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Title: Anaemia in kidney transplant recipients : effects of recombinant human erythropoietin and the potential role of mycophenolate mofetil
Author: Pile, Taryn
ISNI:       0000 0004 2740 9295
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2012
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Background Anaemia is common in patients with functioning kidney transplants. Mycophenolic acid (MPA) is anecdotally associated with anaemia, but the mechanism of action is not proven. The effect of recombinant human erythropoietin (rHuEPO) in this setting is poorly studied. Hypothesis 1) MPA causes decreased erythropoiesis in vitro. 2) rHuEPO treatment attenuates progression of renal failure in Post-Transplant Anaemia (PTA). 3) rHuEPO treatment improves Health Quality of Life (HRQOL) and cardiovascular biomarkers. Methods An in vitro model of erythropoiesis in UT-7 cells (human haemo-Ieukaemic cells responsive to EPO) and murine bone marrow cells was used to study the effects of mycophenolic acid on erythroid cell lines. An open labelled, randomised, controlled trial of the use of rHuEPO in anaemic kidney transplant recipients (KTRs) was performed. The primary end points were renal progression measured by rate of change of estimated Glomerular Filtration Rate (eGFR),; change in Protein: Creatinine Ratio (P: CR) and change in blood pressure (B~). Secondary outcomes were changes in SF-36® Health Quality-of-Life (HRQOL) scores and change in Left Ventricular Mass Index (LVMI). A subgroup of the trial was studied for changes in cardiovascular biomarkers using flow cytometry. Results MPA significantly decreased both the proliferation of UT-7 cells (P < 0.001) and erythropoiesis in murine bone marrow cells (P < 0.0001). This was associated with an increase in caspase-3 activity in UT-7 cells in a dose-dependent manner (P < 0.01). Inhibition was reversed in UT-7 cells and in murine bone marrow by guanosine, but not by caspase inhibitors. The apoptosis induced by MPA was also reversed by guanosine. UT-7 cells treated with MPA showed a decrease IMPDH activity. Epoetin beta (the rHuEPO used) treatment improved haemoglobin concentration resulting in a significant improvement of the Vitality Health Domain scales of the SF-36 QOL in the treatment group (P = 0.02). There was no significant difference in the primary outcomes. There was no difference in LVMI or in cardiovascular biomarkers. Conclusion Mycophenolic acid inhibits proliferation of UT-7 cells and inhibits erythropoiesis in murine bone marrow cells via direct inhibition of IMPDH. These in vitro findings offer an explanation to the clinical association of anaemia and MPA use. The treatment with rHuEPO of PTA was found to be associated with improved HRQOL in certain domains. There were no obvious safety concerns demonstrated. However it did not affect the rate of progression of renal failure. Similarly no effect was seen on biomarkers of cardiovascular morbidity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available