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.
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.
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 suitable 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.
