This is a multi-center randomized controlled trial that will examine the efficacy of IV iron supplementation when compared to placebo, with and without exercise training, on changes in patient exercise capacity. The study aims to provide sufficient data to inform a power calculation for the definitive study to examine whether IV iron therapy in patients with CKD stages 3-4 (non-dialysis) can improve exercise capacity, muscle metabolism and physical function. Specifically, we propose to examine whether a strategy of IV iron therapy in patients with stages 3-4 CKD who are iron-deficient but NOT anaemic leads to improvements in exercise capacity.

Very little is currently known about the effects of iron deficiency on cardiac or skeletal muscle metabolism in patients suffering from CKD. Nevertheless, it seems likely that iron deficiency will contribute to mitochondrial dysfunction and reduced energy production in cardiac or skeletal muscle of CKD patients, and importantly may contribute to the reduced exercise capacity, physical function and overwhelming fatigue commonly reported in this population. The results of this trial will provide data to ascertain whether intravenous iron therapy might be beneficial to exercise capacity, muscle metabolism, physical function, and fatigue and whether iron repletion enhances the effect of an exercise intervention.

Inclusion Criteria:

• Patients with established CKD (Stages 3-4) not on dialysis
• Resting BP ≤ 160/95mmHg
• Men and women aged 18 - 80 years
• Serum ferritin level less than 100μg/L AND/OR transferrin saturation ≤20%
• Haemoglobin 110 - 150 g/L

Exclusion Criteria:

• Pregnancy or breast feeding (Female patients of childbearing age will be asked if there is any possibility they may be pregnant. This is standard of care and no pregnancy test will be requested unless there is doubt about this. IV iron is given to many pregnant patients in standard treatment and there is no evidence of harm to mother or foetus).
• Weight < 50kg
• Known allergy to iron therapy
• Haemochromatosis, porphyria cutanea tarda or history of acquired iron overload
• Intravenous iron within previous 6 weeks
• CRP > 50 mg/L
• Serum phosphate < 0.7 mmol/L.
• Active infection
• Current therapy with ESAs
• Uncontrolled atrial fibrillation
• Use of anticoagulants in those under consideration for muscle biopsy
• Unstable angina or heart attack within the last year
• Presence of solid organ cancer
• Known haemoglobinopathy, myelodysplasia, or myeloma
• Patients with peripheral vascular or musculoskeletal disease, who the investigator deems unable to carry out the 6MWT.
• Known severe aortic stenosis and pacemaker in-situ
• History of severe atopy
• Severe liver disease with serum transaminases > x3 upper limit of normal range according to local laboratory values.
• Severe lung disease with FEV1 known to be <50% predicted in last year
• Known heart failure with a left ventricular ejection fraction <45% in last year
• Any other health condition considered by the local Principal Investigator in which IV iron will be contraindicated.
• Insufficient understanding of the trial