Rituximab treatment prevents the early development of proteinuria following pig-to-baboon xeno-kidney transplantation.
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.
Transplantation Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Masayuki
M
Tasaki
Akira
A
Shimizu
Isabel
I
Hanekamp
Radbeh
R
Torabi
Vincenzo
V
Villani
Kazuhiko
K
Yamada
D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D002478:Cells, Cultured; D005700:Galactosyltransferases / Q000502:physiology; D016030:Kidney Transplantation / Q000009:adverse effects*; D010215:Papio; D050199:Podocytes / Q000473:pathology; D011507:Proteinuria / Q000517:prevention & control*; D000069283:Rituximab; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013552:Swine; D014183:Transplantation, Heterologous
D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab; D005700:Galactosyltransferases; D013108:Sphingomyelin Phosphodiesterase