Abstract: FR-PO1108
Downregulation of Allograft 25-Hydroxyvitamin D3 1 Alpha-Hydroxylase Is an Early Biomarker for Rejection in Kidney Transplantation
Session Information
- Transplantation: Basic
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Transplantation
- 1901 Transplantation: Basic
Authors
- Wang, Youli, Augusta University, Augusta, Georgia, United States
- Harner, Andrew, Augusta University, Augusta, Georgia, United States
- Fang, Xuexiu, Augusta University, Augusta, Georgia, United States
- Merchen, Todd D., Augusta University, Augusta, Georgia, United States
- Ho, Chak-Sum, Gift of Hope Organ & Tissue Donor Network, Itasca, Illinois, United States
- Kleven, Daniel T., Augusta University, Augusta, Georgia, United States
- Thompson, Thomas Z., Augusta University, Augusta, Georgia, United States
- Nahman, N. Stanley, Augusta University, Augusta, Georgia, United States
Background
1a, 25(OH)2 vitaminD3 (1a,25VitD3) results from both renal and extrarenal 25-Hydroxyvitamin D3 1 alpha-Hydroxylase (1a-HOase) activity. Renal 1a-HOase is classically associated with mineral metabolism whereas extrarenal 1a-HOase exhibits immunomodulatory effects. Vitamin D deficiency may also be prevalent in the immediate post-transplant period. In the present study, we investigated the relationship between cytokine secretion, graft 1a-HOase expression, renal cortical epithelial cell injury (RCEC), and allograft rejection in a pig model of kidney transplantation and in cultured human RCEC.
Methods
Outbred Yorkshire pigs underwent autotransplants or mismatched allogeneic kidney transplants as we described (Transplant Immunol 42:40). No immunosuppression was used. The vitamin D axis was assessed 72 hours post transplant. The effect of 1a,25VitD3 and 25VitD3 on T cell proliferation and epithelial-mesenchymal transformation (EMT) were investigated using cultured RCEC.
Results
Circulating levels of 1a,25VitD3 and 25VitD3VitD were increased and decreased, respectively, in 30 pigs following auto (n=5) or allotransplantation (n=25). Allograft 1a-HOase was decreased in rejection showing a negative correlation with the extent of rejection (Banff) (r=-0.712 (p<0.01), and renal function (BUN (r=-0.706 (p<0.01); creatinine (r=-0.673 (p<0.05)). Additionally, IL17 and FGF23 were upregulated, and 1, 25-hydroxyvitamin D3 24-hydroxylase was downregulated in rejecting grafts. 1a-HOase was mainly expressed in RCEC. Activating cultured RCEC with cytokines gave a rapid, 10x reduction of 1a-HOase, associated with dramatic decreases of protective E-cadherin (E-cad) and tight junction protein-1 (TJP1), whereas 1a,25VitD3 attenuated cytokine induction of EMT, as well as normalized expression of E-cad and TJP1. When compared to 25VitD3, 1a,25VitD3 exhibited a 50-fold greater suppression of T cell proliferation.
Conclusion
Allograft 1a-HOase expression may predict allograft rejection, not the circulating 1a,25VitD3. Allograft 1a-HOase may play a key role in the prevention of allograft rejection.
Funding
- Private Foundation Support