Iron-Handling, Lipid-Oxygenation, and Hypoxia-Response Gene Expression in the Renal Cortex of Cats with Chronic Kidney Disease: An Analysis-Plan-Guided Secondary Analysis

Chronic kidney disease (CKD) is common in older cats, but cortical transcript-level relationships among hypoxia response, iron handling, and lipid oxygenation are poorly defined. This analysis-plan-guided, hypothesis-generating secondary analysis used public feline renal RNA-seq data (GSE303653). The internal plan fixed the gene panel, composite construction, primary inferential test, and quality-control thresholds before the review of the present expression results, but was not publicly registered. After technical quality control, 21 renal cortex samples from control, CKD 1/2, and CKD 3/4 cats were analyzed. A 23-gene panel and whole-transcriptome differential expression were evaluated using likelihood ratio testing as the primary panel-level screen, with pairwise DESeq2 contrasts, Spearman summaries, enrichment, medulla, composite, and marker-set analyses as secondary or exploratory context. VEGFA, FTL, and NCOA4 decreased with ordinal disease group, whereas ALOX5 and HIF1A increased; eight panel genes were stage-associated by likelihood ratio testing. The equal-weight composite was nonmonotonic. Advanced CKD enrichment was dominated by immune and inflammatory terms, while GPX4 and ferroptosis-pathway enrichment were not stage-significant. The findings support heterogeneous transcript-level remodeling, including ALOX5-associated inflammatory/lipid-oxygenation signal and HIF1A–VEGFA divergence, rather than evidence of ferroptotic cell death, pathway activation, or cell-specific mechanism.