Drug failure in diabetic kidney disease: translational barriers, target validation and trial de-risking strategies.

Diabetic kidney disease (DKD) remains a difficult therapeutic setting in nephrology, metabolism and clinical pharmacology. Standard care has moved from glucose- and blood-pressure-centred treatment toward disease-modifying therapy built around renin-angiotensin-aldosterone system (RAAS) blockade, sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists and nonsteroidal mineralocorticoid receptor antagonism. Yet DKD drug development is also defined by repeated translational failure. Many agents with strong mechanistic rationale have failed to improve hard kidney outcomes, have produced biomarker signals that did not mature into durable clinical benefit, or have been limited by hyperkalaemia, fluid retention, heart failure, acute kidney injury, anaemia or systemic immunosuppression. This Review treats failure as a source of translational information. We compare successful development paths for SGLT2 inhibitors, finerenone and semaglutide with constrained or unsuccessful programmes involving dual RAAS blockade, bardoxolone methyl, endothelin receptor antagonists, apoptosis signal-regulating kinase 1 (ASK1) inhibition, immunomodulation, sulodexide and pyridoxamine. Across these examples, recurring vulnerabilities emerge in human target validation, animal-to-human translation, renal exposure, target engagement, pharmacodynamic biomarker selection, patient enrichment, endpoint choice and safety-constrained dosing. We propose a de-risking framework that prioritizes human tissue evidence, renal cell-specific causal validation, pharmacokinetic and pharmacodynamic integration, mechanism-aligned biomarkers, adaptive trial design and biology-guided patient selection.