Institute of Pathology, Hannover Medical School, Hannover, Germany.
Transplantation. 2013 May 27;95(10):1242-8. doi: 10.1097/TP.0b013e318291a298.
Thrombotic microangiopathy (TMA) in renal transplants (rTx-TMA) is a serious complication and is usually either recurrent TMA (RecTMA) due to humoral rejection (HR-TMA) or due to calcineurin inhibitor toxicity (CNI-TMA). Although the triggers are known, our knowledge about the thrombogenic transcriptome changes in the microvessels is rudimentary.
We examined the expression of several prothrombotic and antithrombotic genes in 25 biopsies with rTx-TMA (6 RecTMA, 9 HR-TMA, and 10 CNI-TMA) and 8 controls. RNA from microdissected glomeruli of paraffin-embedded tissue was isolated and mRNA transcripts were quantified with real-time polymerase chain reaction after preamplification. Results were correlated with clinicopathologic parameters.
Glomerular mRNA expression of KLF2, KLF4, and tPA was lower and that of PAI-1 was higher in rTx-TMA than in the controls. Glomerular mRNA expression of KLF2 and KLF4 correlated with that of tPA and inversely with that of PAI-1 in rTx-TMA. The mRNA expression of complement regulators CD46 and CD59 were higher in rTx-TMA than in the controls. Only in HR-TMA were glomerular ADAMTS13 and CD55 down-regulated.
The glomerular capillary bed seems to contribute to all subtypes of rTx-TMA by down-regulation of the endothelial transcription factors KLF2 and KLF4, indicating dedifferentiation with subsequent up-regulation of PAI-1 and down-regulation of tPA, resulting in inhibition of local fibrinolysis. Decreased glomerular expression of ADAMTS13 and CD55 could be an additional pathway toward microthrombosis exclusively in HR-TMA.
肾移植后血栓性微血管病（rTx-TMA）是一种严重的并发症，通常是由于体液性排斥反应（HR-TMA）导致的复发性 TMA（RecTMA），或是由于钙调磷酸酶抑制剂毒性（CNI-TMA）所致。虽然其触发因素已为人所知，但我们对微血管内血栓形成转录组变化的了解还很初步。
我们检测了 25 例 rTx-TMA（6 例 RecTMA、9 例 HR-TMA 和 10 例 CNI-TMA）和 8 例对照患者的肾脏活检组织中几种促血栓形成和抗血栓形成基因的表达情况。从石蜡包埋组织的微切割肾小球中分离 RNA，经预扩增后采用实时聚合酶链反应定量 mRNA 转录本。结果与临床病理参数相关联。
rTx-TMA 患者肾小球 KLF2、KLF4 和 tPA 的 mRNA 表达低于对照组，而 PAI-1 的表达则高于对照组。rTx-TMA 患者肾小球 KLF2 和 KLF4 的 mRNA 表达与 tPA 呈正相关，与 PAI-1 呈负相关。rTx-TMA 患者肾小球补体调节因子 CD46 和 CD59 的表达高于对照组。仅在 HR-TMA 患者中，肾小球 ADAMTS13 和 CD55 的表达下调。
肾小球毛细血管床似乎通过下调内皮转录因子 KLF2 和 KLF4 导致内皮细胞去分化，从而导致 PAI-1 上调和 tPA 下调，导致局部纤维蛋白溶解抑制，从而导致所有 rTx-TMA 亚型的形成。HR-TMA 中 ADAMTS13 和 CD55 肾小球表达降低可能是导致微血栓形成的另一种途径。
