Eur J Haematol 2005: 75: 449–460 Copyright Ó Blackwell Munksgaard 2005

All rights reserved

EUROPEAN
JOURNAL OF HAEMATOLOGY

Review article

Alterations in electrolyte equilibrium

in patients with acute leukemia
Filippatos TD, Milionis HJ, Elisaf MS. Alterations in electrolyte Theodosios D. Filippatos,
equilibrium in patients with acute leukemia. Haralampos J. Milionis,
Eur J Haematol 2005: 75: 449–460. Ó Blackwell Munksgaard 2005. Moses S. Elisaf
Department of Internal Medicine, School of Medicine,
Abstract: Background and aim: A wide array of disturbances in University of Ioannina, Ioannina, Greece
electrolyte equilibrium is commonly seen in patients with acute
leukemia (AL). These abnormalities present a potential hazard in these
patients, as that of enhancing the cardiotoxic effects of certain
chemotherapeutic regimens. The literature dealing with AL-related
electrolyte abnormalities and their interactions in leukemic patients was
reviewed. Data synthesis: Sources included MEDLINE and EMBASE.
The search strategy was based on the combination of Ôacute leukemiaÕ,
Ôelectrolyte abnormalitiesÕ, Ôacid-base disordersÕ, ÔpotassiumÕ, ÔsodiumÕ,
ÔmagnesiumÕ, ÔcalciumÕ, and ÔphosphorusÕ. References of retrieved Key words: acute leukemia; acid-base disorders;
articles were also screened. A decrease in serum potassium, mainly electrolyte abnormalities; lysozymuria; potassium
owing to lysozyme-induced tubular damage, appears to be one of the
Correspondence: Moses Elisaf, MD, Professor of
most frequent and potentially hazardous abnormalities. Other clinically
Medicine, Department of Internal Medicine, School of
significant metabolic perturbations include hyponatremia and hyper- Medicine, University of Ioannina, GR 45110 Ioannina,
calcemia. Conclusion: A broad spectrum of electrolyte abnormalities is Greece
encountered in the clinical setting of AL, which are related to the disease Tel: +30 2651 0 97509
process per se and/or to the therapeutic interventions. Clinicians should Fax: +30 2651 0 97016
be vigilant for early detection and appropriate management of these e-mail: egepi@cc.uoi.gr
disorders before the initiation of chemotherapy regimens as well as
during treatment. Accepted for publication 21 July 2005

A diverse group of acid-base balance disorders and
electrolyte abnormalities have been described in
patients with acute leukemia (AL) (1–4). These
disturbances are mainly considered to be associated
with the leukemic process, organ infiltration, cell
death and/or therapeutic interventions (1, 2, 5, 6).
Electrolyte and acid-base perturbations may be
present regardless of the blast cell type [acute
myelogenous leukemia (AML) or acute lymphocy-
tic leukemia (ALL)] or the state of the disease.
These abnormalities present a potential hazard in
patients with AL, as that of enhancing the cardi-
otoxic effects of certain chemotherapeutic regimens.
In fact, fatal complications, such as sudden death
due to malignant arrhythmias, have been reported
in leukemic patients as an associated synergistic
effect between anti-neoplastic drugs and electrolyte
disorders (1, 7–9). Therefore, clinicians should be
vigilant for early detection and appropriate man-
agement of concurrent acid-base and electrolyte
disturbances before the initiation of chemotherapy
regimens as well as during treatment.
Disorders of acid-base and electrolytes are also
frequently encountered in critically ill patients and
in patients with malignant non-hematological dis-
eases, and may be present as metabolic emergencies
(10, 11). Although acid-base and electrolyte dis-
orders may be a result of the underlying patho-
physiology (e.g. renal failure, respiratory failure,
shock), they may also result from the way we
manage these patients (12). Regardless of their
etiology, the presence of these disorders typically
signals the development of an underlying pathol-
ogy. These disturbances can be severe and are often
associated with worse outcome (11).
In the following sections, we focus on specific
leukemia-related acid-base and electrolyte abnor-
malities and their interrelations in leukemic patients
(Tables 1 and 2). Large-scale studies with reference
to this issue are scarce in bibliography. Sources

449
Filippatos et al.

Table 1. Acid-base and electrolyte abnormalities in AL patients

Disturbance (prevalence) Etiology Reference(s)

Hypokalemia (43–64%) Lysozymuria-induced renal tubular injury (14)

Kaliuresis and tubular dysfunction, independent of lysozymuria (3, 15)
Hypomagnesemia (25)
Potassium entry into the metabolically active proliferating tumor cells (26)
Activation of the renin-angiotensin-aldosterone system by paraneoplastic (28)
production of renin-like substances
Antibiotics (e.g. aminoglycosides, piperacillin, amphotericin) (110, 111)
Factitious hypokalemia (29)
Hyperkalemia (rare) Leukemic infiltration of the kidneys and severe leukostasis with (33)
resultant microvascular insufficiency
Tumor-lysis syndrome (39)
Hyponatremia (10%) Hypovolemic hyponatremia (3)
Syndrome of inappropriate anti-diuretic hormone secretion (SIADH) (40)
Leukemia-induced tubular defect and/or salt-losing nephropathy (3, 47)
Hypernatremia (rare) Central diabetes insipidus (50)
Urea-induced osmotic diuresis (56)
Hypomagnesemia (30%) Magnesium shift from the extracellular to intracellular space (58)
Increased gastrointestinal magnesium loss (61)
Inappropriate magnesiuria due to leukemia-induced and/or lysozyme-induced (1, 16, 18)
tubular dysfunction, metabolic acidosis and phosphate depletion
Low magnesium intake (3)
Drugs: cyclical prednisone therapy, aminoglycosides, amphotericin and pentamidine use (64, 68, 70)
Hypophosphatemia (30%) Shift of phosphate ions into rapidly growing tumor cells or inappropriate urinary loss (75–77)
Decreased phosphate intake (76, 77)
Hyperphosphatemia (rare) Tumor-lysis syndrome (84–86)
Renal failure owing to leukemic infiltration of the kidneys (33)
High-dose liposomal amphotericin B (87)
Hypercalcemia (rare) Production of a PTH-like substance (or PTH-related protein, PTHrP) (1, 92, 95)
Production of proinflammatory cytokines [tumor necrosis factor (98)
alpha (TNF-a), interleukin-6 (IL-6)]
Hypocalcemia (rare) Hypoalbuminemia (101)
Coexisting hypomagnesemia (102, 103)
Chronic respiratory alkalosis (104)
Calciuria due to a primary tubular lesion or to hypophosphatemia (107, 108)
Low levels of vitamin D and osteocalcin (66, 109)
Malnutrition, malabsorption (105, 106)
Cytotoxic therapy-mediated hypocalcemia (precipitation of the (39)
calcium-phosphate complex due to the rapid increase in the phosphorus concentration)
Metabolic alkalosis (35%) Volume depletion (2)
Increased upper gastrointestinal losses in concert with hypovolemia and hypokalemia (3)
Metabolic acidosis (10%) Renal failure (2)
Mixed acid-base balance disorders See text This study

included MEDLINE and EMBASE (last search
update performed on June 6, 2005). The search
strategy was based on the combination of keywords
Ôacute leukemiaÕ, Ôelectrolyte abnormalitiesÕ, Ôacid-
base disordersÕ, ÔpotassiumÕ, ÔsodiumÕ, ÔmagnesiumÕ,
and ÔphosphorusÕ. References of retrieved articles
were also screened.
Potassium
Hypokalemia
Hypokalemia is the most pronounced electrolyte
abnormality in patients with AL. Its frequency
ranges from 43% to 64% in this population (3–5,
13). Although frequently noted, hypokalemia
remains a poorly illuminated metabolic distur-
bance, primarily described in patients with acute
monocytic and acute myelomonocytic leukemia
(M4 and M5) (3, 14, 15). In a consecutive series
of 22 patients with AL, Lantz et al. (5) demonstra-
ted that leukemic patients had a significantly lower
potassium concentration per kilogram of body
weight, per kilogram of lean body mass and total
body water when compared with healthy volunteers
(P < 0.001). This was evident during disease
relapse as well as during remission.
Hypokalemia in AL is of multifactorial origin. It
has been mainly attributed to lysozymuria-induced
renal tubular injury with kaliuresis and persists
despite potassium supplementation (5, 14, 16–18).
Osserman and Lawlor (19), as early as 1966,

450
 Table 2. Clues to diagnosis and management of electrolyte abnormalities in patients with acute leukemia

Abnormality Leukemia subtype Related drug therapy Sings and symptoms Electrocardiographic (ECG) findings Treatment

Hypokalemia Mainly AML, ALL Polymyxine B; amphotericin B; penicillins; Muscular weakness, fatigue, muscle Broadening of T waves, prominent U Potassium orally or intravenously. In cases
aminoglycosides cramps waves, premature ventricular of severe hypokalemia (<2.5 mmol/L) and
contractions associated ECG findings, prompt correction
is advised. In refractory hypokalemia,
magnesium levels should also be measured
Hyperkalemia AML, ALL Cytotoxic drugs causing tumor lysis Muscle weakness, abdominal Peaked T waves of increased A metabolic emergency, as it predisposes to
syndrome; co-trimoxazole distension amplitude, widening of the QRS, life-threatening cardiac arrhythmias.
biphasic QRS-T complexes Calcium gluconate 10%, insulin with
dextrose water, inhaled beta2-agonists,
isotonic sodium bicarbonate, potassium-
binding resins, dialysis (if necessary)
Hyponatremia AML, ALL Vincristine; cyclophosphamide; polymyxine Usually asymptomatic; CNS symptoms Water restriction in cases of SIADH or
B; cytosine arabinoside; co-trimoxazole (in patients with serum sodium levels administration of normal saline in hypovo-
<120 mmol/L) lemic patients. The correction rate of
hyponatremia needs to be no more than
0.5 mmol/L/h.
Hypernatremia Mainly AML, ALL Amphotericin B Orthostatic hypotension and oliguria Water drinking and/or administration of
(when dehydration exists). CNS hypotonic solutions intravenously in more
symptoms (in severe cases) severe cases. Vasopressin analog DDAVP
may be considered in rare cases of central
diabetes insipidus
Hypomagnesemia AML, ALL Prednisone; aminoglycosides; amphotericin; Weakness, muscle cramps; in severe Prolonged PR and QT intervals Elemental magnesium orally (250–500 mg
pentamidine cases, neurologic symptoms (lethargy, two to four times daily). In cases of severe
tremor, nystagmus, ataxia, tetany, and hypomagnesemia, intravenous fluids
seizures) containing magnesium chloride or
magnesium sulfate. Infusion rate should be
adjusted to maintain serum magnesium at
levels no more than 1.25 mmol/L
Hypermagnesemia AML, ALL Cytotoxic drugs, causing tumor lysis Seen if serum magnesium level is Prolonged PR, QRS and QT intervals; Avoid magnesium preparations in patients
syndrome >1.65 mmol/L: neuromuscular complete heart block and asystole with renal failure. Severe symptomatic
abnormalities (muscle weakness, hypermagnesemia should be treated with
decreased deep tendon reflexes, 10% calcium gluconate, 10–20 mL over
lethargy) and respiratory failure 10 min intravenously
Hypophosphatemia AML, ALL In severe cases (serum phosphorus Asymptomatic hypophosphatemia requires no
>1 mg/dL, 0.3 mmol/L): muscular therapy except correction of underlying
abnormalities (weakness, rhabdomy- cause. Phosphate supplementation is
olysis), impaired diaphragmatic function, needed only if serum phosphorus is below
neurologic abnormalities (confusion, 1 mg/dL (0.3 mmol/L)
stupor, seizures, coma), hemolysis and
platelet dysfunction (rarely)
Hyperphosphatemia AML, ALL Cytotoxic drugs causing tumor lysis See hypocalcemia Correction of hypovolemia and coexistent
syndrome; liposomal amphotericin B impairment of renal function; management
of the tumor lysis syndrome (see text); oral
phosphate binders (calcium carbonate,
0.5–1.5 g three times daily with meals)

451
Leukemia-associated electrolyte disorders
Filippatos et al.

intravenously over 10–15 min) followed by infusion

and induction of natriuresis (by saline infusion and

(pamidronate, zoledronate); dialysis may be needed

reported that patients with M4 and M5 leukemia

If symptomatic: calcium gluconate 10% (10–20 mL

of 6 g calcium gluconate in 500 mL 5% dextrose

in patients with congestive heart failure or renal

A metabolic emergency. Effective management in
over 4–6 h. Concurrent hypomagnesemia should

cludes: restoration of extracellular fluid volume

excrete large quantities of lysozyme in the urine,

furosemide intravenously); biphosphonates

thus suggesting a possible causal relationship
between lysozymuria and potassium depletion in
leukemic patients.
Treatment

Lysozyme is an enzyme with a molecular weight of

14 000–15 000 kDa originating from granulocytes
and monocytes in blood as well as from tissue
also be corrected

macrophages. After being released from these cells it

insufficiency
appears in serum, nasal and lacrimal secretions and
various body fluids (14). High serum and urinary
lysozyme levels have been demonstrated in patients
with disorders characterized by proliferation of
granulocytes and macrophages (20), such as AL
Cyclosporine as treatment prophylaxis in patients undergoing allogeneic hematopoietic cell transplantation has been associated with a wide array of metabolic disturbances (128). (primarily M4 and M5) (19, 21, 22), multiple myel-
Electrocardiographic (ECG) findings

oma, sarcoidosis and Hodgkin’s disease (23). Lyso-

zyme is normally reabsorbed in the initial portions of
the proximal convoluted tubule and partly degraded
Shortened QT interval
Prolonged QT interval

in the tubular cells (24). Lysozymuria occurring in

patients with leukemia has been ascribed to over-
production of this protein, because of proliferation
and destruction of lysozyme-containing cells (14). It
seems that accumulation of lysozyme may induce a
renal tubular dysfunction and promote kaliuresis
AML, acute myelogenous leukemia; ALL, acute lymphocytic leukemia; SIADH, syndrome of inappropriate anti-diuretic hormone secretion.

(14). In fact, an inverse correlation between serum

lysozyme levels and plasma potassium can be shown
(fatigue, confusion, stupor, coma)
nausea, vomiting, constipation)
Renal (polyuria, nephrolithiasis),

and neurologic manifestations

in a significant proportion of leukemic patients

(Chvostek's sign, Trousseau's
extremities cramps, tetany
Sings and symptoms

exhibiting hypokalemia (17).

gastrointestinal (anorexia,
Paresthesias of lips and

Besides lysozymuria-induced renal potassium-

sign), convulsions

wasting inappropriate kaliuresis of diverse etiology

has been reported in hypokalemic AL patients. In a
study of 66 leukemic patients (3), serum potassium
levels were found to be inversely correlated with
fractional excretion of potassium (FEK+), suggest-
ing the important role of kaliuresis in producing
potassium depletion in leukemic patients. Abnor-
mal urinalysis findings (including granular casts) in
cytotoxic agents; polymyxine B;
Aminoglycosides; pentamidine;

some hypokalemic patients may also indicate an

Related drug therapy

association between renal potassium depletion and

tubular dysfunction beyond lysozymuria (15).
However, serum potassium levels were well corre-
l-asparaginase

Cyclosporine1

lated with serum magnesium levels, while hypo-

magnesemia was noted concurrently with kaliuresis
in a significant proportion of patients (i.e. 27% of
patients) (3). It is well established that hypo-
magnesemia of any cause produces potassium
depletion due to both urinary and fecal losses (25).
Leukemia subtype

Mainly AML, ALL

Hypokalemia may also be induced by the potas-

sium entry into the metabolically active prolifer-
AML, ALL

ating tumor cells (26), which have a measurably

higher sodium–potassium adenosine triphosphatase
activity (27). In this respect, hypokalemia may be
Table 2. (Continued)

evident in patients with alkalemia and marked

leukocytosis.
Hypercalcemia
Hypocalcemia
Abnormality

An activation of the renin-angiotensin-aldoster-

one system (RAAS) in the bone marrow has been
recently described in AML patients (28). Activation
1

452

of the RAAS by paraneoplastic production of
renin-like substances might contribute to the
observed hypokalemia in AL patients.
Finally, in some cases factitious hypokalemia has
been described in leukemic patients as the result of
the uptake of potassium by immature leukemic
cells, when plasma has not been separated imme-
diately after venipuncture (29).
The safest way to treat mild to moderate potas-
sium deficiency is with oral potassium. All potas-
sium formulations are easily absorbed. Intravenous
potassium replacement is indicated for patients
with severe hypokalemia and for those who cannot
take oral supplementation (30, 31). In addition to
potassium administration discontinuation of drugs
causing hypokalemia and correction of magnesium
deficiency may be needed (32).
Hyperkalemia
Some AL patients, especially those who are newly
diagnosed, show elevated serum potassium, phos-
phorus and magnesium levels (1). This could be due
to the accumulation of these electrolytes as a result of
urate nephropathy as well as renal failure as a result
of leukemic infiltration of the kidneys and/or severe
leukostasis with consequent microvascular insuffi-
ciency (33–36). Furthermore, the increase of these
ions could be a result of their release from malignant
cells following cytotoxic therapy. This phenomenon
is known as the Ôtumor-lysis syndromeÕ, which is an
oncologic emergency that is characterized by severe
metabolic derangements, such as hyperkalemia,
hyperphosphatemia, hypocalcemia and hyperuri-
cemia. It typically occurs in patients with lympho-
proliferative malignancies who are exposed to
chemotherapy, radiation, or corticosteroids, but
can occur spontaneously in the absence of treatment
(37). Patients with pre-existing acute or chronic renal
insufficiency are predisposed to developing the
syndrome and are more vulnerable to its effects.
Hyperkalemia may appear from 6 to 72 h after the
initiation of chemotherapy (38) and is the most
serious manifestation of tumor-lysis syndrome. Cell
lysis results in the liberation of large amounts of
intracellular potassium into the extracellular fluid.
Chronic kidney disease, acute renal failure, or
concurrent acidosis may exacerbate hyperkalemia
as the excretory capacity of the kidney can be
overwhelmed by transcellular shifts due to potas-
sium release from lysing cells as well as acidosis (39).
The major goals of the treatment of acute
hyperkalemia are cardiac membrane stabilization,
intracellular shift of potassium, and reduction of
total potassium load. Membrane stabilization is
achieved with 10% calcium gluconate to prevent
life-threatening cardiac arrhythmias. Its duration of
Leukemia-associated electrolyte disorders
action, however, is short lived, and treatment may
need to be repeated. Insulin promotes the intracel-
lular shift of potassium, and is administered with
dextrose to prevent hypoglycemia. Inhaled beta2-
agonists may also produce an intracellular shift of
potassium. Isotonic sodium bicarbonate can be
used to reduce metabolic acidosis and also to shift
potassium intracellularly. However, sodium bicar-
bonate should be administered judiciously in
patients with acute renal failure as it can lead to
inappropriate volume expansion. Potassium-bind-
ing resins, such as sodium polystyrene sulfate,
exchange sodium for potassium cations in the
gastrointestinal tract. As resins typically require a
longer time to effect removal, faster methods of
lowering potassium such as dialysis may be
required, especially in the setting of acute renal
failure (39).
The principles of management of tumor lysis
syndrome should address three critical areas: hydra-
tion, metabolic abnormalities, and supportive treat-
ment of renal failure. Hydration should begin 2 d
prior to, and continue 2–3 d after, chemotherapy.
Volume expansion with isotonic saline reduces
serum concentrations of uric acid, phosphate, and
potassium. Asymptomatic hypocalcemia should not
be treated due to the risk of exacerbating calcium
phosphate precipitation. Intravenous calcium gluc-
onate is indicated for symptomatic hypocalcemia.
Hypocalcemia usually resolves with treatment of the
concomitant hyperphosphatemia. Finally, the cor-
nerstone of prevention and treatment of hyperuri-
cemia includes both inhibiting the formation of uric
acid (allopurinol) as well as increasing its renal
clearance (urine alkalinization) (39).
Sodium
Hyponatremia
Low serum sodium levels are infrequently noticed
in patients with AL. It has been reported to affect
about 10% of leukemic patients (3, 4). Hypo-
volemic hyponatremia appears to be the most
common cause of hyponatremia in most series.
This is usually the result of volume contraction (e.g.
gastrointestinal fluid losses due to vomiting or
diarrhea) noted in leukemic patients at the time of
disease presentation or during treatment (3).
Hyponatremia in AL patients is rarely associated
with the presence of the syndrome of inappropriate
anti-diuretic hormone (ADH) secretion (SIADH)
(40). Even though neoplasias are among the com-
monest causes of SIADH (41, 42), hyponatremia
and hypochloremia secondary to SIADH have been
infrequently reported in the setting of AL relating
either to the leukemic process per se (1) or to high
453
Filippatos et al.
dose cytosine arabinoside chemotherapy (43). Nev-
ertheless, the most relevant context in the everyday
clinical practice for the presence of SIADH is an
underlying infection of the respiratory or central
nervous system (CNS) (44, 45) or disease-related
CNS involvement due to leukemic infiltration (46).
Salt-losing nephropathy can also be diagnosed as
the cause of hyponatremia in patients with evidence
of mild renal function decline, abnormal urine
sediment findings, and hypovolemia (47). In these
patients a meticulous history of any underlying
renal disease or analgesic abuse should be obtained.
In the absence of the above potential causes, a
leukemia-induced tubular defect may be implicated
as the cause of renal sodium wasting (3).
Treatment of hyponatremia includes water
restriction and/or administration of 0.9% saline
with furosemide. The correction rate of hyponatre-
mia need to be no more than 0.5 mmol/L/h in order
to avoid central pontine myelinolysis (48, 49).
Hypernatremia
Elevated serum sodium levels have been reported in
some rare cases of AL. Nakamura et al. (50) have
ascribed hypernatremia to the leukemia-induced
central diabetes insipidus (DI). Central DI is a
rarely observed complication of hematological
malignancies, including myelodysplastic syndrome
and acute myeloid leukemia (51). Indeed, central
DI has been reported in AML patients with specific
cytogenetic abnormalities, such as abnormalities of
chromosomes 3 and 7 (monosomy 7) (52–54). The
proposed mechanism for the development of cen-
tral DI is an inability of the hypothalamo-neuro-
hypophyseal fibers to secrete ADH, probably
because of infiltration by leukemic cells. Typical
symptoms are polydipsia, polyuria, and marked
thirst. However, when the hypothalamic thirst
center is damaged, central DI gives rise to Ôhypo-
dipsic hypernatremiaÕ and dehydration (55).
Interestingly, Dickenmann and Brunner (56)
have claimed free-water loss by urea-induced
osmotic diuresis to be the cause of hypernatremia
in a patient with AL. In this case, the excretion of
large amounts of urea was induced by severe
metabolic stress with high protein turnover requi-
ring large urine volume excretion.
Treatment of hypernatremia consists of encour-
aging water drinking and/or administration of 5%
dextrose in water (i.e. hypotonic solutions) intra-
venously in more severe cases (57).
Magnesium
Hypomagnesemia is a relatively common electro-
lyte abnormality in leukemic patients. It has been
454
reported that low serum magnesium levels may
be detected in as many as 30% of AL patients
(3). An increased transcellular magnesium shift
from the extracellular to the intracellular space
significantly contributes to the decreased serum
magnesium levels, especially in patients with
marked leukocytosis as well as in patients with
alkalemia (58, 59). Furthermore, increased gas-
trointestinal magnesium loss is probably the main
pathogenetic mechanism of hypomagnesemia in
patients with acute or chronic diarrhea as a
consequence of cytotoxic chemotherapy or neu-
tropenia-related gastrointestinal infections (60,
61). However, hypomagnesemia coexisting with
inappropriate magnesiuria has been described in
a significant proportion of patients, suggesting
that increased magnesium urinary losses may play
a key role in the pathogenesis of magnesium
depletion (3).
Inappropriate magnesiuria can be due to leuke-
mia-induced and/or lysozyme-induced tubular dys-
function. It is well known that in patients with AL
renal impairment may be associated with either
glomerular or tubular dysfunction (1, 16, 18).
Indeed, active urinary sediment has been associated
with increased urinary magnesium loss (3). More-
over, it has been shown that leukemic cell products
other than lysozyme are also linked to renal
tubular injury and increased electrolyte excretion
(16). Finally, metabolic acidosis and phosphate
depletion observed in some hypomagnesemic
patients may be held responsible for the inappro-
priate magnesiuria as a result of reduced magnes-
ium reabsorption in the loop of Henle as well as in
the distal tubule (62, 63).
A renal wastage of magnesium may be associated
with cyclical prednisone therapy (64–66), treatment
with aminoglycoside antibiotics, such as amikacin
(66–68), amphotericin (69–71) and pentamidine
(72, 73).
In some patients with AL no apparent cause for
hypomagnesemia (some times severe) can be found.
This pronounced fall in serum magnesium levels in
these patients could be due to low magnesium
intake related to malnutrition and/or a grave
disease course (3).
In patients with mild hypomagnesemia, mag-
nesium oxide is given orally at a dose of 250–
500 mg two to four times daily to replenish
magnesium stores. Treatment of severe hypo-
magnesemia consists of discontinuation of drugs
causing this abnormality and the use of intra-
venous fluids containing magnesium as chloride or
sulfate ion. In this case, serum magnesium levels
must be monitored and dosage adjusted to keep
the concentration from rising above 1.25 mmol/L
(74).

Phosphorus
Hypophosphatemia
Hypophosphatemia is a relatively common distur-
bance in patients with AL. Low serum phosphate
levels have been reported in up to 30% of patients (3,
4). The leading causes of hypophosphatemia in
patients with AL involve a shift of phosphate ions
into rapidly growing tumor cells or inappropriate
urinary losses of phosphate (75–77). An inverse
correlation between serum phosphate levels and the
fractional excretion of phosphate has been des-
cribed, signifying the importance of phosphaturia in
producing phosphate depletion (3).
Hypomagnesemia and acidemia may also be
associated with the development of hypophos-
phatemia and inappropriate phosphaturia. Even
though hypophosphatemia could be the cause of
inappropriate magnesiuria and hypomagnesemia,
in some cases it might also be the result of
hypomagnesemia. In fact, in experimental magnes-
ium depletion, phosphaturia unrelated to parathy-
roid hormone activity is a common finding and is
suggested to be due to a proximal defect in
phosphate transport (78, 79). Acute metabolic
acidosis also causes loss of phosphate in the urine
and enhances cellular release of the phosphate
anions (80).
In cases of unexplained phosphaturia, tubular
dysfunction (indicated by urinary casts and phos-
phate crystals) may be implicated (81). Young et al.
(76) described a case of severe hypophosphatemia
due to both increased utilization of phosphate by
rapidly growing tumor cells, as well as tubular
defect-associated excessive phosphate urinary
losses. The authors suggested that in the presence
of severe hypophosphatemia, intracellular phos-
phate depletion might occur in renal tubular cells,
potentially interfering with urinary phosphate
reabsorption.
Infrequent causes of hypophosphatemia also
include intracellular shift of phosphate in patients
with high white cell counts and/or alkalosis (82), as
well as a decreased intake of phosphorus-rich food
(76, 77).
Treatment of hypophosphatemia consists of
correction of underlying causes. Phosphate supple-
mentation is needed only if serum phosphorus is
below 1 mg/dL (0.3 mmol/L). In this case, frequent
monitoring of serum phosphate levels is needed and
hypomagnesemia and hypokalemia must also be
corrected (83).
Hyperphosphatemia
Patients with AL sometimes exhibit hyperphos-
phatemia, especially in the setting of the Ôtumor-
Leukemia-associated electrolyte disorders
lysis syndromeÕ (84–86) and renal failure owing to
leukemic infiltration (33) or as a consequence of a
large exogenous load of phosphorus during treat-
ment with high-dose liposomal amphotericin B
(87).
Absorption of phosphate can be reduced by
administration of calcium carbonate, 0.5–1.5 g
three times daily with meals (88–90).
Calcium
Hypercalcemia
Hypercalcemia has been reported as a frequent
manifestation of human T-cell lymphotrophic virus
type I-associated adult T-cell leukemia/lymphoma,
which is endemic in the Caribbean, Japan, Mela-
nesia, and Africa (91). Hypercalcemia may be due
to a parathyroid hormone (PTH)-related peptide
derived from leukemic cells (PTHrP) or may be
secondary to leukemic infiltration of bone and
parathyroid glands (1, 92–97). There is also evi-
dence that high levels of circulating proinflamma-
tory cytokines, such as tumor necrosis factor-alpha
(TNF-a), interleukin-6 (IL-6) and soluble IL-2
receptor, contribute to the development of hyper-
calcemia in patients with ALL (98).
The emergency treatment of choice in cases of
hypercalcemia is establishing euvolemia and indu-
cing natriuresis by giving saline with furosemide
(99). Furthermore, biphosphonates are safe and
effective in treatment of hypercalcemia related to
AL and malignancy (98, 100).
Hypocalcemia
Hypocalcemia, in patients with AL, has been
commonly ascribed to coexistent hypoalbuminemia
(101). Low serum calcium levels are often observed
in the presence of hypomagnesemia, which is
known to impair the release of PTH and induce
skeletal resistance to its actions (102, 103). Chronic
respiratory alkalosis may also play a role in the
development of hypocalcemia in some AL patients,
as it has been reported to be associated with renal
PTH resistance and hypercalciuria (104). In a
significant percentage of patients, hypocalcemia
may be of multifactorial origin resulting from
malnutrition, malabsorption, bacteremia or as an
adverse effect of cytotoxic drugs (105, 106).
Hypercalciuria has been reported in a consider-
able number of hypocalcemic AL patients. In such
cases, calciuria has been attributed to a primary
tubular defect (evidenced by an active urinary
sediment) or to coexistent hypophosphatemia,
which stimulates the production of 1,25-dihydroxy-
vitamin D leading to an augmented intestinal
455
Filippatos et al.
calcium absorption with a resulting hypercalciuria
(107, 108). Hypercalciuria has also been demonstra-
ted in children with acute lymphoblastic leukemia
and low levels of vitamin D and osteocalcin (66, 109).
Finally, hypocalcemia has been observed during
treatment with aminoglycoside antibiotics (indu-
cing hypermagnesiuria and hypercalciuria) (68),
pentamidine (73) and cytotoxic agents (due to the
precipitation of the calcium phosphate complex
following cell lysis-induced increase of phosphate
concentrations) (39). In cases of severe sympto-
matic hypocalcemia calcium gluconate 10% (10–
20 mL) administered intravenously over 10–15 min
and then calcium infusion is indicated. Concurrent
hypomagnesemia must be corrected (90).
Acid-base balance
Patients with AL often exhibit acid-base balance
disorders. In a study by Mir and Delamore (2),
metabolic alkalosis was detected in 35% of
patients, and acidemia in another 10%. Metabolic
alkalosis was probably related to volume depletion
and hypokalemia, while acidemia developed in the
presence of renal failure. Respiratory alkalosis due
to respiratory infection and hypoxemia has also
been described (3).
In several studies, a large number of leukemic
patients developed mixed acid-base disorders. Spe-
cial attention should be drawn to the correct and
careful interpretation of acid-base and electrolyte
parameters in order to disclose and elucidate the
underlying mechanisms of these mixed acid-base
disorders. An underlying infection may play a
prominent role in the development of these
derangements. For example, in a series of 66 AL
patients: (i) patients with septicemia exhibited a
combination of respiratory alkalosis (due to hyper-
ventilation) and metabolic acidosis (possibly due to
lactic acidosis), (ii) patients with acute diarrheal
illness showed a combination of diarrhea-induced
hyperchloremic metabolic acidosis and respiratory
Drug Disorder
Vincristine Hyponatremia
Cyclophosphamide Hyponatremia
Cyclosporine1 Hypercalcemia, hypocalcemia, hypophosphatemia, hyperkalemia,
hypokalemia, hypernatremia, hyponatremia, hypermagnesemia,
hypomagnesemia
Polymyxine B Hypokalemia, hyponatremia, hypernatremia, hypocalcemia
Amphotericin B Hypokalemia, hypomagnesemia, hyperphosphatemia
Penicillins (piperacillin) Hypokalemia
Aminoglycoside antibiotics Hypokalemia, hypomagnesemia, hypocalcemia
Pentamidine Hypomagnesemia, hypocalcemia
L-asparaginase Hypocalcemia
1
Cyclosporine as treatment prophylaxis in patients undergoing allogeneic hematopoietic cell transplantation has
been associated with a wide array of metabolic disturbances (128).
456
alkalosis, and (iii) patients with severe lower
respiratory infection and hypoxemia presented with
a combination of respiratory acidosis and meta-
bolic alkalosis (3).
In the clinical setting of acid-base disequilibri-
um in patients with AL, restoration of hypovole-
mia, effective treatment of underlying infections,
and correction of concurrent metabolic distur-
bances are cardinal constituents of the patientsÕ
remedy.
Drug-induced abnormalities (Table 3)
Therapeutic interventions, including abnormal
cell-targeting agents as well as drugs used to
treat infections, represent well-established causes
of potentially hazardous metabolic disturbances in
patients with AL. As mentioned above, sponta-
neous or therapy-induced Ôtumor-lysis syndromeÕ
may result in hyperuricemia, hyperphosphatemia,
hyperkalemia and hypocalcemia and may preci-
pitate renal failure (110). Following vincristine
and cyclophosphamide administration, changes
such as acute or prolonged hyponatremia are
frequently seen and are probably due to SIADH
(6); polymyxine B-induced nephrotoxicity is asso-
ciated with hyponatremia, hypocalcemia and
hypokalemia (1); trimethoprime-sulfamethoxazole
(co-trimoxazole) induces hyperkalemia with meta-
bolic acidosis, and hyponatremia (111–115);
amphotericin B use is related to hypokalemia,
hypomagnesemia, hyperphosphatemia, and
hypernatremia (70, 87, 116–119). Hypocalcemia
seen after l-asparaginase treatment has been
ascribed to the induction of hypoparathyroidism,
while (sometimes severe) hypokalemia is encoun-
tered after the administration of large doses of
antibiotics (antipseudomonal penicillins, such as
piperacillin and ticarcillin) owing to a non-reab-
sorbable anion effect in the distal tubule or
changes in membrane ionic transport of all cells
(1, 67, 120, 121).
Table 3. Therapy-induced electrolyte abnormalities
Reference(s)
(6)
(6)
(128)
(1, 116)
(69, 71, 87)
(1, 120)
(66–68)
(72, 73)
(1)

Cardiotoxicity associated with the use of anthra-
cycline antineoplastic drugs is a well-known serious
complication (122). Chronic effects of anthracycline
therapy is mainly manifested mainly as congestive
heart failure (123), but there are a few reports of
acute cardiotoxicity (124). Scarce cases of malig-
nant arrhythmias leading to sudden death have
been described in AL patients with severe hypo-
kalemia receiving anthracycline agents (7, 125–
127), suggesting the importance of early detection
and appropriate management of electrolyte distur-
bances in these patients.
Severe metabolic abnormalities commonly occur
after allogeneic hematopoietic cell transplantation
(HCT) in patients receiving prophylaxis with
cyclosporine. Recently, Lee et al. (128) in a series
of 311 patients described a wide array of metabolic
disturbances including hyper- and hypocalcemia,
hypophosphatemia, hyper- and hypokalemia,
hyper- and hyponatremia, hyper- and hypomag-
nesemia, hyperlipidemia, hyper- and hypoglycemia,
and hyperuricemia occurring within 100 d follow-
ing allogeneic HCT. A total of 269 patients (86.5%)
experienced serious abnormalities and their occur-
rence was associated with inferior clinical out-
comes. Patients with at least one severe metabolic
abnormality had significantly higher mortality and
lower 5-yr overall survival than those without
severe derangements (128).
Conclusion
In this review, we considered the pathophysiologic
mechanisms responsible for perturbations in acid-
base balance and electrolyte homeostasis in AL
patients. These disturbances are frequently seen,
have a multifactorial pathogenesis and may present
a potential hazard in patients with AL, per se or by
enhancing the cardiotoxicity of certain anti-neo-
plastic agents. Clinicians should be cautious and
vigilant towards the early detection and appropri-
ate treatment of intercurrent acid-base and electro-
lyte disturbances in patients with AL prior to the
initiation of chemotherapy regimens as well as
during treatment.
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