There is a documented association between VEGF inhibitors (e.g. bevacizumab, sunitinib, sorafenib, pazopanib, axitinib) and renal disease. While these agents are usually well tolerated, their toxic effects include proteinuria and hypertension. The incidence of proteinuria has been variable in different studies depending on patient characteristics, cancer type, and signals targeted, though a number of clinical studies report that treatment with bevacizumab (avastin) may be associated with increased proteinuria. For instance, bevacizumab has been associated with proteinuria in 23-38% of patients treated for colorectal cancer and in up to 64% of patients treated for renal cell carcinoma. One meta-analysis of RCTs with patients receiving bevacizumab reports a relative risk of 1.4 for proteinuria at a low dose (2.5 to 7.5 g/kg) and 1.6 for a high dose (10 to 15 mg/kg) of bevacizumab. Proteinuria appears to at least partly resolve with discontinuation of the VEGF inhibitor, though some patients are able to resume therapy without an increase in proteinuria. It is not clear at this time whether there is an association between duration of treatment and the development of proteinuria.
- Collapsing glomerulopathy
- Cryoglobulinemic glomerlonephritis
- Immune complex-associated focal proliferative GN
- Sorafenib-induced acute interstitial nephritis
Currently, there are no evidence-based recommendations for how to specifically treat proteinuria caused by VEGF inhibitors. However, it is reasonable to try conservative treatments such as ACE inhibitors or angiotensin-receptor blockers, particularly in patients with both proteinuria and hypertension.
Of note, this topic of nephrotoxicity associated with VEGF inhibitors has recently made it to the nephrology boards!
Excellent post. Keep up the good work
Interestingly, the patient did NOT have hypertension, which also was somewhat reassuring for us!
That is correct. You get a pre- eclampsia like syndrome with too little VEGF and you get a collapsing FSGS with too much VEGF.
I refer you to a very good and well done study(
I call this VEGF nephropathology.
There is a fine balance of renal vegf for disease process.
Of recently, another drug called cediranib ( recent CJASN article) also had similar anti VEGF.
Some things I learned from a local meeting in Rotterdam last year:
1. Podocytes produce VGEF and are importent for normal function of podocytes and glomerular endothelial cells.
2. The pathology of VGEF induced glomerulopathy resembles the pathology seen in preeclampsia.
(swelling of endothelial cells), TMA.
3. The placenta produces soluble VGEF receptors which are upregulated during preeclampsia.
4. The hypertension of VGEF inhibitors is low renine, high endothelin and low nitric oxide.
About 30% of the subjects treated with Avastin develop HT and some more have proteinuria.
In otherwords we seem to induce a preeclampsia like syndrome in patients treated with VGEF inhibitors.
Nice post. I have been thinking about this mechanism for some time. I do have a question for you. Did the patient have transient hypertension while on the anti-VEGF inhibitor?
Interesting article to show that that the development of hypertension on therapy could correlate with response to therapy (i.e. patients that develop HTN have better tumor response)http://annonc.oxfordjournals.org/content/20/2/200.full.
Also, an interesting article from the lab I am currently in points to the potential role of nitric oxide (decreased) in the pathogenesis of hypertension caused from anti-VEGF agents. http://www.ncbi.nlm.nih.gov/pubmed/19652084