Abstract: SA-PO472

Altered Kynurinine 3-Monooxidase May Mediate Rejection and Tubular Cell Injury in Pig Kidney Transplants

Session Information

Category: Transplantation

  • 1702 Transplantation: Clinical and Translational

Authors

  • Wang, Youli, Augusta University, Evans, Colombia
  • Fang, Xuexiu, Augusta University, Evans, Colombia
  • Kleven, Daniel T., Augusta University, Evans, Colombia
  • Ho, Chak-Sum, Gift of Life Michigan, Ann Arbor, Michigan, United States
  • Nahman, N. Stanley, Medical College of Georgia at Augusta University, Augusta, Georgia, United States
  • Merchen, Todd D., Medical College of Georgia at Augusta University, Augusta, Georgia, United States
Background

The indoleamine 2,3-dioxygenase (IDO) transprotein prevents rejection (RJX) in rodent solid organ transplantation, including kidney transplant (KTx). Thus, the increase in IDO activity in RJX seen in our pig KTx model (JASN 27:723A) and in KTx patients (KI 77:60) is paradoxical. Kynurinine (KYN) 3-monooxidase (KMO) is a downstream enzyme of IDO generating 3-OH-KYN which is both pro-tolerant and cytoprotective. On this basis, we theorized that RJX would blunt KMO activity from rejecting pig kidneys, and in particular, silence tubular epithelial cell (TEC) KMO expression.

Methods

Pigs underwent allogeneic (Allo) (n=9) or auto renal transplants (Auto) (n=10 and as a control for ischemia), as we described (Trans Immunol, in press). For Allo, pairs of mismatched pigs were operated simultaneously with L kidneys exchanged. All Autos were also the L kidney. All pigs then had right nephrectomy (control tissue = RNx) prior to closure, and left Nx at sacrifice after 72 hrs. No immunosuppression was used. In all kidneys, RJX was assessed using Banff criteria; IDO and KMO gene expressions quantitated with qPCR; tissue IDO activity measured by HPLC, and tissue KMO localized and quantitated with immunohistochemistry (IHC).

Results

Postop creatinine was higher in Allo vs Auto (8.12±1.50 vs 2.83±0.60 mg/dL respectively, P=0.006). Auto had mild tubular injury, and no changes in IDO mRNA or activity vs RNx (n=16). Allo showed acute rejection (Banff 1 to 3), with a 6 fold (X) increase in allograft IDO mRNA, and 19.5X increase in tissue IDO activity vs Auto. KMO showed a 2X reduction in Auto, and 5X decrease in Allo RJX kidneys. By IHC KMO activity was constituent in Auto and RNx TEC, but silent in TEC from rejecting Allo.

Conclusion

KMO gene activity and TEC expression are blunted in KTx rejection. KMO may be an important downstream mediator of IDO activity and function in a protolerant and cytoprotective capacity. This may help explain the paradoxical increase in IDO activity seen in KTx rejection.