title: Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis.
abstract: Focal segmental glomerulosclerosis (FSGS) is a glomerular disease characterized by proteinuria, progression to end-stage renal disease, and recurrence of proteinuria after kidney transplantation in about one-third of patients. It has been suggested that rituximab might treat recurrent FSGS through an unknown mechanism. Rituximab not only recognizes CD20 on B lymphocytes, but might also bind sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b) protein and regulate acid sphingomyelinase (ASMase) activity. We hypothesized that rituximab prevents recurrent FSGS and preserves podocyte SMPDL-3b expression. We studied 41 patients at high risk for recurrent FSGS, 27 of whom were treated with rituximab at time of kidney transplant. SMPDL-3b protein, ASMase activity, and cytoskeleton remodeling were studied in cultured normal human podocytes that had been exposed to patient sera with or without rituximab. Rituximab treatment was associated with lower incidence of posttransplant proteinuria and stabilization of glomerular filtration rate. The number of SMPDL-3b(+) podocytes in postreperfusion biopsies was reduced in patients who developed recurrent FSGS. Rituximab partially prevented SMPDL-3b and ASMase down-regulation that was observed in podocytes treated with the sera of patients with recurrent FSGS. Overexpression of SMPDL-3b or treatment with rituximab was able to prevent disruption of the actin cytoskeleton and podocyte apoptosis induced by patient sera. This effect was diminished in cultured podocytes where SMPDL-3b was silenced. Our study suggests that treatment of high-risk patients with rituximab at time of kidney transplant might prevent recurrent FSGS by modulating podocyte function in an SMPDL-3b-dependent manner.
authors.affiliation: Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA. afornoni@med.miami.edu
authors.forename: Alessia
authors.initials: A
authors.lastname: Fornoni
authors.forename: Junichiro
authors.initials: J
authors.lastname: Sageshima
authors.forename: Changli
authors.initials: C
authors.lastname: Wei
authors.forename: Sandra
authors.initials: S
authors.lastname: Merscher-Gomez
authors.forename: Robier
authors.initials: R
authors.lastname: Aguillon-Prada
authors.forename: Alexandra N
authors.initials: AN
authors.lastname: Jauregui
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Adela
authors.initials: A
authors.lastname: Mattiazzi
authors.forename: Gaetano
authors.initials: G
authors.lastname: Ciancio
authors.forename: Linda
authors.initials: L
authors.lastname: Chen
authors.forename: Gaston
authors.initials: G
authors.lastname: Zilleruelo
authors.forename: Carolyn
authors.initials: C
authors.lastname: Abitbol
authors.forename: Jayanthi
authors.initials: J
authors.lastname: Chandar
authors.forename: Wacheree
authors.initials: W
authors.lastname: Seeherunvong
authors.forename: Camillo
authors.initials: C
authors.lastname: Ricordi
authors.forename: Masami
authors.initials: M
authors.lastname: Ikehata
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Rastaldi
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiser
authors.forename: George W
authors.initials: GW
authors.lastname: Burke
mesh_terms: D000293:Adolescent; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology / Q000627:therapeutic use*; D018951:Antigens, CD20 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002478:Cells, Cultured; D002648:Child; D005260:Female; D005455:Fluorescent Antibody Technique; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use; D047468:Immunoprecipitation; D008297:Male; D050199:Podocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies; D000069283:Rituximab; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D007155:Immunologic Factors; D000069283:Rituximab; C508196:SMPDL3B protein, human; D013108:Sphingomyelin Phosphodiesterase