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    Risk factors for thrombotic microangiopathy in allogeneic hematopoietic stem cell recipients receiving GVHD prophylaxis with tacrolimus plus MTX or sirolimus

    发布于：2014年3月2日    文字：【大】【中】【小】

    Bone Marrow Transplant. 2014 Feb 24. doi: 10.1038/bmt.2014.17. [Epub ahead of print]

    Risk factors for thrombotic microangiopathy in allogeneic hematopoietic stem cell recipients receiving GVHD prophylaxis with tacrolimus plus MTX or sirolimus.

    Labrador J, López-Corral L, López-Godino O, Vázquez L, Cabrero-Calvo M, Pérez-López R, Díez-Campelo M, Sánchez-Guijo F, Pérez-López E,Guerrero C, Alberca I, Del Ca?izo MC, Pérez-Simón JA, González-Porras JR, Caballero D.

    Transplantation-associated thrombotic microangiopathy (TA-TMA) is a feared complication of allogeneic hematopoietic SCT (HSCT) owing to its high mortality rate. The use of calcineurin inhibitors or sirolimus (SIR) for GVHD prophylaxis has been suggested as a potential risk factor. However, the impact of tacrolimus (TAC) and SIR combinations on the increased risk of TA-TMA is currently not well defined. We retrospectively analyzed the incidence of TA-TMA in 102 allogeneic HSCT recipients who consecutively received TAC plus SIR (TAC/SIR) (n=68) or plus MTX (TAC/MTX)±ATG (n=34) for GVHD prophylaxis. No significant differences were observed in the incidence of TA-TMA between patients receiving TAC/SIR vs TAC/MTX±ATG (7.4% vs 8.8%, P=0.8). Only grade III-IV acute GVHD, previous HSCT and serum levels of TAC >25?ng/mL were associated with a greater risk of TA-TMA. Patients developing TA-TMA have significantly poorer survival (P<0.001); however, TA-TMA ceased to be an independent prognostic factor when it was included in a multivariate model. In conclusion, the combination of TAC/SIR does not appear to pose a higher risk of TA-TMA. By contrast, we identified three different risk groups for developing TA-TMA.

    异基因造血干细胞移植（HSCT）后发生CKD的三大常见原因为：钙调磷酸酶抑制剂（CNIs）肾毒性、慢性GVHD相关的肾小球肾炎（如膜性肾病）、HSCT相关的血栓性微血管病（TA-TMA）。TA-TMA发病核心仍是内皮细胞损伤，内皮细胞损伤是多种因素共同作用引起：（1）在HSCT前会进行大剂量化疗、全身放疗伴或不伴放射免疫疗法，单纯大剂量化疗就可以引起内皮细胞损伤；HSCT前的全身放疗与TA-TMA的发生密切相关（有人认为TA-TMA就等同于放疗肾病），且与放疗剂量相关，放疗过程中遮挡肾脏或分次放疗可以减少TA-TMA的发生；（2）其他TA-TMA危险因素包括清髓异基因造血干细胞移植、顺式维甲酸、CNIs、GVHD（与供者细胞毒性T细胞激活、细胞因子、VEGF下降和激活凝血相关）、细胞因子、凝血途径异常、感染（曲霉菌、腺病毒、CMV、HHV-6，其中腺病毒可表达可溶性fms-like tyrosine kinase、抑制VEGF）、氨基糖甘、女性受者+男性供者。TA-TMA与预后差相关，TA-TMA 1年死亡率可达50-90%。

    目前的研究表明CNIs和雷帕霉素（sirolimus）（均用于预防GVHD）是TA-TMA的危险因素。但他克莫司（CNIs的一种）和雷帕霉素合用是否增加TA-TMA的发生目前不清楚。本文回顾性分析了102例HSCT患者，分为连续使用他克莫司+雷帕霉素（n=68例）、他克莫司+甲氨蝶呤（n=34例），两组TA-TMA发生率无明显区别（7.4% vs 8.8%，P=0.8）；进一步分析发现III-IV级GVHD、HSCT病史、血他克莫司浓度>25ng/ml与TA-TMA的发生相关。结论为他克莫司和雷帕霉素联用并不会进一步增加TA-TMA风险。

    http://www.ncbi.nlm.nih.gov/pubmed/24566710