Transcriptomic Analysis of Pathways Linking Acute Kidney Injury to Chronic Kidney Disease Progression and Neuropsychiatric Outcomes

Chronic kidney disease (CKD) affects an estimated 37 million adults in the United States, with approximately 15% of the population showing evidence of disease. Acute kidney injury (AKI) is a major factor in CKD development and its advancement to end-stage kidney disease. In addition to its renal effects, CKD is associated with neuropsychiatric complications such as depression, anxiety, and cognitive impairment. These symptoms reduce quality of life and are linked to prolonged hospitalization, decreased adherence to treatment, and increased mortality. Although renal injury, systemic inflammation, and the accumulation of metabolic waste are known to disrupt brain homeostasis, the mechanisms connecting AKI-induced renal damage to long-term neurological dysfunction remain poorly understood. This study aimed to advance understanding of the molecular pathways driving the transition from AKI to CKD and to identify systemic processes that may contribute to downstream effects on brain function. We analyzed 16 published transcriptomic datasets on AKI and CKD across human, rat, and mouse models. Differentially expressed genes (DEGs) were identified using a cutoff of at least 1.5-fold change, and KEGG pathway enrichment analysis was performed using p and q value thresholds of 0.05 to determine conserved and unique pathways across species. We identified five overarching pathway categories: cellular processes, metabolism, organismal systems, genetic information processing, and environmental information processing. Within these categories, 226 conserved pathways were associated with metabolic disturbances, immune dysregulation, and cellular stress responses, including IL-17 and PI3K–Akt signaling. We also identified 141 pathways enriched uniquely in CKD models but not AKI, including ErbB signaling, necroptosis, NOD-like receptor signaling, and pathways related to neurotransmitter-specific synapses and synaptic plasticity, such as long-term potentiation and long-term depression. These CKD-unique pathways may suggest mechanisms through which chronic kidney injury influences neural function. These findings highlight conserved maladaptive pathways that may drive AKI-to-CKD progression and identify molecular signatures that may contribute to the neuropsychiatric disturbances frequently observed in patients with CKD. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.