Acid-Base and Electrolyte Teaching Case Approach to Treatment of Hypophosphatemia
Transcription
Acid-Base and Electrolyte Teaching Case Approach to Treatment of Hypophosphatemia
Acid-Base and Electrolyte Teaching Case Approach to Treatment of Hypophosphatemia Arnold J. Felsenfeld, MD, and Barton S. Levine, MD Hypophosphatemia can be acute or chronic. Acute hypophosphatemia with phosphate depletion is common in the hospital setting and results in significant morbidity and mortality. Chronic hypophosphatemia, often associated with genetic or acquired renal phosphate-wasting disorders, usually produces abnormal growth and rickets in children and osteomalacia in adults. Acute hypophosphatemia may be mild (phosphorus level, 2-2.5 mg/dL), moderate (1-1.9 mg/dL), or severe (⬍1 mg/dL) and commonly occurs in clinical settings such as refeeding, alcoholism, diabetic ketoacidosis, malnutrition/starvation, and after surgery (particularly after partial hepatectomy) and in the intensive care unit. Phosphate replacement can be given either orally, intravenously, intradialytically, or in total parenteral nutrition solutions. The rate and amount of replacement are empirically determined, and several algorithms are available. Treatment is tailored to symptoms, severity, anticipated duration of illness, and presence of comorbid conditions, such as kidney failure, volume overload, hypo- or hypercalcemia, hypo- or hyperkalemia, and acid-base status. Mild/moderate acute hypophosphatemia usually can be corrected with increased dietary phosphate or oral supplementation, but intravenous replacement generally is needed when significant comorbid conditions or severe hypophosphatemia with phosphate depletion exist. In chronic hypophosphatemia, standard treatment includes oral phosphate supplementation and active vitamin D. Future treatment for specific disorders associated with chronic hypophosphatemia may include cinacalcet, calcitonin, or dypyrimadole. Am J Kidney Dis. 60(4):655-661. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. INDEX WORDS: Hypophosphatemia; adenosine triphosphate (ATP); 2,3-diphosphoglycerate (2,3-DPG); fibroblast growth factor 23 (FGF-23). Note from Editors: This article is part of a series of invited case discussions highlighting either the diagnosis or treatment of acid-base and electrolyte disorders. Advisory Board member Horacio Adrogué, MD, served as the Consulting Editor for this case. The present case discussion is the second of 2 articles discussing hypophosphatemia. In this article, Drs Felsenfeld and Levine present their approach to the treatment of hypophosphatemia; in the first teaching case, Drs Bacchetta and Salusky describe a physiologicbased approach to its diagnosis and evaluation.1 INTRODUCTION Hypophosphatemia (phosphorus level ⬍2.5 mg/dL [⬍0.81 mmol/L]) is uncommon in the general population, but occurs in up to 5% of hospitalized patients.2 The incidence of acute hypophosphatemia may be as high as 30%-50% in clinical settings such as alcoholism, sepsis, or patients in intensive care units (ICUs). Sometimes acute hypophosphatemia results from redistribution of phosphate into the intracellular compartment without total-body phosphate depletion. In contrast, chronic hypophosphatemia usually is associated with total-body phosphate depletion. Acute hypophosphatemia with phosphate depletion is associated with many clinical manifestations (Fig 1) and causes increased morbidity and mortality.2 Treatment of hypophosphatemia depends on the cause and factors such as chronicity, severity, symptomatology, and the presence of hyper- or hypocalcemia or kidney failure. The following case highlights imporAm J Kidney Dis. 2012;60(4):655-661 tant issues pertaining to the development and treatment of hypophosphatemia. CASE REPORT Clinical History and Initial Laboratory Data A 50-year-old man presented with abdominal pain, nausea, and vomiting. He had consumed large amounts of alcohol for 9 days. Pertinent history included alcohol dependence, alcohol withdrawal seizures, and alcohol-induced pancreatitis 1 month earlier. Physical examination was remarkable for tachycardia and abdominal tenderness. Initial laboratory data showed metabolic acidosis and elevated serum ethanol (71.8 mg/dL [15.8 mmol/L]), calcium, and phosphorus values (Table 1). From the Departments of Medicine, VA Greater Los Angeles Healthcare System and the David Geffen School of Medicine at UCLA, Los Angeles, CA. Received November 2, 2011. Accepted in revised form June 19, 2012. Originally published online August 6, 2012. Because the feature editor recused himself, the peer-review and decision making processes were handled without his participation. Details of the journal’s procedures for potential editor conflicts are given in the Editorial Policies section of the AJKD website. Address correspondence to Barton Levine, MD, Nephrology Section (111L), 11301 Wilshire Blvd, Los Angeles, CA 90073. E-mail: [email protected] Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. 0272-6386/$0.00 http://dx.doi.org/10.1053/j.ajkd.2012.03.024 655 Felsenfeld and Levine Clinical Manifestaons of Hypophosphatemia Respiratory – respiratory muscle dysfuncon; O2 delivery Cardiac - contraclity; arrhythmias Hematologic – hemolysis; hemolysis leukocyte and platelet dysfuncon Endocrine – insulin resistance Neuromuscular – myopathy; rhabdomyolysis; seizures; altered mental status PseudohypoP d h phosphatemia Mannitol Myeloma Bilirubin CAUSES & EFFECTS OF HYPOPHOSPHATEMIA/PHOSPHATE DEPLETION Acute Leukemia Shi into Cells Acute-w/o depleon Respiratory alkalosis Insulin Catecholamines Acute-with depleon Refeeding a. Starvaon p b. Malabsorpon c. Alcoholism d. Diabetes Hungry Bone S d Syndrome Intake/Absorpon Renal Losses Overlap Starvaon Phosphate binders Malabsorpon p Alcoholism Diabetes Alcoholism PTH FGF23 Fanconi Kidney t transplant l t NaPi2/NHERF mutaon Diabetes Alcoholism Starvaon Malabsorpon Additional Investigations Four liters each of normal saline solution and 5% dextrose-half normal saline solution were administered. After serum glucose level increased to 687 mg/dL (38.1 mmol/L), regular insulin was given. Hypercalcemia resolved with hydration and improved kidney function. Metoprolol and diltiazem were given for supraventricular tachycardia. Two days later, serum phosphorus level was ⬍1.0 mg/dL (⬍0.32 mmol/L; Table 1). Diagnosis The diagnosis of severe hypophosphatemia with phosphate depletion was made. Contributing factors included poor oral intake, vomiting, intracellular redistribution of phosphate, and increased renal losses. Clinical Follow-up During the next 7 days, the patient was given 185 mmol of oral and intravenous potassium phosphate (K-Phos; Beach Pharmaceuticals, tampa.yalwa.com/ID_100750342/Beach-PharmaceuticalsDiv-Of-Beach-Products-Inc.html) for persistent hypophosphatemia (Table 1). DISCUSSION The causes of hypophosphatemia recently were reviewed1 and our focus is on the treatment of this condition. Hypophosphatemia results from decreased intake/absorption, gastrointestinal and renal/extracorporeal losses, or internal redistribution (Fig 1). As illustrated in the present case, acute hypophosphatemia frequently results from redistribution of phosphate superimposed on phosphate depletion. Decreased intake and renal losses both contributed to phosphate depletion in the patient. An intracellular shift of phosphate then produced profound hypophosphatemia. The precipitous decrease in serum phosphorus level after initiating glucose-containing solutions indicates phosphate depletion.3 656 Figure 1. Causes and effects of hypophosphatemia/phosphate depletion. Hypophosphatemia may be acute or chronic and results from decreased intake and/or absorption, gastrointestinal and renal/extracorporeal losses, internal redistribution, or a combination of these factors. Pseudohypophosphatemia may occur in patients with acute leukemia from increased uptake of phosphate by leukemic cells in vitro or may result from interference with the phosphate assay by mannitol, bilirubin, or dysproteinemia. Abbreviations: FGF-23, fibroblast growth factor 23; NaPi2/NHERF, sodium-phosphate 2/sodium-hydrogen exchanger regulatory factor; O2, oxygen; PTH, parathyroid hormone. Chronic hypophosphatemia usually results from gastrointestinal and/or renal losses of phosphate. Renal losses can be caused by either gain-of-function mutations or acquired defects in the fibroblast growth factor 23 (FGF-23)–Klotho axis.2,4 In addition to hypophosphatemia, low or inappropriately normal 1,25dihydroxyvitamin D, normal serum calcium, normal or elevated parathyroid hormone (PTH), and high FGF-23 values generally are present.2,4 Also, mutations in sodiumphosphate 2 (Na-Pi 2) transporters or associated regulatory factors, such as the sodium-hydrogen exchanger regulatory factor (NHERF), produce a similar phenotype, but with elevated 1,25-dihydroxyvitamin D levels, hypercalciuria, and stone disease.2,4 Renal phosphate wasting is common after kidney transplant. Hypophosphatemia usually resolves within a year,5 but can persist.6 Contributing factors include persistent elevation of PTH and FGF-23 levels, low 1,25-dihydroxyvitamin D level, renal tubular damage, immunomodulatory agents,6-8 and, if used, intravenous iron.9 Clinical consequences of hypophosphatemia are varied and differ between acute and chronic hypophosphatemia. Even when severe, acute hypophosphatemia from redistribution alone may have little consequence in the absence of phosphate depletion, and phosphate supplementation does not improve patient outcomes.10 Conversely, severe acute hypophosphatemia with phosphate depletion results in significant clinical manifestations (Fig 1) and requires phosphate repletion. Clinical consequences of chronic hypophosphatemia primarily involve impaired growth and bone formation. Also, there is recent evidence that FGF-23– induced cardiovascular abnormalities may occur in some chronic hypophosphatemic states.11 Am J Kidney Dis. 2012;60(4):655-661 Hypophosphatemia Table 1. Serial Laboratory Values Na (mEq/L) K (mEq/L) Cl (mEq/L) CO2 (mmol/L) SUN (mg/dL) SCr (mg/dL) eGFR (mL/min/1.73 m2) TCa/iCa (mg/dL) P (mg/dL) Mg (mg/dL) Glucose (mg/dL) Total bilirubin (mg/dL) ALT (U/L) AST (U/L) Amylase (U/L) Lipase (U/L) Arterial pH (U) PaCO2 (mm Hg) PaO2 (mm Hg) Arterial HCO3 (mEq/L) Lactate (mEq/L) Day 1 Day 2 Day 3 Day 4 Day 5 (6:06 AM) Day 5 (4:43 PM) Day 6 Day 7 133 4.2 81 126 3.8 93 137 3.5 103 139 3.2 100 139 3.7 103 137 3.6 101 135 3.0 97 134 3.5 26.6 15 13 1.6 49 13.3, 5.92a 7.2 1.7 111 4.0 148 227 686 1851 7.32 18 17 1.4 57 7.7 1.9 1.7 687 4.9 71 NA NA NA 7.41 20 25 1.2 68 8.6 ⬍1.0 1.8 229 NA NA NA NA NA 7.46 20 13 1.1 75 8.3 1.2, 1.9, 2.1a 2.1 291 6.2 61 82 83 102 NA 23 9 0.8 109 7.9 2 1.9 224 2.6 52 59 29 36 NA 30 5 0.7 127 8.2 1.4 2.1 NA NA NA NA NA NA NA 27 4 0.8 109 8 2.6 1.7 211 1.9 42 38 18 25 NA NA 4 0.7 127 8.1 3.2 1.7 296 1.5 35 23 18 27 NA 25.5 95.8 12.7 59.4 33.6 77.1 20.6 13.5 27.7 71.1 19.6 11.7 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA Note: eGFR was calculated using the 4-variable MDRD (Modification of Diet in Renal Disease) Study equation. Conversion factors for units: SUN in mg/dL to mmol/L, ⫻0.357; SCr in mg/dL to mol/L, ⫻88.4; eGFR in mL/min/1.73 m2 to mL/s/1.73 m2, ⫻0.01667; Ca in mg/dL to mmol/L, ⫻0.2495; P in mg/dL to mmol/L, ⫻0.3229; Mg in mEq/L to mmol/L, ⫻0.5; glucose in mg/dL to mmol/L, ⫻0.05551; bilirubin in mg/dL to mol/L, ⫻17.1; lactate in mg/dL to mmol/L, ⫻0.111. No conversion necessary for Na, K, Cl, CO2, and HCO3 in mEq/L and mmol/L. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; Cl, chloride; CO2, carbon dioxide; eGFR, estimated glomerular filtration rate; HCO3, bicarbonate; K, potassium; Mg, magnesium; NA, not available; Na, sodium; P, phosphorus; PaCO2, partial pressure of carbon dioxide (arterial); PaO2, partial pressure of oxygen (arterial); SCr, serum creatinine; SUN, serum urea nitrogen; TCa/iCa, total calcium/ionized calcium. a Serial values based on measurements performed on the same day. The precise cause-and-effect relationship between acute hypophosphatemia with phosphate depletion and morbidity and mortality has been difficult to establish. Adjustment for confounding factors such as comorbid conditions, demographic factors, and nutritional status is problematic. In the ICU setting, hypophosphatemia generally is associated with increased morbidity, including longer durations of mechanical ventilation and hospitalization, decreased left ventricular stroke index and systolic blood pressure, and increased incidence of ventricular tachycardia and postoperative complications.1,12 Correction of severe hypophosphatemia improves myocardial and respiratory function.13-18 The 2 primary mechanisms responsible for the acute symptoms of hypophosphatemia are adenosine triphosphate (ATP) and 2,3-diphosphoglycerate (2,3DPG) depletion resulting in reduced energy stores and impaired oxygen delivery, respectively.3,19 Patients with severe hypophosphatemia from an intracellular shift may remain asymptomatic because intracellular Am J Kidney Dis. 2012;60(4):655-661 phosphate levels are sufficient for ATP and 2,3-DPG production.20 When free intracellular phosphate is moved into the glycolytic or protein synthesis pathways, free intracellular phosphate concentrations decrease and extracellular phosphate shifts into cells.21 Examples include hypophosphatemia from insulin and glucose infusion20,22 and from respiratory alkalosis. Treatment of hypophosphatemia is not necessary because ATP and 2,3-DPG concentrations are maintained. In other situations, such as “hungry bone syndrome” or after the infusion of fructose, phosphate is sequestered in extracellular sites or intracellular pathways that do not produce ATP or 2,3-DPG. When ATP and 2,3-DPG concentrations are compromised, symptoms of hypophosphatemia may be profound and treatment is indicated. Several patient populations are particularly at risk of the development of acute hypophosphatemia. In addition to alcoholics and patients in the ICU, other at-risk settings include refeeding after starvation/ malnutrition, after large weight losses, and in anorexia 657 Felsenfeld and Levine nervosa or kwashiorkor/marasmus. A proportional decrease in sodium, potassium, magnesium, and phosphorus levels occurs in these conditions, but during repletion, phosphate is utilized more rapidly. Surgical patients also are more likely to develop hypophosphatemia because of decreased intake, a catabolic state, and use of medications that decrease serum phosphorus levels. Hypophosphatemia is particularly common after hepatic surgery, possibly because the liver may metabolize phosphaturic factors (phosphatonins) such as matrix extracellular phosphoglycoprotein (MEPE).20,23 With a reduction in liver mass, phosphatonin levels may increase, leading to hypophosphatemia.20 Hypophosphatemia also occurs after parathyroidectomy for primary or secondary hyperparathyroidism due to hungry bone syndrome. Finally, in continuous renal replacement therapy, hypophosphatemia occurs in up to 80% of patients. Our patient was at high risk of the development of hypophosphatemia, but the initial hyperphosphatemia decreased awareness. Serum phosphorus value is a poor indicator of total-body phosphorus level. Phosphate depletion indicates a decrease in body phosphorus level, but serum phosphorus level may be low, normal, or high. Despite being hyperphosphatemic, our patient was phosphate depleted for reasons already discussed. The hyperphosphatemia resulted from a release of phosphate into the extracellular compartment due to metabolic acidosis, a catabolic state, and lack of insulin. However, after hydration, insulin administration, and the transition from metabolic acidosis to respiratory alkalosis, severe hypophosphatemia developed. In certain situations associated with phosphate depletion, hypophosphatemia may be prevented or minimized by judicious phosphate supplementation. During refeeding, intake of fluids, electrolytes, and energy should be introduced gradually.24 Well-nourished patients receiving nutritional support should have serum phosphorus measured daily, whereas malnourished patients should have serum phosphorus levels monitored every 6-12 hours. During hyperalimentation, symptomatic hypophosphatemia can be prevented by administering 11-14 mmol of potassiumphosphate per 1,000 calories in the parenteral feeding.3 In patients undergoing continuous renal replacement therapy, hypophosphatemia can be prevented by adding phosphate to the dialysate or replacement solutions.25 In the surgical setting, preoperative assessment of phosphate balance should ensure that adequate phosphate supplementation is provided.20 Phosphate repletion for acute hypophosphatemia associated with phosphate depletion can be given either orally or intravenously. Oral repletion is safer, but the absorption of oral phosphate is unpredictable 658 Box 1. Key Teaching Points ● ● ● ● ● ● ● Acute versus chronic hypophosphatemia: Acute hypophosphatemia with phosphate depletion when severe or symptomatic requires intravenous treatment. In chronic hypophosphatemia, oral phosphate replacement along with active vitamin D therapy is the appropriate treatment Severity: Mild (2-2.5 mg/dL [0.65-0.81 mmol/L]) or moderate (1-1.9 mg/dL [0.32-0.61 mmol/L]) hypophosphatemia usually can be treated with increased dietary phosphate or oral phosphate supplements. Severe acute hypophosphatemia (⬍1 mg/dL [⬍0.32 mmol/L]) with phosphate depletion, particularly in the intensive care unit setting, generally requires intravenous phosphate replacement Comorbid conditions: When the contribution of hypophosphatemia to symptoms is unclear, the severity of illness should be a determining factor in deciding whether oral or intravenous treatment is preferred Hypocalcemia, hypercalcemia: Phosphate therapy can exacerbate hypocalcemia. In hypercalcemic patients, phosphate therapy can lead to calcium-phosphate precipitation, nephrocalcinosis, and acute kidney injury Kidney failure: In kidney failure, the dose of phosphate replacement should be reduced by at least 50% Use of potassium or sodium phosphate treatment: With hypokalemia, potassium-containing phosphate supplements are preferred, but with hyperkalemia, sodium-containing supplements should be used. With volume overload, avoid sodium-containing phosphate supplements if possible Pseudohypophosphatemia: Pseudohypophosphatemia is important to recognize because treatment is not needed and can result in hyperphosphatemia (see Fig 1 for causes) and may cause diarrhea. Intravenous repletion corrects hypophosphatemia more rapidly, but adverse effects may include hypocalcemia, arrhythmias, ectopic calcification, and acute kidney injury (AKI). A decrease in 1,25-dihydroxyvitamin D values occurs in phosphate-depleted patients after intravenous phosphate repletion, which may contribute to hypocalcemia with its depressive effects on myocardial contractility.26,27 The optimal route of phosphate repletion for acute hypophosphatemia/depletion depends on several factors (Box 1), but prior to treatment, one should ensure that pseudohypophosphatemia (Fig 1) is not present. The severity of hypophosphatemia is important in determining the urgency and mode of treatment. In most instances, mild (phosphate, 2-2.5 mg/dL [0.650.81 mmol/L]) or moderate (1-1.9 mg/dL [0.32-0.61 mmol/L]) acute hypophosphatemia can be treated by increasing dietary phosphate or giving oral supplementation (Table 2). In severe acute hypophosphatemia (phosphorus level ⬍1 mg/dL [⬍0.32 mmol/L]) with phosphate depletion, treatment with intravenous phosphate generally is necessary, particularly in the ICU setting. Intravenous therapy also is indicated in patients who cannot tolerate or are unable to ingest oral medications. The amount of phosphate required to restore serum phosphorus and/or replete total-body phosphate is Am J Kidney Dis. 2012;60(4):655-661 Hypophosphatemia Table 2. Oral and Intravenous Phosphate Preparations and Replacement Guidelines Oral Preparations Preparation Phosphate Content (g) Sodium (mEq) Potassium (mEq) Skim milk (1 L) Phospho-soda (1 mL) K-Phos original #1 (1 tablet) K-Phos original #2 (1 tablet) K-Phos neutral (1 tablet) 1.0 0.150 0.114 0.250 0.250 28 4.8 0 5.80 13.0 38 0 3.70 2.80 1.10 Commonly Used Intravenous Preparations Preparation Phosphate Content (g) Sodium (mEq) Potassium (mEq) Sodium phosphate (1 mL) Potassium phosphate (1 mL) 0.011 0.011 4.0 0 0 4.4 Intravenous Replacement Guidelines Intensive Care Unit Setting Serum Phosphorus (mg/dL) ⬍1 1-1.7 1.8-2.2 a Ward Setting Amount (mmol/kg bwt) Duration (h) Amounta (mmol/kg bwt) Duration (h) 0.6 0.4 0.2 6 6 6 0.64 0.32 0.16 24-72 24-72 24-72 Note: Complications may include diarrhea (oral), thrombophlebitis (K-Phos infusion), hypocalcemia, acute kidney injury, nephrocalcinosis, hyperkalemia, hypernatremia/volume overload, hyperphosphatemia, and metabolic acidosis. Conversion factor for phosphorus in mg/dL to mmol/L, ⫻0.3229. No conversion necessary for sodium and potassium in mEq/L and mmol/L. Abbreviation: bwt, ideal body weight. a In patients who are ⬎130% of their ideal body weight, an adjusted body weight should be used. difficult to estimate because the volume of distribution of phosphate is highly variable.28 Therefore, treatment with either oral or parenteral therapy is empirically determined. When providing oral supplementation for mild to moderate acute hypophosphatemia, 32.3-64.6 mmol/d of phosphate for 7-10 days usually is adequate to replenish stores. However, doses as high as 96.9 mmol/d may be needed initially for severe deficiency. Cow’s milk, preferably skim milk to avoid diarrhea, is a good source of phosphate and contains 1 mg/mL. Oral sodium- and potassiumbased preparations also are available (Table 2). The latter is preferable if concomitant hypokalemia is present. In chronic hypophosphatemia, oral phosphate therapy is indicated to correct abnormal bone pathology and re-establish normal growth in children. Long-term oral therapy may suppress 1,25-dihydroxyvitamin D levels and also result in hyperparathyroidism, nephrocalcinosis, and elevated FGF-23 values. The latter may Am J Kidney Dis. 2012;60(4):655-661 increase the risk of cardiovascular complications.11 To prevent hyperparathyroidism and enhance phosphate absorption, active vitamin D therapy often is given concomitantly, but this can exacerbate the increase in FGF-23 levels and increase the risk of AKI from calcium-phosphate precipitation. Standard treatment for disorders involving the FGF23–Klotho axis includes large doses of oral phosphate and 1,25-dihydroxyvitamin D. In tumor-induced osteomalacia, the goal is removal of the offending tumor if possible. The recommended daily phosphate dose for tumor-induced osteomalacia is 0.48-1.9 mmol/kg/d,29 and for X-linked hypophosphatemia, 1.3-3.3 mmol/kg/d.30 Recently, the calcimimetic cinacalcet has been used with standard therapy in X-linked hypophosphatemia and tumor-induced osteomalacia with the rationale that PTH stimulates FGF-23 production and may also enhance the phosphaturic action of FGF-23.31 In 2 patients with tumor-induced osteomalacia in whom doses of standard phosphate therapy were reduced because of poor tolerance, the addition of cinacalcet for 270 days corrected serum phosphorus levels and osteomalacia. In a short-term trial, Alon et al30 compared the effects of a single dose of phosphate supplementation versus the same dose of phosphate supplementation with cinacalcet in 8 patients with X-linked hypophosphatemia. At 4 hours, serum phosphorus and renal phosphate threshold (tubular maximum phosphate/glomerular filtration rate) values were higher and serum calcium and PTH values were lower with cinacalcet. Other treatments that appear promising include dypyrimadole, which decreases urinary phosphate excretion, calcitonin, and antibodies against FGF-23,12,29,32 but long-term studies are needed for these potential treatments. The current treatment for hypophosphatemia after kidney transplant can be problematic. As stated, phosphate supplementation and calcitriol therapy increase FGF-23 values, aggravating the renal phosphate leak, which can lead to intragraft calcification33 and AKI.6 Therefore, initial treatment should be an increase in dietary phosphate,6 with oral phosphate supplementation reserved for persistent severe hypophosphatemia. Patients should be monitored closely for phosphate nephropathy. Cinacalcet is a potential new treatment in this population. When administered for 2 weeks, cinacalcet corrected the renal phosphate leak and decreased PTH and FGF-23 values.34 Kidney function must be monitored because AKI may occur from hypercalciuria caused by PTH suppression and activation of the renal calcium sensing receptor.33 Because high doses of immunomodulatory agents also enhance bone resorption and renal calcium excretion,33 monitoring urinary calcium excretion after initiating cinacalcet therapy is necessary. 659 Felsenfeld and Levine Intravenous treatment of severe acute hypophosphatemia with phosphate depletion is empirical because the volume of distribution of phosphate is highly variable.28 In 1978, Lentz et al28 provided theoretical recommendations for treatment that varied from 0.08-0.24 mmol/kg per 6 hours of intravenous phosphate depending on the severity of hypophosphatemia. Shortly thereafter, Vannatta et al35 administered 9 mmol (⬃0.14 mmol/kg) of intravenous phosphate per 12 hours in severely hypophosphatemic patients. Three additional doses were needed to achieve a normal serum phosphorus value at 48 hours. In a subsequent study, a dose of 0.32 mmol/kg per 12 hours was used, with an increase to 0.48 mmol/kg per 12 hours if serum phosphorus level did not increase by 0.2 mg/dL (0.065 mmol/L) at 6 hours.36 Seven of 10 patients attained a serum phosphorus level ⱖ2.0 mg/dL (ⱖ0.65 mmol/L) by 24 hours, and all 10, by 48 hours. Because hypophosphatemic patients in the ICU with myocardial and/or respiratory compromise may need more rapid correction of hypophosphatemia, higher doses of intravenous phosphate were evaluated. Patients usually were divided into 2 groups: moderate and severe hypophosphatemia. In severe hypophosphatemia, high doses of 10-20 mmol/h were given for 1-3 hours without serious complications.37-39 Perhaps in a better suited approach (Table 2), doses of 42-67 mmol of intravenous phosphate were given over 6-9 hours.40,41 In moderate hypophosphatemia, lower doses of intravenous phosphate were used. In a few studies, glucose-1-phosphate was used for treatment, but in most studies, either potassium or sodium phosphate was used based on a preinfusion serum potassium value of 4.0 mEq/L. In patients with chronic kidney disease (CKD), hyperphosphatemia is the usual problem, but rarely, severe hypophosphatemia can occur. Patients with CKD are more susceptible to adverse effects from phosphate supplementation (Table 2) and using ⱕ50% of the dose for nonazotemic patients is recommended, with a maximum dose of 7 mmol/h.42 Chang et al43 administered sodium phosphate, 0.080-0.097 mmol/ kg, intravenously at 6- to 8-hour intervals to 15 patients with CKD (9 on hemodialysis therapy) with severe hypophosphatemia. Serum phosphorus levels corrected without incident, but mild hypocalcemia and a PTH level increase occurred in some patients. In patients with CKD, awareness of the sodium and potassium content of the phosphate preparations is important, and the total phosphate dose usually is given over 4-6 hours to prevent side effects (Table 2). A repeated serum phosphorus level should be obtained 2-4 hours after the infusion and the dose should be repeated until serum phosphorus level is ⬎2 mg/dL (⬎0.65 mmol/L). 660 It is unclear what level of serum phosphorus is needed to achieve maximal improvement in myocardial and respiratory function. Importantly, serum phosphorus level may be a poor indicator of intracellular ATP and 2,3-DPG concentrations. Therefore, some have advocated measuring excreted metabolites of ATP, such as urinary inosine and inosine-5=-monophosphate, to monitor intracellular ATP values in guiding therapy.20 Measurement of these excreted metabolites and intracellular 2,3-DPG in red blood cells might provide a reliable means of following up the adequacy of phosphate repletion.20 In summary, the current therapeutic options for treatment of hypophosphatemia are not ideal. Treatment of acute hypophosphatemia includes oral and intravenous phosphate supplementation. For genetic and acquired disorders, treatment includes phosphate supplementation, active vitamin D administration, and possibly cinacalcet. Treatment remains empirically determined, and side effects limiting therapy include hypocalcemia, an increase in PTH and FGF-23 values, ectopic calcification, and AKI. Future treatments may target specific phosphatonins or phosphate transporters. Methods to monitor efficacy are limited and methodology to monitor 2,3-DPG and ATP values is needed. ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests. REFERENCES 1. Bacchetta J, Salusky IB. Evaluation of hypophosphatemia: lessons from patients with genetic disorders. Am J Kidney Dis. 2012;59:152-159. 2. Brunelli SM, Goldfarb S. Hypophosphatemia: clinical consequences and management. J Am Soc Nephrol. 2007;18:1999-2003. 3. Ritz E. Acute hypophosphatemia. Kidney Int. 1982;22:84-94. 4. Levine BS, Kleeman CR, Felsenfeld AJ. 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