Medullary Cast Formation Predicts Kidney Outcomes Beyond Cortical Pathology

Abstract Background Renal biopsy provides important prognostic information for patients with chronic kidney disease (CKD), primarily through evaluation of cortical histopathological lesions, including interstitial fibrosis and tubular atrophy (IFTA). However, the prognostic significance of renal medullary lesions remains poorly understood. We investigated whether medullary pathological findings are independently associated with renal outcomes and whether they improve prognostic discrimination beyond conventional cortical assessments. Methods This single-center retrospective cohort study screened 1,136 adult patients who underwent native kidney biopsy between 2011 and 2023. After applying predefined inclusion and exclusion criteria, 488 patients with adequate medullary tissue were included in the final analysis. Medullary fibrosis, inflammatory cell infiltration, and cast formation were semi-quantitatively graded and evaluated as predictors of renal outcomes. The primary outcome was a composite of ≥40% decline in estimated glomerular filtration rate (eGFR) or initiation of renal replacement therapy. Associations were assessed using Cox proportional hazards models with sequential adjustment for demographic factors, baseline eGFR, proteinuria, and cortical IFTA. Model discrimination was evaluated using Harrell’s concordance-index (C-index). Results During a median follow-up of 2.3 years, 112 patients (23.0%) reached the composite renal outcome. In multivariable analysis adjusted for age, sex, baseline eGFR, and proteinuria, medullary cast formation was significantly associated with adverse renal outcomes (hazard ratio [HR] 1.70, 95% confidence interval [CI] 1.28–2.24). This association remained significant after additional adjustment for IFTA (HR 1.64, 95% CI 1.21–2.21), whereas medullary fibrosis lost significance after IFTA adjustment. Addition of medullary cast formation improved C-index by 0.016, indicating incremental prognostic value beyond conventional predictors. Conclusion Medullary cast formation is independently associated with renal outcomes and improves prognostic discrimination beyond established cortical parameters. Systematic evaluation of medullary lesions during routine kidney biopsy may enhance risk stratification in CKD. Prospective studies are warranted to clarify the causal role of medullary pathology in CKD progression.