Podometrics Could Guide IgAN Treatment While Reducing Invasiveness

New research suggests podometrics might serve as a less invasive marker for monitoring disease, helping to guide treatment strategies in patients with IgA Nephropathy (IgAN).1

Podometrics quantifies podocytes, specialized epithelial cells essential for maintaining the glomerular filtration barrier. The podocyte depletion hypothesis posits that progressive podocyte loss contributes to disease progression, potentially leading to glomerulosclerosis and kidney failure.2

The Oxford Classification of IgAN, developed in 2009, identified 4 histopathologic markers: mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T), with prognostic significance. The 2017 revision added crescents (C), forming the MEST-C scoring system, which remains widely used in clinical practice. These 5 key pathogenic features have demonstrated substantial importance in clinical practice.3

“IgAN is the most prevalent primary glomerular disease worldwide; however, its heterogeneous clinical course complicates prognostic prediction,” wrote study investigator Shoko Ochiai, from the University of Miyazaki, Japan, and colleagues. “The recently proposed ‘podocyte depletion hypothesis’ has been suggested as a potential predictor of renal outcomes in various glomerular diseases. Nevertheless, its correlation with the Oxford classification or the pre-biopsy eGFR slope remains unclear.”1

In this retrospective, single-center observational cohort study, investigators aimed to address this research gap by evaluating the associations between podometric parameters, Oxford MEST-C scores, and pre-biopsy estimated glomerular filtration rate (eGFR) decline.1

Ochiai and colleagues analyzed kidney biopsy specimens using a quantitative, cell-based morphometric approach to measure podocyte number, density, size, and depletion, assessed alongside the Oxford classification. Based on pre-biopsy eGFR slope, patients were categorized into 2 groups: “decline” <60 mL/min/1.73 m² and “non-decline” ≥60 mL/min/1.73 m². 1

Investigated measured urinary messenger RNA (mRNA) levels of podocyte-specific markers nephrin (NPHS1) and podocin (NPHS2), components of the slit diaphragm and cytoskeletal anchoring complex, as markers of podocyte injury or detachment. Independent factors associated with eGFR decline were identified using multivariate nominal logistic regression analysis.1,2

The study included 101 patients with IgAN treated at the University of Miyazaki, Japan. Urinary mRNA measurements were available for 94 patients.1

The results revealed patients with established markers of chronic kidney damage, such as segmental sclerosis (S1) and tubular atrophy/interstitial fibrosis (T1/2), had decreased podocyte density and number. Additionally, investigators found an association between elevated podocy markers, NPHS1 and NPHS2, with E1 and C1/C2 lesions.1

In patients classified as “decline”, investigators observed decreased density and number of podocyte cells, while having an increased podocyte volume compared to the “non-decline” group. Larger podocyte volume may reflect compensatory hypertrophy, which has been linked to podocyte detachment and glomerulosclerosis in prior studies.1,4

In multivariate analysis, decreased podocyte number was the only factor independently associated with eGFR decline, according to investigators.1

“The podocyte number at the time of kidney biopsy was associated with the pre-biopsy estimated glomerular filtration rate decline slope in patients with immunoglobulin A nephropathy. Furthermore, elevated urinary podocyte mRNA levels suggested the presence of E and C lesions,” concluded investigators. “Podometrics may serve as a potentially less invasive marker for monitoring disease activity and guiding treatment strategies.”1

References

1. Ochiai S, Kikuchi M, Kaikita K, Fujimoto S. Association of Podometric Parameters with the Oxford MEST-C Score and Pre-Treatment eGFR Slope in Patients with IgA Nephropathy. Kidney360. Published online December 18, 2025. doi:https://doi.org/10.34067/kid.0000001095

2. Urinary podocyte markers of disease activity, therapeutic efficacy, and long-term outcomes in acute and chronic kidney diseases — Scientific Figure on ResearchGate. ResearchGate. https://www.researchgate.net/figure/Podocyte-depletion-hypothesis-Podocyte-injury-and-depletion-have-different-causes-in_fig1_378479780. Accessed December 22, 2025.

3. Ellahe S, Abolfazl A, Ashouri S, et al. Correlation between MEST-C score in kidney biopsy of IgA nephropathy patients with prognosis. Journal of Renal Injury Prevention. 2024;13(3):e32275-e32275. doi:https://doi.org/10.34172/jrip.2024.32275

4. Puelles VG, Douglas-Denton RN, Cullen-McEwen LA, et al. Podocyte Number in Children and Adults: Associations with Glomerular Size and Numbers of Other Glomerular Resident Cells. Journal of the American Society of Nephrology. 2015;26(9):2277-2288. doi:https://doi.org/10.1681/asn.2014070641