Wednesday, March 11, 2015

#NephMadness #OncoRegion VEGF Inhibitor Toxicity Abstracts

Renal Involvement in Preeclampsia: Similarities to VEGF Ablation Therapy

Janina Müller-Deile and Mario Schiffer

Division of Nephrology and Hypertension, Department of Medicine, IFB-TX Hannover, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany

Received 11 September 2010; Accepted 1 November 2010

Academic Editor: David F. Lewis

Copyright © 2011 Janina Müller-Deile and Mario Schiffer. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Glomerular VEGF expression is critical for the maintenance and function of an intact filtration barrier. Alterations in glomerular VEGF bioavailability result in endothelial as well as in podocyte damage. Renal involvement in preeclampsia includes proteinuria, podocyturia, elevated blood pressure, edema, glomerular capillary endotheliosis, and thrombotic microangiopathy. At least the renal signs, symptoms, and other evidence can sufficiently be explained by reduced VEGF levels. The aim of this paper was to summarize our pathophysiological understanding of the renal involvement of preeclampsia and point out similarities to the renal side effects of VEGF-ablation therapy.

Bevacizumab-Mediated Interference With VEGF Signaling Is Sufficient to Induce a Preeclampsia-Like Syndrome in Nonpregnant Women


Preeclampsia (gestational proteinuric hypertension) complicates 5% to 8% of all pregnancies, and is a major cause of maternal and perinatal morbidity and mortality. It is a multisystem disorder specific to human pregnancy and the puerperium. Although the etiology is unknown, increasing evidence from both animal and human studies suggests that an imbalance in circulating pro-(vascular endothelial growth factor [VEGF], placental growth factor) and anti-angiogenic factors (soluble fms-like tyrosine kinase 1, soluble endoglin) may be important. Bevacizumab (Avastin®; Genentech, South San Francisco, CA), a humanized recombinant monoclonal IgG antibody that binds VEGF, has been shown to inhibit endothelial cell proliferation, suppress angiogenesis, and shrink a variety of solid tumors. We present two cases of bevacizumab toxicity that mimic preeclampsia with a reversible syndrome characterized by acute-onset severe hypertension, proteinuria, central nervous system irritability (headache, photophobia, blurred vision, seizures), abnormal laboratory tests (elevated liver function tests, thrombocytopenia), and evidence of reversible posterior leukoencephalopathy on neuroimaging. In both cases, the clinical and laboratory manifestations returned to normal with discontinuation of bevacizumab therapy and supportive care. Bevacizumab toxicity can mimic preeclampsia in nonpregnant women. These data suggest that interference with VEGF signaling is sufficient to induce a preeclampsia-like syndrome in nonpregnant patients. VEGF signaling therefore appears to play a central role—perhaps the central role—in the pathogenesis of preeclampsia, and provides a potential biomarker for the prediction, prevention, and treatment of this dangerous disorder.
Key words: Bevacizumab, Hypertension, Preeclampsia, Eclampsia, Vascular endothelial growth factor, Reversible posterior leukoencephalopathy syndrome
Anticancer Res. 2007 Sep-Oct;27(5B):3465-70.

Hypertension secondary to anti-angiogenic therapy: experience with bevacizumab.

Pande A(1), Lombardo J, Spangenthal E, Javle M.

Author information:
(1)Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Sts,
Buffalo, NY 14263, USA.

BACKGROUND: Hypertension (HT) is a common complication of anti-angiogenic
therapy. Its incidence, treatment and complications are undefined.
PATIENTS AND METHODS: Retrospective review of patients treated with bevacizumab
(BV) from 2003-5. Common toxicity criteria (CTC) for adverse events version 3.0
were used.
RESULTS: Fifty-five out of the 154 patients treated with BV (35%) experienced HT.
Eleven (20%) developed a new onset HT and 44 (80%) experienced an exacerbation of
pre-existing HT. HT developed after a median of 11 weeks at a median BV dose of
10 mg/kg. HT severity was grade 1 (n =1), grade 2 (n=29) or grade 3 (n=22); 3
experienced hypertensive complications. HT was controlled in 47 (85%); BV was
discontinued in 3. The angiotensin-converting enzyme inhibitor (ACE-I), quinapril
was commonly used and resulted in better HT control than ACE-II, calcium channel
or beta antagonists.
CONCLUSION: HT associated with bevacizumab therapy is a manageable toxicity with
the use of ACE-I.

PMID: 17972502  [PubMed - indexed for MEDLINE]

Am J Kidney Dis. 2007 Feb;49(2):186-93.

Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis.

Zhu X(1), Wu S, Dahut WL, Parikh CR.

Author information:
(1)Division of Nephrology, SUNY at Stony Brook, NY, USA.

BACKGROUND: Angiogenesis inhibitors have emerged as an effective targeted therapy
in the treatment of patients with many cancers. One of the most widely used
angiogenesis inhibitors is bevacizumab, a neutralizing antibody against vascular
endothelial growth factor. The overall risk of proteinuria and hypertension in
patients with cancer on bevacizumab therapy is unclear. We performed a systematic
review and meta-analysis of published clinical trials of bevacizumab to quantify
the risk of proteinuria and hypertension.
METHODS: The databases MEDLINE (OVID, 1966 to June 2006) and Web of Science and
abstracts presented at the American Society of Clinical Oncology annual meetings
from 2004 through 2006 were searched to identify relevant studies. Eligible
studies were randomized controlled trials of patients with cancer treated with
bevacizumab that described the incidence of proteinuria and hypertension.
Relative risk (RR) was calculated by using the fixed-effects model.
RESULTS: A total of 1,850 patients were included in the 7 trials identified from
the literature. Bevacizumab was associated with a significant increased risk of
proteinuria (RR, 1.4 with low-dose bevacizumab; 95% confidence interval [CI], 1.1
to 1.7; RR, 2.2 with high dose; 95% CI, 1.6 to 2.9). Hypertension also was
increased significantly among patients receiving bevacizumab (RR, 3.0 for low
dose; 95% CI, 2.2 to 4.2; RR, 7.5 for high dose; 95% CI, 4.2 to 13.4).
CONCLUSION: There was a significant dose-dependent increase in risk of
proteinuria and hypertension in patients with cancer who received bevacizumab.

PMID: 17261421  [PubMed - indexed for MEDLINE]