Kidney transcriptomics signature of prospective rapid diabetic kidney disease progression

Abstract

Previous cross-sectional transcriptomic studies on diabetic kidney disease (DKD) kidney tissue have shown correlations between gene expression and both disease status and kidney function at time of biopsy, but longitudinal data is scarce. 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 DKD patients. Patients were stratified into “rapid progressors” and “non-rapid progressors” based on clinical parameters (eGFR slope, CKD stage advancement, degree of albuminuria, composite 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. We identified 265 genes in glomeruli and tubulointerstitium that were significantly modulated in rapid vs non-rapid DKD progression. Rapid progression-associated genes showed enrichment for well-established (extracellular matrix organization, inflammation) as well as novel pathways in the context of DKD (circadian rhythm, cytoskeleton reorganization,NOTCHsignaling). 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.