Iron Chelation as a Potential Therapeutic Strategy for AKI Prevention : Journal of the American Society of Nephrology

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Up Front Matters: Reviews

Iron Chelation as a Potential Therapeutic Strategy for AKI Prevention

Sharma, Shreyak; Leaf, David E.

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JASN 30(11):p 2060-2071, November 2019. | DOI: 10.1681/ASN.2019060595
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AKI is a major public health problem that complicates a large number of hospital admissions worldwide.1–4 AKI is strongly associated with higher inpatient mortality,1,5–7 and those who survive an episode of AKI are at greatly increased risk of CKD and ESKD.8–10 Despite years of investigation, no intervention has been demonstrated to reliably prevent AKI. Thus, development of novel therapeutic targets on the basis of an appreciation of AKI pathophysiology is urgently needed.

An important role of iron in the pathophysiology of AKI has been recognized for over three decades.11–15 Iron is essential for many physiologic functions; however, when iron is present in excess it is toxic to the kidneys and other organs because of its ability to catalyze the Fenton and Haber–Weiss reactions, resulting in oxidative injury to cellular membranes, proteins, and DNA.16 Multiple lines of evidence from preclinical models support an important role of iron in AKI (Table 1): exogenous iron infusion exacerbates renal injury,14,17,18 iron content is markedly increased in the kidneys of animals exposed to myriad nephrotoxic insults,13,19,20 and, notably, pharmacologic iron chelation is protective.14,15,20,21 Additionally, genetic manipulation of key proteins involved in iron metabolism, regulation, and transport (including heme oxygenase-1, ferritin, and ferroportin) affect AKI susceptibility,22–24 whereas administration of exogenous hepcidin, the master regulator of systemic iron homeostasis, is protective.25,26 In humans, small studies have investigated the translational potential of these animal models in clinical settings, and have demonstrated encouraging preliminary results.

Table 1. - Evidence from preclinical studies supporting an important role of iron in AKI
Exogenous iron infusion causes or exacerbates AKI
Iron content is increased in the kidneys of animals with various forms of AKI
Iron chelation is protective of AKI
Genetic upregulation of HO-1 protects against AKI, whereas genetic downregulation (or pharmacologic inhibition) increases AKI susceptibility
Genetic deletion of heavy chain ferritin increases AKI susceptibility
Exogenous hepcidin administration is protective of AKI
HO-1, heme oxygenase-1.

In this review, we examine the existing data on iron chelation for AKI prevention in both animal and human studies. We discuss practical considerations for the design of future clinical trials of AKI prevention using iron chelators, including selection of the ideal clinical setting and patient population. Finally, we compare the key pharmacokinetic differences among the currently available iron chelators.

Iron Chelators in Animal Models of AKI


Iron has consistently been implicated in the pathophysiology of AKI across a wide spectrum of animal models. These models have included diverse mechanisms of injury, including ischemia-reperfusion injury (IRI),14,15,27–30 cisplatin,12,31–33 gentamicin,34–36 and many other types of insults (Table 2). In each of these models, administration of an iron chelator attenuated the severity of renal injury, providing compelling evidence for a role of iron as a final common pathway of injury across a wide spectrum of nephrotoxicities.

Table 2. - Animal models demonstrating protective effects of iron chelators in AKI
Reference Animal Model Renal Injury Iron Chelation Regimen Demonstration of Renal Protection Other/ Notes
BUN/Cr a Hist
Shah et al. 85 Rats Glycerol DFO 30 mg/kg IV immediately before glycerol inj, then DFO 30 mg/d SC pump for 24 h Yes Yes
Paller et al. 15 Rats 1. Glycerol 1. DFO 25 mg/kg per h IV for 1 h concomitantly with glycerol inj, then 12 mg/kg per h for 3 h, then 6 mg/kg per h for 3 h Yes NR
2. Hgb 2. DFO 200 mg/kg per h IV for 1 h immediately after Hgb inj Yes NR
3. IRI (Uni) 3. DFO 200 mg/kg per h IV for 1 h immediately before reperfusion Yes NR
Paller et al. 14 Rats IRI (Uni) DFO 50 or 200 mg/kg per h IV infusion for 60 min starting immediately before reperfusion Yes Yes Iron-saturated DFO was not protective
Walker et al. 34 Rats Gent DFO 20 mg IV immediately before gent inj, then 20 mg/d SC pump for 8 d Yes Yes Iron-saturated DFO was only partially protective
Zager et al. 21 Rats Glycerol DFO 120 mg/kg IV infusion for 2 h immediately after glycerol inj; mannitol 12.5 ml/kg IV infusion for 2 h immediately after glycerol inj Yes Yes DFO plus mannitol–treated rats had better functional and histologic protection compared with mannitol only
Gonzalez-Fajardo et al. 27 Rabbits IRI (Bi) DFO 25 mg/kg IV immediately before clamping and immediately before reperfusion No NR
Ben Ismail et al. 35 Rats Gent DFO 100 mg/kg IM concomitantly with gent inj No No
Haraldsson et al. 28 Rabbits IRI (Uni) DFO 30 mg/kg IV immediately before clamping and immediately before reperfusion; mannitol 3 ml/kg IV immediately before clamping and immediately before reperfusion Yes NR DFO plus mannitol–treated rats had a higher Cr clearance compared with mannitol only
Watanabe et al. 31 Rats Cisplatin DFO 100 mg/kg IP 60 min before cisplatin and continued QD for 10 d Yes NR
Baliga et al. 12 Rats Cisplatin DFO 30 mg/d SC pump starting 24 h before cisplatin and continued daily for 4 d Yes Yes
Saad et al. 86 Rats DXR DFO 25, 125, 250, 375, and 500 mg/kg IP ×1 administered 30 min before DXR inj Yes Yes Only rats treated with DFO at 375 or 500 mg/kg had histologic protection
Chander et al. 87 Rats Glycerol DFO 50 and 100 mg/kg SC 30 min before and 12 h after glycerol inj Yes Yes Higher dose provided better renal protection
Ozdemir et al. 32 Mice Cisplatin DFO 100 and 200 mg/kg IP 60 min before cisplatin and continued QD for 10 d Yes Yes GGT (marker of cisplatin toxicity) reduced by DFO
De Vries et al. 29 Mice IRI (Uni) Apotransferrin (0.1, 0.25, 0.5, and 5 mg) IP ×1 just immediately before removal of clamps Yes NR
Naghibi et al. 88 Rats Vanc DHB 50 and 100 mg/kg SC inj starting 30 min before Vanc and continued QD for 7 d Yes Yes
Bulucu et al. 89 Rats Adriamycin (nephrotic syndrome model) DFO 20 mg/kg IV ×1 immediately after adriamycin inj N/A NR DFO compared with sham-treated rats had an attenuated rise in UPCR (Cr levels were not affected by adriamycin)
Petronilho et al. 36 Rats Gent DFO 20 mg/kg SC concomitantly with Gent inj and continued on d 1, 4, and 7; NAC 20 mg/kg SC concomitantly with Gent inj and continued q8h for 7d Yes NR Rats treated with DFO plus NAC compared with either DFO or NAC alone had an attenuated rise in BUN and Cr
Vlahakos et al. 90 Pigs Hepatic IRI DFO 150 mg/kg IV infusion over 24 h starting concomitantly with hepatic artery ligation N/A Yes No significant effect of ischemia or DFO on BUN and Cr
Bernardi et al. 30 Rats IRI (Bi) DFO 20 mg/kg intra-aortic inj immediately before induction of ischemia; NAC 20 mg/kg intra-aortic inj immediately before induction of ischemia Yes NR Rats treated with DFO plus NAC, compared with rats treated with either DFO or NAC alone, had an attenuated rise in Cr
Milona-Jijón et al. 91 Rats Chromium DFO 100, 200, and 400 mg/kg IP administered 30 min before potassium chromium inj Yes Yes Dose-dependent renal protection with higher doses of DFO; DFO administration after chromium inj was unable to attenuate nephrotoxicity
Sivakumar et al. 37 Mice AlCl3 DFP 0.72 mmol/kg PO versus combo of DFP and DFO; dosing for the latter was 0.89 mmol/kg IP starting 30 min after AlCl3 and continued QD for 5 d Yes Yes Protection was seen in both DFP groups compared with sham-treated mice; however, the DFP plus DFO group had greater protection than DFP alone
Makhdoumi et al. 33 Rats Cisplatin DFP 50, 100, and 200 mg/kg PO starting 5 d before cisplatin and continued QD for 10 d Yes Yes Only rats treated with DFP at 100 mg/kg, but not 50 or 200 mg/kg, were protected from nephrotoxicity
×1 refers to a single injection. Cr, creatinine (serum or plasma); Hist, histologic; IV, intravenous; Inj, injection; SC, subcutaneous; NR, Not reported; Hgb, hemoglobin; Uni, unilateral; Gent, gentamicin; Bi, bilateral; IM, intramuscular; IP, intraperitoneal; QD, daily; DXR, doxorubicin; GGT, γ-glutamyl transferase; Vanc, vancomycin; DHB, 2,3- dihydroxybenzoic acid; N/A, Not applicable; UPCR, urine protein-creatinine ratio; AlCl3, aluminum chloride; PO, per os.
aRefers to an attenuated rise in BUN and/or Cr compared with sham-treated animals.

Iron Chelating Agents

Iron chelators form a complex with circulating iron—as well as with intracellular iron, to a varying extent—and thereby promote the excretion of iron via the urinary and fecal routes. The vast majority of animal models demonstrating efficacy of iron chelation in attenuating AKI used deferoxamine (DFO) as the iron chelating agent (Table 2). Deferiprone (DFP), a newer, orally administered iron chelator, was also demonstrated to attenuate AKI in two studies: a cisplatin-induced AKI model in rats,33 and an aluminum chloride–induced AKI model in mice.37 In the latter study, combination therapy with DFP and DFO resulted in even greater renal protection compared with DFP alone.37 Finally, administration of other iron-binding compounds, including apotransferrin and neutrophil gelatinase–associated lipocalin, has been shown to attenuate the severity of renal injury after IRI.29,38

Timing of Administration: Prevention versus Treatment

Most animal models that investigated therapeutic iron chelation were focused on AKI prevention rather than treatment. Specifically, iron chelators were administered immediately before (or concomitantly with) the renal insult in most studies (Table 2). In contrast, administration of iron chelators as a treatment strategy for AKI after the renal injury already occurred has been investigated only to a limited extent. In an aluminum chloride-induced AKI mouse model, Sivakumar et al.37 demonstrated the protective effect of DFP administered alone or in combination with DFO 30 minutes after renal injury occurred. However, no study has investigated whether iron chelators can effectively treat AKI if their administration is delayed by several hours or more.

Route and Number of Dose Administrations

Multiple routes of administration of iron chelators have been investigated, including oral, intraperitoneal, intravenous, and subcutaneous (Table 2). Further, some studies administered only a single dose of an iron chelator, whereas others administered repeated doses before and after the renal insult. Finally, some studies administered iron chelators as a continuous intravenous infusion.

Dosing Regimens

A wide range of iron chelation dosing regimens have been investigated in animal models of AKI. The doses of DFO that were effective in attenuating AKI in animal models, converted to human equivalent doses, are summarized in Table 3. As shown, the human equivalent dose range varied from 3.2 to 64.8 mg/kg, with most studies finding attenuation of AKI with doses ranging between 10 and 32 mg/kg (Table 3). Importantly, these doses are comparable to those used in humans (discussed further below).

Table 3. - Human equivalent doses of deferoxamine in animal models of AKI. Typical doses of DFO administered to humans range between 20 to 40 mg/kg.
*If multiple doses were administered, the initial dose immediately before and/or immediately after injury is represented.
**Animal-to-human conversions: mouse (12.35:1); rat (6.17:1); rabbit (3.09:1). Abbreviations: DFO, deferoxamine; HED, human equivalent dose; IA, intra-aortic; IP, intraperitoneal; IRI, ischemia-reperfusion injury; IV, intravenous; SC, subcutaneous.

Mechanisms of Protection

The mechanisms underlying the protective effects of DFO in animal models of AKI are not entirely understood. However, one likely explanation is that DFO-mediated chelation and removal of toxic forms of nontransferrin-bound iron from the circulation prevents downstream harmful effects caused by nontransferrin-bound iron, such as lipid peroxidation and ferroptosis, a form of iron-dependent, oxidative cell death.39 Interestingly, DFO also prevents H2O2- and artesunate-induced lysosomal iron–mediated cell death via a ferroptosis-independent pathway, suggesting potentially different effects on different iron pools (i.e., lysosomal, mitochondrial, cytosolic, or extracellular iron), which may be involved in mediating unique cell death phenotypes in response to distinct lethal stimuli.39 Finally, DFO may have effects on cell proliferation and survival that are independent of iron, such as upregulation of hypoxia-inducible factor 1α40–42 and direct scavenging of superoxide free radicals (Figure 1).43

Figure 1.:
Renal and extrarenal acute organ injury models in which iron chelation is protective. HIF-1α, hypoxia-inducible factor 1α; NTBI, nontransferrin-bound iron.

Iron Chelators in Animal Models of Extrarenal Acute Organ Injury

Beyond AKI, iron chelators have also been investigated in animal models of extrarenal acute organ injury, notably with respect to the heart, lungs, liver, brain, and immune system (Figure 1), and have shown encouraging results. In various models, administration of DFO attenuates the severity of cardiac IRI and reperfusion-induced arrythmias44–46; mechanical ventilation– and LPS-induced acute lung injury47,48; endotoxemia-mediated and other forms of acute liver injury49,50; and a variety of neurologic injuries, including intracerebral hemorrhage, neurodegeneration, and traumatic spinal cord injury.51–54 Further, DFO attenuates acute organ injury and improves survival in animal models of sepsis.55,56 Because human AKI often occurs in the context of multiorgan failure,57 the protective effect of DFO on these extrarenal organs provides additional compelling support for its therapeutic potential.

Iron Chelators in Human Studies of Acute Organ Injury Prevention and Treatment


Iron chelators in general, and DFO specifically, have been used for over half a century to treat patients with chronic iron overload conditions such as transfusion-dependent β-thalassemia. Beyond their role in treating chronic iron overload conditions, iron chelators have also been investigated in smaller studies for prevention of acute organ injury, including AKI, in various clinical contexts. These studies are summarized in Table 4 and below.

Table 4. - Clinical trials of iron chelators for prevention of renal and extrarenal acute organ injury
Reference Setting N Trial Design Iron Chelation Regimen Findings
Random Placebo-Controlled Blinded
Menasché et al. 58 CPB 24 Y Y N DFO 30 mg/kg IV infusion beginning 30 min before CPB onset and ending 30 min after CPB termination; additionally, DFO 250 mg/L with cardioplegic solution DFO- versus placebo-treated patients had no difference in postoperative SCr levels, but had lower generation of superoxide radicals
Menasché et al. 59 CPB 20 Y Y N DFO 30 mg/kg IV infusion beginning 30 min before CPB onset and ending 4 h after CPB onset; additionally, DFO 250 mg/L was administered via the cardioplegic solution DFO- versus placebo-treated patients had an attenuated rise in the plasma concentration of TBARS postoperatively
Paraskevaidis et al. 60 CPB 45 Y Y Y DFO 4 g IV infusion for 8 h beginning immediately after induction of anesthesia DFO- versus placebo-treated patients had similar postoperative BUN and SCr levels, but had an attenuated rise in plasma concentration of TBARS postoperatively, and a higher postoperative LVEF
Chan et al. 61 STEMI 60 Y Y Y DFO 500 mg IV bolus immediately before PCI, followed by DFO 50 mg/kg IV infusion for 12 h DFO- versus placebo-treated patients had lower serum iron and plasma F2-isoprostane levels immediately after PCI, but no difference in CMRI-determined infarct size
Fraga et al. 62 Critically ill adults with prolonged hypotension 30 Y Y Y DFO 1000 mg IV at 3.75 ml/kg per h plus NAC 250 mg/kg IV versus placebo administered within the first 48 h of documented hypotension Patients treated with DFO plus NAC had lower circulating markers of oxidative stress and lower SCr on hospital discharge compared with placebo-treated patients
Fraga et al. 63 Critically ill adults with prolonged hypotension a 80 Y Y Y DFO 1000 mg IV at 3.75 ml/kg per h plus NAC 250 mg/kg IV versus placebo administered within the first 48 h of documented hypotension Patients treated with DFO NAC- versus placebo-treated patients had a similar incidence of AKI (primary end point), but had lower SCr at hospital discharge (prespecified secondary end point)
Selim et al. 65 ICH 294 Y Y Y DFO 32 mg/kg per d IV infusion for 3 consecutive d DFO- versus placebo-treated patients had no difference in neurologic outcomes or adverse events
Y, yes; N, no; IV, intravenous; SCr, serum creatinine; TBARS, thiobarbituric acid reactive substances; LVEF, left ventricular ejection fraction; STEMI, ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; CMRI, cardiac magnetic resonance imaging; ICH, intracerebral hemorrhage.
aProlonged hypotension was defined as new onset of hypotension for 30 consecutive min, with mean arterial pressure <60 mm Hg and not improving with fluid infusion, or need for vasopressors.

Cardiopulmonary Bypass Surgery

Menasché et al.58 evaluated the effects of DFO compared with placebo in 24 adult patients undergoing cardiopulmonary bypass (CPB) surgery. DFO was administered as a continuous intravenous infusion (30 mg/kg) beginning 30 minutes before CPB onset and ending 30 minutes after CPB termination. Additionally, DFO was added to the cardioplegic solution. Compared with placebo-treated patients, patients treated with DFO produced fewer superoxide radicals in isolated neutrophils. In a follow-up study by the same group, 20 adult patients undergoing CPB surgery were randomly assigned to receive DFO or placebo. DFO-treated patients had lower lipid peroxidation parameters compared with placebo-treated patients.59

In a third study, Paraskevaidis et al.60 randomly assigned 45 adult patients undergoing CPB surgery to receive a continuous 8-hour intravenous infusion of DFO or placebo, beginning immediately before surgery. DFO-treated patients had improved left ventricular ejection fraction postoperatively compared with placebo-treated patients, and these differences persisted at 1-year follow-up. No adverse effects or safety concerns were reported despite the relatively high doses of DFO that were used (4 g, corresponding to 57 mg/kg in a 70 kg adult, as compared with typical doses of DFO, which range between 20 and 40 mg/kg). Notably, the studies conducted by Menasché et al.58,59 and Paraskevaidis et al.60 were not focused on, nor adequately powered for, assessment of postoperative AKI, but were important in establishing feasibility, safety, and early proof-of-concept effects of DFO for attenuation of acute organ injury in the setting of CPB surgery.

Acute Coronary Syndrome

Chan et al.61 conducted a randomized, controlled trial of DFO in 60 patients with ST-elevation myocardial infarction. Patients were randomly assigned to receive a 500 mg intravenous bolus of DFO (administered over 5–10 minutes immediately before percutaneous coronary intervention), followed by a 50 mg/kg intravenous infusion of DFO administered over 12 hours, or placebo. Compared with placebo-treated patients, those treated with DFO had lower serum iron and plasma oxidative stress parameters immediately after percutaneous coronary intervention, but similar infarct size as determined by cardiac magnetic resonance imaging.

Critical Illness

Fraga et al.62 conducted a pilot study of DFO in 30 critically ill adult patients with new-onset, sustained hypotension lasting at least 30 minutes. Patients were randomly assigned to receive combination therapy with a single intravenous dose of DFO (1 g, administered over approximately 1 hour), along with a continuous infusion of N-acetylcysteine (NAC) administered over 48 hours, or placebo. Patients treated with DFO plus NAC had lower circulating markers of oxidative stress and lower serum creatinine on hospital discharge compared with placebo-treated patients.

In a larger follow-up study, Fraga et al.63 randomly assigned 80 critically ill adult patients with sustained hypotension to receive DFO plus NAC (same dosing regimen as their previous study) or placebo. Compared with the placebo-treated patients, those treated with DFO+NAC had a similar incidence of AKI overall, but had a lower incidence of severe AKI, as well as lower serum creatinine at hospital discharge. No severe adverse events from DFO were observed.

Intracerebral Hemorrhage

Selim et al.64 conducted the High Dose DFO in Intracerebral Hemorrhage trial, in which they administered DFO intravenously at 62 mg/kg per day for 5 days, compared with placebo, in patients with intracerebral hemorrhage. The study was stopped early because of a higher incidence of acute respiratory distress syndrome in the DFO group. Selim et al.65 subsequently studied a lower dose of DFO (32 mg/kg per day, administered via daily interrupted infusions [12 hours per day] for 3 days) in a phase 2, randomized, double-blind, placebo-controlled trial in 294 patients with intracerebral hemorrhage. At this dose, no pulmonary toxicity was observed. The primary end point, neurologic status at 90 days, was similar between DFO- and placebo-treated patients. However, neurologic status at 180 days, which was a prespecified secondary end point, was superior in DFO-treated patients. Importantly, DFO at a dose of 32 mg/kg was well tolerated and did not increase the frequency of serious adverse events compared with placebo.

Practical Considerations for Future Trials

Selection of the Right Clinical Setting

The stage has been set for randomized controlled trials of iron chelation for AKI prevention. But which clinical setting is most likely to be successful in establishing the efficacy of this novel therapeutic strategy? As discussed above, animal models demonstrated efficacy of iron chelators in attenuating AKI across a broad spectrum of insults, ranging from IRI to aminoglycoside nephrotoxicity. In humans, elevated circulating concentrations of nonphysiologic toxic forms of iron, known as labile or “catalytic” iron, have been reported in each of the following settings: CPB surgery,66 critical illness,67 severe AKI requiring RRT,68 contrast nephropathy,69 acute coronary syndrome,70,71 and cardiogenic shock.72 Although investigation of iron chelation could be reasonably considered in any of these settings, we believe that CPB surgery is the ideal setting for initial studies.

CPB surgery results in elevated circulating concentrations of catalytic iron because of multiple factors: exposure of red blood cells (RBCs) to nonphysiologic surfaces in extracorporeal circuits, along with shear stress generated by pumps and suction systems, resulting in hemolysis; mechanical fragmentation of RBCs induced by valvular prostheses; transfusion of RBCs; IRI to the kidneys and other organs due to crossclamping of the aorta and intraoperative hypotension; and skeletal muscle injury during CPB, resulting in the release of iron-rich myoglobin into the circulation. Consistent with these mechanisms, we found that longer duration of CPB is associated with higher plasma concentrations of catalytic iron postoperatively, and that higher postoperative concentrations of catalytic iron associate with a higher incidence of AKI requiring RRT or death.66

Thus, CPB surgery exposes patients to an acute iron load resulting from hemolysis, transfusion, rhabdomyolysis, and other factors. This acute iron exposure occurs during a discrete period of time, and thus should be readily targetable by concurrent iron chelation. Unlike in critical illness, CPB surgery is a setting that allows for iron chelation therapy to be initiated in advance of the insult. Accordingly, catalytic iron released into the circulation during CPB surgery could be chelated in real time and before AKI has occurred. This feature of CPB surgery is critical because nearly all animal models using iron chelators investigated AKI prevention rather than treatment (Table 2).

Selection of the Right Patient Population

The ideal patient population for clinical trials of iron chelation for AKI prevention would be enriched for both the outcome of interest (AKI) as well as the likelihood of response to the intervention (iron chelation). Multiple studies have identified the key risk factors for incident AKI after CPB surgery. These include factors known before surgery, such as CKD, diabetes mellitus, congestive heart failure, and type of surgery, as well as factors that cannot be ascertained a priori, such as the duration of CPB and the number of intraoperative RBC transfusions.73 An important limitation of existing clinical risk prediction models for AKI after CPB surgery is that most are focused on AKI requiring RRT rather than more mild forms of AKI, such as a ≥50% increase in serum creatinine (the latter end point would be more appropriate for early phase trials because of sample size considerations).

Enrichment for patients most likely to benefit from iron chelation would involve selection of factors associated with elevated circulating concentrations of catalytic iron postoperatively, such as prolonged CPB time. Although CPB time is unknown in advance, certain factors such as combined coronary artery bypass grafting/valve replacement procedures are known to be associated with longer CPB times, and could be used for enrichment. Other factors, such as chronic liver disease,68 may also be associated with higher circulating catalytic iron levels due to impaired production of transferrin and/or reduced capacity for iron uptake and storage.

Selection of the Right Iron Chelator

Three iron chelators are currently approved by the US Food and Drug Administration (FDA) for the treatment of chronic iron overload disorders: DFO, deferasirox (DFX), and DFP. These agents have important differences in their pharmacokinetics, routes of administration, and adverse effects (Table 5).

Table 5. - Comparison of FDA-approved iron chelators and their properties
Chelator DFO DFX DFP
Brand name Desferal Exjade, Jadenu Ferriprox
Year of FDA approval 1968 2005 2011
Route of administration IV, IM, SC PO PO
Indications Acute and chronic iron overload, Al toxicity in patients with CKD Chronic iron overload Transfusional iron overload due to thalassemia syndromes
Iron-binding affinity, pM 26.6 22.5 19.9
Adverse effects Abdominal discomfort, nausea, vomiting, diarrhea, hypotension, anaphylaxis Nausea, vomiting, diarrhea, abdominal pain, rash, cytopenia, hepatic dysfunction, AKI Nausea, vomiting, abdominal pain, increased ALT, arthralgia, neutropenia
Warnings Auditory and visual toxicity, renal impairment, ARDS Renal failure, hepatic failure, GI hemorrhage Agranulocytosis, teratogenicity
Elimination t 1/2 6 h 8–16 h 1.9 h
Dosing frequency Continuous pump Once per d Three times per d
Metabolism Plasma enzymes Liver (glucuronidation), mainly UGT 1A1 Liver (glucuronidation), mainly UGT 1A6
Excretion Urine, bile/feces Feces (84%), urine (8%) Urine (75%–90%)
Dose adjustment for renal impairment eGFR 10–50: not well studied a eGFR <10: contraindicated eGFR 40–60: ↓dose 50% eGFR <40: contraindicated No adjustment
IV, intravenous; IM, intramuscular; SC, subcutaneous; PO, per os; Al, aluminum; ALT, alanine transaminase; ARDS, acute respiratory distress syndrome; GI, gastrointestinal; UGT, UDP-glucuronosyltransferase; ↓, reduction in the recommended dose.
aA dose reduction to 25%–50% of the normal dose has been recommended by some sources.92


DFO was the first iron chelator approved by the FDA, and thus has the longest clinical track record. DFO is the agent that was used in the vast majority of animal models of renal and extrarenal acute organ injury, and has a higher iron-binding affinity than DFP or DFX (Table 5). DFO is administered parenterally, either through a continuous subcutaneous pump (in the chronic setting) or via intravenous infusion (in the acute setting). DFO binds to iron in the circulation, and the DFO-iron complex (also known as ferrioxamine) is excreted via the urinary and fecal routes (Figure 2). The most serious potential adverse effects of DFO are hypotension and ocular toxicity, and these occur almost exclusively in patients receiving very high doses (e.g., >60 mg/kg).74,75

Figure 2.:
Iron chelation and excretion by DFO. Hgb, hemoglobin.


It took nearly four decades (from 1968 to 2005) for a second iron chelator, DFX, to be approved. DFX is an orally administered iron chelator with a t1/2 of 8–16 hours, which allows for convenient, once-daily dosing. However, DFX causes mild increases in serum creatinine in up to 38% of patients.76 Accordingly, DFX is contraindicated in patients with moderate-to-advanced CKD (eGFR<40 ml/min per 1.73 m2). Thus, DFX would not be well suited for use in AKI prevention studies.


DFP is an orally-administered iron chelator with a t1/2 of approximately 2 hours, and is administered three times per day. An advantageous feature of DFP compared with other iron chelators is its greater lipophilicity and thus greater intracellular penetrance, which facilitates chelation of intracellular iron. This property of DFP has been leveraged to improve chelation of cardiac iron in patients with thalassemia.77,78 In the setting of an AKI prevention study, however, DFP’s oral route of administration and its short t1/2 could create logistical challenges, particularly in critically ill patients who may have an impaired ability to swallow. Nonetheless, in 2011 an extended-release formulation of DFP was investigated for prevention of contrast-associated AKI in a phase 2, randomized, placebo-controlled trial in 60 patients undergoing coronary angiography ( identifier NCT01146925). However, the study was terminated prematurely because of lack of funding, and the results were never published.

Bottom Line

DFO has several properties that make it well suited for use in clinical trials of AKI prevention. Parenteral administration of DFO circumvents the logistical challenges that would likely be encountered with enteral administration of DFP in the setting of acute illness, including concerns related to aspiration and impaired gastrointestinal absorption. DFO has the longest track record of use in both animals and humans, including in the setting of acute organ injury prevention (Table 4), and is well tolerated acutely even at doses up to 32 mg/kg.65 Because patients undergoing CPB surgery are not chronically or “total body” iron overloaded, and the purpose of iron chelation in this setting would be primarily to sequester circulating (rather than intracellular) catalytic iron, low to moderate doses of DFO (10–20 mg/kg) would likely be sufficient.


Abundant evidence exists in both animal and human studies for an important pathologic role of iron in AKI. Accordingly, iron chelators represent a promising therapeutic strategy for AKI prevention. Adequately powered, well designed, randomized, double-blind, placebo-controlled trials are urgently needed to test whether iron chelation can reliably prevent AKI. Other therapeutic strategies could also be considered to mitigate the nephrotoxic effects of iron and iron-containing proteins, including administration of haptoglobin to facilitate sequestration of free hemoglobin,79–81 administration of hepcidin to prevent iron export from intracellular compartments into the circulation,25,26,82 and pharmacologic upregulation of heme oxygenase-1 to accelerate the catabolism of toxic free heme.83,84 Although a strong pathophysiologic basis exists for each of these approaches, few therapeutic strategies for AKI prevention have a foundation of support from both animal and human studies as strong as iron chelation.




Dr. Leaf is supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (K23DK106448) and the National Heart, Lung, and Blood Institute (R01HL144566), and by an American Society of Nephrology Foundation for Kidney Research Carl W. Gottschalk Research Scholar Grant.

Published online ahead of print. Publication date available at

The authors thank Sushrut S. Waikar (Boston Medical Center) and George Karp (Regional Cancer Care Associates), for their critical review of the manuscript.


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    acute renal failure; Acute Kidney Injury; catalytic iron; labile iron; free hemoglobin; ferritin

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