Biological heterogeneity of obesity-related nephrolithiasis risk: an integrative transcriptomic and circulating biomarker study

Abstract Nephrolithiasis and obesity are common and recurrent public health problems, yet current obesity-based risk assessment does not identify which individuals are most susceptible to stone formation. We sought circulating markers linked to obesity-related stone susceptibility and risk heterogeneity rather than a diagnostic assay for immediate clinical use. Public adipose and renal papillary transcriptomic datasets were integrated with a curated human secretome resource. BMI-associated adipose genes and a stone-associated renal papillary co-expression module were intersected with predicted secreted proteins, and candidates were prioritized using least absolute shrinkage and selection operator regression, random forest stability analysis, directional concordance, and feasibility for serum testing. The resulting panel was evaluated in additional transcriptomic datasets, an independent serum cohort of 80 participants, and a mouse model of obesity-enhanced renal mineralization. BMI-associated adipose genes were enriched for inflammatory and extracellular pathways, and the stone-associated papillary module showed a related immune-secretory profile. Cross-tissue integration identified 16 shared secretome-compatible candidates, from which MASP1, LEP, CPA4, and GAL were selected as the final four-gene panel. A locked score based on this panel tracked with adiposity in two adipose transcriptomic datasets and showed exploratory cross-species signal in a rat kidney transcriptomic dataset. In serum, all four proteins were detectable, but marker patterns were heterogeneous and discrimination was weak after internal validation. In mice, obesity alone did not induce renal mineralization, whereas the combined obesity plus glyoxylate condition showed the greatest mineral deposition together with coordinated circulating changes in the four proteins. The MASP1-LEP-CPA4-GAL panel represents an exploratory circulating protein signature associated with biological heterogeneity in obesity-related nephrolithiasis. Its discrimination in the present serum cohort was insufficient for clinical prediction. Larger longitudinal cohorts with standardized sampling, stone composition, and urinary metabolic phenotyping are required to determine its biological and clinical relevance.