Evaluation of Renal Blood Flow Using Contrast Enhanced Ultrasound for Differential Diagnosis of Acute Kidney Injury in Cirrhotic Patients: A Pilot Study

Hepatorenal syndrome (HRS) is a common cause of acute kidney injury (AKI) in cirrhotic
patients and has a one month survival rate of 50% and a 3 month survival rate of 20%. The
leading theory behind HRS is selective vasoconstriction of renal vasculature in the setting
of decreased systemic vascular resistance. Patients with liver cirrhosis suffer from a large
degree of third spacing in the form of peripheral edema and ascites. In addition treatment
with multiple drugs, including diuretics puts these patients at higher risks of prerenal AKI
and ischemic acute tubular necrosis (ATN). AKI occurring due to HRS, prerenal AKI and
ischemic or nephrotoxic ATN have different pathophysiologic mechanisms and are treated
differently with significantly different outcomes. While renal perfusion is expected to be
reduced in HRS and prerenal AKI, it is normal or increased in ATN. Prerenal AKI has the most
favorable prognosis among these pathologies and treatment simply consists of volume
expansion with blood, albumin, crystalloids or colloids. In clinical practice vasoactive
agents such as midodrine and octreotide are used to increase the tone of splanchnic vessels
and to improve renal perfusion. These interventions would not affect renal function in cases
with ATN. Unfortunately, the diagnostic criteria proposed by the International Club for
Ascites (ICA) for HRS are not specific and do not always exclude patients with other forms
of acute kidney injury. Therefore, availability of a simple diagnostic tool for measurement
of renal blood flow (RBF) at the bedside would be of great value in management of cases with
cirrhosis of the liver presenting with acute reduction in kidney function. However,
currently, there are no practical and simple tools available for this purpose.

Contrast enhanced ultrasonography (CEU) involves the intravenous injection of gas-filled
microbubbles to enhance the ultrasound image of the organs and mainly to assess tissue
vascularity and blood flow. We and others have used CEU to assess changes in RBF in response
to physiologic stimuli and therapeutic interventions. Here we propose a prospective, pilot
diagnostic study to validate the use of CEU, in assessing RBF in cirrhotic patients with
AKI, and to assess the utility of CEU to differentiate between causes of AKI in cirrhotic
patients.

Our hypothesis is that CEU will show arteriolar vasoconstriction and decreased blood flow in
the renal cortex in patients with HRS which would not change in response to volume
expansion. On the contrary, patients with prerenal AKI will have reduced RBF which will
increase after volume expansion. Finally, those with ATN will not have a reduced RBF at
baseline.

We plan to enroll 25 patients with liver cirrhosis and acute kidney injury who are admitted
to the University of Virginia hospital into the study.

CEU will be performed on all subjects to measure baseline RBF. CEU will be repeated in all
subjects within 24 hours after volume expansion with at least 1gm/kg of albumin (up to 100
gm/day) to assess a potential change. Hourly urine output and serum creatinine will be
monitored for potential renal response to the volume expansion as part of clinical care. For
the subgroup of subjects who receive treatment with combination therapy with albumin,
midodrine, and octreotide (AMO) RBF assessment with CEU will be repeated after at least 48
hours of receiving this combination. Renal response will be assessed by monitoring urine
output and serum creatinine monitored as part of clinical care. All subjects will have
measurements of fractional excretion of sodium (FENa) and urea (FEUrea) and urine microscopy
as a part of their routine clinical care (work up of AKI). The results of these tests and
the response to volume expansion will be used to categorize subjects into three categories
of AKI (HRS, prerenal AKI, ATN). Correlations between RBF and its changes between different
therapeutic interventions and renal diagnosis will be tested in this study.