Abstract: FR-OR139
G2/M Cycle Arrest in Human Transplanted Kidneys Correlates to Fibrosis, Functional Decline, and Graft Loss
Session Information
- Translational and Transplant Pathology
October 26, 2018 | Location: 6E, San Diego Convention Center
Abstract Time: 05:54 PM - 06:06 PM
Category: Transplantation
- 1802 Transplantation: Clinical
Authors
- Pieters, Tobias, University Medical Center Utrecht, Utrecht, Netherlands
- Vanhove, Thomas, University Hospitals Leuven, Leuven, Belgium
- Nguyen, Tri Q., UMC Utrecht, Utrecht, Netherlands
- Verhaar, Marianne C., University Medical Center Utrecht, Utrecht, Netherlands
- Kuypers, Dirk R., University Hospitals Leuven, Leuven, Belgium
- Goldschmeding, Roel, University Medical Center Utrecht, Utrecht, Netherlands
- Rookmaaker, Maarten B., UMCU, Utrecht, Netherlands
Background
Kidney transplantation (KTx) is the only curative treatment of end-stage renal failure. However, some KTx recipients suffer from long-term graft loss associated with interstitial fibrosis and tubular atrophy (IF/TA), especially after delayed graft function (DGF) due to acute tubular injury (ATI). Maladaptive repair, characterized by G2/M arrested tubular cells, has emerged as a key mediator of IF/TA after ATI in animal experiments, although little is known about its role in human kidney fibrosis. In this retrospective study, we studied the relation between G2/M cell cycle arrest in tubular cells in biopsies and histological and functional outcome of kidney allografts.
Methods
We included 64 patients, of which 32 presented with DGF and 32 with early graft function (EGF). Surveillance biopsies taken at 3 months after KTx were evaluated for G2/M cell cycle arrest by staining for the G2/M marker pHH3 and the proliferation marker Ki67. ATI was quantified morphologically in the indication biopsies taken approximately 7 days after KTx in the DGF group. Renal outcome was evaluated by fibrosis 2 years after KTx (Remuzzi score), kidney function decline in 2 years (CKD-epi), and 10-year death-censored graft survival.
Results
At 3 months after KTx, DGF kidneys had more G2/M arrested cells (median 1.17 cells/mm2 [0.0-3.8] vs median 0.6 cells/mm2 [0.0-1.8]; p<0.05) and the number of arrested cells/mm2 correlated to acute histological damage in the 7 day biopsy (ρ=-0.78 p<0.0005), to histological severity of fibrosis in biopsies taken 2 years after transplantation (ρ =0.52, p<0.01), and to functional decline over these 2 years (ρ = -0.44, p<0.01). Finally, the amount of G2/M arrested cells was associated with a higher risk of 10- year death-censored graft survival (univariate cox regression, HR=3.98, p<0.01).
Conclusion
Our data suggest that in the regenerative response following ATI damaged cells in kidney allografts can get arrested in G2/M and subsequently contribute to progressive IF/TA, functional decline and eventually graft loss.
Funding
- Commercial Support – Astellas Pharma inc.