Kidney failure effects two million people worldwide. Currently, the best treatment option is transplantation however there is a severe shortage of donated kidneys. Of individuals who receive a kidney, around 4% reject the new organ. Failed transplantation is the result of tubular epithelial cell (TEC) injury by the host immune system. Over 20 years ago, the role of IDO was made known to the world when Dr. David Munn and colleagues showed that allogenic rejection is prevented by indoleamine 2, 3-dioxygenase (IDO), published in Science (Munn et al. 1998). Now there is more evidence that downstream catabolites of TRP play a role in the success of kidney transplants.
A recent study published by Dr. Randi Lassiter et al. in Frontiers in Immunology investigated the effects of the kynurenine (KYN) pathway on the outcome of transplantation. In human kidney tissues, kynurenine 3-monooxygenase (KMO) is highly expressed in TEC. In this research the authors used a swine model and compared allograft, where kidneys were transplanted from one individual to another, to autograft, where the kidney was removed from an individual and retransplanted. Rejections were associated with diminished expression of KMO suggesting a protective role whereas, IDO expression did not correlate to allograft rejection. Based on the authors previous work (Wang et al. 2018), TEC were treated with a combination of IFNγ, TNFα, and IL1β. This cytokine challenge caused increased IDO protein expression while KMO expression was decreased. Furthermore, TEC had increased apoptosis as determined by increased Caspase 3 and 8 expression, and reduced expression of Bcl2 and Bcl-xL. Downstream metabolites 3-hydroxykynurenine (3HK) and 3-hydroxyanthranilic acid (3HAA) were shown to help protect TEC from injury and inhibited T cell proliferation following cytokine stimulation. Other research has shown that 3HAA is immunosuppressive and protective (Iken et al. 2012 and Gargaro et al. 2019) Taken together, KMO expression and the subsequent 3HAA and 3HK levels contribute to the overall success of kidney transplantation. Potential future therapies could include 3HAA and 3HK administration, although more research is warranted since 3HK has been shown to be neurotoxic.