Residual Renal Risk in Diabetic Nephropathy Despite Contemporary Therapies

Background/Objectives: Diabetic kidney disease (DKD) is the most prevalent form of chronic kidney disease and kidney failure globally. In the last decade, RAAS inhibitors, SGLT2 inhibitors, GLP-1-receptor agonists, and non-steroidal mineralocorticoid receptor antagonists have made significant advancements. However, despite the use of these drugs, patients with DKD often show a residual renal risk. In this narrative review, we synthesize current evidence on residual renal risk in DKD, focusing on underlying mechanisms, high-risk clinical phenotypes, and therapeutic gaps. Methods: A narrative review of current literature available in clinical trials, post hoc analysis studies, observational studies, and research into mechanisms of action or processes related to DKD was performed. Results: The central element of residual renal risk in DKD is persistent inflammation, fibrosis, tubulointerstitial injury/injury to both renal and vascular systems, and metabolic memory. These represent the four types of renal-related problems that have been identified. Non-albuminuric DKD, rapid progressors, late presenters with multiple comorbidities, tend to exhibit an extreme burden associated with some of these entities. Conclusions: The remaining risk factors that cannot be adequately addressed by current medical treatments represent major opportunities for improved clinical management, i.e., those at high-risk of kidney failure. Future research initiatives are required to further refine and improve therapeutic approaches for early intervention in patients with DKD. In addition, development of specific treatments targeting inflammation, fibrosis and metabolism in the kidney will lead to better therapeutic results and decreased risk of progressive loss of kidney function.