**2. Dysbiosis in chronic kidney disease**

Uremic toxins are substances produced by protein metabolism. This substance accumulates in patients with chronic kidney disease (CKD) and produce deterioration of physiologic and biochemical functions that contribute to gastrointestinal symptoms, malnutrition, and progression of end-stage kidney disease [1].

Under normal circumstances, native bacteria are acquired at birth and during the first year of life, and some other transit bacteria are acquired during our daily food and fluid intake. Acids and bile from gastric and pancreatic enzymes secretion prevent most bacteria to grow in the first part of the gastrointestinal tract; but from past the duodenum until the distal colon, there is a population of some 100 billions bacteria that live in symbiosis with the human host [2], and that studies have shown that have roles in metabolic and nutritional function; protection from invasive infectious agents; proliferation and differentiation of intestinal epithelia; and modulation of immune system [3].

Approximately, 10 g of protein reaches the colon daily, where it is broken down by gut bacteria to metabolites such as ammonium, amines, thiols, phenols, and indoles. These products are normally eliminated by the feces, and a part are absorbed and eliminated by the kidney [4].

With progression of CKD, disorders of the intestinal microflora occur (dysbiosis), and there is an alteration in the quantity and quality of its composition and metabolic activities [5]. Rising urea levels and the spread of urease bacteria increase ammonium production in the intestinal lumen and induce changes in intestinal pH, altering the permeability of the intestinal mucosa, by affecting the enterocytes in the tight junction, producing an infiltration of mononuclear leukocytes in the lamina propria that is associated with an increased thickening of the colonic wall [6].

In addition to the decrease in the clearance of waste products, CKD patients use multiple medications, have a decrease in dietary fiber consumption, and need oral iron and frequent use of antibiotics that also produce alterations in intestinal transit [7]. Patients in hemodialysis have episodes of hypervolemia alternated with ultrafiltration and, sometimes, hypotension that can cause episodes of transient intestinal ischemia and also increase the permeability of the intestinal barrier and, with this, favor the passage of endotoxins [6].

There are more than 100 substances that have been identified as uremic toxins, and studies continue to suggest more each day. There are some characteristics that these substances must meet to be considered as uremic toxins: identification and measurement should be possible and levels should be elevated in CKD patients and when decreased, symptoms should improve [8–10].

There are differences in their physicochemical characteristics, as size, weight and clearance, and site of origin, that have allowed them to be classified into small water-soluble, small middle, medium-middle size, large-middle molecules, and protein-bound compounds. Some of these compounds are derived from endogenous metabolism and are water-soluble, but some are gut derived from dysbiosis and can be water-soluble or protein-bound (**Table 1**) [11, 12].

#### **2.1 Small molecules (water-soluble and protein-bound)**

The water-soluble small molecules have the characteristic that they can be easily removed with any type of dialysis (low-flux hemodialysis). Among these, we have creatine, creatinine, urea, and uric acid. The protein-bound small molecules, such as indoxyl sulfate, P-cresyl sulfate, and homocysteine, are difficult to remove by available dialysis techniques and are known to have toxic activity. Studies have confirmed *Uremic Toxins: The Role of the Gut and the Kidneys DOI: http://dx.doi.org/10.5772/intechopen.109845*


*ADMA: asymmetric dimethylarginine; TMAO: trimethylamine-N-oxide, SDMA: symmetric dimethylarginine; FLC: free light chain; TNF: tumor necrosis factor; FGF: Fibroblast growth factor; AOPP: Advanced oxidative protein products; IL: Interleukin; AGEs: Advanced glycation end products; CX: chemokine; and YKL: chitinase like protein. \* All dialyzer types can remove small water soluble compounds, but for each molecular weight group, there is a dialysis modality with a higher capacity to remove each group of compounds: HD: hemodialysis; HDF: hemodiafiltration;* 

*MCO medium cutoff; HDx: expanded hemodialysis; HCO: high cutoff.*

*\*\* Molecules removed by MCO HDx. Adapted from: Rosner et al. [12].*

#### **Table 1.**

*Classification of uremic toxins.*

that these molecules get better removal with a medium cutoff (MCO) membrane and expanded hemodialysis (HDx) [13, 14].

There are different indoles substances, produced by degradation of tryptophan by intestinal bacteria and subsequently sulfated in the liver. Indoxyl sulfate has been found to be the most abundant in uremic patients [15]. Studies have demonstrated a relation with renal fibrosis and progression of end-stage renal disease and an association with endothelial damage, as this substance can inhibit endothelial repair functions and free radical production [16].

P-cresol is a phenol produced by the metabolism of phenylalanine and tyrosine and then conjugated in the intestinal wall to p-cresyl sulfate and to p-cresyl glucuronide in the liver, being p-cresyl sulfate the main metabolite circulating in the cresol group [17].

#### **2.2 Small middle molecules**

These substances have a higher molecular weight. β2-microglobuline, PTH, and IL-8 can be removed by using high-flux hemodialysis (HD-high flux). The accumulation of β2-microglobuline in osteoarticular or viscera is known as dialysis-associated amyloidosis, and deposits contributes to destructive lesions of bones and joints and vascular damage [18].

#### **2.3 Medium middle molecules**

These molecules can be removed from plasma by using convective (hemofiltration or hemodiafiltration) or large-pore membrane dialysis techniques, such as peritoneal dialysis and high-flux hemodialysis. Some of these are myoglobin, prolactin, interleukins (IL-1B, IL-6, IL-10, and IL-18), and Kappa-free light chain, and they contribute to maintaining a state of chronic inflammation [19].

#### **2.4 Large middle molecules**

These group of molecules are composed by cytokines, growth factors, and signaling proteins; but since they are retained in uremia and clearance for these molecules is difficult with low-flux hemodialysis techniques, the accumulation of these substances is associated with endothelial dysfunction and cardiovascular disease [20].

#### **2.5 Large molecules**

In this group, we find that albumin, but in the presence of uremia, suffers an irreversible nonenzymatic post-translational modification, called carbamylation, that is associated with pro-atherogenic, endothelial dysfunction, monocyte adhesion, and cardiovascular mortality [21].
