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Abstract: FR-PO194

Cellular Senescence Is Associated With CKD Progression in Childhood Cancer Patients With Karyomegalic Interstitial Nephropathy (KIN)

Session Information

Category: Onconephrology

  • 1600 Onconephrology

Authors

  • Keijzer-Veen, Mandy G., Universitair Medisch Centrum Utrecht - Locatie Wilhelmina Kinderziekenhuis, Utrecht, Utrecht, Netherlands
  • Knoppert, Sebastiaan, Universitair Medisch Centrum Utrecht, Utrecht, Utrecht, Netherlands
  • Valentijn, Floris, Universitair Medisch Centrum Utrecht, Utrecht, Utrecht, Netherlands
  • van den Heuvel-Eibrink, M.M., Prinses Maxima Centrum voor Kinderoncologie, Utrecht, Utrecht, Netherlands
  • Berg, Gerrit Van Den, Universitair Medisch Centrum Utrecht - Locatie Wilhelmina Kinderziekenhuis, Utrecht, Utrecht, Netherlands
  • Lilien, Marc, Universitair Medisch Centrum Utrecht - Locatie Wilhelmina Kinderziekenhuis, Utrecht, Utrecht, Netherlands
  • Haveman, Lianne M., Prinses Maxima Centrum voor Kinderoncologie, Utrecht, Utrecht, Netherlands
  • Stokman, Marijn F., Universitair Medisch Centrum Utrecht, Utrecht, Utrecht, Netherlands
  • Janssens, Geert O., Universitair Medisch Centrum Utrecht, Utrecht, Utrecht, Netherlands
  • Broekhuizen, Roel, Universitair Medisch Centrum Utrecht, Utrecht, Utrecht, Netherlands
  • Goldschmeding, Roel, Universitair Medisch Centrum Utrecht, Utrecht, Utrecht, Netherlands
  • Nguyen, Tri Q., Universitair Medisch Centrum Utrecht, Utrecht, Utrecht, Netherlands
Background

Patients with KIN show a clinical picture of interstitial nephropathy with enlarged, irregular and hyperchromatic nuclei of tubular epithelial cells (TECs). The histologic pattern was first described in patients with FAN1 mutations with defective DNA damage repair, but has also been infrequently reported in children treated for childhood cancers with the alkylating agent ifosfamide.

Methods

We included the kidney biopsies of all children treated for childhood cancer in the Princess Máxima Center for Pediatric Oncology with progressive CKD with low molecular weight proteinuria of unknown cause between 2018-2021. Features of karyomegaly and senescence were identified in TECs by automated morphometric assessment of nuclear size distribution, and immunohistochemical markers for DNA damage (γH2AX), cell-cycle arrest (p21+, Ki67-), and nuclear lamina decay (loss of lamin B1).

Results

KIN could be diagnosed in all six children, according to the above described features. (Figure 1A-C) The number of p21 positive cells by far exceeded the typically very small numbers of truly karyomegalic cells. P21 positive TECs were found to contain significantly less lysozyme, testifying to defective resorption as an explanation of the consistent finding of LMW proteinuria. Moreover, in the 5 patients with the largest nuclei, the percentage of p21-positive TECs showed strong inverse correlation with change in eGFR from biopsy to last follow-up (R2=0.93, p<0.01).

Conclusion

Karyomegaly and cellular senescence-associated tubular dysfunction appear to be a more prevalent cause of otherwise unexplained CKD and LMW proteinuria in children treated with ifosfamide. This finding may have important implications for future personalized treatment strategies.

Figure 1A. Enlarged nuclei in KIN are Ki67 negative, p21 positive, (B-C) yH2AX positive, and show less LaminB1 staining.

Funding

  • Private Foundation Support