title: Greater Sensitivity of Blood Pressure Than Renal Toxicity to Tyrosine Kinase Receptor Inhibition With Sunitinib.
abstract: Hypertension and renal injury are off-target effects of sunitinib, a tyrosine kinase receptor inhibitor used for the treatment of various tumor types. Importantly, these untoward effects are accompanied by activation of the endothelin system. Here, we set up a study to explore the dose dependency of these side effects. Normotensive Wistar Kyoto rats were exposed to 3 different doses of sunitinib or vehicle. After 8 days, rats were euthanized. Telemetrically measured blood pressure rose dose dependently, from 13 to 30 mm Hg. Proteinuria was present at all doses, but a rise in cystatin C occurred only at the intermediate and high doses. Compared with vehicle circulating endothelin-1 increased dose dependently, whereas 24-hour urinary endothelin excretion decreased. Light and electron microscopy revealed glomerular endotheliosis and ischemia with the intermediate and high doses of sunitinib but completely absent histological abnormalities with the low dose. Podocyte number per glomerular circumference did not change. Glomerular nephrin, Neph1, podocin, and endothelin-converting enzyme gene expression were downregulated in a dose-dependent manner. We conclude that the sunitinib-induced rise in blood pressure requires lower doses than its induction of renal function impairment and that functional changes in glomerular filtration barrier contribute to the occurrence of proteinuria, given the lack of histopathologic changes with the low dose of sunitinib.
authors.affiliation: From the Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (S.L., M.H.W.K., F.M.M.S., A.H.J.D., A.H.v.d.M.); Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands (H.J.B.); Department of Internal Medicine, Amphia Hospital, Breda, The Netherlands (M.H.W.K.); Department of Pathology, Reinier de Graaf Gasthuis, Delft, The Netherlands (F.M.M.S.); Department of Pathology, Herlev University Hospital, Herlev, Denmark (A.H.); Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands (M.C.C.-v.G.); and Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands (S.S., R.H.JM.).
authors.forename: Stephanie
authors.initials: S
authors.lastname: Lankhorst
authors.affiliation: From the Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (S.L., M.H.W.K., F.M.M.S., A.H.J.D., A.H.v.d.M.); Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands (H.J.B.); Department of Internal Medicine, Amphia Hospital, Breda, The Netherlands (M.H.W.K.); Department of Pathology, Reinier de Graaf Gasthuis, Delft, The Netherlands (F.M.M.S.); Department of Pathology, Herlev University Hospital, Herlev, Denmark (A.H.); Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands (M.C.C.-v.G.); and Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands (S.S., R.H.JM.).
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Baelde
authors.affiliation: From the Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (S.L., M.H.W.K., F.M.M.S., A.H.J.D., A.H.v.d.M.); Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands (H.J.B.); Department of Internal Medicine, Amphia Hospital, Breda, The Netherlands (M.H.W.K.); Department of Pathology, Reinier de Graaf Gasthuis, Delft, The Netherlands (F.M.M.S.); Department of Pathology, Herlev University Hospital, Herlev, Denmark (A.H.); Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands (M.C.C.-v.G.); and Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands (S.S., R.H.JM.).
authors.forename: Mariëtte H W
authors.initials: MH
authors.lastname: Kappers
authors.affiliation: From the Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (S.L., M.H.W.K., F.M.M.S., A.H.J.D., A.H.v.d.M.); Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands (H.J.B.); Department of Internal Medicine, Amphia Hospital, Breda, The Netherlands (M.H.W.K.); Department of Pathology, Reinier de Graaf Gasthuis, Delft, The Netherlands (F.M.M.S.); Department of Pathology, Herlev University Hospital, Herlev, Denmark (A.H.); Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands (M.C.C.-v.G.); and Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands (S.S., R.H.JM.).
authors.forename: Frank M M
authors.initials: FM
authors.lastname: Smedts
authors.affiliation: From the Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (S.L., M.H.W.K., F.M.M.S., A.H.J.D., A.H.v.d.M.); Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands (H.J.B.); Department of Internal Medicine, Amphia Hospital, Breda, The Netherlands (M.H.W.K.); Department of Pathology, Reinier de Graaf Gasthuis, Delft, The Netherlands (F.M.M.S.); Department of Pathology, Herlev University Hospital, Herlev, Denmark (A.H.); Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands (M.C.C.-v.G.); and Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands (S.S., R.H.JM.).
authors.forename: Alastair
authors.initials: A
authors.lastname: Hansen
authors.affiliation: From the Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (S.L., M.H.W.K., F.M.M.S., A.H.J.D., A.H.v.d.M.); Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands (H.J.B.); Department of Internal Medicine, Amphia Hospital, Breda, The Netherlands (M.H.W.K.); Department of Pathology, Reinier de Graaf Gasthuis, Delft, The Netherlands (F.M.M.S.); Department of Pathology, Herlev University Hospital, Herlev, Denmark (A.H.); Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands (M.C.C.-v.G.); and Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands (S.S., R.H.JM.).
authors.forename: Marian C
authors.initials: MC
authors.lastname: Clahsen-van Groningen
authors.affiliation: From the Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (S.L., M.H.W.K., F.M.M.S., A.H.J.D., A.H.v.d.M.); Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands (H.J.B.); Department of Internal Medicine, Amphia Hospital, Breda, The Netherlands (M.H.W.K.); Department of Pathology, Reinier de Graaf Gasthuis, Delft, The Netherlands (F.M.M.S.); Department of Pathology, Herlev University Hospital, Herlev, Denmark (A.H.); Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands (M.C.C.-v.G.); and Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands (S.S., R.H.JM.).
authors.forename: Stefan
authors.initials: S
authors.lastname: Sleijfer
authors.affiliation: From the Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (S.L., M.H.W.K., F.M.M.S., A.H.J.D., A.H.v.d.M.); Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands (H.J.B.); Department of Internal Medicine, Amphia Hospital, Breda, The Netherlands (M.H.W.K.); Department of Pathology, Reinier de Graaf Gasthuis, Delft, The Netherlands (F.M.M.S.); Department of Pathology, Herlev University Hospital, Herlev, Denmark (A.H.); Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands (M.C.C.-v.G.); and Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands (S.S., R.H.JM.).
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
authors.affiliation: From the Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (S.L., M.H.W.K., F.M.M.S., A.H.J.D., A.H.v.d.M.); Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands (H.J.B.); Department of Internal Medicine, Amphia Hospital, Breda, The Netherlands (M.H.W.K.); Department of Pathology, Reinier de Graaf Gasthuis, Delft, The Netherlands (F.M.M.S.); Department of Pathology, Herlev University Hospital, Herlev, Denmark (A.H.); Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands (M.C.C.-v.G.); and Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands (S.S., R.H.JM.). a.vandenmeiracker@erasmusmc.nl.
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
authors.affiliation: From the Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (S.L., M.H.W.K., F.M.M.S., A.H.J.D., A.H.v.d.M.); Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands (H.J.B.); Department of Internal Medicine, Amphia Hospital, Breda, The Netherlands (M.H.W.K.); Department of Pathology, Reinier de Graaf Gasthuis, Delft, The Netherlands (F.M.M.S.); Department of Pathology, Herlev University Hospital, Herlev, Denmark (A.H.); Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands (M.C.C.-v.G.); and Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands (S.S., R.H.JM.).
authors.forename: Anton H
authors.initials: AH
authors.lastname: van den Meiracker
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000494:pharmacology* / Q000633:toxicity; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D011758:Pyrroles / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D011921:Rats, Inbred WKY; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D000077210:Sunitinib
keywords: endothelin-1; hypertension; proteinuria; sunitinib; vascular endothelial growth factor A