The Association of Renal Dysfunction with Gut Dysbiosis in Heart Failure, LVAD and Heart Transplant Patients - A Mediation Analysis

Abstract

<h3>Purpose</h3> Cystatin C (CysC), a marker of renal function not affected by muscle mass, is superior to conventional creatinine-based assessment in advanced heart failure (HF). Gut dysbiosis, gut-derived metabolites, such as trimethylamine-N-oxide (TMAO), oxidative stress, inflammation and endotoxemia have been implicated in the progression of renal dysfunction. Herein, we aim to investigate the association of the above listed mediators with CysC-estimated glomerular filtration rate (eGFR_CysC) across a broad spectrum of HF categories (HF, LVAD, Heart Transplant (HT)). <h3>Methods</h3> Concomitant blood and stool samples were prospectively collected in a cohort of advanced HF pts. LVAD and HT pts were longitudinally sampled at serial time points. CysC, TMAO, and biomarkers of inflammation (TNFα), oxidative stress (isoprostane) and endotoxemia (LPS) were measured in serum. Stool samples were analyzed using 16S rRNA sequencing. Alpha diversity (number and distribution of bacterial taxa within samples) was defined using Shannon Index. Adjusted linear mixed models were used to regress eGFR_CysC on Shannon Index and other biomarkers. <h3>Results</h3> Among 200 pts (58±13 y, 82%M), a total of 282 blood and 282 stool samples (HF=90, LVAD=104, HT=88) were collected. Decreased Shannon Index and higher levels of TMAO, TNFα, isoprostane, but not LPS, were correlated with lower eGFR_CysC. The association between Shannon Index and eGFR_CysC remained significant in models including TMAO and isoprostane, but statistical significance was lost when TNFα was included (Fig.1A). The lowest eGFR_CysC was found in pts with the lowest tertile of Shannon index and highest tertile of TMAO (Fig.1B). <h3>Conclusion</h3> Gut dysbiosis, TMAO, inflammation and oxidative stress are associated with renal dysfunction among advanced HF pts. The association of gut dysbiosis with renal dysfunction is attenuated after adjustment for TNFα, suggesting that inflammation may act as a causal mediator of this relationship.