Description of the condition

Acute kidney injury (AKI) is associated with significant adverse health outcomes and financial burden (Devarajan 2006). Despite advances in diagnostic technologies and therapeutic interventions, AKI continues to be a growing health challenge that has considerable short‐ and long‐term implications. Although there has been no appreciable decrease in AKI‐related mortality over the past five decades (Ympa 2005), timely intervention can aid disease regression and enhance recovery (Vaidya 2008).

The Acute Kidney Injury Network (AKIN) defines AKI as “an abrupt (within 48 hours) reduction in kidney function defined as an absolute increase in serum creatinine level of 26.4 μmol/L (0.3 mg/dL) or a percentage increase in serum creatinine level of 50% (1.5‐fold from baseline) or a reduction in urine output (documented oliguria < 0.5 mL/kg/hours > 6 hours)”. This definition has been validated, gained wide acceptance (Mehta 2007), and stimulated early diagnosis and management of AKI.

AKI reduces kidney function attributable to structural and functional kidney decline. Causes of AKI can include systemic disease, hypovolaemia, hypotension, infection, some pharmaceutical agents, surgery, and urinary tract obstruction (Lameire 2008). AKI is commonly either ischaemic or toxic, can manifest as oliguric or non‐oliguric disease, and causes retention of nitrogenous and non‐nitrogenous waste products (Mehta 2004). These changes are verified by laboratory evaluation to detect elevated blood urea and serum creatinine (SCr) values.

AKI incidence has been assessed at 522/100,000 people (Hsu 2007); and can be anticipated in 19/1000 admissions (Mehta 2004), and 5.7% of critically ill patients (Uchino 2005). The respective rates of chronic kidney disease (CKD) and end‐stage kidney disease (ESKD) after an AKI episode are 7.8 and 4.9/100 patient‐years (Coca 2009). Among patients who recover from AKI after variable periods on renal replacement therapy (RRT), CKD is observed in 41% of people and five‐year survival is about 50% (Nash 2002). Significantly more than half (60.3%) of all critically ill patients with AKI die during hospital stays and 13% of survivors become dialysis‐dependent (Uchino 2005).

Description of the intervention

Fenoldopam mesylate, a benzazepine derivative, is a short acting, selective dopamine A1 receptor agonist with no effect on dopamine‐2 and α1 receptors. The chemical structure of fenoldopam is 6‐chloro‐2,3,4,5‐tetrahydro‐1‐(p‐hydroxy‐phenyl)‐1H‐3‐benzazepine‐7,8‐diol methanesulfonate (salt) (Figure 1). Fenoldopam induces selective vasodilation of the renal, mesenteric, peripheral, and coronary arteries. Fenoldopam product information indicates that the FDA‐approved dose as an antihypertensive for adults is 0.025 to 0.3 μg/kg/min by intravenous infusion. Steady‐state plasma concentrations are achieved rapidly (about 20 minutes; four half‐lives), and are proportional to the infusion rate (Hammer 2008). Plasma concentrations and clinical effects dissipate quickly when infusion is stopped (Hammer 2008).

Figure 1

---

---

Fenoldopam chemical structure

Source: www.drugs.com/pro/fenoldopam.html

In an animal study, Bloom 2011 reported that six healthy, awake beagles were administered 180 minute fenoldopam constant rate infusions at 0.8 μg/kg/min followed by a 120 minute washout. Steady‐state plasma fenoldopam concentrations of 20 ± 17 ng/mL (mean ± standard deviation (SD) were achieved within 10 minutes of starting the infusion. Area under the plasma concentration–time curve was 3678 ± 3030 ng/mL/min, and plasma clearance was 66 ± 43 mL/min/kg. Elimination was achieved rapidly in all dogs.

In a comparative study of the effects of dopamine and fenoldopam on renal blood flow and prostacyclin excretion, Bughi 1989 reported that renal blood flow measured by para‐aminohippurate clearance increased among normal patients during fenoldopam infusion (1185 ± 71 to 1533 ± 84 L/min/m²). This was associated with an increase in prostacyclin PGI2 (6‐keto‐PGF1) excretion (149 ± 19 versus 214 ± 32 ng/g Cr; P < 0.02).

Clearance of parent (active) fenoldopam is not altered in adult patients with ESKD on continuous ambulatory peritoneal dialysis (CAPD). The effects of haemodialysis on the pharmacokinetics of fenoldopam have not been evaluated. Furthermore, 90% of infused fenoldopam is eliminated in urine and 10% in faeces (Bloom 2011).

Common side effects of fenoldopam therapy include headache, flushing, dizziness, tachycardia and hypotension. Side effects usually occur in the first 24 hours of infusion and improve thereafter (Murphy 2001). Episodes of hypotension, caused by reduced perfusion pressure during fenoldopam infusion, have given cause for concern about inducing or worsening AKI (Lameire 2009). Since there is no standard of care, studies have used various comparators including placebo, no treatment, or low dose dopamine. In a meta‐analysis of 61 studies, no benefit was found to be derived from low dose dopamine (≤ 5 μg/kg of body weight/min) in patients with AKI or at risk of developing the condition (Friedrich 2005). It was further reported that low dose dopamine was associated with a significant increase in urine output (ratio of means 1.24, 95% CI 1.14 to 1.35; P < 0.001) on day 1 of therapy. A statistically significant difference in adverse events between low dose dopamine and control group participants was not demonstrated (Friedrich 2005). In animal studies, dopamine has been reported to increase outer medullary blood flow by 35%, but not medullary PO₂, which is a crucial parameter of tissue oxygen delivery during ischaemia reperfusion injury (Jo 2007). In a cross‐over prospective study, renal vascular resistance (RI) increased significantly under dopamine infusion (median RI from 0.77 to 0.81; P < 0.01) in 22 patients with AKI aged over 55 years compared with patients who did not have AKI (Lauschke 2006). These investigational studies partly explain the lack of success with this agent.

How the intervention might work

Possible mechanisms of fenoldopam action are decreased peripheral vascular resistance, increased blood flow, and oxygen delivery to the kidneys. These actions increase blood flow to the renal cortex and outer medullary structures which enhances diuresis and natriuresis and improves creatinine clearance (CrCl). Because fenoldopam is receptor‐selective, theoretically there should be fewer cardiac side effects such as arrhythmias and hypotension compared with non‐selective agonists.

Why it is important to do this review

AKI therapeutic principles are based on treating underlying aetiology, maintaining fluid and electrolyte balance, and ensuring optimal nutrition (Lameire 2008). Prevention in vulnerable groups and early supportive management with fluids, drugs and dialysis in select groups is beneficial. However, the efficacy of n‐acetyl cysteine, dopamine, diuretics, sodium bicarbonate, fenoldopam, deriphylline, erythropoietin and antioxidants have yet to be proven in the capacity of reversing or preventing AKI (Lameire 2009). High rates of AKI morbidity and mortality indicate need for clear evidence about the efficacy and safety of these interventions as preventive and treatment options for people with AKI.

Randomised controlled trials (RCTs) involving fenoldopam have yielded conflicting reports; benefits have mainly been observed following cardiac surgery and after administration of radiocontrast media. These studies have generally recruited small numbers of patients, and investigated various doses and durations of fenoldopam infusion. Two meta‐analyses (Landoni 2007; Landoni 2008) that involved postoperative and intensive care patients suggested that fenoldopam infusion was beneficial both in reducing requirements for RRT and in numbers of deaths. Landoni 2007 included studies (abstracts, randomised, non‐randomised) published before October 2005, but did not address prevention and treatment of AKI individually, and excluded radiocontrast nephropathy prevention studies. Studies on radiocontrast nephropathy have drawn divergent results, with some showing benefit and others reporting no significant effect. A meta‐analysis of radiocontrast nephropathy included two studies that investigated fenoldopam (Kelly 2008).

AKI clinical guidelines from the Kidney Disease: Improving Global Outcomes (KDIGO) are in the development phase, but the UK Renal Association (RA) (Lewington 2011) has recently released AKI clinical practice guidelines. The RA guidelines cite the Landoni 2007 meta‐analysis of pre‐2005 studies, but does not specify systematic review methodology applied in the development of the guidelines.

In this review, we will seek to evaluate the available evidence for the use of fenoldopam as a preventive and treatment strategy for both people with AKI and those at risk of AKI. We plan to conduct separate analyses of prevention and treatment studies because timing of interventions can influence outcomes, and fenoldopam can yield differing results in both groups. Our analysis of AKI prevention will consider radiocontrast nephropathy and other at risk groups, such as those undergoing cardiovascular surgeries (Bove 2005; Ranucci 2010).