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Review

Chronic kidney disease‑associated encephalopathy: Clinical features, pathomechanisms and emerging therapeutic strategies (Review)

  • Authors:
    • Nanling Zeng
    • Ling Jiang
    • Yang Zhang
    • Jian Liu
    • Qiong Zhang
    • Lishang Liao
    • Qiongdan Hu
  • View Affiliations / Copyright

    Affiliations: Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China, Department of Blood Transfusion, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China, Department of Neurosurgery, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
  • Article Number: 259
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    Published online on: July 21, 2026
       https://doi.org/10.3892/mmr.2026.13969
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Abstract

Chronic kidney disease (CKD) is a progressive disorder whose systemic effects extend to the central nervous system, leading to CKD‑associated encephalopathy. Epidemiological data indicate that the prevalence of cognitive impairment in patients with CKD is as high as 40%, while mood disorders such as depression and anxiety exceed 60% among those receiving hemodialysis, and the risk of cerebrovascular events is also notably increased. These complications substantially impair the quality of life of patients, functional independence and long‑term prognosis, thereby constituting a considerable clinical burden. The key pathological mechanisms involve disruption of the ‘gut‑kidney‑brain axis’. Declining renal function leads to the accumulation of gut microbiota‑derived uremic toxins, such as indoxyl sulfate, p‑Cresyl sulfate and trimethylamine N‑oxide. Through multiple pathways, including disruption of blood‑brain barrier integrity, induction of neuroinflammation, promotion of oxidative stress and direct neurotoxicity, these toxins collectively contribute to the injury of the neurovascular unit, neuronal dysfunction and even neurodegeneration. The present review systematically outlines the clinical manifestations, the aforementioned core pathogenic mechanisms and emerging therapeutic strategies for CKD‑associated encephalopathy. Clinically, early identification of neurological complications (such as through neuropsychological assessment, gait analysis and neuroimaging), along with monitoring of specific biomarkers, is crucial for timely intervention and improved prognosis. In terms of treatment, the targeted interventions on the gut‑kidney‑brain axis (such as specific probiotics and intestinal adsorbents), and the advantages and disadvantages of stem cells and gene therapy are summarized in the present review. A deeper understanding of these mechanisms will provide a solid theoretical foundation for the development of innovative treatments and ultimately improve neurological outcomes in patients with CKD.
View Figures

Figure 1

Systemic effects and common
complications of chronic kidney disease. When renal function is
abnormal, it can cause pathological changes in numerous systems of
the whole body. Patients may present with a variety of
complications, including cerebrovascular accidents (cerebral
infarction and cerebral hemorrhage), movement disorders (dystonia,
chorea, tremor and reticular myoclonus), cognitive disorders
(neurodegenerative diseases and cognitive decline), systemic
inflammation and pain, bone diseases, vascular damage and
cardiopulmonary complications. The figure was created using
Figdraw.

Figure 2

Gut-kidney-brain axis. 1. In patients
with CKD, the renal excretion of gut-derived metabolites (IS, pCS
and TMAO) is impaired. 2. IS translocates to the CNS and activates
the AhR, leading to the overproduction of ROS and subsequent
oxidative stress. 3. IS exacerbates cellular oxidative damage by
inhibiting the Nrf2 pathway. 4. IS activates the NF-κB signaling
pathway, upregulating the expression of pro-inflammatory cytokines
(TNF-α, IL-6 and IL-1β). 5. AhR, along with NF-κB, synergistically
activates the NLRP3 inflammasome. 6. pCS activates the EGFR, which
further upregulates the expression and activity of MMP-2/9. 7. pCS
also triggers the NF-κB pathway, promoting the release of
inflammatory mediators (TNF-α and IL-6). 8. TMAO inhibits the TGF-β
signaling pathway, downregulating the expression of tight junction
proteins and compromising BBB integrity. 9. TMAO activates the
NLRP3 inflammasome, amplifying the inflammatory cascade. 10.
Collectively, these pathways lead to BBB disruption. The figure was
created using Figdraw. CKD, chronic kidney disease; IS, indoxyl
sulfate; pCS, p-Cresyl sulfate; TMAO, trimethylamine N-oxide; CNS,
central nervous system; AhR, aryl hydrocarbon receptor; ROS,
reactive oxygen species; Nrf2, nuclear factor erythroid 2-related
factor 2; BBB, blood-brain barrier; NLRP3, NOD-like receptor family
pyrin domain-containing protein 3; ZO-1, zonula occludens 1.

Figure 3

Schematic diagram of treatment of
CKD-related encephalopathy. The treatments for CKD-related
encephalopathy can be divided into conventional therapy, such as
pharmacotherapy and hemodialysis, lifestyle and rehabilitation
interventions, including a scientific diet and regular exercise,
kidney transplantation, intestinal microecological intervention,
stem cell therapy and gene therapy, such as gene editing
technology. The figure was created using Figdraw. CKD, chronic
kidney disease.
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Copy and paste a formatted citation
Spandidos Publications style
Zeng N, Jiang L, Zhang Y, Liu J, Zhang Q, Liao L and Hu Q: Chronic kidney disease‑associated encephalopathy: Clinical features, pathomechanisms and emerging therapeutic strategies (Review). Mol Med Rep 34: 259, 2026.
APA
Zeng, N., Jiang, L., Zhang, Y., Liu, J., Zhang, Q., Liao, L., & Hu, Q. (2026). Chronic kidney disease‑associated encephalopathy: Clinical features, pathomechanisms and emerging therapeutic strategies (Review). Molecular Medicine Reports, 34, 259. https://doi.org/10.3892/mmr.2026.13969
MLA
Zeng, N., Jiang, L., Zhang, Y., Liu, J., Zhang, Q., Liao, L., Hu, Q."Chronic kidney disease‑associated encephalopathy: Clinical features, pathomechanisms and emerging therapeutic strategies (Review)". Molecular Medicine Reports 34.3 (2026): 259.
Chicago
Zeng, N., Jiang, L., Zhang, Y., Liu, J., Zhang, Q., Liao, L., Hu, Q."Chronic kidney disease‑associated encephalopathy: Clinical features, pathomechanisms and emerging therapeutic strategies (Review)". Molecular Medicine Reports 34, no. 3 (2026): 259. https://doi.org/10.3892/mmr.2026.13969
Copy and paste a formatted citation
x
Spandidos Publications style
Zeng N, Jiang L, Zhang Y, Liu J, Zhang Q, Liao L and Hu Q: Chronic kidney disease‑associated encephalopathy: Clinical features, pathomechanisms and emerging therapeutic strategies (Review). Mol Med Rep 34: 259, 2026.
APA
Zeng, N., Jiang, L., Zhang, Y., Liu, J., Zhang, Q., Liao, L., & Hu, Q. (2026). Chronic kidney disease‑associated encephalopathy: Clinical features, pathomechanisms and emerging therapeutic strategies (Review). Molecular Medicine Reports, 34, 259. https://doi.org/10.3892/mmr.2026.13969
MLA
Zeng, N., Jiang, L., Zhang, Y., Liu, J., Zhang, Q., Liao, L., Hu, Q."Chronic kidney disease‑associated encephalopathy: Clinical features, pathomechanisms and emerging therapeutic strategies (Review)". Molecular Medicine Reports 34.3 (2026): 259.
Chicago
Zeng, N., Jiang, L., Zhang, Y., Liu, J., Zhang, Q., Liao, L., Hu, Q."Chronic kidney disease‑associated encephalopathy: Clinical features, pathomechanisms and emerging therapeutic strategies (Review)". Molecular Medicine Reports 34, no. 3 (2026): 259. https://doi.org/10.3892/mmr.2026.13969
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