Fibrosis with inflammation at one year predicts transplant functional decline

Abstract

Lack of knowledge regarding specific causes for late loss of kidney transplants hampers improvements in long-term allograft survival Kidney transplants with both interstitial fibrosis and subclinical inflammation but not fibrosis alone after 1 year have reduced survival This study tested whether fibrosis with inflammation at 1 year associates with decline of renal function in a low risk cohort and characterized the nature of the inflammation We studied 151 living donor, tacrolimus/mycophenolate-treated recipients without overt risk factors for reduced graft survival Transplants with normal histology (n = 86) or fibrosis alone (n = 45) on 1-year protocol biopsy had stable renal function between 1 and 5 years, whereas those with both fibrosis and inflammation (n = 20) exhibited a decline in GFR and reduced graft survival Immunohistochemistry confirmed increased interstitial T cells and macrophages/dendritic cells in the group with both fibrosis and inflammation, and there was increased expression of transcripts related to innate and cognate immunity Pathway- and pathologic process specific analyses of microarray profiles revealed that potentially damaging immunologic activities were enriched among the overexpressed transcripts (e g, Toll-like receptor signaling antigen presentation/dendritic cell maturation IFN-gamma-inducible response, cytotoxic T lymphocyte associated and acute rejection associated genes) Therefore, the combination of fibrosis and inflammation in 1-year protocol biopsies associates with reduced graft function and survival as well as a rejection-like gene expression signature, even among recipients with no clinical risk factors for poor outcomes Early interventions aimed at altering rejection like inflammation may improve long term survival of kidney allografts