Emotional and cognitive changes in chronic kidney disease

Abstract

Chronic kidney disease (CKD) leads to cognitive impairment and emotional changes. However, the precise mechanism underlying the crosstalk between the kidneys and the nervous system is not fully understood. Inflammation and cerebrovascular disease can influence the development of depression in CKD. CKD is one of the strongest risk factors for cognitive impairment. Moreover, cognitive impairment occurs in CKD as patients experience the dysregulation of several brain functional domains due to damage caused to multiple cortical regions and to subcortical modulatory neurons. The differences in structural brain changes between CKD and non-CKD dementia may be attributable to the different mechanisms that occur in CKD. The kidney and brain have similar anatomical vascular systems, which may be susceptible to traditional risk factors. Vascular factors are assumed to be involved in the development of cognitive impairment in patients with CKD. Vascular injury induces white matter lesions, silent infarction, and microbleeds. Uremic toxins may also be directly related to cognitive impairment in CKD. Many uremic toxins, such as indoxyl sulfate, are likely to have an impact on the central nervous system. Further studies are required to identify therapeutic targets to prevent changes in the brain in patients with CKD.

Keywords: Brain; Cognitive dysfunction; Depressive disorder; Kidney failure, chronic; Uremia.

Figure 1

Behaviors of depression and anxiety in chronic kidney disease (CKD) rats. (A) The light-dark transition test apparatus consisted of a cage (30 × 30 × 30 cm) divided into two compartments by a black partition with a small opening that allowed the rat to move between the two compartments. One of the compartments was darkened, while the other was brightly illuminated. Rats were placed in the illuminated compartment and allowed to move freely for 5 minutes. The total time spent in the bright compartment was used as an indicator of anti-anxiety behavior. The light/dark transition number and the total time spent in the light compartment by CKD rats were lower than those of controls. (B) The elevated plus-maze test apparatus consisted of an elevated, plus-shaped (+) apparatus with two open arms and two enclosed arms. Rats were placed in an elevated (60 cm above the floor) plus maze that had two opposite open arms (50 × 10 cm each) and two opposite closed arms (50 × 10 cm each); the height of the walls was 50 cm. The number of entries into the maze and the time spent in individual arms were measured for 5 minutes. The percentage of entries into the open arms and the total number of entries in the elevated plus-maze were reduced for CKD rats compared to controls. (C) The forced swimming test was performed to measure depression-like behaviors. Rats were individually placed in a plastic cylinder (50 cm in height, 30 cm in diameter), which was filled with water (23°C ± 3°C). Their behavior was observed for 5 minutes, and their immobility time was calculated. The time spent immobile was taken as an indicator of depression-like behavior. During the forced swimming test, the percentages of immobility were higher for CKD rats than controls. A decreased latency to immobility was observed in CKD rats. Data are presented as the mean ± standard error of the mean. Modified from Yu et al. [62]. ^ap < 0.01, ^bp < 0.001, one-way analysis of variance.

Figure 2

Proposed scheme of indoxyl sulfate-induced neurotoxicity. Indoxyl sulfate disrupts the integrity of the blood-brain barrier. In addition, indoxyl sulfate inhibits organic anion transporter 3 (OAT3) and efflux transport of endothelial cells, resulting in the accumulation of indoxyl sulfate in the brain. Furthermore, indoxyl sulfate increases reactive oxygen species (ROS) in astrocytes, inhibiting the mitogen-activated protein kinase (MAPK) pathway and inducing apoptosis. Moreover, indoxyl sulfate binds with aryl hydrocarbon receptor (AhR), and activates the signaling of AhR in astrocytes. The activated AhR inhibits the transcription of nitric oxide synthase (NOS), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and C-C motif chemokine ligand 2 (CCL2), which show antiinflammatory effects. Finally, indoxyl sulfate suppresses nuclear factor-κB (NF-κB) signals in astrocytes, which promote inflammation and neurodegeneration in the CNS. NRF2, nuclear factor erythroid 2-related factor 2.