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在以血管内皮细胞成长因子(VEGF)bevacizumab治疗的病患中发现有蛋白尿和高血压；3月13日的新英格兰医学期刊中，研究者报告指出，以bevacizumab治疗的病患出现肾丝球损伤，可能是因为VEGF抗血管新生治疗的直接标靶作用。
资深作者、多伦多Mount Sinai医院Samuel Lunenfeld研究中心的Susan Quaggin医师表示，接受bevacizumab的病患有21%至64%出现蛋白尿，还不清楚这是否准确，因为测量蛋白尿的方法未标准化，且在一些研究中不太适合；我们预期，这可能在VEGF更广泛使用之后成为讨论议题，将对这些药物的效果有重要影响。
因为使用bevacizumab者增加，相关的不良反应也更频繁地被报告；除了蛋白尿之外，有3%至36%的病患出现高血压，也有1%至2%病患出现肾病范围蛋白尿，这表示肾丝球过滤出现构造损伤。
Quaggin医师向Medscape肿瘤学表示，还不清楚显著肾脏损伤的实际证据，这将是有待解决的重要议题。
虽然认为有许多原因造成这类型的蛋白尿，但作者指出，难以从非癌组织抑制内升性VEGF讯号的直接效果中分辨治疗的一般效果，例如免疫反应。
Quaggin等人在他们的报告中发表了 6个接受bevacizumab治疗的癌症病患且后续发生蛋白尿者的案例研究，这6个病患中，肾脏切片显示有血栓性小血管病变的传统病理特征；不过，肾功能、蛋白尿以及血压在停止bevacizumab治疗之后都获得改善，表示这些过程是暂时的且可以逆转的。
研究者也使用老鼠模式进行研究，接受bevacizumab治疗的病患发生血栓性小血管病变是否可以用肾丝球VEGF生物功能衰退来解释；他们建立一个实验用的老鼠模式，只针对肾丝球VEGF产生的主要来源－足细胞。
条件运算模式中，在有四环素衍生物之下，删除目标基因，以从足细胞中删除VEGF基因；研究的老鼠的年纪为3、12和 24周；选定这些时间以确保肾丝球体在VEGF删除时有完整功能；在给予doxycycline之前，所有的足细胞表现有VEGF。
总共有62只实验老鼠在给予doxycycline 4周之后发现有蛋白尿，9只的平均白蛋白-肌酸酐比率为4010 ± 3839 (单位为ng/μg)，11只控制组则为26 ± 14；第9周时，肾脏看起来灰白且缩小，试纸检查发现蛋白尿达最大值。
研究者指出，足细胞的出现改变了疾病进程，发现微细血管内的栓塞和无血的微细血管环被肿胀的内皮细胞抹灭；虽然免疫组织化学分析补体成份和免疫复合物为阴性，但是纤维素为阳性；取自7只突变老鼠的血液抹片中，58%有碎裂的红血球，但未出现血小板过低。
除了发生肾丝球损伤之外，足细胞缺乏VEGF的老鼠也出现了高血压。
根据案例研究和实验模式，Quaggin 医师建议所有接受VEGF 抑制剂的病患监测肾功能、血压和蛋白尿。
她表示，最好是谨慎监测已经有肾脏疾病的病患，必须进行已有疾病病患之风险的前溯研究，试着厘清哪些因素会使病患风险增加。
该研究接受加拿大健康研究中心、加拿大肾脏基金会、加拿大癌症研究中心的Terry Fox New Frontiers 计划 ，以及加拿大政府卓越学者计划Tier II之资金赞助。
Quaggin医师接受Genentech之谘询费用，Genzyme之资金支持，且服务于Amgen的谘询小组；共同作者、 Hans-Peter Gerber博士以及Napoleone Ferrara医师分别是Seattle Genetics 和Genentech的雇员。
Treatment With VEGF Inhibitors May Cause Renal Thrombotic Microangiopathy
By Roxanne Nelson
Medscape Medical News
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.
"Proteinuria 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.