Characteristic morphological changes in anti‐VEGF therapy‐induced glomerular microangiopathy

AIMS: Agents targeting vascular endothelial growth factor (VEGF) have increasingly been used for the treatment of advanced malignancies, and have been found to induce renal thrombotic microangiopathy (TMA) and proteinuria. However, histomorphological changes in human biopsies in this setting and the underlying mechanism are not yet fully understood. Therefore, we collected renal biopsy cases with a history of aVEGF therapy to review and compare morphological kidney changes in this context. METHODS AND RESULTS: Renal biopsies of 15 patients who had received anti-VEGF (aVEGF) therapy evaluated between 2013 and 2017 at a single centre were morphologically characterised with light microscopy, electron microscopy, and immunohistochemistry (IgA, IgG, IgM, C1q, and C3), and compared with cases with acute TMA caused by atypical haemolytic-uraemic syndrome or hypertension. Morphological overlap with immune complex and cryoglobulinaemic membranoproliferative glomerulonephritis, diabetic glomerulopathy and pre-eclampsia-induced glomerulopathy are discussed. Segmental glomerular capillary microaneurysms and segmental hyalinosis were typical morphological features of aVEGF therapy-induced glomerular microangiopathy, whereas fibrin or platelet thrombi or fragmented erythrocytes were rarely found or were absent. aVEGF therapy-associated microangiopathy was diffusely distributed in the glomeruli, spared preglomerular vessels, and showed morphological characteristics of chronic TMA. In individual cases, aVEGF therapy-induced glomerular microangiopathy was accompanied by immune-complex glomerulonephritis. CONCLUSION: aVEGF therapy-induced glomerular microangiopathy has a characteristic morphology and clinical presentation that helps to differentiate it from other causes of TMA. Awareness of these light microscopic findings allows identification of aVEGF therapy as a trigger of renal disease in critically ill cancer patients, and might therefore help in deciding on further therapy.