Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling

Area of Science:

• Nephrology
• Immunology
• Genomics

Background:

• Acute renal allograft rejection presents variable clinical courses and outcomes, challenging reliable prediction using current markers.
• Hypothesized molecular heterogeneity underlies variability in acute rejection and treatment response.

Purpose of the Study:

• To investigate molecular heterogeneity in acute renal allograft rejection using gene-expression profiling.
• To identify distinct subtypes of acute rejection and their clinical correlations.

Main Methods:

• DNA microarrays analyzed gene-expression patterns in normal and dysfunctional renal allograft biopsy samples.
• Exploratory and supervised bioinformatic methods analyzed gene-expression profiles.
• Immunohistochemical staining characterized immune infiltrates.

Main Results:

• Distinct gene-expression patterns differentiated acute rejection, drug toxicity, chronic nephropathy, and normal kidneys.
• Acute rejection exhibited at least three gene-expression subtypes, differing in immune activation and proliferation, yet indistinguishable by light microscopy.
• Dense CD20+ B-cell infiltrates strongly correlated with glucocorticoid resistance (P=0.01) and graft loss (P<0.001).

Conclusions:

• Gene-expression analysis offers insights into renal allograft rejection biology and pathogenesis.
• Subtypes of acute rejection, molecularly distinct despite similar histology, show varied clinical courses.
• Dense B-cell infiltrates in biopsies are associated with severe rejection, indicating a critical role for B cells.