Angiogenesis inhibition, by targeting VEGF or its receptors, has become an established treatment for various tumor types but is associated with adverse effects including hypertension, proteinuria and renal injury with activation of the endothelin-1 system. Sunitinib is an orally active angiogenesis inhibitor that blocks VEGF receptors -1, -2 and -3 and other tyrosine kinase receptors, including platelet derived growth factor (PDGF) and c-Kit receptors. VEGFR-1 and VEGFR-2 are predominantly expressed on vascular endothelial cells and peritubular capillary endothelial cells, whereas VEGFR-3, stimulated by VEGF-C, is restricted to lymphatic endothelial cells. Since the occurrence of side effects can be a reason to lower the sunitinib dose or even to discontinue anticancer therapy, thereby compromising its potential efficacy, exploring therapeutic approaches to counteract these side effects is important, not only from an academic point of view, but also from a clinical point of view. To determine the most optimal way to prevent the sunitinib-induced adverse effects and to explore their interdependency, we investigate in Chapter 4 the therapeutic potential of the dual endothelin receptor antagonist macitentan, the calcium channel blocker amlodipine, the angiotensin-converting enzyme inhibitor captopril and the phosphodiesterase type 5 inhibitor sildenafil. In Chapter 5 we test the dose-dependency of these side effects, using a low, intermediate and high dose of sunitinib, aiming to find a dose that, with regard to hemodynamic and renal side effects, is comparable to the dose applied in patients. With this approach, we also want to explore whether the proteinuria observed during antiangiogenic treatment occurs irrespective of the presence of glomerular histological changes. In Chapter 6 we aimed to explore the salt dependency of angiogenesis inhibition-induced hypertension by exposing animals to a low and high salt diet in combination with sunitinib, using a dose of sunitinib that does not impair renal function as based on the findings obtained in chapter 5. As a second aim, we explore whether sunitinib administration impairs the formation of lymph vessels within the skin, leading to skin sodium accumulation and salt-sensitivity of blood pressure. In Chapter 7, we investigate the consequences of a high salt diet in combination with sunitinib administration on renal histopathology. Especially, we want to explore whether in addition to glomerular lesions, the combination of a high salt diet and sunitinib is accompanied by tubulointerstitial injury and/or peritubular rarefaction. The renal injury during angiogenesis inhibition closely resembles the renal abnormalities observed in preeclampsia and associates with podocyte injury. It has been suggested that the appearance of podocytes in urine, i.e., podocyturia, could be a sensitive marker for ongoing glomerular disease. In Chapter 8 we aimed to examine whether podocyturia occurs in patients treated with the VEGF inhibitor bevacizumab, using a recently developed qPCR technique, and whether the podocyturia does or does not relate to the degree of proteinuria and cumulative dose of bevacizumab

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A.H.J. Danser (Jan) , A.H. van den Meiracker (Anton) , M.H.W. Kappers (Mariette)
Erasmus University Rotterdam
Financial support by the Dutch Heart Foundation and the Dutch Kidney Foundation for the publication of this thesis is gratefully acknowledged. Additional financial support for publication of this thesis was generously provided by: Actelion Pfizer B.V., ABN AMRO
Erasmus MC: University Medical Center Rotterdam

Lankhorst, S. (2016, January 27). Hypertension and renal toxicity during angiogenesis inhibition. Erasmus University Rotterdam. Retrieved from http://hdl.handle.net/1765/79353