Elsevier

Seminars in Nephrology

Volume 30, Issue 6, November 2010, Pages 591-601
Seminars in Nephrology

Hypertension Induced by Vascular Endothelial Growth Factor Signaling Pathway Inhibition: Mechanisms and Potential Use as a Biomarker

https://doi.org/10.1016/j.semnephrol.2010.09.007Get rights and content

Summary

Drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway are a rapidly growing chemotherapy class for treatment of solid tumors. This targeted therapy is more specific than traditional chemotherapy, causing fewer side effects. However, VEGF-targeted therapies cause hypertension in 30% to 80% of patients. Unlike traditional off-target side effects, hypertension is a mechanism-dependent, on-target toxicity, reflecting effective inhibition of the VEGF signaling pathway rather than nonspecific effects on unrelated signaling pathways. In this article, we review current understanding of the mechanisms of VEGF-targeted therapy-induced hypertension, discuss similarities with preeclampsia, review implications for therapy of this increasingly common clinical problem, and discuss the potential use of blood pressure increase as a biomarker for proper drug dosing and effective VEGF pathway inhibition.

Section snippets

Hypertension with VEGF Inhibition

As VEGF-targeted therapies entered the clinic, it became clear that hypertension and proteinuria were major toxicities of this drug class—both the biologics and the small molecules. Proteinuria as a consequence of VEGF inhibition is discussed by Eremina and Quaggin in an accompanying article in this issue of Seminars in Nephrology (see p. 582), therefore this article will focus on hypertension in patients treated with VEGF-targeted therapy. Hypertension occurs in up to 80% of patients on some

Mechanisms of VEGF-Associated Hypertension: Clues from Preeclampsia

Recent advances in our understanding of preeclampsia give reason to believe that hypertension in both patients with preeclampsia and patients taking anti-angiogenic therapy share a common pathogenesis. Preeclampsia is a disease of pregnancy affecting 5% to 7% of women in their second and third trimesters, and is marked by hypertension, proteinuria, and edema. This condition is characterized by systemic endothelial dysfunction, and, if left untreated, ascites, pulmonary edema, thrombocytopenia,

Inhibition of Endothelium-Derived Relaxing Factors

High-dose VEGF infusion into rabbits induces systemic vasodilation and causes an immediate decrease in blood pressure28 that can be inhibited by the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) (Fig. 2).26 VEGF, acting through VEGFR-2, activates eNOS activity through AKT,26 leading to increased vasodilatory NO production (Fig. 3). Bevacizumab has been shown to decrease NO levels in vitro,29 and given that preeclampsia is characterized by deficient NO production, these observations

Capillary Rarefaction

Substantial evidence exists to show that chronic VEGF inhibition causes capillary rarefaction, both in preclinical models and in human beings. This capillary rarefaction may increase afterload and thereby contribute to the pathophysiology of hypertension induced by VEGF signaling pathway (VSP) inhibition. Chronic VEGF depletion causes reduced microvascular EC survival, ultimately leading to a net reduction in tissue microvessel density.35 The endothelial insult may additionally cause local

Alterations in the Pressure Natriuresis Relationship

Many decades of hypertension research have established the kidney's ability to excrete sodium in response to chronic increases in arterial pressure (the pressure-natriuresis relationship) as a critical regulatory response to increased blood pressure. For chronic hypertension to occur, a defect in renal sodium excretion has been seen in all forms of hypertension examined.38 At least two lines of evidence suggesting that VEGF inhibition might similarly shift the pressure-natriuresis curve as an

The Renin-Angiotensin Axis

Although endothelial dysfunction might be expected to cause glomerular ischemia with up-regulation of the renin-angiotensin-aldosterone axis, in fact no experimental evidence supports a role for this pathway. Facemire et al,30 using DC101, a VEGF-receptor inhibitor in mice, showed that renin messenger RNA (mRNA) and aldosterone urinary excretion were actually decreased when compared with control mice. In the only published study examining this in human beings, renin and aldosterone levels were

Other Vasoconstrictive Pathways

Emerging data support a possible role for increased vasoconstrictive endothelin-1 (ET-1) in the pathogenesis of hypertension induced by anti-VEGF therapy. First, there is evidence that ET-1 plays a role in hypertension induced by a rat model of preeclampsia. Alexander et al43 from the Granger group showed increased levels of preproendothelin mRNA in renal medulla during preeclampsia, and also showed marked attenuation of blood pressure by an endothelin type A–receptor antagonist. In a follow-up

Hypertension as a Biomarker of Tumor Response

In addition to the importance of understanding these side effects for purposes of clinical management, there is increasing evidence that an increase in blood pressure in patients on these medications may predict better tumor response.46 The rationale is that hypertension is a mechanism-dependent effect of VSP inhibition (ie, it reflects effective in vivo inhibition of the VEGF signaling pathway).47 This raises a natural question: are patients who do not develop hypertension on these drugs being

Management of Hypertension Induced by Anti-Angiogenic Therapy

Although an abundance of data exist for managing essential hypertension, very little data exist to guide treatment of hypertension induced by VSP-inhibitor blockade. Nevertheless, the condition is clinically important and several general recommendations can be made, based in part on a recent interdisciplinary working group convened to study this topic.55 First, patients should have controlled blood pressure before starting therapy because they may be expected to have exacerbation of

Conclusions

The use of anti-angiogenic therapies is growing rapidly and nephrologists increasingly will be called upon to manage the renal and vascular side effects of these drugs. Hypertension on VEGF-targeted therapies is common and causes significant morbidity but it can be managed effectively and also may be a biomarker for tumor responsiveness. Understanding the mechanisms of VEGF-inhibitor–induced hypertension will lead to rational treatment of this complication, and may illuminate our understanding

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  • Cited by (0)

    This work was supported by National Institutes of Health grants DK073628 and DK084316, and a pilot grant from Harvard Catalyst: National Institutes of Health grant UL1 RR 025758-02, with financial contributions from participating institutions (all to B.D.H.), and a grant from the National Kidney Foundation (E.S.R.). S.A.K. is listed as a co-inventor on multiple patents held by the Beth Israel Deaconess Medical Center for the diagnosis and therapy of preeclampsia. These patents have been nonexclusively licensed to multiple companies. S.A.K. is a consultant to Beckman Coulter, Johnson & Johnson, Roche, and Abbott Diagnostics, which are developing biomarkers for preeclampsia diagnosis/prediction.

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