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HEPATORENAL SYNDROME


HEPATORENAL SYNDROME
Hepatorenal syndrome (HRS) occurs when there is a decrease in renal perfusion secondary to advanced hepatic disease. Patients may have advanced liver disease due to cirrhosis, alcoholic hepatitis, metastatic cancers, or other causes. HRS is a common complication of liver failure, affecting up to 10% of patients with ascites, and is associated with a significant risk of mortality. As a result, serum creatinine is included in the MELD score (model for end-stage liver disease) used to evaluate patients for possible liver transplantation.


HEPATORENAL SYNDROME

PATHOPHYSIOLOGY
The pathogenesis of HRS appears to be related to vasodilation of the splanchnic circulation, which leads to systemic arterial underfilling. The current evidence indicates that nitric oxide is the primary mediator of splanchnic vasodilation, and several mechanisms have been proposed to trigger its release. First, increased portal venous pressure leads to increased expression of endothelial nitric oxide synthase (eNOS). In addition, as portal hypertension worsens, bacteria traverse from the intestinal lumen into mesenteric lymph nodes, triggering release of inflammatory mediators (such as TNF-) that further promote eNOS activation. Finally, other vasodilators (including endocannabinoids and prostaglandins), as well as endothelial resistance to vasoconstrictors, are also thought to contribute to the ongoing splanchnic vasodilation.
At first, activation of the sympathetic nervous system and renin-angiotensin-system increases cardiac output and vascular tone to maintain systemic perfusion pressures. As the hepatic disease progresses, however, further compensation becomes impossible. The hepatorenal syndrome thus ensues, in which severe renal vasoconstriction and declining renal perfusion result in a reduced glomerular filtration rate. The consequent retention of sodium and water leads, in turn, to worsening ascites and edema.
In the setting of these processes, several factors can precipitate an acute decompensation in renal function. In patients with advanced liver disease, clinicians must be vigilant about these exacerbating factors:
·     Diuretics reduce the intravascular volume, exacerbating the effective volume depletion.
·  Occult gastrointestinal bleeding, which may occur because of coagulopathies secondary to advanced liver disease, can worsen volume depletion.
·     Large volume paracentesis (especially without the concomitant provision of intravenous albumin, when indicated) can also worsen volume depletion.
·  Spontaneous bacterial peritonitis can trigger a dramatic increase in splanchnic inflammatory mediators, promoting further splanchnic vasodilation and worsening effective volume depletion.
·     NSAIDs block tubuloglomerular feedback and thus prevent vasodilation of the afferent arteriole in response to poor renal perfusion pressure.

PRESENTATION AND DIAGNOSIS
Patients with HRS often have the typical stigmata of liver disease, which include jaundice, ascites, coagulopathies, and occasionally encephalopathy. Effective intraarterial volume depletion causes tachycardia, low-normal blood pressure, and low jugular venous pressure. The prerenal state leads to oliguria, edema, and worsening ascites.
Suggestive laboratory findings include an elevated serum creatinine concentration, benign urine sediment, and FENa less than 1%. The BUN: Cr ratio may be elevated, indicative of a prerenal state, but BUN must be carefully interpreted since gastrointestinal bleeding and malnutrition can both affect its value. In addition, hyperbilirubinemia may cause granular and epithelial cell casts, which should not be misinterpreted as evidence of acute tubular necrosis.
Several renal diseases can be associated with specific hepatic diseases; these should be considered and, if possible, ruled out. Examples include IgA nephropathy associated with alcoholic hepatitis; membranous glomerulonephritis associated with hepatitis B; and membranoproliferative glomerulonephritis and cryoglobulinemia associated with hepatitis C.
After a thorough evaluation, the diagnosis of hepatorenal syndrome can be established if the criteria set by the International Club of Ascites are met. Once the diagnosis is confirmed, patients are classified into one of two subtypes based on their rate of progression. Type 1 HRS features rapidly progressive renal failure, defined as a doubling of the initial serum creatinine to a level greater than 2.5 mg/dL in less than 2 weeks. Type 1 HRS usually occurs secondary to a precipitating event, particularly spontaneous bacterial peritonitis or gastrointestinal bleeding, and it has a very poor prognosis. Meanwhile, type 2 HRS features a slower progression of renal failure, manifest as a slowly progressive worsening of serum creatinine to greater than 1.5 mg/dL, and typically occurs without a precipitant.
Note that because of the reduced muscle mass in patients with liver failure, serum creatinine may remain in the normal range during the early stages of renal dysfunction, leading to underdiagnosis. Nonetheless, the serum creatinine concentration steadily increases, although the rate may be as little as 0.1 mg/dL/day, with intermittent periods of stabilization or even slight improvement.

HEPATORENAL SYNDROME

TREATMENT
The treatment of hepatorenal syndrome aims to reverse the underlying circulatory problem until the hepatic disease improves or liver transplantation occurs. Administration of medications that counteract splanchnic vasodilation can help restore renal perfusion, increasing glomerular filtration rate. Multiple pharmacologic therapies have been studied, including vasopressin analogues, midodrine, and octreotide. Transjugular intrahepatic portosystemic shunt (TIPS) is a portalcaval shunt that reduces portal pressure and can improve renal perfusion, but it can also precipitate hepatic encephalopathy and other complications. The use of renal replacement therapy can provide electrolyte stabilization as a bridge to liver transplantation; however, in the absence of planned liver transplantation, dialysis does not significantly improve mortality.
At this time, liver transplantation is the only effective and permanent treatment for hepatorenal syndrome.
Unless the renal ischemia is severe enough to cause severe acute tubular necrosis and/or fibrosis, the kidneys remain histologically intact and regain normal function in a majority of cases. Indeed, the kidneys of patients with hepatorenal syndrome are often still suit- able for donation to other recipients. Some patients, however, will develop intrinsic renal disease that is advanced enough to warrant a combined liver-kidney transplantation.

PROGNOSIS
The prognosis is very poor in HRS if treatment is not rapidly provided. Mortality of untreated type I disease, for example, is up to 80% in 2 weeks. Patients with type 2 have a slightly better prognosis, with a median survival of months rather than weeks. Nonetheless, their survival is still shorter than that of a cirrhotic patient with ascites but without renal dysfunction.