Subclinical papillary tip calcifications in stone-naïve kidneys: micro-ct quantification, osteopontin expression, and...

Subepithelial papillary calcifications, encompassing both Randall's plaques (interstitial) and Randall's plugs(intraluminal), are established niduses for stone formation, yet their distribution and determinants in stone-naïve individuals remain poorly characterized. We hypothesized that subclinical papillary calcifications are present in non-stone-formers and associated with urinary and clinical risk factors similar to those in stone formers. In this retrospective cross-sectional study, we analyzed 50 patients undergoing nephrectomy for renal or upper urinary tract cancer (June 2019-January 2023). Patients with prior stone disease, calcium/vitamin supplementation, or metabolic disorders were excluded. High-resolution micro-computed tomography (micro-CT, 20 μm voxels) quantified mineral-to-parenchyma (M/P) ratios across papillary zones, and osteopontin (OPN) immunohistochemistry was performed on matched sections. Given the 20 μm spatial resolution limit of micro-CT, any papillary tip calcified lesion (PCL) ≥ 1 mm³ was considered clinically relevant; such lesions were present in 46% of kidneys. PCL + patients were older, more frequently hypertensive, and exhibited lower urine volume (median 1200 vs. 1600 mL, p < 0.001), lower urinary citrate (p = 0.002), higher urine specific gravity (p = 0.001), and elevated M/P ratios in the middle medullary zone (p = 0.003). OPN staining was increased in loops of Henle in PCL + cases and correlated with mineral burden. Multivariable analysis identified lower urine volume, higher urinary calcium, and hypertension as independent predictors of PCL (area under curve = 0.93). These findings indicate that PCLs are common in stone-naïve kidneys and are associated with specific urinary and systemic risk factors. Early interventions targeting urine chemistry and vascular health may influence mineral deposition and delay kidney stone development.