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 ϭ 86) or fibrosis alone (n ϭ 45) on 1-year protocol biopsy had stable renal function between 1 and 5 years, whereas those with both fibrosis and inflammation (n ϭ 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-␥-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.

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“…Biopsies were classified as normal ( 3,12,19 There is also a paucity of literature on late protocol biopsies performed after 12 months in kidney transplant recipients, and our study fills the scarcity of knowledge in this area with our findings that late protocol SAR+IF/TA is significantly associated with rate of eGFR decline over long-term follow-up. Other studies have shown that interstitial fibrosis alone in early protocol biopsy may not predict graft functional decline in allografts with good baseline function; however, ongoing inflammation with interstitial fibrosis leads to graft functional decline, 9 which was also shown in our study where there was increasing percentage of recipients with fibrosis in the inflammation groups in late protocol biopsy and thus the presence of progressive fibrosis in inflamed kidneys predicted graft function. It could be speculated that, although early protocol biopsies are a useful tool, late protocol biopsies more likely have prognostic value in predicting long-term graft function.…”

“…7 Interstitial fibrosis and/or tubular atrophy on its own do not predict long-term renal allograft survival, but the combination of inflammation and fibrosis has been shown to be a surrogate marker for progressive graft functional decline. 8,9 Therefore, it becomes critical to examine the predictive ability of histologic abnormalities in early and in late protocol biopsies on long-term renal allograft function.…”

Infiltrating cellular pattern in kidney graft biopsies translates into forkhead box protein 3 up-regulation and p16INK4α senescence protein down-regulation in patients treated with belatacept compared to cyclosporin A

“…However, the related increased interstitial inflammation by IL-17A-producing CD4 + T cells observed in these biopsies suggests an ongoing persistent chronic alloimmune response, resulting in increased presence of inflammatory infiltrates and interstitial fibrosis and more senescence. Previous studies demonstrated that concomitant interstitial fibrosis and inflammation in protocol biopsies obtained in the first year correlates with later allograft dysfunction and loss [25]. Finally, belatacept treatment allowed maintaining a stable number of FoxP3 + cells at tissue level which, in turn, could contribute to preserve in-situ tolerance mechanisms [26].…”

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

“…Studies of mRNA and miR in kidneys with fibrosis reveal that many molecular changes associated with fibrosis are related to inflammation and matrix remodeling (21)(22)(23)(24)(25). 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).…”