Banff Human Organ Transplant Transcripts Correlate with Renal Allograft Pathology and Outcome: Importance of Capillaritis and Subpathologic Rejection

Abstract

Background: To seek insights into the pathogenesis of chronic active antibody-mediated rejection (CAMR), we performed mRNA analysis and correlated transcripts with pathologic component scores and graft outcomes. Methods: We utilized the NanoString nCounter platform and the Banff Human Organ Transplant gene panel to quantify transcripts on 326 archived renal allograft biopsy samples. This system allowed correlation of transcripts with Banff pathology scores from the same tissue block as well as correlation with long-term outcomes. Results: The only pathology score that correlated with AMR pathways in CAMR was peritubular capillaritis (ptc). C4d, cg, g, v, i, t, or ci scores did not correlate. DSA-negative CAMR had lower AMR pathway scores than DSA-positive CAMR. Transcript analysis in non-CAMR biopsies yielded evidence of increased risk of later CAMR. Among 108 patients without histologic CAMR, 23 developed overt biopsy-documented CAMR within 5 years and as a group had higher AMR pathway scores (p=3.4x10-5). Random forest analysis correlated three-year graft loss with elevated damage, innate immunity, and macrophage pathway scores in CAMR and TCMR.. Graft failure in CAMR was associated with TCMR transcripts but not with AMR transcripts, and graft failure in TCMR was associated with AMR transcripts but not with TCMR transcripts. Conclusions: Peritubular capillary inflammation and DSA are the primary drivers of AMR transcript elevation. Transcripts revealed subpathological evidence of AMR, which often preceded histological CAMR and subpathological evidence of TCMR that predicted graft loss in CAMR.

Mechanism and treatment for chronic antibody‐mediated rejection in kidney transplant recipients

“…also performed mRNA analysis on 326 samples to elucidate the pathogenesis of AMR and correlate transcripts with pathological scores and renal transplant outcomes. According to this study, PTC was the only factor that correlated with the AMR pathway in patients with chronic active AMR, while scores, such as C4d, cg, g, and v did not 65 . Although the g‐score has been the preferred MVI finding in the Banff classification to date, PTC could be a key factor for AMR diagnosis in the future.…”

Soluble and cell-based markers of immune checkpoint inhibitor-associated nephritis

“…QC assessment and normalization were performed as described. 21 The NanoString Advanced Analysis software V.2.0 was used to define IL-2 signaling and T cell receptor pathway scores using the first principal component of the gene sets shown in online supplemental table S3. 22 Diagnostic groups were compared using Kruskal-Wallis test.…”

Soluble and cell-based markers of immune checkpoint inhibitor associated nephritis

“…QC assessment and normalization were performed as described. (21) The NanoString Advanced Analysis software 2.0 was used to define IL-2 signaling and T cell receptor pathway scores using the first principal component of the gene sets shown in Supplemental Table 3 (22). Diagnostic groups were compared using Kruskal-Wallis test.…”

“…This panel was selected because of the pathologic similarities of acute interstitial nephritis to acute cellular rejection, and because it is enriched for immune cell genes. QC assessment and normalization were performed as described (21). The NanoString Advanced Analysis software 2.0 was used to define IL-2 signaling and T cell receptor pathway scores using the first principal component of the gene sets shown in Supplemental Table3…”