Upregulation of CD80 on glomerular podocytes plays an important role in development of proteinuria following pig-to-baboon xeno-renal transplantation – an experimental study

Christopher J. Rivard, Tatsu Tanabe, Miguel A. Lanaspa, Hironosuke Watanabe, Shunichiro Nomura, Ana Andres-Hernando, Krystle Garth, Mitsuhiro Sekijima, Takuji Ishimoto, Yuichi Ariyoshi, Gabriela E. Garcia, Jigesh Shah, Boyd Lennan, Masayuki Tasaki, Thomas Pomposelli, Akira Shimizu, David H. Sachs, Richard J. Johnson, Kazuhiko Yamada

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

We have previously reported that co-transplantation of the kidney with vascularized donor thymus from α-1,3-galactosyltransferase gene knockout pigs with an anti-CD154 with rituximab-based regimen led to improved xenograft survival in baboons with donor-specific unresponsiveness. However, nephrotic syndrome emerged as a complication in which the glomeruli showed mild mesangial expansion with similarities to minimal change disease (MCD) in humans. Since MCD is associated with CD80 expression in glomeruli and elevated urinary excretion, we evaluated a potential role for CD80 in xenograft nephropathy. Study 1 confirmed high urinary CD80 excretion in nephrotic animals with renal xenografts showing CD80 expression in glomeruli. In Study 2, baboons receiving xenografts received CTLA4-Ig once a week from the second postoperative week or no CTLA4-Ig. The non-CTLA4-Ig group developed severe proteinuria with modest mesangial expansion with high urinary excretion of CD80 and documented CD80 expression in glomerular podocytes. All of the recipients in non-CTLA4-Ig groups had to be euthanized before POD 60. In contrast, CTLA4-Ig group showed a marked reduction in proteinuria and survived significantly longer, up to 193 days. These results demonstrate that anti-CD80 targeted therapy represents a promising strategy for reduction of proteinuria following renal xeno-transplantation with improved survival.

Original languageEnglish (US)
Pages (from-to)1164-1177
Number of pages14
JournalTransplant International
Volume31
Issue number10
DOIs
StatePublished - Oct 2018
Externally publishedYes

Keywords

  • CD80
  • kidney transplantation
  • large animal model
  • proteinuria
  • xenograft

ASJC Scopus subject areas

  • Transplantation

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