*Purpose: Transcriptomics based tests for ABMR are now available commercially. The reliability of these tests in clinical settings where allograft tissue is damaged by antibody-antigen complexes of infectious, paraneoplastic, and autoimmune origin has not been well investigated. We evaluated membranoproliferative glomerulonephritis (MPGN) as a prototype disease to address this issue. It is notable that endocapillary inflammation and glomerular basement membranes duplication seen in MPGN are respectively indistinguishable from glomerulitis and chronic transplant glomerulopathy that is seen in ABMR.

*Methods: RNA-seq was performed on laser capture micro-dissected glomeruli from 15 formalin fixed paraffin embedded (FFPE) renal biopsies, 5 with ABMR, 5 with systemic lupus erythematosus (SLE) associated MPGN, and 5 with stable (STA) renal function. DESeq2 package for R software was used to define differentially expressed genes (DEGs) between biopsy categories (fold change >2.0, p-value <0.05). Comparative expression of 95 genes that have been used in the literature to define the ABMR molecular signature was assessed by calculating the geometric mean of the fold change between ABMR, MPGN, and STA samples.

*Results: The mean gene expression of known ABMR transcripts was not significantly different between FFPE ABMR and FFPE MPGN biopsies analyzed by us. The upregulation of 26/95 known ABMR genes described in fresh frozen tissue could be confirmed in FFPE ABMR compared to FFPE STA biopsies (ANXA1, CCL3, EMP3, FCGR3A, IER5, PECAM1, THBD, CCL4, CXCL10, CXCL11, PLA1A, CD74, CDH5, CX3CR1, ECSCR, ENG, GNLY, ICAM2, IFNG, MALL, MCAM, MYBL1, VWF, PLK2, RHOJ, ADGRL4). The first 11/26 genes in this list could also be detected in FFPE MPGN biopsies. Eight transcripts upregulated in FFPE MPGN biopsies have been previously described as being ABMR specific (HYAL2, KLF2, KLF4, TNF, TRIB1, APOBEC3A, AGR2, IFI27). This is also true of three transcripts downregulated in our FFPE MPGN biopsies (SOST, CETP, CRHBP).

*Conclusions: There is substantial overlap between gene expression profiles of biopsies with ABMR and MPGN. These observations highlight why molecular signatures of biopsy pathology should be interpreted not in isolation but in the context of the underlying histologic findings. Both false positive and false negative molecular diagnoses can potentially underlie the increasingly recognized lack of concordance between molecular and histologic diagnoses rendered on the same biopsy.

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