Intra-Renal Therapy of Diuretic Unresponsive Acute Kidney Injury

Acute kidney injury (AKI) is a common complication of hospitalized patients and is
associated with increased morbidity and mortality 1. The pathogenesis of AKI is a complex,
time dependent process involving multiple variables including significant reductions in
renal blood flow (RBF), interstitial infiltration by activated neutrophils and obstruction
of tubule lumens with necrotic debris. In both human studies and animal models, the change
in RBF is an early event with reductions in RBF between 40-50%. The mechanisms by which
blood flow falls after the onset of AKI is unknown, but release of multiple vasoconstrictors
coupled with a loss of autoregulation leads to prolonged reductions in RBF 2. The loss of
the ability to vasodilate and autoregulate renal blood flow increases the sensitivity to
additional ischemic and nephrotoxic insults.

Because reductions in RBF contribute to progression of AKI, clinical maneuvers that restore
blood flow to ischemic kidneys offer the potential to significantly reduce patient
mortality3. Consequently, numerous vasodilators have been investigated to determine whether
restoring blood flow clinically to reduces the incidence of dialysis dependent AKI. Some
agents including fenoldopam mesylate have shown encouraging results in specific
sub-populations, but the benefits of other agents including atrial natriuretic peptide were
offset by the development of systemic hypotension. The hypotenisve effects of these agents
are a significant limitation to efforts to restore blood flow to ischemic kidneys. Moreover,
the potential for additive hypotension and other side effects impedes the creation of
"cocktails" of multiple agents which could have the ability to simultaneously activate
numerous different protective pathways. Recent work using the FlowMedica Benephit catheter
has shown that intra-renal delivery of vasodilators allows for targeted organ protection
without the development of systemic side-effects. Moreover, the intra-renal delivery of
fenoldopam mesylate and other vasodilators allows for supra-pharmacologic doses leading to
and prolonged beneficial effects on RBF and GFR. We hypothesize that intra-renal delivery of
fenoldopam mesylate to patients with early AKI will significantly reduce the number patients
requiring renal replacement therapy. To investigate this hypothesis, we propose to study
patients with "diuretic-resistant" AKI and randomize patients to supportive care with
intermittent diuretics versus a 24 hour intra-renal infusion of fenoldopam mesylate in
combination with intermittent diuretic therapy. The trial will be a randomized prospective,
open-labeled study of 35 patients with early AKI defined as a 1.0 mg/dl rise in serum
creatinine above baseline and/or two consecutive hours of urine output less than 20 mls/hr.
The primary endpoint of the study will be peak serum creatinine at day #4 and the number of
patients requiring renal replacement therapy or dying within 8 days of the onset of AKI.
Additional data will be collected on the safety of implementation and the complications
associated with a 24 hour infusion of fenoldopam using the Angiodynamics Benephit catheter

Inclusion Criteria:

- Inclusion Criteria:

1. Any patient age 18 or over with a 1.0 mg/dl rise in serum Cr within 48 hours or
a fall in urine output of less than 20 mls/min X 2 consecutive hours.

AND one of the two following Options

2. Failure to double urine output within two hours of a 1.5 mg/kg bolus Furosemide
-OR-

3. Failure to maintain a 50% increase in urine output for 4 consecutive hours
following a single 1.5 mg/kg bolus of furosemide WITH an MD performed Urinalysis
documenting the presence of 3 or more "muddy brown casts" per low powered field
(LPF) or the presence of a "free renal tubular cells"

Exclusion Criteria:

- Exclusion Criteria:

1. Patients with APACHE scores greater than 25 (or felt by the principle
investigators not to survive more than 24 hours)

2. Patients with a MAP < 65 on two or more vasopressor or any patient requiring 3
or more presser agents (nor epinephrine, + epinephrine or vasopressin) to
maintain a MAP of 65 mm Hg .

3. Patients receiving acute or chronic peritoneal or hemodialysis during current
hospitalization

4. Patients receiving dopamine or fenoldopam infusion within the previous 24 hours

5. Patients requiring hemodynamic support with an intra-aortic balloon pump

6. Patients with known HIV seropositivity

7. Pregnant or lactating women

8. Patients actively receiving NSAIDS or COX-2 antagonists

9. Patients with history of uncontrolled cardiac arrhythmia

10. Patients who cannot give informed consent.

11. Patients with a known hypersensitivity to fenoldopam mesylate

12. Patients with known bleeding diathesis

13. Patients known blockage to one or more renal arteries

14. Patients with known condition that would increase the likelihood of vascular
perforation, trauma, or dissection such as Marfan's syndrome, cystic medial
necrosis, abdominal or thoracoabdominal aortic dissection, mycotic aneurysm,
abdominal aneurysm, thoracoabdominal aneurysm, renal artery aneurysm, thoracic
aneurysm involving the visceral region of the aorta, and severe calcification in
the area of the renal arteries