Hydronephrosis-Associated Renal Fibrosis: Clinical Validation of Spp1 as a Biomarker and Therapeutic Target

Renal fibrosis is a key driver of chronic kidney disease, often leading to end-stage renal disease (ESRD). Secreted phosphoprotein 1 (Spp1) is implicated in fibrotic processes, but its specific role in renal fibrosis, particularly associated with hydronephrosis, remains underexplored. This study investigates Spp1's involvement using transcriptomic analysis, machine learning, and clinical data integration.

Renal tissues from sham-operated mice with unilateral ureteral obstruction for 7 days were analyzed via transcriptome sequencing to identify differentially expressed genes (DEGs). Hub genes were identified through Weighted Gene Co-Expression Network Analysis and pathway enrichment. LASSO regression pinpointed potential biomarkers, with Spp1 validated in mouse and human samples through RT-PCR and immunohistochemistry. Clinical correlations were drawn from hydronephrosis patient data.

Transcriptomic analysis revealed 5,219 DEGs, highlighting key pathways including IL-17, TNF, and PI3K/AKT. Spp1 emerged as a significant biomarker, strongly associated with tubular injury and fibrosis markers such as neutrophil gelatinase-associated lipocalin. Logistic regression and receiver operating characteristic (ROC) analysis confirmed Spp1 and urinary transferrin (U-TRF) as predictors of severe hydronephrosis, with high diagnostic accuracy (area under the ROC curve: 0.898 for Spp1; 0.938 for U-TRF).

Spp1 is a critical mediator in renal fibrosis and a promising biomarker for assessing hydronephrosis severity. Its diagnostic value, particularly when combined with U-TRF, underscores the need for further research into Spp1-targeted therapies in renal fibrosis.