Clonal hematopoiesis of indeterminate potential is associated with reduced risk of cognitive impairment in patients with chronic kidney disease.

INTRODUCTION: Clonal hematopoiesis of indeterminate potential (CHIP) and dementia disproportionately burden patients with chronic kidney disease (CKD). The association between CHIP and cognitive impairment in CKD patients is unknown. METHODS: We conducted time-to-event analyses in up to 1452 older adults with CKD from the Chronic Renal Insufficiency Cohort who underwent CHIP gene sequencing. Cognition was assessed using four validated tests in up to 6 years mean follow-up time. Incident cognitive impairment was defined as a test score one standard deviation below the baseline mean. RESULTS: Compared to non-carriers, CHIP carriers were markedly less likely to experience impairment in attention (adjusted hazard ratio [HR] [95% confidence interval {CI}] = 0.44 [0.26, 0.76], p = 0.003) and executive function (adjusted HR [95% CI] = 0.60 [0.37, 0.97], p = 0.04). There were no significant associations between CHIP and impairment in global cognition or verbal memory. DISCUSSION: CHIP was associated with lower risks of impairment in attention and executive function among CKD patients. HIGHLIGHTS: Our study is the first to examine the role of CHIP in cognitive decline in CKD. CHIP markedly decreased the risk of impairment in attention and executive function. CHIP was not associated with impairment in global cognition or verbal memory.

Expression of axon guidance ligands and their receptors in the cornea and trigeminal ganglia and their recovery after corneal epithelium injury.

Axon guidance proteins are essential for axonal pathfinding during development. In adulthood, they have been described as pleiotropic proteins with multiple roles in different organs and tissues. While most studies on the roles of these proteins in the cornea have been performed on the Semaphorin family members, with few reports on Netrins or Ephrins, their function in corneal epithelium wound healing and functional nerve regeneration is largely unknown. Here, we studied the expression of ligands belonging to three distinct axon guidance families (Semaphorins, Ephrins, and Netrins) and their most commonly associated receptors in the cornea and trigeminal ganglia (TG) using immunofluorescence staining and RT-qPCR. We also evaluated how their expression recovers after corneal epithelium injury. We found that all ligands studied (Sema3A, Sema3F, EphrinB1, EphrinB2, Netrin-1, and Netrin-4) are abundantly expressed in both the TG and corneal epithelium. Similarly, their receptors (Neuropilin-1, Neuropilin-2, PlexinA1, PlexinA3, EphB2, EphB4, Neogenin, UNC5H1 and DCC) are also expressed in both tissues. Upon corneal epithelium injury, quick recovery of both ligands and receptors was observed at the protein and gene expression levels. While the timing and expression levels vary among these proteins, in general, most of them remained upregulated for several weeks after injury. We propose that the initial protein expression recovery may be related to corneal epithelium recovery since Sema3A, EphrinB2 and Netrin-4 accelerated corneal epithelial cells wound healing. The sustained high expression levels may be functionally related to nerve regeneration and/or patterning. Whilst further studies are required to test this hypothesis, this work contributes to unraveling their function in normal and injured cornea.