MTOR INHIBITORS INDUCE ERYTHROPOIETIN RESISTANCE IN RENAL TRANSPLANT RECIPIENTS

Jefferies R1, Puttagunta H1, Olynyk J1,2, Krishnan A3, Irish A1, Swaminathan R1

1Fiona Stanley Hospital, Murdoch, Australia, 2Edith Cowan University, Joondalup, Australia, 3Sir Charles Gairdner Hospital, Nedlands, Australia

Aim: To elucidate the role of mTOR inhibitors on iron, hepcidin and erythropoietin-mediated regulation of hemopoiesis in stable renal transplant recipients (RTR).

Background: Impaired hemopoiesis is common following renal transplantation managed using mTOR inhibitors. The mechanisms responsible are uncertain but include direct effects on iron, hepcidin or erythropoietin-mediated hemopoiesis.

Methods: We conducted a single centre prospective case-control study of 26 adult RTR with stable allograft function. RTR received stable mTOR dosing (cases, 11/26[42%]) or stable tacrolimus dosing (controls, 15/26[58%]). Baseline demographics, full blood count, renal function, iron studies, hepcidin-25, Interleukin-6 (IL-6) and erythropoietin (EPO) levels were determined.

Results: There were no differences in age, gender or allograft function. Mean daily sirolimus dose for cases was 1.72mg, with mean trough level of 8.46ng/mL. Mean daily tacrolimus dose for controls was 4.3mg, with mean trough level of 5.8ng/mL. There were no differences in mean hemoglobin (143 vs 147 g/L; p=0.59), MCV (88 vs 90 fL; p=0.35), serum ferritin (150 vs 85.7 μg/L;  p=0.06), transferrin saturation (26 vs 23.3%;p=0.46), IL-6 (11 vs 7.02 pg/ml; p=0.14) or hepcidin-25 (3.62 vs 3.26 nM; p=0.76) between the groups. EPO levels were significantly higher in the group receiving mTOR therapy compared with controls (16.8 vs 8.49 IU/L; mean difference 95% CI 0.97 – 15.7, p=0.028).

Conclusion: Higher levels of EPO in the absence of deranged iron biochemistry or hepcidin-25 levels suggest that EPO resistance rather than impaired iron metabolism may contribute to the impaired haemopoiesis previously demonstrated in RTR on mTOR therapy.


Biography:

Reece Jefferies is currently in his final year of basic physician training at Fiona Stanley Hospital in Perth with a keen interest in transplant medicine. He is applying for advanced training in respiratory medicine with the aim of pursuing a career in the field of advanced lung disease, pulmonary hypertension and lung transplant.

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