This lecture was conducted during the Nephrology Unit Grand Ground by Medical Student rotated under Nephrology Division under the supervision and administration of Prof. Jamal Al Wakeel, Head of Nephrology Unit, Department of Medicine and Dr. Abdulkareem Al Suwaida, Chairman of the Department of Medicine. Nephrology Division is not responsible for the content of the presentation for it is intended for learning and /or education purpose only.

Presented by: Adel Al Mudaibegh Medical Student February 2009

 Refers to the development of acute renal failure in a patient who usually has advanced liver disease due to: o cirrhosis o severe alcoholic hepatitis o metastatic tumor (less often)  Can occur in a substantial proportion of patients with fulminant hepatic failure from any cause.

 The hepatorenal syndrome usually represents the end-stage of a sequence of reductions in renal perfusion induced by increasingly severe hepatic injury.  It is a prerenal disease, as the kidneys are histologically normal.

INCIDENCE  Incidence of 10% among hospitalized patients with cirrhosis and ascites.  Equal in both sexes.  All people with CLD are at risk for HRS.  4 th to 8 th decades of life.

PATHOGENESIS  Splanchnic vasodilatation appears to play an important role in the decline in renal function in hepatic disease.  Progressive  in cardiac output &  in SVR despite local increments in renal & femoral vascular resistance from induction of RAS & sympathetic systems.  May be in part due to nitric oxide.   in Renal Perfusion is assoc. with  in GFR and Na+ excretion, as well as a  in MAP.

 Other suspects include an  in ratio of vasoconstrictor thromboxanes / vasodilator prostaglandins.  Arterial vasodilation theory: Proposes that HRS is the result of the effect of vasoconstrictor systems acting on the renal circulation and activated as a homeostatic mechanisms to improve the extreme underfilling of the arterial circulation. That leads to decreased renal perfusion and glomerular filtration rate (GFR) but tubular function is preserved.

Liver cirrhosis & PHT Splanchnic VD Decreased effective ABV Increased VC systems Renal Vasoconstriction HRS Systemic VC

ESTIMATION OF RENAL FUNCTION  The reduction in GFR in patients with hepatic disease is often masked clinically.  Both urea and creatinine production may be substantially reduced due to the liver disease and to ↓ muscle mass and ↓ protein and meat intake (plasma creatinine may appear to be within the normal range (1 to 1.3 mg/dL or 88.4 to 115 µmol/L).

 The BUN is variable. It may be lower than expected from the GFR if urea production is reduced or it may be elevated, out of proportion to the plasma creatinine concentration, if urea production is adequate.  GFR more accurately measured by 24-hr creatinine clearance to demonstrate  in production.

CLINICAL PRESENTATION  Oliguria  Generally benign urine sediment  Very low rate of sodium excretion  Progressive rise in the plasma creatinine concentration

Types of Hepatorenal Syndrome:  Based upon the speed of onset of renal failure, two forms of hepatorenal syndrome have been described:  Type I hepatorenal syndrome (more serious type)  Type II hepatorenal syndrome (less severe)

 Type I hepatorenal syndrome:  At least a 50% lowering of the creatinine clearance to a value below 20 mL/min in less than a two week period or  At least a twofold increase in serum creatinine to a level greater than 2.5 mg/dL (221 µmol/L).  Commonly oliguric.  Median survival time is only 2 weeks.

 Type II hepatorenal syndrome:  Characterized by ascites that is resistant to diuretics.  Less severe than type I.  Associated with relatively preserved liver function.  Median survival time is about 6 months.

Precipitants  GI bleeding  Infection (Spontaneous bacterial peritonitis)  Diuretics can cause azotemia, this improves with cessation of therapy and fluid repletion. In comparison, the HRS worsens, even after diuretics are stopped.

DIAGNOSTIC CRITERIA 1) Chronic or acute hepatic disease with advanced hepatic failure and portal hypertension. 2) Plasma creatinine concentration >1.5 mg/dL (133 µmol/L) that progresses over days to weeks. 3) The absence of any other apparent cause (paranchymal renal disease, shock, ongoing infection, obstruction, nephrotoxic medications).

4) Proteinuria < 500 mg/day. 5) Lack of improvement in renal function after volume expansion with IV albumin (or 1.5 L of isotonic saline) for at least two days and withdrawal of diuretics.

 Additional criteria: ○ Urine red cell excretion < 50 cells per high power field ○ Urine volume < 500 mL/d ○ Urine sodium level <10 mEq/L ○ Urine osmolality > plasma osmolality ○ Serum sodium concentration <130 mEq/L

Diagnosis  The diagnosis of the hepatorenal syndrome is one of exclusion.  Both glomerulonephritis and vasculitis can occur in patients with liver disease and should be suspected in patients with an active urine sediment containing red cells and red cell and other casts.

 It is particularly important to exclude spontaneous bacterial peritonitis, which is complicated by acute renal failure that may be reversible in 30 to 40% of patients.

DDx  Acute tubular necrosis Patients with cirrhosis may develop ATN after  a course of aminoglycoside therapy  the administration of a radiocontrast agent  an episode of sepsis or bleeding. The following criteria may be useful for diagnosis: ↑urine sodium conc. fractional excretion of sodium above 2% granular & epithelial cell casts in the urine sediment. Urine/serum osmolarity ratio<1

 Prerenal disease Decreased renal perfusion can also be induced by: Gastrointestinal losses or bleeding. Shock. Therapy with a diuretic or a NSAID.

TREATMENT  Liver transplant: o The ideal treatment of HRS is liver transplantation. o Long-term survival rates are excellent, with the survival rate at 3 years approaching approximately 60%. o Effective alternative therapies to increase survival chances for patients with HRS are urgently needed until transplantation can be performed.

 Medical treatment:  IV sympatholytic agent clonidine In early stages can raise the GFR by as much as 25%. Lowering renal sympathetic tone and renal vascular resistance. This benefit does not appear to be sustained with chronic oral therapy.

 Midodrine and octreotide  Combination therapy with midodrine (a selective alpha-1 adrenergic agonist) and octreotide (a somatostatin analog) may be highly effective and safe.  Since midodrine is a systemic vasoconstrictor and octreotide is an inhibitor of endogenous vasodilator release, combined therapy would improve renal and systemic hemodynamics.

 Treatment with midodrine & octreotide was associated with:  Significant reduction in mortality and  Significantly higher incidence of a reduction in serum creatinine concentration to less than 1.5 mg/dL (133 µmol/L).

 Norepinephrine plus albumin  Showed a reduction in serum creatinine concentration.  Also provides significant blood pressure support.

 Other therapies:  Vasopressin analougs (ornipressin and terlipressin) reduce splanchnic vasodilation When administered with circulating volume expansion there was an increase in GFR & improved renal function.

 Prostaglandin analog, misoprostol.  N-acetylcysteine.  ACE inhibitors. Tried with conflicting evidence of benefit, or evidence of harm. So cannot be recommended.

 Transjugular intrahepatic portosystemic shunt (TIPS): Insertion of TIPS was associated with a gradual improvement in glomerular filtration rate. TIPS 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.

 Peritoneovenous shunt Insertion of a peritoneovenous shunt can improve systemic hemodynamics and modestly reduce the plasma creatinine concentration. However, survival is not improved and complications limit use of this procedure. Have no role in type I HRS

 Dialysis Patients with hepatorenal syndrome who progress to renal failure can be treated with dialysis. Most commonly done when patients are awaiting a liver transplant or when there is the possibility of improvement in liver function. In addition, dialysis improves the priority score for the transplant.

Treatment summary:  Combination therapy with midodrine and octreotide or single agent therapy with norepinephrine should be considered in patients with HRS.  Also administer IV albumin at approximately 1 g/kg per day (100 g maximum) for two or more days.  Liver transplant candidates who develop end- stage renal disease usually undergo hemodialysis.

PROGNOSIS  Overall, the mortality of patients with liver failure is substantially worse if they develop hepatorenal syndrome.  The outcome of patients with hepatorenal syndrome is strongly dependent on reversal of the hepatic failure.

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