VEGF Inhibitors & Kidney Disease

Vascular Endothelial Growth Factor Inhibitors & Tyrosine Kinase Inhibitors-

New agents capable of causing kidney disease.

Ramy M. Hanna MD FACP FASN

Clinical Instructor-UCLA David Geffen School of Medicine.

Vascular endothelial growth factor (VEGF) inhibitors started entering clinical use in the late 1990s as new anti-cancer drugs. Bevacizumab was the first agent and is an antibody against VEGF. It is currently indicated for non-small cell lung cancer, renal cell carcinoma, breast cancer, and ovarian cancer, and gliomas- a type of brain tumor), and other malignancies.  Its side effect profile when given as an intravenous drug has been extensively studied and includes high blood pressure, protein in the urine, and a disease of clotting in small blood vessels called thrombotic microangiopathy.

Bevacizumab inhibits blood vessel proliferation (also known as angiogenesis) by direct binding of VEGF and inhibiting VEGF signaling. VEGF receptors are predominately present on blood vessel wall cells (vascular endothelium), but they are also important for renal “foot cells” (podocytes) where they line the blood-urine barrier.  Abnormal VEGF signaling has been implicated in protein leakage due to pre-eclampsia, protein leakage due to diabetic nephropathy, and protein leakage from various other immunosuppressive drugs like sirolimus and everolimus.

Because VEGF is a crucial regulator of blood vessel health and growth, it has become an attractive target for treating eye diseases caused by excessively proliferating blood vessels. Bevacizumab, has increasingly been used in the clinical practice as an ‘off-label’ (without FDA approval) intra-eye treatment option for the management of proliferative eye disorders due to diabetes. Thus, these drugs are in use in patients with non-cancerous conditions as well as in patients with cancer.

There is some data that intra-eye injections of anti VEGF drugs can cause worsening of high blood pressure like the systemically given drugs do. The side effects of intra eye injections are still being explored, but the scope and severity of side effects from drugs given systemically are much better documented.

Both intravenous and intra-eye anti VEGF injections have been documented to cause glomerular disease, and high blood pressure due to abnormalities of nitric oxide signaling. Tables 1 and 2 show the reported cases of inflammatory kidney diseases that occurred in patients treated with bevacizumab and aflibercept. Table 1 focuses on diseases of patients who got drug intravenously, and table 2 focuses on diseases of patients who got drug as an intra-eye injection.

Given the extensive use of intra eye anti VEGF drugs in diabetics with eye disease (retinopathy) we are carefully studying changes in proteinuria and blood pressure after these injections in our patients. We noted new studies reflecting that anti VEGF agents injected in eye are absorbed by the body, actively suppress VEGF in the patient. There are animal studies that show anti-VEGF drugs binding to the kidneys of monkeys up to one week after eye injection with anti VEGF drugs. There are newer anti VEGF drugs like pegaptanib are not as readily absorbed that may offer better safety and less side effects than the aforementioned drugs.

Another closely related class of agents that have been linked to kidney disease include tyrosine kinase inhibitors (TKIs). These agents target the proteins down that are activated downstream from the VEGF receptor and affect cellular proliferation. They are increasingly being used in the treatment of various cancers as targeted chemotherapy.

These agents affect signaling in podocytes-the foot cells that line the “blood-urine” barrier. They can also affect signaling in blood vessel wall cells of the kidneys and elsewhere. These agents like sorafenib, sunitinib, and many others have been reported to cause protein leakage in urine as well as clotting disorders like thrombotic microangiopathy. Please see Table 1 and Figure 1 for details about conditions associated with TKI use.

Table 1: Cases of proteinuria and thrombotic microangiopathy associated with VEGF and TKI agent use.

Table 2: Intravitreal (eye injections) agents causing glomerular disease (disease in kidneys)

Disclaimer: The UCLA Health System cannot guarantee the accuracy of such information. The information is provided without warranty or guarantee of any kind. Please speak to your Physician before making any changes.