Abstract
Background
Some patients with diabetic kidney disease (DKD) experience rapid loss of kidney function despite minimal proteinuria; however, the cellular and pathological features associated with this phenotype remain unclear. In this study, we aimed to characterize the cell-specific transcriptional and pathological alterations associated with sustained rapid kidney function decline in low-proteinuric DKD.

Methods
We performed single-cell RNA sequencing of kidney biopsy specimens from three patients with low-proteinuric DKD with sustained rapid kidney function decline (DKD-RD), defined by a urinary protein-to-creatinine ratio < 0.15 g/g creatinine, an absolute estimated glomerular filtration rate (eGFR) slope < − 5 mL/min/1.73 m²/year, and an annual relative eGFR decline > 10% over at least 2 years. Non-diabetic kidney tissues from two nephrectomy specimens served as controls. Donor-level pseudobulk differential-expression and pathway analyses were integrated with histopathological and ultrastructural findings. We also conducted an exploratory comparison with a published classical/proteinuric DKD dataset.

Results
Analysis of 35,352 cells showed lower expression of genes related to endothelial differentiation, vascular integrity, and vascular development in DKD-RD, accompanied by higher NOX4 expression and reactive oxygen species-related programs. Tubular cells exhibited segment-specific remodeling, characterized by increased expression of CUBN and LRP2 in proximal tubular cells alongside reduced expression of several sodium-dependent solute transporter genes. Glomerular lesions were mild and heterogeneous; electron microscopy showed focal endothelial abnormalities in some cases, while podocyte foot processes were largely preserved. Immune cell analysis revealed no evidence of a uniform inflammatory activation state. Comparison with a published classical/proteinuric DKD dataset showed limited concordance in disease-associated transcriptional patterns.

Conclusions
Low-proteinuric DKD with sustained rapid kidney function decline is associated with endothelial and tubular transcriptional alterations without uniform advanced glomerular filtration-barrier lesions. These findings raise the possibility that this phenotype has a transcriptional profile distinct from that of classical/proteinuric DKD, although confirmation in larger cohorts is needed.