The findings of the present study suggested that ESKD-MCI results in more impairments in multiple cognitive domains, including global cognition, visuospatial and executive function, and memory, when compared to ESKD-NCI. VBM analysis revealed that both the ESKD-MCI and ESKD-NCI groups presented with diffuse reductions in GM volumes compared to HCs. Notably, the extent of compromised GM was broader in the ESKD-MCI group compared to the ESKD-NCI group. The GM volumes of the right HIP, right PHG, right ROL, and right SMG were lower in the ESKD-MCI than the ESKD-NCI group, using a more liberal uncorrected statistical threshold. Moreover, in the ESKD-MCI group, the volumes of the right HIP and PHG were found to have a negatively correlation with serum calcium levels.

We observed that in comparison to HCs, patients with ESKD-MCI exhibited poorer performance across various cognitive domains, including global cognition, visuospatial and executive function, attention, memory, and processing speed. Compared to patients with ESKD-NCI, patients with ESKD-MCI performed poorly in global cognition, visuospatial and executive function, delayed recall, and immediate recall. These findings align with the hallmark features of MCI, characterized by subtle deficits in one or more crucial cognitive domains (Petersen 2011). While MCI does not interfere with patients’ activities of daily life, it may reduce adherence to complex regimens routinely prescribed to patients with ESKD, and influence the decision-making of ESKD treatment options (Kurella Tamura and Yaffe 2011). Consequently, it becomes imperative for clinicians to heighten their focus on screening for cognitive function among individuals with ESKD. Medical history and neuropsychological examinations are the primary tools used to diagnose MCI. Among the neuropsychological methods, the MoCA stands out as a specifically designed tool for MCI screening (Nasreddine et al. 2005). It is widely used in the auxiliary diagnosis of MCI-related disease entities such as AD-MCI (Julayanont et al. 2014), PD-MCI (Dalrymple-Alford et al. 2010), and hypertension-MCI (Mehra et al. 2020), due to its high sensitivity and superiority over the Mini-Mental State Examination (MMSE) (Pinto et al. 2019). A previous research had indicated that CI, including MCI and dementia, is prevalent among young (21–44 years, approximately 10%) and middle-aged (45–54 years, nearly 20%) hemodialysis patients with ESKD (Kurella Tamura and Yaffe 2011). To mitigate the potential influence of age and dialysis treatment on morphological brain changes, our study deliberately selected young and middle-aged patients with ESKD who had not undergone dialysis. Furthermore, delving into the neurobiological mechanisms underpinning the development of MCI in patients with ESKD would offer valuable insights.

We actually observed that patients with ESKD are not clinically screened for MCI among patients with ESKD, potentially attributed to the lack of effective interventions. A previous study’s findings underscored the significant role played by ESKD-related vascular factors and uraemic neurotoxins in CI (Viggiano et al. 2020b). Although there are no effective drugs for treating MCI, vascular risk factors control and physical and mental activities present promising avenues for patients with ESKD. These strategies can enhance the well-being of patients and caregivers and reduce the risk of poor outcomes (Kurella Tamura and Yaffe 2011; Langa and Levine 2014). Furthermore, our study’s results indicated that patients categorized as having with ESKD-NCI were considered to lack cognitive decline, still differed from HCs in global cognition, memory, and processing speed. These results indicate that patients with ESKD who rely on clinical symptoms and cognitive scales to be divided into groups without CI still may have mild cognitive decline and should be closely monitored.

The VBM analysis revealed that in comparison to HCs, both the ESKD-MCI and ESKD-NCI groups presented a reduction in diffuse GM volumes. As expected, the ESKD-MCI group had a greater extent of brain damage than the ESKD-NCI group. Specifically, the ESKD-MCI group displayed lower GM volume in the right IFG, left ORBsup, left PreCG, left PoCG, left STG, left MTG, left ROL, right ITG, right FFG, left REC, right PHG, and certain right cerebellar regions. These brain regions are implicated in various aspects of cognitive function. For instance, the FFG is primarily responsible for advanced visual functions like face perception and object recognition (Rapcsak 2019). The REC, also called the straight gyrus, situated at the base of the prefrontal cortex, and although its specific function has not yet been elucidated, it may be involved in higher cognitive functioning (e.g., personality) (Selden et al. 1998). The cerebellum plays a role in cognitive and emotional functions, with right-lateralised observed for language and left-lateralised for spatial functions (Schmahmann 2019). Neurodegeneration and direct neuronal injury caused by shared risk factors for the brain and kidney, nephrogenic risk factors, and ESKD treatment-associated risk factors are the primary pathophysiological mechanisms of CI in patients with ESKD (Kurella Tamura and Yaffe 2011). The findings of our study indicate that patients with ESKD-MCI exhibit diffuse structural brain damage that may underlie impairments in multiple cognitive domains.

Previous studies have shown extensive changes in GM volumes alterations among patients with ESKD (Qiu et al. 2014; Li et al. 2018; Wang et al. 2022; Chiu et al. 2019; Gu et al. 2021; Chai et al. 2015), although the results of these studies may vary depending on the sample selection and analytical methodologies. Few studies, however, have stratified the degree of CI among patients with ESKD. Zhang et al. divided patients with ESKD receiving dialysis into minimal nephro-encephalopathy (MNE) and non-nephro-encephalopathy groups, based on their clinical symptoms and attention function (Zhang et al. 2013). This study showed GM volume reduction in the right middle frontal gyrus, right PoCG, right occipital lobe, and left insula in ESRD patients with MNE. These patients receiving dialysis and different evaluation criteria for CI may be the reasons that the results differed from our findings. Recently, a study using diffusion kurtosis imaging found that disrupted brain micro-structures in patients with ESKD-MCI (Zheng et al. 2022). However, this result was based on comparisons between ESKD-MCI and HCs. In the context of our study, it is noteworthy that the observed subtle decrease in GM volume in the right HIP, right PHG, right SMG, and right ROL may signify brain regions in susceptible to damage in patients with ESKD-MCI, in contrast to patients with ESKD-NCI. It is well known that the HIP plays a critical role in episodic memory and navigation (Lisman et al. 2017), and the right HIP is more involved in the memory of locations within the environment (Burgess et al. 2002). An animal study using adult male Sprague − Dawley rats indicated that ESKD can induce cell death in HIP CA1 (Kim et al. 2014). Adjacent to the hippocampus, the PHG is a part of the limbic system. This region plays an important role in memory encoding and retrieval, scene recognition, and social context identification (Squire et al. 2004). The SMG within the inferior parietal lobule plays a role in visual word recognition (Stoeckel et al. 2009). One study showed that the right SMG may also be associated with the maintenance of the ability to recognize emotion (Wada et al. 2021). Therefore, specific damaged regions of the brain in patients with ESKD-MCI may be involved in memory, spatial localisation, visual word recognition, and auditory information processing, which is consistent with the cognitive test results in the present study. The results suggested imaging markers may be provide a relatively objective entry point for the diagnosis of MCI in ESKD patients. Unfortunately, we did not find a direct correlation between these abnormal brain regions and the cognitive scales, possibly due to the small sample size in our study. This underscores the need for larger-scale investigations to unveil potential relationships between structural brain changes and cognitive performance in the context of ESKD-MCI.

Initially, our study did not find significant correlations between the different regions of the brain and clinical measures (p < 0.05, FWE-corrected). However, using a more liberal uncorrected threshold (p < 0.001), we observed the right HIP and PHG volumes were negatively correlated with serum calcium levels in the ESKD-MCI group. Serum calcium plays critical physiological and biochemical roles in the human body, including neurotransmitter release, signal transduction, muscle contraction, and the electrophysiological stabilisation of cell membranes (Obi et al. 2018), and calcium homeostasis in the human body plays a critical role in many underlying neurological dysfunctions in chronic brain diseases during the aging process (Khachaturian 1994). Excessive calcium entry into the cell leads to an intracellular calcium overload and nerve death. Disturbances in calcium metabolism in patients with ESKD can lead to impaired neuronal Ca2+ handling, which in turn causes a series of downstream outcomes, such as synapse loss, amyloid β-peptide accumulation, mitochondrial dysfunction, oxidative stress, and inflammation (Alzheimer's Association Calcium Hypothesis Workgroup 2017), ultimately leading to CI. One study showed that calcium channel blockers have therapeutic effects on CI, due to a variety of causes (López-Arrieta and Birks 2000). These mechanisms include the inhibition of Ca2+ overload in neural cells and the blocking of the common channel of neural cell death. The authors hypothesized that the correlation between the decrease in HIP/PHG volumes and increased serum calcium in patients with ESKD-MCI may be due to increased intracellular calcium influx, leading to neuronal death in the HIP/PHG. The findings underscored the significance of maintaining calcium homeostasis as a critical factor in the prevention of CI among patients with ESKD. This insight not only highlights the potential contribution of calcium dysregulation to cognitive decline but also underscores the importance of investigating and optimizing calcium-related interventions to improve CI in this population.

The present study has several limitations. Firstly, it was a cross-sectional study with a small sample size. Sample size expansion and further longitudinal studies are needed to evaluate the changes in brain morphology and CI in patients with ESKD. Additionally, animal studies may better explore the molecular mechanisms of GM volume changes and elucidate their causal relationships. Moreover, the diagnosis of MCI in patients with ESKD requires more comprehensive diagnostic criteria. Therefore, objective and stable imaging diagnostic markers need to be explored further. Incorporating such markers might improve the precision of identifying CI and tracking their progression.