Suppression of the nitric oxide pathway in metastatic renal cell carcinoma patients receiving vascular endothelial growth factor-signaling inhibitors

Emily S. Robinson, Eliyahu V. Khankin, Toni K. Choueiri, Mallika S. Dhawan, Miranda J. Rogers, S. Ananth Karumanchi, Benjamin D. Humphreys

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

Abstract

Therapies that target the vascular endothelial growth factor (VEGF) pathway cause hypertension, but the mechanism remains unknown. This cross-sectional study tested the hypothesis that VEGF inhibition causes hypertension by suppressing VEGF-mediated vasodilatory pathways. Urine was collected from 80 patients with metastatic renal cell carcinoma from 2002 to 2009, 40 at baseline and 40 while on VEGF inhibitors. Measured urinary biomarkers include albumin, metabolites of the nitric oxide (NO) pathway and its downstream effector cGMP, and prostaglandin pathway biomarkers prostaglandin E2, 6-keto prostaglandin F1α, and cAMP, all normalized to urinary creatinine. The mean age in both groups was 61.8 years, 76% were men, and urinary albumin was higher in patients receiving VEGF inhibitors (median: 18.4 versus 4.6 mg/g; P=0.009). cGMP/creatinine was suppressed in patients on VEGF inhibitors (0.28 versus 0.39 pmol/μg; P=0.01), with a trend toward suppression of nitrate/creatinine (0.46 versus 0.62 μmol/mg; P=0.09). Both comparisons were strengthened when patients on bevacizumab were excluded, and only those receiving small molecule tyrosine kinase inhibitors were analyzed (cGMP/creatinine: P=0.003; nitrate/creatinine: P=0.01). Prostaglandin E2, 6-keto prostaglandin F1α, and cAMP did not differ between groups. These results suggest that hypertension induced by VEGF inhibitors is mediated by suppression of NO production. Prospective studies are needed to explore whether these biomarkers may be useful predictors of efficacy in patients receiving VEGF-targeted therapies.

Original languageEnglish
Pages (from-to)1131-1136
Number of pages6
JournalHypertension
Volume56
Issue number6
DOIs
StatePublished - Dec 2010

Keywords

  • NO
  • VEGF
  • albuminuria
  • angiogenesis inhibitors
  • hypertension

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