Can Podocyte Number and Density Predict the Response to Therapy in Patients with Primary FSGS?

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Background: Podocyte loss is a key event in primary focal segmental glomerulosclerosis (FSGS). Common first-line therapy for patients with primary FSGS involves steroid therapy with or without blood pressure control; however 40-70% of patients achieve no remission. Animal studies have shown that treatment efficacy is achieved partly through preservation of podocyte number, as well as podocyte protective effects. Animal studies have also determined that podocyte number and density are predictive of FSGS severity. Therefore, this study aimed to determine if podocyte number and density can predict the response to therapy in patients with primary FSGS. Methods: A retrospective cohort study of renal biopsies was conducted from 2009-2020 in Melbourne, Australia at a tertiary hospital (Monash Medical Centre). Patients diagnosed with primary FSGS were screened (n=84). Patients were excluded for lack of consent for samples to be used for research purposes (n=38), risks of other forms of FSGS (n=13), insufficient clinical data available (n=2), no biopsy tissue available (n=7) or <6 glomerular profiles available in the biopsy (n=5). Included patients were allocated into groups of treatment responders (n=11) or non-responders (n=8) based on urinary/serum data 6 months following initial diagnosis and commencement of treatment. Biopsies were immunofluorescently stained for podocyte-specific markers. Model-based stereology was used to estimate podometrics. Sections were re-stained with PAS to measure the glomerulosclerotic index (GSI). Results: Podocyte number per glomerulus in responders (347 (215-606); median (IQR)) was 45% higher than in non-responders (190; 143-263) (P=0.03). Podocyte density in responders (76; 58-142 per 106μm3 of glomerular volume) was similar to non-responders (66; 44-88 per 106μm3 of glomerular volume) (P=0.38). GSI was significantly higher in non-responder patients (1.1; 0.6-2.3) than responders (0.6; 0.2-0.9) (P=0.04), and was significantly and negatively correlated with podocyte number (r = -0.64; P=0.003) and podocyte density (r = -0.48; P=0.04). Conclusions: Podocyte number per glomerulus in diagnostic renal biopsies could be used as a predictor of treatment response for patients with primary FSGS. Funding: Government Support - Non-U.S.

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