Molecular Correlates of Scarring in Kidney Transplants: The Emergence of Mast Cell Transcripts

Abstract

In the Banff consensus, infiltrates in areas of scarring are ignored. This study aimed to characterize the molecular correlates and clinical significance of scarring and inflammation in scarred areas.We assessed the extent of interstitial infiltrates, tubulitis and scarring in 129 clinically indicated renal allograft biopsies, and correlated the results with microarray expression data and allograft survival. Findings were validated in 50 additional biopsies.Transplants with scarring had a worse prognosis if the scarred area showed infiltrates. Infiltration in unscarred and scarred areas was associated with reduced death censored graft survival. In microarray analysis, infiltration in unscarred areas strongly (>r ± 0.4) correlated with 484 transcripts associated with cytotoxic T cells, interferon-gamma, macrophages and injury. Scarring correlated with a distinct set of 172 transcripts associated with B cells, plasma cells, and others of unknown significance. The strongest correlation was with four mast cell transcripts. In biopsies with scarring, high expression of mast cell transcripts was associated with reduced graft survival and poor functional recovery.In renal allograft biopsies, infiltrates in scarred areas have implications for poor outcomes. Scarring is associated with a distinct pattern of inflammatory molecules, including B cell/immunoglobulin but particularly mast cell-associated transcripts, which correlated with poor outcomes.

An Integrated View of Molecular Changes, Histopathology and Outcomes in Kidney Transplants

“…(5). The molecular phenotype is reviewed in a companion paper (6) but the lessons from the molecular studies are incorporated here to propose an integrated approach to interpreting biopsy findings and outcomes, (13), mast cell transcripts (14) and FOXP3 mRNA (15). (22).…”

Relationships among injury, fibrosis, and time in human kidney transplants

“…We previously reported that fibrosis in human kidney transplants was associated with transcripts expressed in certain inflammatory cells: mast cell transcripts (MCATs) such as carboxypeptidase 3 (CPA3) (26) and immunoglobulin transcripts (IGTs) representing plasma cells (27). Such transcripts do not correlate with TCMR or ABMR.…”

“…27; MCATs, ref. 26; and AKI and FICOL transcripts, ref. 14); then we explored all fibrosis-associated transcript changes, correcting for the time of the biopsy after transplant (TxBx).…”

Chronic Calcineurin Inhibitor Nephrotoxicity

“…As might be expected, the noncompliant patients demonstrated more inflammatory changes but were also found to have more interstitial fibrosis and identical degrees of arteriolar hyalinosis than the compliant patients. In kidney transplantation, it is now becoming apparent that the presence of fibrosis and atrophy may not predispose to graft failure; a more critical variable is evidence of ongoing inflammation (47,48). In a recent report from the Deterioration of Kidney Allograft Function study group (49), 60% of patients with allograft dysfunction 7 yr after transplantation had donor-specific antibody, C4d staining, or both.…”