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Management of hyperphosphatemia in chronic kidney disease
Authors:Michael Berkoben, MDL Darryl Quarles, MDSection Editor:Jeffrey S Berns, MDDeputy Editor:Shveta Motwani, MD, MMSc, FASN
Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2018. | This topic last updated: Oct 18, 2018.
INTRODUCTION — The tendency toward phosphate retention develops early in chronic kidney disease (CKD) due to the reduction in the filtered phosphate load. Overt hyperphosphatemia develops when the estimated glomerular filtration rate (eGFR) falls below 25 to 40 mL/min/1.73 m2 [1-3].

Hyperphosphatemia has been associated with increased mortality and morbidity [4-10].

This topic reviews recommendations regarding target phosphate concentration and treatment options for hyperphosphatemia for CKD patients.

Recommended goals for serum parathyroid hormone (PTH) concentration for patients with CKD are discussed elsewhere. (See "Management of secondary hyperparathyroidism in dialysis patients", section on 'Treat high parathyroid hormone'.)

Mechanisms underlying the physiologic response to phosphate retention are discussed elsewhere. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

MONITORING — In patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, we routinely monitor serum phosphate, calcium, intact parathyroid hormone (iPTH), and 25-hydroxyvitamin D levels.

The frequency with which these measurements are performed 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 renal function worsens.

The following monitoring schedule is reasonable and based upon the 2017 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines [11].

Estimated GFR 30 to 59 mL/min/1.73 m2 — In patients with estimated glomerular filtration rate (eGFR) 30 to 59 mL/min/1.73 m2, we measure serum phosphate and calcium every 6 to 12 months. 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. We measure 25-hydroxyvitamin D every 12 months and every 6 months if the patient is being treated.

Estimated GFR 15 to 29 mL/min/1.73 m2 — In patients with estimated glomerular filtration rate (eGFR) 15 to 29 mL/min/1.73 m2, we measure serum phosphate and calcium every three to six months. We measure iPTH every 6 to 12 months and every 6 months if the baseline concentration is elevated or if the patient is being treated. 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 dialysis patients) — In patients with estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2, we measure serum phosphate and calcium every one to three months. We measure iPTH every three to six months and every three months if the baseline concentration is elevated or if the patient is being treated. We measure 25-hydroxyvitamin D every 12 months and every 6 months if the patient is being treated for vitamin D deficiency.

TREATMENT APPROACH

Nondialysis chronic kidney disease patients — In nondialysis CKD patients, we try to maintain the serum phosphate level in the normal range (ie, <4.5 mg/dL [1.45 mmol/L]); this level is consistent with the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines [11-13]. Progressive or persistent hyperphosphatemia >4.5 mg/dL is an indication for treatment.

We do not attempt to reduce phosphate to lower than normal values or prevent an increase in serum phosphate among patients who have a normal phosphate concentration.

Hyperphosphatemia has been associated with increased mortality among nondialysis CKD patients [10,14-17]. This was best shown in a meta-analysis of three studies with 4651 nondialysis CKD patients, in which there was a 35 percent increase in mortality per mg increase in phosphate 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 phosphate >3.5 mg/dL (1.13 mmol/L) was an independent predictor of all-cause mortality [14].

Hyperphosphatemia is a stimulus for hyperparathyroidism. Studies also suggest that there is progressive cardiovascular risk associated with hyperphosphatemia in patients with normal kidney function, as well in CKD patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 who are not on dialysis [14,17-19].

Some other studies have not demonstrated an association between serum phosphate and mortality among nondialysis CKD patients [20,21]. One study published after the cited meta-analysis did not show an association between quartiles of serum phosphate and mortality over a mean follow-up of 2.3 years [20]. 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 eGFR of 44 to 48 mL/min/1.73 m2) compared with prior studies.

No intervention to lower serum phosphate has been shown to affect clinically important outcomes among nondialysis CKD patients.

Two methods are used to treat hyperphosphatemia in nondialysis CKD patients [12]:

●Restriction of dietary phosphate intake

●Administration of phosphate binders to block absorption of ingested phosphate from the intestine

Usually, we try dietary restriction first and only use a phosphate binder if the phosphate is persistently and/or progressively elevated despite dietary phosphorus restriction. In patients who present with very high phosphate (ie, >6 mg/dL), we start phosphate binders concurrently with dietary restriction because it is unlikely that restriction alone will be effective.

We suggest a moderate restriction of phosphate intake (approximately 900 mg/day) in nondialysis CKD patients, provided that this can be done without compromising nutritional status (table 1A-B). These recommendations are consistent with the Kidney Disease Outcomes Quality Initiative (KDOQI) and KDIGO guidelines [11,12,22]. (See 'Phosphate restriction' below.)

Many patients have increased serum phosphate despite dietary phosphate restriction. For most patients who have persistently and progressively elevated phosphate despite dietary phosphate restriction, we suggest phosphate binders [12,22-24].

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 [25]. In addition, the use of phosphate binders was associated with a stable parathyroid hormone (PTH) value versus an increase in the placebo group.

No randomized trials have shown a benefit of phosphate binders on clinically relevant endpoints, however. A retrospective cohort of nondialysis CKD patients demonstrated a 23 percent decrease in mortality associated with phosphate binder therapy [26]. However, this apparent benefit could stem from unequal periods of follow-up; the median period of follow-up was approximately four years for patients not given phosphate binders compared with just two years for patients treated with phosphate binders.

Some experts do not recommend phosphate binders, since no randomized trials have demonstrated a clinically relevant benefit of phosphate binders. Also, as noted above, studies have suggested that phosphate binders are only minimally effective in lowering serum phosphate levels [25,27].

In addition, the prescription of a phosphate binder increases the patient's pill burden.

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 'Specific treatment' below.)

The selection of type of phosphate binder is the same for dialysis and nondialysis CKD patients and is discussed below. (See 'Specific treatment' below.)

Dialysis patients

Initial therapy — In most dialysis patients, we try to maintain the serum phosphate concentration between 3.5 and 5.5 mg/dL (1.13 and 1.78 mmol/L), although there are no data that this improves outcomes. Serum phosphate >5.5 mg/dL (1.78 mmol/L) is an indication for treatment.

Increased serum phosphate is associated with increased mortality among dialysis patients [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 dialysis patients), serum phosphate >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 phosphate, the mortality risk increased by 18 percent (95% CI 1.12-1.25).

A target phosphate goal between 3.5 and 5.5 mg/dL (1.13 and 1.78 mmol/L) is consistent with the KDOQI guidelines [22]. This target differs from the more recent KDIGO guidelines, which recommend lowering levels toward the normal range but do not specify a target threshold [11,12]. We feel that the KDIGO recommendations do not provide a practical goal.

The initial therapy includes phosphate restriction and phosphate binders [12,28].

We suggest a moderate restriction of phosphate intake in dialysis patients, provided that this can be done without compromising nutritional status. These recommendations are consistent with the KDOQI and KDIGO guidelines [11,22].

We restrict dietary phosphate to 900 mg/day. Among dialysis patients, phosphate restriction should be done under the supervision of a dietician. This is because many dialysis patients have either overt or borderline malnutrition. For such patients, protein supplementation (which contributes to phosphorus intake) rather than protein restriction is the goal. In this setting, the patient should be encouraged to avoid unnecessary dietary phosphate (such as phosphate-containing food additives, dairy products, certain vegetables, many processed foods, and colas), while increasing the intake of high-biologic-value sources of protein (such as meat and eggs) [29,30]. (See 'Phosphate restriction' below.)

While we may try dietary restriction first and only use a phosphate binder if the phosphate is persistently and progressively elevated after one or two months of dietary phosphorus restriction, most patients will also require a phosphate binder. Many clinicians will start dietary phosphate restriction and phosphate binders simultaneously in all patients with hyperphosphatemia.

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

●In a prospective, observational study of incident dialysis patients followed for one year, the use of phosphate binders was associated with a 25 percent lower one-year mortality [31].

●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 [32].

Randomized trials are needed to determine whether the use of phosphate binders provides a benefit on clinically important endpoints among dialysis patients.

The choice of phosphate binder is discussed below. (See 'Specific treatment' below.)

In addition to phosphate restriction and binders, it is important to make sure patients are adequately dialyzed and achieving recommended Kt/V targets. (See "Prescribing and assessing adequate hemodialysis".)

However, in patients who are undergoing standard in-center hemodialysis (which represents most hemodialysis patients), we do not generally increase the dialysis above the recommended dose, as this has not been shown to improve clinically important outcomes.

Although an exception may be made for exceptionally motivated patients who may be willing to undergo more dialysis, most patients find it difficult to increase the dialysis time sufficiently to reduce the serum phosphate. Standard dialysis (ie, three times weekly for four hours per session) is limited in its ability to remove phosphate. The average standard dialysis session removes approximately 900 mg of phosphate.

Some patients may consider daily or nocturnal (ie, usually prolonged and nightly) hemodialysis. Frequent or prolonged hemodialysis leads to greater removal of phosphate and can substantially lower serum phosphate levels. In fact, in some patients undergoing frequent or prolonged hemodialysis, serum phosphate can be controlled without the use of phosphate binders. However, many factors impact a decision to undergo daily dialysis, and hyperphosphatemia alone is rarely the deciding factor. (See "Outcomes associated with nocturnal hemodialysis", section on 'Phosphate' and "Short daily hemodialysis", section on 'Phosphate'.)

Occasionally, hyperphosphatemia will be refractory to these methods. (See 'Refractory hyperphosphatemia' below.)

Refractory hyperphosphatemia — Among dialysis patients, hyperphosphatemia is occasionally refractory to dietary restriction and phosphate binders, and patients may be unwilling or unable to undergo frequent or prolonged hemodialysis.

In such patients, the treatment of hyperparathyroidism should be reviewed. Both high PTH and the specific treatments of hyperparathyroidism may be contributing to high phosphate.

●PTH-stimulated release of phosphorus from bone may contribute to hyperphosphatemia [33].

●The treatment of hyperparathyroidism with high doses of active vitamin D analogs increases the gastrointestinal absorption of phosphate.

Among such patients, the phosphate may be reduced by decreasing PTH using calcimimetics instead of calcitriol or vitamin D analogs (ie, which suppresses PTH-induced bone efflux and removes effects of vitamin D to increase gastrointestinal absorption of phosphorus) or by parathyroidectomy, which reduces bone efflux. (See "Management of secondary hyperparathyroidism in dialysis patients", section on 'Refractory hyperparathyroidism' and "Refractory hyperparathyroidism and indications for parathyroidectomy in dialysis patients", section on 'Symptomatic patients'.)

Specific treatment

Phosphate restriction — Dietary phosphate restriction can be effective in reducing the serum phosphate concentration [30], although the effect is inconsistent, and interventions designed to reduce dietary phosphate intake may have minimal effects on serum and urinary phosphate concentrations [34,35]. Moreover, no adequately powered studies have examined the efficacy of dietary phosphate restrictions on patient-important outcomes.

Approximately 900 mg/day of dietary phosphate is a level that at least some patients will find acceptable. Phosphate 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 phosphate [36]. In addition to having high phosphate content, processed foods provide a more easily absorbed form of phosphate compared with fresh animal- and plant-based foods [29]. We agree with the KDIGO guidelines that patients should receive education on the absorbability of phosphate from different food [11].

Some nephrologists recommend a more vegetarian-based diet in order to control phosphate. Phosphate bioavailability may be less with a vegetarian compared with animal protein [37]. Many foods that have traditionally been labeled high phosphate (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 [11]. This is because plant-derived phosphate 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].

A randomized study of hemodialysis patients showed that careful instruction on avoiding foods with phosphorus additives resulted in larger declines in serum phosphate compared with control patients who did not receive such instruction [30].

Very few studies have examined the efficacy of dietary phosphate restrictions on patient-important outcomes among dialysis patients. In a post-hoc analysis of data from the Hemodialysis (HEMO) study, prescribed phosphate restriction was not associated with improved survival of hemodialysis patients [38]. In fact, there was a stepwise trend toward better survival with less restrictive prescribed phosphate intake in this study. However, the HEMO study was performed prior to an awareness of the importance of food additives as a source of phosphate; as a result, phosphate restriction may have been achieved by the restriction of nutritionally beneficial food. Supporting this possibility, phosphate restriction tended to be associated with poorer nutritional indices and a persistently greater need for nutritional supplementation in this study.

Phosphate binders — Phosphate binders are categorized as calcium containing and noncalcium containing. Calcium-containing binders include calcium carbonate and calcium acetate. Major noncalcium-containing binders include sevelamer and lanthanum. Other agents include ferric citrate and sucroferric oxyhydroxide. All are equivalently effective in lowering phosphate [22].

For most patients we suggest that noncalcium-containing binders be used. Exceptions may be made where noncalcium-containing binders are not available or affordable. In addition some experts continue to use calcium-containing binders when the serum calcium is very low and PTH is elevated.

However many experts argue that calcium-containing binders should be avoided in all patients [11].

A number of studies and two meta-analyses have suggested that noncalcium-containing phosphate binders decrease mortality among CKD patients [39-49].

A meta-analysis of 11 open-label, randomized trials (4622 patients) revealed a 22 percent decrease in all-cause mortality among patients randomly assigned to receive noncalcium-based binders (sevelamer, 10 studies including 3268 patients, or lanthanum, one study including 1354 patients) compared with calcium-based binders (relative risk [RR] 0.78, 95% CI 0.61-0.98) [50]. The results of this meta-analysis were driven in large part by the study that used lanthanum carbonate not sevelamer. Analysis of dialysis and nondialysis CKD patients 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 no difference in mortality, possibly because of insufficient power [50]. This analysis did not look at cardiovascular mortality.

A second meta-analysis also reported a decrease in all-cause mortality with sevelamer compared with calcium-based binders (13 studies, n = 3799, RR 0.54, 95% CI 0.32-0.93) [51]. Although there was a large reduction in cardiovascular mortality (four studies, n = 2712, RR 0.33, 95% CI 0.07-1.64), this reduction was not statistically significant. 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 phosphate. There was considerable heterogeneity among the studies.

In addition to the possible effects on mortality, calcium-containing binders, but not noncalcium-containing binders, are associated with hypercalcemia, adynamic bone disease, and vascular calcification, all which could result in increased morbidity [25,39,41,43,44,51,52].

Even in the absence of hypercalcemia, a positive calcium balance may 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. This was demonstrated in a well-conducted randomized, placebo-controlled crossover study that examined the effect of oral calcium carbonate administration on calcium and phosphate balance in eight CKD patients with a mean eGFR of 15 to 59 mL/min/1.73 m2 [53]. 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 and urine 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 week 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 [54]. In studies of longer duration in predialysis CKD, 24-hour phosphate excretion substantially declined when calcium-containing binders were used [25].

It is not clear that the potential benefits of noncalcium-containing phosphate binders are observed in all CKD patients. This is an important issue since noncalcium-containing binders are much more expensive than calcium-containing binders.

Dose and specific agents — For all phosphate buffers, the lowest dose that is effective should be used. If calcium-containing buffers are selected, we suggest that the total dose of elemental calcium (including dietary sources) 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 [12,13,22].

Phosphate binders are only effective if taken with meals [55].

Specific agents are discussed here.

●Sevelamer ─ Sevelamer hydrochloride (Renagel) and sevelamer carbonate (Renvela) are nonabsorbable cationic polymers that bind phosphate through ion exchange [56].

Sevelamer is effective in lowering serum phosphate levels [41,42,57-64]. Conventional dosing is three times daily.

Sevelamer hydrochloride, but not sevelamer carbonate, may induce metabolic acidosis. (See "Pathogenesis, consequences, and treatment of metabolic acidosis in chronic kidney disease".)

Sevelamer is much more expensive than calcium-containing phosphate binders [65,66]. By one estimate in the United States, approximately 780 million dollars would be required per year in order to provide sevelamer to all who met KDOQI criteria for its use [65].

●Lanthanum ─ Lanthanum is a rare-earth element that is effective in lowering phosphate levels in dialysis patients [67-74] and nondialysis CKD patients [75]. Compared with calcium-containing phosphate binders, lanthanum appears to be associated with lower incidences of oversuppression of PTH levels [67-69,71,73,74,76-78].

An additional benefit of lanthanum, compared with other phosphate binders, may be a reduced daily tablet burden [79]. In addition, lanthanum tablets are chewed rather than swallowed whole.

Among dialysis patients, no significant adverse effects have been reported with lanthanum [67-69,71,73,74,76-78]. The safety of lanthanum administered for up to two years was evaluated in 1359 hemodialysis patients randomly assigned to lanthanum (maximum dose of 3000 mg/day) or their prestudy phosphate binder [73]. The incidence of adverse effects was similar in both groups, which principally consisted of gastrointestinal effects. No evidence of hepatic toxicity was observed.

●Calcium-containing binders – Calcium-containing phosphate binders include calcium carbonate and calcium acetate [80-82]. Calcium acetate may be a more efficient phosphate binder than calcium carbonate [83-85].

As noted above, calcium-containing phosphate binders may lead to extraskeletal calcium phosphate deposition, particularly in the setting of hyperphosphatemia [80,86-91]. 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] (see 'Specific treatment' above). In addition, the dose of active vitamin D analogs should be lowered or discontinued until calcium levels return to normal.

Careful monitoring of the serum calcium concentration is essential with the chronic administration of calcium, particularly in patients on hemodialysis, where the dialysate calcium concentration can vary and therefore impact the ability to administer calcium-containing phosphate binders. (See 'Monitoring' above.)

As noted above however, even in the absence of hypercalcemia, a positive calcium balance, which is generally not detectable without careful balance studies, could increase the risk of vascular calcification. (See 'Phosphate binders' above.)

●Other agents – Other agents include sucroferric oxyhydroxide, ferric citrate, nicotinamide, tenapanor, aluminum hydroxide, and calcium citrate. We generally do not use these agents, some of which have not been approved or are available.

•Sucroferric oxyhydroxide (Velphoro) – Sucroferric oxyhydroxide is a chewable phosphate binder for patients with eGFR <15 mL/min/1.73 m2 [92]. Sucroferric oxyhydroxide appears to be comparable with sevelamer in efficacy and safety and may be associated with a lower pill burden [93,94]. 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.

•Ferric citrate ─ Ferric citrate is effective in reducing serum phosphate concentration and may increase serum iron [95-97].

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.

•Nicotinamide and tenapanor ─ Nicotinamide, a metabolite of nicotinic acid (niacin, vitamin B3), may lower phosphate levels by reducing gastrointestinal tract phosphate absorption:

-In a pilot study of 20 dialysis patients, prolonged-release nicotinic acid (Niaspan) was administered in slowly increasing doses, with 17 patients eventually tolerating >1000 mg/day [98]. Among such patients, treatment for 12 weeks significantly lowered serum phosphate values (7.2 to 5.9 mg/dL [2.33 to 1.91 mmol/L]) and increased serum high-density lipoprotein (HDL) cholesterol levels.

-A randomized, placebo-controlled, crossover trial of 33 patients found that niacinamide (titrated from 500 to 1500 mg/day) significantly lowered phosphate levels (6.26 to 5.47 mg/dL [0.65 to 1.77]) [99]. Adverse effects were similar with both groups.

Further study is required to better understand the efficacy and safety of nicotinamide in this setting.

•Aluminum hydroxide ─ In all patients with CKD, we avoid aluminum hydroxide, except for short-term therapy (a single, four-week course) of severe hyperphosphatemia in acute kidney injury (see "Overview of the management of acute kidney injury in adults", section on 'Hyperphosphatemia'). Aluminum-based phosphate binders are associated with aluminum toxicity. The major manifestations of aluminum toxicity are vitamin D-resistant osteomalacia, microcytic anemia, bone and muscle pain, and dementia. There appears to be no dose of aluminum in CKD that is safe yet effective in controlling serum phosphate. (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 CKD patients since citrate can markedly increase intestinal aluminum absorption [100,101]. The use of calcium citrate has been associated with aluminum neurotoxicity and the rapid onset of symptomatic osteomalacia [102]. (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 [100,101]. The ensuing decrease in free calcium increases permeability of tight junctions between cells, which can markedly enhance passive aluminum absorption (figure 1) [100,101].

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

●In patients with estimated glomerular filtration rates (eGFR) <60 mL/min/1.73 m2, we recommend monitoring serum phosphate, calcium, intact parathyroid hormone (iPTH), and 25-hydroxyvitamin D levels. The frequency of monitoring depends on the eGFR as outlined above. (See 'Monitoring' above.)

●We suggest treating hyperphosphatemia in patients with chronic kidney disease (CKD) (Grade 2C). While high phosphate levels are shown to be associated with increased mortality in patients with CKD, the specific interventions suggested below have been shown to lower phosphate levels in most patients have not been shown to improve mortality or other clinical outcomes. (See 'Treatment approach' above.)

●For nondialysis CKD patients, we treat phosphate values that are persistently and progressively higher than normal (ie, 4.5 mg/dL), while, for dialysis patients, we treat phosphate concentrations that are persistently >5.5 mg/dL. These somewhat arbitrary thresholds are those that have been shown to be associated with mortality in observational studies. (See 'Treatment approach' above.)

●Our treatment approach begins with dietary phosphate restriction of 900 mg/day. The patient should be encouraged to avoid unnecessary dietary phosphate while maintaining the intake of high-biologic-value sources of protein. (See 'Phosphate restriction' above.)

●If hyperphosphatemia persists with dietary restriction we administer phosphate binders. However, alternative approaches are also reasonable:

•Many experts do not use phosphate binders among nondialysis CKD patients, since clinically relevant benefits have not been demonstrated.

•Other experts prescribe phosphate binders simultaneously with phosphate restriction in dialysis patients. (See 'Phosphate binders' above.)

●When phosphate binders are prescribed, for most patients we suggest noncalcium-containing binders (Grade 2B). Studies have suggested lower mortality associated with the use of noncalcium-containing binders compared with calcium-containing binders. However, the increased cost and restricted availability of these agents make calcium-containing binders an acceptable alternative in some circumstances. (See 'Phosphate binders' above.)

●For refractory hyperphosphatemia, extended or increased hemodialysis is effective in lower phosphate; however, this is not a practical option for most patients. Such patients may benefit from a modification of treatment of hyperparathyroidism. (See 'Refractory hyperphosphatemia' above.)

ACKNOWLEDGMENT — The authors and the editorial staff at UpToDate would like to acknowledge Robert E Cronin, MD, who contributed to earlier versions of this topic review.