A Clinically Occult Tubular Phenotype in Type 2 Diabetes Despite Normoalbuminuria and Preserved eGFR : Multiscale Human Kidney Evidence

ABSTRACT Aims To determine the prevalence of a low‐molecular‐weight protein (LMWP)‐defined tubular phenotype in adults with Type 2 diabetes, normoalbuminuria and preserved estimated glomerular filtration rate (eGFR), its relation to UACR, and its human kidney context. Materials and Methods We studied 4046 adults with Type 2 diabetes, UACR < 30 mg/g, eGFR ≥ 60 mL/min/1.73 m 2 , and paired morning urinary α1‐microglobulin (α1MG) and β2‐microglobulin (β2MG). The phenotype required α1MG > 12 mg/L and β2MG > 0.20 mg/L. We tested associations with UACR and performed medication, admission‐context, high‐eGFR and liver‐function sensitivity analyses. Independent microdissected tubular, single‐cell/single‐nucleus and CosMx datasets were analysed. Results The phenotype was present in 797 patients (19.7%). UACR alone did not discriminate the phenotype (AUC 0.466, 95% CI: 0.443–0.489), and ln(UACR+1) was not associated with it after clinical adjustment (OR: 0.873, 95% CI: 0.710–1.075; p = 0.201). Medication adjustment produced a similar estimate (OR: 0.871, 95% CI: 0.708–1.072; p = 0.191), with consistent findings in the other sensitivity analyses. In microdissected tubules, a 10‐gene injury score was higher in DKD ( p < 0.001); sample‐level injured proximal‐tubular fractions were highest in DKD in the single‐cell atlas ( p = 0.029), and spatial profiling resolved five injured proximal‐tubular subclusters. Conclusions An LMWP‐defined tubular phenotype was present in nearly one in five adults with Type 2 diabetes despite normoalbuminuria and preserved eGFR, and was poorly captured by UACR. Independent human kidney datasets showed related proximal‐tubular injury‐associated programmes with marked cellular and spatial heterogeneity. These findings support tubular phenotyping as a complementary approach to kidney assessment in Type 2 diabetes and warrant prospective validation.