#3478 Lenvatinib-associated hyaline occlusive glomerular microangiopathy

Abstract Background and Aims Immunotherapies and small molecules have transformed therapeutic protocols in modern oncology, resulting in improved quality of life and patient outcome. However, severe adverse events (SAE) may compromise the duration of administration of such treatments. Lenvatinib is an oral receptor tyrosine kinase inhibitor that targets multiple proangiogenic and oncogenic pathways related to vascular endothelial growth factor (VEGF) and fibroblast growth factor receptors, among others. Although not studied directly with lenvatinib, it is postulated that the reported SAE of proteinuria, hypertension, and rarely thrombotic microangiopathy could be related to the inhibition of VEGF/VEGF receptors signaling pathways in podocytes and/or vascular endothelial cells. Herein, we described a distinct histopathological glomerular pattern of injury, previously reported in few patients treated with bevacizumab or anti VEGFR2 antibodies, but not with lenvatinib. Method Case report. Results We present a 56-year-old male patient with a medical history of hypertension, dyslipidemia, and metastatic papillary thyroid carcinoma, who was referred to our nephrology department because of uncontrolled hypertension (194/121 mmHg), acute kidney injury (creatinine 1.8 mg/dL), and nephrotic syndrome, with lower limb swelling, pulmonary edema, hypoalbuminemia (1.67 g/dL), protein to creatinine ratio 3.99 g/g and microscopic hematuria. Twenty-seven months prior to the current presentation, the patient was started on lenvatinib 18 mg/d. During oncology clinic follow-up, his blood pressure was stable on Valsartan, his serum creatinine levels were 0.8–0.9 mg/dL, and serum albumin levels remained normal until 9 months prior to current presentation. 24-h urine collections contained 151 mg, 240 mg, and 980 mg of protein prior to, 7, and 13 months after the initiation of lenvatinib, respectively. When admitted to our department, lenvatinib was stopped. Comprehensive clinical and laboratory evaluation were performed. Of note, full immunologic panel and viral serology were negative. Complement factors (C) 3 and 4, electrolytes, liver function test, c-reactive protein, and complete blood count were within normal limits. A kidney biopsy revealed a) thickened eosinophilic glomerular basement membranes (GBM) with double-contour areas, b) glomerular capillary hyaline globuli (pseudothrombi) and subendothelial hemicrescents, which were positive for IgM (+2 to +3), C1q (+2 to +3), lambda and kappa (+2), C4d (strong +3), IgA (+2), IgG (+1 to +2 ), and fibrinogen (+1 to +2) immunostaining, and negative for C3 and CD61, c) the eosinophilic bright hemicrescents were PAS-positive, silver-negative, and red in Masson's trichrome staining, d) electron microscopy showed multilayered GBM with subendothelial fine granular electron-dense material in the dilated glomerular capillaries, with intact podocyte foot processes in one glomerulus and widespread effacement in another, e) tubular injury, and f) one artery showed myxoid intimal proliferation with narrowed lumen. These findings were summarized as hyaline occlusive glomerular microangiopathy. Following the discontinuation of lenvatinib and adjustment of blood pressure medications, kidney function and blood pressure significantly improved, and proteinuria normalized within two months. Conclusion Our case exemplifies the importance of kidney needle biopsy in elucidating putative mechanisms of drug-related nephrotoxicity and proteinuria in cancer patients. To the best of our knowledge, this is the first documented case of hyaline occlusive glomerular microangiopathy associated with lenvatinib therapy. We suggest that this rare entity is reversible and could be linked to the inhibition of the VEGF-VEGFR2 pathway and endothelial injury.