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

Anne Robdrup Tinning, Camilla Bengtsen, Niels Viggo Jensen, Lars Bastholt, Boye Lagerbon Jensen, Kirsten Madsen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

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.

Original languageEnglish
JournalHypertension
Volume71
Issue number3
Pages (from-to)473-480
ISSN0194-911X
DOIs
Publication statusPublished - Mar 2018

Keywords

  • Journal Article
  • Hypertension
  • Vascular endothelial growth factor A
  • Nitric oxide
  • Endothelin-1
  • Kidney
  • Prospective Studies
  • Follow-Up Studies
  • Humans
  • Middle Aged
  • Hypertension/chemically induced
  • Male
  • Nitric Oxide/metabolism
  • Dose-Response Relationship, Drug
  • Pyrimidines/adverse effects
  • Time Factors
  • Carcinoma, Renal Cell/drug therapy
  • Female
  • Sulfonamides/adverse effects
  • Kidney Neoplasms/drug therapy
  • Glomerular Filtration Rate
  • Drug Administration Schedule
  • Risk Assessment
  • Administration, Oral
  • Hospitals, University
  • Neoplasm Invasiveness/pathology
  • Denmark
  • Aged
  • Neoplasm Staging
  • Cohort Studies

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