Work

A healthy donor kidney aging signature estimable from PAS histology and its association with progression of diabetic kidney disease

Year: 2026

Type: preprint

Abstract: Background. As kidneys age, their cells change in arrangement and gene expression. Whether these changes are also present in diabetic kidney disease (DKD), and whether they relate to how quickly kidney function is lost, is not known. Methods. Zero-time biopsies from 24 healthy living kidney donors (aged 36-66 years) and biopsies from 28 patients with DKD were profiled by single-cell-level spatial transcriptomics with a 5,101-gene panel. In the donors, we identified how cell neighborhoods and cell-type gene expression change with age and summarized the expression changes as tissue-aging scores. The scores were applied unchanged to DKD and related to the rate of eGFR decline after biopsy in 24 patients, with adjustment for age, sex, baseline eGFR, and proteinuria. We also estimated the scores from routine periodic acid-Schiff (PAS) slides, using models that did not include the patient being scored. Results. In older donors, immune cells were less often found next to tubular epithelium, and contacts between endothelial cells and podocytes and between stromal and epithelial cells were fewer, although cell proportions changed little. Expression of stress-response and cell-cycle regulators (FOXO3, CDKN1A, BBC3, PINK1, IRAK1, SOCS1) increased. Changes in cell contacts in DKD tissue largely followed the same direction as those in older donors. In DKD, higher tissue-aging scores were associated with faster eGFR loss independently of age, sex, baseline eGFR, and proteinuria (overall score, partial ρ = −0.61); this held for tubular, endothelial, immune, and parietal epithelial cell scores but not for the podocyte score. Scores estimated from PAS slides correlated with the transcriptomic scores (mean ρ = 0.62) and were also associated with faster eGFR loss (partial ρ, −0.44 to −0.56). Conclusions. Healthy kidney aging involves a selective loss of cell contacts together with a coordinated stress-response program. DKD kidneys that carry this aging phenotype lose function faster, and the phenotype can be estimated in part from the routine diagnostic PAS slide.

Source: medRxiv

DOI: 10.64898/2026.11.05.26367347