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 KCa3.1 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.