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Renal Effects of Anti-angiogenesis Therapy: Update for the Internist

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Abstract

Angiogenesis has become an innovative target in cancer therapy. Agents that inhibit vascular endothelial growth factor (VEGF), one of the most potent promoters of angiogenesis, and its receptor have significant implications for clinical practice. Bevacizumab, sorafenib, sunitinib and other anti-VEGF drugs are frequently complicated by mild proteinuria and hypertension. Other unique renal effects, such as high-grade proteinuria and acute kidney injury, have been described. The most common histopathologic kidney lesion is thrombotic microangiopathy, with other glomerular lesions and interstitial nephritis occurring less frequently. The mechanism for anti-VEGF therapy-induced hypertension is not well understood; however, nitric oxide pathway inhibition, rarefaction, and oxidative stress may be important in its pathogenesis. Glomerular injury may develop from loss of VEGF effect on maintaining the filtration barrier. Adverse effects of anti-VEGF class of drugs are manageable but require close attention and follow-up. Understanding the fundamentals of anti-VEGF drugs' mechanism of action and their clinical implications is crucial when caring for patients receiving anti-VEGF therapy.

Section snippets

Tumor Angiogenesis Theory

In 1971, Dr. Judah Folkman proposed a revolutionary hypothesis: tumor growth and metastasis are angiogenesis-dependent processes.1 He postulated that the formation of new vessels from an existing vascular bed is the key step in tumor progression. New capillaries grow into the neoplasm and provide it with nutrients. In addition, neovascularization allows the tumor cells to disseminate to distant organs. He proposed that tumor cells communicate with vascular endothelial cells within a developing

VEGF Family

Vascular endothelial growth factor (VEGF) is one of the most potent promoters of angiogenesis. Seven members of VEGF family are identified: VEGF-A, -B, -C, -D, -E, placenta growth factor 1 (PlGF1), and placenta growth factor 2 (PlGF2), with VEGF-A playing the most critical role in angiogenesis.2, 3 VEGF is the ligand for vascular endothelial growth factor receptor (VEGFR), a tyrosine kinase receptor. Three types of VEGFR are studied: VEGFR-1 or Flt-1, VEGFR-2 or KDR/Flk-1, and VEGFR-3. Upon

Anti-Angiogenesis Therapy: Anti-VEGF Therapy

Angiogenesis has become a novel target in cancer therapy. Elucidating VEGF pathways on the molecular level has aided the development of multiple anti-VEGF agents, which are currently under clinical investigation.6, 7 Several important anti-VEGF drugs are under various phases of study, and their use has implications for clinical practice (Table 1).

Bevacizumab, the first and most researched anti-VEGF agent, is a recombinant humanized monoclonal antibody to VEGF (Figure 2). It is composed of the

Overview of Adverse Effects of Anti-VEGF Therapy

As new and promising anti-angiogenesis therapy is on the rise, so are the unique adverse effects of the anti-VEGF class of drugs. Standard chemotherapy is typically associated with cytotoxic effects: myelosuppression, gastrointestinal side effects, and alopecia. Anti-VEGF agents, on the contrary, cause either dose-dependent or dose-independent vascular adverse reactions (Table 2). The incidence of side effects varies among studies, depending on patient characteristics, predisposing factors or

Hypertension

Hypertension is a common side effect of anti-VEGF therapy, with incidence ranging from 11% to 43% in various studies.10, 11, 19 In a meta-analysis by Zhu and colleagues, bevacizumab was associated with a 7-8–fold increased relative risk for hypertension.20 Both sunitinib and sorafenib cause similar rates of hypertension, with incidence rates ranging from 16% to 43%, and overall rates of 21.6% and 23.4%, respectively.21, 22 The mechanism of elevated blood pressure in patients treated with

Proteinuria

Proteinuria is a common dose-dependent adverse reaction of anti-VEGF therapy. The incidence of proteinuria after treatment with low-dose bevacizumab was 21% to 41%; proteinuria was even more frequent, 22% to 63%, in a high-dose bevacizumab group.20 Most cases of proteinuria were grade 1 (transient albuminuria defined as 2+ protein on urine dipstick) or grade 2 (persistent albuminuria defined as 2+ protein on urine dipstick), with nephrotic-range seen in 1%-1.8% of the patients treated with

Conclusion

Anti-VEGF therapy is a promising treatment option for patients with many solid cancers. As we learn more about benefits of anti-angiogenesis agents, we should also be aware of their potential adverse reactions. Many adverse renal effects of anti-VEGF therapy are manageable but require close attention and follow-up. Hypertension and non-nephrotic proteinuria should be treated with drugs that reduce blood pressure and proteinuria without discontinuing this anticancer therapy. However, malignant

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    Funding: None.

    Conflicts of Interest: None.

    Authorship: Both authors contributed equally to writing the manuscript.

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