ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

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