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-γ-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.

Figures

Figure 1.

Death-censored graft survival and longitudinal trends in GFR indicate progressive renal functional loss in KTx recipients with IF+i on T12 surveillance biopsies. (A) A Kaplan-Meier plot is shown for death-censored graft survival after T12 surveillance biopsy for KTx recipients with normal histology, IF alone, and IF+i at T12. Time of graft loss = time of return to dialysis or decline in estimated GFR to ioth and expressed as a percentage of the baseline value at 1 month (1m) are shown for 1, 12, 24, 36, and 48 months after transplantation. Groups were categorized by Banff '97 scoring of T12 surveillance biopsies as having normal histology (Normal), IF alone, and IF+i. †P ≤ 0.05 for normal versus IF+I; *P ≤ 0.05 for IF alone versus IF+i.

Figure 2.

Increased immunostaining for T cells and macrophages/DCs in T12 surveillance biopsies with IF+i by Banff '97 criteria. (A and B) Results are shown graphically for digital image analysis of tissue sections from T12 surveillance biopsies stained by immunoperoxidase for T cells (CD3; A) and macrophages/DCs (CD68; B). Sections were stained from groups categorized by Banff '97 scoring as having normal histology (Normal), IF alone, and IF+i. Results are shown as cells/mm2 of the total cortical interstitial space. ○, results for individual biopsies; thick bars, group mean results. P values indicate results of between-group comparisons by unpaired t test.