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