Ferric citrate

Ferric Citrate

1. Identity: Chemical Names, Composition, and Physical Forms

The chemical name of ferric citrate coordination complex is iron(III)-(2-hydroxy-1,2,3-propanetricarboxylic acid)x(H₂O)y. In systematic chemical nomenclature it is also rendered as iron(III) citrate or ferric iron citrate. The molecular formula for the nominal species is C₆H₅FeO₇, with the trihydrate form represented as C₆H₁₁FeO₁₀. The active pharmaceutical ingredient (API) used in the prescription product Auryxia is not a single compound but rather a solid mixture of ferric citrate coordination complexes (FCCCs) with the chemical formula iron(+3), x(anion of 1,2,3-propanetricarboxylic acid, 2-hydroxy-), y(H₂O), where x ranges from 0.70 to 0.87 and y ranges from 1.9 to 3.3.

The ferric citrate complex is a light brown to beige, slightly hygroscopic amorphous solid, highly soluble in water. Different crystalline polymorphs of ferric citrate are known in the literature, but all contain different counter ions. The structure of ferric citrate has been elucidated by high-resolution mass spectrometry (positive and negative ionisation), UV spectroscopy, ¹H and ¹³C NMR spectroscopy, and Mössbauer spectroscopy. As opposed to iron salts, which readily dissociate into their component ions in water, the bonds that coordinate the central metal atom with the surrounding ligands allow the complex to retain its identity as a unit with properties different from those of its components.

Ferric citrate should be distinguished from several related compounds that appear in both clinical and nutritional contexts:

• Ferric citrate (iron(III) citrate): The core compound discussed in this article, containing trivalent iron (Fe³⁺) coordinated with citrate.
• Ferric citrate hydrate (FCH): A pharmaceutical-grade hydrated form approved in Japan and other markets for iron deficiency anemia in the general population.
• Ferric citrate coordination complex (FCCC): The specific proprietary form (Auryxia/Fexeric) approved by the FDA and EMA for use in chronic kidney disease (CKD).
• Ferric ammonium citrate: A related iron-containing salt historically used in tonics and food fortification, but chemically distinct from ferric citrate.
• Ferric pyrophosphate citrate (FPC): A different iron compound, a non-colloidal, highly water-soluble, complex iron salt that consists of iron(III) complexed with one pyrophosphate and two citrate molecules, approved parenterally and distinct from standard ferric citrate.

Ferric citrate is widely used as a food additive in flour, formula milk, crackers, and similar products, and is on the registered list of food ingredients from the Ministry of Health, Labour and Welfare of Japan, and the Code of Federal Regulations (CFR) of the United States.

2. Traditional and Historical Use

Iron compounds, including citrate-complexed forms, have a long pre-modern and early modern medical history. Ferric compounds were noted to cause hypophosphatemia when used to treat anemia as early as the 1940s. Indeed, ferric compounds were shown to bind to dietary phosphate and reduce phosphorus absorption when used to treat anemia in the early 1940s. This observation — that iron-based preparations used as anemia treatments incidentally reduced phosphate absorption — would later become the foundation for their development as phosphate binders in CKD.

In the 19th century, iron-citrate preparations occupied a prominent place in Western pharmacy. A detailed history and preparation of citro-ammoniacal pyrophosphate of iron was published in the Boston Medical and Surgical Journal as early as 1862. Iron-containing tonics and elixirs — including various ferric and ferrous citrate preparations — were widely prescribed by physicians across Europe and North America throughout the Victorian era for conditions associated with pallor, fatigue, and weakness, which physicians of the time attributed to deficient blood formation. The mild taste and appreciable water solubility of iron citrate salts made them more palatable than cruder iron salts such as ferrous sulfate, contributing to their inclusion in commercial patent medicines and dispensatory preparations of the period.

Ferric compounds were noted to cause hypophosphatemia when used to treat anemia in the 1940s, and later these compounds were used in small studies to treat the hyperphosphatemia of CKD. This pharmacological reappraisal accelerated considerably in the late 20th and early 21st centuries, culminating in controlled clinical trials and regulatory approvals.

3. Key Constituents and Established Mechanisms of Action

3.1 Phosphate Binding

Ferric citrate is an oral, insoluble, aluminum-free, calcium-free, ferric iron-based phosphate binder that exerts its effects in the gastrointestinal (GI) tract. After administration, the product dissociates into its ferric iron (Fe³⁺) and citrate (C₆H₄O₄⁻) components. This allows the ferric iron ion to bind multiple phosphate ions and create a ferric phosphate precipitate that is excreted in the stool, thereby reducing absorption of dietary phosphate. The resultant effect is a lowering of the serum phosphate concentration.

Current guidelines recommend first-line use of oral dietary phosphate binders to reduce phosphate concentrations in patients with eGFR values below 60 mL/min/1.73 m² through end-stage disease requiring dialysis. The serum phosphate-lowering ability of oral phosphate binders is second only to dialysis in its effectiveness, since the gut absorbs 60% to 80% of dietary phosphate and the process of phosphate absorption is non-saturable.

3.2 Iron Absorption and Erythropoiesis

Ferric citrate achieves its iron absorption and phosphate-lowering effects via two contrasting mechanisms: ferric iron from ferric citrate, enzymatically reduced to ferrous iron, is absorbed in the small intestine, and concurrently, ferric iron from ferric citrate binds to dietary phosphorus to form an insoluble complex that promotes the fecal excretion of phosphorus.

Auryxia is believed to use the conventionally described and highly regulated enterocytic pathway of iron absorption, in which ferric iron is enzymatically reduced to the ferrous state, absorbed primarily in the duodenum, and finally transported into plasma and made available for erythropoiesis. Not all iron ions dissociated from ferric citrate attach to phosphate; some are reduced to ferrous iron via ferric reductase in the intestinal mucosa, becoming retained in the duodenum and effectively reabsorbed into the systemic circulation, replenishing iron reserves as needed.

3.3 Interaction with Hepcidin and FGF23

It is remarkable that ferric citrate corrects iron deficiency in the setting of CKD, and even end-stage renal disease, as these are states with high hepcidin levels. Hepcidin is the master iron-regulatory hormone, binding to and inhibiting ferroportin, the only known cellular iron exporter. In the setting of high hepcidin levels, the activity of ferroportin — located on the basal surface of enterocytes — is decreased, thus inhibiting dietary and medicinal iron absorption from the gastrointestinal lumen.

Ferric citrate may not only restore iron stores in individuals who are iron deficient, but by lowering FGF23 concentrations, ferric citrate may increase local and systemic concentrations of 1,25-dihydroxyvitamin D, a powerful inhibitor of hepcidin synthesis, potentially attenuating the increase in hepcidin following oral iron supplementation.

In mouse models of CKD, ferric citrate administration was associated with higher mRNA expression of the renal 1,25-dihydroxyvitamin D anabolic enzyme CYP27B1 and lower mRNA of the catabolic CYP24A1. These preclinical findings raise the hypothesis that ferric citrate may modulate vitamin D metabolism indirectly, though this mechanism requires further characterization in human studies.

3.4 Food Effect on Absorption

Results from a crossover study demonstrate an increase in serum iron levels under both fasting and fed conditions, with no apparent decrease in iron absorption due to food. There is therefore no apparent clinically meaningful food effect on iron absorption from ferric citrate hydrate. This is notable because iron absorption after the administration of oral iron preparations following a meal is generally reduced compared with fasting for conventional iron formulations.

4. Scientific Evidence by Area of Use

4.1 Hyperphosphatemia in Dialysis-Dependent CKD

Regulatory status: Ferric citrate is an oral, calcium-free, iron-based phosphate binder that was approved by the United States Food and Drug Administration on September 5, 2014. The European Commission approved Fexeric (ferric citrate coordination complex) for the control of elevated serum phosphorus levels in adults with CKD, including both dialysis and pre-dialysis patients. The European Commission considered ferric citrate coordination complex a New Active Substance, which provides 10 years of data and marketing exclusivity in Europe.

Key phase 3 evidence: The long-term safety and efficacy of ferric citrate in CKD patients on dialysis was studied in a phase 3 clinical trial with a 52-week, randomized, active-controlled period comparing ferric citrate to sevelamer carbonate and/or calcium acetate, followed by a 4-week randomized, placebo-controlled period. In this study, ferric citrate reduced and maintained serum phosphorus levels similarly to the active control and significantly better than placebo, and had a similar safety profile to that of the active control group.

The European Commission's decision for Fexeric was based on evidence from approximately 1,900 patients, including two key clinical trials: a Phase 2 non-dialysis study and a 58-week Phase 3 registration trial. In the Phase 3 trial, ferric citrate effectively reduced serum phosphorus levels to within the KDOQI guidelines range of 3.5 mg/dL to 5.5 mg/dL (p<0.0001).

Meta-analytic evidence: A meta-analysis including 16 randomized clinical trials involving 1,754 participants showed that ferric citrate could significantly reduce serum phosphorus in CKD patients compared to placebo control groups (mean difference −1.76 mg/dL, 95% CI −2.78 to −0.75; p = 0.0007). This review suggests that ferric citrate is an effective and safe treatment option for CKD patients with hyperphosphatemia and anemia, though the authors note that more scientific studies are warranted to validate the findings.

4.2 Iron Deficiency Anemia in Non-Dialysis-Dependent CKD

Regulatory status: Ferric citrate (Auryxia) gained US FDA approval in 2017 for treatment of iron deficiency anemia in adults with CKD who are not on dialysis. This additional indication makes ferric citrate the only oral treatment option available for these patients at the time of approval.

Pivotal phase 3 trial (NDD-CKD): The supplemental new drug application approval was based on results from a 24-week, placebo-controlled Phase 3 clinical trial in 234 adults with stage 3–5 non-dialysis-dependent CKD. Patients enrolled had hemoglobin levels between 9.0 g/dL and 11.5 g/dL and were intolerant to or had an inadequate response to prior treatment with oral iron supplements. The starting dose in the study was three tablets per day taken with meals; the mean dose was five tablets per day. During the study, patients were not allowed to receive any intravenous (IV) or oral iron, or erythropoiesis-stimulating agents (ESAs). Treatment with ferric citrate demonstrated significant increases in hemoglobin levels of more than 1 g/dL at any point during the 16-week efficacy period in the majority of patients (52.1%, n=61/117) compared to 19.1% (n=22/115) in the placebo group.

Additional evidence: Two randomized, placebo-controlled trials conducted in patients with non-dialysis-dependent CKD, iron deficiency anemia, and normal or elevated serum phosphorus demonstrated that ferric citrate significantly increased hemoglobin and decreased serum phosphate concentrations. Ferric citrate significantly reduced serum phosphate (relative change from baseline to week 16: −0.21 mg/dL; 95% CI −0.39 to −0.03 mg/dL; P=0.02) and significantly increased serum bicarbonate (relative change from baseline to week 16: 1.2 mmol/L; 95% CI 0.1 to 2.4 mmol/L; P=0.03).

Long-term use (Phase 4 study): Ferric citrate is FDA-approved as an oral iron replacement for adults with iron deficiency anemia (IDA) and non-dialysis-dependent CKD and as a phosphate binder in adults with dialysis-dependent CKD. For IDA, the recommended starting dose is 1 tablet (1 g, containing 210 mg of ferric iron) 3 times daily, titrated to maintain hemoglobin goal. One long-term study investigated the efficacy and safety of various ferric citrate regimens for IDA treatment in adults with NDD-CKD stages 3–5. This 48-week, Phase 4, randomized, open-label, multicenter study compared ferric citrate 1 g tablet TID (3 g/day) versus 2 tablets BID (4 g/day).

Systematic review (NDD-CKD): A systematic review and meta-analysis including eight trials with a total of 1,281 NDD-CKD patients found that the phosphorus-lowering effect of ferric citrate was greater compared to the control group (WMD −0.55, 95% CI −0.81 to −0.28; I²=86%, p<0.001). The recently updated Kidney Disease Improving Global Outcomes (KDIGO) guidelines emphasize that lowering serum phosphate with ferric citrate improves the prognosis of CKD patients, but there are not enough clinical trials with NDD-CKD patients, raising concerns about whether ferric citrate is effective and safe in this population.

4.3 Anemia and Iron Parameters in Dialysis-Dependent CKD

Ferric citrate is an iron-containing phosphate binder that has been shown to effectively decrease serum phosphate, increase hemoglobin, and replete iron stores in patients with CKD. Intestinal absorption of iron from ferric citrate results in increases in serum iron, ferritin, and transferrin saturation, effects that occur over 12 to 24 weeks and subsequently appear to plateau. As a result, use of erythropoiesis-stimulating agents and intravenous iron is reduced significantly, and in clinical trials in patients receiving hemodialysis, the majority of subjects were able to discontinue intravenous iron use completely.

In the phase 3 active-controlled trial, 441 subjects were randomized (292 to ferric citrate and 149 to sevelamer carbonate and/or calcium acetate) and followed for 52 weeks. Subjects on ferric citrate had increased ferritin and transferrin saturation (TSAT) levels compared with subjects on the active control by week 12 (change in ferritin: 114.1±29.35 ng/mL; P<0.001; change in TSAT: 8.62%±1.57%; P<0.001).

One-year safety data indicated that ferric citrate-treated subjects had reduced rates of hospitalization and reduced serious adverse events related to gastrointestinal, infectious, and cardiovascular causes, although the mechanism for this finding is unclear.

4.4 Advanced CKD (Pre-Dialysis): Pilot RCT

A randomized trial enrolled 199 patients with eGFR <20 mL/min per 1.73 m², assigned 2:1 to ferric citrate coordination complex or usual care. Treatment with ferric citrate coordination complex significantly increased hemoglobin, ferritin, and transferrin saturation and significantly reduced FGF23, while maintaining serum phosphate in the normal range in the majority of patients. It also significantly reduced use of erythropoiesis-stimulating agents and intravenous iron, hospital admissions, hospital days, and time to the composite end point of death, provision of dialysis, or kidney transplantation. These results, while clinically notable, derive from a single pilot RCT and require confirmation in larger trials.

4.5 Iron Deficiency Anemia in the General Population (Non-CKD)

Ferric citrate hydrate (Japan/non-CKD): In Japan, a hydrated form of ferric citrate (ferric citrate hydrate, FCH) has been approved for the general treatment of iron deficiency anemia, distinct from the CKD indications prevalent in Western markets. Ferric citrate hydrate treatment achieved an 80% hemoglobin target success rate by week 4 in patients with iron deficiency anemia. It demonstrated improved tolerability, reducing nausea and vomiting incidence from 100% to 63.3%, and enhancing patients' quality of life. A 100% medication completion rate was reported, with significant improvements in Short-Form 36-Item Health Survey v2 subscales. FCH has been proposed as an attractive first-line treatment for IDA, offering better adherence and less burden compared to traditional oral iron supplements.

A phase 3 non-inferiority study comparing ferric citrate hydrate to sodium ferrous citrate in Japanese patients with iron deficiency anemia further characterized the agent's efficacy profile. The primary endpoint was the change in hemoglobin concentration from baseline to Week 7. These results support efficacy in non-CKD populations, though the evidence base for the general population is considerably narrower than for the CKD indications, and independent replication in Western populations is limited.

A randomized, open-label, two-cohort, two-period, single-dose crossover study investigated the effect of food on iron absorption following ferric citrate hydrate administration in patients with iron deficiency anemia, with 500 mg ferric citrate hydrate (approximately 120 mg of ferric iron) administered under fasted and fed conditions.

4.6 Effect on FGF23 Levels

Ferric citrate as a phosphate binder with meals has been proven by studies to be efficient in lowering FGF23 and boosting iron parameters in NDD-CKD. In a clinical trial in advanced CKD, treatment with ferric citrate coordination complex significantly increased hemoglobin, ferritin, and transferrin saturation and significantly reduced FGF23. FGF23 (fibroblast growth factor 23) is a phosphate-regulating hormone associated with CKD progression and adverse cardiovascular outcomes. Hyperphosphatemia and elevated levels of FGF23 have been identified as key independent risk factors for the adverse cardiovascular outcomes that frequently occur in patients with CKD. Whether reduction of FGF23 by ferric citrate translates to improved hard clinical endpoints (mortality, cardiovascular events) has not yet been established in dedicated outcomes trials.

4.7 Evidence Gaps and Limitations

There is no compelling scientific evidence that phosphate management improves patient clinical outcomes, including all-cause mortality and cardiovascular issues. Several prospective studies are registered on ClinicalTrials.gov to investigate the function of phosphate binding in enhancing clinical outcomes.

To fully analyze the advantages and dangers of ferric citrate therapy, further studies on long-term efficacy are urged. The included trials in existing meta-analyses employed a variety of pharmacological dosages and treatment durations, and research follow-up periods were often brief. A substantial degree of heterogeneity was discovered in some outcomes, and individual studies gradually raised the ferric citrate dosage while others used several doses or stable amounts throughout therapy.

5. Body Systems and Health Areas

5.1 Renal System

The primary clinical application of ferric citrate is in patients with CKD. CKD is a major cause of morbidity and premature mortality and represents a significant global public health issue. Underlying this burden are many complications of CKD, including mineral and bone disorders, anemia, and accelerated cardiovascular disease. Ferric citrate addresses two of these simultaneously — hyperphosphatemia and iron deficiency anemia — through its dual mechanism of action.

5.2 Hematologic System

In addition to its phosphate-lowering effects, ferric citrate provides the added benefit of improved iron parameters for CKD patients, including increases in ferritin, iron, and transferrin saturation (TSAT). These improvements in iron parameters support erythropoiesis and contribute to increases in hemoglobin levels. Oral ferric citrate, as a phosphate binder, provides absorbable iron that has been shown to increase serum ferritin and TSAT and decrease IV iron requirements in hemodialysis patients.

5.3 Gastrointestinal System

Unlike other oral iron supplements, ferric citrate is associated more with diarrhea than with constipation. This distinguishing feature is clinically relevant, as most conventional ferrous iron supplements are constipating. Gastrointestinal tolerability is considered a key factor in patient adherence.

5.4 Mineral Metabolism and Bone

Prolonged oral administration of citrate has no effect on the skeletal system at doses equivalent to the maximum recommended human dose of ferric citrate. Systemic administration of citrate leads to a transient increase in bone turnover in healthy patients. Beneficial effects of ferric citrate on the skeletal system have been demonstrated in rat models of chronic kidney disease.

5.5 Vitamin D Metabolism

In mouse models of CKD, ferric citrate-treated mice showed higher renal CYP27B1 (the 1,25-dihydroxyvitamin D anabolic enzyme) mRNA and lower CYP24A1 (catabolic enzyme) mRNA. This finding suggests a potential indirect benefit on vitamin D activation, though translational evidence in humans is preliminary and largely mechanistic at this stage.

5.6 Cardiovascular System

Elevated FGF23 and hyperphosphatemia are associated with increased cardiovascular risk in CKD. By lowering both, ferric citrate has been hypothesized to reduce cardiovascular risk, but there is no compelling scientific evidence that phosphate management improves patient clinical outcomes, including all-cause mortality and cardiovascular issues. The observation that one-year safety data showed ferric citrate-treated subjects had reduced rates of hospitalization and reduced serious adverse events related to gastrointestinal, infectious, and cardiovascular causes is intriguing but its mechanism remains unexplained and should be confirmed in prospective outcomes trials.

6. Dosage Forms and Reported Dosages

Ferric citrate is available in the following pharmaceutical forms:

• Oral tablet (Auryxia, USA; Fexeric, EU; Nephoxil, Taiwan): Each tablet of ferric citrate 1 gram is equivalent to 210 mg of ferric iron. Auryxia comes as a 210 mg (ferric iron) tablet taken by mouth three times per day with meals.
• Hyperphosphatemia in dialysis-dependent CKD: In clinical practice, an average starting dose of 6 tablets/day has been observed in retrospective real-world data, with dose titration based on serum phosphorus response.
• Iron deficiency anemia in NDD-CKD: The recommended ferric citrate starting dose for IDA is 1 tablet (1 g, containing 210 mg ferric iron) 3 times daily, titrated to maintain hemoglobin goal. The starting dose in the pivotal Phase 3 study was 3 tablets daily with meals; the mean dose achieved was 5 tablets per day.
• Long-term Phase 4 dosing (NDD-CKD): Patients received either ferric citrate 1 g tablet TID (3 g/day) or 2 tablets BID (4 g/day). At week 12, if hemoglobin was <10 g/dL or changed <0.5 g/dL from baseline, the dose was increased to 2 tablets TID (from 1 TID) or 3 tablets BID (from 2 BID).
• Ferric citrate hydrate (Japan, IDA in general population): Studies used 500 mg ferric citrate hydrate (approximately 120 mg of elemental ferric iron) as a single dose; patients were administered two tablets of 250 mg ferric citrate hydrate.
• Advanced CKD pilot RCT: A fixed dose of two tablets per meal (210 mg ferric iron per tablet) of ferric citrate coordination complex was administered in a randomized pilot trial for 9 months or until 3 months after starting dialysis.

Ferric citrate is also incorporated as a food additive and iron fortification ingredient in flour, crackers, and infant formula at nutritional rather than pharmacological doses, governed by national food regulations rather than pharmaceutical dosing guidelines.

7. Safety Considerations and Drug Interactions

7.1 Gastrointestinal Adverse Effects

The most common adverse events reported in the phase 3 study of ferric citrate for IDA in NDD-CKD were diarrhea, constipation, discolored feces, nausea, abdominal pain, and hyperkalemia. In a phase 3 trial for NDD-CKD, the most common treatment-emergent adverse events were gastrointestinal in both the ferric citrate and placebo groups and included diarrhea (18.1% vs 2.9%), discolored feces (11.1% vs 2.9%), abdominal discomfort (8.3% vs 5.9%), constipation (6.9% vs 14.7%), and abdominal pain (5.6% vs 1.5%).

In clinical trial data for hemodialysis patients, the adverse event profile included diarrhea (21%), discolored feces (19%), nausea (11%), constipation (8%), vomiting (7%), and cough (6%).

7.2 Iron Overload

Ferric citrate is contraindicated in patients with iron overload syndromes, such as hemochromatosis. Increases in serum ferritin and transferrin saturation (TSAT) were observed in clinical trials, which may lead to excessive elevations in iron stores. Auryxia carries a warning for iron overload, which may lead to excessive elevation in iron stores; serum ferritin and TSAT should be assessed prior to initiating therapy and monitored while on therapy. Patients receiving concomitant intravenous iron may require a reduction in dose or discontinuation of IV iron therapy.

7.3 Pediatric Overdose Risk

Accidental ingestion and resulting overdose of iron-containing products is a leading cause of fatal poisoning in children under 6 years of age. Patients must be advised of the risks to children and to keep ferric citrate out of the reach of children.

7.4 Long-Term Safety

No evidence for chronic toxicity or tumorigenicity of ferric citrate was found in mice administered long-term and low-dose (0.06% and 0.12%) supplementation, and no changes in brain weight of adult rats were observed under high-dose ferric citrate (up to 4%) oral supplementation for 13 weeks. In a 24-week clinical study, no new safety signals emerged over the study period. In systematic review of trials in NDD-CKD, serious side effects such as infection and hospitalisation were not recorded in the included trials.

7.5 Drug Interactions

Iron's capacity to complex with other molecules in the GI tract creates the potential for reduced oral absorption of co-administered drugs. The following interactions have been characterized in pharmacokinetic studies reviewed during regulatory assessment:

• Doxycycline: Ferric citrate will decrease the level or effect of doxycycline by drug binding in the GI tract. Doxycycline should be administered at least 1 hour before ferric citrate.
• Ciprofloxacin: Ferric citrate will decrease the level or effect of ciprofloxacin by drug binding in the GI tract. Ciprofloxacin should be taken at least 2 hours before or after ferric citrate.
• Deferiprone: Ferric citrate decreases levels of deferiprone by enhancing GI absorption (applies only to the oral form of both agents; therapy modification required). Deferiprone may bind polyvalent cations such as iron; administration should be separated by at least 4 hours.
• No clinically significant interaction identified with: levofloxacin; anticoagulants/antiplatelets including aspirin, clopidogrel, and warfarin; antidiabetics including glimepiride and sitagliptin; antihyperlipidemics including atorvastatin, fluvastatin, and pravastatin; antihypertensives including amlodipine, diltiazem, enalapril, losartan, metoprolol, and propranolol; the cardiac glycoside digoxin; and vitamin D analogs including calcitriol and doxercalciferol.

The complexing properties of iron suggest that ferric citrate may interact with other orally co-administered drugs, resulting in a decrease in the absorption of the co-administered agent. Separation of administration times is the primary management strategy for known interactions.

7.6 Effect of Gastric Acid Suppression

The drug's effectiveness is unaffected by gastrointestinal tract pH or the concurrent administration of antacids or H2 receptor antagonists. Ferric citrate needs to be dissolved in the stomach to exert its phosphate-lowering and iron absorption effects; however, a previous study showed ferric citrate had a similar phosphate-lowering effect in CKD patients with hyperphosphatemia undergoing hemodialysis when treated with or without a concomitant histamine-2 receptor antagonist.

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