Proteinuria in a Patient Receiving Anti-VEGF Therapy

Discussion of Diagnosis

Targeting VEGF in cancer treatment has recently received considerable attention. Anti-VEGF antibody therapy has mainly been used in clinical trials for metastatic colorectal cancer and renal cell carcinoma,^[3,4,5] but recent data indicate that these antibodies also have activity in breast cancer and lung cancer.^[6,7] The role of VEGF in human renal physiology is not known; however, VEGF is constitutively expressed by podocytes, and its receptors are found on normal glomerular capillary endothelial cells.^[8] Anti-VEGF therapy has been associated with the development of proteinuria in 23-38% of patients with colorectal cancer, and in up to 64% of patients with renal cell carcinoma.^[3,5] Although this proteinuria has largely been asymptomatic and low-grade, it exceeded 3.5 g/day in 6.5% of all renal cell carcinoma patients in one large study.^[5] These findings indicate that VEGF might be involved in the maintenance of the glomerular capillary permeability barrier. To date, there have been no descriptions of kidney histology from patients receiving anti-VEGF therapies. In this Case Study, we report the renal pathologic findings of a patient treated with bevacizumab. The kidney biopsy demonstrated glomerular capillary endothelial injury indicative of a thrombotic microangiopathy, a finding consistent with the notion that VEGF is important for glomerular capillary integrity. The additional observation of an IgA-predominant immune-complex glomerulonephritis was surprising, and is difficult to explain in the context of VEGF's currently known biologic activities. Interestingly, a partial nephrectomy specimen from a second patient treated with bevacizumab was also consistent with endothelial injury secondary to a thrombotic microangiopathy, but lacked any evidence of immune-complex glomerulonephritis (Figure 6 and Figure 7).

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Figure 6.

Electron micrograph of a glomerular capillary loop from a partial nephrectomy specimen from the patient described in Figure 7. The specimen was taken after treatment with bevacizumab plus interferon α2b for 9 months. Subendothelial electron-lucent widening with amorphous material (asterisk) is shown (original magnification ×12,000).

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Figure 7.

Evidence of glomerular endothelial injury in another patient treated with bevacizumab plus interferon α2b.

To explain the development of a thrombotic microangiopathy during anti-VEGF antibody treatment, it is reasonable to postulate that blocking VEGF prevents the repair of endothelial damage that probably occurs daily in blood vessels. Anti-VEGF therapy also commonly causes hypertension, which could contribute to such endothelial injury.^[3,5] This endothelial injury might create a thrombogenic endothelium and predispose to intravascular clotting. Relevant to this hypothesis, arterial thrombosis is a recognized side effect of bevacizumab therapy.^[3] Furthermore, decreased levels of VEGF have been associated with sirolimus-induced thrombotic microangiopathy in kidney transplant recipients, and administering VEGF in experimental thrombotic microangiopathies improved glomerular capillary healing.^[8] A caveat in the cases presented is that interferon α therapy has also been associated with the development of renal thrombotic microangiopathy.^[9] It will, therefore, be important to look at kidney pathology in patients treated with anti-VEGF antibodies in the absence of treatment with interferon α.

The finding of glomerular IgA deposition in the main case presented, and its absence in the second patient (Figure 7), is intriguing. The glomerular IgA deposition was not a pre-existing condition, a conclusion based on immunofluorescence and electron microscopy examinations of the patient's original nephrectomy specimen before any chemotherapy had been given. While systemic and renal VEGF expression might be altered in IgA nephropathy,^[10] there is no evidence that blocking the actions of VEGF predisposes to the development of IgA immune complexes. Similarly, interferon α treatment has not been associated with de novo IgA nephropathy, although it has been suggested that the treatment exacerbates existing IgA nephritis.^[11] It will be important to determine whether IgA immune-complex glomerulonephritis is found in other patients treated with anti-VEGF antibodies who develop renal insufficiency and high-grade proteinuria, but not in patients who develop only minor proteinuria. If the case described here does not represent an isolated finding, and if glomerular IgA deposition occurs in the absence of interferon α therapy, then there could be implications for the understanding of the pathogenesis of IgA nephropathy.

Manipulation of the VEGF axis in experimental animals supports the importance of VEGF in glomerular capillary integrity. In normal mice, administration of antibodies to VEGF, or neutralization of VEGF with soluble VEGF receptor 1, caused a significant increase in proteinuria within 3 hours; this increase was associated with hypertrophy of glomerular endothelial cells, endothelial detachment from the basement membrane, and loss of slit diaphragms.^[12] These animals also showed reduced glomerular expression of nephrin. The chronic administration of anti-VEGF receptor 2 antibodies to mice prone to systemic lupus erythematosus markedly increased mortality and accelerated the development of lupus nephritis and proteinuria.^[1] Finally, podocyte-specific deletion of the VEGF gene caused proteinuria, glomerular endotheliosis, and the eventual loss of endothelial fenestrations in heterozygous mice, while VEGF-null mice failed to develop endothelial fenestrations at all.^[13] Interestingly, in human preeclampsia, fenestrated endothelium is especially vulnerable to injury, and the placenta overproduces a soluble VEGF receptor that acts as a VEGF antagonist.^[14,15]

VEGF is also important in glomerular capillary repair after immune injury. Infusing VEGF into rats with crescentic antiglomerular basement membrane antibody nephritis or anti-Thy-1.1 mesangial proliferative glomerulonephritis enhanced recovery, decreased proteinuria, and improved glomerular histology.^[16,17] Furthermore, steroid treatment of rats given anti-Thy-1.1 significantly attenuated the expected increase in VEGF expression (found in untreated anti-Thy-1.1 rats), and was associated with a threefold increase in proteinuria.^[18]

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