Fibrosis With Inflammation Predicts Kidney Transplant Failure

Fran Lowry

September 18, 2010

September 2, 2010 — The combination of fibrosis and inflammation at 1 year is associated with kidney transplant failure, even in recipients with no clinical risk factors for poor outcomes.

The finding, from a new study published online first in the Journal of the American Society of Nephrology, highlights the importance of early surveillance histology and analysis of immune pathways to identify these abnormalities and potentially thwart graft deterioration.

"Lack of knowledge regarding specific causes for late loss of kidney transplants hampers improvements in long-term allograft survival," Walter D. Park, MD, from Mayo Clinic, Rochester, Minnesota, and colleagues write. "We and others have sought to understand better the causes of late [kidney transplant] loss through intensive clinical testing and sequential surveillance ('protocol') allograft biopsies up to ≥5 years after transplantation."

In this study, the researchers sought to determine whether early histologic abnormalities could predict decline of renal function in a low-risk cohort.

They performed surveillance biopsies in 151 living-donor, tacrolimus-treated, and mycophenolate-treated recipients who had no clinical risk factors for poor graft survival. They found that 86 recipients (57%) had normal histologic findings, 45 recipients (30%) had fibrosis alone, and 20 recipients had both fibrosis and inflammation.

In the fibrosis plus inflammation group, immunohistochemistry confirmed increased numbers of interstitial T cells, macrophages, and dendritic cells, as well as an increased expression of transcripts related to innate and cognate immunity.

All groups were followed up for a mean of 4 years after their biopsy. Graft survival was lowest for recipients with fibrosis and inflammation, the researchers report. Overall, the rate of survival among recipients with fibrosis and inflammation was 85%, compared with 91% for those who had fibrosis alone and 97% for those with normal histologic findings.

In addition, the researchers found that there was a greater decrease in the glomerular filtration rate (GFR) in patients with fibrosis plus inflammation. By 48 months, the mean ± SD GFR had decreased to 44 ± 20 mL/min in those recipients, compared with 68 ± 24 (P = .01) in those with normal histologic findings and 64 ± 23 (P = .05) in those with fibrosis alone.

Without routine "protocol" biopsies, warning signs of graft rejection would go undetected until clinical abnormalities developed, senior study author Mark D. Stegall, MD, Mayo Clinic, Rochester, Minnesota, said in a statement. "The use of protocol biopsies allows for more detailed investigations of the intragraft environment. Such routine biopsies could provide a unique way to predict which kidney transplant recipients may be at increased risk for loss of kidney function or to identify potential targets for early preventive treatment."

The study was limited to patients who received kidneys from living donors, did not have risk factors for early rejection, and did not experience complications in the first year; therefore, the results of this study may not apply to other groups of transplant recipients, the study authors noted.

They conclude, "Early interventions aimed at altering rejection-like inflammation may improve long-term survival of kidney allografts."

The study was supported by State of Minnesota Partnership for Biotechnology and Medical Genomics award and by Science Foundation Ireland. The study authors have disclosed no relevant financial relationships.

J Am Soc Nephrol. Published online September 2, 2010.

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