Diabetic Kidney Disease: From Pathogenesis to Multimodal Therapy -Current Evidence and Future Directions

Hui Zhang¹Hairui Zhao¹Keding Wang¹Bowen Qin¹Xiaojing Cai²Manyi Wu²Junhua Li^2*Jielian Wang^1*

• ¹Tianyou Hospital，Wuhan University of Science and Technology, Wuhan, China
• ²Tongii Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

Diabetic kidney disease (DKD) is a common and serious complication of diabetes mellitus, affecting 20–40% of individuals with diabetes. China bears the heaviest burden globally, with approximately 114 million diabetic patients. DKD has overtaken primary glomerular diseases as the leading cause of chronic kidney disease (CKD), significantly contributing to mortality in type 2 diabetes. The pathogenesis of DKD involves a complex network of mechanisms, including metabolic dysregulation, hemodynamic changes, inflammation, and fibrosis. Persistent hyperglycemia acts as the initiating factor, summarized by the concept of "one origin, multiple pathways, and interlinked loops." Recent studies highlight additional mechanisms such as gut microbiota dysbiosis, exosomal signaling, autophagy impairment, ferroptosis, and epigenetic alterations. Effective DKD management requires an integrated approach, combining pharmacologic, lifestyle, and interdisciplinary strategies. Evidence from large clinical trials emphasizes the importance of glycemic, blood pressure, and lipid control. Sodium restriction also plays a critical non-pharmacologic role. Modern management centers around a “four-pillar” strategy: (1) renin-angiotensin-aldosterone system inhibitors (RAASi), (2) sodium-glucose co-transporter-2 inhibitors (SGLT2i), (3) glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and (4) nonsteroidal mineralocorticoid receptor antagonists (ns-MRAs), supported by lifestyle interventions. Given DKD’s multifactorial nature, combination pharmacotherapy is central to current practice. Integrated use of RAASi, SGLT2i, GLP-1 RAs, and MRAs improves renal and cardiovascular outcomes. Survival models suggest triple therapy may reduce risks of cardiovascular events by 35%, heart failure hospitalization by 55%, and CKD progression by 58%. The emerging Renal Triple Therapy (RTT)—RAASi + SGLT2i + ns-MRA—shows particular promise. Integration of Traditional Chinese Medicine (TCM) with Western drugs is also promising; several multicenter RCTs report reduced proteinuria when combining TCM preparations with RAASi. Ongoing research continues to explore therapeutic targets for metabolic dysfunction, inflammation, and fibrosis. Strategies targeting gut microbiota and stem cell therapies show early potential. Future studies should focus on long-term RCTs, head-to-head comparisons, biomarker-guided precision therapy, molecular synergy of triple agents, real-world registries, and cost-effectiveness to advance DKD care and improve outcomes.