Disseminated candidiasis caused by the fungus Candida albicans is a major clinical problem in individuals with kidney disease and accompanying uremia; disseminated candidiasis fatality is twice as common in patients with uremia as those with normal kidney function. Many antifungal drugs are nephrotoxic, making treatment of these patients particularly challenging. The underlying basis for this impaired capacity to control infections in uremic individuals is poorly understood. Here, we show in multiple models that uremic mice exhibit an increased susceptibility to systemic fungal infection. Uremia inhibits Glut1-mediated uptake of glucose in neutrophils by causing aberrant activation of GSK3β, resulting in reduced ROS generation and hence impaired killing of C. albicans in mice. Consequently, pharmacological inhibition of GSK3β restored glucose uptake and rescued ROS production and candidacidal function of neutrophils in uremic mice. Similarly, neutrophils isolated from patients with kidney disease and undergoing hemodialysis showed similar defect in the fungal killing activity, a phenotype rescued in the presence of a GSK3β inhibitor. These findings reveal a mechanism of neutrophil dysfunction during uremia and suggest a potentially translatable therapeutic avenue for treatment of disseminated candidiasis.

由真菌白色念珠菌引起的播散性念珠菌病是患有肾病并伴有尿毒症的个体的一个主要临床问题；尿毒症患者的播散性念珠菌病死亡率是肾功能正常患者的两倍。许多抗真菌药物具有肾毒性，使得这些患者的治疗特别具有挑战性。尿毒症患者控制感染能力受损的根本原因尚不清楚。在这里，我们在多个模型中表明，尿毒症小鼠表现出对全身真菌感染的易感性增加。尿毒症通过引起 GSK3β 的异常激活来抑制中性粒细胞中 Glut1 介导的葡萄糖摄取，导致 ROS 生成减少，从而损害对小鼠白色念珠菌的杀灭作用。因此，GSK3β 的药理学抑制可恢复尿毒症小鼠的葡萄糖摄取并挽救 ROS 产生和中性粒细胞的念珠菌功能。同样，从患有肾病并接受血液透析的患者中分离出的中性粒细胞在杀真菌活性方面也表现出类似的缺陷，这种表型在 GSK3β 抑制剂的存在下得以挽救。这些发现揭示了尿毒症期间中性粒细胞功能障碍的机制，并提出了治疗播散性念珠菌病的潜在可转化治疗途径。