Influence of Tyrosine Kinase Inhibitors on Hypertension and Nephrotoxicity in Metastatic Renal Cell Cancer Patients

Abstract

Renal cell carcinoma (RCC) is one of the most common kidney malignancies. An upgraded comprehension of the molecular biology implicated in the development of cancer has stimulated an increase in research and development of innovative antitumor therapies. The aim of the study was to analyze the medical literature for hypertension and renal toxicities as the adverse events of the vascular endothelial growth factor (VEGF) signaling pathway inhibitor (anti-VEGF) therapy. Relevant studies were identified in PubMed and ClinicalTrials.gov databases. Eligible studies were phase III and IV prospective clinical trials, meta-analyses and retrospective studies that had described events of hypertension or nephrotoxicity for patients who received anti-VEGF therapy. A total of 48 studies were included in the systematic review. The incidence of any grade hypertension ranged from 17% to 49.6%. Proteinuria and increased creatinine levels were ascertained in 8% to 73% and 5% to 65.6% of patients, respectively. These adverse events are most often mild in severity but may sometimes lead to treatment discontinuation. Nephrotoxicity and hypertension are related to multiple mechanisms; however, one of the main disturbances in those patients is VEGF inhibition. There is a significant risk of developing hypertension and renal dysfunction among patients receiving anti-VEGF treatment; however, there is also some evidence that these side effects may be used as biomarkers of response to antiangiogenic agents.

Keywords: hypertension; nephrotoxicity; renal cell carcinoma; tyrosine kinase inhibitor.

Figure 1

Flow chart of the literature selection process.

Figure 2

The pathogenesis of hypertension in patients receiving the vascular endothelial growth factor signaling pathway inhibitor (anti-VEGF) therapy. VEGF inhibition leads to decreased transcription of endothelial nitric oxide synthase (eNOS), decreased activation of phospholipase A₂, and increased production of the endothelin-1 (ET-1). Decreased production of nitric oxide (NO), increased production of prostacyclin (PGI₂), and the endothelin-1 (ET-1) resulting in vasoconstriction. The inhibition of VEGF leads to endothelial cell damage and, thereafter, to a reduction in microvascular density. The vasoconstriction and rarefaction resulting from an increase in vascular resistance. Anti-VEGF treatment also results in increased blood volume via sodium retention caused by the decreased NO production. An increased vascular resistance and an increased blood volume are directly related to hypertension development.