Department of Nephrology and Kidney Transplantation, Laboratori Experimental de Nefrologia i Transplantament, Hospital Clínic, Barcelona, Spain.
Nephrol Dial Transplant. 2012 Feb;27(2):537-41. doi: 10.1093/ndt/gfr318. Epub 2011 Jul 22.
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.
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).
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.
mTOR inhibition induces microcytosis and polyglobulia, but not anaemia in healthy rats. This might be caused by growth inhibition of erythroid precursor cells.
贫血和小细胞性是肾移植后常见的问题。本研究旨在评估雷帕霉素靶蛋白（mTOR）抑制在正常动物和体外人红细胞培养物中贫血和小细胞性发展中的潜在作用。
肾功能正常的大鼠分别接受西罗莫司（n = 7）或载体（n = 8）治疗 15 周。此后测定血球计数。在研究的西罗莫司停药部分，大鼠接受西罗莫司（SRL）治疗 67 天（n = 4），每周 3 次，每次 1mg/kg，或治疗 30 天（n = 4），并观察至第 120 天。定期进行血球计数。从健康对照者（HC；n = 8）、接受西罗莫司治疗且有（SRL + MC）或无小细胞性（SRL - MC）的肾移植患者中分离并培养外周血单个核细胞，在无或有 SRL（5ng/mL）的情况下培养。
与对照组相比，SRL 治疗动物在治疗 15 周后红细胞平均体积（MCV）降低，红细胞计数升高。这种影响早在 4 周时就很明显（MCV：61.5 ± 1.8 比 57 ± 1.7fL；P = 0.0156；红细胞计数 7.4 ± 0.3×10（9）/L 比 8.6 ± 0.5×10（9）/L；P = 0.0156），在 SRL 停药 90 天后恢复正常。SRL 在红细胞培养物培养基中导致来自 HC 以及肾移植患者的培养物中的集落数量减少（无 SRL：34.2 ± 11.4 比有 SRL：27.5 ± 9.9 BFU-E 衍生集落，P = 0.03），无论培养物来自具有正常细胞性或小细胞性红细胞的受者。培养基中存在他克莫司对集落的数量和大小没有影响。
mTOR 抑制在正常大鼠中引起小细胞性和多血症，但不引起贫血。这可能是由于红系前体细胞的生长抑制所致。
