Distinct mechanisms of diabetic nephropathy progression. Diabetic nephropathy is a heterogeneous condition that may involve diverse mechanisms. This may explain why a portion of patients with diabetic kidney disease continue to experience disease progression, despite optimal therapy with the current standard of treatments, including angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. These current therapies do not address the underlying mechanisms that drive the progression of diabetic kidney disease, which may include ongoing intrinsic tubular injury, manifested by elevated levels of KIM-1; endothelial/microvascular injury and chronic inflammation, manifested by elevated levels of TNFR1 and TNFR2; and maladaptive repair and unopposed inflammation, manifested by elevated levels of MCP-1. These biomarkers may discern distinct pathways of injury and inform therapeutic interventions for diabetic nephropathy. Abbreviations: KIM-1, kidney injury molecule-1; MCP-1, monocyte chemoattractant protein-1; TNFR, tumor necrosis factor receptor.