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Chronic kidney disease and neurological disorders: are uraemic toxins the missing piece of the puzzle?

ABSTRACT: Chronic kidney disease (CKD) perturbs the crosstalk with others organs, with the interaction between the kidneys and the heart having been studied most intensively. However, a growing body of data indicates that there is an association between kidney dysfunction and disorders of the central nervous system. In epidemiological studies, CKD is associated with a high prevalence of neurological complications, such as cerebrovascular disorders, movement disorders, cognitive impairment and depression. Along with traditional cardiovascular risk factors (such as diabetes, inflammation, hypertension and dyslipidaemia), non-traditional risk factors related to kidney damage (such as uraemic toxins) may predispose patients with CKD to neurological disorders. There is increasing evidence to show that uraemic toxins, for example indoxyl sulphate, have a neurotoxic effect. A better understanding of factors responsible for the elevated prevalence of neurological disorders among patients with CKD might facilitate the development of novel treatments. Here, we review (i) the potential clinical impact of CKD on cerebrovascular and neurological complications, (ii) the mechanisms underlying the uraemic toxins' putative action (based on pre-clinical and clinical research) and (iii) the potential impact of these findings on patient care.

SUBMITTER: Liabeuf S

PROVIDER: S-EPMC8713157 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AIDS dementia complex (ADC) and HIV-associated neurocognitive disorders (HAND) are complications of HIV-1 infection. Viral infections are risk factors for the development of neurodegenerative disorders. Aging is associated with low-grade inflammation in the brain, i.e., the inflammaging. The molecular mechanisms linking immunosenescence, inflammaging and the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease, are largely unknown. ADC and HAND share some pathological features with AD and may offer some hints on the relationship between viral infections, neuroinflammation, and neurodegeneration. ?2-microglobulin (?2m) is an important pro-aging factor that interferes with neurogenesis and worsens cognitive functions. Several studies published in the 80-90s reported high levels of ?2m in the cerebrospinal fluid of patients with ADC. High levels of ?2m have also been detected in AD. Inflammatory diseases in elderly people are associated with polymorphisms of the MHC-I locus encoding HLA molecules that, by associating with ?2m, contribute to cellular immunity. We recently reported that HLA-C, no longer associated with ?2m, is incorporated into HIV-1 virions, determining an increase in viral infectivity. We also documented the presence of HLA-C variants more or less stably linked to ?2m. These observations led us to hypothesize that some variants of HLA-C, in the presence of viral infections, could determine a greater release and accumulation of ?2m, which in turn, may be involved in triggering and/or sustaining neuroinflammation. ADC is the most severe form of HAND. To explore the role of HLA-C in ADC pathogenesis, we analyzed the frequency of HLA-C variants with unstable binding to ?2m in a group of patients with ADC. We found a higher frequency of unstable HLA-C alleles in ADC patients, and none of them was harboring stable HLA-C alleles in homozygosis. Our data suggest that the role of HLA-C variants in ADC/HAND pathogenesis deserves further studies. If confirmed in a larger number of samples, this finding may have practical implication for a personalized medicine approach and for developing new therapies to prevent HAND. The exploration of HLA-C variants as risk factors for AD and other neurodegenerative disorders may be a promising field of study.

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Chronic kidney disease and neurological disorders: are uraemic toxins the missing piece of the puzzle?

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