VEGF inhibition and renal thrombotic microangiopathy.
The glomerular microvasculature is particularly susceptible to injury in thrombotic microangiopathy, but the mechanisms by which this occurs are unclear. We report the cases of six patients who were treated with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), in whom glomerular disease characteristic of thrombotic microangiopathy developed. To show that local reduction of VEGF within the kidney is sufficient to trigger the pathogenesis of thrombotic microangiopathy, we used conditional gene targeting to delete VEGF from renal podocytes in adult mice; this resulted in a profound thrombotic glomerular injury. These observations provide evidence that glomerular injury in patients who are treated with bevacizumab is probably due to direct targeting of VEGF by antiangiogenic therapy.
Eremina
Vera
V
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
Jefferson
J Ashley
JA
Kowalewska
Jolanta
J
Hochster
Howard
H
Haas
Mark
M
Weisstuch
Joseph
J
Richardson
Catherine
C
Kopp
Jeffrey B
JB
Kabir
M Golam
MG
Backx
Peter H
PH
Gerber
Hans-Peter
HP
Ferrara
Napoleone
N
Barisoni
Laura
L
Alpers
Charles E
CE
Quaggin
Susan E
SE
D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D005260:Female; D018390:Gene Targeting; D006801:Humans; D007678:Kidney Glomerulus / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation / Q000187:drug effects; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D050199:Podocytes / Q000378:metabolism*; D011507:Proteinuria / Q000139:chemically induced; D012333:RNA, Messenger / Q000378:metabolism; D012079:Renal Circulation; D015398:Signal Transduction; D013927:Thrombosis / Q000139:chemically induced*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab