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Case Report *Corresponding author Jonathan E. Zuckerman, UCLA, Center for Health Sciences, 10833 Le Conte Ave, Los Angeles CA, 90095, Tel: 310-794-1485; Email: JZuckerman@ Renal Hemosiderosis with Submitted: 31 July 2017 Bevacizumab Induced Accepted: 10 August 2017 Published: 18 August 2017 Thrombotic Microangiopathy ISSN: 2379-0652 Copyright in a Patient with Hereditary © 2017 Zuckerman et al. OPEN ACCESS
Keywords Hemorrhagic Telangiectasia • Bevacizumab Jonathan E. Zuckerman* and Anthony Sisk • Hemosiderosis • Thrombotic microangiopathy Department of Pathology and Laboratory Medicine, University of California, U.S.A • Hereditary hemorrhagic telangiectasia • Renal biopsy Abstract Bevacizumab has become a frequently used therapeutic option for bleeding complications in hereditary hemorrhagic telangiectasia (HHT). Renal limited thrombotic microangiopathy is a well- documented complication of Bevacizumab therapy. We present an unusual case of Bevacizumab induced thrombotic microangiopathy complicated by glomerular predominant renal hemosiderosis in a patient with HHT-associated bleeding requiring numerous blood and iron transfusions. As most patients with HHT are likely to receive multiple transfusions with many of them also on bevacizumab as maintenance therapy, this case highlights a possible combined toxicity that may complicate the management of these patients.
BACKGROUND telangiectasia (HHT) presents with slowly rising serum creatinine and proteinuria following Bevacizumab therapy. The patient has Hereditary hemorrhagic telangiectasia (HHT) is a disorder a 17-year history of HHT that has been complicated by recurrent of unbalanced angiogenesis resulting in vascular dysplasia gastrointestinal (GI) bleeding and high iron and blood transfusion and clinical manifestations of mucocutaneous telangiectasias, requirements – up to 1 to 3 units weekly – over the past 4 years. epistaxis, gastrointestinal bleeding, and iron- The patient has been receiving intermittent Bevacizumab [1]. Vascular endothelial growth factor (VEGF) levels in tissues therapy for 2 years with marked symptomatic improvement in and blood are elevated in these patients. Whiledeficiency more commonly anemia his GI bleeding resulting in reduced transfusion requirements. used as an adjunct therapy in certain malignancies, the VEGF Approximately 6 months before his renal biopsy, the patient inhibitor Bevacizumab is as an effective treatment for intractable was found to have heavy proteinuria (>3 grams) and mildly bleeding in patients with HHT [2,3]. Unfortunately, it is known elevated serum creatinine (1.9 mg/dL). Bevacizumab therapy to cause a renal limited, but usually reversible thrombotic was subsequently discontinued. Over the next 3 months, the microangiopathy (TMA) due to a direct effect of its VEGF binding proteinuria improved (urinary protein to creatinine ratio 1.2); activity [4,5]. however, his serum creatinine continued to slowly rise (2.3 mg/ dL at time of biopsy). A renal biopsy was performed to investigate Rare cases of Bevacizumab renal toxicity show continued the cause of the patient’s worsening renal function. renal functional decline despite discontinuation of therapy [6]. Understanding the etiology behind renal functional decline By light microscopy (Figure 1) there were 11 non-sclerotic in these patients is important for determining appropriate glomeruli sampled. All glomeruli displayed mildly increased interventions and avoiding future episodes. mesangial matrix and cellularity. Most glomeruli exhibited segmental capillary loop double contours and occasional Here we report a novel case where Bevacizumab induced TMA is complicated by glomerular predominant renal hemosiderosis mesangiolysis or active thrombosis. Mesangial regions also resulting in progressive renal functional impairment despite exhibitendocapillary hemosiderin hypercellularity. deposition, highlighted There on was iron nostain. definite There Bevacizumab discontinuation. were no segments of sclerosis, necrotizing lesions, fuchsinophilic deposits, or crescents. There was mild tubulointerstitial injury CASE REPORT and scarring as well as focal mild hemosiderin deposition in A 73-year-old man with a history of hereditary hemorrhagic tubules and interstitial spaces.
Cite this article: Zuckerman JE, Sisk A (2017) Renal Hemosiderosis with Bevacizumab Induced Thrombotic Microangiopathy in a Patient with Hereditary Hemorrhagic Telangiectasia. J Clin Nephrol Res 4(4): 1074. Zuckerman et al. (2017) Email:
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Figure 1
(A) Light microscopic renal biopsy findings. (left panel) Glomerulus with segmental double contour formation suggestive of chronic thrombotic microangiopathy, Jone’s silver stain. (middle panel) Glomerulus with hemosiderin deposits and widened hypercellular mesangial regions, Periodic acid-Schiff (PAS). (right panel) Glomerular hemosiderin deposition highlighted on iron stain. All light microscopy images are 40x magnification. (B) Electron micrographs of glomerular hemosiderin deposition and thrombotic microangiopathy. Hemosiderin deposits in (i) mesangial cells (ii) podocytes, and (iii) endothelial cells. (iv) Capillary loop with widened subendothelial space and neomembrane formation consistent with chronic thrombotic microangiopathy. DISCUSSION Direct immunofluorescence miscopy revealed no significant glomerular staining with any antibody. Fibrinogen- staining did not reveal any vascular thrombi. Ultra structural examination was Renal hemosiderosis is a known complication of intravascular notable for abundant membrane bound electron dense coarsely (PNH)hemolysis, [7- specifically in the setting of mechanical heart valves, granular material present within the cytoplasm of endothelial sickle cell anemia, and paroxysmal nocturnal hemoglobinuria cells, mesangial cells, podocytes in all glomeruli and rare 9] as well as hereditary hemochromatosis [10]. interstitial macrophages. Capillary loops exhibited segmental Interestingly, to our- knowledge, there are no published reports of widening of subendothelial spaces with interposition of electron secondary renal hemosiderosis due to long term blood and iron lucent flocculent material and neomembrane formation. Other transfusion. Heme containing- compounds have cytotoxic effects include disruption of the cellular membranes, denaturation of findings included patchy mild podocyte foot process- effacement and mild widening of mesangial regions by matrix. There were DNA, and activation of cell damaging enzymes [11]. Most accounts no tubuloreticular structures or immune complex type deposits. of hemosiderin- related renal injury describe accumulation- of hemosiderin within proximal tubular epithelium [8] and The biopsy was interpreted as glomerular predominant rarely as intra tubular casts [7]. Reports of intra glomerular renal hemosiderosis likely complicating chronic/resolving hemosiderin deposition are rare [10,12]. Furthermore, besides Bevacizumab induced thrombotic microangiopathy. this report, there are no reports to our knowledge demonstrating J Clin Nephrol Res 4(4): 1074 (2017) 2/3 Zuckerman et al. (2017) Email:
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Cite this article Zuckerman JE, Sisk A (2017) Renal Hemosiderosis with Bevacizumab Induced Thrombotic Microangiopathy in a Patient with Hereditary Hemorrhagic Telangiec- tasia. J Clin Nephrol Res 4(4): 1074.
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