282 Correspondence | JNCI Vol. 100, Issue 4 | February 20, 2008 CORRESPONDENCE A Preeclampsia-like Syndrome Characterized by Reversible Hypertension and Proteinuria Induced by the Multitargeted Kinase Inhibitors Sunitinib and Sorafenib The oral multitargeted kinase inhibitors (MTKI) sunitinib (SU11248, Sutent; Pfizer, New York) and sorafenib (BAY 43-9006, Nexavar; Bayer Pharmaceuticals, West Haven, CT, and Onyx Pharmaceuticals, Emeryville, CA) are increasingly used to treat malignant solid tumors. These small- molecule agents inhibit signaling through receptor tyrosine kinases such as vascular endothelial growth factor (VEGF) recep- tor, platelet-derived growth factor recep- tor, and c-KIT, among others (1). In the kidney, glomerular podocytes express VEGF and glomerular endothelial cells express VEGF receptors. Podocyte-specific deletion of a single VEGF allele causes proteinuria and capillary endotheliosis in rodents, and disrupted glomerular VEGF signaling is strongly implicated in the pathogenesis of human preeclampsia (2–4). In the institutional review board– approved case series described here, seven patients developed a preeclampsia-like syn- drome characterized by hypertension and proteinuria after starting therapy with MTKI. Patients were identified clinically after developing edema, hypertension, proteinuria, and/or hypoalbuminemia (Table 1). New or exacerbated hypertension required on average two additional antihy- pertensive medications and occurred on average 27 weeks after the start of therapy (range, 2–116 weeks). All seven patients developed proteinuria (average 3.8 g /g, range 1.1–10.4 g/g), with peak urine pro- tein excretion occurring at a median of 24 weeks. There was no serologic evidence of glomerulonephritis or microangiopathic hemolytic anemia in four patients tested. In most patients, the MTKI dose was either reduced or discontinued. Subsequently, in patients with follow-up information, there was dramatic improvement (patients 1, 2, 3), with one patient whose proteinuria was not further quantified except by urinalysis (patient 7). Since 2003, at least 298 patients have been treated with sunitinib or sorafenib at our institutions; thus, the cumulative crude incidence of renal adverse events is 2.3%. However, the true prevalence of MTKI-associated renal toxicity is likely higher because patients were not routinely screened in a systematic, prospective, and long-term manner for the development of new proteinuria. VEGF antagonism in rodents repro- duces the clinical and pathologic charac- teristics of preeclampsia, suggesting that inhibition of glomerular VEGF receptor signaling by MTKI is a plausible mecha- nism to account for the renal toxic effects we observe. Additional evidence for this is that bevacizumab (Avastin; Genentech, South San Francisco, CA), a VEGF- depleting humanized monoclonal anti- body, is associated with a dose-dependent risk of proteinuria and hypertension (5). The gradual rise in blood pressure observed in this series may reflect the delayed devel- opment of glomerular endotheliosis. Hypertension and/or proteinuria are probably shared toxic effects among all antiangiogenic therapies targeting the VEGF pathway. In a phase 1 trial of the small-molecule VEGF receptor antagonist KRN951, 14 of 15 patients developed hypertension and three patients developed dose-limiting proteinuria (6). MTKI- associated renal toxic effects appear to be reversible if detected early enough. All patients starting antiangiogenic therapy should undergo a baseline urinalysis with regular surveillance throughout the course of therapy, in addition to close monitoring of blood pressure and renal function. In patients receiving antiangiogenic therapy, the development of hypertension may be a biomarker of effective VEGF sig- naling inhibition and superior antitumor activity (7). Whether the development of proteinuria might also serve as a surrogate marker of antitumor efficacy is unknown. Treatment options for these life-threaten- ing advanced cancers are limited, and opti- mizing safe and effective drug dosing may be critical to achieve the best therapeutic impact. Clinicians should be aware of the challenges of determining the appropriate criteria for withholding this effective anti- cancer therapy and should make use of multidisciplinary consultative input to decide how best to manage these treat- ment-associated toxic effects. TEJAS V. PATEL JEFFREY A. MORGAN GEORGE D. DEMETRI SUZANNE GEORGE ROBERT G. MAKI MICHAEL QUIGLEY BENJAMIN D. HUMPHREYS References 1. Stein MN, Flaherty KT. CCR drug updates: sorafenib and sunitinib in renal cell carcinoma. Clin Cancer Res. 2007;13(13):3765–3770. 2. Eremina V, Sood M, Haigh J, et al. Glomerular- specific alterations of VEGF—a expression lead to distinct congenital and acquired renal diseases. J Clin Invest. 2003;111(5):707–716. 3. Maynard SE, Min JY, Merchan J, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunc- tion, hypertension, and proteinuria in pre- eclampsia. J Clin Invest. 2003;111(5):649–658. 4. Maynard S, Epstein FH, Karumanchi SA. Preeclampsia and angiogenic imbalance. Annu Rev Med. 2008;59:61–78. 5. Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevaci- zumab, an antibody against vascular endothelial growth factor: systematic review and meta- analysis. Am J Kidney Dis. 2007;49(2):186–193. 6. Eskens FA, Planting A, Van Doorn L, et al. An open-label phase I dose escalation study of KRN951, a tyrosine kinase inhibitor of vascu- lar endothelial growth factor receptor 2 and 1 in a 4 week on, 2 week off schedule in patients with advanced solid tumors. J Clin Oncol. 2006;24(87s):Abstract 2035. 7. van Heeckeren WJ, Ortiz J, Cooney MM, Remick SC. Hypertension, proteinuria and antagonism of vascular endothelial growth factor signaling: clinical toxicity, therapeutic target, or novel biomarker? J Clin Oncol. 2007;25(21):2993–2995. Funding National Institutes of Health (DK73628 and P01-CA47179); Pfizer (A6181047, A6181004, and A6181030 to R.G.M. and G.D.D.); and from philanthropic support by the following sources: The Shuman Family Fund for GIST Research (to R.G.M.), The Virginia and Daniel K. Ludwig Trust for Cancer Research, Leslie’s Links, the Quick Family Fund for Cancer Research, and the GIST Cancer Research Fund (to G.D.D.). Notes Affiliations of authors: Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA (TVP, BDH); Dana Farber Cancer Institute, Boston, MA (JAM, GDD, SG, MQ); Harvard Medical School, Boston, MA (TVP, JAM, GDD, SG, BDH); Memorial Sloan-Kettering Cancer Center, by guest on September 23, 2016 http://jnci.oxfordjournals.org/ Downloaded from