Abstract: TH-OR101
Unbiased Proteomics Distinguishes Chronic and Acute Antibody-Mediated Rejection in Donor-Specific Antibody-Positive Kidney Transplant Recipients
Session Information
- Transplantation: Basic and Translational Advances
October 24, 2024 | Location: Room 25, Convention Center
Abstract Time: 04:40 PM - 04:50 PM
Category: Transplantation
- 2101 Transplantation: Basic
Authors
- Manion, Kieran, Toronto General Research Institute, Toronto, Ontario, Canada
- Allen, Maya A., Toronto General Research Institute, Toronto, Ontario, Canada
- Clotet Freixas, Sergi, McMaster University, Hamilton, Ontario, Canada
- John, Rohan, University Health Network, Toronto, Ontario, Canada
- Konvalinka, Ana, Toronto General Research Institute, Toronto, Ontario, Canada
Background
Nearly a million North Americans have end-stage renal disease, for which transplantation of a new kidney is the best treatment; however, >50% of grafts fail by 10 years due mainly to antibody-mediated rejection (ABMR), where recipient donor-specific antibodies (DSA) can drive tissue injury. Unfortunately, presence of DSA alone cannot predict ABMR, as 30-60% of DSA+ patients do not develop rejection. We aim to identify factors regulating kidney protein expression in DSA+ kidney transplant recipients with and without ABMR.
Methods
Kidney biopsies were obtained from DSA+ kidney transplant recipients with no rejection (NR; n=45) or ABMR (acute, n=25; chronic, n=25; mixed ABMR/cellular rejection, n=25). Glomeruli (glom) and tubulointerstitium (TI) extracted from kidney biopsies using laser capture microdissection were digested to peptides and analyzed by liquid chromatography mass spectrometry. MaxQuant and Perseus software were used for protein identification and differential expression. Differentially expressed proteins (ANOVA, p<0.05) were mapped to signaling pathways using pathDIP (FDR: BH, q<0.05).
Results
180 glomerular and 325 tubulointerstitial proteins were significantly differentially expressed between DSA+ patients with NR or with a subtype of ABMR (Fig 1). Proteins upregulated in acute or mixed ABMR mapped significantly to pathways for MHC and interferon (IFN) signaling in TI (MHC pathway, q=5.5e-12; IFN signaling, q=3.3e-8). In contrast, proteins upregulated in chronic ABMR mapped to the complement cascade (glom, q=2.9e-3; TI, q=6.8e-11) and extracellular matrix organization (glom, q=2.1e-7; TI, q=2.5e-4) in both compartments. DSA+ patients with any ABMR subtype showed significant downregulation of proteins linked to pyruvate metabolism in both compartments compared to NR (glom, q=2.7e-4; TI, q=6.9e-14).
Conclusion
Our results suggest that while both acute and chronic ABMR in DSA+ kidney transplant patients involve altered metabolism, distinct immune-mediated mechanisms may drive tissue damage in the individual subtypes.
Funding
- Government Support – Non-U.S.