Cognitive decline is common in patients with chronic kidney disease (CKD); however, the mechanisms linking these two conditions is unclear. New research suggests that disruption of the blood–brain barrier (BBB) by uraemic toxins may lead to microglial activation and subsequent IL-1 receptor (IL-1R)-mediated neuronal impairment.

Exposure of neurons to plasma from patients with CKD did not induce their activation; by contrast, exposure of microglia to uraemic plasma induced microglial activation, with similar findings observed in a mouse model of CKD. The activation of microglia stimulated the release of IL-1β. Mechanistically, the researchers show that the activation of microglia is driven by increased microglial potassium efflux, which primes microglia for IL-1β maturation and release through p38–MAPK signalling. Inhibition of potassium efflux with an inhibitor of the calcium-dependent potassium channel K_Ca3.1 prevented microglial activation and protected mice from CKD-associated cognitive decline. Similarly, pharmacologic or genetic inhibition of IL-1R signalling in neurons attenuated cognitive decline in mice with CKD.

认知能力下降在慢性肾脏病 (CKD) 患者中很常见；然而，连接这两种情况的机制尚不清楚。新研究表明，尿毒症毒素对血脑屏障 (BBB) 的破坏可能导致小胶质细胞激活和随后的 IL-1 受体 (IL-1R) 介导的神经元损伤。

将神经元暴露于 CKD 患者的血浆中并不会诱导其激活；相比之下，将小胶质细胞暴露于尿毒症血浆会诱导小胶质细胞活化，在 CKD 小鼠模型中观察到类似的结果。小胶质细胞的激活刺激了 IL-1β 的释放。从机制上讲，研究人员表明，小胶质细胞的激活是由小胶质细胞钾流出增加驱动的，这为小胶质细胞通过 p38-MAPK 信号传导促进 IL-1β 成熟和释放做好准备。用钙依赖性钾通道 K _Ca 3.1 抑制剂抑制钾流出，可防止小胶质细胞激活，并保护小鼠免受 CKD 相关认知能力下降。同样，对神经元中 IL-1R 信号传导的药物或遗传抑制可减轻 CKD 小鼠的认知能力下降。