New research, published in Science Translational Medicine, shows that acute kidney injury (AKI) is associated with increased risk of developing papillary renal cell carcinoma (pRCC) and tumour relapse. These results suggest that pRCCs with no apparent association with known risk factors could be related to AKI episodes and that AKI prevention and risk stratification protocols should be developed.

Analysis of data from patients with RCC and monitoring for 1 year before diagnosis showed that 16.2% had an AKI episode, corresponding to 420 AKI episodes per 10,000 person-years. Nationwide data from Denmark showed that subsequent incidence of RCC among patients with AKI was 0.06% the first year after AKI diagnosis and 0.1% >1 year after the first AKI episode. Incidence of previous AKI episodes was significantly increased in patients diagnosed with pRCC but not for those diagnosed with clear cell RCC. In particular, type 2 pRCC development was associated with previous AKI.

Postoperative AKI after tumour resection for localized pRCC was associated with significantly decreased 5-year recurrence-free survival, and multivariate analysis showed that postoperative AKI was positively correlated with recurrence in single-centre and multicentre analyses.

Mechanistically, assessment of AKI-activated signalling pathways showed that decreased expression of mTOR, β-catenin and VHL and increased expression of NOTCH1 were associated with advanced pRCC stage. Differences in the expression of distinct AKI-related signalling pathways were seen between type 1 and type 2 pRCC; mTOR, β-catenin and VHL were increased in type 1 pRCC, whereas increased NOTCH1 was associated with type 2 pRCC. Increased expression of NOTCH1 was associated with worse prognosis and was found to be a crucial prognostic factor for type 2 pRCC.

In vivo, long-term follow-up monitoring of wild-type mice that underwent ischaemia–reperfusion injury (IRI) showed that development of type 1 and 2 pRCC was time dependent. At 4 weeks after IRI, no tumours were visible, but at 12 and 36 weeks 55.6% of mice had papillary adenomas. At 36 weeks, 22.2% of mice showed pRCC; mice that did not undergo IRI did not develop tumours. Lineage tracing of tubular epithelial cells (TECs) at the single-cell level revealed that >95% of type 1 and 2 papillary tumours were monoclonal in origin. Induction of overexpression of Notch1 in PAX8+ TECs plus IRI caused accelerated development of pRCC in transgenic mice. Notch1 overexpression in renal progenitors plus IRI resulted in the development of type 2 pRCC tumours. Blocking endogenous AKI-induced NOTCH1 activation led to fewer tumours developing.

In vitro, overexpression of NOTCH1 in human renal progenitor cells caused a pRCC-like phenotype, increased cell proliferation and resulted in aberrant mitosis. In tissue samples from patients with AKI, nuclear expression of NOTCH1 was observed in tubular cells, particularly CD133+ cells. Single-cell RNA sequencing showed that the transcriptome of human renal progenitor cells was similar to PT1, which is the putative cell of origin of human pRCC.

Together, these data suggest that AKI is a risk factor for the development and recurrence of pRCC in humans and that NOTCH1 overexpression could be the mechanism by which pRCC is induced after AKI. Thus, AKI prevention and risk stratification programmes should be developed to prevent and monitor the development of pRCC after AKI.