Spatial multiomic analyses reveal carcinogenic pathways in end-stage renal disease

Abstract Patients with end-stage renal disease (ESRD) are at increased risk for acquired cystic kidney disease (ACKD) and renal tumours, but the molecular basis of such disorders remains elusive. Here, we performed spatial immunogenomic analyses on 268 specimens from 43 patients with ACKD and associated tumours. The molecular landscape of ESRD-associated tumours 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 the 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 tumours and will pave the way for improving the prognosis of patients with ESRD.