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Abstract: FR-PO852

Accelerated Cellular Senescence Associated with CFHR3-1 Variants Influences Graft Survival in IgA Nephropathy Transplanted Patients

Session Information

  • Transplantation: Basic
    October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Transplantation

  • 1801 Transplantation: Basic

Authors

  • Pesce, Francesco, University of Bari, Bari, Italy
  • Divella, Chiara, University of Bari, Bari, Italy
  • Stea, E. D., University of Bari, Bari, Italy
  • Accetturo, Matteo, University of Bari - Dept. Emergency and Organ Transplants, Bari, Italy
  • Cianciotta, Francesca, Università di Bari, Bitetto, Italy
  • Rossini, M., University of Bari, Department of Emergency and Organ Transplantation, Nephrology Unit, Bari, Italy
  • Fontò, Giulia, University of Bari, Bari, Italy
  • Lucarelli, G., University of Bari, Bari, Italy
  • Gesualdo, Loreto, University of Bari, Bari, Italy
  • Castellano, Giuseppe, UNIVERSITA STUDI BARI, BARI, Italy
Background


The deletion of complement factor H-related genes 1 and 3 (CFHR3-1Δ) has been associated with a decreased risk of IgA nephropathy (IgAN) and is in linkage disequilibrium (LD) with the SNP rs6677604 (“A” allele), which can be used as a proxy to detect it. We hypothesized that CFHR3-1Δ is also implicated in the processes that influence graft survival in recipients with IgAN and tested whether cellular senescence is involved in mediating the damage.

Methods

A total of 67 biopsy-proven IgAN patients who received a renal transplant at the Kidney Transplant Center of the Department of Emergency and Organ Transplantations (D.E.T.O), University of Bari between 1993 and 2017 where included in the study. The region in CFHR3-1 encompassing the SNP rs6677604 was amplified using PCR and sequenced by Sanger.
Immunohistochemical expression of p16INK4A was performed on paraffin-embedded kidney transplant biopsies of 8 patients (4 with rs6677604-AA vs 4 with rs6677604-GA), and quantified using the Aperio Positive Pixel Count Algorithm. Masson's trichrome staining and quantification of positive area was performed.
Clinical data at baseline and during the follow-up were recorded. An eGFR < 60mL/min/1.73m2 (MDRD equation) was considered as main outcome at a univariate and multivariate analyses.

Results

The rs6677604-A allele was found in 22 (32.8%) patients (genotype rs6677604-AG) whereas 45 (67.2%) carried the GG genotype. These two groups had no difference as for demographic features, donor and transplant-related variables (incidence of delayed graft function and acute rejection episodes). Patients with the rs6677604-GG had a worse outcome during a mean follow-up of 69 ± 62 months at univariate (P=5.81E-05) and multivariate analysis (HR 30.8; 95% IC 3.3-285.5; P=0.003). Graft biopsies in this group featured a significantly higher expression of the senescence marker p16INK4a (P=0.001) in tubular epithelial cells showing increased levels of fibrosis (P=0.005).

Conclusion

These findings suggest that CFHR3-1Δ and its proxy rs6677604 are associated with long term graft function in transplant recipients with IgAN nephropathy through mechanisms involving accelerated cellular senescence.