Managing hyperphosphataemia in adults with CKD

Introduction

The tendency toward phosphate retention begins early in chronic kidney disease (CKD), when reduced phosphate filtering load impairs renal excretion. Adaptive responses that reduce phosphate reabsorption in the proximal tubule prevent the development of overt hyperphosphatemia until chronic kidney disease has reached advanced stages. Hyperphosphatemia may develop when the estimated glomerular filtration rate (eGFR) falls below 25–40 mL/min/1.73 m2 [1–3].

Justifications for treatment

The rationale for treatment of hyperphosphatemia is based largely on observational studies that have shown the association of elevated serum phosphorus with increased cardiovascular morbidity and mortality [4–10]. Here are some of these data regarding non-dialysis CKD patients and dialysis CKD patients:

• Non-dialysis chronic kidney disease —The majority of studies have reported an increase in mortality associated with hyperphosphatemia in nondialysis patients with CKD [10–15]. This was best demonstrated in an analysis of three studies including about 5000 patients with non-dialysis CKD, which showed a 35% increase in mortality for every 1 mg/dL increase in phosphorus above normal values ​​(95% CI: 1.16–1.57) [10]. The average duration of follow-up in individual studies was about one to two years. In one study, which was included in the meta-analysis, serum phosphorus >3.5 mg/dL (1.13 mmol/L) was an independent predictor of all-cause mortality [11].

However, other studies have not shown an association between serum phosphorus and mortality in patients with CKD not undergoing dialysis [16,17]. One study published after the aforementioned analysis did not show an association between serum phosphorus values ​​and mortality during an average follow-up of more than two years [16]. Differences between the studied population groups are likely to be a reason for the discrepancies between the results of the studies [3]. For example, individuals in the later study had much milder renal dysfunction, with a mean eGFR of 44–48 ml/min/1.73 m2, compared to previous studies.

Studies also indicate a progressively increased cardiovascular risk associated with hyperphosphatemia in people with normal renal function, as well as in CKD patients with an eGFR less than 60 mL/min/1.73 m2 who are not on dialysis [11,14,18,19].

• Chronic kidney disease in dialysis patients —High serum phosphorus is associated with increased mortality in patients undergoing hemodialysis [4–10]. This was best demonstrated in an analysis of 12 studies including 92,345 patients with CKD, more than 97% of whom were on dialysis [10].

Of 10 studies considered adequately controlled, seven of which were in dialysis patients, serum phosphorus >5.5 mg/dL (1.78 mmol/L) was associated with increased mortality. Based on 13 studies that reported a continuous relative risk for each 1 mg/dL increase in phosphorus, the risk of mortality increased by 18% (95% CI: 1.12–1.25). Both the amount of phosphorus elevation and the duration of hyperphosphatemia were associated with mortality.

Monitoring

In patients with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m2, we routinely monitor serum levels of phosphorus, calcium, parathyroid hormone (iPTH), and 25-hydroxyvitamin D.

These measurements should usually be performed at least once a year, but the frequency of measurements also depends on the eGFR value, the presence or absence of underlying disorders, and whether therapeutic measures have been taken. Monitoring may also be done more frequently if eGFR is falling rapidly. Values ​​should be rechecked if renal function worsens. Serial measurements of phosphorus levels are important because patients often switch between inside and outside the target range.

Treatment thresholds and goals

Optimal treatment thresholds and target values for serum phosphorus in CKD have not yet been determined [21]. However, we believe that the target phosphorus values ​​given below for nondialysis patients and dialyzed patients are reasonable and achievable in most patients.

Non-dialysis patients

In non-dialysis patients with CKD, we begin dietary modification when the serum phosphorus level is above normal, i.e. ≥4.5 mg/dL (1.45 mmol/L), with the goal of reducing serum phosphorus to the normal range.

Phosphate binders are only initiated when serum phosphorus remains persistently elevated >5.5 mg/dL despite dietary restriction [22–25].

In patients receiving phosphate binders in addition to nutritional modification, we target serum phosphorus ≤5.5 mg/dL.

This approach is generally consistent with KDIGO guidelines [20,23,26].

Patients undergoing dialysis

In dialysis patients, serum phosphorus >5.5 mg/dL (1.78 mmol/L) is an indication for treatment.

In most patients, we aim to maintain serum phosphorus between 3.5 and 5.5 mg/dL, including both thresholds, 1.13 and 1.78 mmol/L, although there are no data from trials demonstrating that lowering serum phosphorus to less than 5.5 mg/dL improves clinical outcomes.

This target range for phosphorus is consistent with the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines [22], but differs from later KDIGO guidelines, which recommend lowering phosphorus levels toward the normal range without specifying a numerical value [20,23].

Treatment

We treat hyperphosphatemia in a gradual and/or cumulative manner.

In the patients we treat, we begin by modifying the diet, optimizing the dialysis regimen of patients on dialysis, and then adding phosphate binders and other measures if necessary if hyperphosphatemia remains uncontrolled.

However, some doctors initiate dietary restriction and phosphate binders simultaneously in patients whose phosphorus levels are very high at presentation, eg >6.5 mg/dL, because dietary restriction alone is ineffective in many of these patients.

Restrict dietary phosphorus in all patients

Our therapeutic approach begins with moderate restriction of dietary phosphorus to between 800 and 1000 mg per day (25.8–32.3 mmol per day), provided this can be done without compromising nutritional status.

Since many dialysis patients suffer from obvious or borderline malnutrition, phosphorus restriction in dialysis patients should be performed under the supervision of a nutritionist.

Phosphorus restriction should be focused primarily on processed foods and cola-type soft drinks, not on foods of high biological value such as meat and eggs.

Food additives found in processed foods and medicines are an important source of dietary phosphorus [27–29].

In addition to containing a large amount of phosphorus, processed foods provide a form of phosphorus that is easier to absorb compared to fresh animal and plant foods [30,31].

The bioavailability of phosphate may be lower in a plant-based diet compared to an animal protein-based diet [33].

Many foods traditionally classified as rich in phosphorus, such as beans and nuts, may in fact be acceptable, provided they are not too rich in potassium, because phosphate from these sources is absorbed slowly [20,31].

This is because plant phosphorus found in unprocessed foods exists in the form of phytate phosphorus, and the human intestine does not secrete phytase, the enzyme needed for its absorption [30].

In addition, a diet rich in legumes, nuts, and whole grains may increase fiber intake while allowing for broader dietary choices [31].

Although dietary restriction may be effective in lowering serum phosphorus concentrations [27], few studies have examined the effectiveness of dietary phosphorus restriction on outcomes important to the patient.

In a post hoc analysis of Hemodialysis (HEMO) study data, prescribed phosphorus restriction was not associated with improved survival in hemodialysis patients [34].

In fact, in this study, a gradual trend toward better survival was found the less severe the prescribed phosphorus restriction.

However, the HEMO study was conducted before the importance of food additives as a source of phosphorus was realized; Therefore, phosphorus restriction may be achieved by restricting nutritionally beneficial foods.

This possibility is supported by the fact that phosphorus restriction tended to be associated with worse nutritional indicators and a greater and persistent need for nutritional supplements in this study.

Improve the dialysis system

In addition to dietary phosphorus restriction, we ensure that dialysis patients meet the recommended Kt/V targets, in order to optimize extracorporeal phosphate removal.

Given the limited ability of hemodialysis to remove phosphate—a standard dialysis session removes on average about 900 mg of phosphorus—most patients on conventional hemodialysis find it difficult to increase the duration of dialysis long enough to reduce serum phosphorus.

In addition, higher doses of conventional lavage have not been shown to improve clinically significant outcomes.

However, hyperphosphatemia may prompt some patients on conventional hemodialysis to consider daily or nocturnal hemodialysis, i.e. prolonged hemodialysis usually performed at night.

Although hyperphosphatemia is rarely a deciding factor when choosing a dialysis mode, frequent or prolonged hemodialysis results in greater phosphate removal and can significantly lower serum phosphorus levels.

In many patients undergoing frequent or prolonged hemodialysis, serum phosphorus can be controlled without the use of phosphate binders.

Adding phosphate binders if phosphorus is not controlled

We add treatment with phosphate binders in patients for whom dietary restriction alone is not sufficient.

The choice of phosphate binder type is similar in dialysis and nondialysis patients with CKD and is discussed below.

Choosing a phosphate binder

Phosphate bonds are classified into calcium-containing bonds and non-calcium-containing bonds.

We generally prefer non-calcium binders, but the choice of a specific phosphate binder should depend on the patient's affordability, side effects, and patient preferences, such as the number of tablets and whether they prefer to chew or swallow.

When doses are titrated appropriately within the recommended dose ranges, all phosphate binders are equally effective in reducing phosphate [22,35].

Non-calcium based binders are preferred

For most CKD patients treated with phosphate binders, we suggest using non-calcium binders instead of calcium-containing binders.

Exceptions may exist when non-calcium binders are not available or affordable, or when serum calcium is low and PTH is high, as in patients treated concomitantly with calcimimetics.

However, many experts believe that calcium-containing compounds should be avoided in all patients [20].

The most important non-calcium binders include:

Sevelamer

Lanthanum

Other non-calcium binders include:

Ferric citrate

Sucroferric oxyhydroxide

Phosphate binders containing calcium include:

Calcium carbonate

Calcium acetate

The use of these agents is discussed in detail below.

Evidence supporting non-calcium-containing binders

Several trials and meta-analyses have indicated that non-calcium-containing phosphate binders, compared with calcium-containing binders, reduce mortality in patients with CKD [36–48].

An analysis of 11 open-label, randomized trials involving 4,622 patients showed reduced all-cause mortality in patients randomized to receive non-calcium-based binders — sevelamer in 10 studies of 3,268 patients, or lanthanum in 1 study of 1,354 patients — compared with calcium-based binders: 18.9% versus 21.6%; RR 0.78, 95% CI 0.61–0.98 [49].

The results of this analysis were largely driven by the study that used lanthanum carbonate, not sevelamer.

Analysis of dialysis patients and non-dialysis CKD patients showed a similar reduction in mortality.

Most studies in this meta-analysis were limited to 24 months; Analysis of studies with 36- and 42-month follow-up showed similar reductions in mortality, but these reductions were not statistically significant [49].

This analysis did not examine cardiovascular mortality.

A second analysis including 13 studies and 3799 patients showed a reduction in all-cause mortality with sevelamer compared with calcium-based combinations: 17.5% versus 23.3%; RR 0.54, 95% CI 0.32–0.93 [50].

The reported reduction in cardiovascular mortality was not statistically significant: four studies, n=2712, RR 0.33, 95% CI 0.07–1.64.

Patients who received sevelamer had lower levels of cholesterol, LDL cholesterol, and calcium, as well as a lower risk of hypercalcemia.

There was no difference between the two groups in serum phosphorus.

There was significant heterogeneity between studies.

However, subsequent studies in dialysis patients comparing non-calcium to calcium-containing binders reported similar rates of cardiovascular events and all-cause mortality in the two groups [51,52].

In addition to potential effects on mortality, calcium-containing compounds, unlike non-calcium-containing compounds, are associated with hypercalcemia, adynamic bone disease, and vascular calcification, all of which may lead to increased morbidity [36,38,40,41,50,53,54].

Calcium-containing ligands and calcium homeostasis

The use of calcium-containing binders may result in a positive calcium balance, thereby increasing vascular calcification.

Given that normal dietary intake of calcium is about 1,000 mg per day, prescribing 1,500 mg daily of elemental calcium — that is, calcium carbonate 1,250 mg three times daily with food — increases calcium intake by about 2.5 times.

Calcium excretion is also decreased in CKD due to decreased calcium filter load.

The combination of increased calcium intake and decreased calcium excretion may result in a positive calcium balance, even in the absence of hypercalcemia.

These concerns were well illustrated by the results of a randomized, crossover, placebo-controlled study that studied the effect of oral calcium carbonate administration on calcium and phosphate balance in eight patients with CKD whose eGFR was between 15 and 59 ml/min/1.73 m2 [55].

Participants received a controlled diet with either a calcium carbonate supplement — 1,500 mg of calcium daily — or a placebo during two three-week balance assessment periods.

Fasting blood and urine samples were collected at baseline and at the end of each week.

All stool and urine samples were collected during the second and third weeks of each equilibrium period.

The calcium isotope 45CaCl2 was given orally and intravenously to determine calcium kinetics.

Patients were in a balanced state of calcium and phosphorus while using placebo.

Administration of calcium carbonate resulted in a positive calcium balance without affecting phosphorus balance.

Calcium carbonate administration, compared to placebo, also resulted in a slight reduction in urinary phosphorus excretion.

Calcium kinetics showed a positive net bone balance.

However, the amount of calcium deposited in the bone was less than the total positive calcium balance, indicating that some degree of deposition in the soft tissue had occurred.

Fasting blood biochemical measurements of calcium and phosphate homeostasis were not affected by calcium carbonate, indicating the futility of relying solely on blood concentrations to determine mineral overload or accumulation.

Interpretation of these data may be limited due to the short duration of the study.

It is possible that patients did not reach a stable condition after a period not exceeding one to three weeks of calcium administration.

If so, the short-term positive calcium balance observed may be an appropriate response to compensate for years of bone calcium deficiency, and thus may decline over time [56].

In longer-term studies in predialysis patients with CKD, phosphate excretion within 24 hours was significantly reduced when calcium-containing binders were used [53].

Dosage and specific pharmacological agents

For all phosphate binders, the lowest effective dose should be used.

Phosphate binders are only effective if taken with meals [57].

Below are the doses of these medications.

Preferred factors

Based on cost and favorable side effect profile, we generally use non-calcium-containing binders, namely sevelamer or lanthanum.

Our choice of one over the other is guided by patient affordability, side effects, and patient preference.

For example, we prescribe lanthanum to patients who prefer to chew the medication rather than swallow it whole.

Sevelamer (Sevelamer)

Sevelamer hydrochloride and sevelamer carbonate are non-absorbable cationic polymers that bind phosphate through ion exchange [58].

Sevelamer is effective in lowering serum phosphate levels [38,39,59–66].

The usual dosage range for sevelamer is 800 to 2400 mg three times daily with meals.

Sevelamer hydrochloride, unlike sevelamer carbonate, may cause metabolic acidosis.

For this reason, sevelamer carbonate is preferred over sevelamer hydrochloride in nondialysis patients with CKD and in any patient with metabolic acidosis.

Sevelamer is much more expensive than calcium-containing phosphate binders [67,68].

Lanthanum (Lanthanum)

Lanthanum is a rare earth element that is effective in lowering phosphate levels in dialysis patients [69–76] and in nondialysis patients with CKD [77].

Compared with calcium-containing phosphate binders, lanthanum appears to be associated with a lower rate of excessive suppression of PTH levels [69–71,73,75,76,78–80].

A potential additional benefit of lanthanum, compared to other phosphate binders, is a reduced daily tablet burden [81].

Lanthanum tablets are chewed rather than swallowed whole.

The usual dosage range is 500 to 1000 mg three times daily with meals.

In studies in dialysis patients, no significant adverse effects have been reported with lanthanum [69–71,73,75,76,78–80].

The safety of lanthanum use for up to 2 years was evaluated in 1359 hemodialysis patients who were randomized to receive lanthanum at a maximum dose of 3000 mg daily or the phosphate binder they were taking before the study [75].

The incidence of side effects was similar in both groups, and were mainly gastrointestinal effects.

No evidence of hepatotoxicity was observed.

Other non-calcium-containing binders

Other non-calcium phosphate binders include sucroferric oxyhydroxide and ferric citrate.

A potential advantage of sucrose iron oxyhydroxide is the lower tablet count compared to other binders.

Ferric citrate may be useful in patients with hyperphosphatemia who also suffer from iron deficiency.

Sucrose iron oxyhydroxide (Sucroferric oxyhydroxide)

Sucrase iron oxyhydroxide chewable phosphate binder for patients with an eGFR less than 15 mL/min/1.73 m².

It appears to be comparable to sevelamer in terms of efficacy and safety, and may be associated with a lower tablet burden [82,83].

Side effects are primarily gastrointestinal, and include diarrhea, nausea, abnormal taste of the drug, constipation, and vomiting.

The starting dose of sucrose iron oxyhydroxide is 2.5 g three times daily with meals, or if the dose is expressed in terms of elemental iron, 500 mg three times daily with meals.

Most of the iron in sucrase iron oxyhydroxide is not absorbed systemically, but slight increases in transferrin and ferritin saturation have been observed with use [84].

Ferric citrate (Ferric citrate)

Ferric citrate is effective in lowering serum phosphate concentrations to the same extent as other phosphate binders [85–88].

In addition, ferric citrate raises hemoglobin, serum iron, transferrin saturation, and ferritin [89].

Dialysis patients receiving ferric citrate may also receive intravenous iron as part of their anemia management regimen; Therefore, serum iron, transferrin saturation, and ferritin should be carefully monitored in these patients to avoid iron overload.

Citrate has been shown to increase aluminum absorption, increasing the risk of aluminum toxicity.

For this reason, some of them recommend avoiding all citrate-containing products in patients with CKD or patients undergoing dialysis.

However, no aluminum toxicity was observed in ferric citrate recipients in one trial in dialysis patients [85].

Calcium-containing phosphate binders

For most patients, we suggest using non-calcium binders.

However, if calcium-containing binders are chosen, the total dose of elemental calcium, including dietary sources, should not exceed 2000 mg per day [22].

The amount of elemental calcium contained in the phosphate binder should not exceed 1500 mg per day.

Type and dose

Calcium-containing phosphate binders include calcium carbonate and calcium acetate [90–92].

Calcium acetate may be more efficient at binding phosphate than calcium carbonate [93–95].

The usual dosage range for calcium carbonate is 1,250 to 3,750 mg daily, in divided doses with meals.

The usual dosage range for calcium acetate is 1,334 to 2,001 mg three times daily with meals.

The upper limits of these usual dose ranges represent about 1500 mg per day of elemental calcium.

Because dietary calcium intake is typically about 1,000 mg per day, patients taking calcium-containing compounds at the upper end of the usual dosing range will often have a total daily intake of elemental calcium above the recommended level of 2,000 mg per day.

Monitor for hypercalcemia

Careful monitoring of serum calcium concentration is essential with chronic use of calcium-containing binders, especially in hemodialysis patients.

The combination of hypercalcemia and hyperphosphatemia may be particularly problematic in patients using both calcium-containing phosphate binders and active vitamin D analogues.

In these patients, if hypercalcemia develops, the dose of calcium-containing phosphate binder should be reduced [22].

The dose of effective vitamin D analogues should be reduced or discontinued until calcium levels return to normal.

As mentioned above, even in the absence of hypercalcemia, positive calcium balance may increase the risk of vascular calcification, especially in the presence of hyperphosphatemia [90,96–101].

Uncertain role of combination therapy

In dialysis patients in whom phosphorus control is difficult, concurrent treatment with two types of phosphate binders—such as sucrose iron oxyhydroxide with sevelamer or calcium acetate—may be effective [102].

The main disadvantages of combination therapy with phosphate binders are the increased number of tablets at mealtimes, cost, and the potential for increased gastrointestinal side effects.

Other factors

Nicotinamide (Nicotinamide)

We do not use nicotinamide to lower phosphorus levels in patients with CKD.

Nicotinamide, a metabolite of nicotinic acid—niacin or vitamin B3—may lower serum phosphate by reducing phosphate absorption from the gastrointestinal tract [86,87].

However, randomized trials that studied nicotinamide as a phosphate-lowering treatment in nondialysis and dialysis patients with CKD showed limited efficacy, poor tolerability, and some safety concerns [103,104].

For example, in a randomized trial of over 700 hemodialysis patients using phosphate binders, the use of nicotinamide as add-on treatment reduced phosphate levels compared to placebo after 24 weeks, but this effect was not sustained at 52 weeks of follow-up [104].

In addition, nicotinamide treatment has been associated with higher rates of side effects, including diarrhea, pruritus, and thrombocytopenia.

Aluminum hydroxide (Aluminum hydroxide)

We do not use aluminum hydroxide for long-term phosphorus control in patients with CKD.

Aluminum hydroxide is effective in controlling serum phosphorus, but the safety of aluminum-based phosphate binders in CKD has not been established.

Excessive exposure to aluminum in CKD patients may lead to aluminum toxicity.

The main manifestations of aluminum toxicity are vitamin D-resistant osteomalacia, microcytic anemia, bone and muscle pain, and dementia.

Calcium citrate (Calcium citrate)

Calcium citrate was used as a phosphate binder.

Calcium citrate should be avoided in all CKD patients, because citrate can significantly increase intestinal aluminum absorption [105,106].

The use of calcium citrate has been associated with aluminum neurotoxicity and rapid onset of symptomatic osteomalacia [107].

Citrate appears to increase aluminum absorption in two ways: first, by keeping aluminum in a soluble form through the formation of aluminum citrate within the intestinal lumen; Secondly, by binding to luminal calcium [105,106].

The resulting decrease in free calcium increases the permeability of tight junctions between cells, which may significantly increase the passive uptake of aluminum [105,106].

Bonds containing magnesium

Magnesium-containing ligands can lower serum phosphorus in CKD patients [108].

However, we generally avoid magnesium binders in CKD due to the risk of magnesium toxicity.

Benefits of treatment with phosphate binders

It is uncertain whether the use of phosphate binders provides benefit with respect to important clinical endpoints.

Non-dialysis patients

In non-dialysis patients with chronic kidney disease, the effect of phosphate binders on serum phosphorus levels may be variable.

In a randomized trial, the use of phosphate binders, compared with placebo, was associated with greater reductions in serum phosphate and in 24-hour urine phosphate after three, six, and nine months, although the effect size was small [53].

In addition, the use of phosphate binders was associated with a stable PTH value, compared to an increase in the placebo group.

Although some observational data suggest that treatment with phosphate binders may provide a mortality benefit in non-dialysis patients with CKD [110], randomized trials have not shown that phosphate binders affect clinically important outcomes in this patient population [109,111].

Patients undergoing dialysis

Two observational studies have suggested that phosphate binders are associated with reduced mortality in dialysis patients:

• In a prospective observational study of patients who had recently started dialysis and followed for 1 year, the use of phosphate binders was associated with a 25% reduction in 1-year mortality [112].
• Among 6797 patients who participated in a prospective observational study entitled Current Management of Secondary Hyperparathyroidism: A Multicenter Observational Study (COSMOS), patients prescribed phosphate binders had a 29% reduction in the risk of all-cause mortality and a 22% reduction in the risk of cardiovascular mortality [113].

Treatment-resistant hyperphosphatemia

In patients with CKD, hyperphosphatemia is sometimes refractory to dietary restriction and the use of phosphate binders, and hemodialysis patients may be unwilling or unable to undergo frequent or prolonged hemodialysis.

In these patients, our stepwise approach is as follows:

Review of treatment for hyperparathyroidism

The treatment of hyperparathyroidism, which varies depending on the patient's condition, should be reviewed regarding dialysis.

Non-dialysis patients

We generally do not give calcitriol or active vitamin D analogues to non-dialysis patients with chronic kidney disease who suffer from hyperphosphatemia, because these drugs increase phosphate absorption from the gastrointestinal tract.

We also do not use calcimimetics, such as cinacalcet, to lower PTH in non-dialysis CKD patients.

Patients undergoing dialysis

In dialysis patients with refractory hyperphosphatemia receiving treatment for hyperparathyroidism, we use calcimimetics to suppress PTH and minimize the use of calcitriol or active vitamin D analogues.

In dialysis patients, both inadequately treated hyperparathyroidism and the use of high doses of calcitriol or potent vitamin D analogues can contribute to hyperphosphatemia via different mechanisms.

High levels of PTH increase bone resorption and the release of phosphate from bone [114], while active forms of vitamin D increase phosphate absorption from the gastrointestinal tract.

Addition of Tenapanor in dialysis patients

In patients receiving adequate dialysis whose serum phosphorus levels persist >5.5 mg/dL despite dietary restriction, optimal treatment of hyperparathyroidism, and appropriate use of phosphate binders, we suggest adding Tenapanor to the regimen.

Tenapanor is an intestinal sodium/hydrogen exchanger type 3 (NHE3) inhibitor that was developed to treat irritable bowel syndrome with constipation, but it has also been found to lower serum phosphate by preventing its intercellular transport from the intestinal lumen [88].

Because there are no data demonstrating that reducing phosphate to 5.5 mg/dL or less improves clinical outcomes, some experts use higher levels of serum phosphorus, such as >6.5 mg/dL, as the threshold for adding tenapanor.

The usual dosage range for Tenapanor is 10 to 30 mg twice daily.

The main side effect of Tenapanor is increased stool frequency, thought to be due to increased water content in the stool.

Diarrhea occurs in about half of patients treated with tenapanor [115], but is usually not severe; Diarrhea leads to stopping the drug in about 5% of patients.

In hemodialysis patients, multiple trials have shown that tenapanor reduces phosphorus to a moderate extent [116–122].

In an analysis of randomized trials, treatment with tenapanor compared with placebo resulted in a mean reduction in serum phosphorus of 1.79 mg/dL [115].

In a pilot trial, 169 hemodialysis patients with hyperphosphatemia despite treatment with one or more phosphate binders were randomized to tenapanor or placebo, with phosphate binders maintained in both groups [120].

Serum phosphorus in patients treated with tenapanor was 1.76 mg/dL lower compared to patients in the placebo group.

Diarrhea occurred in 63.1% of patients in the tenapanor group versus 14.1% in the placebo group, but was described as mild or moderate in all cases.

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