Non-Proteinuric Diabetic Kidney Disease: A Comprehensive Review

Diabetic kidney disease (DKD) persists as the leading cause of chronic kidney disease (CKD) and often leads to end-stage renal disease (ESRD). Worldwide, 30-50% of patients with diabetes are affected by DKD, while DKD contributes to about half of ESRD. Previously, DKD had been defined based on overt proteinuria-that is, a urine albumin-to-creatinine ratio (UACR) above 300 mg/g-after a stage of microalbuminuria (UACR 30-300 mg/g). However, emerging data suggest that a significant number of patients develop renal functional decline without albuminuria, suggesting that DKD can occur in the absence of protein excretion. This phenotype of normoalbuminuric or non-proteinuric DKD (NA-DKD or NP-DKD) is emerging as an important clinical entity. It is characterized by a gradual decline in renal function, commonly with an annual reduction in estimated glomerular filtration rate (eGFR) > 3 mL/min/1.73 m² or an eGFR < 60 mL/min/1.73 m², while the UACR remains < 30 mg/g. Growing rates of NP-DKD expose limitations inherent in traditional models of DKD pathogenesis and underscore the need for diagnostic and therapeutic paradigms that are not reliant on albuminuria-only criteria. Here, we present a comprehensive review of the NP-DKD to guide a more inclusive model of DKD pathogenesis, its diagnosis, and therapy.