Vasodilators and Anti-Oxidant Therapy in Early ATN

• ClinicalTrials.gov Identifier: NCT00286403
• Recruitment Status: Withdrawn
• First Posted: February 3, 2006
• Last Update Posted: March 28, 2016
• Sponsor: Southeast Renal Research Institute
• Collaborator: Dialysis Clinic, Inc.
• Information provided by: Southeast Renal Research Institute

Study Description

Brief Summary:

Patients developing kidney failure after open heart surgery experience an abrupt decrease in blood flow to the kidney. The investigators hypothesize that administration of fenoldopam mesylate (a drug that increases blood flow to the kidney) to patients early in the course of their disease could reduce progression to dialysis-dependent acute renal failure. The investigators also hypothesize that restoring blood flow could induce additional injury to the kidney through the release of reactive oxygen species. Therefore, patients in this protocol will be randomized to receive a fenoldopam or the anti-oxidant MESNA. The investigators hypothesize that combination treatment with Fenoldopam and MESNA will decrease the incidence of death or dialysis at 21 days in patients with early post-operative acute renal failure.

Condition or disease	Intervention/treatment	Phase
Acute Renal Failure	Drug: Fenoldopam Mesylate and/or MESNA	Phase 2; Phase 3

Detailed Description:

Primary Hypotheses:

• Combination therapy with intravenous fenoldopam mesylate and MESNA will reduce the incidence of dialysis and all cause mortality at 21 days in patients with established acute tubular necrosis (ATN).
• The combination of fenoldopam mesylate and Intravenous MESNA reduces the level of reactive oxygen species released following restoration of renal blood flow in patients with ischemic ATN.

Specific Aims

1. To conduct a multicenter, double blind, trial comparing the efficacy of a 72-hour infusion of fenoldopam mesylate or combination of fenoldopam plus intravenous MESNA to reduce the incidence of dialysis or all-cause mortality at 21 days in patients with ischemic ATN.
2. To determine the effects of fenoldopam mesylate alone or in combination with MESNA on reperfusion injury as evidenced by changes in the level of urinary 15-F2t-isoprostanes The rational is that failure of parenteral vasodilators to reduce the incidence of death or dialysis among patients with ATN may involve the extension of tubular injury through normalization of renal blood flow and subsequent reperfusion injury. Moreover, the generation of reactive oxidative species in areas of hypoxia could blunt impair regional blood flow in the kidney through inhibition of nitric oxide production.
3. To serially measure the urinary content of ICAM-1, VCAM-1, KIM-1, P-selectin, E-selectin, MCP-1and Cyr-61 and determine the ability of specific markers to identify patients progressing to dialysis dependent ATN.

The rational is that ICAM-1 is expressed by ischemic endothelium and facilitates neutrophile migration into areas of necrotic epithelium. We will determine whether rising urinary ICAM-1 will identify patients with progressive dialysis-dependent ATN. Specific aim #3 will also examine whether a reduction in dialysis or all cause mortality by fenoldopam mesylate correlates with reduced urinary expression of ICAM-1 or other cell adhesion molecules. The serum, plasma, urine supernatant and urinary casts obtained from patients enrolled in this trial will be made available to other investigators involved in the study of early ATN.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 0 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: Combination Fenoldopam Mesylate and Intravenous MESNA (2-mercaptoethane Sulphonate)in Early Acute Kidney Injury (AKD): A Randomized, Double-Blind Placebo Controlled Clinical Trial
• Study Start Date: August 2008
• Actual Primary Completion Date: October 2008
• Actual Study Completion Date: October 2008

Arms and Interventions

Outcome Measures

Primary Outcome Measures :

1. Incidence of Death or Dialysis at 21 days

Secondary Outcome Measures :

1. Peak serum Cr and Duration of ICU stay

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Post-operative patients with serum creatinine (Cr) rising 0.3 mg/dl or more than 25% above admission levels within a single 24-hour period will be considered eligible.
• Central Venous Access: [CVP > 6 cm H2O without mechanical ventilation] [CVP > 9 cm H2O with mechanical ventilation]

• Mean arterial pressure > 70 mm Hg receiving up to two vasopressors including:

  • Nor-epinephrine (0.01-1.5g/kg/min)
  • Phenylephrine (0.1-7.0g/kg/min
  • Vasopressin (0.1-1.5 mU/kg/min)

Exclusion Criteria:

• Patients with APACHE scores greater than 30 (or felt by the principal investigators to be unlikely survive more than 24 hours).
• Patients requiring 3 or more presser agents to maintain a MAP of 70 mm Hg or greater.
• Patients on two vasopressors with a MAP < 70 mm Hg will not be considered for enrollment
• Patient with baseline serum Cr > 3.0 mg/dl
• Patients with known bacteremia and/or the Systemic Inflammatory Response Syndrome (SIRS)
• Patients ATN secondary to aminoglycosides or amphotericin B or equivalent anti-fungal drug
• Patients on chronic peritoneal or hemodialysis
• Patients receiving acute peritoneal or hemodialysis during current hospitalization
• Patients on dopamine infusion within the previous 12 hours
• Patients with known HIV seropositivity and past history of opportunistic infection
• Pregnant or lactating women
• Patients with history of uncontrolled atrial or ventricular cardiac arrhythmia
• Patients under the influence of alcohol or other drugs
• Patients enrolled in a previous investigational study within15 days of enrollment
• Patients with a known hypersensitivity to fenoldopam mesylate
• Patients with a known history of glaucoma.
• Patients with cirrhosis of the liver and/or portal hypertension
• Patients with toxic levels of calcineurin inhibitors (FK-506 or CsA) or acute allograft rejection

Contacts and Locations

Locations

United States, District of Columbia

Chawala, M. MD

Washington, District of Columbia, United States, 20037

United States, Tennessee

Mandeep Grewal

Chattanooga, Tennessee, United States, 37403

Sponsors and Collaborators

Southeast Renal Research Institute

Dialysis Clinic, Inc.

Investigators

• Principal Investigator: James A Tumlin, MD; Southeast Renal Research Institute
• Study Director: Micheal Kutner, Ph.D.; Rollins School Public Health

More Information

Publications:

Tumlin JA, Finkel KW, Murray PT, Samuels J, Cotsonis G, Shaw AD. Fenoldopam mesylate in early acute tubular necrosis: a randomized, double-blind, placebo-controlled clinical trial. Am J Kidney Dis. 2005 Jul;46(1):26-34.

• Responsible Party: James A. Tumlin, MD, Southeast Renal Research Institute
• ClinicalTrials.gov Identifier: NCT00286403
• Other Study ID Numbers: MCAT-1
• First Posted: February 3, 2006
• Last Update Posted: March 28, 2016
• Last Verified: March 2016

Keywords provided by Southeast Renal Research Institute:

Acute Tubular Necrosis; antioxidants; Fenoldopam

Additional relevant MeSH terms:

Acute Kidney Injury; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Fenoldopam; Physiological Effects of Drugs; Antihypertensive Agents; Vasodilator Agents; Dopamine Agonists; Dopamine Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action