Rituximab treatment prevents the early development of proteinuria following pig-to-baboon xeno-kidney transplantation.

Journal Article (Journal Article)

We previously reported life-supporting α1,3-galactosyltransferase knockout (GalTKO) thymokidney xenograft survival of >2 months in baboons. However, despite otherwise normal renal function, recipients developed proteinuria with morphologic changes (podocyte effacement), a condition that presents a major obstacle to long-term studies in this model. A recent clinical study showed that rituximab therapy after allogeneic transplant prevented proteinuria possibly associated with loss of sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b). Here, we demonstrate that rituximab prevents the disruption of pig podocytes in an SMPDL-3b-dependent manner in vitro and the early development of proteinuria after xenogeneic kidney transplantation in baboons. Immunofluorescence showed SMPDL-3b expression in pig glomerular epithelium; immunoprecipitation demonstrated rituximab binding to SMPDL-3b in glomeruli. Culture of isolated pig podocytes with naive baboon sera, which has preformed antipig natural antibodies, reduced SMPDL-3b expression, disrupted podocyte morphology, and decreased podocyte proliferation, whereas pretreatment with rituximab prevented these effects. Six baboons received rituximab before transplantation to deplete B cells and again in the peri-transplant period; 18 baboons treated only before transplantation served as historical controls. The onset of post-transplant proteinuria was significantly delayed in a B cell-independent manner in the animals that received peri-transplant rituximab treatment. Although further optimization of this protocol is required, these data provide intriguing clues to the mechanisms of post-transplant proteinuria in xenogeneic kidney transplantation and a potential strategy for its prevention.

Full Text

Duke Authors

Cited Authors

  • Tasaki, M; Shimizu, A; Hanekamp, I; Torabi, R; Villani, V; Yamada, K

Published Date

  • April 2014

Published In

Volume / Issue

  • 25 / 4

Start / End Page

  • 737 - 744

PubMed ID

  • 24459229

Pubmed Central ID

  • 24459229

Electronic International Standard Serial Number (EISSN)

  • 1533-3450

International Standard Serial Number (ISSN)

  • 1046-6673

Digital Object Identifier (DOI)

  • 10.1681/asn.2013040363

Language

  • eng