PMID- 37792603
OWN - NLM
STAT- MEDLINE
DCOM- 20231113
LR  - 20240404
IS  - 1096-9896 (Electronic)
IS  - 0022-3417 (Linking)
VI  - 261
IP  - 4
DP  - 2023 Dec
TI  - Cellular senescence in kidney biopsies is associated with tubular dysfunction and 
      predicts CKD progression in childhood cancer patients with karyomegalic 
      interstitial nephropathy.
PG  - 455-464
LID - 10.1002/path.6202 [doi]
AB  - 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 
      (gammaH2AX), 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 (R(2)  = 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. (c) 2023 The Authors. The 
      Journal of Pathology published by John Wiley & Sons Ltd on behalf of The 
      Pathological Society of Great Britain and Ireland.
CI  - (c) 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd 
      on behalf of The Pathological Society of Great Britain and Ireland.
FAU - Knoppert, Sebastiaan N
AU  - Knoppert SN
AUID- ORCID: 0000-0002-4543-9792
AD  - Department of Pathology, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - Keijzer-Veen, Mandy G
AU  - Keijzer-Veen MG
AD  - Department of Pediatric Nephrology, Wilhelmina Children's Hospital, Utrecht, The 
      Netherlands.
FAU - Valentijn, Floris A
AU  - Valentijn FA
AD  - Department of Pathology, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - van den Heuvel-Eibrink, Marry M
AU  - van den Heuvel-Eibrink MM
AD  - Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
FAU - Lilien, Marc R
AU  - Lilien MR
AD  - Department of Pediatric Nephrology, Wilhelmina Children's Hospital, Utrecht, The 
      Netherlands.
FAU - van den Berg, Gerrit
AU  - van den Berg G
AD  - Department of Pediatric Nephrology, Wilhelmina Children's Hospital, Utrecht, The 
      Netherlands.
FAU - Haveman, Lianne M
AU  - Haveman LM
AD  - Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
FAU - Stokman, Marijn F
AU  - Stokman MF
AD  - Department of Genetics, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - Janssens, Geert O
AU  - Janssens GO
AD  - Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
AD  - Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - van Kempen, Sven
AU  - van Kempen S
AD  - Department of Pathology, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - Broekhuizen, Roel
AU  - Broekhuizen R
AD  - Department of Pathology, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - Goldschmeding, Roel
AU  - Goldschmeding R
AD  - Department of Pathology, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - Nguyen, Tri Q
AU  - Nguyen TQ
AUID- ORCID: 0000-0001-6475-0706
AD  - Department of Pathology, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
LA  - eng
GR  - 170KG20/Nierstichting/
GR  - CP1805/Nierstichting/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20231004
PL  - England
TA  - J Pathol
JT  - The Journal of pathology
JID - 0204634
RN  - EC 3.2.1.17 (Muramidase)
RN  - UM20QQM95Y (Ifosfamide)
SB  - IM
MH  - Humans
MH  - Child
MH  - *Nephritis, Interstitial/genetics
MH  - Muramidase/genetics
MH  - Ifosfamide
MH  - In Situ Hybridization, Fluorescence
MH  - *Neoplasms/pathology
MH  - *Renal Insufficiency, Chronic/diagnosis/genetics/complications
MH  - Proteinuria/pathology
MH  - Kidney/pathology
MH  - Biopsy
MH  - Cellular Senescence
MH  - Polyploidy
OTO - NOTNLM
OT  - DNA damage
OT  - cellular senescence
OT  - childhood cancer patients
OT  - chronic kidney disease
OT  - ifosfamide
OT  - karyomegalic interstitial nephropathy
EDAT- 2023/10/04 18:42
MHDA- 2023/11/13 06:43
CRDT- 2023/10/04 13:03
PHST- 2023/07/12 00:00 [revised]
PHST- 2022/11/15 00:00 [received]
PHST- 2023/08/14 00:00 [accepted]
PHST- 2023/11/13 06:43 [medline]
PHST- 2023/10/04 18:42 [pubmed]
PHST- 2023/10/04 13:03 [entrez]
AID - 10.1002/path.6202 [doi]
PST - ppublish
SO  - J Pathol. 2023 Dec;261(4):455-464. doi: 10.1002/path.6202. Epub 2023 Oct 4.