Kidney transcriptomics signature of prospective rapid diabetic kidney disease progression

BACKGROUND: Previous cross-sectional transcriptomics studies on diabetic kidney disease (DKD) kidney tissue have shown correlations between gene expression and both disease status and kidney function at the time of biopsy; however, longitudinal data are scarce. METHODS: We utilized clinical follow-up data up to five years post-biopsy, linking the transcriptomes of diagnostic kidney biopsies to progression rates and outcomes in 19 patients with DKD. Patients were stratified into “rapid progressors” and “non-rapid progressors” based on clinical parameters (eGFR slope, CKD stage advancement, degree of albuminuria, composite outcome of kidney failure or 40% eGFR decline). Differential expression and pathway enrichment analyses were performed to identify dysregulated genes and pathways associated with rapid progression. RESULTS: We identified 265 genes in the glomeruli and tubulointerstitium that were significantly modulated between rapid and non-rapid DKD progression. Rapid progression-associated genes were enriched for well-established (extracellular matrix organization, inflammation) and novel pathways in the context of DKD (circadian rhythm, cytoskeleton reorganization, NOTCH signaling). CONCLUSIONS: This study illuminates kidney gene expression patterns that may be predictive of rapid progression in DKD and are distinct from those associated with cross-sectional kidney function. CLINICAL TRIAL NUMBER: Not applicable.