Intravenous versus oral iron supplementation for correction of post-transplant anaemia in renal transplant patients.

PROJECT RATIONALE AND OBJECTIVES Post-transplant anaemia (PTA) remains a common problem after kidney transplantation, with an incidence ranging from nearly 80% at day 0 to about 25% at 1 year. It has been associated with poor graft outcome, and recently has also been shown to be associated with increased mortality. PTA may occur at any time after renal transplantation. Early PTA (post surgery until 3 months) is most likely to be related to pre-transplant anaemia, the surgery itself, iron deficiency, immunosuppression and infection. Later PTA is more likely to be related to consequences of long-term immunosuppression or a failing graft. All the large scale studies to date have focused mainly on late PTA, and there is a lack of studies looking at the management of early PTA, in particular, the optimal management of iron deficiency. Our unit routinely administers oral ferrous sulphate to all post transplant patients, however this is not without problems including gastrointestinal intolerance, and interference with the absorption of immunosuppressant medications by leading to significant constipation. Recently, we have observed that several dialysis patients serendipitously given intravenous iron for treatment of iron deficiency anaemia immediately prior to transplantation, have had better Hb levels in the post-transplant period, without needing oral iron supplementation. In a retrospective case series, Gillespie and Symonds used intravenous ferrous gluconate to treat 15 paediatric and young adult renal transplant recipients and found that doses of up to 250mg induced a statistically significant increase in mean haemoglobin levels. There were only 4 adverse events reported in 3 patients, all self limiting and none life threatening.9 However, there are no trials to date comparing the efficacy of intravenous versus oral iron replacement. We surmise that giving a single dose of intravenous iron (as ferrous gluconate - Ferrosig®) may be better than a protracted course of oral iron. Aim To compare the time to normalisation of Hb post-transplant in patients given a single dose of iv iron as compared with oral iron. STUDY PROTOCOL AND METHODS 1. Patients All adult patients receiving a renal transplant at the Princess Alexandra Hospital will be invited to participate in the study. Informed consent will be obtained from all participants. Inclusion criteria 1.New live or cadaveric donor renal transplant recipient 2.18 years or over 3.Able to give written informed consent. Exclusions 1.Patients with transferrin saturation >50% or ferritin >800µg/l. 2.Women lactating, pregnant or of child-bearing potential not using a reliable contraceptive method. 3.Patients with a history of psychological illness or condition which interferes with their ability to understand or comply with the requirements of the study. 4.Patients who have received a new investigational drug within the last 4 weeks. 5.Intolerance of intravenous or oral iron supplements 6.As the following medications can have interactive effects, they cannot be administered during the course of the study: -All new investigational medications Design: This is an open-label, randomised, controlled clinical trial in which the primary outcome measure will be the mean time to resolution of PTA (defined as Hb =110 g/l). Patients meeting the inclusion criteria and consenting to participate in the study will be randomly allocated in a 1:1 ratio to either (a) oral iron (ferrous sulphate slow-release 2 tablets mane – the most current practice in the transplant unit) or (b) intravenous iron polymaltose as a 500 mg single dose given within the first 5 days after transplantation. Randomisation will occur by the use of sequentially numbered, sealed, opaque envelopes with stratification for calcineurin inhibitor type (cyclosporin or tacrolimus). Immunosuppressive therapy will be managed according to our unit’s standard protocols. Patients will have blood tests checked as per our unit’s follow up protocol for recent transplant recipients. We would use these to monitor full blood count, renal function, and calcineurin inhibitor trough levels on a weekly basis, as well as iron studies, B12, and folate at one monthly intervals. Power and Statistical Analysis Prospective power calculations have indicated that a minimum of 48 patients in each group would have to be followed up for 3 months in order to have a 90% probability of detecting a halving of the time to correction of haemoglobin levels to =110 g/l in iron-treated patients, assuming an a of 0.05. Adverse Events During the Investigation Each patient will be observed closely during the period of the study looking for adverse events. The patient will be removed from the study on clinical grounds in the event of any significant adverse reaction and will then be investigated extensively for the cause. Pre-existing conditions will be excluded from reporting; treatment-emergent signs and symptoms as well as post-treatment adverse events will be recorded on the Adverse Event Case Report Form. Any significant adverse events will be notified to the Ethics Committee of PAH. Gastrointestinal adverse effects will be defined as the onset of nausea, vomiting, abdominal cramping or diarrhoea. Infusion related reactions will be described as self-limiting flushing sweating, chills, myalgias, arthralgias, bronchospasm and chest pain occurring at the time of the infusion. All infectious episodes and the results of subsequent microbiological investigation will be recorded during the study period. CLINICAL TRIAL DRUGS A standard slow-release oral ferrous sulphate (Ferro-gradumet®, Abbott) one tablet daily (equivalent to 105 mg of elemental iron per day) or single intravenous dose of Iron polymaltose (Ferrosig®, Sigma, 500 mg) will be used. PROCEDURES INVOLVING THE SUBJECT Patients enrolled in the study will have no extra blood samples collected beyond those normally collected as part of routine transplant follow up. ASSESSMENT OF PATIENTS The treating renal physician will be required to give his or her approval prior to patient inclusion in the study.