Abstract
BACKGROUND: Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease. Conventional research focuses on renal-intrinsic pathophysiology, yet emerging evidence reveals bidirectional neuroimmune communication along the brain-kidney axis critically modulates DKD progression. Emerging evidence reveals that bidirectional neuroimmune communication along the brain-kidney axis critically modulates DKD progression through inflammatory, cholinergic, and metabolic pathways5, yet the clinical translational potential remains incompletely defined. OBJECTIVE: To comprehensively evaluate the neuroimmune regulatory mechanisms of the brain-kidney axis in DKD, identify key therapeutic targets (TNF-α/NF-κB pathway, α7nAChR, SGLT inhibitors, GLP-1 receptor agonists), and assess their efficacy and central nervous system safety profiles. METHODS: We performed a comprehensive literature search of PubMed, Cochrane Library, Web of Science, and Embase from inception to November 2025, supplemented by hand-searching reference lists. Studies investigating neuroimmune mechanisms, therapeutic interventions, or multimodal imaging biomarkers related to the brain-kidney axis in DKD were critically appraised and narratively synthesized using a thematic analysis approach. Evidence quality was evaluated using GRADE criteria. RESULTS: We identified three core pathways: TNF-α/NF-κB-mediated neuroinflammation amplification (primarily preclinical evidence), α7nAChR-driven cholinergic anti-inflammatory responses (very low-quality evidence), and SGLT-dependent metabolic modulation. High-quality randomized controlled trials demonstrate that SGLT2 inhibitors reduce hard renal endpoints by 30-40%, while GLP-1 receptor agonists improve renal outcomes but raise concerns regarding autonomic dysfunction and neuropathy. Multimodal imaging reveals correlative brain-kidney functional connectivity alterations, supporting axis involvement in DKD pathogenesis; however, the proposed ‘brain-kidney connectivity score’ remains an exploratory concept that requires validation through standardized multimodal registration and algorithm development. CONCLUSION: The brain-kidney axis provides a novel framework for DKD pathophysiology. While high-quality evidence supports SGLT2 inhibitors and GLP-1 receptor agonists for renoprotection, central nervous system safety monitoring remains critical. Future research must validate dynamic multimodal imaging tools and develop personalized combination therapeutic strategies to optimize clinical translation.