The nurse preparing to administer a dose of calcium acetate to a patient with chronic kidney disease

Approach Considerations

The major strategies for treating hyperphosphatemia are as follows:

Diagnosis of the cause in order to initiate specific therapy: For example, patients with hyperphosphatemia due to administration of liposomal amphotericin B who continue to require antifungal therapy may be switched to the amphotericin B lipid complex formulation, which contains less inorganic phosphate [43]
Limitation of phosphate intake: Patients with chronic kidney disease [CKD] are advised to avoid foods that are especially high in phosphate; high-phosphate foods include dairy products; meats, nuts, and other high-protein foods; processed foods; and dark colas. Kidney Disease: Improving Global Outcomes [KDIGO] guidelines note that it is reasonable to consider phosphate source in making dietary recommendations, as approximately 40-60% of animal-based phosphate is absorbed, compared with 20-50% of plant-based phosphate, and that fresh and homemade foods are preferable to processed foods, which often contain inorganic phosphate additives. [37]
Enhancement of renal excretion of phosphate: Hyperphosphatemia due to tumor lysis responds to enhancement of urinary losses through forced saline diuresis

The clinical condition most often requiring curtailment of ingestion is CKD. Because intestinal absorption of phosphate and phosphate content in a typical diet is high, maintenance of phosphate homeostasis is dependent on renal excretion of the ingested excess. Therefore, when CKD develops and hyperphosphatemia ensues, the sole means of controlling it is limitation of intake.

Serum phosphate levels follow a circadian rhythm, which must be considered when interpreting patient phosphate levels. [44] Ix et al note a trough at 8 AM, with peaks at 4 AM and 4 PM. In patients with CKD, these authors found that differences in phosphate levels with lowest-phosphate versus highest-phosphate diets were smallest at 8 AM and largest at 4 PM. The low-phosphate diet altered the circadian rhythm such that the 4 AM and 4 PM peaks were absent. [45]

Optimal phosphate control in dialysis patients is extremely challenging. Despite the remarkable improvements made in dialysis techniques over the years, phosphate control has not been substantially improved. In addition, variances in dialytic removal of phosphate, enteral phosphate absorption unexplained by diet or vitamin D intake, and binder efficacy may account for hyperphosphatemia in dialysis patients rather than nonadherence to therapy. [12]

An alternative approach for dialysis-dependent patients that is presently being investigated is daily nocturnal dialysis. Dialysis performed in this manner, as opposed to intermittent thrice-weekly dialysis, seems to markedly decrease or even abolish the necessity for phosphate binders. [46]

Dey et al reported achieving phosphate control with thrice-weekly sessions by using hemodiafiltration, which combines diffusion and convection, rather than hemodialysis. Their program consisted of nocturnal sessions lasting a median of 8 hours. In the 14 patients in their study, pre-dialysis phosphate levels fell from a mean of 1.52 ± 0.4 to 1.06 ± 0.1 mmol/L [P< 0.05], and use of phosphate binders became unnecessary. [47]

Surgical care

Surgery may sometimes be required for removal of large calcium phosphate deposits occurring in patients with tumoral calcinosis or long-standing CKD. Perform parathyroidectomy in patients with CKD who have tertiary [autonomous] hyperparathyroidism complicated by hypercalcemia, hyperphosphatemia, and severe bone disease.

Consultations

The following consultations may be required:

Endocrinologist: To determine whether the patient has hypoparathyroidism or one of the various forms of pseudohypoparathyroidism
Nephrologist: To evaluate and treat hyperphosphatemia associated with CKD

Monitoring

Calcium levels, phosphate levels, and kidney function should be monitored at intervals consonant with the severity of the underlying disorder. KDIGO guidelines stress that in patients with CKD, the development of metabolic bone disease [MBD] involves a complex interaction of phosphate, calcium, and parathyroid hormone [PTH]. Consequently in patients with stage G3a–G5D CKD, the KDIGO recommends serial assessments of all three parameters, considered together, in order to guide treatment of MBD. [37]

KDIGO recommends monitoring serum levels of calcium, phosphate, PTH, and alkaline phosphatase activity beginning in CKD stage G3a [in children, stage G2], at a frequency based on the presence and magnitude of abnormalities, and the rate of progression of CKD. [37] Reasonable monitoring intervals would be as follows:

CKD G3a–G3b – Serum phosphate and calcium, every 6–12 months; PTH, based on baseline level and CKD progression
CKD G4 – Serum phosphate and calcium, every 3–6 months; PTH, every 6–12 months
CKD G5, including G5D – Serum phosphate and calcium, every 1–3 months; PTH, every 3–6 months

Investigational therapy

Tenapanor—an inhibitor of the sodium/hydrogen exchanger isoform 3 [NHE3] that acts locally in the gut to reduce absorption of sodium and phosphate¯is approved for treatment of irritable bowel syndrome with constipation in adults and is being studied in the treatment of CKD patients with hyperphosphatemia requiring dialysis. [48] In a phase 1 study in healthy Japanese adults, tenapanor treatment reduced intestinal absorption of sodium and phosphate. [49]

In a phase 3 randomized, double-blind trial of tenapanor, 219 patients with hyperphosphatemia receiving maintenance hemodialysis were given oral tenapanor [3, 10, or 30 mg twice-daily] for 8 weeks. All three groups had significant decreases in seurm phospate [eductions of 1.00, 1.02, and 1.19 mg/dl,respectively]. Patients were then rerandomized 1:1 to continue receiving their assigned dose or placebo for a 4-week period. The placebo goup experienced a mean increase of 0.85 mg/dl versus a mean increase of 0.02 mg/dl across the three groups continuing to receive tenapanor. [50]

In another phase 3 trial of tenapanor in 236 patients receiving maintenance hemodialysis with hyperphosphatemia despite receiving phosphate binders, 116 were randomly assigned to receive 30 mg oral tenapanor twice-daily for 4 weeks while 119 patients received a placebo. Both groups continues to receive phospate binders. Patients in the tenapanor group had a larger mean change in serum phosphorus concentration from baseline to week 4 compared with patients taking the placebo plus binder [−0.84 versus −0.19 mg/dl, P< 0.001]. [51]

A preclinical study of the effects of tenapanor and sevelamer carbonate on urinary phosphorus excretion reported that combined tenapanor and sevelamer decreased urinary phosphorus excretion in rats significantly more than either agent administered alone. This result was consistent across varying sevelamer dose levels. [52]

Phosphate Binders

Dietary restriction alone may suffice for control of hyperphosphatemia in persons with mild kidney insufficiency, but it is inadequate for patients with advanced kidney insufficiency or complete kidney failure. Such individuals require the addition of phosphate binders to inhibit gastrointestinal absorption of phosphate. These medications, which are taken concomitantly with meals, directly interact with the phosphate in the food, preventing intestinal absorption. The following classes of phosphate binders are widely used [53] :

Aluminum-containing phosphate binders
Calcium-containing phosphate binders
Phosphate binders that contain no aluminum or calcium

Administration of phosphate binders is the only truly long-term therapy for chronic hyperphosphatemia due to kidney failure. Monitor calcium and phosphate levels, especially when treating patients with calcium-containing phosphate binders, because of the possibility of severe, life-threatening hypercalcemia. [54]

Calcium citrate and aluminum-containing binders should probably not be used together, because the citrate may enhance aluminum absorption.

A systematic review by Sekercioglu et al of the comparative effectiveness of phosphate binders in patients with chronic kidney disease–mineral and bone disorder [CKD-MBD] found moderate-quality evidence that calcium-containing phosphate binders result in higher mortality than sevelamer in particular and non–calcium-based phosphate binders in general. These authors concluded that their results “raise questions about whether administration of calcium as an intervention for CKD-MBD remains ethical.” [55]

Aluminum-containing phosphate binders

The aluminum-containing binders were the first to be used to treat hyperphosphatemia, but they have largely been abandoned because of the toxic effects of absorbed aluminum. Initially, the amount of aluminum absorbed was thought to be trivial; with long-term use, however, many patients developed a constellation of clinical symptoms attributable to aluminum, including dementia, severe osteomalacia, and anemia.

Bone biopsies performed on patients with aluminum intoxication revealed deposition of aluminum along the mineralizing front of bone, preventing normal mineralization. Aluminum levels in the fasting state and after a challenge with desferrioxamine confirmed the increased total body aluminum load. Aluminum-containing phosphate binders should be used only when other agents have failed to adequately control phosphate levels.

Calcium-containing phosphate binders

The next phosphate binders to be introduced were the calcium-containing binders, such as calcium carbonate and calcium citrate. These drugs, which are still used extensively, have the advantage of inhibiting phosphate absorption while providing the patient with a required mineral, calcium. The disadvantage of these drugs has been the relatively high incidence of hypercalcemia occurring in patients. There have also been concerns about the contribution of large exogenous calcium loads to the occurrence of soft tissue calcification in end-stage renal disease.

Several studies, including the Calcium Acetate Renagel Evaluation [CARE] study, have shown that calcium acetate is more cost-effective than sevelamer [discussed below] as a phosphate binder. Although concern has been raised about its purported link to cardiovascular calcification, calcium acetate can be used effectively with doses of elemental calcium that meet the Kidney Disease Outcome Quality Initiative [KDOQI] guidelines.

Phosphate binders with no aluminum or calcium

The above concerns about calcium-containing binders led to the development of a class of phosphate binders that contain neither aluminum nor calcium. At present, several drugs in this class, including the following, are in clinical use:

Sucroferric oxyhydroxide [Velphoro]
Sevelamer [Renagel]
Lanthanum carbonate [Fosrenol]
Ferric citrate [Auryxia]

Sucroferric oxyhydroxide and ferric citrate are iron-based phosphate binders that reduce serum phosphorus comparably to calcium-based binders and sevelamer. These agents may offer the advantages of providing iron supplementation, low pill burden, and high efficacy, but their place in therapy requires further evaluation. [56, 57]

For patients taking calcium-containing phosphate binders who have had demonstrable extraskeletal calcification or recurrent hypercalcemia, sevelamer and sucroferric oxyhydroxide are excellent alternatives and are well-tolerated in the control of serum phosphorus in dialysis patients.

Sucroferric oxyhydroxide

Sucroferric oxyhydroxide [Velphoro] is an iron-based phosphate binder that when taken with meals adsorbs dietary phosphate in the GI tract.

Approval for sucroferric oxyhydroxide [1-3 g/day] was based on the results of a phase 3 study that compared the drug’s dose titration and maintenance phases with those of sevelamer [2.4-14.4 g/day]. Sucroferric oxyhydroxide and sevelamer efficacy were maintained during long-term use, with no notable difference in safety observed between the treatment groups. Moreover, sucroferric oxyhydroxide had a lower pill burden than did sevelamer. [58, 59]

In an open-label phase 3 extension study that compared sucroferric oxyhydroxide with sevelamer in 644 dialysis patients with hyperphosphatemia, sucroferric oxyhydroxide maintained its serum phosphorus-lowering effect over 1 year. Sucroferric oxyhydroxide was generally well tolerated over the long term, and patients showed no evidence of iron accumulation. [60]

Increased ferritin levels have been reported after long-term sucroferric oxyhydroxide treatment in patients undergoing hemodialysis. [61]

Sevelamer

Sevelamer and calcium-containing phosphate binders can be used in combination to minimize adverse effects; however, the major barrier to their use is patient noncompliance. The patient is required to ingest 3-6 large capsules with every meal, which is more than most patients can comply with for extended periods. A study, however, demonstrated that once-daily sevelamer was as effective as thrice-daily sevelamer in the control of serum phosphorus, which may improve patient compliance. [62]

In addition to its effects as a phosphate binder, sevelamer has also been shown to improve the lipid profile in patients with hyperphosphatemia.

Lanthanum carbonate

Lanthanum has been shown to be a safe and equally efficacious agent in short-term studies, but concerns of long-term administration and toxicity exist. Furthermore, these agents are significantly more expensive than calcium salts, which may contribute to patient noncompliance. A 16-week, phase 4 study conducted by Vemuri et al found that patients who converted from other phosphate-binder medications to lanthanum carbonate maintained productive serum phosphorus levels with much satisfaction and lessened tablet burden. [63]

Ferric citrate

Oral ferric citrate was approved in 2014 for the control of serum phosphorus levels in patients with CKD who are on dialysis. Approval was based on a randomized trial in 441 adults with end-stage renal disease who were receiving hemodialysis or peritoneal dialysis 3 times per week for at least 3 months. Participants were treated either with ferric citrate or with active control [calcium acetate or sevelamer carbonate] for 52 weeks.

Phosphorus levels were similar in the ferric citrate and active control groups, as were adverse events, which occurred in 39.1% of patients receiving ferric citrate and 49.0% of patients receiving active control. Patients receiving ferric citrate had significantly higher mean ferritin levels [899 ng/mL vs 628 ngmL; P < 0.001], transferrin saturation [39% vs 30%; P < 0.001], and less need for IV iron [12.95 mg/week vs 26.88 mg/week; P < 0.001] compared with active control. [64]

Cardiovascular considerations

Although long-term ingestion of aluminum-containing binders has known toxic effects, no definitive studies suggest that the long-term use of any of the other binders confers either a benefit or a disadvantage in terms of mortality.

Theoretically, the high calcium load of a calcium-containing phosphate binder could perpetuate or worsen vascular calcification, which does correlate with cardiovascular mortality in CKD patients, when compared with non–calcium-containing phosphate binders. In fact, the use of non–calcium-containing binders does result in less vascular calcification; however, a beneficial effect on mortality has not been consistently demonstrated. [65, 66, 67, 68, 69, 70, 71]

Increased Renal Excretion

The strategy for treatment of hyperphosphatemia in patients with normal kidney function is to enhance renal excretion. This can be accomplished most effectively by volume repletion with saline coupled with forced diuresis with a loop diuretic such as furosemide or bumetanide.

The marked increase in intravascular volume with saline globally inhibits proximal renal tubule absorption of solutes, in this specific case, phosphate, thus promoting phosphaturia.

The increased distal tubule delivery of phosphate overwhelms the ability of that portion of the nephron to absorb phosphate, leading to a negative phosphate balance.

Management of Secondary Hyperparathyroidism

Just as better control of hyperphosphatemia in patients with kidney failure helps to prevent the nearly universal development of secondary hyperparathyroidism, better control of hyperphosphatemia is achieved through control of secondary hyperparathyroidism. The agents commonly used to control secondary hyperparathyroidism are vitamin D metabolites and the calcium-sensing receptor agonists.

A study by Hansen et al found that alfacalcidol and paricalcitol were equally effective in the suppression of secondary hyperparathyroidism in patients on hemodialysis. [72]

Management of Hypoparathyroidism

For the rare cases of hypoparathyroidism, calcium and vitamin D are prescribed, predominantly for treatment of the hypocalcemia. Given with meals, the oral calcium can ameliorate the hyperphosphatemia of hypoparathyroidism, although this effect has to be carefully balanced against the phosphate absorption–promoting effects of the vitamin D. Over the long term, this therapy may result in nephrocalcinosis. Recombinant PTH injections can be considered but are not commonly used in clinical practice, because of the efficacy of calcium and vitamin D, as well as the cost and inconvenience of injected PTH.

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Author

Eleanor Lederer, MD, FASN Professor of Medicine, Chief, Nephrology Division, Director, Nephrology Training Program, Director, Metabolic Stone Clinic, Kidney Disease Program, University of Louisville School of Medicine; Consulting Staff, Louisville Veterans Affairs Hospital

Eleanor Lederer, MD, FASN is a member of the following medical societies: American Association for the Advancement of Science, American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Transplantation, International Society of Nephrology, Kentucky Medical Association, National Kidney Foundation

Disclosure: Serve[d] as a director, officer, partner, employee, advisor, consultant or trustee for: American Society of Nephrology
Received income in an amount equal to or greater than $250 from: Healthcare Quality Strategies, Inc.

Coauthor[s]

Vibha Nayak, MD Assistant Professor of Nephrology, Director of Home Dialysis, Kidney Disease Program, University of Louisville School of Medicine

Vibha Nayak, MD is a member of the following medical societies: American Society of Nephrology