Subclinical papillary tip calcifications in stone-naïve kidneys: micro-ct quantification, osteopontin expression, and associations with urinary and clinical risk factors

Abstract

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.

Keywords: 24-hour urine; Kidney stones; Micro-computed tomography; Osteopontin; Randall’s plaque.