Spatial Multiomic Analyses Reveal Carcinogenic Pathways in End-Stage Renal Disease.

UNLABELLED: Patients with end-stage renal disease (ESRD) are at increased risk of acquired cystic kidney disease (ACKD) and renal tumors, but the molecular basis of such disorders remains elusive. In this study, we performed spatial immunogenomic analyses on 268 specimens from 43 patients with ACKD and associated tumors. The molecular landscape of ESRD-associated tumors is different from that of sporadic renal cell carcinoma. Single-cell and spatial analyses have shown that ACKD is under an inflammatory environment and that the renal cysts in ACKD are derived from proximal tubular cells that have survived the destructive effects of inflammation. Interestingly, we revealed that cysts are formed by clonal expansion and that paracrine activation of the MET tyrosine kinase pathway by the surrounding environment nurtures cysts. Collectively, our results identify the oncogenic mechanisms of ESRD-associated renal tumors and will pave the way for improving the prognosis of patients with ESRD.

SIGNIFICANCE: We elucidated the molecular basis of renal cancer arising in patients with ESRD and show that the inflammatory environment of ESRD gives rise to field cancerization. See related commentary by Sager et al., p. 426.