A new era in the treatment of renal anaemia

Anaemia is defined as a state in which the quality and/or quantity of circulating red blood cells (RBC) are below normal.(1) Anaemia is a common complication of chronic kidney disease (CKD), which can develop in the early stages. As the kidney function declines, the greater the association with lower haemoglobins and a higher prevalence and severity of the anaemia.(2)

Anaemia in CKD results from a reduction in the production of the hormone erythropoietin (EPO), which is produced within the juxtaglomerulary cells of the kidney. This, in conjunction with reduced iron absorption from the gastrointestinal tract (GI), leads to a reduction in the number of circulating RBCs.

CKD anaemia management has been improved dramatically since the introduction of recombinant human erythropoietin (rHuEPO), and replacement with this is the primary method of treating CKD-associated anaemia. However, rHuEPO is only one part of the anaemia management strategy and it must only be used in those patients in whom other causes of anaemia have been ruled out. They must also have sufficient levels of iron as well as other co-factors such as vitamin B12 and folate.(3,4)

In patients with functioning erythropoiesis not requiring rHuEPO, treatment with oral or intravenous (IV) iron is often sufficient to treat the anaemia. However, when rHuEPO is required, iron is used to optimise treatment. The current haemoglobin target in the UK is 100–120g/l.(1)

Iron deficiency is a main cause of a patient not responding sufficiently to rHuEPO replacement. Iron deficiency can be divided into two categories: absolute iron deficiency and functional iron deficiency. Absolute iron deficiency refers to the depletion of iron stores and the absence of sustainable iron in the bone marrow. Functional iron deficiency is a clinical condition where stored iron is sufficient but circulating iron is deficient. It can occur when rHuEPO therapy stimulates RBC production beyond the available supply of iron necessary for haemoglobin synthesis; it can also be caused by chronic inflammation.(5)

The treatment of iron deficiency (absolute or functional) is simple and comprises iron supplementation to replace and replenish the iron stores within the body.

Oral iron supplementation is recommended as first-line treatment for iron deficiency because it is inexpensive, readily available and easy to administer. Its adverse affects are mild and usually localised to the GI tract. GI side effects, however, are often the main cause of non-adherence to therapy.

Oral iron absorption from the GI tract varies depending on concurrent medication, presence of food and other co-morbidities. Intestinal iron absorption is enhanced in patients with iron deficiency and declines with the correction of the deficiency and repletion of the iron store. In the presence of uraemia, which is a chronic inflammatory state, levels of many acute phase proteins, such as C-reactive protein, ferritin and interleukin (6) (IL-6), are increased. These pro-inflammatory cytokines interact with hepcidin, a hormone involved in regulating iron absorption and utilisation, increasing its levels within the plasma. High levels of hepcidin inhibit the intestinal iron absorption.(6) This theory explains why patients with end-stage renal disease (ESRD) and uraemia respond poorly to oral iron, thereby limiting its use.

Intravenous iron provides a treatment option for these patients when oral iron is no longer effective. There are multiple studies that show iron given intravenously is superior to oral iron treatment in patients with ESRD.(7)

All IV iron-containing preparations consist of a similar molecular structure, that is, a carbohydrate shell surrounding a central iron core. One of the main differentiating factors between the compounds is molecular size, which determines the maximum single dose and rate of administration: the larger the molecule, the greater the maximum single dose that can be administered. The risk of anaphylaxis also varies between the compounds. True anaphylaxis is linked to dextran-containing compounds, where antibodies to the dextran component are formed, producing the anaphylactic reaction. Anaphylaxis-like reactions can also occur if too much iron is given as a single dose, which can overload the normal regulatory systems of the body, leading to high levels of ‘free iron’. These are not antibody mediated and can occur in theory with any iron preparation.8 The lower levels of free iron can lead to reduced incidence of iron-related anaphylaxis.

There are five IV iron preparations currently available in Europe, and all are licensed for the treatment of iron-deficient anaemia (IDA) in CKD. These are Cosmofer® (iron dextran), Venofer® (iron sucrose), Monofer® (iron isomaltoside), Ferinject® (ferric carboxymaltose), and the recently licensed Rienso® (ferumoxytol).

CKD leads to a chronic inflammatory process that increases hepcidin production from the liver. High levels of hepcidin inhibit the amount of iron absorbed via the GI tract. Therefore, as CKD progresses, the amount of iron absorbed by the GI tract and available for erythropoiesis reduces constantly and body’s iron stores become depleted. Ferumoxytol is a colloidal iron–carbohydrate complex. It includes iron oxide particles with an iron oxide core surrounded by a polyglucose sorbitol–carboxymethylether shell. The shell isolates bioactive iron from plasma components until the iron–carbohydrate complex enters the reticuloendothelial system; that is, macrophages of the liver, spleen and bone marrow. The iron is released intracellularly from the iron–carbohydrate complex within vesicles in macrophages. Iron is then able to enter the intracellular storage iron pool (for example, ferritin) or is transferred to plasma transferrin for transport to erythroid precursor cells for incorporation into haemoglobin (Hb).(8)

It is available in vials containing 510mg ferumoxytol. Each 510mg dose is administered as an IV injection. For patients receiving two doses, the second 510mg dose is administered 2–8 days later. It can be administered to haemodialysis (HD) patients as single doses of 510mg, and is the only IV iron licensed for this type of administration.

It is administered as an undiluted IV injection, at a rate of up to 1ml/second (30mg/second), that is, at least 17 seconds per vial. Administration is followed with a slow flush of sodium chloride 0.9% to clear the line. Patients should be monitored for signs and symptoms of hypotension and hypersensitivity for 30 minutes following administration of ferumoxytol.

Spinowitz and colleagues evaluated the efficacy of ferumoxytol as an IV iron replacement therapy in CKD stages 1–5 compared with oral iron.(9,10) Two 510mg doses of ferumoxytol were administered to 437 non-HD patients versus 200mg oral iron administered to 149 non-HD patients over a 35-day period. Ferumoxytol treatment resulted in a higher mean increase in Hb levels than oral iron at trial end (35 days): there was an increase of 1.24±1.25g/dl versus 0.5±0.98g/dl (p<0.0001) and 0.82±1.24g/dl versus 0.16±1.02g/dl, respectively (p<0.0001). Ferumoxytol was associated with a significant twofold increase in the number of patients achieving ≥1g/dl increase in Hb levels at trial end compared with oral iron: 52.9% versus 18.2% (p<0.0001) and 39% versus 18.4%, respectively (p<0.001). Ferumoxytol treatment significantly increased transferrin saturation and serum ferritin levels compared with oral iron at trial end (p<0.0001).

Provenzano and colleagues studied 223 patients with CKD stage 5 receiving HD.(11) A total of 110 patients were given two doses of 510mg of ferumoxytol versus 113 patients given 200mg daily of oral iron. Ferumoxytol resulted in a significantly higher mean increase in Hb levels than oral iron at trial end (1.02±1.13g/dl versus 0.46±1.06g/dl; p<0.0002). Ferumoxytol was also associated with a significant twofold increase in patients achieving ≥1g/dl increase in Hb levels at trial end compared with oral iron: 49% versus 25% (p=0.0002). Transferrin saturation levels were also increased significantly by ferumoxytol at trial end compared with oral iron (p<0.0001).

The Ferumoxytol Compared to IRon Sucrose Trial (FIRST), reported by Macdougal and colleagues in 2011, was a head-to-head trial comparing ferumoxytol with iron sucrose in patients with CKD stage 1–5 and 5D. This trial showed that ferumoxytol was non-inferior to iron sucrose, with an increase in Hb levels from baseline to end of trial (five weeks) and an increase of 0.71g/dl and 0.61g/dl, respectively.(12)

The safety and tolerability of IV ferumoxytol against oral iron was reported by Spinowitz and colleagues.(10) This study showed that 35% of ferumoxytol patients and 52% of patients treated with oral iron reported adverse effects (AEs); 11% versus 24%, respectively, had AEs thought to be related to study treatment. The most frequently occurring AEs (>1% in any group) considered to be treatment-related were nausea (1.8%), dizziness (1.8%) and diarrhoea (1.4%).

The FIRST study adverse events that were considered to be related to the study drug were reported in 10% (8/80) and 16% (13/82) of patients treated with ferumoxytol and iron sucrose, respectively. Serious adverse events that were related to the study treatment occurred in one patient on ferumoxytol (anaphylactoid reaction after first dose and the patient did not receive the second dose) and one patient on iron sucrose (hypotension, which recurred after the first and second doses).

In the ferumoxytol group, the most frequently reported AEs related to the drug were anaphylaxis, dysgeusia, feeling hot, flushing, headache, injection site reaction, injection site pain, nausea (n=1 per reaction). In the iron sucrose group, the most frequently reported AEs related to the drug parosmia (n=30), feeling hot (n=1), injection site pain (n=2), diarrhoea (n=2), hypotension (n=6), cold sweat, constipation, injection site haemorrhage, myalgia, unresponsive to stimuli (n=1 per reaction).

In February 2013, ferumoxytol was reviewed by the Scottish Medicines Consortium.13 It accepted ferumoxytol for restricted use within NHS Scotland for treatment of IDA in non-HD CKD patients when oral iron preparations are ineffective or cannot be used.

Ferumoxytol has been shown to be an effective IV iron for use in patients with CKD-related IDA compared with oral iron and IV iron sucrose. It has been used across the US and has been shown to maintain Hb between 100 and 120g/l.(14)

Its benefits are that it can deliver a large dose of iron, rapidly to both pre-dialysis and dialysis patients. It has low levels of ‘free iron’, which may reduce the incidences of free iron-related anaphylaxis.

Financially, it is more costly per gram that iron dextran and iron sucrose but more cost effective than iron isomaltoside and ferric carboxymaltose.

For patients requiring doses > 510mg iron for replacement, two outpatient appointments will be required and this will incur costs. Two administrations will double the cost of nursing time and disposables required to administer the injection compared with once-daily formulations, such as iron dextran, iron isomaltoside and ferric carboxymaltose. In the UK, the current tariff for providing IV iron is either £299 (SAO4F) or £424 (SAO4D), depending on how complicated it is to treat the patient.(15) This tariff is payable on each visit and not per treatment course.

For the administration of 1020mg IV iron, ferumoxytol offers a reduction in the number of outpatient visits compared with IV iron sucrose. However, it can increase the number of outpatient visits compared with iron dextran, which can be administered over six hours, iron isomaltoside, which can be administered over one hour, and ferric carboxymaltose, which can be administered over 15 minutes.(16–18)

Iron dextran is limited to being administered in a hospital environment owing to the length of time for the infusion and the previous incidences of anaphylaxis relating to antibodies directed against the dextran component of this molecule. Iron isomaltoside infusions are also limited to being administered in a hospital setting.(17) Therefore, for those wishing to provide an IV iron service in a community setting, ferumoxytol confers a potential advantage.

Ferumoxytol is less costly per gram than both iron isomaltoside and ferric carboxymaltose. This makes it attractive to health providers wishing to optimise the financial gain from the current tariff prices. Identifying whether there is an opportunity for ferumoxytol to reduce costs to the health economy, as a whole, will require research into the local IDA population’s average IV iron dosing requirements and frequency of outpatient visits.

Ferumoxytol is an effective and well-tolerated IV iron. It is easy to administer and competitively priced. The ability to administer 510mg in a single dose to patients receiving HD may lead to a reduction in overall use of IV iron; however, further studies are needed in this area.