Abstract

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 center 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 1.72 mg, with mean trough level of 8.46 ng/mL. Mean daily tacrolimus dose for controls was 4.3 mg, with mean trough level of 5.8 ng / 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 (16.8 vs. 8.49 IU / L; p = 0.028). On logistic regression analysis EPO level was the only variable that had a significant impact providing an odds ratio of 0.84 (95%CI 0.66–0.98). The area under the receiver operator characteristic curve (ROC) for the analysis was 0.77 (95%CI 0.54–0.94) with p = 0.04. 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 hemopoiesis previously demonstrated in RTR on mTOR therapy.

Document Type

Journal Article

Date of Publication

2-22-2022

Volume

9

Publication Title

Frontiers in Medicine

Publisher

Frontiers

School

School of Medical and Health Sciences

RAS ID

43589

Funders

Spinnaker Health Research Foundation

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

Comments

Jefferies, R., Puttagunta, H., Krishnan, A., Irish, A., Swaminathan, R., & Olynyk, J. K. (2022). mTOR Inhibitors Induce Erythropoietin Resistance in Renal Transplant Recipients. Frontiers in Medicine, 9. https://doi.org/10.3389/fmed.2022.722058

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Link to publisher version (DOI)

10.3389/fmed.2022.722058

Link to publisher version (DOI)

10.3389/fmed.2022.722058