An Interesting Case: Sunitinib-Induced Microangiopathic Hemolytic Anemia and Nephrotic Syndrome

9. de la Morena-Barrio B, Orlando C, de la Morena-Barrio ME, Vicente V, Jochmans K, Corral J. Incidence and features of thrombosis in children with inherited antithrombin deficiency. Haematologica 2019;104:2512-2518. 10. Di Minno MN, Ambrosino P, Ageno W, Rosendaal F, Di Minno G, Dentali F. Natural anticoagulants deficiency and the risk of venous thromboembolism: a meta-analysis of observational studies. Thromb Res 2015;135:923-932.


To the Editor,
Sunitinib is a heterodimeric oral tyrosine kinase inhibitor that targets a large number of receptors, including VEGFR and PDGFR. Anti-VEGF treatments can cause hypertension, proteinuria, neutropenia, anemia, and thrombocytopenia [1]. It has been shown in animal experiments that vascular endothelial growth factor (VEGF) contributes to the repair of glomerular endothelium in experimental microangiopathia and anti-VEGF antibodies cause proteinuria by glomerular dissociation and downregulation of nephrin receptors [2]. The increase of VEGF levels in the blood 2-3 weeks after thrombotic microangiopathy (TMA) supports the idea of VEGF-mediated repair of the glomerular endothelium [3]. Anti-VEGF treatment may cause thrombosis due to the procoagulant phospholipids released as a result of the disruption of plasma membrane integrity and due to the decrease in the levels of nitric oxide and prostaglandin I2, which contributes to the production of VEGF [4].
A 54-year-old woman was receiving sunitinib for a metastatic gastrointestinal stromal tumor (GIST). She presented to the clinic 8 months after the initiation of therapy with microangiopathic hemolytic anemia (MAHA) and nephrotic syndrome (NS). Proteinuria (3.5 g) was detected in the 24-h urine collection. The platelet count was 35000/mm 3 , white blood cell count was 6700/mm 3 , and hemoglobin was 7 g/dL. In the blood smear, normochromic normocytic anemia, diffuse schistocytes, and fragmented erythrocytes were present ( Figure  1). Sunitinib was discontinued and methylprednisone was  Renal biopsy showed microangiopathic anemia [5]. A second reported case involved metastatic renal cell carcinoma; hypertension, nephrotic proteinuria, azotemia, creatinine increase, oliguria, thrombocytopenia, and anemia developed and kidney biopsy showed focal segmental glomerulosclerosis and TMA. After the cessation of sunitinib, the patient recovered [6]. A third case involved hypertension and proteinuria; a kidney biopsy showed TMA. This patient improved with the cessation of sunitinib and steroids [7]. In a fourth case of metastatic GIST, the patient presented with hypertension, loss of vision, seizures, anemia, thrombocytopenia, acute renal failure, and posterior leukoencephalopathy with schistocytes in the blood smear. After the cessation of sunitinib, he improved [8]. A fifth case involved metastatic renal cell carcinoma with nephrectomy as well as nephrotic proteinuria. TMA was confirmed by kidney biopsy. Kidney functions and proteinuria almost entirely improved after stopping sunitinib and starting steroids [9]. In another case of metastatic renal cell carcinoma, three weeks after the start of sunitinib, hypertension, proteinuria, thrombocytopenia, and anemia developed. Schistocytes were noticed in the blood smear. The patient's symptoms improved after the discontinuation of sunitinib [10].
In contrast to many cases discussed, the case that we present here was not a case of renal cell carcinoma but rather metastatic GIST. Generally, sunitinib is used in the first line of treatment for renal cell carcinoma, but it is used after imatinib in GIST treatment, as we did for this patient. Therefore, it is interesting that this toxicity developed after the second tyrosine kinase inhibitor. In this regard, it is an infrequent phenomenon. Similar to other patients mentioned, hypertension was detected in our patient before the development of toxicity. As in most of the other cases, our patient's condition improved almost completely after stopping sunitinib. Our patient did not undergo a kidney biopsy because she had thrombocytopenia and therefore rejected the kidney biopsy. Furthermore, the diagnosis was made clinically, so a biopsy was not required.
The use of anti-VEGF drugs has become widespread and there are limited published data about such severe toxicities (Table  1). For this reason, we wanted to present this rare case that we found and we believe that it can contribute to the literature.

Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study received no financial support.

To the Editor,
Kimura disease is a benign chronic inflammatory disease with unknown etiology, which usually presents with lymphadenopathies in the head and neck, peripheral blood eosinophilia, and elevated serum immunoglobulin E (IgE) levels. It is mostly observed in young males of Asian descent in the second and third decades of life, but sporadic cases in other ethnic groups have also been reported [1,2]. Here we present a patient with Kimura disease and concomitant nephrotic syndrome who presented with lymphadenopathies of atypical locations.
A 25-year-old male patient presented with new-onset hypertension, decreased urine output, and lower extremity swelling. His past medical history was unremarkable with no history of allergies. On examination, his blood pressure was 140/100 mmHg, heart rate was 90/min, and body temperature was 37 °C. He had bilateral 2+ pitting edema of the bilateral lower extremities and an enlarged, soft, nontender 3-cm left inguinal lymph node. Laboratory evaluation results were as follows: white blood cells, 6790/µL; eosinophils,