Pazopanib-Induced Hypertension in Patients With Renal Cell Carcinoma Is Associated With Low Urine Excretion of NO Metabolites

Drugs targeting VEGF (vascular endothelial growth factor) are often associated with rapid development of hypertension by a yet not fully understood mechanism. VEGF is expressed in renal epithelial cells and stimulates NO production. In the renal medulla, inhibition of NO formation by local L-NAME or...

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Published in:	Hypertension (Dallas, Tex. 1979) Vol. 71; no. 3; pp. 473 - 480
Main Authors:	Tinning, Anne Robdrup, Bengtsen, Camilla, Jensen, Niels Viggo, Bastholt, Lars, Jensen, Boye Lagerbon, Madsen, Kirsten
Format:	Journal Article
Language:	English
Published:	United States American Heart Association, Inc 01-03-2018
Subjects:	Administration, Oral Aged Carcinoma, Renal Cell - drug therapy Carcinoma, Renal Cell - mortality Carcinoma, Renal Cell - pathology Cohort Studies Denmark Dose-Response Relationship, Drug Drug Administration Schedule Female Follow-Up Studies Glomerular Filtration Rate Hospitals, University Humans Hypertension - chemically induced Hypertension - epidemiology Hypertension - physiopathology Kidney Neoplasms - drug therapy Kidney Neoplasms - mortality Kidney Neoplasms - pathology Male Middle Aged Neoplasm Invasiveness - pathology Neoplasm Staging Nitric Oxide - metabolism Nitric Oxide - urine Prospective Studies Pyrimidines - adverse effects Pyrimidines - therapeutic use Risk Assessment Sulfonamides - adverse effects Sulfonamides - therapeutic use Time Factors Denmark kidney nitric oxide endothelin-1 hypertension vascular endothelial growth factor A
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Summary:	Drugs targeting VEGF (vascular endothelial growth factor) are often associated with rapid development of hypertension by a yet not fully understood mechanism. VEGF is expressed in renal epithelial cells and stimulates NO production. In the renal medulla, inhibition of NO formation by local L-NAME or by impaired endothelin-1 leads to hypertension. The present study was designed to test the hypothesis that VEGF receptor inhibitor treatment leads to hypertension through decreased renal medullary formation of NO and endothelin-1. With a single-center prospective observational design, patients with metastatic renal cell carcinoma (n=27) treated with the receptor tyrosine kinase inhibitor pazopanib were included in the study. Home blood pressure was measured, and plasma and urine samples were collected at baseline and after 4 and 8 weeks of treatment. After 4 weeks, systolic and diastolic blood pressures increased, whereas heart rate decreased significantly; urine protein/creatinine ratio increased significantly, whereas estimated glomerular filtration rate was unchanged. Urine nitrite/nitrate (NOx) and cGMP/creatinine ratios decreased significantly, whereas urine endothelin-1/creatinine ratio and FENa+ were unchanged. In plasma, NOx, cGMP, and brain natriuretic peptide decreased significantly, whereas endothelin-1 was significantly elevated. Blood leukocyte count decreased significantly with unchanged CRP (C-reactive protein). In summary, pazopanib treatment of patients with advanced renal cell carcinoma is associated with hypertension, proteinuria, myelosuppression, and decreased urine and plasma NO metabolites. Results are compatible with a significant role of reduced renal medullary NO bioavailability in VEGF inhibitor-induced hypertension.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Undefined-1 ObjectType-Feature-3 content type line 23
ISSN:	0194-911X 1524-4563
DOI:	10.1161/HYPERTENSIONAHA.117.10225