Introduction

With the advancement of dialysis technology, the life cycle of End-stage renal disease (ESRD) patients is prolonged. However, cognitive impairment (CI), including mild cognitive impairment (MCI) and dementia, has merged as critical factor affecting the quality of life for ESRD patients¹. While MCI doesn’t significantly affect patients' daily activities, it substantially elevates the risk of progressing to irreversible dementia. The underlying neurobiological mechanism for ESRD patients with MCI (ESRD-MCI) remains unclear. This study aimed to explore alterations in brain structure and identify clinical risk factors in ESRD- MCI patients.

Methods

This study protocol was registered at ClinicalTrials. gov (NCT03961724, https://clinicaltrials.gov/ct2/show/NCT03961724) and received local ethics committee approval (XJTU1AF-CRF-2018-006). Patients with ESRD who received regular hemodialysis were recruited from the Department of Nephrology at the local hospital. Health controls (HCs) were recruited by posting advertisements in the local community. All MR examinations were performed on a 3.0T MR scanner (Discovery MR750: GE Healthcare, Chicago, IL, USA) equipped with a 24-channel head-neck unite coil. Structural image data for each participant were obtained using a three-dimensional brain volume imaging sequence (3D-BRAVO) with the following parameters: echo time = 3.2 ms; repetition time = 8.2 ms; flip angle = 15°; slice thickness = 1 mm; matrix = 256 × 256; slices number = 140. All participants completed Montreal Cognitive Assessment (MoCA) assessment and were divided into three groups (MoCA scores ≥26, ESRD with non-CI (ESRD-NCI) group and HCs group; MoCA scores 18-26, ESRD-MCI group). Clinical blood indicators were collected for ESRD patients. T1 image data were processed using the Computational Anatomy Toolbox 12 software (CAT12, http://www.neuro.uni-jena.de/cat/) in MATLAB 2021a (MathWorks Inc., Natick, USA). General clinical data were analyzed using SPSS software (version 26.0; IBM Corp, Armonk, NY, USA). And grey matter (GM) volume differences among the three groups were analyzed using voxel-based morphometry (VBM) with CAT12. In addition, correlation analysis using SPSS software was performed to determine the association among GM volume changes, clinical risk factors, and MCI.

Results

A total of 65 ESRD patients (34 ESRD-MCI and 31 ESRD-NCI) and 55 HCs were included (Figure 1). Compared with HCs, both ESRD-MCI and ESRD-NCI patients showed decline in multiple cognitive domains function (Table 1) and reduction in diffuse GM volume (p < 0.05 FWE-corrected) (Figure 2A-B). In addition, when compared with ESRD-NCI patients, ESRD-MCI patients showed decreased GM volume in the left middle temporal gyrus (MTG) (p < 0.05 FWE-corrected) (Figure 2C). In the ESRD-MCI group, significant correlations were found among GM volume, MoCA scores, and serum phosphorus levels. A further mediation analysis showed decreased GM volume in the left MTG completely mediates the effect of serum phosphorus levels on MCI (Figure 3).

Discussion

MCI in ESRD encompasses impairment in multiple cognitive domains, including executive function, attention, memory, language, etc. MCI exhibits high heterogeneity with various underlying etiologies, such as Alzheimer’s disease and vascular cognitive impairment². These distinct etiologies of MCI have different mechanisms and treatment strategies. Therefore, early identification of MCI in ESRD patients can provide a theoretical basis for precise clinical treatment such as TMS intervention targets. Neuroimaging techniques, particularly MRI, provide a simple, objective, and reproducible detection method for the identification of MCI. In comparison to HCs, a previous study has found extensive structural brain abnormalities in ESRD patients with MCI³. But few studies have compared brain structural differences between ESRD-MCI and ESRD-NCI patients. Our study found that ESRD-MCI patients showed decreased GM volume of the left MTG compared to ESRD-NCI. The left MTG is primarily responsible for storing semantic knowledge, a crucial component of our daily behaviors and communication^4,5. Furthermore, our mediation analysis indicated that the decreased GM volume of the left MTG fully mediated the impact of serum phosphorus levels on MCI. Maintaining appropriate serum phosphorus levels is vital for cellular function. Elevated serum phosphate levels in dialysis patients can result from variation in varying dialytic removal, phosphate absorption, and phosphate binder efficacy⁶. Previous studies have shown that hyperphosphatemia is associated with CI, although the mechanism remains unclear. It may be related to elevated phosphate leading to medial calcification and endothelial dysfunction, which induces vascular injury, and then causes CI⁷. However, hypophosphatemia can also adversely affect the brain. Therefore, determining the appropriate range for serum phosphorus control in the clinical practice is essential for the prevention of MCI in ESRD patients.

Conclusion

We found that the left MTG is a critical brain region for MCI and increased serum phosphate maybe a risk factor for MCI in ESRD patients. This result provides a theoretical basis for clinical intervention for MCI in ESRD patients.

References

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