KDIGO Clinical Practice Guideline for Acute Kidney Injury
Fenoldopam for the prevention or treatment of AKI: Recommendations and Rationale

Fenoldopam for the prevention or treatment of AKI

Fenoldopam mesylate is a pure dopamine type-1 receptor agonist that has similar hemodynamic renal effects as low-dose dopamine, without systemic α- or β-adrenergic stimulation.²¹³

• 3.5.2: We suggest not using fenoldopam to prevent or treat AKI. (2C)

Rationale

The results of animal experiments and small human studies measuring perioperative GFR in patients undergoing coronary artery bypass graft and aortic cross-clamp surgery suggested that fenoldopam might prevent or ameliorate the course of AKI.¹³⁹ Cogliati et al.,²¹⁴ conducted a double-blind, randomized trial of fenoldopam infusion for renal protection in 193 high-risk cardiac surgery patients, who were randomized to receive a continuous infusion of fenoldopam,

Figure 11 | Effect of low-dose dopamine on mortality. Reprinted from Friedrich JO, Adhikari N, Herridge MS et al. Meta-analysis: low-dose dopamine increases urine output but does not prevent renal dysfunction or death. Ann Intern Med 2005; 142: 510–524 with permission from American College of Physicians²¹²; accessed http://www.annals.org/content/142/7/510.full

0.1 µg/kg/min (95 patients) or placebo (98 patients) for 24 hours. AKI was defined as a postoperative SCr level of ≥2 mg/dl ( ≥177 µmol/l) with an increase in SCr level of ≥0.7 mg/dl ( ≥ 61.9 µmol/l) from preoperative to maximum postoperative values. AKI developed in 12 of 95 (12.6%) patients receiving fenoldopam and in 27 of 98 (27.6%) patients receiving placebo (P = 0.02), and RRT was started in 0 of 95 and 8 of 98 (8.2%) patients, respectively (P = 0.004). These results suggested that a 24-hour infusion of 0.1 µg/kg/min of fenoldopam prevented AKI in a high-risk population undergoing cardiac surgery. A meta-analysis of 1059 patients in 13 studies that included this trial found that fenoldopam reduces the need for RRT and in-hospital death in cardiovascular surgery patients.²¹⁵ However, the pooled studies included both prophylactic and early therapeutic studies, as well as propensity-adjusted case-matched studies (rather than purely randomized trials). A 1000-patient RCT of fenoldopam to prevent the need for RRT after cardiac surgery is currently underway (ClinicalTrials.gov identifier: NCT00621790); meanwhile, this remains an unproven indication for fenoldopam therapy.

Finally, Morelli et al.,²¹⁶ in a prospective, double-blind trial, randomized 300 septic patients without renal dysfunction to receive infusions of fenoldopam (0.09 µg/kg/min) and compared these individuals to a placebo group; the treatment continued as long as the patient was in the ICU. The fenoldopam group had a significantly lower rate of AKI (29 vs. 51 patients, P = 0.006; OR of 0.47, P = 0.005), and shorter ICU stays, without any increase in complications. The incidence of severe AKI, dialysis, and death were not different between the groups. This study requires a larger confirmatory trial, which should be powered to test effectiveness in improving dialysis-free survival.

Emerging data from experimental AKI models suggest that fenoldopam may have multiple protective effects in AKI, including anti-inflammatory effects independent of any vasodilatory action.^217,218 Further large studies will be required to determine if fenoldopam is an effective renoprotective agent.^213,219 As discussed elsewhere in this guideline (Section 4), despite promising pilot study findings, fenoldopam was ultimately found to be ineffective for the prevention of CI-AKI,²²⁰ and as a potent antihypertensive (the only approved indication for the drug), fenoldapam carries a significant risk of hypotension.

Fenoldopam mesylate has also been studied for early treatment of AKI. Tumlin et al.,²²¹ conducted a randomized, placebo-controlled pilot trial of low-dose fenoldopam mesylate in ICU patients with early AKI and found no benefit, though they did show a trend towards lower 21-day mortality and decreased need for dialysis in fenoldopamtreated patients (11% difference in dialysis-free survival). In secondary analyses, fenoldopam tended to reduce the

Figure 12 | Effect of low-dose dopamine on need for RRT. Reprinted from Friedrich JO, Adhikari N, Herridge MS et al. Meta-analysis: low-dose dopamine increases urine output but does not prevent renal dysfunction or death. Ann Intern Med 2005; 142: 510–524 with permission from American College of Physicians²¹²; accessed http://www.annals.org/content/142/7/510.full

primary end-point in patients without diabetes and postoperative cardiothoracic surgery patients with early ATN.

Brienza et al.,²²² conducted a prospective, multicenter, RCT of fenoldopam therapy for early AKI in critically ill patients. The study included hemodynamically stable adults with renal dysfunction. This 100- subject study compared 4- day infusions of fenoldopam (0.1 µg/kg/min) or dopamine (2 µg/kg/min); there was no placebo arm. The primary endpoint of the study was a between-group comparison of the maximum change of SCr over time during the 4-day study period. The peak SCr values and maximum increments during the study did not differ between the fenoldopam and dopamine groups; however, in the fenoldopam group at the end of infusion, SCr had decreased by 0.29 ± 0.77 mg/dl (25.6 ± 68.1 mmol/l), a value significantly different from the dopamine group (0.09 ± 0.94 mg/dl [7.96 ± 83.1 mmol/l]; P = 0.05). Also, the maximum decreases of SCr levels from study entry were significantly larger in the fenoldopam group. There was no difference in heart rate, blood pressure, incidence of hypotension, or urinary output (apart from a transiently higher value within the first study day in the dopamine group). The authors concluded that, for critically ill patients with impaired renal function, a continuous infusion of fenoldopam 0.1 µg/kg/min improves renal function when compared to renal-dose dopamine, without significant adverse effects. The study has, however, a number of deficiencies, including the lack of a true control, unblinding of the investigators, and an unorthodox AKI definition, among other limitations, but taken together with other positive trends in the literature, these results add to the discourse around fenoldopam’s use to treat early AKI in critically ill patients. Similarly, Landoni et al.,²²³ in a recently published meta-analysis found that fenoldopam decreased the risk of requiring acute RRT and resulted in a lower allcause, in-hospital mortality (15.1%) compared to controls (18.9%; OR 0.64; 95% CI 0.4–0.91), along with a nonsignificant trend towards more hypotension or pressor use in the fenoldopam group.

Our analysis revealed three suitable prophylactic studies of adequate size and study design (Suppl Tables 5 and 6) that reported AKI incidence in patients randomized to fenoldopam (n = 1790) vs. placebo (n = 1839). The pooled RR and 95% CI was 0.96 (0.76–1.2), P = NS. Only one study reported mortality (8-day) in sepsis patients randomized to fenoldopam (35%, n = 150) vs. placebo (44%, n = 150), with a RR of 0.79 (95% CI 0.59–1.05; P = 0.1).

In our analysis of the two suitable studies of fenoldopam therapy for AKI, only one study²²¹ reported (21-day) mortality in critically ill patients with early AKI randomized to fenoldopam (11/80; 13.8%) vs. placebo (n = 19/75, 25.3%; P = 0.068) (Suppl Tables 7 and 8). The other study²²² reported the change in renal function in AKI patients randomized to fenoldopam (n = 50) vs. dopamine (n = 50), defined by the absolute SCr change between the beginning and end of the study drug infusion and maximum decrease from study entry, which were significantly larger in the fenoldopam group with a pooled RR of 0.96 (95% CI 0.76–1.2; P = NS). These two studies reported new RRT incidence in patients with AKI randomized to fenoldopam (n = 130) vs. placebo (n = 125). In the study by Tumlin et al., no difference in requirement of RRT was found (with fenoldopam, 13 of 80 patients; 16.25%); with placebo (19 of 75 patients; 25.3%; P = 0.163). Requirement of RRT was very rare in the study of Brienza et al., and was prescribed in a total of only five patients; three in the dopamine group and two in fenoldopam group (P = NS). Overall, no data from adequately powered multicenter trials with clinically significant end-points and adequate safety are available to recommend fenoldopam to either prevent or treat AKI. The guideline recommendation against using fenoldopam places a high value on avoiding potential hypotension and harm associated with the use of this vasodilator in high-risk perioperative and ICU patients, and a low value on potential benefit, which is currently only suggested by relatively lowquality single-center trials.