This was a nationwide cohort study to investigate the impact of anti-A/B and donor-specific anti-HLA (HLA-DSA) antibodies on the clinical outcomes in kidney transplant recipients (KTRs). We classified a total of 1964 KTRs into four groups: transplants from ABO-incompatible donors (ABOi, n = 248); transplants in recipients with HLA-DSA (HLAi, n = 144); transplants from combined ABOi and HLAi donors (ABOi + HLAi, n = 31); and a control group for whom neither ABOi nor HLAi was applicable (CONT, n = 1541). We compared the incidence of biopsy-proven acute rejection (BPAR), allograft and patient survival rates. The incidence of BPAR was higher in the HLAi and ABOi + HLAi groups relative to the CONT group; in contrast, it was not higher in the ABOi group. Death-censored graft survival rates did not differ across the four groups. However, relative to the CONT group, patient survival rate was reduced in the ABOi and ABOi + HLAi groups, and with infection being the most common cause of death. Further, multivariable analysis revealed that desensitization therapy because of ABOi or HLAi was independent risk factors for patient mortality. HLAi was a more important risk factor for BPAR compared with ABOi. However, pretransplant desensitization therapy for either ABOi or HLAi significantly increased the risk of infection-related mortality.

Recently, we showed that tacrolimus‐induced renal injury was closely associated with impairment of autophagy clearance, and Klotho deficiency aggravated tacrolimus‐induced renal injury. In this study, we evaluated the effect of Klotho treatment on autophagy clearance in tacrolimus‐induced renal injury. We evaluated the effect of Klotho on tacrolimus‐induced renal injury in an experimental mouse model and in vitro by treatment with tacrolimus and/or recombinant mouse Klotho. In vivo and in vitro studies showed that tacrolimus treatment impaired lysosomal acidification and decreased cathepsin B activity, expression of lysosome‐associated membrane protein 2, and expression of transcription factor EB (TFEB), a master regulator for lysosomal biogenesis. These results were improved by Klotho treatment. Moreover, addition of bafilomycin A1, an inhibitor of lysosomal function, abolished the protective effect of Klotho, indicating that the protective effect of Klotho was closely associated with lysosome function. Klotho induced nuclear translocation of TFEB through inhibition of phosphorylation of glycogen synthase kinase 3β (GSK3β) by confirming using CHIR99021, a GSK3β inhibitor. Collectively, our data suggest that Klotho improves autophagy clearance via activation of lysosomal function in tacrolimus‐induced nephrotoxicity.—Lim, S. W., Shin, Y. J., Luo, K., Quan, Y., Ko, E. J., Chung, B. H., Yang, C. W. Effect of Klotho on autophagy clearance in tacrolimus‐induced renal injury. FASEB J. 33, 2694–2706 (2019). www.fasebj.org

We previously reported that oxidative stress induced by long-term tacrolimus treatment impairs mitochondrial function in pancreatic beta cells. In this study, we aimed to investigate the therapeutic potential of coenzyme Q₁₀, which is known to be a powerful antioxidant, in mitochondrial dysfunction in tacrolimus-induced diabetic rats. In a rat model of tacrolimus-induced diabetes mellitus, coenzyme Q₁₀ treatment improved pancreatic beta cell function. The administration of coenzyme Q₁₀ improved insulin immunoreactivity within islets, which was accompanied by reductions in oxidative stress and apoptosis. Assessment of the mitochondrial ultrastructure by electron microscopy revealed that coenzyme Q₁₀ treatment increased the size, number, and volume of mitochondria, as well as the number of insulin granules compared with that induced by tacrolimus treatment alone. An in vitro study using a pancreatic beta cell line showed that tacrolimus treatment increased apoptosis and the production of mitochondrial reactive oxygen species, while cotreatment with coenzyme Q₁₀ effectively attenuated these alterations. At the subcellular level, tacrolimus-induced impairment of mitochondrial respiration was significantly improved by coenzyme Q₁₀, as evidenced by the increased mitochondrial oxygen consumption and ATP production. Our data indicate that coenzyme Q₁₀ plays an important role in reducing tacrolimus-induced oxidative stress and protects the mitochondria in pancreatic beta cells. These findings suggest that supplementation with coenzyme Q₁₀ has beneficial effects in tacrolimus-induced diabetes mellitus.

The antioxidant function of Klotho is well-documented as a regulatory factor implicated in countering the aging process. This study investigated whether ginseng upregulates Klotho and its anti-aging signaling in a setting of calcineurin inhibitor-induced oxidative stress. Although tacrolimus treatment reduced Klotho level in the serum and kidney, ginseng treatment was found to reverse the levels. Tacrolimus-induced oxidative stress was reduced by ginseng treatment, with functional and histological improvements. Effect of ginseng on Klotho-induced manganese superoxide dismutase signaling pathway during tacrolimus treatment in mice revealed that ginseng suppressed phosphatidylinositol 3-kinase/serine-threonine kinase Akt-mediated phosphorylation of forkhead box protein O3a and promoted the binding of forkhead box protein O3a to manganese superoxide dismutase promoter. In the mitochondria, ginseng reduced mitochondrial reactive oxygen species production, mitochondrial membrane potential, and oxygen consumption rate, whereas blocking phosphatidylinositol 3-kinase activity with LY294002 enhanced them. These findings together suggested that ginseng attenuated tacrolimus-induced oxidative stress via signaling between Klotho and the phosphatidylinositol 3-kinase/serine-threonine kinase Akt/forkhead box protein O3a-related antioxidant pathway.

The major side effect of tacrolimus (Tac) is nephrotoxicity. We studied whether supplementation of coenzyme Q ₁₀ , (CoQ ₁₀ ) a potent antioxidant, can reduce Tac‐induced nephrotoxicity via improving mitochondrial function. In an in vitro study, CoQ ₁₀ reduced the production of Tac‐induced mitochondrial reactive oxygen species and abolished the loss of mitochondrial membrane potential in proximal tubular cell line. Assessment of mitochondrial function revealed that CoQ ₁₀ decreased oxygen consumption and mitochondrial respiration rate increased by Tac, suggesting improvement of mitochondrial function to synthesize ATP with CoQ ₁₀ treatment. The effect of the CoQ ₁₀ in vitro study was observed in an experimental model of chronic Tac‐induced nephropathy. CoQ ₁₀ attenuated Tac‐induced oxidative stress and was accompanied by function and histologic improvement. On electron microscopy, addition of CoQ ₁₀ increased not only the number but also the volume of mitochondria compared with Tac treatment only. Our data indicate that CoQ ₁₀ improves Tac‐induced mitochondrial dysfunction in kidney. Supplementary CoQ ₁₀ treatment may be a promising approach to reduce Tac‐induced nephrotoxicity.—Yu, J. H., Lim, S. W., Luo, K., Cui, S., Quan, Y., Shin, Y. J., Lee, K. E., Kim, H. L., Ko, E. J., Chung, B. H., Kim, J. H., Chung, S. J., Yang, C. W. Coenzyme Q ₁₀ alleviates tacrolimus‐induced mitochondrial dysfunction in kidney. FASEB J. 33, 12288‐12298 (2019). www.fasebj.org

In kidney transplantation (KT), overcoming donor shortage is particularly challenging in patients with preexisting donor-specific antibodies (DSAs) against human leukocyte antigen (HLA), called HLA-incompatible KT (HLAi KT), carrying the risk of rejection and allograft loss. Thus, it is necessary to accurately evaluate the degree of sensitization before HLAi KT, and undertake appropriate pretreatment strategies. To determine the degree of sensitization, complement-dependent cytotoxicity has been the only method employed; the development of a method using flow cytometry further improved the test sensitivity. However, these tests present disadvantages, including the need for living cells, with a solid-phase assay developed to resolve this problem. Currently, the method using Luminex (Luminex Corp.) is widely used in clinical practice. As this method measures DSAs using single antigen beads, it is possible to classify immunological risks by measuring the type and amount of DSAs. Furthermore, there have been major advances in methods that involve DSA removal before HLAi KT. In the early stages of desensitization, plasmapheresis and intravenous immunoglobulins were the main treatment methods employed; however, the introduction of CD20 monoclonal antibody and proteasome inhibitors further increased the success rate of desensitization. Currently, HLAi KT has been established as an important transplant method, but an understanding of DSAs and a novel desensitization treatment are warranted.