Association of Phenylacetylglutamine and Cognitive Impairment in CKD

Abstract

Introduction: Chronic kidney disease (CKD) leads to the accumulation of uremic toxins (UTs). Studies have suggested that UTs are associated with cognitive impairment (CI) in patients with CKD. Recently, studies reported that phenylacetylglutamine (PAG) contributes to the association between CKD and CI. However, this association has not been investigated in nondialysis-dependent adults with CKD.

Methods: The CKD-Renal Epidemiology and Information Network (CKD-REIN) cohort study included 3033 patients with CKD stages 2 to 5. This cross-sectional analysis included those with a PAG measurement and a mini-mental state examination (MMSE) score within 3 months of each other. CI was defined as an MMSE score ≤ 26 out of 30. Logistic regression was used to assess the association between PAG and CI.

Results: Of the 2590 patients included (mean [SD] age: 67 [13] years, mean [SD] estimated glomerular filtration rate [eGFR]: 34 [13] ml/min per 1.73 m², median [interquartile range, IQR] PAG level: 2.1 [1.2-3.6] mg/l), 908 (35%) presented an MMSE score ≤ 26 out of 30. After adjustment for sociodemographic factors (age, male sex, and educational level), cardiovascular risk factors, cerebrovascular disease, current depression, eGFR, urinary albumin-to-creatinine ratio (uACR), and UTs known to be associated with CI risk, a 2-fold increase in the PAG level was associated with CI (odds ratio [OR] [95% confidence interval]: 1.12 [1.01-1.23]).

Conclusion: This study shows that a higher serum PAG level was associated with CI in nondialysis-dependent adults with CKD and highlight a new UT associated with CI in patients with CKD. Further studies are needed to confirm the causal nature of the association and to explore strategies for reducing serum PAG levels to protect cognition.

Keywords: chronic kidney disease; cognition; phenylacetylglutamine; uremic toxins.

Graphical abstract

Figure 1

Study flowchart. MMSE, Mini-Mental State Examination; UTs, uremic toxins.

Figure 2

Association between log₂[total PAG] and a MMSE score ≤ 26/30, in unadjusted and adjusted logistic regressions (N = 2590). Model 1 was adjusted for log₂[total PAG], age, male sex, and educational level. Model 2 was adjusted for log2[total PAG], age, male sex, educational level, hypertension, diabetes mellitus, dyslipidemia, obesity, current smoking, cerebrovascular disease, depression, log₂Σ(total TMAO, free IS, free pCS). Model 3 was adjusted for Log2 [total PAG], age, male sex, educational level, hypertension, diabetes mellitus, dyslipidemia, obesity, current smoking, cerebrovascular disease, depression, log2S(total TMAO, free IS, free pCS), eGFR and uACR. CI, confidence interval; eGFR, estimated glomerular filtration rate oxide; IS, indoxyl sulfate; MMSE, Mini-Mental State Examination; OR, odds ratio; PAG, phenylacetylglutamine; pCS, p-cresyl sulfate; TMAO, trimethylamine; uACR, urinary albumin-to-creatinine ratio.