminant liver failure is about 30% and 55%, respectively

Classification of the hepatorenal syndrome

• Type 1: cirrhosis with rapidly progressive acute renal failure

• Type 2: cirrhosis with subacute renal failure

• Type 3: cirrhosis with types 1 or 2 HRS superimposed on chronic kidney disease or acute renal injury

• Type 4: fulminant liver failure with HRS

Causes of AKI in pts with cirrhosis

• Acute tubular necrosis (41.7%)

• Pre-renal failure (38%)

• Hepatorenal syndrome (20%)

• Post-renal failure (0.3%)

Major diagnostic criteria for hepatorenal syndrome

• Cirrhosis with ascites

• Serum creatinine > 1.5 mg/dL

• No improvement in serum creatinine (decrease to a level of <1.5 mg/dL) after at least 2 days with 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/day

• Absence of shock

• No current or recent treatment with nephrotoxic drugs

• Absence of parenchymal kidney disease as indicated by proteinuria >500 mg/day, microhematuria (<50 RBC/high power field) and/or abnormal renal ultrasonography

Minor diagnostic criteria for hepatorenal syndrome

• Urine volume < 500 mL/24 h

• Urine sodium <10 mEq/L

• Urine osmolality greater than plasma osmolality

• Urine red blood cells < 50 per high power field

• Serum sodium <130 mEq/L

Type 1 hepatorenal syndrome

• The serum creatinine level doubles to greater than 2.5 mg/dL within 2 weeks

• It is characterized by its rapid progression and high mortality, with a median survival of only 1 to 2 weeks

• It can be precipitated by spontaneous bacterial peritonitis and variceal hemorrhage

• In some cases acute hepatic injury, superimposed on cirrhosis, may lead to liver failure and HRS

Type 2 hepatorenal syndrome

• Serum creatinine increases slowly and gradually during several weeks or months

• Many patients with type 2 HRS eventually progress to type 1 HRS because of a precipitating factor

• The median survival of type 2 HRS is about 6 months

Type 3 hepatorenal syndrome

• 85% of end-stage cirrhotics have intrinsic renal disease on renal biopsy

• Patients with long-standing diabetic nephropathy, obstructive renal disease, or chronic glomerulonephritis can develop HRS from a precipitating event or worsening liver failure

Type 4 hepatorenal syndrome

• More than half of patients with ALF develop HRS, although the frequency varies depending on the ALF etiology

• The pathophysiology of HRS in ALF is believed to be similar to that postulated for HRS occurring in cirrhosis

Pathogenesis

• Portal hypertension leads to arterial vasodilatation and pooling of blood in the splanchnic bed, with a decrease in systemic vascular resistance

• The modulation of cardiac output is relatively unable to prevent the severe reduction of effective circulating volume due to the splanchnic arterial vasodilation

• Activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system and stimulation of antidiuretic hormone release become necessary to maintain arterial blood pressure

• As the liver disease worsens these circulatory changes gradually increase until systemic hemodynamic stability depends on vasoconstriction of the extrasplanchnic vascular beds

Nitric oxide

• Nitric oxide (NO) is a potent vasodilator that is elevated in the peripheral circulation of patients with cirrhosis

• The imbalance between NO and vasoconstrictors such as endothelin-1 in the renal microcirculation has been proposed to be responsible for the progressive deterioration in kidney function in these patients

• Nitric oxide has a very short half-life; therefore, measurement of the NO metabolites, nitrite and nitrate (NOx), are commonly used to estimate NO levels in the circulation

• Because both metabolites are excreted predominantly by the kidney, decreased renal clearance rather than overproduction could account for the elevated level of NOx in decompensated cirrhosis

• L-Arginine (L-Arg), a nonessential amino acid, is the precursor for NO production by nitric oxide synthase

• The liver is the major site for arginine metabolism, where arginine generated in the urea cycle is rapidly converted to urea and ornithine by arginase-1

• NOS and arginase-1 compete for available arginine and it is possible that the overproduction of NO results from an excess availability of substrate

• Patients with either compensated cirrhosis, cirrhotic patients with ascites, refractory ascites (RA) or chronic hepatorenal syndrome (HRS) type II were included in the sudy

• Normal healthy volunteers, organ donors and chronic renal failure (CRF) patients without liver disease were included as controls

• After adjusting for all demographics and variables, HRS was the only disease state predicting high levels of NOx in the peripheral circulation (P < 0.001)

• Multivariate analysis also revealed that HRS was an independent factor predicting high levels of L-Arg (P = 0.03)

• Chronic renal failure and stages of progressive renal dysfunction in decompensated cirrhosis were not independently associated with peripheral levels of NOx or L-Arg  

• Peripheral levels of NOx reliably reflect NOx levels in the splanchnic circulation, suggesting that peripheral levels of NOx can be used diagnostically as a marker for disease state

Treatment

• TIPS

• Significant suppression of the endogenous vasoconstrictor systems

• Decrease in creatinine levels

• More easily controllable ascites

Midodrine/octreotide

• Combination therapy with midodrine (a selective alpha-1 adrenergic agonist) and octreotide (a somatostatin analog) may be effective and safe

• Midodrine is a systemic vasoconstrictor and octreotide is an inhibitor of endogenous vasodilator release, combined therapy would improve renal and systemic hemodynamics

• These drugs were used in three pilot studies in a total of 79 patients

• A complete recovery of renal failure was observed in 49% of patients.

• In most patients midodrine administration started at 5-10 mg t.i.d. orally, with the goal of increasing the dose to 12.5 or 15 mg t.i.d. if a reduction of serum creatinine was not observed

• Octreotide administration started at 100 μg subcutaneously t.i.d. with the goal of increasing the dose to 200 μg subcutaneously t.i.d. if a reduction of serum creatinine was not observed

Terlipressin

• Terlipressin, an agonist of the V1 vasopressin receptors, is inactive in its native form, but is transformed into the biologically active form, lysine-vasopressin through enzymatic cleavage of glycyl residues by tissue peptidases

• Because of this modification, terlipressin has a prolonged biological half-life compared with other vasopressin analogues

Terlipressin: Meta Analysis

• Five studies involving 243 patients with HRS were identified

• Pooling of study results showed a significant increase in HRS reversal among patients who received terlipressin versus those who received placebo (the pooled odd ratio OR of HRS reversal was 8.09 p=0.0001)

• The rate of severe ischemic events was higher in study than control patients, (pooled OR=2.907 p=0.032)

• Terlipressin use had no significant impact upon survival (pooled OR for survival rate, 2.064 p=0.07)