Trimarchi Hernán, Forrester Mariano, Lombi Fernando, Pomeranz Vanesa, Iriarte Romina, Raña María Soledad, Young Pablo
Division of Nephrology, Department of Medicine, Hospital Británico de Buenos Aires, 1280 Buenos Aires, Argentina.
Int J Nephrol. 2012;2012:427060. doi: 10.1155/2012/427060. Epub 2012 May 21.
Primary glomerulonephritis stands as the third most important cause of end-stage renal disease, suggesting that appropriate treatment may not be as effective as intended to be. Moreover, proteinuria, the hallmark of glomerular damage and a prognostic marker of renal damage progression, is frequently resistant to thorough control. In addition, proteinuria may be the common end pathway in which different pathogenetic mechanisms may converge. This explains why immunosuppressive and nonimmunosuppressive approaches are partly not sufficient to halt disease progression. One of the commonest causes of primary glomerulonephritis is mesangioproliferative glomerulonephritis. Among the triggered intracellular pathways involved in mesangial cell proliferation, the mammalian target of rapamycin (mTOR) plays a critical role in cell growth, in turn regulated by many cytokines, disbalanced by the altered glomerulopathy itself. However, when inhibition of mTOR was studied in rodents and in humans with primary glomerulonephritis the results were contradictory. In light of these controversial data, we propose an explanation for these results, to dilucidate under which circumstances mTOR inhibition should be considered to treat glomerular proteinuria and finally to propose mTOR inhibitors to be prospectively assessed in clinical trials in patients with primary mesangioproliferative glomerulonephritis, for which a satisfactory standard immunosuppressive regimen is still pending.
原发性肾小球肾炎是终末期肾病的第三大重要病因，这表明适当的治疗可能并未达到预期效果。此外，蛋白尿作为肾小球损伤的标志以及肾脏损伤进展的预后指标，往往难以得到彻底控制。另外，蛋白尿可能是不同致病机制汇聚的共同终末途径。这就解释了为什么免疫抑制和非免疫抑制方法在一定程度上不足以阻止疾病进展。原发性肾小球肾炎最常见的病因之一是系膜增生性肾小球肾炎。在参与系膜细胞增殖的触发细胞内途径中，雷帕霉素靶蛋白（mTOR）在细胞生长中起关键作用，而mTOR又受多种细胞因子调控，在肾小球病变改变时会失衡。然而，在啮齿动物和原发性肾小球肾炎患者中研究mTOR抑制作用时，结果相互矛盾。鉴于这些有争议的数据，我们对这些结果提出一种解释，以阐明在何种情况下应考虑抑制mTOR来治疗肾小球蛋白尿，最终建议对原发性系膜增生性肾小球肾炎患者进行前瞻性临床试验评估mTOR抑制剂，目前针对该疾病仍有待一种令人满意的标准免疫抑制方案。
