Management of hyperphosphatemia in adults with chronic kidney disease

INTRODUCTION — The tendency toward phosphate retention develops early in chronic kidney disease (CKD) when a reduction in the filtered phosphate load leads to impaired kidney excretion. Adaptive responses that decrease the proximal tubular reabsorption of phosphate prevent development of overt hyperphosphatemia until advanced CKD. Hyperphosphatemia may develop when the estimated glomerular filtration rate (eGFR) falls below 25 to 40 mL/min/1.73 m² [1-3].

This topic reviews recommendations regarding target serum phosphorus concentration and treatment options for hyperphosphatemia for patients with CKD.

Recommended goals for serum parathyroid hormone (PTH) concentration for patients with CKD and mechanisms underlying the physiologic response to phosphate retention are discussed elsewhere:

●(See "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease".)

●(See "Management of secondary hyperparathyroidism in adult patients on dialysis".)

●(See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

RATIONALE FOR TREATMENT — The rationale for treating hyperphosphatemia is based largely on observational studies reporting associations between higher serum phosphorus and increased cardiovascular morbidity and mortality [4-10]. Some of these data for nondialysis chronic kidney disease (CKD) and dialysis CKD are presented below:

●Nondialysis CKD – A predominant number of studies report an increased mortality in association with hyperphosphatemia among patients with nondialysis CKD [10-15]. This was best illustrated in a meta-analysis of three studies with nearly 5000 patients with nondialysis CKD, which showed a 35 percent increase in mortality per mg increase in phosphorus above normal values (95% CI 1.16-1.57) [10]. The median follow-up in individual studies was approximately 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 demonstrated an association between serum phosphorus and mortality among patients with nondialysis CKD [16,17]. One study published after the cited meta-analysis did not show an association between quartiles of serum phosphorus and mortality over a mean follow-up of over two years [16]. Differences in study populations are a likely reason for the discrepancy between studies [3]. As an example, individuals in the later study had much milder kidney dysfunction (with mean estimated glomerular filtration rate [eGFR] of 44 to 48 mL/min/1.73 m²) compared with prior studies.

Studies also suggest that there is progressive cardiovascular risk associated with hyperphosphatemia in patients with normal kidney function, as well as in patients with CKD with eGFR <60 mL/min/1.73 m² who are not on dialysis [11,14,18,19].

●Dialysis CKD – Increased serum phosphorus is associated with increased mortality among patients on dialysis [4-10]. This was best shown in a meta-analysis of 12 studies that included 92,345 patients with CKD, over 97 percent of whom were on dialysis [10]. Among 10 studies that were perceived to be adequately adjusted (in which seven studies were of patients on dialysis), serum phosphorus >5.5 mg/dL (1.78 mmol/L) was associated with increased mortality. Based upon 13 studies that reported a continuous relative risk for each mg/dL increase in phosphorus, the mortality risk increased by 18 percent (95% CI 1.12-1.25). Both the degree of phosphorus elevation and the duration of hyperphosphatemia correlated with mortality.

MONITORING — In patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m², we routinely monitor serum phosphorus, calcium, intact parathyroid hormone (iPTH), and 25-hydroxyvitamin D levels. Typically, these measurements should be done at least once per year, but the frequency with which these measurements are performed also depends on the eGFR and whether baseline abnormalities are present or therapeutic measures have been taken. In addition, monitoring may be performed more frequently if the eGFR is rapidly decreasing. Values should be rechecked if kidney function worsens. Serial assessments of phosphorus levels are important, as patients often go in and out of the target range.

The following approach is consistent with Kidney Disease: Improving Global Outcomes (KDIGO) guidelines [20]:

Estimated GFR 30 to 59 mL/min/1.73 m2 — In patients with eGFR 30 to 59 mL/min/1.73 m², we measure serum phosphorus and calcium at least every 12 months and every 6 months if the patient has or is being treated for hyperphosphatemia. We measure iPTH at least every 12 months and every 6 months if the baseline concentration is elevated or if the patient is being treated for secondary hyperparathyroidism. We measure 25-hydroxyvitamin D every 12 months and every 6 months if the patient is being treated for vitamin D deficiency.

Estimated GFR 15 to 29 mL/min/1.73 m2 — In patients with eGFR 15 to 29 mL/min/1.73 m², we measure serum phosphorus and calcium at least every six months and every three months if the patient has or is being treated for hyperphosphatemia. We measure iPTH at least every 12 months and every 6 months if the baseline concentration is elevated or if the patient is being treated for secondary hyperparathyroidism. We measure 25-hydroxyvitamin D every 12 months and every 6 months if the patient is being treated for vitamin D deficiency.

Estimated GFR <15 mL/min/1.73 m2 (including patients on dialysis) — In patients with eGFR <15 mL/min/1.73 m², we measure serum phosphorus and calcium at least every three months and every month if the patient has or is being treated for hyperphosphatemia. Most patients on dialysis have serum phosphorus and calcium levels checked monthly. We measure iPTH at least every six months and every three months if the baseline concentration is elevated or if the patient is being treated for secondary hyperparathyroidism. We measure 25-hydroxyvitamin D every 12 months and every 6 months if the patient is being treated for vitamin D deficiency.

TREATMENT THRESHOLDS AND TARGETS — Optimal treatment thresholds and targets for serum phosphorus in chronic kidney disease (CKD) have not yet been established [21]. However, we believe the goal phosphorus values presented below for nondialysis CKD and dialysis CKD are reasonable and obtainable in most patients.

Patients not on dialysis — For patients with nondialysis CKD, we initiate dietary modification when the serum phosphorus level is above normal (ie, ≥4.5 mg/dL [1.45 mmol/L]) with the goal of lowering serum phosphorus into the normal range. We only start phosphate binders when the serum phosphorus level is persistently elevated >5.5 mg/dL despite dietary restriction [22-25]. For patients treated with a phosphate binder in addition to dietary modification, we target a serum phosphorus ≤5.5 mg/dL.

This approach is generally consistent with the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines [20,23,26].

Patients on dialysis — For patients on dialysis, serum phosphorus >5.5 mg/dL (1.78 mmol/L) is an indication for treatment. In most patients, we aim to maintain the serum phosphorus concentration between 3.5 and 5.5 mg/dL inclusive (1.13 and 1.78 mmol/L), although there are no trial data demonstrating that lowering serum phosphorus to <5.5 mg/dL improves outcomes.

This target phosphorus range is consistent with the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines [22] but differs from the later KDIGO guidelines which recommend lowering phosphorus levels toward the normal range without specifying a numerical value [20,23]. We feel that the KDIGO recommendations do not provide a practical goal.

TREATMENT — Our treatment of hyperphosphatemia is stepwise and additive. For patients whom we treat (see 'Treatment thresholds and targets' above), we start with dietary modification, optimize the dialysis regimen for patients on dialysis, and then add phosphate binder therapy and other measures if needed for uncontrolled hyperphosphatemia (algorithm 1). However, some clinicians start dietary restriction and phosphate binders concurrently in patients who present with very high phosphorus levels (eg, >6.5 mg/dL), since dietary restriction alone in many such patients is ineffective.

Dietary phosphorus restriction in all patients — Our treatment approach begins with a moderate dietary phosphorus restriction of between 800 and 1000 mg/day (25.8 and 32.3 mmol/day) provided this can be done without compromising nutritional status (table 1A-B). Because many patients on dialysis have either overt or borderline malnutrition, phosphorus restriction in the dialysis setting should be done under the supervision of a dietician. These recommendations are consistent with the Kidney Disease Outcomes Quality Initiative (KDOQI) and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines [20,22,23].

Phosphorus restriction should primarily include processed foods and colas and not high-biologic-value foods such as meat and eggs (table 1A-B). Food additives (as are found in processed foods) and medications are an important source of dietary phosphorus [27,28]. In addition to having high phosphorus content, processed foods provide a more easily absorbed form of phosphorus compared with fresh animal- and plant-based foods [29,30]. We agree with the KDIGO guidelines that patients should receive education on the absorbability of phosphorus from different foods [20].

Some nephrologists recommend a more vegetarian-based diet to control phosphorus [31]. Phosphate bioavailability may be less with a vegetarian diet compared with an animal protein-based diet [32]. Many foods that have traditionally been labeled high-phosphorus (such as beans and nuts) may actually be acceptable (providing they are not too high in potassium) because phosphate from these sources is absorbed slowly [20,30]. This is because plant-derived phosphorus found in unprocessed foods is in the form of phytate phosphorus, and the human intestine does not secrete phytase, the enzyme required for absorption [29]. In addition, such a diet rich in legumes, nuts, and whole grains may also result in higher fiber intake while offering wider food choices [30].

Although dietary restriction can be effective in reducing the serum phosphorus concentration [27], few studies have examined the efficacy of dietary phosphorus restriction on patient-important outcomes. In a post hoc analysis of data from the Hemodialysis (HEMO) study, prescribed phosphorus restriction was not associated with improved survival of patients on hemodialysis [33]. In fact, there was a stepwise trend toward better survival with less restrictive prescribed phosphorus intake in this study. However, the HEMO study was performed prior to an awareness of the importance of food additives as a source of phosphorus; as a result, phosphorus restriction may have been achieved by the restriction of nutritionally beneficial food. Supporting this possibility, phosphorus restriction tended to be associated with poorer nutritional indices and a persistently greater need for nutritional supplementation in this study.

Optimize dialysis regimen — In addition to dietary phosphorus restriction, we ensure that patients on dialysis are achieving recommended Kt/V targets so that extracorporeal removal of phosphate is optimized. (See "Prescribing and assessing adequate hemodialysis" and "Prescribing peritoneal dialysis".)

For patients on conventional in-center hemodialysis (ie, three times weekly for four hours per session), we generally do not increase dialysis above the recommended dose. Because hemodialysis is limited in its ability to remove phosphate (the average standard dialysis session removes approximately 900 mg of phosphorus), most patients on conventional hemodialysis find it difficult to increase their dialysis time sufficiently to reduce serum phosphorus. In addition, higher conventional dialysis doses have not been shown to improve clinically important outcomes.

However, hyperphosphatemia may prompt some patients on conventional hemodialysis to consider daily or nocturnal (ie, usually prolonged and nightly) hemodialysis. Although hyperphosphatemia is rarely a deciding factor when choosing a dialysis modality, frequent or prolonged hemodialysis leads to greater removal of phosphate and can substantially lower serum phosphorus levels. In many patients undergoing frequent or prolonged hemodialysis, serum phosphorus can be controlled without the use of phosphate binders. (See "Short daily hemodialysis", section on 'Phosphate' and "Outcomes associated with nocturnal hemodialysis", section on 'Phosphate'.)

Add binders if phosphorus uncontrolled — We add phosphate binder therapy for patients in whom dietary restriction alone is inadequate (algorithm 1) (see 'Treatment thresholds and targets' above). The selection of phosphate binder type is the same for patients with dialysis and nondialysis chronic kidney disease (CKD) and is discussed below.

Choice of phosphate binder — Phosphate binders are categorized as calcium-containing and non-calcium-containing. We generally prefer non-calcium-containing binders, but otherwise the choice of a specific phosphate binder should be dictated by affordability to the patient, side effects, and patient preference (eg, pill burden, chew versus swallow). When titrated appropriately within recommended dose ranges, all phosphate binders are equivalently effective in lowering phosphate [22,34].

●Non-calcium-containing binders are preferred – For most patients with CKD who are being treated with phosphate binder therapy, we suggest using non-calcium-containing rather than calcium-containing binders. Exceptions may be made where non-calcium-containing binders are not available or affordable or when the serum calcium is low and parathyroid hormone (PTH) is elevated, such as in patients concomitantly treated with calcimimetics. However, many experts argue that calcium-containing binders should be avoided in all patients [20].

Major non-calcium-containing binders include sevelamer and lanthanum. Other non-calcium-containing binders include ferric citrate and sucroferric oxyhydroxide. Calcium-containing phosphate binders include calcium carbonate and calcium acetate. The use of these agents is detailed below. (See 'Dose and specific agents' below.)

●Evidence supporting non-calcium-containing binders – A number of trials and two meta-analyses have suggested that non-calcium-containing phosphate binders, compared with calcium-containing phosphate binders, decrease mortality among patients with CKD [35-45].

A meta-analysis of 11 open-label, randomized trials (4622 patients) reported lower all-cause mortality among patients randomly assigned to receive non-calcium-based binders (sevelamer, 10 studies including 3268 patients, or lanthanum, one study including 1354 patients) compared with calcium-based binders (18.9 versus 21.6 percent; relative risk [RR] 0.78, 95% CI 0.61-0.98) [46]. The results of this meta-analysis were driven in large part by the study that used lanthanum carbonate not sevelamer. Analysis of patients on dialysis and those with nondialysis CKD showed similar reductions in mortality. Most studies in this meta-analysis were limited to 24 months; analysis of studies with follow-up at 36 and 42 months showed similar reductions in mortality, but these reductions were not statistically significant [46]. This analysis did not look at cardiovascular mortality.

A second meta-analysis that included 13 studies (3799 patients) also reported lower all-cause mortality with sevelamer compared with calcium-based binders (17.5 versus 23.3 percent; RR 0.54, 95% CI 0.32-0.93) [47]. The reported reduction in cardiovascular mortality was not statistically significant (four studies, n = 2712, RR 0.33, 95% CI 0.07-1.64). Patients receiving sevelamer had lower cholesterol, low-density lipoprotein (LDL)-cholesterol, calcium, and decreased risk of hypercalcemia. There was no difference between groups in serum phosphorus. There was considerable heterogeneity among the studies.

However, a large, observational cohort study of over 4000 older patients on incident dialysis found that the risk of fatal or nonfatal cardiovascular events or all-cause mortality was not different among patients treated with either sevelamer or calcium acetate [48].

In addition to the possible effects on mortality, calcium-containing binders, but not non-calcium-containing binders, are associated with hypercalcemia, adynamic bone disease, and vascular calcification, all which could result in increased morbidity [35,37,39,40,47,49,50].

●Calcium-containing binders and calcium balance – The use of calcium-containing binders may induce a positive calcium balance and thereby increase vascular calcification. Because normal dietary calcium intake is roughly 1000 mg per day, prescription of 1500 mg elemental calcium per day (ie, calcium carbonate 1250 mg three times daily with meals) increases calcium ingestion by roughly 2.5-fold. In addition, calcium excretion is reduced in CKD because of a reduced filtered load of calcium. The combination of increased calcium ingestion and decreased calcium excretion could lead to positive calcium balance, even in the absence of hypercalcemia.

These concerns are well illustrated by the results of a randomized, placebo-controlled crossover study that examined the effect of oral calcium carbonate administration on calcium and phosphate balance in eight patients with CKD with a mean estimated glomerular filtration rate (eGFR) of 15 to 59 mL/min/1.73 m² [51]. Subjects received a controlled diet with either a calcium carbonate supplement (1500 mg/day calcium) or placebo during two three-week balance periods. Fasting blood and urine were collected at baseline and at the end of each week. All feces and urine were collected during weeks 2 and 3 of each balance period. An oral and intravenous calcium isotope (⁴⁵CaCl₂) was administered to determine calcium kinetics.

Patients were in neutral calcium and phosphorus balance while on the placebo. Calcium carbonate supplementation caused a positive calcium balance and had no effect on phosphorus balance. In addition, compared with placebo, calcium carbonate supplementation produced a small reduction in urine phosphorus excretion. Calcium kinetics demonstrated positive net bone balance. However, the amount of calcium that was deposited in bone was less than the overall positive calcium balance, suggesting that some degree of soft-tissue deposition occurred. Fasting blood biochemistries of calcium and phosphate homeostasis were unaffected by calcium carbonate, suggesting that it is futile to rely solely on blood concentrations to determine mineral excess or accumulation.

The interpretation of these data may be limited by the short-term nature of the study. It is possible that patients were not in steady state after only one to three weeks of calcium administration. If so, the short-term positive calcium balance that was observed may have been an appropriate response to correct years of bone calcium depletion and thus may decrease over time [52]. In studies of longer duration in predialysis CKD, 24-hour phosphate excretion substantially declined when calcium-containing binders were used [49].

Dose and specific agents — For all phosphate binders, the lowest dose that is effective should be used. Phosphate binders are only effective if taken with meals [53]. Dosing of these agents is presented below.

●Preferred agents – Based on cost and favorable side effect profiles, we generally use the non-calcium-containing binders sevelamer or lanthanum. Our choice of one agent over the other is guided by affordability to the patient, side effects, and patient preference. For example, we prescribe lanthanum to patients who prefer to chew medication rather than swallow it whole.

•Sevelamer – Sevelamer hydrochloride and sevelamer carbonate are nonabsorbable cationic polymers that bind phosphate through ion exchange [54]. Sevelamer is effective in lowering serum phosphate levels [37,38,55-62]. The usual dose range of sevelamer is 800 to 2400 mg three times daily with meals.

Sevelamer hydrochloride, but not sevelamer carbonate, may induce metabolic acidosis. For this reason, sevelamer carbonate is preferred over sevelamer hydrochloride in patients with nondialysis CKD and in any patient with metabolic acidosis. (See "Pathogenesis, consequences, and treatment of metabolic acidosis in chronic kidney disease".)

Sevelamer is much more expensive than calcium-containing phosphate binders [63,64].

•Lanthanum – Lanthanum is a rare-earth element that is effective in lowering phosphate levels in patients on dialysis [65-72] and patients with nondialysis CKD [73]. Compared with calcium-containing phosphate binders, lanthanum appears to be associated with lower incidences of oversuppression of PTH levels [65-67,69,71,72,74-76].

An additional benefit of lanthanum, compared with other phosphate binders, may be a reduced daily tablet burden [77]. In addition, lanthanum tablets are chewed rather than swallowed whole. The usual dose range of lanthanum is 500 to 1000 mg three times daily with meals.

In studies of patients on dialysis, no significant adverse effects have been reported with lanthanum [65-67,69,71,72,74-76]. The safety of lanthanum administered for up to two years was evaluated in 1359 patients on hemodialysis randomly assigned to lanthanum (maximum dose of 3000 mg/day) or their prestudy phosphate binder [71]. The incidence of adverse effects was similar in both groups, which principally consisted of gastrointestinal effects. No evidence of hepatic toxicity was observed.

●Other non-calcium-containing binders – Other non-calcium-containing phosphate binders include sucroferric oxyhydroxide and ferric citrate. A potential advantage of sucroferric oxyhydroxide is a lower pill burden compared with other binders. Ferric citrate may be helpful in patients with hyperphosphatemia who also are iron deficient.

•Sucroferric oxyhydroxide – Sucroferric oxyhydroxide is a chewable phosphate binder for patients with eGFR <15 mL/min/1.73 m². Sucroferric oxyhydroxide appears to be comparable with sevelamer in efficacy and safety and may be associated with a lower pill burden [78,79]. Adverse effects are primarily gastrointestinal (diarrhea, nausea, abnormal product taste, constipation, and vomiting).

The starting dose of sucroferric oxyhydroxide is 2.5 g three times daily with meals or, if dosing is expressed in terms of elemental iron, 500 mg three times daily with meals. The majority of iron from sucroferric oxyhydroxide is not systemically absorbed, although small increases in transferrin saturation and ferritin have been observed with use [80].

•Ferric citrate – Ferric citrate is effective in reducing serum phosphate concentration by approximately the same degree as other phosphate binders [81-84]. In addition, ferric citrate raises hemoglobin, serum iron, transferrin saturation, and ferritin [85]. Patients on dialysis who take ferric citrate also may be receiving parenteral iron as part of an anemia management regimen; serum iron, transferrin saturation, and ferritin should be carefully monitored in such patients to avoid iron overload.

Citrate has been shown to enhance the absorption of aluminum, which increases the risk of aluminum toxicity. Because of this, some have recommended avoidance of all citrate-containing products in patients with CKD or who are on dialysis. However, in one trial of patients on maintenance dialysis, there was no aluminum toxicity noted among recipients of ferric citrate [81].

●Calcium-containing binders – For most patients, we suggest that non-calcium-containing binders be used (see 'Choice of phosphate binder' above). However, if calcium-containing binders are selected, 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. This is consistent with both the KDOQI and KDIGO guidelines [22,23,26].

•Type and dose – Calcium-containing phosphate binders include calcium carbonate and calcium acetate [86-88]. Calcium acetate may be a more efficient phosphate binder than calcium carbonate [89-91].

The usual dose range for calcium carbonate is 1250 to 3750 mg per day in divided doses with meals. The usual dose range for calcium acetate is 1334 to 2001 mg three times daily with meals. The higher ends of these usual dose ranges represent approximately 1500 mg daily of elemental calcium. Because dietary calcium intake is typically on the order of 1000 mg per day, patients taking calcium-containing binders at the high end of the usual dose range often have total daily intakes of elemental calcium that exceed the recommended level of 2000 mg per day.

•Monitoring for hypercalcemia – Careful monitoring of the serum calcium concentration is essential with the chronic administration of calcium-containing binders, particularly in patients on hemodialysis (see 'Monitoring' above). Combined hypercalcemia and hyperphosphatemia is a particular problem among patients who are on both calcium-containing phosphate binders and active vitamin D analogs. In such patients who develop hypercalcemia, the dose of the calcium-containing phosphate binder should be decreased [22]. In addition, the dose of active vitamin D analogs should be lowered or discontinued until calcium levels return to normal. (See "Management of secondary hyperparathyroidism in adult patients on dialysis".)

As noted above, even in the absence of hypercalcemia, a positive calcium balance may increase the risk of vascular calcification, particularly in the setting of hyperphosphatemia [86,92-97]. (See 'Choice of phosphate binder' above.)

●Uncertain role for combination therapy – For patients on dialysis with hard to control phosphorus, concurrent treatment with two types of phosphate binder (eg, sucroferric oxyhydroxide plus sevelamer or calcium acetate) may be effective [98]. The major downsides of combination phosphate binder therapy are an increased pill burden at mealtime, cost, and, potentially, an increase in gastrointestinal side effects. With the advent of tenapanor as add-on therapy for patients on dialysis who are taking an appropriately up-titrated phosphate binder, the role of combination phosphate binder therapy is uncertain. (See 'Refractory hyperphosphatemia' below.)

●Other agents – We generally do not use the following agents due to lack of efficacy or concern over adverse effects.

•Nicotinamide – We do not use nicotinamide to reduce phosphorus levels in patients with CKD. Nicotinamide, a metabolite of nicotinic acid (niacin, vitamin B3), may lower serum phosphate by reducing gastrointestinal tract phosphate absorption [82,83]. However, randomized trials examining nicotinamide as a treatment to lower phosphate in patients with nondialysis CKD and patients on dialysis have demonstrated limited efficacy, poor tolerance, and some safety concerns [99,100]. For example, in a randomized trial that included over 700 patients on hemodialysis who were using phosphate binders, nicotinamide as add-on therapy lowered phosphate levels compared with placebo at 24 weeks, but this effect was not maintained at 52 weeks of follow-up [100]. In addition, nicotinamide therapy was associated with higher rates of side effects, including diarrhea, pruritus, and thrombocytopenia.

•Aluminum hydroxide – We do not use aluminum hydroxide for long-term phosphorus control in patients with CKD. Aluminum hydroxide is effective at controlling serum phosphorus, but the safety of aluminum-based phosphate binders in CKD has not been established. Excess aluminum exposure in CKD can result in aluminum toxicity. The major manifestations of aluminum toxicity are vitamin D-resistant osteomalacia, microcytic anemia, bone and muscle pain, and dementia. (See "Aluminum toxicity in chronic kidney disease".)

•Calcium citrate – Calcium citrate has been used as a phosphate binder. Calcium citrate should be avoided in all patients with CKD since citrate can markedly increase intestinal aluminum absorption [101,102]. The use of calcium citrate has been associated with aluminum neurotoxicity and the rapid onset of symptomatic osteomalacia [103]. (See "Aluminum toxicity in chronic kidney disease".)

Citrate appears to enhance aluminum absorption both by keeping aluminum soluble (via the formation of aluminum citrate) in the intestinal lumen and by complexing with luminal calcium [101,102]. The ensuing decrease in free calcium increases permeability of tight junctions between cells, which can markedly enhance passive aluminum absorption (figure 1) [101,102].

•Magnesium binders – Magnesium-containing binders can lower serum phosphorus in patients with CKD [104]. However, we generally avoid magnesium binders in CKD because of the risk of magnesium toxicity.

Benefits of binder therapy — It is uncertain whether the use of phosphate binders provides a benefit on clinically important endpoints.

●Patients not on dialysis – For patients with nondialysis CKD, the effect of phosphate binders on serum phosphorus levels can be variable. In a randomized trial, compared with placebo, the use of phosphate binders was associated with a greater decrease in serum phosphate and in 24-hour urine phosphate at three, six, and nine months, although the effect was small [49]. In addition, the use of phosphate binders was associated with a stable PTH value versus an increase in the placebo group. In another trial, use of a phosphate binder (sevelamer) led to no improvement in serum phosphate [105].

Because no intervention to lower serum phosphorus has been shown to affect clinically important outcomes among patients with nondialysis CKD [105,106], some experts do not endorse the use of phosphate binders in this population. An additional concern is that calcium-containing phosphate binders may induce positive calcium balance in patients with CKD, which could lead to vascular calcification. (See 'Choice of phosphate binder' above.)

●Patients on dialysis – Two observational studies have suggested that phosphate binders are associated with decreased mortality among patients on dialysis:

•In a prospective, observational study of patients on incident dialysis followed for one year, the use of phosphate binders was associated with a 25 percent lower one-year mortality [107].

•Among 6797 patients enrolled in an observational, prospective study (Current Management of Secondary Hyperparathyroidism: A Multicenter Observational Study [COSMOS]), patients prescribed phosphate binders had a 29 percent lower risk of all-cause mortality and a 22 percent lower risk of cardiovascular mortality [108].

Refractory hyperphosphatemia — Among patients with CKD, hyperphosphatemia is occasionally refractory to dietary restriction and the use of phosphate binders (see 'Add binders if phosphorus uncontrolled' above), and patients on hemodialysis may be unwilling or unable to undergo frequent or prolonged hemodialysis. In such patients, our stepwise approach is as follows (algorithm 1):

Review treatment of hyperparathyroidism — The treatment of hyperparathyroidism, which varies by dialysis status, should be reviewed.

●Patients not on dialysis – Patients with nondialysis CKD and hyperphosphatemia should not be treated with calcitriol or active vitamin D analogs since these agents increase the gastrointestinal absorption of phosphate. We do not use calcimimetics (eg, cinacalcet) to lower PTH in patients with nondialysis CKD. (See "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease".)

●Patients on dialysis – In patients on dialysis who have refractory hyperphosphatemia and who are being treated for hyperparathyroidism, we use calcimimetics to suppress PTH and minimize the use of calcitriol or vitamin D analogs. (See "Management of secondary hyperparathyroidism in adult patients on dialysis".)

In patients on dialysis, both inadequately treated hyperparathyroidism and the use of high doses of calcitriol or active vitamin D analogs may contribute to hyperphosphatemia through different mechanisms. High levels of PTH increase bone resorption and the release of phosphate from bone [109], and active vitamin D moieties increase the gastrointestinal absorption of phosphate.

Add tenapanor for patients on dialysis — In adequately dialyzed patients who have serum phosphorus levels persistently >5.5 mg/dL despite dietary restriction, optimal treatment of hyperparathyroidism, and the appropriate use of phosphate binders (see 'Add binders if phosphorus uncontrolled' above), we suggest adding tenapanor to the medical regimen. Tenapanor is an inhibitor of intestinal sodium/hydrogen exchanger 3 that was developed to treat irritable bowel syndrome with constipation but was also found to lower serum phosphate by blocking its paracellular transport from the intestinal lumen [84]. Since no data demonstrate that lowering phosphate levels to 5.5 mg/dL or below improves clinical outcomes, some experts use higher levels of serum phosphorus (eg, >6.5 mg/dL) as a threshold for tenapanor add-on therapy.

The usual dose range of tenapanor is 10 to 30 mg twice daily. The major adverse effect of tenapanor is an increase in stool frequency, thought to be due to an increase in stool water content. Diarrhea occurs in approximately half of tenapanor-treated patients [110] but is usually not severe; diarrhea leads to drug discontinuation in approximately five percent of patients.

In patients on hemodialysis, multiple trials have demonstrated that tenapanor lowers phosphorus to a modest degree [111-116]. In a meta-analysis of randomized trials, tenapanor therapy compared with placebo resulted in a mean decrease in serum phosphorus of 1.79 mg/dL [110]. In one representative trial, 169 patients on hemodialysis with hyperphosphatemia despite treatment with one or more phosphate binders were randomized to tenapanor or placebo; phosphate binders were continued in both groups [115]. Patients treated with tenapanor had a serum phosphorus 1.76 mg/dL lower than patients in the placebo group. Diarrhea occurred in 63.1 and 14.1 percent of patients in the tenapanor and placebo groups, respectively, but was reported as mild or moderate in all cases.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Rationale for treatment – High phosphorus levels are associated with increased mortality in patients with chronic kidney disease (CKD). However, specific interventions that lower phosphorus levels have not been shown to improve mortality or other clinical outcomes. (See 'Rationale for treatment' above.)

●Monitoring serum phosphorus – In patients with estimated glomerular filtration rates (eGFR) <60 mL/min/1.73 m², we recommend monitoring serum phosphorus, calcium, intact parathyroid hormone (iPTH), and 25-hydroxyvitamin D levels. The frequency of monitoring depends on the eGFR and whether baseline abnormalities are present or therapeutic measures have been taken. (See 'Monitoring' above.)

●Treatment thresholds and targets – Optimal treatment thresholds and targets for serum phosphorus in CKD have not yet been established. However, we believe the goal phosphorus values presented below for nondialysis CKD and dialysis CKD are reasonable and obtainable in most patients. (See 'Rationale for treatment' above.)

•Patients not on dialysis – For patients with nondialysis CKD, we initiate dietary modification when the serum phosphorus level is above normal (ie, ≥4.5 mg/dL [1.45 mmol/L]) with the goal of lowering serum phosphorus into the normal range. We only start phosphate binders when the serum phosphorus level is persistently elevated >5.5 mg/dL (1.78 mmol/L) despite dietary restriction. (See 'Patients not on dialysis' above.)

•Patients on dialysis – For patients on dialysis, serum phosphorus >5.5 mg/dL (1.78 mmol/L) is an indication for treatment. In most patients, we aim to maintain the serum phosphorus concentration between 3.5 and 5.5 mg/dL inclusive (1.13 and 1.78 mmol/L). (See 'Patients on dialysis' above.)

●Treatment – Our treatment of hyperphosphatemia is stepwise and additive (algorithm 1).

•Dietary phosphorus restriction – For most patients who have nondialysis CKD with serum phosphorus ≥4.5 mg/dL (1.45 mmol/L) and for most patients on dialysis with serum phosphorus >5.5 mg/dL (1.78 mmol/L), we suggest dietary phosphorus restriction (Grade 2C). For patients treated with dietary phosphorus restriction, we suggest targeting a phosphorus intake of between 800 and 1000 mg/day (25.8 and 32.3 mmol/day) (Grade 2C). Phosphorus restriction should primarily include processed foods and colas and not high-biologic-value foods such as meat and eggs. (See 'Dietary phosphorus restriction in all patients' above.)

•Optimize dialysis regimen – In addition to dietary phosphorus restriction, we ensure that patients on dialysis are achieving recommended Kt/V targets so that extracorporeal removal of phosphate is optimized. (See 'Optimize dialysis regimen' above.)

•Phosphate binders – For patients with nondialysis CKD and for patients on dialysis who have serum phosphorus >5.5 mg/dL (1.78 mmol/L) despite dietary phosphorus restriction, we suggest phosphate binder therapy and dietary restriction rather than dietary restriction alone (Grade 2C). (See 'Benefits of binder therapy' above.)

-For most patients treated with phosphate binders, we suggest non-calcium-containing binders rather than calcium-containing binders (Grade 2B). Studies have suggested lower mortality associated with the use of non-calcium-containing binders compared with calcium-containing binders. (See 'Choice of phosphate binder' above.)

-For all phosphate binders, the lowest dose that is effective should be used. Phosphate binders are only effective if taken with meals. (See 'Dose and specific agents' above.)

•Refractory hyperphosphatemia – Patients with refractory hyperphosphatemia may benefit from a modification of treatment of hyperparathyroidism. For patients on dialysis, an intensified dialysis regimen may lower serum phosphorus. However, many patients are unwilling or unable to undergo intensified dialysis solely for phosphorus control. In adequately dialyzed patients who have serum phosphorus levels persistently >5.5 mg/dL (1.78 mmol/L) despite dietary restriction, optimal treatment of hyperparathyroidism, and the appropriate use of phosphate binders, we suggest treatment with tenapanor and phosphate binders rather than phosphate binders alone (Grade 2B). (See 'Refractory hyperphosphatemia' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert E Cronin, MD, and Michael Berkoben, MD, who contributed to earlier versions of this topic review.