Case Report

Renal thrombotic microangiopathy caused by anti-VEGF-antibody treatment for metastatic renal-cell carcinoma

Nephrotic syndrome in patients with cancer may be related to the primary malignancy or chemotherapeutic therapy. Solid organ cancers may cause membranous glomerulonephritis which is manifested by nephrotic syndrome; other less common histologic presentations include focal and segmental glomerulosclerosis and minimal change disease. In addition, chemotherapy agents may cause renal toxicity by affecting the small blood vessels, glomeruli, tubules, and interstitium. Tyrosine kinase inhibitors such as sunitinib may cause endothelial and podocyte damage leading to thrombotic microangiopathy affecting only the kidney and manifested by proteinuria and hypertension. We report a case of an elderly man with gastrointestinal stromal tumor (GIST) on treatment with sunitinib who had as a complication a thrombotic microangiopathy manifested with nephrotic syndrome and a hypertension of difficult control, which was finally controlled by stopping this drug but had a fatal outcome due to its malignancy.

El síndrome nefrótico en los pacientes con cáncer se puede asociar a su enfermedad de base o al tratamiento quimioterapéutico. El cáncer de órganos sólidos puede producir una glomerulonefritis membranosa que se manifiesta con síndrome nefrótico; otras presentaciones histológicas menos frecuentes son la glomeruloesclerosis focal y segmentaria y la enfermedad de cambios mínimos. Adicionalmente, los tratamientos quimioterapéuticos pueden causar toxicidad renal por afección de los pequeños vasos sanguíneos, los glomérulos, los túbulos y el intersticio. Los inhibidores de la tirosin quinasa como el sunitinib pueden causar daño endotelial y podocitario, produciendo una microangiopatía trombótica limitada a los riñones, que se manifiesta con proteinuria e hipertensión. Se presenta el caso de un hombre anciano con tumor de GIST que fue tratado con sunitinib y como complicación presentó una microangiopatía trombótica manifestada con síndrome nefrótico e hipertensión de difícil control, que se controló al suspender este medicamento pero con desenlace fatal por su neoplasia maligna.

The introduction of novel molecularly targeted therapies in the last 2 decades has significantly improved the patient survival compared to standard conventional chemotherapies. However, this improvement has been accompanied by a whole new spectrum of kidney adverse events. Although known as “targeted,” many of these agents lack specificity and selectivity, and they have a tendency to inhibit multiple targets including those in the kidneys. Early detection and correct management of kidney toxicities is crucial to preserve kidney functions. The knowledge of these toxicities helps guide optimal and continued utilization of these potent therapies. The incidence, severity, and pattern of nephrotoxicity may vary depending on the respective target of the drug. Here, we review the mechanism of action, clinical findings of kidney adverse events, and their proposed management strategies.

La microangiopathie thrombotique (MAT) est un ensemble de troubles caractérisés par une anémie hémolytique mécanique avec thrombopénie. Il s’y associe des lésions ischémiques d’organe de sévérité variable, potentiellement mortelle, touchant le plus souvent les reins et le cerveau avec, à l’histologie, une microvasculopathie occlusive disséminée. La MAT représente 15 % des insuffisances rénales aiguës en oncologie, principalement en raison de l’introduction, au cours de la dernière décennie, d’agents anti-angiogéniques. Elle est plus rarement induite par le cancer lui-même. La MAT d’origine iatrogène peut être classée en 2 types : la MAT de type I, secondaire à la chimiothérapie (mitomycine C, gemcitabine), expose à une lésion rénale chronique dose-dépendante ainsi qu’à une augmentation de la morbi-mortalité ; la MAT de type II, secondaire aux agents anti-angiogéniques, entraîne une atteinte rénale dose-indépendante et la récupération fonctionnelle rénale est habituelle à l’arrêt du médicament. Il n’existe pas d’essai contrôlé randomisé étudiant la MAT iatrogène et définissant une conduite de type evidence-based medicine pour sa prise en charge. Cependant, l’étude des voies d’activation du complément et des facteurs de régulation a permis de comprendre les mécanismes des lésions endothéliales. De ce fait, la tendance actuelle inclut l’utilisation d’agents immunosuppresseurs au cours d’une MAT récidivante ou réfractaire à la plasmaphérèse.

Thrombotic microangiopathy (TMA) is a group of disorders characterized by mechanical hemolytic anemia with thrombocytopenia and an ischemic organic lesion of variable and potentially fatal importance affecting mostly the kidneys and the brain with histologically a disseminated and occlusive microvasculopathy. The incidence of TMA represents 15% of acute kidney failure in oncological setting, largely due to the introduction of anti-angiogenic agents over the past decade. It may be more rarely related to cancer itself. The iatrogenic TMA can be classified into 2 types: The type I, secondary to chemotherapy (mitomycin C, gemcitabine), exposes to a chronic dose-dependent renal injury as well as an increase in morbidity and mortality; iatrogenic type II, secondary to anti-angiogenic agents’, results in a dose-independent renal involvement and renal functional recovery is usual when the drug is discontinued. There is no randomized controlled trial to establish EBM-type management in TMA support. However, complement activation pathways and regulatory factors analyses allowed us to understand the mechanisms of endothelial lesions. As a result, the current trend includes the use of immunosuppressive agents in recurrent or plasmapheresis-refractory MAT.

Thrombotic microangiopathy (TMA) is a poorly recognized cause of collapsing glomerulopathy. The frequency and significance of collapsing glomerulopathy associated with renal TMA have not been specifically studied in native kidney biopsy specimens. Here we retrospectively documented clinicopathologic features of 53 patients with histologically proven TMA in the native kidney, with special emphasis on changes due to focal segmental glomerulosclerosis (FSGS). Histological TMA was related to hypertensive nephropathy in 21 patients, genetic complement abnormalities in 9, drugs in 7, and to other causes in 16 patients. Almost half (26 patients) presented with arteriolar, 6 with glomerular, and 21 with mixed TMA. Using the Columbia classification system for the 53 patients with histological TMA, 33 had concurrent FSGS lesions with collapsing glomerulopathy the dominant variant in 19 patients (58% of the FSGS cases), not otherwise specified in 9 patients, cellular in 3, and perihilar or tip lesions in 1 patient each. The presence of FSGS was associated with a poor renal prognosis, with no prognostic difference between collapsing glomerulopathy and other FSGS variants. Thus, collapsing glomerulopathy is frequently found in native kidney biopsies with TMA, suggesting that endothelial injury may play an important role in the pathophysiology of FSGS.

Thrombotic microangiopathy (TMA) is a complication that can develop directly from certain malignancies, but more often results from anticancer therapy. Currently, the incidence of cancer drug–induced TMA during the last few decades is >15%, primarily due to the introduction of anti–vascular endothelial growth factor (VEGF) agents. It is important for clinicians to understand the potential causes of cancer drug–induced TMA to facilitate successful diagnosis and treatment. In general, cancer drug–induced TMA can be classified into 2 types. Type I cancer drug–induced TMA includes chemotherapy regimens (ie, mitomycin C) that can potentially promote long-term kidney injury, as well as increased morbidity and mortality. Type II cancer drug–induced TMA includes anti-VEGF agents that are not typically associated with cumulative dose–dependent cell damage. In addition, functional recovery of kidney function often occurs after drug interruption, assuming a type I agent was not given prior to or during therapy. There are no randomized controlled trials to provide physician guidance in the management of TMA. However, previously accumulated information and research suggest that endothelial cell damage has an underlying immunologic basis. Based on this, the emerging trend includes the use of immunosuppressive agents if a refractory or relapsing clinical course that does not respond to plasmapheresis and steroids is observed.