Identification of Putative and Model-Agnostic and Acute-Specific Biomarkers of Intrinsic Acute Kidney Injury Distinct from Chronic Kidney Disease

Acute kidney injury (AKI) has a profound clinical impact, contributing to both morbidity and mortality. Standard diagnostic methods, such as measuring serum creatinine (SCr) and urine output levels (UO), are insensitive to early injury. This study’s purpose was to identify AKI biomarkers conserved across models and determine these genes’ dysregulation in chronic kidney disease (CKD). We hypothesized that a core set of dysregulated genes is present across multiple RNA-Seq datasets, regardless of model, and that a subset of these gene products could be secreted into blood or urine. Six Mus musculus RNA-Seq datasets (2 per AKI model: ischemia reperfusion injury (IRI), cisplatin-induced injury (CDDP), and lipopolysaccharide-induced injury (LPS)) from NCBI were analyzed. All models represent intrinsic tubular injury etiologies of AKI. Fourteen genes were identified as highly upregulated across all AKI models, portraying a conserved acute-phase gene signature. Genevestigator® comparison revealed that most genes were downregulated in CKD datasets, suggesting acute injury responses are absent in chronic renal pathology. Of these, only three were secreted in blood and urine and are well known in AKI literature: LCN2, SDC1, and CD14. Kidney Tissue Atlas analysis showed that the area of CD14 expression was similar in healthy and AKI kidneys, while LCN2 and SDC1 expression shifted to different kidney cell clusters. These consensus genes appear to participate in complementary mechanistic pathways underlying AKI pathogenesis. Together, these findings indicate that AKI activates conserved acute and stress response mechanisms that are suppressed or absent in CKD, displaying a molecular distinction between AKI and CKD.