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      A rare case of renal thrombotic microangiopathy associated with Castleman’s disease


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          Castleman’s disease (CD) is an uncommon, heterogeneous lympho-proliferative disorder leading to high circulating levels of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF). Renal involvement has been only described in a limited number of small studies. Herein, we report a rare case of renal thrombotic microangiopathy (TMA) associated with CD and investigate the podocyte expression of VEGF in the renal biopsy prior to initiation of treatment.

          Case presentation

          An 18-year-old male presented with fever, diarrhea, diffuse lymphadenopathy, ascites and acute kidney injury. Laboratory tests for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura were negative. The kidney biopsy showed TMA. An excisional lymph node biopsy was consistent with CD, plasma cell variant. Immunofluorescence staining showed suppressed podocyte VEGF expression. Chemotherapy that inhibits production of inflammatory mediators including IL-6 and VEGF led to complete recovery of renal function.


          Our case illustrates a rare renal histological feature of CD. IL-6 and VEGF are postulated to suppress glomerular VEGF expression, thereby causing renal TMA. Therapy directed against these inflammatory mediators may have important therapeutic implications.

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          Most cited references16

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          Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases.

          Kidney disease affects over 20 million people in the United States alone. Although the causes of renal failure are diverse, the glomerular filtration barrier is often the target of injury. Dysregulation of VEGF expression within the glomerulus has been demonstrated in a wide range of primary and acquired renal diseases, although the significance of these changes is unknown. In the glomerulus, VEGF-A is highly expressed in podocytes that make up a major portion of the barrier between the blood and urinary spaces. In this paper, we show that glomerular-selective deletion or overexpression of VEGF-A leads to glomerular disease in mice. Podocyte-specific heterozygosity for VEGF-A resulted in renal disease by 2.5 weeks of age, characterized by proteinuria and endotheliosis, the renal lesion seen in preeclampsia. Homozygous deletion of VEGF-A in glomeruli resulted in perinatal lethality. Mutant kidneys failed to develop a filtration barrier due to defects in endothelial cell migration, differentiation, and survival. In contrast, podocyte-specific overexpression of the VEGF-164 isoform led to a striking collapsing glomerulopathy, the lesion seen in HIV-associated nephropathy. Our data demonstrate that tight regulation of VEGF-A signaling is critical for establishment and maintenance of the glomerular filtration barrier and strongly supports a pivotal role for VEGF-A in renal disease.
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            Localized mediastinal lymphnode hyperplasia resembling thymoma.

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              Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman's disease.

              Castleman's disease is a syndrome consisting of giant lymph node hyperplasia with plasma cell infiltration, fever, anemia, hypergammaglobulinemia, and an increase in the plasma level of acute phase proteins. It has been reported that clinical abnormalities disappear after the resection of the affected lymph nodes, suggesting that products of lymph nodes may cause such clinical abnormalities. Interleukin-6 (IL-6) is a cytokine inducing B-cell differentiation to immunoglobulin-producing cells and regulating biosynthesis of acute phase proteins. This report demonstrates that the germinal centers of hyperplastic lymph nodes of patients with Castleman's disease produce large quantities of IL-6 without any significant production of other cytokines. In a patient with a solitary hyperplastic lymph node, clinical improvement and decrease in serum IL-6 were observed following surgical removal of the involved lymph node. There was a correlation between serum IL-6 level, lymph node hyperplasia, hypergammaglobulinemia, increased level of acute phase proteins, and clinical abnormalities. The findings in this report indicate that the generation of IL-6 by B cells in germinal centers of hyperplastic lymph nodes of Castleman's disease may be the key element responsible for the variety of clinical symptoms in this disease.

                Author and article information

                BMC Nephrol
                BMC Nephrol
                BMC Nephrology
                BioMed Central (London )
                10 February 2017
                10 February 2017
                : 18
                : 57
                [1 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Division of Nephrology 8126, Department of Internal Medicine, , Washington University School of Medicine, ; 660 S. Euclid Ave., St. Louis, MO 63110 USA
                [2 ]Arkana Laboratories, Little Rock, AR USA
                [3 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Department of Pathology & Immunology, , Washington University School of Medicine, ; St. Louis, MO USA
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                : 10 September 2016
                : 1 February 2017
                Funded by: NIH/NIDDK
                Award ID: K08DK089015 and R03DK106451
                Award Recipient :
                Funded by: Halpin Foundation-American Society of Nephrology
                Funded by: Children’s Discovery Institute of Washington University and St. Louis Children's Hospital
                Award ID: Faculty Scholar Award (MD-FR-2013-336)
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000862, Doris Duke Charitable Foundation;
                Award ID: Clinical Scientist Development Award (Grant 2015100)
                Award Recipient :
                Funded by: Nephrotic Syndrome Study Network (NEPTUNE)
                Award ID: Career Development Award
                Award Recipient :
                Funded by: Central Society for Clinical and Translational Research (CSCTR)
                Award ID: Early Career Development Award
                Award Recipient :
                Funded by: Washington University Division of Nephrology
                Award ID: Renal Translational Innovation Grant
                Award Recipient :
                Case Report
                Custom metadata
                © The Author(s) 2017

                thrombotic microangiopathy,castleman’s disease,vegf,podocytes
                thrombotic microangiopathy, castleman’s disease, vegf, podocytes


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