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. The journey from
vitamin D-resistant rickets to the regulation of renal phosphate
transport. Clin J Am Soc Nephrol. 2009;4:1866-1877.
5. Evenepoel P, Meijers BKI, de Jonge H, et al. Recovery of
hyperphosphatoninism and renal phosphorus wasting one year
after successful renal transplantation. Clin J Am Soc Nephrol.
2008;3:1829-1836.
6. Riella LV, Rennke HG, Grafals M, Chandraker A. Hypophosphatemia in kidney transplant recipients: report of acute phosphate
nephropathy as a complication of therapy. Am J Kidney Dis.
2011;57:641-645.
7. Sakhee K. Post-renal transplantation hypophosphatemia. Pediatr Nephrol. 2010;25:213-220.
8. Levi M. Post-transplant hypophosphatemia. Kidney Int. 2001;
59:2377-2387.
9. Mani LY, Nseir G, Venetz JP, Pascual M. Severe hypophosphatemia after intravenous administration of iron carboxymaltose
in a stable renal transplant recipient. Transplantation. 2010;90:804805.
Am J Kidney Dis. 2012;60(4):655-661
Hypophosphatemia
10. Geerse DA, Bindels RJM, Kuiper MA, Roos AN, Spronk
PE, Schultz MJ. Treatment of hypophosphatemia in the intensive
care unit: a review. Crit Care. 2010;14:R147.
11. Faul C, Amaral AP, Oskouei B, et al. FGF23 induces left
ventricular hypertrophy. J Clin Invest. 2011;121:4393-4408.
12. Prie D, Blanchet FB, Essig M, Jourdain M, Friedlander G.
Dyprimadole decreases renal phosphate leak and augments serum
phosphorus in patients with low renal phosphate threshold. J Am
Soc Nephrol. 1998;9:1264-1269.
13. Newman JH, Neff TA, Ziporin P. Acute respiratory failure
associated with hypophosphatemia. N Engl J Med. 1977;296:11011103.
14. Aubier M, Murciano D, Lecocguic Y, et al. Effect of
hypophosphatemia on diaphragmatic contractility in patients with
acute respiratory failure. N Engl J Med. 1985;313:420-424.
15. O’Connor LR, Wheeler WS, Bethune JE. Effect of hypophosphatemia on myocardial performance in man. N Engl
J Med. 1985;297:901-903.
16. Davis SV, Olichwier KK, Chakko SC. Reversible depression of myocardial performance in hypophosphatemia. Am J Med
Sci. 1988;295:183-187.
17. Gravelyn TR, Brophy N, Siegert C, Golden MP. Hypophosphatemia-associated respiratory muscle weakness in a general
inpatient population. Am J Med. 1988;84:870-876.
18. Agusti AGN, Torres A, Estopa R, Vidal AA. Hypophosphatemia as a cause of failed weaning: the importance of metabolic
factors. Crit Care Med. 1984;12:142-143.
19. Lichtman MA, Millier DR, Cohen J, Waterhouse C. Reduced red cell glycolysis, 2,3-diphosphoglycerate and adenosine
triphosphate concentration, and increased Hgb-oxygen affinity
caused by hypophosphatemia. Ann Intern Med. 1971;74:562-568.
20. Datta HK, Malik M, Neely RDG. Hepatic surgery-related
hypophosphatemia. Clin Chim Acta. 2007;380:13-23.
21. Rubin MF, Narins RG. Hypophosphatemia: pathophysiological and practical aspects of its therapy. Semin Nephrol. 1990;10:536545.
22. Rasmussen A, Kimose HH, Segel E, Hessoy I. Postoperative and glucose-induced hypophosphatemia in relation to adenosine triphosphate and 2,3-diphosphoglycerate in erythrocytes. Acta
Chir Scand. 1989;155:81-87.
23. George R, Shiu MH. Hypophosphatemia after major hepatic resection. Surgery. 1992;111:281-286.
24. de Menezes FS, Leite HP, Fernandez J, Benzecry SG, de
Carvalho WB. Hypophosphatemia in critically ill children. Rev
Hosp Clin Fac Med S Paulo. 2004;59:306-311.
25. Broman M, Carlsson O, Friberg H, Wieslander A, Godaly
G. Phosphate-containing dialysis solution prevents hypophosphatemia during continuous renal replacement therapy. Acta Anaesthesiol Scand. 2011;55:39-45.
26. Mikhail N, El-Bialy A, Grosser J. Severe hypocalcemia: a
rare cause of reversible heart failure. Congest Heart Fail. 2001;7:
256-258.
27. Andress DL, Felsenfeld AJ, Vannata JB, Dokoh S, Haussler
MR, Llach F. Phosphorus administration in patients with profound
hypophosphatemia. Kidney Int. 1984;25:551-556.
Am J Kidney Dis. 2012;60(4):655-661
28. Lentz RD, Brown DM, Kjellstrand C.M. Treatment of
severe hypophosphatemia. Ann Intern Med. 1978;89:941-944.
29. Bergwitz C, Collins MT, Kamath RS, Rosenberg AE. Case
33-2011: a 56-year-old man with hypophosphatemia. N Engl
J Med. 2011;365:1625-1635.
30. Alon US, Levy-Olomucki R, Moore WV, Stubbs J, Liu S,
Quarles LD. FGF-23 and 1,25 D in children with hypophospatemic
rickets: effect of treatment with phosphate, cinacalcet and rocaltrol. Clin J Am Soc Nephrol. 2008;3:658-664.
31. Geller JL, Khosravi A, Kelly MH, Riminucci M, Adams JS,
Collins MT. Cinacalcet in the management of tumor-induced
osteomalacia. J Bone Miner Res. 2007;22:931-937.
32. Liu ES, Carpenter TO, Gundberg CM, Simpson CA, Insogna KL. Calcitonin administration in X-linked hypophosphatemia. N Engl J Med. 2011;364:1678-1680.
33. Seikrit C, Mühlfeld A, Groene HJ, Floege J. Renal allograft
failure in a hyperparathyroid patient following initiation of a
calcimimetic. Nat Rev Nephrol. 2011;7:237-241.
34. Serra AL, Wuhrmann C, Wüthrich RP. Phosphatemic effect
of cinacalcet in kidney transplant recipients with persistent hyperparathyroidism. Am J Kidney Dis. 2008;6:1151-1157.
35. Vannatta JB, Whang R, Papper S. Efficacy of intravenous
phosphorus therapy in the severely hypophosphatemic patient.
Arch Intern Med. 1981;141:885-887.
36. Vannatta JB, Andress DL, Whang R, Papper S. High-dose
intravenous phosphorus therapy for severe complicated hypophosphatemia. Southern Med J. 1983;76:1424-1426.
37. Bollaert PE, Levy B, Nace L, Laterre PF, Larcan A. Hemodynamic and metabolic effects of rapid correction of hypophosphatemia in patients with septic shock. Chest. 1995;107:16981701.
38. Charron T, Bernard F, Skrobik Y, Simoneau N, Gagnon N,
Leblanc M. Intravenous phosphate in the intensive care unit: more
aggressive repletion regiments for moderate and severe hypophosphatemia. Intensive Care Med. 2003;29:1273-1278.
39. Perreault MM, Ostrop NJ, Tierney MG. Efficacy and safety
of intravenous phosphate replacement in critically ill patients. Ann
Pharmacother. 1997;31:683-688.
40. Taylor BE, Huey WY, Buchman TG, Boyle WA, Coopersmith CM. Treatment of hypophosphatemia using a protocol based
on patient weight and serum phosphorus level in a surgical
intensive care unit. J Am Coll Cardiol. 2004;198:198-204.
41. Brown KA, Dickerson RN, Morgan LM, Alexander KH,
Minard G, Brown RO. A new graduated dosing regimen for
phosphorus replacement in patients receiving nutrition support. J
Parenter Enteral Nutr. 2006;30:209-214.
42. Kraft MD, Btaiche IF, Sacks GS, Kudsk KA. Treatment of
electrolyte disorders in adult patients in the intensive care unit.
Am J Health Syst Pharm. 2005;62:1663-1682.
43. Chang JM, Tsai JC, Hwang SJ, Chen HC, Guh JY, Lai YH.
Intravenous repletion of phosphorus deficiency in the chronic renal
failure patients with severe hypophosphatemia. Kaohsiung J Med.
1997;13:540-547.
661