Absorbents therapy, as a conservative option, can improve kidney function in chronic kidney disease

1. Context

Chronic kidney disease (CKD) is characterized as the disruption of renal structure or renal function (1). Many therapies have been suggested for CKD, including renal transplantation, hemodialysis (HD), and peritoneal dialysis (PD). However, there are certain disadvantages associated with the use of these methods. Additionally, both HD and PD are invasive and expensive (2). In HD, the waste and excess water are eliminated through an external filter called a dialyzer, which contains a semipermeable membrane. The separation of wastes is done by making a counter-current flow gradient. In PD, the peritoneum is used as a natural semipermeable membrane and eliminates waste and water into the dialyzate (the material or fluid that passes through the membrane of the dialysis). In fact, the important point involved in dialysis is the movement or diffusion of solute particles across a semipermeable membrane (3). Despite their advantages, HD and PD involve several side effects associated with the removal of uremic solutes, water, and electrolytes, all of which increase the morbidity and mortality of renal patients (4). Previous studies have reported that the main side effects are headaches, muscle cramps, abdominal pain, hypotension, hypertension, vomiting, and constipation (4). Therefore, a convenient treatment option is needed for patients with CKD who refuse to undergo HD. Conservative care can be defined as a new technique for the management of end-stage kidney disease patients who refuse to undergo HD (5). It is well-accepted that conservative therapies, such as absorbent compounds, are new treatment methods alongside HD, PD, and renal transplantation, particularly in elderly individuals with severe comorbidity (6, 7).

2. Evidence Acquisition

Luijtgaarden et al. identified that conservative care has been prescribed for 10% of European CKD patients (8). In 2020, Verberne demonstrated that non-dialytic conservative care can be an alternative option for dialysis (9). Additionally, Keller et al. (10) identified a simple method for treating CKD through perspiration. It has been shown that perspiration can provide some of the most important currently recognized therapeutic goals in treating CKD, such as reducing interdialytic weight gain and serum potassium levels. In another study, intestinal dialysis (ID) and colonic dialysis were found to be successful in the treatment of CKD patients, given their minimal cost compared to the existing options (1, 11). ID can be defined as the use of a dietary supplement to shift the urinary excretion of nitrogenous waste products to intestinal excretion (12). Intestinal fluids of CKD patients have 70 g of blood urea nitrogen (BUN), 2.9 g of creatinine, and 2.5 g of uric acid in a day, which is higher than the normal amount (13). There is a negative correlation between kidney function and the concentration of nitrogenous waste products within the intestinal tract (2). The excretion of creatinine, BUN, and uric acid is higher in the gastrointestinal (GI) tract than in the urine (13). Recent evidence has proposed that different materials and techniques can remove nitrogenous waste products from the body using the GI tract. In addition, some studies have examined the application of a special polymer to improve the symptoms of CKD individuals (11). In the present review, we will focus on different absorbents as a conservative treatment to remove uremic waste metabolites from the GI tract for the improvement of kidney function in CKD.

3. Results

3.1. GI Tract Complications in CKD Patients

Patients with CKD often experience a number of GI tract complications, such as gastritis, decreased bowel mucosal permeability, delayed motility disorders, stomatitis, and microbiological floral change. In chronic renal failure, patients have a higher GI pH value than healthy individuals (14). Furthermore, Aguilera et al. identified that patients with PD usually show high levels of fecal sugar (15). Delayed GI movement in patients with HD may cause recurrent GI symptoms. It has been established that CKD patients usually experience impaired GI motility and elevated rates of glucagon and gastric inhibitory peptide levels, compared to healthy controls, which could be part of the complex multifactorial pattern of intestinal abnormalities in dialysis patients (16-18). In patients undergoing dialysis, changes in microbiome composition increase the C-reactive protein level (19). It has been demonstrated that the presence of urease and uricase bacteria changes the gut microbiome in patients with CKD (20, 21). Therefore, suppressing pathogenic species can improve the health of patients with CKD (22). It was clearly demonstrated that different factors may alter the gut microbiota, including dietary alteration, antibiotics, and pathogen infection (23).

3.2. Passing Time through the GI Tract and CKD

The GI tract is a dynamic environment, and the transport process can be affected by different factors. The passing time through the GI tract plays an important role in improving the absorption procedure (24). Usually, the transport time for small bowels is four hours, but it can range from two to six hours. In contrast, the transport time of the colon is between six and seven hours.

HD patients have longer colonic transit times than healthy individuals, particularly in the right and rectosigmoid segments. Currently, treatment options for chronic constipation are far from clear. In fact, chronic constipation is a common symptom of treatments for various diseases, such as HD in patients with CKD. Several documents have reported that 63.1% of patients undergoing long-term HD therapy experienced constipation (25).

The etiology of the higher prevalence of constipation in long-term HD patients is multifactorial. Lifestyle, phosphorus binders, a diet that includes low potassium and fluid intake, primary renal disease, and various diseases, such as diabetes, cerebrovascular disease, and heart failure, contribute to the higher prevalence of constipation in HD patients (25).

Wu et al. (26) calculated colonic transit times in HD patients and healthy control subjects. They reported that colonic transit time was effectively prolonged in HD patients, compared to healthy controls. In addition, viscosity can influence the absorption process. It has been established that the viscosity of the GI tract rises distally and can slow down absorption in semi-static conditions (24).

Here, we focus on adsorbent and absorbent agents.

3.3. Adsorbents and Absorbents

3.3.1. Starch

Starch (oxystarch) is combined with charcoal and used as a nitrogen sorbent in clinical trials (38). Starch has a high ammonia capacity (27). Starch absorbs urea at a capacity of 178-277 mmoles/mole (28). The administration of starch at a dose of 30 to 40 g/day for over two years can maintain BUN concentration (15). Unfortunately, the oxidized starch depolymerizes slowly in the buffered solution or in solutions of urea or ammonia. Therefore, this problem should be taken seriously.

3.3.2. Activated Charcoal

Activated charcoal can be used in the treatment of uremic pruritus, which is a sign of uremic toxicity. It has been established that creatinine can be adsorbed on active carbon efficiently (24). Activated charcoal binds with waste products and increases fecal nitrogen excretion (29). Active carbon is a potential non-specific adsorbent. In addition, it can reduce IS (Indoxyl Sulfate), p-cresol sulfate, and p-cresol serum levels (30). The combination of orally activated charcoal and a low-protein diet has been introduced as a new treatment for CKD patients (31).

3.3.3. AST-120 (Kremezin)

The action mechanism of AST-120 is that it can absorb uremic toxins within the GI tract and excrete them in the feces (18, 32). It was found that the mean survival of nephrectomized rats increased after being treated with AST-120 (33). AST-120 can improve the severity of anemia and prolong the interval between an azotemic patient’s serum creatinine level reaching 6 mg/dl and the start of maintenance HD (34). Indole is derived from the bacterial metabolism within the GI tract. It could be adsorbed by AST-120 (32). It is also effective in delaying the initiation of dialysis in patients with chronic renal failure (35). It is reported that AST-120 can delay the progression of chronic kidney and also cardiovascular disease (36). It has been reported that AST-120 can improve lipid abnormalities in experimental uremic rats. AST-120 significantly decreases the concentration of TG and cholesterol. In conclusion, AST-120 can improve the plasma lipid profile and prevent the progression of renal disease (2). It was highlighted that orally activated charcoal and AST-120 would minimize uremic toxins, such as p-cresol sulfate, IS, and p-cresol serum levels, in CKD patients (37). Chen et al. reported that early IS elimination by synergistic AST-120 administration in the early stage of acute kidney injury (AKI) is a valuable approach in the prevention of the AKI to CKD transition (38).

3. 3. 4. Lactulose

Lactulose can decrease the level of various deleterious elements. In a prospective study, the application of lactulose decreased urea concentration from 70.35 mg/dL to 64.50 mg/dL, creatinine concentration from 4.04 mg/dL to 3.45 mg/dL, and uric acid concentration from 7.31 mg/dL to 6.71 mg/dL. In addition, lactulose can increase the number of bacteria that metabolize ammonia (24).

3.3.5. Fructooligosaccharides

Fructooligosaccharides (FOS) are composed of short fructose chains. FOS occurs naturally in many plants, such as blue agave, yacon root, and garlic. Sudhanshu assessed the beneficial effects of FOS on rats. It has also been established that FOS is a positioned product that can significantly decrease proteinuria, blood creatinine, and urea (30).

3.3.6. Inulin

Inulin is a group of naturally occurring polysaccharides produced by many types of plants, most often extracted industrially from chicory. Inulin is a type of dietary fiber called fructan.

3.3.7. Licorice (Gan Cao)

Licorice can prevent hyperkalemia in CKD patients. It can reduce plasma-potassium concentration by enhancing intestinal potassium loss (39). Licorice is one of the most prescribed herbs in Chinese traditional medicine (40). In a clinical trial, licorice reduced plasma-potassium concentration, and the frequency of hyperkalemia was also decreased from 9% to 0.6% (39).

Limitation of ID

It can be claimed that a single agent in absorbent therapy is unable to remove a wide spectrum of metabolites from the GI tract. The administration of a sorbent mixture into the intestinal bypass can effectively remove urea, potassium, and water. During the treatment of anephric animals, the administration of sorbents can stabilize the serum urea nitrogen level at about five times normal and remove nitrogen at a clearance of up to 40% of that of normal kidneys. However, larger molecules, such as creatinine and uric acid, and middle molecules are poorly removed by ID.

4. Conclusion

Conservative care, such as absorbent therapy, is suggested as a new technique for the management of CKD patients who refuse to undergo HD because of its severe complications. Absorbent therapy is described as the use of a dietary supplement to shift the urinary excretion of nitrogenous waste products to the intestinal excretion since the excretion of creatinine, BUN, and uric acid is higher in the GI tract than in the urine. Therefore, absorbent therapy can provide some of the therapeutic goals in treating CKD, such as decreasing inter-dialytic weight gain and serum potassium levels. The present study reviewed some adsorbent and absorbent agents for the improvement of kidney function in CKD patients. For example, starch, in combination with charcoal, is used as a nitrogen sorbent in patients with CKD. Additionally, activated charcoal can be used in the treatment of uremic pruritus, which is a sign of uremic toxicity. These results suggest that AST-120 delays the decline in renal function.