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

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 m2, 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.