Clinicopathological and Molecular Characteristics of Plasma Cell-Rich Rejection in Renal Transplant Biopsies

Plasma cell-rich rejection (PCRR) is an ill-defined type of renal allograft rejection currently considered a subtype of T cell-mediated rejection. Our study analyzed the clinical course, Banff lesion scores, and mRNA expression of PCRR compared with archetypical types of (late) rejection to better understand and define this presentation in kidney transplants.

We retrospectively scored the last known biopsy in 263 renal transplant recipients, including 42 PCRR cases. Banff lesion scores and clinical outcomes were assessed. Bulk RNA sequencing with CIBERSORTx deconvolution and gene set variation analysis profiled immune-cell composition and pathway activity in an additional set of 140 renal transplant biopsies. Dimensionality reduction (principal component analysis, uniform manifold approximation and projection, and diffusion maps) and unsupervised clustering evaluated the relationship between PCRR and other rejection types.

PCRR was associated with higher Banff chronic lesion scores and chronicity index but not activity scores. Graft survival and renal function were comparable with other forms of late rejection. Plasma-cell abundance correlated positively with CD8 T cells but negatively with B cells and plasmacytoid dendritic cells. PCRR biopsies showed enrichment for endothelial injury and fibrosis-related pathways and mast-cell/B-cell activation modules. The overall pathway signature of PCRR most closely resembled chronic-active T cell-mediated rejection. Principal component analysis, uniform manifold approximation and projection, and diffusion analysis revealed no distinct transcriptional cluster separating PCRR from other (late) rejection types.

PCRR exhibits chronic tissue injury, innate/humoral pathway activation, and shares the greatest molecular similarity with chronic-active T cell-mediated rejection, supporting its placement within the continuum of late kidney allograft rejection.