Intra-Renal Therapy of Diuretic Unresponsive Acute Kidney Injury

Kidney Failures, Acute Clinical Trial

— IR-FTA  

Official title:

Effect of Combination Intra-Renal Infusion of Fenoldopam Mesylate and High Dose Diuretics on Peak Serum Creatinine and Incidence of Renal Replacement Therapy in Patients With Early Acute Kidney Injury

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT01073189
• Other study ID #: IR-FTA
• Status: Withdrawn
• Phase: Phase 4
• First received: February 22, 2010
• Last updated: March 25, 2016
• Start date: April 2010
• Est. completion date: January 2011

Study information

• Verified date: March 2016
• Source: Southeast Renal Research Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review BoardUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

Randomized prospective trial of patients with diuretic unresponsive acute kidney injury where patients will receive standard supportive therapy with diuretics versus intra-renal delivery of the vasodilator fenoldopam mesylate.

Patients with rising creatinine who fail to respond to bolus diuretics will be treated with a prolonged course of diuretics or undergo placement of a catheter within the renal arteries that allows for infusion of fenoldopam mesylate. The rational is that early delivery of a high dose vasodilator may reverse the decline of renal function in patients with severe acute kidney injury.

Description:

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

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: January 2011
• Est. primary completion date: January 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Kidney Injury
• Kidney Failures, Acute
• Renal Insufficiency

Intervention

Drug:
• Intra-Renal Fenoldopam
Placement of an intra-renal catheter for infusion of fenoldopam mesylate
• Furosemide
Patients randomized to the Diuretic Control group will receive intravenous furosemide as an active control

Locations

Country	Name	City	State
United States	Erlanger Medical Center	Chattanooga	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
Southeast Renal Research Institute

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Peak creatinine at day 4 Renal replacement therapy at 8 days All-cause mortality at 21 days		Day 4, Day 8 and Day 21	Yes
Secondary	24 hour urinary volume at 72 hours Time to > 2.0 liters/24 hours Time to serum Cr < 2.5 mg/dl All cause mortality at 90 and 180 days		All cause mortality at 90 and 180 days	No