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Previous Volume 349:125-138 July 10, 2003 Number 2 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Supplementary Material Editorial by Marsden, P. A. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background The causes and clinical course of acute rejection vary, and it is not possible to predict graft outcome reliably on the basis of available clinical, pathological, and genetic markers. We hypothesized that previously unrecognized molecular heterogeneity might underlie some of the variability in the clinical course of acute renal allograft rejection and in its response to treatment.

Methods We used DNA microarrays in a systematic study of gene-expression patterns in biopsy samples from normal and dysfunctional renal allografts. A combination of exploratory and supervised bioinformatic methods was used to analyze these profiles.

Results We found consistent differences among the gene-expression patterns associated with acute rejection, nephrotoxic effects of drugs, chronic allograft nephropathy, and normal kidneys. The gene-expression patterns associated with acute rejection suggested at least three possible distinct subtypes of acute rejection that, although indistinguishable by light microscopy, were marked by differences in immune activation and cellular proliferation. Since the gene-expression patterns pointed to substantial variation in the composition of immune infiltrates, we used immunohistochemical staining to define these subtypes further. This analysis revealed a striking association between dense CD20+ B-cell infiltrates and both clinical glucocorticoid resistance (P=0.01) and graft loss (P<0.001).

Conclusions Systematic analysis of gene-expression patterns provides a window on the biology and pathogenesis of renal allograft rejection. Biopsy samples from patients with acute rejection that are indistinguishable on conventional histologic analysis reveal extensive differences in gene expression, which are associated with differences in immunologic and cellular features and clinical course. The presence of dense clusters of B cells in a biopsy sample was strongly associated with severe graft rejection, suggesting a pivotal role of infiltrating B cells in acute rejection.

Source Information

From the Departments of Pediatrics (M.S., M.-S.C., S.-C.H., T.S., O.S.), Pathology (N.K., M.M.), and Surgery (O.S.), Stanford University, Stanford, Calif.

Address reprint requests to Dr. Sarwal at the Department of Pediatrics, G320, 300 Pasteur Dr., Stanford, CA 94305, or at msarwal{at}stanford.edu.

Full Text of this Article

Related Letters:

Molecular Heterogeneity in Acute Renal Allograft Rejection and DNA Microarrays
Wright P. K., Raine C.
Extract | Full Text | PDF  
N Engl J Med 2003; 349:2269, Dec 4, 2003. Correspondence

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