BACKGROUND: Anaemia and microcytosis are common post kidney transplantation. The aim of this study was to evaluate the potential role of mammalian target of rapamycin (mTOR) inhibition in the development of anaemia and microcytosis in healthy animals and in human erythroid cultures in vitro. METHODS: Rats with normal kidney function were treated with sirolimus (n = 7) or vehicle (n = 8) for 15 weeks. Hemograms were determined thereafter. In the sirolimus withdrawal part of the study, rats received sirolimus (SRL) for 67 days (n = 4) 1 mg/kg three times per week or for 30 days (n = 4) and were observed until Day 120. Hemograms were performed regularly. Peripheral blood mononuclear cells from healthy controls (HC; n = 8), kidney transplant patients with sirolimus treatment with (SRL + MC; n = 8) or without microcytosis (SRL - MC; n = 8) were isolated and cultured in the absence or presence of SRL (5 ng/mL). RESULTS: SRL-treated animals had a reduced mean corpuscular volume (MCV) and elevated erythrocyte count compared with control animals after 15 weeks of treatment. This effect was evident as early as 4 weeks (MCV: 61.5 ± 1.8 versus 57 ± 1.7 fL; P = 0.0156; Red blood count 7.4 ± 0.3 × 10(9)/L versus 8.6 ± 0.5 × 10(9)/L; P = 0.0156) and was reversible 90 days after SRL withdrawal. SRL in the culture medium of erythroid cultures led to fewer colonies in cultures from HC as well as from kidney transplant patients (without SRL: 34.2 ± 11.4 versus with SRL: 27.5 ± 9.9 BFU-E-derived colonies P = 0.03), regardless if the cultures were derived from recipients with normocytic or with microcytic erythrocytes. The presence of tacrolimus in the culture medium had no influence on the number and size of colonies. CONCLUSION: mTOR inhibition induces microcytosis and polyglobulia, but not anaemia in healthy rats. This might be caused by growth inhibition of erythroid precursor cells.
BACKGROUND:Anaemia and microcytosis are common post kidney transplantation. The aim of this study was to evaluate the potential role of mammalian target of rapamycin (mTOR) inhibition in the development of anaemia and microcytosis in healthy animals and in human erythroid cultures in vitro. METHODS:Rats with normal kidney function were treated with sirolimus (n = 7) or vehicle (n = 8) for 15 weeks. Hemograms were determined thereafter. In the sirolimus withdrawal part of the study, rats received sirolimus (SRL) for 67 days (n = 4) 1 mg/kg three times per week or for 30 days (n = 4) and were observed until Day 120. Hemograms were performed regularly. Peripheral blood mononuclear cells from healthy controls (HC; n = 8), kidney transplant patients with sirolimus treatment with (SRL + MC; n = 8) or without microcytosis (SRL - MC; n = 8) were isolated and cultured in the absence or presence of SRL (5 ng/mL). RESULTS:SRL-treated animals had a reduced mean corpuscular volume (MCV) and elevated erythrocyte count compared with control animals after 15 weeks of treatment. This effect was evident as early as 4 weeks (MCV: 61.5 ± 1.8 versus 57 ± 1.7 fL; P = 0.0156; Red blood count 7.4 ± 0.3 × 10(9)/L versus 8.6 ± 0.5 × 10(9)/L; P = 0.0156) and was reversible 90 days after SRL withdrawal. SRL in the culture medium of erythroid cultures led to fewer colonies in cultures from HC as well as from kidney transplant patients (without SRL: 34.2 ± 11.4 versus with SRL: 27.5 ± 9.9 BFU-E-derived colonies P = 0.03), regardless if the cultures were derived from recipients with normocytic or with microcytic erythrocytes. The presence of tacrolimus in the culture medium had no influence on the number and size of colonies. CONCLUSION:mTOR inhibition induces microcytosis and polyglobulia, but not anaemia in healthy rats. This might be caused by growth inhibition of erythroid precursor cells.
Authors: Jacky Chung; Daniel E Bauer; Alireza Ghamari; Christopher P Nizzi; Kathryn M Deck; Paul D Kingsley; Yvette Y Yien; Nicholas C Huston; Caiyong Chen; Iman J Schultz; Arthur J Dalton; Johannes G Wittig; James Palis; Stuart H Orkin; Harvey F Lodish; Richard S Eisenstein; Alan B Cantor; Barry H Paw Journal: Sci Signal Date: 2015-04-14 Impact factor: 8.192
Authors: Frauke Neff; Diana Flores-Dominguez; Devon P Ryan; Marion Horsch; Susanne Schröder; Thure Adler; Luciana Caminha Afonso; Juan Antonio Aguilar-Pimentel; Lore Becker; Lillian Garrett; Wolfgang Hans; Moritz M Hettich; Richard Holtmeier; Sabine M Hölter; Kristin Moreth; Cornelia Prehn; Oliver Puk; Ildikó Rácz; Birgit Rathkolb; Jan Rozman; Beatrix Naton; Rainer Ordemann; Jerzy Adamski; Johannes Beckers; Raffi Bekeredjian; Dirk H Busch; Gerhard Ehninger; Jochen Graw; Heinz Höfler; Martin Klingenspor; Thomas Klopstock; Markus Ollert; Jörg Stypmann; Eckhard Wolf; Wolfgang Wurst; Andreas Zimmer; Helmut Fuchs; Valérie Gailus-Durner; Martin Hrabe de Angelis; Dan Ehninger Journal: J Clin Invest Date: 2013-07-25 Impact factor: 14.808
Authors: Jintao Wang; Jennifer Tran; Hui Wang; Chiao Guo; David Harro; Andrew D Campbell; Daniel T Eitzman Journal: Br J Haematol Date: 2016-03-31 Impact factor: 8.615