Cellular senescence in kidney biopsies is associated with tubular dysfunction and predicts CKD progression in childhood cancer patients with karyomegalic interstitial nephropathy

Abstract

Karyomegalic interstitial nephropathy (KIN) has been reported as an incidental finding in patients with childhood cancer treated with ifosfamide. It is defined by the presence of tubular epithelial cells (TECs) with enlarged, irregular, and hyperchromatic nuclei. Cellular senescence has been proposed to be involved in kidney fibrosis in hereditary KIN patients. We report that KIN could be diagnosed 7–32 months after childhood cancer diagnosis in 6/6 consecutive patients biopsied for progressive chronic kidney disease (CKD) of unknown cause between 2018 and 2021. The morphometry of nuclear size distribution and markers for DNA damage (γH2AX), cell‐cycle arrest (p21+, Ki67−), and nuclear lamina decay (loss of lamin B1), identified karyomegaly and senescence features in TECs. Polyploidy was assessed by chromosome fluorescence in situ hybridization (FISH). In all six patients the number of p21‐positive TECs far exceeded the typically small numbers of truly karyomegalic cells, and p21‐positive TECs contained less lysozyme, testifying to defective resorption, which explains the consistently observed low‐molecular‐weight (LMW) proteinuria. In addition, polyploidy of TEC was observed to correlate with loss of lysozyme staining. Importantly, in the five patients with the largest nuclei, the percentage of p21‐positive TECs tightly correlated with estimated glomerular filtration rate loss between biopsy and last follow‐up (R2 = 0.93, p < 0.01). We conclude that cellular senescence is associated with tubular dysfunction and predicts CKD progression in childhood cancer patients with KIN and appears to be a prevalent cause of otherwise unexplained CKD and LMW proteinuria in children treated with DNA‐damaging and cell stress‐inducing therapy including ifosfamide. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

An unscheduled switch to endocycles induces a reversible senescent arrest that impairs growth of theDrosophilawing disc

“…Moreover, in mice and humans, iECs can repair damaged kidney tubules through CCH, but these iECs subsequently senesce and contribute to kidney fibrosis and cancer. 18,[126][127][128][129] Altogether, these observations suggest that there may be limits to iEC cell growth that can lead to tissue malformations and neoplasia.…”