Vasodilators and Anti-Oxidant Therapy in Early ATN
| Status: | Withdrawn |
|---|---|
| Conditions: | Renal Impairment / Chronic Kidney Disease |
| Therapuetic Areas: | Nephrology / Urology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/21/2016 |
| Start Date: | August 2008 |
| End Date: | October 2008 |
Combination Fenoldopam Mesylate and Intravenous MESNA (2-mercaptoethane Sulphonate)in Early Acute Kidney Injury (AKD): A Randomized, Double-Blind Placebo Controlled Clinical Trial
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.
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.
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.
- 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.
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
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