Gut-Derived Protein-Bound Uremic Toxins

Abstract

Chronic kidney disease (CKD) afflicts more than 500 million people worldwide and is one of the fastest growing global causes of mortality. When glomerular filtration rate begins to fall, uremic toxins accumulate in the serum and significantly increase the risk of death from cardiovascular disease and other causes. Several of the most harmful uremic toxins are produced by the gut microbiota. Furthermore, many such toxins are protein-bound and are therefore recalcitrant to removal by dialysis. We review the derivation and pathological mechanisms of gut-derived, protein-bound uremic toxins (PBUTs). We further outline the emerging relationship between kidney disease and gut dysbiosis, including the bacterial taxa altered, the regulation of microbial uremic toxin-producing genes, and their downstream physiological and neurological consequences. Finally, we discuss gut-targeted therapeutic strategies employed to reduce PBUTs. We conclude that targeting the gut microbiota is a promising approach for the treatment of CKD by blocking the serum accumulation of PBUTs that cannot be eliminated by dialysis.

Protection of Residual Renal Function and Nutritional Treatment: First Step Strategy for Reduction of Uremic Toxins in End-Stage Kidney Disease Patients

“…Two major factors are relevant in the kinetics of protein-bound uremic toxins in ESKD patients [ 81 ]: the first is the conservation and protection of the RKF [ 82 , 83 ], which still allows the removal; the second is the reduced production, obtained by using a lower protein intake and dietary changes inducing modifications of intestinal microbiota. Therefore, the patient in the ESKD stage can enter in a “soft” way into innovative purification strategies in which the transition from the conservative therapy with low-protein diet to the full dialysis dose can be defined as “incremental.” The first step may be represented by an OWHD regimen coupled with LPD in the non-dialysis days.…”

Medium Cut-Off Dialysis Membrane and Dietary Fiber Effects on Inflammation and Protein-Bound Uremic Toxins: A Systematic Review and Protocol for an Interventional Study

“…Most UTs have negative effects on cardiovascular, inflammatory and fibrogenic systems and may importantly contribute to high morbidity and mortality in chronic kidney disease (CKD) [ 2 ]. The clearance of some middle–large uremic toxins is insufficient by modern hemodialysis methods, while protein-bound uremic toxins (PBUTs) are even more difficult to eliminate due to their strong binding to serum proteins, with only a small fraction of the unbound solutes being removed by dialysis [ 3 ]. It is quite possible that a significant portion of the adverse effects of the residual uremic syndrome observed in today’s dialysis population is the result of the inadequate clearance of these larger and poorly eliminated PBUTs.…”

“…When considering possible strategies to reduce PBUT generation and absorption, it is important to note that many PBUTs are produced by the metabolism of food constituents in the gut microbiota, mainly amino acid metabolites, such as indoles and phenols [ 3 ]. The best studied representatives of this group are p -cresyl sulfate (PCS) and indoxyl sulfate (IS).…”

Dietary Patterns and Progression of Impaired Kidney Function in Japanese Adults: A Longitudinal Analysis for the Fukushima Health Management Survey, 2011–2015

“…In kidney function impairment, the persistent low-grade inflammation has a prominent feature, and gut microbiota dysbiosis is a source of microinflammation [ 8 ]. Studies indicated that the most harmful uremic toxins produced by the gut microbiota are protein-bound and are recalcitrant to removal by dialysis [ 9 ]; the function of uremic toxins such as indoxyl sulfate may play roles in CVD development through altered monocytes activation, intensified inflammatory process, and augmented oxidative stress [ 10 , 11 ]. In addition, CKD and Type 2 diabetes have similar negative effects on both intestinal microbiota and function [ 12 ].…”