Plasma Short-Chain Fatty Acids and Cytokine Profiles in Chronic Kidney Disease: A Potential Pathophysiological Link

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Abstract
Sarcopenia is highly prevalent among patients with chronic kidney disease (CKD) and chronic heart failure (CHF), yet the underlying immunometabolic mechanisms remain insufficiently understood. Short-chain fatty acids (SCFAs), inflammatory cytokines, and body-composition alterations may jointly contribute to the development of muscle dysfunction in this population. In this cross-sectional study, 80 patients with CKD and CHF underwent comprehensive clinical, biochemical, bioimpedance, inflammatory, and SCFA profiling. Sarcopenia was diagnosed according to EWGSOP2 criteria. Multivariable logistic regression, LASSO feature selection, correlation analysis, PCA, and Random Forest modeling were used to identify key determinants of sarcopenia. Sarcopenia was present in 39 (49%) participants. Patients with sarcopenia exhibited significantly lower body fat percentage, reduced ASM, and slower gait speed. Hexanoic acid (C6) showed an independent positive association with sarcopenia (OR = 2.24, 95% CI: 1.08–5.37), while IL-8 showed an inverse association with sarcopenia (OR = 0.38, 95% CI: 0.13–0.94), indicating that lower IL-8 levels were more frequently observed in individuals with sarcopenia. Correlation heatmaps revealed distinct SCFA–cytokine coupling patterns depending on sarcopenia status, with stronger pro-inflammatory clustering in C6-associated networks. The final multivariable model integrating SCFAs, cytokines, and body-composition metrics achieved excellent discrimination (AUC = 0.911) and good calibration. Sarcopenia in CKD–CHF patients represents a systemic immunometabolic disorder characterized by altered body composition, chronic inflammation, and dysregulated SCFA signaling. Hexanoic acid (C6) and IL-8 may serve as informative biomarkers of muscle decline. These findings support the use of multidimensional assessment and highlight potential targets for personalized nutritional, microbiota-modulating, and rehabilitative interventions.

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