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).

tant issues pertaining to the development and treat-

Note from Editors: This article is part of a series of invited
case discussions highlighting either the diagnosis or treat-
ment 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 sec-
ond of 2 articles discussing hypophosphatemia. In this ar-
ticle, Drs Felsenfeld and Levine present their approach to
the treatment of hypophosphatemia; in the first teaching
case, Drs Bacchetta and Salusky describe a physiologic-
based approach to its diagnosis and evaluation.1
INTRODUCTION
Hypophosphatemia (phosphorus level ⬍2.5 mg/dL
[⬍0.81 mmol/L]) is uncommon in the general popula-
tion, 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 alcohol-
ism, sepsis, or patients in intensive care units (ICUs).
Sometimes acute hypophosphatemia results from re-
distribution of phosphate into the intracellular compart-
ment without total-body phosphate depletion. In con-
trast, 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, symptomatol-
ogy, and the presence of hyper- or hypocalcemia or
kidney failure. The following case highlights impor-
ment 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. Physi-
cal 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: blevine@ucla.edu
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

Am J Kidney Dis. 2012;60(4):655-661 655

 Felsenfeld and Levine

Clinical Manifesta
ons of Hypophosphatemia

Respiratory – respiratory muscle dysfunc
on; O2 delivery
Cardiac - contrac
lity; arrhythmias
Pseudohypo-
P d h Hematologic – hemolysis;
hemolysis leukocyte and platelet dysfunc
on
phosphatemia Endocrine – insulin resistance
Neuromuscular – myopathy; rhabdomyolysis; seizures; altered
Mannitol mental status
Myeloma
Bilirubin Figure 1. Causes and effects of hy-
Acute Leukemia
CAUSES & EFFECTS OF HYPOPHOSPHATEMIA/PHOSPHATE DEPLETION
pophosphatemia/phosphate depletion. Hy-
pophosphatemia may be acute or chronic
Shi into Cells Intake/Absorp
on Renal Losses Overlap
and results from decreased intake and/or
Acute-w/o Acute-with absorption, gastrointestinal and renal/extra-
deple
on deple
on corporeal losses, internal redistribution, or a
Respiratory Refeeding Starva
on Diabetes Diabetes combination of these factors. Pseudohy-
alkalosis a. Starva
on Phosphate binders Alcoholism Alcoholism pophosphatemia may occur in patients with
Insulin p
b. Malabsorp
on Malabsorp
on
p PTH Starva
on acute leukemia from increased uptake of
Catecholamines c. Alcoholism Alcoholism FGF23 Malabsorp- phosphate by leukemic cells in vitro or may
d. Diabetes Fanconi
on result from interference with the phosphate
Hungry Bone Kidney assay by mannitol, bilirubin, or dysproteine-
S d
Syndrome t
transplant
l t mia. Abbreviations: FGF-23, fibroblast growth
NaPi2/NHERF factor 23; NaPi2/NHERF, sodium-phosphate
muta
on 2/sodium-hydrogen exchanger regulatory fac-
tor; O2, oxygen; PTH, parathyroid hormone.

Additional Investigations Chronic hypophosphatemia usually results from

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 kid-
ney function. Metoprolol and diltiazem were given for supraven-
tricular 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 in-
take, vomiting, intracellular redistribution of phosphate, and in-
creased 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 Pharmaceu-
ticals, tampa.yalwa.com/ID_100750342/Beach-Pharmaceuticals-
Div-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/extracor-
poreal losses, or internal redistribution (Fig 1). As
illustrated in the present case, acute hypophos-
phatemia frequently results from redistribution of
phosphate superimposed on phosphate depletion. De-
creased intake and renal losses both contributed to
phosphate depletion in the patient. An intracellular
shift of phosphate then produced profound hypophos-
phatemia. The precipitous decrease in serum phospho-
rus level after initiating glucose-containing solutions
indicates phosphate depletion.3
gastrointestinal and/or renal losses of phosphate. Re-
nal 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 1,25-
dihydroxyvitamin D, normal serum calcium, normal or
elevated parathyroid hormone (PTH), and high FGF-23
values generally are present.2,4 Also, mutations in sodium-
phosphate 2 (Na-Pi 2) transporters or associated regula-
tory factors, such as the sodium-hydrogen exchanger
regulatory factor (NHERF), produce a similar pheno-
type, but with elevated 1,25-dihydroxyvitamin D levels,
hypercalciuria, and stone disease.2,4 Renal phosphate
wasting is common after kidney transplant. Hypophos-
phatemia usually resolves within a year,5 but can per-
sist.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 hypophos-
phatemia. 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 phos-
phate depletion results in significant clinical manifes-
tations (Fig 1) and requires phosphate repletion. Clini-
cal consequences of chronic hypophosphatemia
primarily involve impaired growth and bone forma-
tion. Also, there is recent evidence that FGF-23–
induced cardiovascular abnormalities may occur in
some chronic hypophosphatemic states.11

656 Am J Kidney Dis. 2012;60(4):655-661

Hypophosphatemia

Table 1. Serial Laboratory Values

Day 1 Day 2 Day 3 Day 4 Day 5 (6:06 AM) Day 5 (4:43 PM) Day 6 Day 7

Na (mEq/L) 133 126 137 139 139 137 135 134

K (mEq/L) 4.2 3.8 3.5 3.2 3.7 3.6 3.0 3.5
Cl (mEq/L) 81 93 103 100 103 101 97 26.6
CO2 (mmol/L) 15 18 20 20 23 30 27 NA
SUN (mg/dL) 13 17 25 13 9 5 4 4
SCr (mg/dL) 1.6 1.4 1.2 1.1 0.8 0.7 0.8 0.7
eGFR (mL/min/1.73 m2) 49 57 68 75 109 127 109 127
TCa/iCa (mg/dL) 13.3, 5.92a 7.7 8.6 8.3 7.9 8.2 8 8.1
P (mg/dL) 7.2 1.9 ⬍1.0 1.2, 1.9, 2.1a 2 1.4 2.6 3.2
Mg (mg/dL) 1.7 1.7 1.8 2.1 1.9 2.1 1.7 1.7
Glucose (mg/dL) 111 687 229 291 224 NA 211 296
Total bilirubin (mg/dL) 4.0 4.9 NA 6.2 2.6 NA 1.9 1.5
ALT (U/L) 148 71 NA 61 52 NA 42 35
AST (U/L) 227 NA NA 82 59 NA 38 23
Amylase (U/L) 686 NA NA 83 29 NA 18 18
Lipase (U/L) 1851 NA NA 102 36 NA 25 27
Arterial pH (U) 7.32 7.41 7.46 NA NA NA NA NA
PaCO2 (mm Hg) 25.5 33.6 27.7 NA NA NA NA NA
PaO2 (mm Hg) 95.8 77.1 71.1 NA NA NA NA NA
Arterial HCO3 (mEq/L) 12.7 20.6 19.6 NA NA NA NA NA
Lactate (mEq/L) 59.4 13.5 11.7 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 nutri-
tional status is problematic. In the ICU setting, hy-
pophosphatemia generally is associated with in-
creased morbidity, including longer durations of
mechanical ventilation and hospitalization, decreased
left ventricular stroke index and systolic blood pres-
sure, and increased incidence of ventricular tachycar-
dia 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 (2,3-
DPG) 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
phosphate levels are sufficient for ATP and 2,3-DPG
production.20 When free intracellular phosphate is
moved into the glycolytic or protein synthesis path-
ways, free intracellular phosphate concentrations de-
crease and extracellular phosphate shifts into cells.21
Examples include hypophosphatemia from insulin
and glucose infusion20,22 and from respiratory alkalo-
sis. Treatment of hypophosphatemia is not necessary
because ATP and 2,3-DPG concentrations are main-
tained. 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

Am J Kidney Dis. 2012;60(4):655-661 657


nervosa or kwashiorkor/marasmus. A proportional de-
crease in sodium, potassium, magnesium, and phospho-
rus levels occurs in these conditions, but during reple-
tion, phosphate is utilized more rapidly. Surgical
patients also are more likely to develop hypophos-
phatemia 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 (phospha-
tonins) such as matrix extracellular phosphoglycopro-
tein (MEPE).20,23 With a reduction in liver mass,
phosphatonin levels may increase, leading to hy-
pophosphatemia.20 Hypophosphatemia also occurs af-
ter parathyroidectomy for primary or secondary hyper-
parathyroidism due to hungry bone syndrome. Finally,
in continuous renal replacement therapy, hypophos-
phatemia 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. Phos-
phate depletion indicates a decrease in body phospho-
rus level, but serum phosphorus level may be low,
normal, or high. Despite being hyperphosphatemic,
our patient was phosphate depleted for reasons al-
ready discussed. The hyperphosphatemia resulted from
a release of phosphate into the extracellular compart-
ment due to metabolic acidosis, a catabolic state, and
lack of insulin. However, after hydration, insulin
administration, and the transition from metabolic aci-
dosis to respiratory alkalosis, severe hypophos-
phatemia 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-nour-
ished patients receiving nutritional support should
have serum phosphorus measured daily, whereas mal-
nourished patients should have serum phosphorus
levels monitored every 6-12 hours. During hyperali-
mentation, symptomatic hypophosphatemia can be
prevented by administering 11-14 mmol of potassium-
phosphate per 1,000 calories in the parenteral feed-
ing.3 In patients undergoing continuous renal replace-
ment therapy, hypophosphatemia can be prevented by
adding phosphate to the dialysate or replacement
solutions.25 In the surgical setting, preoperative assess-
ment of phosphate balance should ensure that ad-
equate 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
Felsenfeld and Levine
Box 1. Key Teaching Points
● Acute versus chronic hypophosphatemia: Acute hypophos-
phatemia with phosphate depletion when severe or symptom-
atic requires intravenous treatment. In chronic hypophos-
phatemia, 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, particu-
larly in the intensive care unit setting, generally requires
intravenous phosphate replacement
● Comorbid conditions: When the contribution of hypophos-
phatemia 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 exac-
erbate hypocalcemia. In hypercalcemic patients, phosphate
therapy can lead to calcium-phosphate precipitation, nephro-
calcinosis, 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 im-
portant to recognize because treatment is not needed and
can result in hyperphosphatemia (see Fig 1 for causes)
and may cause diarrhea. Intravenous repletion cor-
rects hypophosphatemia more rapidly, but adverse
effects may include hypocalcemia, arrhythmias, ecto-
pic calcification, and acute kidney injury (AKI). A
decrease in 1,25-dihydroxyvitamin D values occurs in
phosphate-depleted patients after intravenous phos-
phate repletion, which may contribute to hypocalce-
mia with its depressive effects on myocardial contrac-
tility.26,27
The optimal route of phosphate repletion for acute
hypophosphatemia/depletion depends on several fac-
tors (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 [0.65-
0.81 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 supplemen-
tation (Table 2). In severe acute hypophosphatemia
(phosphorus level ⬍1 mg/dL [⬍0.32 mmol/L]) with
phosphate depletion, treatment with intravenous phos-
phate generally is necessary, particularly in the ICU
setting. Intravenous therapy also is indicated in pa-
tients 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 increase the risk of cardiovascular complications.11
Replacement Guidelines To prevent hyperparathyroidism and enhance phos-
Oral Preparations phate absorption, active vitamin D therapy often is
given concomitantly, but this can exacerbate the in-
Phosphate Sodium Potassium
Preparation Content (g) (mEq) (mEq)
crease in FGF-23 levels and increase the risk of AKI
from calcium-phosphate precipitation.
Skim milk (1 L) 1.0 28 38 Standard treatment for disorders involving the FGF-
Phospho-soda (1 mL) 0.150 4.8 0 23–Klotho axis includes large doses of oral phosphate
K-Phos original #1 (1 tablet) 0.114 0 3.70 and 1,25-dihydroxyvitamin D. In tumor-induced osteo-
K-Phos original #2 (1 tablet) 0.250 5.80 2.80 malacia, the goal is removal of the offending tumor if
K-Phos neutral (1 tablet) 0.250 13.0 1.10 possible. The recommended daily phosphate dose for
tumor-induced osteomalacia is 0.48-1.9 mmol/kg/d,29
Commonly Used Intravenous Preparations and for X-linked hypophosphatemia, 1.3-3.3 mmol/kg/d.30
Phosphate Sodium Potassium Recently, the calcimimetic cinacalcet has been used
Preparation Content (g) (mEq) (mEq) with standard therapy in X-linked hypophosphatemia
and tumor-induced osteomalacia with the rationale
Sodium phosphate (1 mL) 0.011 4.0 0 that PTH stimulates FGF-23 production and may also
Potassium phosphate (1 mL) 0.011 0 4.4 enhance the phosphaturic action of FGF-23.31 In 2
Intravenous Replacement Guidelines patients with tumor-induced osteomalacia in whom
doses of standard phosphate therapy were reduced
Intensive Care Unit Setting Ward Setting
Serum because of poor tolerance, the addition of cinacalcet
a
Phosphorus Amount Duration Amounta Duration for 270 days corrected serum phosphorus levels and
(mg/dL) (mmol/kg bwt) (h) (mmol/kg bwt) (h)
osteomalacia. In a short-term trial, Alon et al30 com-
pared the effects of a single dose of phosphate supple-
⬍1 0.6 6 0.64 24-72
mentation versus the same dose of phosphate supple-
1-1.7 0.4 6 0.32 24-72
mentation with cinacalcet in 8 patients with X-linked
1.8-2.2 0.2 6 0.16 24-72
hypophosphatemia. At 4 hours, serum phosphorus and
Note: Complications may include diarrhea (oral), thrombophle- renal phosphate threshold (tubular maximum phos-
bitis (K-Phos infusion), hypocalcemia, acute kidney injury, nephro-
calcinosis, hyperkalemia, hypernatremia/volume overload, hyper-
phate/glomerular filtration rate) values were higher
phosphatemia, and metabolic acidosis. Conversion factor for and serum calcium and PTH values were lower with
phosphorus in mg/dL to mmol/L, ⫻0.3229. No conversion neces- cinacalcet. Other treatments that appear promising
sary for sodium and potassium in mEq/L and mmol/L. include dypyrimadole, which decreases urinary phos-
Abbreviation: bwt, ideal body weight. phate excretion, calcitonin, and antibodies against
a
In patients who are ⬎130% of their ideal body weight, an
adjusted body weight should be used. FGF-23,12,29,32 but long-term studies are needed for
these potential treatments.
difficult to estimate because the volume of distribu- The current treatment for hypophosphatemia after
tion of phosphate is highly variable.28 Therefore, kidney transplant can be problematic. As stated, phos-
treatment with either oral or parenteral therapy is phate supplementation and calcitriol therapy increase
empirically determined. When providing oral supple- FGF-23 values, aggravating the renal phosphate leak,
mentation for mild to moderate acute hypophos- which can lead to intragraft calcification33 and AKI.6
phatemia, 32.3-64.6 mmol/d of phosphate for 7-10 Therefore, initial treatment should be an increase in
days usually is adequate to replenish stores. However, dietary phosphate,6 with oral phosphate supplementa-
doses as high as 96.9 mmol/d may be needed initially tion reserved for persistent severe hypophosphatemia.
for severe deficiency. Cow’s milk, preferably skim Patients should be monitored closely for phosphate
milk to avoid diarrhea, is a good source of phosphate nephropathy. Cinacalcet is a potential new treatment
and contains 1 mg/mL. Oral sodium- and potassium- in this population. When administered for 2 weeks,
based preparations also are available (Table 2). The cinacalcet corrected the renal phosphate leak and
latter is preferable if concomitant hypokalemia is decreased PTH and FGF-23 values.34 Kidney func-
present. tion must be monitored because AKI may occur from
In chronic hypophosphatemia, oral phosphate therapy hypercalciuria caused by PTH suppression and activa-
is indicated to correct abnormal bone pathology and tion of the renal calcium sensing receptor.33 Because
re-establish normal growth in children. Long-term oral high doses of immunomodulatory agents also enhance
therapy may suppress 1,25-dihydroxyvitamin D levels bone resorption and renal calcium excretion,33 moni-
and also result in hyperparathyroidism, nephrocalcino- toring urinary calcium excretion after initiating cina-
sis, and elevated FGF-23 values. The latter may calcet therapy is necessary.

Am J Kidney Dis. 2012;60(4):655-661 659


Intravenous treatment of severe acute hypophos-
phatemia with phosphate depletion is empirical be-
cause 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 hypophos-
phatemia. Shortly thereafter, Vannatta et al35 adminis-
tered 9 mmol (⬃0.14 mmol/kg) of intravenous phos-
phate 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 evalu-
ated. 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 treat-
ment, 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 ob-
tained 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
Felsenfeld and Levine
It is unclear what level of serum phosphorus is
needed to achieve maximal improvement in myocar-
dial and respiratory function. Importantly, serum phos-
phorus 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=-monophos-
phate, 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. Treat-
ment 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 val-
ues, ectopic calcification, and AKI. Future treatments
may target specific phosphatonins or phosphate trans-
porters. 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.
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