Strategic timing of contralateral nephrectomy after ischemic acute kidney injury prevents chronic kidney disease by enhancing progenitor proliferation, attenuating polyploidization and reshaping the immune response.

Abstract

Kidneys have a limited capacity for self-repair, and injury frequently progression leads to chronic kidney disease (CKD). Remarkably, successful recovery is observed in models of unilateral acute kidney injury (AKI) upon contralateral nephrectomy. Here, we aim to better understand the cellular and molecular mechanisms underlying this enhanced recovery. Six rodent studies were performed, including optimization and time-course experiments in Wistar rats and C57BL/6J mice to define left ischemia conditions, right nephrectomy delay times, and functional outcome. Kidneys were analyzed by quantitative histomorphometry (pathomics) on whole slide sections, immunostaining, and qPCR. Bulk RNA sequencing was conducted in two independent mouse time-course studies to discern repair and injury trajectories. Clonal expansion of tubular progenitor cells was assessed by lineage tracing in PAX2/Confetti mice. Tubular epithelial cell proliferative dynamics and polyploidization were analyzed using live cell cycle and DNA content profiling in PAX8/FUCCI2aR mice. Nephrectomy at day three after AKI induced full functional recovery in rats and mice, whereas longer delays (10 and 20 days) failed to prevent CKD progression. Early nephrectomy reduced tubular atrophy, fibrosis, and inflammation. Pathomics revealed distinct tubular morphological trajectories distinguishing between atrophy and repair, as adaptive signatures. Transcriptomic analyses with orthogonal validation demonstrated attenuation and reshaping of immune cell signatures and inflammatory pathways. Additionally, specific gene sets unique to nephrectomy-induced repair were identified. Lineage tracing showed that nephrectomy enhanced clonal expansion of tubular progenitor cells, beyond the levels of spontaneous repair. Cell cycle and DNA-content analysis of tubular cells demonstrated a strong polyploid response immediately after the ischemic insult, while early nephrectomy attenuated persistent tubular cell polyploidization, a contributor to CKD. Early nephrectomy in experimental AKI triggers efficient repair by modulating immune responses, promoting tubular regeneration, inducing pro-repair transcriptional reprogramming, and counteracting progression to CKD through attenuation of sustained polyploidization.