Introduction Podocyte injury is central to the pathogenesis of most glomerulonephritides (GN) and causes segmental glomerulosclerotic lesions that predict progression in IgA Nephropathy (IgAN). Recent advances in high-resolution microscopy and AI-assisted image analysis have enabled detailed quantification of podocyte foot process (FP) morphology. However, whether nanoscale podocyte morphometrics can predict disease progression or treatment response in GN has not been investigated.

Aim To evaluate whether nanoscale podocyte morphometric parameters predict clinical characteristics, disease progression, and treatment response in GN, with a focus on IgAN.

Method Podocyte morphometrics were analyzed in kidney biopsies from patients with GN using high-resolution microscopy and the deep learning-based tool Automatic Morphometric Analysis of Podocytes (AMAP). Four morphometric parameters were quantified: slit diaphragm length (SDL), FP area, FP circularity and FP perimeter. These parameters were correlated with clinical characteristics, conventional electron microscopy (EM) findings and longitudinal follow-up data.

Results The study included 37 patients with GN from Danderyd University Hospital (Stockholm, Sweden), with IgAN representing the largest diagnostic subgroup (n = 19). The median follow-up for the cohort was 3.0 years. SDL correlated significantly with urine albumin-to-creatinine ratio (uACR; p = 0.021), whereas conventional EM measurements did not (p = 0.22). Within the IgAN subgroup, lower SDL was associated with a steeper decline in eGFR, higher FP area with increased long-term proteinuria, and higher FP circularity with improvement in uACR during the first year. The association between lower SDL and eGFR decline remained as a trend in IgAN patients not treated with corticosteroids (p = 0.068) but was absent in the treatment group (p = 0.59).

Conclusion In this proof-of-concept study, nanoscale podocyte morphometrics demonstrated greater sensitivity than conventional EM in quantifying podocyte injury and predicting progression in IgAN. These findings suggest that high-resolution morphometrics may improve risk stratification in IgAN but require validation in larger, independent cohorts before clinical implementation.

The authors RE, AF, KB, LB, TB, HB & DUJ declare that they are co-founders and shareholders of Magnephy AB with RE, TB & DUJ also being board members. All other authors declare no conflict of interest.

We acknowledge microscopy support from the Advanced Light Microscopy (ALM) Facility, Royal Institute of Technology (KTH), SciLifeLab Solna, Sweden and the National Microscopy Infrastructure, NMI (VR-RFI 2023-00163). The work was supported by grants to HB from the Clinical Technology Development Project at SciLifeLab. RE and DUJ were funded by the Torsten Söderbergs Stiftelse, Stockholm, Sweden. RE were also funded by Stiftelsen Stig och Gunborg Westman for research on kidney disease, transplantation and organ donation. RE was supported through funding and clinical fellowship with AIDA, Analytic Imaging Diagnostics Areana, Linköping, Sweden. DUJ was supported by funding from University of Cologne, Germany. TB is supported by the German Research Foundation, TRR/CRU 422, project A1.

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Ethical approval for the BIONEF DS project has been received by the Swedish Ethical Review Authority with Dnr 2018/803-31 with approved amendments Dnr 2023-01265-02, Dnr 2024-01876-02, and and Dnr 2025-05680-02 pertaining to the present study. Written informed consent was obtained from all subjects at recruitment. The study was conducted in accordance with the Declaration of Helsinki.

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