Fenoldopam Mesylate Enhances the Survival of Mesenchymal Stem Cells Under Oxidative Stress and Increases the Therapeutic Function in Acute Kidney Injury.

Mesenchymal stem cells (MSCs) have gained interest as an alternative therapeutic option for renal diseases, including acute kidney injury (AKI). However, their use is often limited owing to low survival rates in vivo. Fenoldopam mesylate (FD) is a selective dopamine D1 receptor agonist with antioxidative and anti-apoptotic roles. Herein, we investigated whether FD can enhance the survival of MSCs undergoing oxidative stress in vitro. In addition, the therapeutic effect of MSCs and FD-treated MSCs (FD-MSCs) was compared in a mouse model of AKI induced by cisplatin. The survival of MSCs under oxidative stress was augmented by FD treatment. FD induced the phosphorylation of cAMP response element-binding protein and AKT, contributing to enhanced growth compared with untreated MSCs. The expression of nuclear factor erythroid-2-related factor 2 (NRF2) and heme oxygenase-1 was increased by FD treatment, and nuclear translocation of NRF2 was found exclusively in FD-MSCs. FD downregulated BAX expression, increased the mitochondrial membrane potential, reduced reactive oxygen species generation, and decreased the apoptotic death of MSCs induced by oxidative stress. Moreover, renal function and tubular injury were improved in FD-MSCs compared with non-treated MSCs. Furthermore, tubular injury, apoptosis, and macrophage infiltration, as well as the serum level of tumor necrosis factor-α were reduced, while tubular cell proliferation was markedly increased in FD-MSCs compared with MSCs. Our study demonstrated that FD increases the survivability of MSCs in an oxidative environment, and its use may be effective in preparing robust therapeutic MSCs.

Pharmacologic Control of Blood Pressure in Infants and Children.

Alterations in blood pressure are common during the perioperative period in infants and children. Perioperative hypertension may be the result of renal failure, volume overload, or activation of the sympathetic nervous system. Concerns regarding end-organ effects or postoperative bleeding may mandate regulation of blood pressure. During the perioperative period, various pharmacologic agents have been used for blood pressure control including sodium nitroprusside, nitroglycerin, ß-adrenergic antagonists, fenoldopam, and calcium channel antagonists. The following manuscript outlines the commonly used pharmacologic agents for perioperative BP including dosing regimens and adverse effect profiles. Previously published clinical trials are discussed and efficacy in the perioperative period reviewed.

Effects of fenoldopam on renal blood flow in hypertensive chronic kidney disease.

BACKGROUND AND AIM: The synthetic drug fenoldopam mesylate (FM) may have a renoprotective role, and a "renal dose" of 0.1 µg/kg/min intravenous (IV) infusion of FM has been reported as able to increase renal blood flow without affecting systemic blood pressure. But conclusive data are still lacking. We aimed to investigate by color-Doppler ultrasonography the effects of IV administration of FM at this dosage in hypertensive chronic kidney disease (CKD) patients, and verify whether it may induce any systemic hemodynamic alteration. METHODS: In 60 hypertensive CKD patients, we measured by duplex Doppler ultrasonography, at baseline and during infusion of 0.1 µg/kg/min of FM, the systolic and diastolic flow velocity (sampled at the renal hilum, intermediate section and origin of both renal arteries) and the intra-parenchymal renal resistive index (RRI) sampled on interlobular arteries of both kidneys. Patients were divided into four subgroups (I-IV) according to classification of National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-DOQI). RESULTS: Infusion of 0.1 µg/kg/min FM significantly decreased the RRI (0.73 ± 0.05 vs. 0.65 ± 0.06; p < 0.0001) and increased the systolic and diastolic flow velocities in all renal artery tracts examined. No single episode of systemic hypotension was observed. CONCLUSIONS: Very low-dose FM may significantly increase renal blood flow and exert a renal protective effect in hypertensive CKD patients. Infusion of FM at such low dosage appears also to be quite safe, even in CKD and hypertensive patients.

Effect of fenoldopam on use of renal replacement therapy among patients with acute kidney injury after cardiac surgery: a randomized clinical trial.

IMPORTANCE: No effective pharmaceutical agents have yet been identified to treat acute kidney injury after cardiac surgery. OBJECTIVE: To determine whether fenoldopam reduces the need for renal replacement therapy in critically ill cardiac surgery patients with acute kidney injury. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, double-blind, placebo-controlled, parallel-group study from March 2008 to April 2013 in 19 cardiovascular intensive care units in Italy. We randomly assigned 667 patients admitted to intensive care units after cardiac surgery with early acute kidney injury (≥50% increase of serum creatinine level from baseline or oliguria for ≥6 hours) to receive fenoldopam (338 patients) or placebo (329 patients). We used a computer-generated permuted block randomization sequence for treatment allocation. All patients completed their follow-up 30 days after surgery, and data were analyzed according to the intention-to-treat principle. INTERVENTIONS: Continuous infusion of fenoldopam or placebo for up to 4 days with a starting dose of 0.1 µg/kg/min (range, 0.025-0.3 µg/kg/min). MAIN OUTCOMES AND MEASURES: The primary end point was the rate of renal replacement therapy. Secondary end points included mortality (intensive care unit and 30-day mortality) and the rate of hypotension during study drug infusion. RESULTS: The study was stopped for futility as recommended by the safety committee after a planned interim analysis. Sixty-nine of 338 patients (20%) allocated to the fenoldopam group and 60 of 329 patients (18%) allocated to the placebo group received renal replacement therapy (P = .47). Mortality at 30 days was 78 of 338 (23%) in the fenoldopam group and 74 of 329 (22%) in the placebo group (P = .86). Hypotension occurred in 85 (26%) patients in the fenoldopam group and in 49 (15%) patients in the placebo group (P = .001). CONCLUSIONS AND RELEVANCE: Among patients with acute kidney injury after cardiac surgery, fenoldopam infusion, compared with placebo, did not reduce the need for renal replacement therapy or risk of 30-day mortality but was associated with an increased rate of hypotension. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00621790.

Hemodynamic correlates of drug-induced vascular injury in the rat using high-frequency ultrasound imaging.

Several classes of drugs have been shown to cause drug-induced vascular injury (DIVI) in preclinical toxicity studies. Measurement of blood flow and vessel diameter in numerous vessels and across various tissues by ultrasound imaging has the potential to be a noninvasive translatable biomarker of DIVI. Our objective was to demonstrate the utility of high-frequency ultrasound imaging for measuring changes in vascular function by evaluating blood flow and vessel diameter in the superior mesenteric arteries (SMA) of rats treated with compounds that are known to cause DIVI and are known vasodilators in rat: fenoldopam, CI-1044, and SK&F 95654. Blood flow, vessel diameter, and other parameters were measured in the SMA at 4, 8, and 24 hr after dosing. Mild to moderate perivascular accumulations of mononuclear cells, neutrophils in tunica adventitia, and superficial tunica media as well as multifocal hemorrhage and necrosis in the tunica media were found in animals 24 hr after treatment with fenoldopam and SK&F 95654. Each compound caused marked increases in blood flow and shear stress as early as 4 hr after dosing. These results suggest that ultrasound imaging may constitute a functional correlate for the microscopic finding of DIVI in the rat.

Evaluation of von Willebrand factor and von Willebrand factor propeptide in models of vascular endothelial cell activation, perturbation, and/or injury.

Pharmacologically, vasoactive agents targeting endothelial and/or smooth muscle cells (SMC) are known to cause acute drug-induced vascular injury (DIVI) and the resulting pathology is due to endothelial cell (EC) perturbation, activation, and/or injury. Alteration in EC structure and/or function may be a critical event in vascular injury and, therefore, evaluation of the circulatory kinetic profile and secretory pattern of EC-specific proteins such as VWF and VWFpp could serve as acute vascular injury biomarkers. In rat and dog models of DIVI, this profile was determined using pharmacologically diverse agents associated with functional stimulation/perturbation (DDAVP), pathological activation (lipopolysaccharide [LPS]/endotoxin), and structural damage (fenoldopam [FD], dopamine [DA], and potassium channel opener (PCO) ZD6169). In rats, FD caused moderate DIVI and time-related increase in plasma VWF levels ∼33% while in control rats VWF increased ∼5%. In dogs, VWF levels transiently increased ∼30% when there was morphologic evidence of DIVI by DA or ZD6169. However, in dogs, VWFpp increased >60-fold (LPS) and >6-fold (DDAVP), respectively. This was in comparison to smaller dynamic 1.38-fold (LPS) and 0.54-fold (DDAVP) increases seen in plasma VWF. Furthermore, DA was associated with a dose-dependent increase in plasma VWFpp. In summary, VWF and VWFpp can discriminate between physiological and pathological perturbation, activation, and injury to ECs.

The effect of various fenoldopam doses on renal perfusion in patients undergoing cardiac surgery.

BACKGROUND: The hypothesis that fenoldopam mesylate, by increasing renal flow, could reduce renal damage in patients undergoing cardiac surgery with cardiopulmonary bypass has gained great interest. The aim of the current study was to quantify the relationship of the increase of the renal blood flow as a function of the fenoldopam dose in these patients and to evaluate renal flow distribution within the renal parenchyma using Doppler. METHODS: Twenty-five patients admitted to cardiac surgery have been enrolled. We used the Doppler technique to measure renal blood flow at the level of the renal, segmental, interlobar, and interlobular arteries. We calculated both the resistive and pulsatility indexes in all the renal segments. Moreover, we calculated echographically all the variables of preload, afterload, and cardiac index. Measurements were performed at baseline and after the infusion of fenoldopam mesylate at the doses of 0.05, 0.1, 0.2, and 0.3 microg x kg(-1) x min(-1). RESULTS: Fenoldopam infusion at doses more than 0.1 microg x kg(-1) x min(-1) significantly increases blood flow in all renal compartments, thus improving the resistive and pulsatility indexes starting at a dose of 0.1 microg x kg(-1) x min(-1). The highest renal flow increase is observed with 0.3 microg x kg(-1) x min(-1). Fenoldopam seems to increase the renal flow directed to the most external kidney areas. Systemic hemodynamically significant changes are observed only in patients receiving doses more than 0.1 microg x kg(-1) x min(-1). CONCLUSIONS: In hemodynamically stable patients undergoing cardiac surgery with preserved renal function, fenoldopam shows a pharmacodynamic dose-dependent profile: it significantly increases renal flow and reduces the resistances of the renal circulation starting at a dose of 0.1 microg x kg(-1) x min(-1).

Renal effects of fenoldopam in critically ill pediatric patients: A retrospective review.

OBJECTIVE: Published data describe the use of fenoldopam in adults for treatment of oliguria/anuria and for renal perfusion and protection, but pediatric data are scant. We assessed the effects of fenoldopam on urine output and potential deleterious changes in hemodynamics or serum creatinine in children. DESIGN: Retrospective analysis. SETTING: Academic institution. PATIENTS: : All patients or=24 hrs of fenoldopam therapy. Exclusion criteria included mechanical circulatory support, initiation of fenoldopam in the operating room, and age >18 yrs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographics, renal function, fenoldopam dosing, concomitant inotropes, and inotrope score data were collected and analyzed. Thirteen patients (age 0.3-18.7 yrs, median 5.5 yrs) received a mean infusion dose of 0.07 +/- 0.08 microg/kg/min (range 0.01-0.26 microg/kg/min) over the first 24 hrs of therapy. Eight patients received fenoldopam to augment urine output, and five patients received fenoldopam to increase renal perfusion. Nine (69%) patients received dopamine concurrently. Mean inotrope score at the beginning of therapy was 11.3 +/- 7.6 and did not change during therapy. Mean urine output increased from 1.82 +/- 1.5 mL/kg/hr to 2.74 +/- 1.4 mL/kg/hr (p = .009) in the first 24 hrs of fenoldopam therapy. No change in serum creatinine occurred (p not significant). Blood urea nitrogen was significantly different from baseline (41.7 +/- 18.7 vs. 49.0 +/- 19.8 mg/dL, p = .02). Patients with lower baseline urine output had a greater increase in urine output with fenoldopam. One patient experienced clinically significant hypotension while receiving fenoldopam, which was thought to be due to a concurrent nitroprusside infusion. CONCLUSIONS: Fenoldopam increases urine output in select critically ill pediatric patients without requiring escalation of inotropic support. There were no adverse hemodynamic effects or alterations in serum creatinine. Further prospective pediatric studies to define the role of fenoldopam in children are warranted.

Fenoldopam mesylate in early acute tubular necrosis: a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Acute tubular necrosis (ATN) occurs commonly in critically ill patients and is associated with increased morbidity and mortality. Fenoldopam is a dopamine receptor alpha1-specific agonist that increases renal blood flow in patients with kidney failure. We hypothesized that administration of low-dose fenoldopam during early ATN would decrease the need for dialysis therapy and/or incidence of death at 21 days. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled, clinical trial in 155 patients with early ATN. Patients were considered eligible for enrollment if serum creatinine level increased to 50% greater than admission levels within 24 hours and mean arterial pressure was greater than 70 mm Hg. Patients were randomly assigned to the administration of placebo or fenoldopam for 72 hours. RESULTS: Overall, 22 of 80 patients (27.5%) in the fenoldopam group reached the primary end point compared with 29 of 75 patients (38.7%) in the placebo group (P = 0.235). This 11% absolute reduction in the primary end point was not statistically significant (P = 0.23). Similarly, there was no difference in the incidence of dialysis therapy between patients randomly assigned to fenoldopam (13 of 80 patients; 16.25%) versus the placebo group (19 of 75 patients; 25.3%; P = 0.163). Moreover, there was no statistically significant difference in 21-day mortality rates between the 2 groups (fenoldopam, 13.8% versus placebo, 25.3%; P = 0.068). In secondary analyses, fenoldopam tended to reduce the primary end point in patients without diabetes and postoperative cardiothoracic surgery patients with early ATN (fenoldopam patients without diabetes, 14 of 54 patients [25.9%] versus placebo patients without diabetes, 23 of 52 patients [44.2%]; P = 0.048) and postoperative cardiothoracic patients (6 of 34 patients [17.6%] versus 14 of 36 patients [38.8%]; P = 0.049). Conversely, fenoldopam did not improve the primary end point in patients with diabetes or those with acute renal failure from other causes. A larger multicenter trial using separate randomizations for patients with and without diabetes will be needed to determine the efficacy of fenoldopam mesylate in specific subpopulations with ATN. CONCLUSION: Fenoldopam does not reduce the incidence of death or dialysis therapy in intensive care unit patients with early ATN.

Fenoldopam mesylate and renal function in patients undergoing liver transplantation: a randomized, controlled pilot trial.

To test the relative effects on serum creatinine (CRE), blood urea nitrogen (BUN), and urine output of small-dose dopamine and fenoldopam in patients undergoing liver transplantation, we randomized 43 patients to 1 of 2 continuous infusions over 48 h, starting with anesthesia induction: fenoldopam, 0.1 microg . kg(-1) . min(-1) or dopamine, 2 microg . kg(-1) . min(-1). We used predetermined hemodynamic and intravascular volume goals (intrathoracic blood volume index 800-1000 mL/m(2), extravascular lung water index <7 mL/kg) to manage patients with an algorithm for use of mannitol and furosemide to maintain urine output >1 mL . kg(-1) . h(-1). At postoperative day 3, the median CRE increase was 0.2 mg/dL (interquartile range [IQR] -0.2-0.5) with fenoldopam and 0.5 mg/dL (IQR 0.3-0.9, P = 0.004) in the dopamine group. The BUN increase was median 2 mg/dL (IQR -2-8) versus 8.5 mg/dL (IQR 5-12, P = 0.01), respectively, with fenoldopam versus dopamine. Urine output was similar; however, significantly fewer fenoldopam patients required furosemide compared with dopamine patients (median 1 [IQR 0-3] versus 3 [IQR 2-4], respectively, P = 0.003). The hemodynamic effects of dopamine and fenoldopam were similar. Compared with dopamine, in the setting of liver transplantation, fenoldopam is associated with better CRE and BUN values.

Fenoldopam versus nitroprusside for the treatment of hypertensive emergency.

BACKGROUND: While sodium nitroprusside remains first-line therapy for hypertensive emergency (HEM), fenoldopam is increasingly being used because of its benign safety profile and potential renal protective effects. OBJECTIVE: To compare the efficacy, safety, and cost of sodium nitroprusside versus fenoldopam for the treatment of HEM. METHODS: This study was a retrospective analysis of consecutive patients with HEM admitted to a university-affiliated, level 1 trauma center from 1999 to 2001 and treated with either nitroprusside (n = 21) or fenoldopam (n = 22) for >30 minutes. Time to reach mean arterial pressure (MAP) goal, change in MAP over time, time to initiation of oral antihypertensive therapy, change in renal function, incidence of cyanide toxicity, and cost of therapy were compared between groups. RESULTS: Demographic parameters were similar between groups, except renal failure, which was more prevalent in the fenoldopam group (10% vs 46%; p = 0.009). Neither the mean +/- SD pretreatment MAP (nitroprusside 168 +/- 19; fenoldopam 163 +/- 19; p = 0.45), time to reach MAP goal (3.6 [0.4-30] vs 4 [1-22] h; p = 0.51), nor infusion duration (18 [0.7-113] vs 18 [3-74] h; p = 0.45) differed between the patient groups. Time to initiation of oral antihypertensive therapy was similar between nitroprusside--(4.5 h [0.5-22] and fenoldopam--(6.5 h [1-100] treated patients; p = 0.65). Additional intravenous antihypertensives were administered to 16 patients in each group (p = 0.80). Change in creatinine clearance and incidence of tachycardia did not differ between groups. No symptoms of cyanide toxicity were detected. Cost of drug therapy was greater with fenoldopam (597.60 dollars, 199.20-6675.20 dollars); than nitroprusside (2.66 dollars, 1.68-3.48 dollars; p < 0.001). CONCLUSIONS: Treatment of HEM with fenoldopam appears to result in patient outcomes equivalent to those with nitroprusside but at a substantially higher cost. Further study is required to delineate the exact role of fenoldopam for treatment of HEM.

Contrast nephropathy.

Contrast nephropathy will increase mortality up to 30% following angiographic procedures. Before performing such procedures a careful reassessment of the risk/benefit ratio should be performed. Mannitol and diuretics play no role in prevention. Hydration and correction of abnormal electrolyte levels should be done in all patients. Pre-treatment with acetylcysteine and theophylline is a well-accepted strategy and should always be utilized. If creatinine levels are above 2.5 to 3 mg/dl, fenoldopam may provide additional protection, particularly in diabetic patients. However, the role of fenoldopam is controversial. Prophylactic hemodialysis may prove to be an additional tool in the fight against this disease in selected patients.

Fenoldopam, a dopamine agonist, for hypertensive emergency: a multicenter randomized trial. Fenoldopam Study Group.

UNLABELLED: Despite successful therapies for chronic hypertension, hospital admissions for hypertensive emergency more than tripled between 1983 and 1992. OBJECTIVE: To examine the safety and efficacy of fenoldopam, the first antihypertensive with selective and specific action on vascular dopamine (DA1) receptors, in a clinical trial involving emergency department patients with true hypertensive emergencies. METHODS: Patients with a sustained diastolic blood pressure (DBP) of > or =120 mm Hg and evidence of target organ compromise were randomized in a double-blinded manner to one of four fixed doses of intravenous fenoldopam (0.01, 0.03, 0.1, or 0.3 microg/kg/min) for 24 hours. The primary endpoint was the magnitude of DBP reduction in each of the three higher-dose groups after four hours of fenoldopam treatment compared with the lowest-dose group. RESULTS: One hundred seven participants from 21 centers were enrolled, and 94 patients received fenoldopam. Evidence of acute target-organ damage included new renal dysfunction or hematuria (50%), acute congestive heart failure or myocardial ischemia (48%), and papilledema or grade III-IV hypertensive retinopathy (34%). The DBP decreased in a dose-dependent fashion, with significant differences between the 0.1- and 0.3-microg/kg/min groups compared with the lowest-dose group. Treatment was well tolerated, and there were no deaths or serious adverse events during follow-up, up to 48 hours. All patients were successfully transitioned to oral or transdermal antihypertensives with maintenance of blood pressure control. CONCLUSIONS: Fenoldopam safely and effectively lowers blood pressure in a dose-dependent manner in patients with hypertensive emergencies. Observations supporting potential risk factors for hypertensive emergency are discussed.

Sustained hemodynamic effects of the selective dopamine-1 agonist, fenoldopam, during 48-hour infusions in hypertensive patients: a dose-tolerability study.

Eight patients with stage I-II hypertension received a continuous IV infusion of the selective dopamine-1 agonist, fenoldopam, for up to 48 hours at rates from 0.4 to 1.9 micrograms/kg/min. Hemodynamics and clinical symptoms during infusion were compared to the same parameters in the 24-hour periods before and after infusion. Fenoldopam lowered blood pressure and increased heart rate. Greatest changes occurred during the first 12 hours of infusion and gradually returned toward preinfusion values throughout the remaining 36 hours in the six patients who completed 48 hours of infusion. Fenoldopam was discontinued within 2 hours of starting the infusion in two patients who received drug rates of 0.9 microgram/kg/min and 1.9 micrograms/kg/min because of precipitous bradycardia. Clinical symptoms noted at fenoldopam doses higher than 0.8 microgram/kg/min were headache, dizziness, diaphoresis, nausea and vomiting, and restlessness. In this pilot study, fenoldopam effectively reduced blood pressure in patients with stage I-II hypertension for up to 48 hours, but fixed-dose infusion rates above 0.8 microgram/kg/min were associated with a high frequency of clinically significant and often intolerable adverse effects.

Fenoldopam: a new dopamine agonist for the treatment of hypertensive urgencies and emergencies.

Fenoldopam is a selective dopamine agonist that is being considered for the parenteral treatment of systemic hypertension. In both an oral and parenteral form, the drug causes peripheral vasodilation by stimulating dopamine-1 adrenergic receptors. Its pharmaco-dynamics are reviewed in this article, along with the clinical experiences in patients with hypertensive urgencies and emergencies. Intravenous fenoldopam may provide advantages over sodium nitroprusside because it can induce both a diuresis and natriuresis, is not light sensitive, and is not associated with cyanide toxicity. There is no evidence for rebound hypertension after discontinuation of fenoldopam influsion.