Metabolic Wastes That Cannot Be Removed By Dialysis——a Detailed Account Of Gut-derived Uremic Toxins

Uremic toxins refer to substances that cannot be cleared through urine and remain in the body with toxic effects in end-stage renal disease (ESRD). The physical and chemical characteristics of uremic toxins can be divided into [1]:

Water-soluble small molecule toxins: relative molecular mass <500, such as creatinine, urea nitrogen, 1-methyl guanidine, trimethylamine oxide (TMAO), homocysteine and oxalate, etc.

Middle molecular toxins: relative molecular weight 500~10000, such as parathyroid hormone (PTH), cystatin C, tumor necrosis factor α, etc.

Protein-binding toxins (PBUTs): relative molecular mass > 10 000, including p-cresyl sulfate (PCS), indyl sulfate (IS), indole-3-acetic acid (IAA), phenylacetic acid, hippuric acid, etc.

Clinically, uremic toxins can be divided into three categories according to the source of their production [2]:

Endogenous metabolites: the body's metabolites, such as creatinine, uric acid, etc.

Microbial metabolites: the precursors of most microbial metabolites are synthesized by intestinal flora in the gut, that is, gut-derived uremic toxins, such as indoles, phenols, etc.

Exogenous ingestion substances: such as oxalate, etc.

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It is worth noting that most of the PBUTs are gut-derived toxins, which are difficult to be removed by dialysis due to their relatively large molecular weight due to protein binding, which poses a significant challenge for the treatment of ESRD.

Where does gut-derived uremic toxin come from?

It is related to the dysbiosis of gut microbiota

There is a complex bidirectional association between CKD and the gut microbiome:

In CKD patients, due to impaired renal function, some toxins in the body cannot be excreted in time, the intestinal transit time is slowed down, protein assimilation is impaired, dietary fiber intake is reduced, iron supplements and frequent use of antibiotics, etc. The composition and metabolism of intestinal flora change, and lead to the destruction of the intestinal epithelial barrier. Factors such as drug use and diet change further cause the disturbance of intestinal microecology.

After the intestinal flora changes, its function of maintaining the intestinal mucosal barrier is weakened. Intestinal acid-base imbalance and the occurrence of intestinal wall edema also damage the intestinal barrier function. Toxins produced by bacterial translocation or bacterial metabolism enter the blood circulation, and intestinal-derived uremic toxins such as IS, pCS, and TMAO accumulate in the body. At the same time, endotoxin exposure and inflammatory reactions further aggravate the progression of kidney disease. A vicious circle is formed.

Injury to the body caused by intestinal urea toxin accumulation

In uremic patients, the binding sites of serum albumin to target solutes are highly saturated, the expression of organic anion transporters (OATs) in renal tubular epithelial cells is significantly reduced, and the ability to clear protein-bound toxins is impaired, resulting in Such toxins are increasingly accumulated in the body. Serum albumin is unable to further bind high concentrations of protein-bound toxins in the body, resulting in increasing concentrations of free, ie, unbound toxins in the body [4]. Serum levels of free hippuric acid, IS, pCS and other toxins in patients with CKD stages 3-5 increased significantly and increased with the decline of renal function, and the protein binding rate decreased accordingly.

The free gut-derived uremic toxin can accelerate renal fibrosis and damage cardiovascular endothelial function and the central nervous system by mediating oxidative stress, activating inflammatory response, inhibiting anti-aging gene expression, and promoting Klotho gene hypermethylation It can also inhibit the main enzyme activity in the body and affect the metabolism of drugs in the body.

Strategies to reduce gut-derived uremic toxins

01 dietary adjustment

Proteins are the source of metabolic substrates for enterotoxins. High dietary protein intake is associated with worsening renal function and is related to protein sources: increased intake of red meat increases the risk of ESRD, while beans and low-fat dairy products can reduce the corresponding risk. A diet rich in dietary fiber also helps to regulate the flora structure, which can significantly reduce the levels of IS and PCS in the plasma of maintenance hemodialysis patients [5].

02 Intestinal microecological modulator

Intestinal microecological modulators [5] include:

①Probiotics: preparations containing bacteria or bacterial components, such as Bifidobacterium, Lactobacillus, etc.;

② Prebiotics: Some indigestible food components, such as bifidum factors and various oligosaccharides, can promote the growth of probiotics.

③ Synbiotics: a combination of probiotics and prebiotics. Studies have shown that the use of intestinal microecological regulators can reduce the levels of pCS and IS in the plasma of hemodialysis patients.

03 Reduce intestinal toxin accumulation

Since gut-derived toxins are mainly produced by the gut, theoretically, the use of intestinal adsorbents to absorb gut-derived toxins and their precursors, or the use of laxatives to promote the excretion of toxins, may reduce the accumulation of gut-derived toxins. AST-120 is a carbon adsorbent invented in Japan. Studies have found that AST-120 can reduce serum IS levels in uremia patients, reduce intestinal mucosal permeability, inhibit the translocation of intestinal-derived endotoxin, and reduce the micro-inflammatory state[5].

Domestic studies have found that rhubarb, a traditional Chinese medicine for dredging the bowels, has inhibitory effects on various gram-positive and harmful bacteria in the intestinal tract, such as Staphylococcus aureus, Escherichia coli, and Bacteroides fragilis. Chengqi decoction can reduce the number of various pathogenic bacteria in the intestine, reduce the secretion of short-chain fatty acid metabolites of intestinal flora, inhibit the production of toxins such as propionic acid, and improve renal pathological damage and renal function decline [6].

04 Blood purification

Methods of blood purification include HD, hemodiafiltration (HDF), hemofiltration (HF), hemoperfusion, plasma exchange, immunoadsorption, etc. The IS and PCS reduction rates of conventional HD treatment were 31.8% and 29.1%, respectively. The use of high-flux hemodialysis (HFHD) and prolonged HD can improve the clearance of PBUTs. In addition, improved dialyzer technology can also help. Large-pore superflux (SF) cellulose triacetate membranes have higher clearance than low-flux (LF) cellulose triacetate membranes. The removal effect of plasma separation and adsorption technology on PCS is significantly better than that of high-flux dialysis, but the cost of plasma separation and adsorption technology is high, and it cannot be promoted clinically at present [5].

Ibuprofen, furosemide, and tryptophan have the same plasma albumin-binding sites as IS, IAA, etc. These molecules are called albumin-binding replacement agents, which can increase the free level of PBUTs when infused during dialysis, Increasing the clearance rate of toxins [5].

05 Alpha-glucosidase inhibitors

Acarbose is an α-glucosidase inhibitor present in the intestinal brush border, which can hinder the hydrolysis of polysaccharides and oligosaccharides into monosaccharides such as glucose. Undigested carbohydrates favor the growth of saccharolytic bacteria, while proteolytic bacteria are significantly reduced, leading to lower pCS production in the colon [2].

Summary

In CKD patients, due to the imbalance of intestinal flora, the accumulation of uremic toxins leads to systemic inflammatory response and oxidative stress response, which accelerates the progress of CKD and forms a vicious circle. Gut-derived uremic toxins are the main protein-bound toxins. Limiting high-protein foods, increasing dietary fiber, supplementing probiotics or prebiotics, and regulating intestinal flora can help reduce the excessive production of gut-derived toxins at the root. At the same time, the use of Chinese and Western medicines to promote the excretion of toxins and relieve The accumulation of intestinal toxins and the preservation of residual renal function as much as possible can help to delay the progression of CKD and reduce uremic complications and mortality. How to reduce the production of intestinal-derived uremic toxins from the root and improve the clearance of protein-bound toxins is worthwhile—clinical and researcher concerns.

Reference

1. Zhang Wenting, Cai Meishun. Research progress on gut-derived uremic toxins [J]. China Blood Purification, 2022, 21(11):831-834.

2. Niu Jie, Zhu Lin, Wang Yuqing, et al. Effects of changing intestinal microecology on chronic kidney disease[J]. Chinese Journal of Integrative Medicine and Nephrology, 2023,24(4):375-376.

3. Wang Gehao, Yu Shengqiang. Interaction between chronic kidney disease and intestinal microecology [J]. Journal of Clinical Nephrology, 2019,19(9):700-705.

4. Xiangxuemei, Li Yihang, Mou Zengyi, et al. Based on the "gut-kidney axis" to explore the research progress of gut-derived uremic toxins in chronic kidney disease[J]. Chinese Journal of Experimental Formulas, 2023, 29(7 ):274-282.

5. Cheng Yun, Cao Xuesen, Zou Jianzhou. Research progress on p-cresol sulfate and indoxyl sulfate of gut-derived uremic toxins[J]. Chinese Clinical Medicine, 2015(6):815-818.

6. Wang Huiling. Progression and intervention strategies of erogenous uremic toxins and chronic renal failure [J]. Chinese Journal of Integrated Traditional Chinese and Western Medicine Nephrology, 2020, 21(1):79-81.