CASE PRESENTATION
A 63-year-old man with metastatic renal cell carcinoma, diagnosed five years ago and treated with 50 mg of Sunitinib daily for about four months, presented to the emergency department of Imam Reza Hospital in Tabriz with altered mental status and petechia. The patient had been experiencing progressive symptoms of weakness and lethargy since last week. Gradually, petechiae and purpura appeared on the skin and the oral cavity. Physical examinations and imaging did not show any CNS lesion. Initial laboratory data showed a decrease in platelets(PLT: 14,000/mm3) and hemoglobin(Hb:10.5g/dL), white blood cell:10000  per microliter, elevated serum level of lactate dehydrogenase and total bilirubin. High serum creatinine and granular cast in urine sedimentation suggested acute kidney injury. Initial and secondary urine analysis did not show evidence of proteinuria. Schistocytes were found in the peripheral blood smear.
Upon diagnosis of TMA, the patient underwent four plasmapheresis sessions for four consecutive days. Improvement in consciousness and renal function was observed after four days. The patient was discharged in good general condition after two weeks of ICU admission.
DISCUSSION
Renal cell carcinoma (RCC) is the most common kidney cancer, and it represents about 3% of the whole adult malignancies (12, 13). In addition, about Thirty percent of RCC patients present with metastatic disease (14). Anti-VEGF antibody therapy is increasingly used in renal cell carcinoma and metastatic colorectal cancer therapy (15-17). The two main treatments for metastatic RCC are immunotherapy and vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs) (18). The oral multi-targeted kinase inhibitors (MTKI) such as Sunitinib, Sorafenib, and Brivanib block the VEGF signalling pathway, while Bevacizumab blocks the action of circulating VEGF. Sunitinib is a multi-targeted tyrosine kinase that inhibits VEGF receptor 1 and 2 platelet-derived growth factor receptors (PDGFR) (19).
Although The most frequent side effects reported in these drugs are diarrhea, nausea, hypertension, fatigue, and skin lesions, After therapy with this agent, multiple studies have reported the development of proteinuria or acute renal failure. Recent studies described several patients treated with Sunitinib who developed a preeclampsia-like syndrome characterised by proteinuria, edema, and severe hypertension(7, 20, 21).
Studies showed that Genetic deletion or drugs that disrupted VEGF signalling lead to the loss of normal glomerular capillary endothelial cells, microvascular injury, and TMA (22,23).In the kidney, podocytes consistently express VEGF, and its receptors are expressed by glomerular endothelial cells(23). Anti-VEGF therapy by blocking VEGF receptors caused Endothelial injury is implicated in the pathogenesis of hypertension and arterial thrombosis and TMA (24). Daniel Roncone et al. (25) study shows the damage of glomerular capillary endothelial suggests thrombotic microangiopathy. Hohenstein et al. (26) demonstrate that following glomerular endothelium injury, platelets influx and after activation, they form microthrombi. This finding explains that VEFG has a crucial role in glomerular capillary integrity and the prevention of endothelial damage.