Glomerular TRPC5 and Palladin immunohistochemical profiling in focal segmental glomerulosclerosis: tissue heterogeneity and exploratory clinical associations (PRIME-PATH I)
Year: 2026
Type: article
Study design: Observational Study
Abstract: Introduction Focal segmental glomerulosclerosis (FSGS) is a shared histopathologic pattern arising from biologically diverse podocyte injuries. Transient receptor potential canonical 5 (TRPC5) has been implicated in calcium–cytoskeletal signaling and entered clinical evaluation, whereas Palladin is an actin-associated scaffold involved in cytoskeletal organization. Their glomerular immunohistochemical patterns in human FSGS remain poorly characterized. Methods In this single-center retrospective biopsy cohort, 182 adults with biopsy-diagnosed FSGS between 2010 and 2020 were screened; 103 with adequate archived tissue, at least two evaluable glomeruli, and at least 24 months of follow-up comprised the analytic cohort. TRPC5 was scored as 0 (nuclear-only/no reproducible capillary-granular staining), 1 (discontinuous capillary-granular staining), or 2 (continuous/diffuse capillary-granular staining); scores 1–2 were grouped as TRPC5-positive. Palladin showed capillary-granular immunoreactivity in all evaluable biopsies and was classified as discontinuous or diffuse. Twenty-four-month treatment response was based on 24-hour urinary protein excretion. Poor response was the primary clinical outcome; kidney failure (maintenance dialysis or kidney transplantation) was evaluated during follow-up. Results TRPC5 immunoreactivity was present in 70/103 biopsies (68.0%) and absent in 33/103 (32.0%); Palladin staining was diffuse in 75/103 (72.8%) and discontinuous in 28/103 (27.2%). Poor response occurred in 54/103 (52.4%) and kidney failure in 33/103 (32.0%). TRPC5-positive patients more often had poor response (64.3% vs. 27.3%; P < 0.001) and kidney failure (42.9% vs. 9.1%; P < 0.001). In the primary adjusted model, TRPC5 positivity was associated with poor response (OR, 3.28; 95% CI, 1.13–9.52; P = 0.029) and kidney failure (OR, 5.51; 95% CI, 1.25–24.23; P = 0.024). Estimates were similar after adjustment for global glomerulosclerosis but attenuated and imprecise after IFTA adjustment ( n = 70). Palladin distribution was not independently associated with either outcome and did not improve model fit. Conclusion PRIME-PATH I identifies heterogeneous glomerular TRPC5 immunoreactivity as a tissue-level phenotype within morphologically defined FSGS, with Palladin providing complementary cytoskeletal staining-distribution information. These associations are hypothesis-generating, and independent prognostic value remains uncertain after accounting for chronic structural injury. The findings do not establish functional TRPC5 activation or treatment predictiveness but support prospective studies integrating etiologic classification, cell-specific localization, pathway activity, and therapeutic response.
Source: Frontiers in Medicine
Authors: Zeynep Ural, Betül Ogüt, Ipek Isık Gönül, Galip Güz
Institution: Gazi University
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
Funder: Gazi Üniversitesi
OpenAlex ID: W7223175262