血管内皮生长因子(VEGF)抑制剂可引起肾脏损害

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血管内皮生长因子(VEGF)抑制剂可引起肾脏血栓性微血管病变
Treatment With VEGF Inhibitors May Cause Renal Thrombotic Microangiopathy

Roxanne Nelson

March 12, 2008 — Proteinuria and hypertension have been observed in patients treated with the vascular endothelial growth factor (VEGF) bevacizumab. In the March 13 issue of the New England Journal of Medicine, researchers report that the glomerular injury seen in patients who are treated with bevacizumab is probably due to direct targeting of VEGF by antiangiogenic therapy.

\"roteinuria has been reported in 21% to 64% of patients who receive bevacizumab,\" said senior author Susan Quaggin, MD, an investigator from Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario. \"It is not yet clear if this is an accurate reflection, as methods of measuring proteinuria were not standardized and were suboptimal in some studies. It is possible that this might become more of an issue as the use of VEGF inhibitors expands and, we predict, will be an important class effect of these drugs.\"

As the use of bevacizumab increases, associated adverse effects are being reported more frequently. In addition to proteinuria, hypertension has been observed in 3% to 36% of treated patients, and nephrotic-range proteinuria, which denotes structural damage in the glomerular filtration barrier, occurs in 1% to 2% of patients.

\"What is not known yet is the true incidence of significant renal injury,\" Dr. Quaggin told Medscape Oncology. \"This will be an important issue to resolve.\"

Although several potential causes of this type of proteinuria have been suggested, the authors point out that it is difficult to differentiate the general effects of therapy, such as immunologic response, from the direct effects of the inhibition of endogenous VEGF signaling in noncancerous tissues.

In their paper, Dr. Quaggin and colleagues present 6 case studies of cancer patients who received bevacizumab and subsequently developed proteinuria. In all 6 patients, renal biopsy showed the classic pathologic features of thrombotic microangiopathy. However, renal function, proteinuria, and blood pressure improved after the discontinuation of bevacizumab therapy, suggesting that these processes are transient and can be reversed.

The researchers also investigated, using a murine model, whether or not renal thrombotic microangiopathy in patients receiving bevacizumab could be explained by a biologic reduction in glomerular VEGF. They created an experimental mouse model that only targeted podocytes, which are the major source of glomerular VEGF production.

A conditional expression model, in which the target gene is deleted in the presence of a tetracycline derivative, was used to delete the VEGF gene from podocytes. The mice were studied at 3, 12, and 24 weeks of age; these points in time were selected to ensure that the glomeruli were fully functional when VEGF was eliminated. All podocytes expressed VEGF before the administration of doxycycline.

All of the 62 experimental mice had pronounced proteinuria 4 weeks after receiving doxycycline, and 9 had a mean abumin-to-creatinine ratio of 4010 ± 3839 (measured in nanograms per microgram), compared with 26 ± 14 in 11 controls. At 9 weeks, their kidneys appeared pale and shrunken, and proteinuria had increased to maximal levels on dipstick testing.

The appearance of the podocytes changed as the disease progressed, and intracapillary thrombi and bloodless capillary loops that were obliterated by swollen endothelial cells were observed, the researchers note. Although immunohistochemical analysis was negative for complement components and immune complexes, it was positive for fibrin. In 58% of blood smears taken from 7 of the mutant mice, fragmented red cells were observed, but without thrombocytopenia.

In addition to experiencing glomerular injury, hypertension also developed in the mice lacking VEGF in podocytes.

Based on their case studies and experimental research, Dr. Quaggin recommends that all patients receiving VEGF inhibitors be monitored for kidney function, blood pressure, and proteinuria.

\"It would be prudent to monitor patients with preexisting renal disease carefully and, ideally, it would be great to have a prospective study that addresses risk in patients with preexisting disease, to try to identify what factors might put a patient at increased risk,\" she said.

The study was supported by grants from the Canadian Institutes of Health Research, the Kidney Foundation of Canada, the Terry Fox New Frontiers Program of the National Cancer Institute of Canada, and the Canada Research Chair Tier II.

Dr. Quaggin received consulting fees from Genentech, grant support from Genzyme, and serves on an advisory panel for Amgen. Coauthors Hans-Peter Gerber, PhD, and Napoleone Ferrara, MD, are employees of Seattle Genetics and Genentech, respectively.

N Engl J Med. 2008; 358:1129-1136.
2008年3月12日，应用血管内皮生长因子贝伐单亢治疗的病人观察到有蛋白尿和高血压。在3月13出版的新英格兰杂志中，研究者报告，在贝伐单亢治疗的病人中的肾小球损伤，可能源于血管紧张素治疗下血管内皮生长因子的直接的靶向作用。
安大略省多伦多市西奈山医院Samuel Lunenfeld研究所的研究员，医学博士，高级学者Susan Quaggin说：据报道，接受贝伐单亢治疗的病人中有21％到64％患蛋白尿。目前还不清楚这方面是否是正确的反映，因为蛋白尿的测量方法还没有标准化，而且在一些研究中不合适。随着血管内皮生长因子抑制剂的扩大利用，这有可能不止是一个问题，我们预测，这可能是这些药物的一类非常重要的作用。
随着贝伐单亢的使用增加，相关的副作用报道的也越来越频繁。治疗的病人，蛋白尿之外，还观察到有3％到36％有高血压，同时，标志着肾小球滤过膜屏障结构损害的肾病范围的蛋白尿，发生于1％到2％的病人。Quaggin告诉 Medscape Oncology，显著的肾脏损伤的真实发生率还不知道，这是一个需要解决的重要问题。虽然这种类型蛋白尿的几个潜在原因已提出，作者指出，很难区分治疗的一般作用，例如免疫抑制反应，在非癌组织中直接抑制内源性血管内皮生长因子信号的作用。
Quaggin博士和同事在他们的论文中，显示了6例肿瘤病人的研究，他们接受贝伐单亢治疗并随后发展到蛋白尿。在所有6各病人中，肾活检显示血栓性微血管病的基本病理特征。然而，停止贝伐单亢治疗后，肾功能、蛋白尿和血压都得到改善，这意味着这些过程是暂时的可逆的。
研究者也用鼠类模型研究，看贝伐单亢治疗的病人肾脏血管性微血管病是否可以被肾小球血管内皮生长因子生物学活性降低解释。他们制造了一个实验的鼠模型，只定向于足突细胞，它是肾小球血管内皮生长因子产生的主要来源。一个有条件的表达模型用来从足突细胞中删除VEGF基因，在四环素衍生物的出现下靶基因被删除。研究3、12、24周的鼠的情况，及时选择这些点，来确定VEGF基因删除的肾小球具有完全功能。在多西环素注射之前，所有的足突细胞都表达VEGF。62只实验鼠接受多西环素注射后四周都出现了蛋白尿，其中9只血清白蛋白肌酐比值平均为4010 ± 3839（纳克每微克测量），对照组为26 ± 14。在第九周，他们的肾脏显示苍白和萎缩，蛋白尿增加到了浸渍检测法的最高值。
研究者记录到，随着疾病进展，足突细胞形态变化，观察到囊内血栓和被肿胀的内皮细胞阻塞导致的失血的毛细血管袢。虽然对补体成分和免疫复合物的免疫组化分析是阴性的，纤维蛋白原是阳性的。取材于7只突变鼠的血涂片中，58％观察到碎片红细胞，但是没有血小板减少。除了经历肾小球损伤，足突细胞缺少VEGF的鼠也发生了高血压。
经过病例分析和实验室检查，Quaggin博士建议所有接受VEGF抑制剂治疗的病人都要监测肾功能、血压和蛋白尿。她说，监测病人的潜在肾功能损害要小心谨慎，并且，理论上，如果有一个关于病人潜在疾病的危险因素的前瞻性讲究就很好了，可以尝试去辨别什么因素增加了病人的患病危险。

这项研究得到了加拿大健康研究中心、加拿大肾脏基金会、加拿大国家肿瘤中心 Terry Fox前沿项目和加拿大研究主席列II的支持。