Uremic Toxins Directly Affect The Life Of Patients! How To Clear More Effectively?

Many discomfort symptoms in uremic patients, such as fatigue, anorexia, skin itching, and damage to multiple systems such as cardiovascular and immune systems, it is often attributed to the role of uremic toxins in clinical practice.

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Today we take a look at these uremic toxins and how blood purification removes them.

Uremic toxins refer to substances that accumulate in body tissues and blood as renal function declines and cause uremia symptoms, structural damage and dysfunction of cells, tissues, and organs, and metabolic disorders of the body. At present, there are more than 200 known uremic toxins, and there are about 30 substances that may have uremic toxic effects, and the number of newly recognized toxins is still increasing [1].

At present, according to their properties and molecular weight, they can usually be divided into three categories:

①Small molecule water-soluble solutes: relative molecular weight <500Da, such as urea, creatinine, uric acid, etc.

②Medium and macromolecular toxins: relative molecular weight ≥500Da, such as β2 microglobulin, leptin, parathyroid hormone (PTH), etc.

③Protein-binding toxoids: represented by p-cresol sulfate, indoxyl sulfate, indole-3-acetic acid, hippuric acid, etc. Although the relative molecular weight of such toxins is generally less than 500 Da, most blood purification modes are less effective at removing them because they can be combined with serum albumin. /10[1].

 Uremic toxins damage the human body

small molecule toxin

Small molecule toxins are urea, creatinine, uric acid, etc. that we see in the renal function test sheet. Because of their small molecular weight, they are easily removed by conventional hemodialysis. One hemodialysis can reduce the serum concentration of urea by ≥70%. Therefore, such toxins are less harmful to the human body and will not be discussed in detail here.

In comparison, the latter two types of toxins are difficult to be removed by conventional hemodialysis due to their large molecular weight and are easy to remain in the body. Studies in recent years have proved that they are closely related to cardiovascular events, the leading cause of death in uremia patients. Therefore, we mainly introduce the research progress and clearance methods of some middle molecular toxins and protein-bound toxins.

middle molecule toxin

β2 microglobulin is produced by lymphocytes, platelets, and polymorphonuclear leukocytes, with a molecular weight of 11,800 Da. It can only be metabolized by the kidney, and 99% of it is reabsorbed and decomposed by the renal tubules.

Factors such as acidosis, micro-inflammation environment, and dialysis mode in patients with uremia increase the production of β2 microglobulin. In patients with end-stage renal disease (ESRD), due to the accumulation of β2 microglobulin in the body, amyloid fibrils are formed in bones, joints, and internal organs, which in turn causes organ damage, which is called dialysis-associated amyloidosis and is a common complication of ESRD.

β2 microglobulin, as a representative of middle molecular toxins, is used to judge the adequacy of dialysis. Studies have shown that β2 microglobulin is related to all-cause mortality in patients with ESRD, and a concentration of less than 27.5mg/L can obtain the best survival rate.

PTH

PTH is secreted by parathyroid chief cells with a molecular weight of about 9400Da. Elevated PTH can cause bone and mineral metabolism disorders, namely chronic kidney disease mineral and bone metabolism disorders (CKD-MBD). In addition to the skeletal system, PTH has toxic effects on multiple systems throughout the body.

The higher concentration of PTH in the blood can increase the calcium content in red blood cells, thereby affecting its integrity and increasing the destruction of red blood cells. PTH can also act on white blood cells and inhibit immune responses. High concentrations of PTH can also directly inhibit the energy metabolism of cardiomyocytes, causing myocardial hypertrophy and heart failure.

Leptin

Leptin is a protein product encoded by obesity genes, most of which is secreted by white adipose tissue. Its main physiological functions include: reducing appetite, controlling energy intake and body consumption, directly inhibiting fat synthesis, affecting the endocrine, participating in the regulation of hematopoiesis and the immune system, promoting growth, and affecting reproduction, and other extensive peripheral biological effects.

Leptin is mainly metabolized by the kidneys, and leptin levels are significantly elevated in patients with ESRD. Many studies at home and abroad have shown that leptin is related to malnutrition in hemodialysis patients. Leptin levels were also associated with hemodialysis-associated muscle spasms.

protein-bound toxin

Homocysteine:

It is well known that hyperhomocysteinemia is an independent risk factor for cardiovascular events.

Studies have shown that hyperhomocysteinemia can damage endothelial cells and inhibit the repair and regeneration of blood vessels. At the same time, it is closely related to higher cardiovascular and all-cause mortality in uremic patients.

p-cresol sulfate

A prospective cohort study of elderly hemodialysis patients showed that patients with lower serum p-cresol sulfate concentrations had lower all-cause and cardiovascular event mortality than patients with higher serum p-cresol sulfate concentrations, after adjusting for age, After gender, albumin, hemoglobin levels, and other influencing factors, p-cresol sulfate was still closely related to all-cause and cardiovascular mortality.

Indoxyl Sulfate (IS)

Indole is a metabolite of tryptophan through the action of intestinal bacteria, which is further converted into indoxyl sulfate in the liver. IS has both vascular toxicity and nephrotoxicity.

Studies have found that the induction of systemic oxidative stress by IS is the key link in causing cardiovascular damage. IS can cause oxidative stress in renal tubular cells, interstitial cells, vascular smooth muscle cells, cardiomyocytes, and osteoblasts. In addition, it can cause Endothelial injury, inhibition of endothelial proliferation, and repair. Thus involved in the progression of cardiovascular disease and osteodystrophy in patients with chronic kidney disease.

The latest research shows that IS can up-regulate the expression of epithelial growth factor receptors, thereby enhancing the signal conduction of angiotensin Ⅱ, and finally leading to atherosclerosis. IS promotes the infiltration of monocytes/macrophages in the renal interstitium, produces a variety of pro-fibrotic factors, and induces renal interstitial fibrosis.

Removal of uremic toxins by different blood purification

Currently, blood purification methods commonly used in clinical practice include conventional hemodialysis, high-flux hemodialysis, hemofiltration, and hemoperfusion. As mentioned earlier, conventional hemodialysis is easy to remove small molecule toxins, but it is difficult to remove middle molecule and protein-bound toxins, which requires other blood purification methods to help remove them.

High-flux hemodialysis is a dialysis method that uses a large membrane pore size and a high-molecular polymer dialysis membrane. It has good diffusivity and permeability. It can not only remove small molecule toxins through diffusion and convection, but also removes macromolecular toxins through adsorption, and at the same time reduces inflammatory stress response [3].

Hemodiafiltration combines the advantages of both hemodialysis and hemofiltration and imitates the principle of renal tubular reabsorption and glomerular filtration to remove medium and large molecular toxins in the blood of uremic patients.

Hemoperfusion is the earliest adsorption mode used for the clinical removal of protein-bound toxoids. Since hemoperfusion itself cannot remove water, nor can it regulate electrolyte and acid-base balance, it is often used in conjunction with conventional hemodialysis.

A domestic study showed that hemoperfusion combined with hemodialysis is more effective in removing protein-bound toxoids than high-flux hemodialysis and hemodialysis [4]. But which of the three is stronger and weaker, and whether they can be replaced by the other cannot be summed up in one word.

Because there are many types of uremic toxins, but currently there are few toxins used as a standard for judging toxin clearance. For example, we often use β2 microglobulin as an indicator for judging the adequacy of dialysis. However, many other toxins are difficult to measure, so it is impossible to accurately judge the effect of different blood purification methods on removing this toxin, and which method is better.

For example, a study showed that both high-flux hemodialysis and hemodiafiltration can effectively remove large, medium, and small molecular toxins in the blood. The former can efficiently remove PTH, while the latter can better remove β2 microbes globulin.

Therefore, clinically, to help uremic patients effectively remove toxins, the above three methods are often combined to achieve a more comprehensive effect of removing toxins.

How does Cistanche treat Uremia?

Cistanche is a herb traditionally used in Chinese medicine for treating various diseases, including those related to the kidneys. Uremia is a condition in which there is an excess of waste products in the blood due to poor kidney function. Cistanche is believed to help in treating uremia by enhancing kidney function and reducing inflammation. It contains compounds such as echinacoside, acteoside, and verbascoside, which have antioxidant and anti-inflammatory properties. These compounds may help protect the kidneys from oxidative stress and inflammation caused by the accumulation of waste products in the blood. In addition, cistanche is also believed to help in repairing damaged kidney tissue and improving blood flow to the kidneys. This may help in improving kidney function and reducing the symptoms of uremia.

References:

[1] Shi Yuanyuan, Ding Feng. Research progress in blood purification and clearance of protein-bound uremic toxins [J]. Shanghai Medicine, 2018, 39 (9): 13-15

[2] Chen Bin, Li Yanhua, Liu Yang. Research progress of uremic toxins [J]. Jilin Medicine, 2013, 34 (22): 4513-4514

[3] Zeng Fuyuan, Shi Xiaoteng. Effects of different blood purification methods on toxin levels and inflammatory factors in patients with uremia [J]. Medical Theory and Practice, 2020, 33(21): 3562-3564

[4] Liu Weijun, Wu Xixin, Jiang Xia. Research status of protein-bound uremic toxin and blood purification [J]. Modern Hospital, 2020, 20 (7): 1053-1056