Phosphate Binders and Non-Phosphate Effects in the Gastrointestinal Tract

Abstract

Phosphate binders are commonly prescribed in patients with end-stage kidney disease (ESKD) to prevent and treat hyperphosphatemia. These binders are usually associated with gastrointestinal distress, may bind molecules other than phosphate, and may alter the gut microbiota, altogether having systemic effects unrelated to phosphate control. Sevelamer is the most studied of the available binders for non-phosphate-related effects including binding to bile acids, endotoxins, gut microbiota-derived metabolites, and advanced glycation end-products. Other binders (calcium- and non-calcium-based binders) may bind vitamins, such as vitamin K and folic acid. Moreover, the relatively new iron-based phosphate binders may alter the gut microbiota as some of the iron or organic ligands may be utilized by the gastrointestinal bacteria. The objective of this narrative review is to provide the current evidence for the non-phosphate effects of phosphate binders on gastrointestinal function, nutrient and molecule binding, and the gut microbiome.

Introduction

Phosphate binders are commonly prescribed in patients with end-stage kidney disease (ESKD) to prevent and treat hyperphosphatemia (1). Phosphate binders can be classified as calcium and non-calcium-based. Calcium-based phosphate binders use has been decreasing, as they may lead to a positive calcium balance (2) and increased risk of extra-skeletal calcifications and poor outcomes (3). Contrarily, the use of non-calcium-based phosphate binders (e.g., sevelamer) has increased and has been associated with improved outcomes and survival compared to calcium-based phosphate binders (4, 5). Besides the phosphate-lowering effects, phosphate binders may have other effects within the gastrointestinal (GI) tract, and these effects may extend systemically.

There are several changes in the function of the GI tract as kidney function declines. These include impaired digestion and absorption of nutrients (6), increased gut permeability (7), increased prevalence of GI symptoms (8), increased risk of upper GI inflammation and bleeding (9), and alterations in the gut microbiome (10). Phosphate binders may have effects in these GI functions as they impair the absorption of nutrients (e.g., vitamins and minerals), may impact gut integrity, and alter the gut microbiome (Table 1). However, these functions are often overlooked and have not been studied extensively.

Table 1.

Effects of phosphate binders on nutrient and molecule absorption, gastrointestinal function, and the gut microbiota

Type of phosphate binder	Best pH for binding	Nutrient absorption impairment	Gastrointestinal effects	Gut microbiota and metabolites	Other
Calcium carbonate	3	- Binds to vitamin K2 (MK7) in the presence of phosphate	- Constipation	- ↑ Clostridium spp.* - ↑ SCFA*	- N.A.
Calcium Acetate	6	- Binds to vitamin K2 (MK7) in the presence and absence of phosphate	- Nausea - Vomiting	- ↓ Firmicutes-to-Bacteroidetes (?)	- N.A.
Lanthanum Carbonate	3	- Binds to oxalate - Binds to vitamin K2 (MK7) in the absence of phosphate	- Nausea - Vomiting - Abdominal Pain - If not chewed completely, possible GI accumulation	- Oxalobacter formigenes (?)	- N.A.
Sevelamer Hydrochloride/Carbonate	5.5/3	- Binds to bile acids: ↓ absorption of fat-soluble vitamins (vitamins D and K) - Binds to folic acid	- Nausea - Vomiting - Diarrhea - Dyspepsia - Abdominal pain - Flatulence - Constipation	- Binds to indole, indoxyl sulfate, p-cresol, and SCFA -	- Binds AGEs - Binds LPS - ↓ CRP, TNFα, IL6 - ↓ LDL due to binding to bile acids - Improved glucose homeostasis
Sucroferric Oxyhydroxyde	3	- ?	- Diarrhea - Discolored feces - Nausea	- ?	- N.A.
Ferric Citrate	2-8	- ?	- Diarrhea - Nausea - Constipation - Vomiting	- Non-absorbed iron (?)	- Improves markers of iron-deficiency anemia.

^*Study in healthy adults (22).

^22.Trautvetter U, Camarinha-Silva A, Jahreis G, Lorkowski S, and Glei M. High phosphorus intake and gut-related parameters - results of a randomized placebo-controlled human intervention study. Nutr J. 2018;17(1):23.

The gut microbiome is the genomically-diverse community of microorganisms that includes bacteria, archaea, fungi, parasites, and viruses within the GI tract (11). In chronic kidney disease (CKD), the gut microbiota has been described to have lower relative abundance of commensal bacteria thought to perform beneficial functions, such as short-chain fatty acid (SCFA) production by Bifidobacteria spp. and Lactobacillus spp., and a higher relative abundance of potential pathobionts, such as species within the Enterobacteriaceae family and Clostridium perfringens (7). In patients with ESKD, bacteria with indole and p-cresol-forming enzymes are increased, while bacteria with enzymes needed for SCFA (i.e., butyrate) production are reduced (12). Subsequently, there is an increase in plasma metabolites originally derived from gut bacterial metabolism, such as p-cresyl sulfate and indoxyl sulfate (13). These metabolites have been associated with the pathogenesis and progression of kidney disease, cardiovascular disease, CKD- mineral and bone disorder (MBD), and vascular calcification (14). Moreover, newer iron-based phosphate binders may have an effect on the gut microbiome, as some of the iron or its associated ligands may be metabolized by the gut microbiota (15). As phosphate binders are one of the most prescribed medications in ESKD, the effects of these medications on the composition and function of the gut microbiome is of interest. The objective of this narrative review is to synthesize the current literature on the non-phosphate binding effects of phosphate binders, including gastrointestinal function, nutrient and molecule binding, and the gut microbiome.

Calcium-based Phosphate Binders

Calcium Carbonate and Calcium Acetate

Calcium carbonate provides ~500mg of elemental calcium per 1250mg tablet and is traditionally used as an antacid or dietary calcium supplement, but also acts as a phosphate binder. Similarly, calcium acetate provides 169mg of elemental calcium per 667mg tablet. When taken with food, calcium and phosphate form an insoluble complex, which is excreted in feces. In an in vitro study by Schumacher et al. (16), calcium carbonate bound more phosphate at a pH of 3, while calcium acetate bound more phosphate at pH of 6.

GI symptoms are the most common side effects with the use of calcium-based phosphate binders and a frequent reason for their discontinuation (17). Constipation is commonly reported with calcium carbonate, while nausea (6.1%) and vomiting (4.1%) are common with calcium acetate (17). The prevalence of constipation has been reported to be as high as 63% in ESKD patients (18). Constipation may be related to factors other than the use of phosphate binders, such as reduced physical activity, low dietary fiber intake, various medications, and other comorbidities (i.e., diabetes) (18). A longer transit time may increase the production and absorption of indoles and phenols derived from the bacterial metabolism of tryptophan and tyrosine, respectively (13). These indoles and phenols can be then absorbed into portal circulation and modified in the liver to the uremic toxins indoxyl sulfate and p-cresyl sulfate, respectively (13). It is unknown, however, if calcium carbonate-induced constipation increases the bacterial fermentation of these amino acids.

Calcium carbonate and calcium acetate may bind other nutrients. Neradova et al. (19) showed in vitro that calcium carbonate and calcium acetate bound vitamin K2 (menaquinone-7; MK7) in a solution with a pH of 6 with and without phosphate. Vitamin K is needed for the carboxylation of some proteins, including matrix γ-carboxyglutamate (Gla) protein (MGP), which is an inhibitor of vascular calcification (20). Dietary intake of vitamin K and serum concentrations have been reported to be low in CKD and ESKD patients (21). Therefore, based on in vitro studies, calcium-based binders may contribute to two risk factors for vascular calcification: positive calcium balance and reduced absorption of vitamin K2, leading to reduced carboxylation of MGP.

There is limited evidence of the effect of calcium-based phosphate binders on the gut microbiota. In a study that assessed the effects of high dietary phosphorus with or without supplemented calcium (as calcium carbonate) in healthy individuals, Trautvetter et al. (22) found an increase in the fecal excretion of SCFA and increased relative abundance of species from the Clostridium cluster XVIII in those supplemented with calcium carbonate. However, the results may not be generalized to the CKD population. Similarly, there are no studies on the effects of calcium acetate on the gut microbiota. In a mouse model for hypertension, Marques et al. (23) showed that the supplementation of acetate, similarly to a high fiber diet, reduced the firmicutes-to-bacteroidetes ratio and attenuated the development of hypertension. However, the effects of calcium acetate in patients with ESKD are unknown.

Non-calcium-based phosphate binders

Lanthanum Carbonate

Lanthanum is a rare earth element that has a high affinity for phosphate. It is minimally absorbed in the GI tract and then excreted through bile (24). Lanthanum binds phosphate and dissociates from carbonate at a pH of 3, forming an insoluble complex that is excreted in feces (24).

The most common GI symptoms associated with lanthanum are nausea (11%), vomiting (9%), and abdominal pain (5%) (17). Some of these symptoms, however, may decrease with the continuous use of the binder. After 52 weeks of substituting sevelamer hydrochloride with lanthanum carbonate, the constipation score was reduced (25). Another consequence of the use of lanthanum is the resistance to dissolution, which can cause GI deposition (26).

Lanthanum has been shown to bind vitamin K in vitro in the absence of phosphate, suggesting competitive binding between vitamin K2 and phosphate (19). As mentioned earlier, this may have a detrimental effect on the carboxylation of MGP and increased risk of vascular calcification. However, the in vivo effects of lanthanum on vascular calcification are limited. Toussaint et al. (27) showed that aortic calcification progression was lower in hemodialysis patients treated with lanthanum for 18 months, compared with calcium carbonate. Lanthanum may also bind oxalates. In a study in rats that were given oral oxalates, lanthanum prevented their absorption, showing a blunted effect on oxaluria and calcium oxalate crystals (28). Gut bacteria, particularly Oxalobacter formigenes can degrade oxalate and decrease urinary oxalate excretion (29). However, the effect of lanthanum on oxalate metabolism and Oxalobacter formigenes abundances in the CKD gut remains to be explored.

Sevelamer Hydrochloride/Carbonate

Sevelamer is a non-specific anion exchange resin with a backbone of multiple amines. Once sevelamer binds to an anion, it exchanges it for chloride or carbonate. In an in vitro study, sevelamer carbonate was shown to bind more phosphate in a solution with a pH of 3, while sevelamer hydrochloride binds more phosphate at pH of 5.5 (16). Since the use of sevelamer hydrochloride was associated with acidosis in patients with CKD, the use of sevelamer carbonate is now more common (30).

GI symptoms are a common cause for discontinuation of sevelamer, where as much as 55% of patients discontinued sevelamer due to GI upset (17), the highest among phosphate binders. Among the GI symptoms, vomiting (24%), nausea (25%), diarrhea (21%), dyspepsia (16%), and constipation (13%) are common with sevelamer carbonate, while diarrhea (16%), dyspepsia (11%), and vomiting (12%) have been reported with sevelamer hydrochloride (31).

Sevelamer has been reported to have the most pleiotropic effects; it is also the most studied of the available binders and thus some findings may or may not be true for other binders. Sevelamer can bind molecules that are considered detrimental, such as lipopolysaccharide (LPS)/endotoxin, bile acids, uremic toxins (i.e., indoles and phenols), and advanced glycation end products (AGEs). However, it can also bind beneficial molecules, such as folic acid, and its use has been associated with increased levels of homocysteine (32).

Sevelamer reduces endotoxemia and inflammation

LPS is derived from the outer membrane of Gram-negative bacteria. In CKD and ESKD, circulating LPS may be increased due to the uremia-induced effect on gut barrier integrity, leading to increased bacterial translocation (7). Additionally, in patients with ESKD, intestinal edema and gut ischemia due to the hemodialysis treatment may also lead to bacterial translocation and endotoxemia (33). LPS has immunostimulatory effects as it activates macrophages, neutrophils, and endothelial cells leading to the release of pro-inflammatory cytokines (34). Limiting endotoxemia is important in CKD, as inflammation is associated with increased risk of cardiovascular events, kidney disease progression, protein-energy wasting, and all-cause mortality (35).

A dose-response reduction in LPS with sevelamer has been shown in vitro (36). In a rat model of kidney disease (5/6 nephrectomy), the use of sevelamer reduced LPS and inflammatory markers (37). In patients undergoing hemodialysis, sevelamer use was associated with lower plasma LPS (38). In a prospective, randomized controlled study in hemodialysis patients, a 3-month treatment with sevelamer was associated with a reduction of C-reactive protein (CRP), interleukin-6 (IL-6), and LPS compared with calcium acetate (39). The latest meta-analysis revealed that sevelamer reduced all-cause mortality, compared with calcium-based binders (5). However, it is not clear if the reduction on mortality risk is related to the phosphate-lowering effect, a reduction in LPS and inflammation, or a combination of these and other factors.

Sevelamer binds to bile acids and leads to improved metabolic profile

Sevelamer has been shown to bind bile acids and limit the highly effective enterohepatic recirculation, which recovers ~95% of bile acids (40). In a mouse model of non-alcoholic fatty liver disease (NAFLD), sevelamer improved liver steatosis and inhibited the nuclear farnesoid-X receptor (FXR) (41). FXR induces the ileum transcription of fibroblast-growth factor (FGF) 15/19 and inhibits the transcription of cholesterol 7-hydroxylase (CYP7A1) in the liver, the rate-limiting enzyme for bile acid synthesis. When bile acids are bound to sevelamer, their enterohepatic recirculation is reduced and this inhibits the FXR-negative feedback loop, increasing bile acid synthesis and reducing total cholesterol and low-density lipoprotein (LDL) (41).

Sevelamer has been associated with improved glucose homeostasis, likely mediated by the Takeda G protein receptor 5 (TGR5) located in the L-cells in the colon. When bile acids bind to sevelamer, they reach the L-cells and activate TGR5, which increases glucagon-like peptide-1 (GLP-1) production and secretion. Harach et al. (42) demonstrated that anion-exchanger resins released GLP-1 with glucose-lowering effect mediated by TGR5. A study in patients with diabetes (43) found that sevelamer was associated with reduced fasting plasma glucose, LDL, and unconjugated bile acids, while it increased triglycerides, glucagon, and C4 (a product CYP7A1 conversion from cholesterol to bile acids). Interestingly, these changes were not associated with changes in the gut microbiota, but this was not a primary end-point.

Bile acids may be also related to vascular calcification. Deoxycholic acid has been shown to induce vascular mineralization in experimental models (44). Deoxycholic acid is a secondary bile acid derived from the deconjugated primary bile acid cholic acid through gut microbial metabolism (hydrolysis and dehydroxylation), which is passively diffused to portal circulation (45). Deoxycholic acid may inhibit FXR, and this inhibition has been shown to prevent vascular calcification in a mice model of CKD (46). Jovanovich et al. (44) recently reported a positive association between deoxycholic acid and coronary artery vascular calcification in CKD patients. However, the effect of sevelamer on bile acid metabolism in CKD and the effect through binding of bile acids is unknown.

Finally, due to its binding to bile acids sevelamer may impair the absorption of fat-soluble vitamins. The use of sevelamer has been associated with reductions in serum levels of vitamin D (25-hydroxyvitamin D), compared to lanthanum carbonate (47). Westenfeld et al. (48) found no association between the use of sevelamer and Vitamin K (menaquinone) levels, despite in vitro studies showing affinity of sevelamer for vitamin K; although only a small proportion of patients were prescribed sevelamer. Sevelamer has no effect on absorption of vitamins A and E (49).

Sevelamer may bind to gut microbiota-derived metabolites

Metabolites derived from protein fermentation (phenols and indoles) and dietary fiber fermentation (SCFA) by the gut microbiota have been reported to be bound or to be reduced with sevelamer. In vitro (50), sevelamer binds to indole, indoxyl sulfate, and p-cresol, but not tryptophan (a precursor of indoles) at different pH solutions. In a study of five patients undergoing hemodialysis, the use of sevelamer reduced serum levels of p-cresyl sulfate, but not indoxyl sulfate (50). Similarly, a cross-sectional study in peritoneal dialysis patients receiving sevelamer had lower plasma p-cresol, a surrogate marker for the p-cresol conjugates p-cresyl sulfate and p-cresyl glucuronide (51). However, the reduction in uremic toxins has been inconsistent in vivo. Phan et al. (52) showed no effect on uremic toxins, including indoxyl sulfate, after an 8-week use of sevelamer in apoE^−/− uremic female mice; while Brandenburg et al. (53) found no change in indoxyl sulfate and an increase in serum p-cresol after 8 weeks of sevelamer.

SCFA are the predominant anions in the colon, where sevelamer reaches its final equilibrium. Wrong and Harland (54) commented that one mole of SCFA removed by sevelamer hydrochloride was equal to one mole of bicarbonate lost and a gain of chloride; the hypothesized reason of sevelamer hydrochloride-induced acidosis. As sevelamer may bind undesirable microbial metabolites (i.e., indoles and phenols), but also the desirable metabolites (i.e., SCFA), the effects of sevelamer on the microbial metabolome remains to be explored.

Sevelamer reduces advanced glycation end products (AGEs)

AGEs result in part from the non-enzymatic reactions (Maillard reactions) between amine-containing molecules and reducing sugar molecules. AGEs are produced endogenously and are also consumed in the diet. High concentrations of AGEs have been reported to contribute to the progression of kidney disease and are positively associated with vascular calcification (55). Sevelamer has been shown to bind to AGEs and reduce the endothelial expression of the receptor for AGEs (RAGE) in vitro (56). In a randomized open-label study in patients with diabetic kidney disease, sevelamer carbonate, compared with calcium carbonate, reduced serum carboxymethyllysine and methylglyoxal, two of the main AGEs, and RAGE in peripheral blood mononuclear cells (57). Similar results were observed in a randomized crossover study in patients with diabetic nephropathy (58). In a randomized clinical trial, the use of sevelamer compared with calcium carbonate reduced coronary artery calcification and maintained plasma pentosidine, an AGE biomarker (59). However, the effect on artery calcification may also be due to the possible positive calcium balance with the use of calcium carbonate.

A diet low in AGEs has been shown to alter the gut microbiota in peritoneal dialysis patients (60). Particularly, there was a reduction in the relative abundance of Prevotella copri and Bifidobacterium animalis, and an increase in the relative abundance of Alistipes indistinctus, Clostridium citroniae, Clostridium hathewayi, and Ruminococcus gauvreauii. In this study, 60% and 70% of the patients were prescribed phosphate binders in the high and low AGE diet, respectively, but the authors did not mention what type of binder the patients used.

Ferric Citrate

Ferric citrate is an iron-based phosphate binder that improves markers of CKD-MBD (61) and iron-deficiency anemia (62). Ferric iron dissociates from citrate and a portion of ferric iron binds to phosphate forming ferric phosphate, which is excreted in feces. Yaguchi et al. (63), showed in vitro that phosphate binding capacity was across pH levels of 2-8. GI symptoms are a common side effect of the use of ferric citrate including diarrhea (21%), nausea (11%), constipation (8%), and vomiting (7%) (64).

Ferric citrate has not been reported to bind other nutrients. However, of special interest is the iron contained in the compound which may act as an oral iron supplement and may shift the gut microbiota. Iron acts as the catalytic center for redox enzymes in processes such as electron-transport, activation of oxygen, and DNA synthesis and repair (65). Some bacteria, particularly Gram-negative bacteria, increase their relative abundance when the access to iron is increased (66). The utilization of iron by gut bacteria will depend in part on their ability to dissociate the iron from compounds (e.g., phytate, polyphenols, and other minerals), chelate iron through siderophores, internalize the iron, and reduce iron (67). These mechanisms are present in pathogenic bacteria and an increased amount of iron reaching the colon may promote virulence of these bacteria, inducing a pro-inflammatory environment (15). Kortman et al. showed in an in vitro kinetic model of the human colon that iron increased protein fermentation metabolites, such as branched-chain fatty acids and ammonia (68). In a recent study of 5/6 nephrectomized rats, Lau et al. (69) showed that a 6-week use of a 4% ferric citrate diet increased fecal α-diversity (species richness), reduced the relative abundance of Firmicutes, and increased the relative abundance of the Akkermansia genus and the Clostridiaceae and Enterobacteriaceae families, compared to the untreated CKD rats. However, as the gut microbiota of rats and humans are different, the effect of ferric citrate in patients with CKD and ESKD remains to be explored.

Sucroferric Oxyhydroxyde

Sucroferric oxyhydroxyde has been shown to bind more phosphate at pH of 3, compared to pH of 6 in vitro (16). The sucrose and starches that are part of the initial chewable tablet are digested and absorbed in the proximal small intestine, exposing the iron-oxyhydroxide core that binds phosphate (70). GI symptoms are the most common side effects: diarrhea (24%), discolored feces (16%), and nausea (10%) (71). Binding of sucroferric oxyhydroxyde to other vitamins or minerals has not been tested (19). Furthermore, to date, there are no studies assessing the effects of this binder on the gut microbiome. However, one can speculate that there may be minor effects as only minimal iron is released from the binder to be utilized by the gut microbiota.

Conclusion

Phosphate binders have effects other than reducing phosphate absorption. These pleiotropic effects may cause physiological changes in the GI tract and alter the gut microbiota and their function. Phosphate binders may bind molecules other than phosphate that are of importance, such as vitamin K, but also others that are detrimental, such as LPS, AGEs, indoles, and phenols, having systemic effects that are often overlooked in CKD. Importantly, these systemic effects may directly affect outcomes in patients with CKD as they impact inflammation, vascular calcifications, and improve the metabolic profile. Studies that assess the changes in the gut microbiome composition and function and their association with outcomes in this clinical population are necessary.