Gut-Brain Axis, Chronic Inflammation Important Targets for Treating CKD and Depression

Depression is often prevalent during chronic kidney disease (CKD), with experts suggesting a bidirectional relationship in which 1 condition exacerbates the other. When these conditions are both triggered, it can complicate the already complex challenge of symptom management in patients. Authors of a review published in Behavioural Brain Research evaluate the complex relationship of CKD and depression, specifically focusing on the clinical challenges and emerging insights into potential therapeutic options to improve patient outcomes.

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The authors conducted a narrative review of experimental and observational studies in both animals and humans, as well as meta-analyses to explore specific mechanisms of depression in patients with CKD and its treatment. There are similar symptoms that characterize both depression and CKD, according to the authors, including fatigue and sleep disturbances, as well as cognitive impairment or disturbances, making it somewhat difficult to differentiate between them. Experts often must use self-reported questionnaires or evaluations from patients to help diagnose and treat depression and CKD. The authors explained that fostering collaboration between nephrology and psychiatry can strengthen diagnostic accuracy.

Additionally, prior findings indicate that patients with CKD—particularly those with reduced estimated Glomerular Filtration Rate (eGFR) below 60 mL/min/1.73 m²—have a higher risk of experiencing depressive symptoms compared with those who have a normal kidney function. One study found that lower baseline eGFR, both calculated from creatinine (eGFRcr) and cystatin C (eGFRcr-cys), was significantly associated with higher depression scores over a 4-year follow-up period. Conversely, depression may also act as a risk factor for the onset of CKD. Another study demonstrated that people with depression have an approximate 38% higher risk of developing CKD compared with those who do not have depression, and depressive symptoms are associated with a higher risk of rapidly declining eGFR.

In their review, the investigators determine that the gut-brain axis is central in depression. Additionally, CKD results in an accumulation of gut-derived uremic toxins. The accumulation of tryptophan-derived uremic toxins—such as kynurenines or indoxyl sulfate whose serum concentration progressively increases with the stage of CKD (up to 100-fold in stage 5)—plays an important role within depression mechanisms by activating aryl hydrocarbon receptors, decreasing brain concentrations of serotonin, in some cases, by approximately 40%, increasing brain inflammation via activation of microglia and astrocytes, as well as the release of TNFα, IL-6, and NO.

Further, the authors also explained that disruptions in the microbiota-gut-brain axis—especially in CKD—can intensify systemic inflammation while contributing to mood dysregulation, therefore contributing to depressive symptoms. Dysbiosis, which is characterized by reduced populations of beneficial bacteria (eg, Faecalibacterium) and increased intestinal permeability, promotes systemic inflammation and contributes to neuroinflammatory processes. Changes in microbiota composition impact the production of neurotransmitters, in particular serotonin, and alter the brain’s function through microbial metabolites (eg, short-chain fatty acids). Such effects underline there is a bidirectional relationship between gut health and mental well-being, in which dysbiosis exacerbates both systemic inflammation and mood dysregulation. In addition, these mechanisms, when viewed in the context of CKD, could further be intensified by the accumulation of uremic toxins.

This information, according to the authors, emphasizes a significant need for integrated care approaches in which patients are routinely screened to receive timely management of their depressive and CKD-related symptoms. Such innovations can help improve clinical outcomes and enhance the quality of life for individuals affected by both conditions.

REFERENCE

Lefrère A, Burtey S, Bobot S, Belzeaux R, Bobot M. Depression in chronic kidney disease: Particularities, specific mechanisms and therapeutic considerations, a narrative review. Behav Brain Res. 2025;483:115467. doi:10.1016/j.bbr.2025.115467Top of FormBottom of Form