The Journal for Nurse Practitioners
Volume 8, Issue 1 , Pages 56-60, January 2012

Hyperphosphatemia: Consequences and Management Strategies

  • Timothy V. Nguyen, PharmD

      Affiliations

    • Timothy V. Nguyen, PharmD, CCP, FASCP, is an assistant professor of pharmacy practice at Arnold & Marie Schwartz College of Pharmacy and Health Sciences at Long Island University (AMSCOP-LIU), an adjunct pharmacology professor at the graduate nursing program at Saint Peter's College, and a clinical pharmacy specialist in nephrology and dialysis at the Mount Sinai Medical Center.
    • ,
  • Amy Wang, PharmD

      Affiliations

    • Amy Wang, PharmD, MBA, BCPS, is an assistant professor of pharmacy practice at the AMSCOP-LIU in Brooklyn and clinical pharmacy specialist in cardiology at New York Methodist Hospital. In compliance with national ethical guidelines, the authors report no relationships with business or industry that would pose a conflict of interest.

Article Outline

Abstract 

Phosphorus si an essential element of the body and has many important functions. Hyperphosphatemia, or elevated levels of phosphorus, is defined based on patients' clinical status and often occurs in patients with acute or chronic kidney diseases. Prolonged periods of hyperphosphatemia are associated with such consequences as vascular calcification, organ failure, and mortality. Management includes correcting the underlying cause, hydrating patients to increase phosphorus excretion, and administering oral phosphate binders. Nurse practitioners and pharmacists should work together to identify and avoid exogenous sources of phosphorus, optimize patients' pharmacological therapy, and monitor patients' electrolytes.

Keywords:  acute kidney injury , chronic kidney disease , hyperphosphatemia , phosphate binder , phosphorus

 

Phosphorus is an essential element and the most abundant anion in the body. An average adult has approximately 600 grams of phosphorus stored in the body, and approximately 85% of that is found in bone and teeth. Phosphorus is also present in soft tissues, erythrocytes, and approximately 1% is found in the extracellular fluid. Phosphorus plays major role in various biological functions, including bone mineralization, cell signaling through protein phosphorylation, and energy metabolism. The average daily dietary phosphorus intake is approximately 800 to 1,200 mg.1 shosphoruP homeostasis is regulated by multiple organs systems and other regulatory mechanisms, including the kidney, bone, parathyroid gland, vitamin D, and phosphatonin.

Plasma phosphorus concentration is determined by intestinal phosphate intake, release of phosphate from bone and soft tissue, and excretion via urine or feces. The kidney has a major role in phosphate metabolism because of its effective ability to excrete phosphate under physiological conditions and to influence bone and mineral metabolism through the activation of vitamin D synthesis.1 Renal phosphate excretion is important to maintain homeostasis. With a normal diet and normal parathyroid function, the kidneys reabsorb approximately 90% of filtered phosphorus.2 In kidney disease, homeostasis state is disrupted and hyperphosphatemia or elevated phosphate levels develops overtime. The normal range of serum phosphorus levels varies with disease states (Table 1).3, 4

Table 1. Normal Phosphorus Levels3, 4
Disease StateReference Range (mg/dL)
No disease state2.5–4.5
CKD stages 3 and 42.7–4.6
CKD stage 53.5–5.5
Critically ill2.7–4.5

CKD = chronic kidney disease.

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Etiology 

Hyperphosphatemia may be a result of excessive phosphate supplementation or abnormal physiological processes.5 As the kidney is the main organ responsible for excretion of phosphorus, renal insufficiency is the most common cause of hyperphosphatemia. Serum phosphorus level starts to increase when glomerular filtration rate (GFR) decreases to less than 60 mL/min. However, hyperphosphatemia rarely occurs in patients whose GFR is above 25 mL/min. As the kidney has a compensatory mechanism, the residual functional nephrons increase its level of phosphorus excretion in an attempt to maintain normal physiological levels.3, 5

Patients with chronic kidney disease (CKD) commonly have disturbances in mineral metabolism, which can begin as early as at stages 3 and 4. The failed kidney is not able to fully excrete a phosphorus load, resulting in secondary hyperparathyroidism. Vitamin D, phosphatonin, and fibroblast growth factor-23 (FGF23) are factors thought to have regulatory roles in mineral metabolism, and abnormalities occur early in CKD before changes in calcium, phosphate, and parathyroid hormone (PTH).6 The body attempts to maintain phosphorus balance by increasing urinary phosphorus excretion and FGF23.7 Although patients with advanced CKD are in positive phosphorus balance, phosphorus levels are maintained in the normal range through phosphaturia induced by increases in FGF23 and PTH. FGF23 is now thought to be the main regulator of phosphate homeostasis, and increasing levels have been associated with mortality in dialysis patients, an effect independent of serum phosphate.8 The mechanisms of this association with mortality remain unknown.

Tumor lysis syndrome, or lysis of cancer cells, releases tremendous amounts of intracellular phosphate into the extracellular space, resulting in hyperphosphatemia.3, 5 Rhabdomyolysis causes massive release of myoglobin, which leads to renal failure and phosphate accumulation.5 Renal excretion and phosphorus reabsorption are altered by metabolic acidosis, hypoparathyroidism, or excessive growth hormone levels, which could lead to hyperphosphatemia.5 Critically ill patients have higher energy requirements, and increased levels of phosphate may be released as a result of cell lysis during hypercatabolism.3, 5 Additionally, hyperphosphatemia may be a result of exogenous sources, such as medications, tube feedings, or total parenteral nutrition (TPN).3 Medications such as phosphate-containing enemas or laxatives, intravenous or oral phosphate supplements, and vitamin D are some of the main causes of hyperphosphatemia.3, 5

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Consequences 

Prolonged periods of elevated phosphorus levels may result in hypocalcemia from chelation between calcium and phosphorus. The patient may experience hypocalcemia symptoms, such as muscle weakness, confusion, and drowsiness. Severe cases of hypocalcemia may lead to tetany and arrhythmias.9 Calcium and phosphorus precipitation is more likely to occur when the product of serum calcium concentration multiplied by the serum phosphorus concentration exceeds 55-60 mg/dL. Acidosis increases solubility of this calcium-phosphorus product, whereas alkalosis decreases solubility. The precipitant will be deposited in various organs, such as lungs, kidney, and heart, potentially causing severe organ damage.3, 5 In addition, hyperphosphatemia has been associated with increased risks for coronary artery disease and delayed recovery from anesthesia after surgery.9, 10

Impairment of phosphorus homeostasis affects many physiological processes. Studies have shown that higher serum phosphate concentrations are associated with a greater prevalence of vascular calcification, CKD progression, left ventricular hypertrophy, and death.10, 11 Higher phosphate level is associated with increased mortality in CKD and dialysis patients.12, 13 Patients with the lowest serum phosphate had the best survival rate.13 Vascular calcification is common among CKD patients.10 Reports suggest that alterations in calcium and phosphorus metabolism and prolonged elevations in plasma PTH are the contributors.14 Some suggested minimizing calcium sources such as calcium-based phosphate binders may decrease rates of progression.13

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Treatment 

Non-Pharmacological Treatment 

The first step in hyperphosphatemia management is the removal of underlying cause.3, 5 All phosphate-containing medications should be discontinued and abnormal hormone levels should be corrected. Patients should be placed on a dietary restriction of less than 1 gram of phosphorous per day.5 Intravenous fluid should be administered to increase renal excretion.9

Pharmacological Treatment (Table 2) 

Calcium-based ehosphatP Binders 

Calcium salts, such as calcium acetate or calcium carbonate, are effective for lowering phosphate levels and are relatively inexpensive. Calcium-based phosphate binders have been widely used for hyperphosphatemia control in CKD. The National Kidney Foundation's Kidney Disease Outcome Quality Initiatives (NKF-KDOQI) guidelines recommended less than 1,500 mg of elemental calcium intake per day from calcium-based phosphate binders and no more than 2,000 mg per day from total intake (including dietary calcium).4 Studies have linked vascular calcification in CKD patients to calcium-based phosphate binders.10

Table 2. Clinical Considerations When Selecting Phosphate Binders3, 4, 10, 14, 15, 16, 17, 18
Phosphate BindersInitial DosesAdvantagesDisadvantages
Calcium-based (calcium carbonate, calcium acetate)
Calcium carbonate: 1–2 g 3 times daily with meals

Calcium acetate: 1334 mg oral 3 times daily with meals

Available in chewable formulations, inexpensive, some formulations available over the counterMay worsen calcium-phosphorus precipitation, greater binding affinity with calcium acetate-based compares to calcium carbonate-based GI side effects (eg, constipation), may cause hypercalcemia
Non-calcium based (sevelamer, lanthanum carbonate)
Sevelamer: 800 to 1,600 mg oral 3 times daily with meals

Lanthanum: 500 mg oral 3 times daily with meals

No alteration of electrolytes, available in powder and chewable formsGI side effects (eg, constipation), avoid in GI obstruction, may bind to other vitamins, more expensive, HCl-based versus carbonate-based
Magnesium-based300 to 600 mg oral 3 times a day with mealsInexpensive, available over the counterAvoid in CKD, may cause diarrhea, electrolyte abnormalities
Aluminum-based300 to 600 mg oral 3 times a day with mealsInexpensive, available over-the-counter, efficacious for short-term useGI side effects (eg, constipation), aluminum toxicity, avoid in CKD

GI = gastrointestinal; HCl = hydrochloric acid; CKD = chronic kidney disease.

Calcium acetate has been shown to be more efficacious than calcium carbonate because it binds to more phosphate per millimole of elemental calcium. Prolonged use of calcium salts increases serum calcium levels and may further worsen the precipitation of calcium and phosphate ions.15

Magnesium and Aluminum-based Phosphate Binders 

Magnesium salts may be used but are less efficacious than calcium-containing products. Prolonged use may lead to hypermagnesemia and diarrhea. Aluminum salts, one of the first agents for hyperphosphatemia management, works by binding to phosphate ions in the blood and in the gut to prevent systemic absorption. Aluminum salts are very effective for lower serum phosphate levels but are associated with aluminum toxicity. Therefore, aluminum salts are not commonly used but may be reserved as a salvage therapy for patient refractory to other lines of therapy.15

Non—Calcium-based Phosphate Binders 

Sevelamer and lanthanum carbonate are considered non—calcium-based phosphate binders, and they do not significantly affect serum electrolytes. Sevelamer is a non-absorbable, cationic, polymeric iron-exchange resin for phosphate and is available as a tablet (sevelamer hydrochloride) and as powder for suspension (sevelamer carbonate).16 Sevelamer is usually administered 3 times daily with food, and the tablet dosage form cannot be crushed.15, 16 Long-term use may cause constipation, and it is contraindicated in patients with bowel obstruction.

Moreover, sevelamer hydrochloride contains 17% hydrochloride by weight and can put patients at risk for metabolic acidosis.15, 16 Thus, lrteriaa blood gases and pH must be monitored closely as sevelamer hydrochloride may worsen acid-based disorders in critically ill patients or patients with chronic respiratory disorders.

Lanthanum is available as a chewable tablet and must be crushed or chewed before administration. Patients who receive medications through feeding tubes should take the powder form (sevelamer carbonate) or lanthanum and avoid the tablet form of sevelamer hydrochloride. Similar to sevelamer, lanthanum is to be given 3 times daily with meals but should be used cautiously in patients with peptic ulcer disease, Crohn's disease, ulcerative colitis, or bowel obstruction.

Both sevelamer and lanthanum may bind to and decrease the bioavailability of concomitantly administered medications, such as antibiotics and thyroid supplements. Patients who are on medications where the bioavailability significantly impacts efficacy and toxicity should take the interacting medication at least 1 hour before or 3 hours after taking sevelamer or at least 2 hours before or after the time of lanthanum administration.15, 16

In vitro and pre-clinical studies showed decreased folic acid levels in patients taking sevelamer.17 Other studies have linked utilization of certain high-flux dialysis membranes to folic acid deficiency along with poor dietary intake.18 The manufacturer of sevelamer recommends regular monitoring of serum folic acid levels.16

The Dialysis Clinical Outcomes Revisited (DCOR) study involved 75 centers and 2,103 hemodialysis patients randomly allocated to receive either sevelamer or a calcium-based phosphate binder for a mean follow-up period of approximately 20 months.19 Sevelamer-treated patients experienced comparable all-caused mortality (HR 0.93, 95% CI 0.79-1.1) and cardiovascular mortality (HR 0.93, 95% CI 0.74-1.17) to patients receiving calcium-based binders. The intention-to-treat analyses and the Centers for Medicare and Medicaid Services data demonstrated no significant differences in overall or cardiovascular mortality and no significant interaction between age and treatment effect.20

Overall, most phosphate binders work by binding to phosphate content of food in the gastrointestinal tract and preventing phosphate absorption into the systemic circulation.15, 16 Thus, this class of drugs may not be efficacious for patients who are not able to eat. Patients on aluminum, magnesium, or calcium-containing products must be monitored closely for abnormalities in electrolyte or renal function.3, 15

Given the high cost, sevelamer or lanthum should be used for patients who are refractory to calcium and magnesium salts or for those with elevated calcium, aluminum, or magnesium level.3, 15 Factors to take into account when selecting a phosphate binder include CKD stage, comorbidities, compliance, parallel therapies, and side effects. Patients who have calcifications around the vasculature should try to use non—calcium-containing binders or use combination. Finally, dialysis may be used in patients with acute or CKD and have elevated phosphate levels despite pharmacologic therapy.5

Prolonged hyperphosphatemia can be harmful and lead to cardiovascular events.4 Lowering phosphate level can improve survival for CKD patients. The DCOR study showed beneficial effects on hospitalization (p = 0.02) and hospital days (p = 0.03).20

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Monitoring 

Frequent monitoring is usually not necessary for patients with acute kidney injury as correction may take a long time to occur. Clinicians may consider checking serum electrolytes every 24 to 48 hours and more often in patients who are severely ill or on renal replacement therapy.3

The NKF-KDOQI guidelines recommend maintaining serum phosphorus levels in the normal range for patients with CKD stages 3-5 and lowering elevated phosphorous levels toward the normal range in patients on dialysis with a target of up to 5.5 mg/dL. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend that the phosphate be lowered toward normal.21 Targeting normal ranges for phosphorus and calcium in patients with CKD is an important measure, and the KDIGO allows for more flexibility.

Serum levels of calcium, phosphorus, PTH, and alkaline phosphatase should be monitored regularly in patients with CKD.4, 21 ehT KDIGO included monitoring of serum alkaline phosphatase because this is an important marker for bone turnover that was not included in the KDOQI guidelines. Table 3 outlines monitoring parameters.

Table 3. Monitoring Parameters3, 4, 21
Disease StateCalcium and phosphateParathyroid hormoneAlkaline phosphatase
CKD stage 36 to 12 monthsBaseline and CKD progressionN/A
CKD stage 43 to 6 months6 to 12 monthsAnnually or more
CKD stage 51 to 3 months3 to 6 monthsif PTH is elevated
Acute kidney injury24 to 48 hoursN/AN/A

CKD = chronic kidney disease; PTH = parathyroid hormone.

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Discussion 

High phosphate could result from high phosphate diet and various conditions, such as CKD or acute kidney injury. The source of dietary can have an effect on phosphorus levels.22 Dietary restriction of phosphate is difficult because many foods have high phosphate contents (such as organ meat, dairy and bean products, whole grain, and seeds).22 tatienP counseling and restricted dietary intake are among important considerations to manage overall mineral metabolism.

Overall, the underlying causes of hyperphosphatemia should be identified and corrected. If possible, phosphate-containing medications should be held until patients' phosphorus levels are normalized. Nurse practitioners (NPs) should work together with the pharmacists and take extra precaution to ensure that patients' electrolytes are normal before prescribing phosphate-binders.

Some of the challenges in selecting therapy for managing hyperphosphatemia are the multiple phosphate-binders available, costs associated with therapy, drug safety profiles, and limited long-term randomized trials. NPs can communicate with the pharmacists to determine the optimal management strategy based on patient-specific factors, compliance, cost-related issues, and insurance coverage to avoid delay in therapy. If patients are to be started on pharmacological therapy, NPs should collaborate with pharmacists and select the most appropriate phosphate binder based on clinical status and diet. After initiation of pharmacological therapy, NPs and pharmacists should continue to monitor patients' electrolytes and adjust therapy as needed.

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References 

  1. Amanzadeh J , Reilly BF . Hypophosphatemia: an evidence-based approach to its clinical consequences and management . Nat Clin Pract Nephrol . 2006;136–148
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PII: S1555-4155(11)00256-X

doi:10.1016/j.nurpra.2011.05.007

The Journal for Nurse Practitioners
Volume 8, Issue 1 , Pages 56-60, January 2012

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