Deep endotyping of kidney damage in type 2 diabetes: ex uno, plures

Kidney damage in type 2 diabetes exemplifies a complex, multisystemic disorder with substantial heterogeneity in clinical trajectory, histopathology, and molecular drivers. Traditional clinical markers, albuminuria and glomerular filtration rate, fail to capture this diversity because many patients follow atypical trajectories such as nonalbuminuric progression, rapid estimated glomerular filtration rate decline, or regression of albuminuria. Deep endotyping approaches integrating clinical dynamics, renal histopathology, and multi-omics profiling can define biologically distinct endotypes. Transcriptomic, proteomic, metabolomic, and single-cell spatial analysis reveal molecular signatures of autoimmunity, inflammation, fibrosis, and cellular injury associated with variable prognosis and therapeutic response. This heterogeneity extends systemically, with diabetic kidney impairment intersecting with cardiac and hepatic dysfunction, retinopathy, neuropathy, and vascular disease. A holistic, system-level approach, evaluating cardio-liver-kidney-retinal-vascular endotypes in tandem, is therefore required both for translational science and for comprehensive patient care. Recently approved and emerging therapies modulate inflammation, oxidative stress, autoimmunity, and fibrosis, offering pleiotropic benefits that must be aligned with the disease pathobiology of type 2 diabetes endotypes. This approach underscores the need to transition from uniform treatment toward precision medicine. This mini review highlights how integration of kidney biopsy, omics, imaging, and multiorgan profiling can refine endotypes in type 2 diabetes, advancing personalized therapy. Shifting from a "one disease" model to a "many pathways" framework represents a necessary evolution in the management of kidney damage in type 2 diabetes.