Weak Expression of Terminal Complement in Active Antibody-Mediated Rejection of the Kidney

COMBAT Consortium, Gesa Tiller, Rosa G. M. Lammerts, Jessy J. Karijosemito, Firas F. Alkaff, Arjan Diepstra, Robert A. Pol, Anita H. Meter-Arkema, Marc. A. Seelen, Marius C. van den Heuvel, Bouke G. Hepkema, Mohamed R. Daha, Jacob van den Born, Stefan P. Berger*

*Corresponding author for this work

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Abstract

Background: The role of the complement system in antibody-mediated rejection (ABMR) is insufficiently understood. We aimed to investigate the role of local and systemic complement activation in active (aABMR). We quantified complement activation markers, C3, C3d, and C5b-9 in plasma of aABMR, and acute T-cell mediated rejection (aTCMR), and non-rejection kidney transplant recipients. Intra-renal complement markers were analyzed as C4d, C3d, C5b-9, and CD59 deposition. We examined in vitro complement activation and CD59 expression on renal endothelial cells upon incubation with human leukocyte antigen antibodies.

Methods: We included 50 kidney transplant recipients, who we histopathologically classified as aABMR (n=17), aTCMR (n=18), and non-rejection patients (n=15).

Results: Complement activation in plasma did not differ across groups. C3d and C4d deposition were discriminative for aABMR diagnosis. Particularly, C3d deposition was stronger in glomerular (P<0,01), and peritubular capillaries (P<0,05) comparing aABMR to aTCMR rejection and non-rejection biopsies. In contrast to C3d, C5b-9 was only mildly expressed across all groups. For C5b-9, no significant difference between aABMR and non-rejection biopsies regarding peritubular and glomerular C5b-9 deposition was evident. We replicated these findings in vitro using renal endothelial cells and found complement pathway activation with C4d and C3d, but without terminal C5b-9 deposition. Complement regulator CD59 was variably present in biopsies and constitutively expressed on renal endothelial cells in vitro.

Conclusion: Our results indicate that terminal complement might only play a minor role in late aABMR, possibly indicating the need to re-evaluate the applicability of terminal complement inhibitors as treatment for aABMR.

Original languageEnglish
Article number845301
Number of pages17
JournalFrontiers in Immunology
Volume13
DOIs
Publication statusPublished - 13-Apr-2022

Keywords

  • antibody-mediated rejection
  • kidney transplantation
  • complement system
  • membrane-attack complex
  • C5b-9
  • RENAL-ALLOGRAFT REJECTION
  • ECULIZUMAB
  • ACTIVATION
  • CELLS
  • C4D
  • INHIBITION
  • DEPOSITION
  • THERAPY
  • CD59
  • TH17

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