nintedanib and Proteinuria

Agents that block vascular endothelial growth factor (VEGF) and its downstream pathway have been reported to be associated with nephrotoxicity including hypertension, proteinuria, and renal dysfunction. Bevacizumab, a monoclonal antibody against VEGF, is known to cause thrombotic microangiopathy (TMA), while tyrosine kinase inhibitors (TKIs) that block VEGF downstream are mainly associated with minimal change disease or focal segmental glomerulosclerosis. The question regarding the source of the diverse phenotypes of nephrotoxicity associated with these agents remains enigmatic. Nintedanib, a multitargeted TKI, blocks fibroblast growth factor and platelet-derived growth factor receptor as well as VEGF receptor, and is indicated for the treatment of idiopathic pulmonary fibrosis. We describe a case of a 45-year-old male who presented with isolated proteinuria of 1.3 g/g Cr 3 years after beginning nintedanib treatment. The kidney biopsy revealed histological features consistent with renal TMA. He underwent single lung transplantation 6 months later, which enabled cessation of nintedanib, and, 1 month later, his proteinuria results were negative. Unlike other types of TKIs, the pathological findings of nintedanib-induced nephrotoxicities have been limitedly reported. This is the first case of isolated proteinuria likely caused by nintedanib-induced TMA.

Topics: Humans; Idiopathic Pulmonary Fibrosis; Indoles; Kidney Diseases; Male; Middle Aged; Protein Kinase Inhibitors; Proteinuria; Thrombotic Microangiopathies

Nintedanib, a triple tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, has been used in idiopathic pulmonary fibrosis and adenocarcinoma in advanced non-small cell lung cancer. Although vascular endothelial growth factor inhibitors have been reported to cause endothelial injury and glomerular microangiopathy, nintedanib-induced glomerular microangiopathy has not been reported. A 68-year-old man with a history of primary aldosteronism, idiopathic pulmonary fibrosis, and pleomorphic carcinoma of the lung developed proteinuria and leg edema after nintedanib initiation. Kidney biopsy revealed prominent endothelial and mesangial injury. Proteinuria improved after nintedanib withdrawal. To the best of our knowledge, this is the second case report of nintedanib-induced glomerular microangiopathy. Although the incidence of nephropathy among patients receiving nintedanib is unknown at this moment, we recommend monitoring urinary protein excretion and blood pressure in patients receiving nintedanib and performing kidney biopsy to determine any histopathological change.

Topics: Aged; Carcinoma; Endothelium, Vascular; Glomerular Mesangium; Humans; Hyperaldosteronism; Idiopathic Pulmonary Fibrosis; Indoles; Kidney; Kidney Diseases; Lung Neoplasms; Male; Protein Kinase Inhibitors; Proteinuria; Receptors, Fibroblast Growth Factor; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Thrombotic Microangiopathies; Withholding Treatment

Novel agents to reduce angiogenesis by targeting vascular endothelial growth factor and other proangiogenic signaling pathways are being developed for advanced nonsmall cell lung cancer. Antibody-based therapies (e.g., aflibercept) and multitargeted tyrosine kinase inhibitors (e.g., sorafenib, sunitinib, and BIBF 1120) are being evaluated in phase III clinical trials. Some antiangiogenic agents have demonstrated distinct profiles in producing a variety of nonhematologic toxicities, including bleeding/hemorrhage, venous and arterial thromboembolic events, gastrointestinal perforation, hypertension, and proteinuria. Elucidating the molecular basis of these toxicities may lead to clinical benefits by improving patient selection and allowing for the development of effective prevention and management strategies.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Bevacizumab; Blood Coagulation Disorders; Carcinoma, Non-Small-Cell Lung; Humans; Hypertension; Indoles; Intestinal Perforation; Lung Neoplasms; Niacinamide; Phenylurea Compounds; Proteinuria; Pyridines; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Sorafenib; Vascular Endothelial Growth Factor A; Wound Healing