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  • br Introduction Chronic kidney disease CKD

    2024-04-17


    Introduction Chronic kidney disease (CKD) is a worldwide public health problem. This problem is even worse in socioeconomically deprived countries because lower income and social deprivation are associated with higher incidence of reduced GFR, progressive kidney function loss and end stage renal disease (ESRD) [1], [2], [3]. Therefore, CKD is likely to be higher in China and other socioeconomically deprived countries with rising burden of diabetes and hypertension than in western countries [4], [5]. CKD is associated with the accumulation of various metabolites, i.e., uremic retention solutes. With the progression of CKD, various uremic toxins accumulate in the body, subsequently causing renal damage and hypertension [6], [7], [8]. Most of these uremic retention solutes are derived from gut amino acid, which can be metabolized by colonic microbiota. Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are among the most extensively studied uremic retention solutes derived from gut microbiota, and their role in CKD has been demonstrated. They are associated with the incidence of cardiovascular disease, overall mortality and CKD progression. While in some cases, even if IS and PCS were lowered, no change in CKD progression may be observed. For example, as reported in recent EPPIC trail, although IS and PCS was decreased by a kind of gut absorbant (AST-120), no change in CKD progression has been observed [9], [10], [11]. IS and PCS are prototypic protein-bound uremic toxin molecules, which are not only biomarkers for renal function but also actively participate in the development of CKD progression [12]. They share some similarities, including their production by gut bacteria [13], strong albumin binding at Sudlow II site [14], significant renal metabolism, low dialytic clearance [15], [16] and an emerging role in cardiovascular disease and mortality in renal patients [17], [18]. Most of uremic retention solutes are derived from gut protein and amino apexbio dilution metabolism. Therefore, protein was restricted in CKD patients diet. After protein was metabolized into amino acid, amino acid can be further transformed into uremic retention solutes precursor. For example, tryptophan and tyrosine are metabolized by gut microbiota into indole and p-cresol in the colon. Indole and p-cresol can be absorbed through the intestinal wall, and metabolized into IS and PCS in the gut and liver by sulfation metabolism pathway [14], [19], [20]. Thereafter, IS and PCS also undergo extensive renal clearance, which was mediated by transporters (e.g. OAT1 and OAT3) [6], [21], [22].
    Materials and methods
    Results
    Discussion CKD is a progressive, pathological condition characterized by the progressive destruction of renal parenchyma and the loss of functional nephrons over time [28]. Various pathophysiological conditions, including diabetes, hypertension, hyperlipidemia, obesity, smoking and aging, are risk factors for the progression of CKD [29], [30], [31], [32]. Although the progression of CKD may depend upon the capacity of residual nephrons to overcome stress, the mechanisms underlying the progression of CKD remain poorly understood [33]. Although various animal CKD models have been reported, rodent models tend to be more commonly employed in experimental CKD studies [23]. 5/6Nx rats model is a common model for studying the pathology of CKD, which can reflect some physiological and pathological characteristics of CKD, such as the accumulation of various metabolites. The nephrectomized rat model has been used extensively to investigate pathological changes in CKD. The remnant kidney of nephrectomized rats exhibits adaptive, compensatory growth in the days following injury, which is similar to the course of human disease [23], [24], [25]. Because most uremic toxins are excreted into urine, once uremic toxins accumulate in CKD patients, their elimination is very difficult because of reduced renal function, which also explained why the plasma concentration of IS, PCS increased in 5/6 Nx rat [26].