Abstract: FR-PO727
Unbiased Proteomics Analysis Shows Distinct Graft Protein Expression in Donor-Specific Antibodies (DSA+) Kidney Transplant Recipients with Antibody-Mediated Rejection
Session Information
- Transplantation: Basic
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Transplantation
- 2101 Transplantation: Basic
Authors
- Manion, Kieran, University Health Network, Toronto, Ontario, Canada
- Allen, Maya A., University Health Network, Toronto, Ontario, Canada
- Clotet Freixas, Sergi, University Health Network, Toronto, Ontario, Canada
- John, Rohan, University Health Network, Toronto, Ontario, Canada
- Konvalinka, Ana, University Health Network, Toronto, Ontario, Canada
Background
Nearly 1,000,000 North Americans have end-stage renal disease (ESRD), where the kidneys no longer function. Transplantation is the best treatment for ESRD; however, 50% of grafts fail by 10 years, due mainly to antibody-mediated rejection (ABMR), where recipient donor-specific antibodies (DSA) are thought to drive tissue injury. Unfortunately, predicting ABMR onset is challenging, as 30-60% of DSA+ transplant patients do not develop ABMR. We aim to identify factors that regulate kidney protein expression in DSA+ kidney transplant recipients with and without ABMR.
Methods
Glomeruli and tubulointerstitium isolated from DSA+ABMR (n=24) and DSA+ no ABMR (NA; n=21) kidney biopsies using laser capture microdissection were digested to peptides and analyzed by liquid chromatography mass spectrometry. MaxQuant and Perseus software were used to assess protein identification and differential expression. Significantly differentially expressed proteins (t-test, p<0.05) were then mapped to signaling pathways using the pathDIP database (FDR with Benjamini Hochberg adjustment, q<0.05).
Results
120 glomerular and 246 tubulointerstitial proteins were significantly differentially expressed between DSA+ABMR and DSA+NA patients, with 55% of these proteins upregulated in ABMR (Figure 1). pathDIP analysis showed that upregulated proteins mapped significantly to pathways involving the immune system (glomeruli, q=7.6e-8; tubulointerstitium, q=3.8e-11), antigen processing (glomeruli, q=5.6e-11) and integrin activity (tubulointerstitium, q=1.0e-8), while downregulated proteins mapped to tight junction regulation (glomeruli, q= 1.0e-3) and cellular metabolism (tubulointerstitium, q=1.8e-9).
Conclusion
Our preliminary results suggest that ABMR in DSA+ patients is strongly linked to dysregulated immune and cellular responses in multiple kidney tissues. These findings will ultimately help us identify novel targets for the development of therapeutics for kidney transplant recipients.
Fig1. Differentially expressed (p<0.05) proteins in the glomeruli (left) and tubulointerstitium (right) of DSA+ kidney transplant recipients with vs without ABMR.
Funding
- Government Support – Non-U.S.