Diabetic kidney disease with normoalbuminuria: clinical phenotype and contemporary approach

Abstract

Diabetic kidney disease (DKD) has traditionally been described as a condition in which increasing albuminuria precedes a progressive decline in glomerular filtration rate. Evidence accumulated over the past two decades has challenged this classical concept by demonstrating that a substantial proportion of patients with type 2 diabetes mellitus (T2DM) develop chronic kidney disease with reduced estimated glomerular filtration rate (eGFR) despite persistently normal urinary albumin excretion. This phenotype is commonly referred to as normoalbuminuric or non-albuminuric diabetic kidney disease and is usually defined by an eGFR <60 mL/min/1.73 m² in the presence of a urinary albumin-to-creatinine ratio (UACR) <30 mg/g, after alternative causes of kidney dysfunction have been considered. Epidemiological studies indicate that this phenotype accounts for a substantial proportion of patients with T2DM and impaired kidney function. Compared with classical albuminuric DKD, affected patients tend to be older, are more frequently female, and generally have lower blood pressure and HbA1c levels and a lower prevalence of diabetic retinopathy. Histopathological studies demonstrate marked heterogeneity, with vascular and tubulointerstitial injury sometimes predominating over typical diabetic glomerular lesions. Although kidney function generally declines more slowly than in albuminuric DKD, reduced eGFR remains an independent marker of adverse kidney and cardiovascular outcomes. Thus, normal urinary albumin excretion should not be interpreted as evidence of preserved kidney health. Contemporary assessment of patients with diabetes requires simultaneous evaluation and longitudinal monitoring of both UACR and eGFR, careful exclusion of non-diabetic kidney disease, and implementation of appropriate cardiorenal protective strategies. Sodium-glucose cotransporter 2 inhibitors are particularly relevant because their kidney-protective effects extend to patients with low or normal levels of albuminuria.