ACKD

Sodium and Potassium Dysregulation in the

Patient With Cancer
Praveen Ratanasrimetha, Biruh T. Workeneh, and Harish Seethapathy

Sodium and potassium disorders are pervasive in patients with cancer. The causes of these abnormalities are wide-
ranging, are often primary or second-order consequences of the underlying cancer, and have prognostic implications.
The approach to hyponatremia should focus on cancer-related etiologies, such as syndrome of inappropriate antidiuretic
hormone, to the exclusion of other causes. Hypernatremia in non-iatrogenic forms is generally due to water loss rather
than excessive sodium intake. Debilitated or dependent patients with cancer are particularly vulnerable to hypernatremia.
Hypokalemia can occur in patients with cancer due to gastrointestinal disturbances, resulting from decreased intake or
increased losses. Renal losses can occur as a result of excessive mineralocorticoid secretion or therapy-related nephro-
toxicity. The approach to hyperkalemia should be informed by historical and laboratory clues, and pseudohyperkalemia
is particularly common in patients with hematological cancers. Hyperkalemia can be seen in primary or metastatic dis-
ease that interrupts the adrenal axis. It can also develop as a consequence of immunotherapy, which can cause adrena-
litis or hypophysitis. Tumor lysis syndrome (TLS) is defined by the development of hyperkalemia and is a medical
emergency. Awareness of the electrolyte abnormalities that can befall patients with cancer is vital for its prompt recog-
nition and management.
Q 2022 by the National Kidney Foundation, Inc. All rights reserved.
Key Words: Onconephrology, Hyponatremia, Hypokalemia, Hyperkalemia, Electrolytes

P atients with malignancies commonly experience ab-

normalities in serum electrolytes, with sodium and po-
tassium disorders being the most prevalent. The causes of
these abnormalities are broad and often second-order con-
sequences to the underlying cancer. For example, a signif-
icant segment of patients with cancer receive medications,
such as diuretics or antidepressants, that might contribute
to sodium and potassium disorders. We have limited the
scope of this review to focus on sodium and potassium
disorders that are principally the consequence of cancer
and cancer therapy. We have utilized a case-based
approach to highlight the diagnostic approach and man-
agement of sodium and potassium disorders in patients
with cancer.
HYPONATREMIA
Hyponatremia is the most common electrolyte disorder in
patients with cancer, with an estimated prevalence of
20-
50%.1,2 Hyponatremia, and the failure to normalize SNa,
have been associated with poor cancer outcomes.3-8
While the approach to hyponatremia in a patient with
cancer is the same as in a noncancer patient, and
elucidating causes specific to cancer, its treatment and
concomitant processes becomes essential.
Case
A 64-year-old man with advanced biliary tract cancer,
pulmonary nodules, and malignant ascites is admitted
after outpatient labs showed SNa of 115 mEq/L (2 weeks
prior, SNa was 129 mEq/L). He reports limited oral
intake over the last month, relying primarily on small
portions of homemade soup. Second-line treatment
with nivolumab was started 6 months ago after pro-
gressive disease on cisplatin and gemcitabine. His
serum osmolality was 262 mOsm/kg, his urine sodium
was ,20 mEq/L, and his urine osmolality was 579
mOsm/kg. His SNa is gradually corrected with 3% sa-
line and desmopressin. Therapeutic considerations
included the placement of an indwelling peritoneal
catheter and choice of solute-rich liquids he could
consume in lieu of solid food to prevent redevelopment
of hyponatremia.
The causes of hyponatremia in patients with cancer are
much more clustered than in the noncancer patient, but
one must caution against heuristic decision-making
because often hyponatremia can be unrelated to cancer
or cancer therapy. Thus, having an approach focusing on
cancer, but not at the exclusion of other etiologies, can
make it easier for the clinician to arrive at the cause and
develop a treatment plan.9,10
Confirm Hypo-Osmolar Hyponatremia. Iso-osmolar (275-
290 mOsm/kg) or hyperosmolar (.290 mOsm/kg) hypo-
natremia is uncommon and can be quickly ruled out by
the measurement of serum osmolality. In patients with
cancer, iso-osmolar hyponatremia is most often seen in
patients with multiple myeloma who have severe para-
proteinemia.11,12 In normal individuals, the noncellular
component of blood (plasma) comprises 93% water
and 7% solids such as fats and proteins. Labs using an
indirect ion-potentiometry method depend on an exact
quantity of the sample to measure sodium and assume
this ratio when the sample is diluted. Hence, in instances
From the Section of Nephrology. The University of Texas MD Anderson
Cancer Center, Houston, TX (P.R., B.T.W.); and Division of Nephrology, Mas-
sachusetts General Hospital, Boston, MA (H.S.).
Financial Disclosure: B.T.W. has received honoraria as a consultant for As-
traZeneca. H.S. has received a fellowship grant award from Relypsa Inc. P.R. de-
clares that he has no relevant financial interests.
Address correspondence to Harish Seethapathy, MBBS, Division of
Nephrology, Massachusetts General Hospital, 55 Fruit St, Boston, MA
02114. E-mail: hseethapathy@mgh.harvard.edu
Ó 2022 by the National Kidney Foundation, Inc. All rights reserved.
1548-5595/$36.00
https://doi.org/10.1053/j.ackd.2022.01.003

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172 Ratanasrimetha et al

where the balance is shifted (.7% solids, ,93% water), electrolyte abnormalities with mannitol have been re-
the measured value may be falsely low, even though the ported after a single dose.17,18
sodium concentration in the smaller quantity of water is
normal. Using direct ion-potentiometry, such as those Evaluate the State of Activation of Antidiuretic Hormone.
used in rapid analyzers to measure blood gases, negates Once iso-osmolar or hyperosmolar hyponatremia is ruled
this effect and provides a true sodium value.13 Iso- out, the next step in assessing hypo-osmolar hyponatre-
osmolar hyponatremia is also seen in patients receiving mia is evaluating antidiuretic hormone (ADH) activity.
isotonic fluids containing exogenous solutes (glycine, ADH or vasopressin, a nonapeptide hormone produced
sorbitol) used for hysteroscopy in patients with endome- in the hypothalamus and secreted in the posterior pitui-
trial cancer and during prostate and laparoscopic sur- tary, primarily regulates extracellular fluid volume. The
geries.14 When such sodium-free irrigant solutions are physiologic stimulus for ADH secretion comes from car-
absorbed into the intravascular space, the sodium con- diac baroreceptors and atrial stretch receptors, which
centration drops. Although the measured osmolality is detect volume, or through hypothalamic osmoreceptors,
normal (275-290 mOsm/kg), the calculated osmolality which sense serum osmolality. Nonphysiologic stimuli
will be lower, giving rise to an osmolar gap in these pa- for ADH release include activation of the limbic system
tients (Fig 1). through pain, nausea, trauma, etc. ADH binds to V2 re-
Hyperosmolar hyponatremia occurs primarily ceptors in the distal tubule and collecting duct in its acti-
because of the addition of osmotically active substances vation state, resulting in phosphorylation of aquaporin
to the plasma and subsequent dilution of the plasma (AQP2) vesicles that bind to create a water channel in
through intracellular water movement into the extracel- the apical membrane. This facilitates water reabsorption,
lular space. In cases where the serum osmolality is only creating concentrated urine and reducing plasma osmo-
mildly elevated, the diagnosis of hyperosmolar hypona- lality. ADH also has a second function, which is to in-
tremia can also be made by measuring the osmolar gap, crease peripheral resistance by its action on vascular
and it should be suspected when there is a gap of .10 smooth muscle cells to induce vasoconstriction. The state
mOsm/kg between the of ADH activation can be as-
measured and calculated CLINICAL SUMMARY sessed by measuring urine
osmolality. While hyperos- osmolality. A urine osmo-
molar hyponatremia may  Electrolyte abnormalities, particularly sodium and lality of ,100 mOsm/kg in-
be labeled ‘dilutional,’ potassium disorders, are common in patients with cancer dicates a state of ADH
these are instances of true and are associated with worse outcomes. inactivation or suppression,
hyponatremia, whereby and a urine osmolality of
 A stepwise approach to diagnosis should be adopted to
the sodium concentration .100 mOsm/kg denotes a
elucidate etiologies related to the underlying cancer and
in the plasma is low. state of at least partial ADH
cancer therapy.
Intravenous immunoglob- activation.
ulin (IVIG), used in cancers  Treatment should focus on preserving or improving quality
such as multiple myeloma of life and avoiding hospital admissions. Antidiuretic Hormone–
and chronic lymphocytic Independent Hyponatremia
leukemia, can cause hypona- (UOsm #100 mOsm/kg). Nor-
tremia in certain patients. The dose of immunoglobulin mal individuals can dilute their urine to around 50-100
administered is insufficient to cause pseudohyponatremia, mOsm/kg. A typical Western diet consists of solute
such as severe paraproteinemia in multiple myeloma.15,16 intake between 600 and 800 mOsm/day, approximately
However, hypertonic sucrose-containing IVIG formula- half of which is electrolytes and half urea, and urine vol-
tions can cause acute kidney injury (AKI), and the subse- ume can range from ,1 L/day to .15 L/day depending
quent sugar portion which accumulates can act as an on the action of ADH. Thus, even with ADH suppressed,
effective osmole and lead to hyperosmolar hyponatremia. solute intake plays a crucial role in determining the
High-dose intravenous mannitol (100-200 g) is used in amount of fluid an individual can drink. In individuals
head and neck cancers to reduce intracranial pressure by with cancer, this is an important contributor to low so-
‘dehydrating’ the brain tissue. Mannitol is freely filtered dium levels and significantly affects treatment. Our pa-
and is not reabsorbed in the kidneys. It induces osmotic tient, whose solute intake has likely been around 300
diuresis, which can lead to hyponatremia. It can also mOsm/kg, can only produce
5 L of urine if his urine
accumulate in patients with AKI, leading to dilutional osmolality was 60 mOsm/kg. If his urine osmolality
hyponatremia. Such cases are also accompanied by hy- were higher than 100 mOsm/kg, he could drink ,3 L
perkalemia, which can be severe. When mannitol draws of fluids before becoming hyponatremic.
water out of the cells, it also causes a potassium shift
into the extracellular space, hypothesized to occur by Antidiuretic Hormone–Dependent Hyponatremia (UOsm
solvent drag or passive transport when its intracellular .100 mOsm/kg). The primary stimulus for the ADH,
concentration rises. Mannitol, by itself, can cause AKI above maintaining osmolality, is to conserve effective
through renal vasoconstriction and tubular vacuoliza- circulating volume. Activation of ADH in states of low
tion, but that has only been reported in patients circulating volume produces concentrated urine. Gastro-
receiving high repeated doses of mannitol. In contrast, intestinal (GI) symptoms such as nausea and vomiting

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 Sodium and Potassium Disorders in Cancer 173

Physiologic ADH acvaon:

Step 1 Step 2 Step 3 ¾ Hypovolemia
Measure Assess effecve Chemotherapy induced N/V/D
Measure CAR-T induced capillary leak
Plasma Urine circulang Diurecs*
osmolality volume Adrenalis/hypophysis (ICIs)*
osmolality
<275 >100 ¾ Heart Failure
Urine Na<20 mEq/L, Anthracyclines
mOsm/kg Hypo-osmolar mOsm/kg ADH symptoms/signs of volume Trastuzumab
hyponatremia dependent depletion or third-spacing
Low ¾ Liver failure
Metastases
≥275 ≤100 Radiaon injury
mOsm/kg
Iso-osmolar or
mOsm/kg ADH Drugs – lapanib, ICIs
Hyper-osmolar Sinusoidal obstrucon syndrome
hyponatremia independent
Sodium loss
Iso-osmolar Low solute intake ¾ Cisplan renal salt wasng
Urine Na≥20 mEq/L, no
¾ Pseudohyponatremia ¾ Intraperitoneal catheters
signs of circulatory failure
(Mulple myeloma,
obstrucve jaundice
Normal or High
with ↑Lipoprotein-X)
¾ Exogenous solutes SIADH:
(glycine, sorbitol) ¾ Ectopic producon of ADH
Small-cell-lung cancer
Hyper-osmolar Head & neck cancer
¾ IVIG Brain & pulmonary metastases
¾ Mannitol
¾ Drugs affecng concentraon ability
Bortezomib
Cyclophosphamide, ifosfamide
Cisplan
Methotrexate
Vincrisne, Vinblasne
Pazopanib

¾ Other:
Pulmonary infecons
Nausea, pain

Figure 1. A stepwise approach to the diagnosis of hyponatremia in a patient with cancer. *Patients with thiazide-induced hy-
ponatremia also have polydipsia and ADH-independent water reabsorption. Hyponatremia in patients with adrenalitis occurs
through two mechanisms: i) cortisol deficiency–induced release of corticosyntropin-releasing hormone, an ADH secreta-
gogue, ii) aldosterone deficiency causing sodium loss and subsequent ADH activation. Only the second mechanism is evident
in hypophysitis. Abbreviations: N/V/D, nausea/vomiting/diarrhea; CAR-T, chimeric antigen receptor T cell; ICI, immune check-
point inhibitor; ADH, antidiuretic hormone.

and insufficient oral (salt) intake are prevalent in patients
with cancer, especially after intensive chemotherapy
regimens. Add to this increased hypotonic fluid intake
(eg, soup with low salt/solute content, soft drinks, water,
tea, etc.), and the possibility of hypo-osmolar hyponatre-
mia becomes high. GatoradeÒ, despite its reputation for
an electrolyte repletion solution, is principally
electrolyte-free and, despite an osmolality of .300
mOsm/kg, can contribute to hyponatremia.19 Therapies
such as chimeric antigen receptor T cell can lead to hypo-
natremia in up to half of patients, as a result of volume
depletion, cortisol release, or IL-6–mediated vasopressin
release.20 Hyponatremia is frequently seen in patients
receiving immune checkpoint inhibitors, which can be
the result of immune toxicity such as primary or second-
ary adrenal insufficiency or hypothyroidism. In cases
where hypotension exists as a result of adrenal insuffi-
ciency, ADH stimulation can be the cause of or can
worsen hyponatremia.21
Appropriate ADH stimulation also occurs in patients
with cancer and heart or liver failure because of decreased
effective blood volume. Anthracycline- or trastuzumab-
induced cardiomyopathy can lead to congestive heart fail-
ure with low effective circulating volume and high ADH
levels.22 Hyponatremia is seen in end-stage liver disease
when its synthetic function has been severely compro-
mised by primary cancer, metastases, radiation injury, or
drugs. Lapatinib, a dual tyrosine kinase inhibitor (HER-
2/neu and EGFR) used in breast cancer and checkpoint
inhibitors, especially anti-CTLA-4 agents, can cause hepa-
titis, resulting in end-stage liver disease. Sinusoidal
obstruction syndrome, a rare but often fatal complication
following a stem cell transplant, can also cause severe liver
injury that can lead to hyponatremia.23
Loss of total-body sodium, although rare, can occur in
specific scenarios. Renal salt wasting has been described
with drugs causing tubular injury (site of sodium
absorption), such as cisplatin, and can be severe. Intraper-
itoneal catheters used to relieve malignant ascites
commonly cause hyponatremia, with an incidence of
nearly 85% reported.24 In a large study (n ¼ 309) of patients
with intraperitoneal catheters, the median fluid removed
per week in those with hyponatremia was 7 L, amounting
to a loss of nearly 1000 mEq of sodium each week. Such pa-
tients are also more vulnerable to inadequate solute intake
and have an abysmal prognosis, with a median survival of
,40 days.
Nonphysiologic Antidiuretic Hormone Activation.
Nonphysiologic ADH activation was described over
60 years ago by Schwarz and colleagues in a patient
with lung cancer and described what is now known as
syndrome of inappropriate ADH (SIADH).25 It is the
most common cause of hyponatremia in patients with
cancer and should be suspected in patients with normal
effective circulating volume (urine sodium.20 mEq/L)
and a urine osmolality.100 mEq/L (in the presence of hy-
ponatremia). Serum copeptin levels have been proposed
as a surrogate marker of vasopressin concentration to
differentiate between the different causes of hyponatre-
mia, although clinically meaningful use is uncommon.
Small cell lung cancer (SCLC) is a predominant cancer
known to be associated with hyponatremia due to ectopic
production of vasopressin (incidence
10-16%), with
head and neck cancers (incidence
3%) also commonly
reported to cause hyponatremia by the identical mecha-
nism.26,27 SIADH, although rare, has been reported in
many solid organ and hematological malignancies and

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174
is also associated with manifestations of cancer such as
pulmonary infections and metastases, nausea, and pain.
Many chemotherapeutic drugs (Fig 1) have also been
associated with enhancing the concentrating ability of
the kidneys through an ADH and, rarely, an ADH-
independent mechanism.
Approach to Management of Hyponatremia. The man-
agement of low sodium levels should consider the patient’s
baseline physical and nutritional status. Similar to those
with a history of extensive alcoholism, malnourished
hospitalized patients have a higher risk of osmotic demy-
elination syndrome from overcorrection of severe hypona-
tremia (Na,120 mEq/L).28 Hence, such patients should be
assumed to have high-risk chronic hyponatremia and have
their sodium levels gradually corrected—current guide-
lines recommend a goal rate of 4-6 mEq/L, with a recom-
mendation not to exceed 8 mEq/L in 24 hours. The most
convenient method to avoid overcorrection is with 3% sa-
line and a desmopressin clamp until hyponatremia is no
longer severe.29 Many patients have hyponatremia of
mixed etiology and severity. Hence, subsequent manage-
ment should take into consideration oral palatability (eg,
urea, salt tablets), comorbidities (liver cancer/metastases:
V2 receptor antagonists contraindicated), and underlying
severity of hyponatremia (isolated free water restriction
should not be instituted in patients with Uosm.500
mOsm/kg or those with a urine-to-serum cation ratio
[Urine Na 1 K/Serum Na] .1.0).30,31 Focus should be
placed on the quality of life and avoiding recurrent hospi-
tal admissions for hyponatremia management (Fig 2).
HYPERNATREMIA
Hypernatremia in noniatrogenic forms is generally due to
water loss rather than excessive sodium intake. Debilitated
cancer patients are particularly vulnerable when they have
to depend on others for free water intake when brain me-
tastases impair their thirst mechanism or critically ill and
have high insensible losses.
High Urine Osmolality (.300 mOsm/kg)
The loss of water can be through the skin or through the GI
tract, such as vomiting or, rarely, cancers that cause watery
diarrhea, such as VIPoma.32 Partial diabetes insipidus,
which is still possible with a not maximally dilute urine
osmolality, should also be kept in mind. Rarely, adminis-
tration of hypertonic sodium bicarbonate in patients
with tumor lysis syndrome and AKI, or to prevent
methotrexate-induced AKI or administration of hyperton-
ic (3%) saline in instances of increased intracranial pres-
sure, can lead to hypernatremia. Urinary losses can occur
due to drugs such as mannitol, which causes osmotic
diuresis and hypernatremia in patients with normal kid-
ney function who quickly excrete water and mannitol
into the urine.33 In patients with dysphagia, high-
protein-containing formulas used for nasogastric or oro-
gastric feeding can also produce osmotic diuresis and
water loss.34
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Ratanasrimetha et al
Low Urine Osmolality (,300 mOsm/kg)
Hypernatremia with low urine osmolality occurs due to
abnormalities in ADH secretion or ADH responsiveness.
Central diabetes insipidus is primarily seen in patients
with hypothalamic or pituitary metastases and can
sometimes be the isolated presentation leading to cancer
diagnosis.35 It can also occur in intracranial cancer involve-
ment such as lymphoma or leukemia or after brain surgery
for intracranial tumors. Rarely, temozolomide, an alkalat-
ing agent used to treat central nervous system tumors, can
lead to central diabetes insipidus by affecting ADH pro-
duction.36 Nephrogenic diabetes insipidus can be induced
by drugs that produce tubular injuries such as the plat-
inum compounds, pemetrexed, or ifosfamide.37
Approach to Management of Hypernatremia
Unlike hyponatremia, rapid correction has not been as
strongly associated with neurologic sequelae in hyperna-
tremia, but caution is still advised.38 While a correction
limit of 12 mEq/L/24 hours is recommended, some experts
believe SNa1 levels can be corrected with no significant
adverse events.39 The current water deficit should be
calculated, free water should be administered through a
nasogastric tube or intravenous dextrose (5%), and rates
should be adjusted considering ongoing losses.40
HYPOKALEMIA
Case
A 50-year-old female who was recently diagnosed with
ovarian cancer was found to have hypokalemia after the
second round of cisplatin-based chemotherapy. She has
been complaining of nausea, vomiting, and insufficient
oral intake for 3 days. She complained of palpitations,
and her EKG showed occasional premature ventricular
contractions and flattened T waves. Her serum potassium
(sK)1 level was found to be 2.5 mEq/L, serum bicarbonate
16 mEq/L, serum magnesium 1.1 mg/dL, and urinary po-
tassium/Cr was 2.0 mEq/mmol.
Hypokalemia is characterized by a sK1 level
, 3.5 mmol/L and is the second most common electrolyte
disorder in patients with cancer. More than 98% of potas-
sium is sequestered in the intracellular compartment
owing to sodium-potassium exchange across the cell
membrane and is essential for maintaining the resting
membrane potential of cells. Intracellular potassium also
plays a vital role in acid-base disturbance by exchanging
with extracellular hydrogen ions. Patients with cancer
frequently present with multiple electrolyte abnormalities
simultaneously. The cause of hypokalemia can usually be
obtained after complete history taking and physical exam-
ination (see Fig 3). The patient can report nausea, vomit-
ing, decrease oral intake, or diuretic use. If, after careful
history taking and examination, the cause is unclear,
then the next step would involve further laboratory
evaluation.
Exclude Pseudohypokalemia. Pseudohypokalemia does
not occur as commonly as pseudohyperkalemia. This phe-
nomenon occurs most frequently in patients with acute
Adv Chronic Kidney Dis. 2022;29(2):171-179
 Sodium and Potassium Disorders in Cancer 175

Candidate for
fluid restriction
as isolated Rx
Severe Mild-moderate
hyponatremia • Urine osmolality <500 mOsm/kg
hyponatremia (consider diuretics to washout
(<120 mEq/L) (≥120 mEq/L) medullary gradient and ↓Uosm)
• 24-hour urine volume >1.5L
• (UNa + UK) < PlasmaNa

Consider all Correctable Chronic management:

cancer patients cause
as high-risk* • Stop offending agent/treat
ectopic ADH producing
Not a candidate cancer
Yes No for fluid • Increase solute intake
restriction as • Fluid restriction
Goal correction rate Hold chemotherapy Most often SIADH
4-6 mEq/L/24 hours IVF for hypovolemia isolated Rx Solute intake
Increase solute intake (mOsm/day) day
3% saline + • Urine osmolality >500 mOsm/kg
Stop salt wasting meds
desmopressin • 24-hour urine volume <1.5L 400 600 800
• (UNa + UK) > PlasmaNa

Osm (mOsm/kg)
SIADH Urine
400 1L 1.33L* 2L*

600 0.67L 1L 1.33L*

Urea 15g bid 800 0.5L 0.75L 1L

Tolvaptan 7.5mg qd or qod
Salt tablets (2g tid) *Fluid restriction of 1L may be
of some utility

Figure 2. A stepwise approach to management of hyponatremia in a patient with cancer. Desmopressin is usually adminis-
tered at a dose of 2 mg every 8 hours and 3% saline at a rate of 20-35 cc/hour and titrated per urine output and serum sodium
levels. Abbreviations: UNa, urine sodium; UK, Urine potassium; ADH, antidiuretic hormone.

leukemia with white cell counts exceeding 100,000/mL and ation is refeeding syndrome, which can occur in
is caused by a transcellular shift into leukemic blast cells malnourished patients. It can occur iatrogenically
in vitro if the sample is held before being analyzed for a when feeding is resumed, stimulating insulin release
prolonged period.41 Other factors such as elevated temper- and the development of hypokalemia, hypophosphate-
ature of the laboratory and recent administration of insulin mia, and hypomagnesemia.43
can also result in spurious sK1 values. The history, labora-
tory findings, and EKG changes make it unlikely in the Determine Renal vs. GI Losses. Urinary potassium excre-
case described. tion can be measured in a 24-h urine collection to measure
urine potassium loss. In a hypokalemic state, urine potas-
Determine Acid-Base Status. In addition to determina- sium excretion should be less than 20 mmol/day. If urine
tion of urinary losses of potassium, serum acid-base status potassium excretion is higher than 15 mmol/day, then it
should be taken into consideration because it can provide might indicate that the cause of hypokalemia is from renal
information about the etiology. For example, the presence wasting (Fanconi syndrome, current diuretic use,
of metabolic alkalosis can suggest primary or secondary cisplatin). This is the most accurate method but may not
causes of hyperaldosteronism. Metabolic alkalosis with
low urinary potassium excretion (eg, urine potassium
,20 mEq/L or urine potassium/Cr , 1.5) suggests vomit-
ing, previous diuretic use. Finally, a metabolic alkalosis Confirmation of true hypokalemia
with high urinary potassium excretion suggests diuretic
use. History taking and physical
The presence of metabolic acidosis with low urinary examination
potassium excretion can suggest GI loss due to laxative 24 hours urine potassium excretion/
use or a precancerous lesion–like villous adenoma. A (spot urine potassium to creatinine ratio)
number of chemotherapeutic drugs, such as cisplatin,
ifosfamide, and others, can cause renal tubular acidosis,
and the presence of hypokalemia and metabolic acidosis
with high urinary potassium excretion can suggest this Urine K/Cr ratio < 1.5 Urine K/Cr ratio > 1.5
diagnosis.
• Decreased intake • Renal tubular acidosis
Consider Transcellular Shifts. Transcellular shifts as a • GI loss • Diuretic use, Fanconi syndrome
• Transcellular shift • Hypomagnesemia, adrenal
result of cancer or cancer complications can result in adenoma
hypokalemia. A rapid increase in cell production in • Cisplatin, Ifosfamide
the blast phase of leukemia is associated with hypoka- • Lysozymuria
lemia but can also occur in nonblastic leukemias.42 Figure 3. Diagnostic algorithm for hypokalemia. The key
Also, the rapid development of metabolic alkalosis, measure for the differentiating the cause of hypokalemia is
which can occur due to intense and prolonged vomit- the urine potassium-to-creatinine ratio (Urine K/Cr). Abbre-
ing associated with traditional chemotherapy, can cause viations: ICI, immune checkpoint inhibitor; RAAS, renin
massive potassium shifts into cells. Another consider- angiotensin aldosterone system.

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176
be convenient for patients. Another useful laboratory is
spot urine-potassium-to creatinine ratio. In a hypokalemic
state, the spot urine-potassium-to-creatinine ratio should
be less than 1.5. If the spot urine-potassium-to-creatinine
ratio is higher, it is likely to indicate a renal loss.44
Hypokalemia can occur in cancers that elaborate
ectopic adrenocorticotrophic hormone (ACTH) such as
bronchial carcinoma, thyroid medullary carcinoma, as
well as SCLC that stimulates renal potassium wasting
from excess cortisol production. Cisplatin is platinum-
based chemotherapy used in several malignancies and
as mentioned is commonly associated with the develop-
ment of hypokalemia. Other platinum-based chemother-
apies include oxaliplatin, carboplatin. Cisplatin can
cause renal injury via multiple mechanisms, but primar-
ily it affects the proximal tubule cells, which undergo
apoptotic injury. The hypomagnesemia related to
cisplatin is dose-related and can persist several months
after discontinuation of cisplatin, and this can result in
enduring hypokalemia. Cisplatin-induced renal magne-
sium wasting results from downregulation of TRPM-6
magnesium channel in distal tubules.45 Magnesium reg-
ulates the renal outer medullary potassium channel
(ROMK), and when levels of magnesium levels are
low, a high efflux of potassium from ROMK results.
Therefore, it is important in the clinical case above to cor-
rect hypomagnesemia along with hypokalemia. Hypoka-
lemia as a result of renal losses has also been described
in association with renal tubular acidosis in patients
receiving immune checkpoint inhibitors, although the
mechanism is unknown.46
VIPoma or villous adenoma is frequently associated with
hypokalemia, but these conditions are not very common.
Other GI-related etiologies of hypokalemia involve
decreased intake frequently seen in head and neck cancers,
anorexia, radiation injury, mucositis associated with high-
dose chemotherapy, or other causes that render the patient
unable to feed adequately. Furthermore, toxicity from
chemotherapy, radiation, and immunotherapy can all
cause diarrhea and consequent hypokalemia.47
Management of Hypokalemia. The approach to potas-
sium replacement in patients with cancer is the same as
the normal population. Frequently, sK1 may not be a reli-
able marker for total-body potassium because extracel-
lular potassium accounts for only 2% of the whole-body
store and there may be significant ongoing renal losses.
Therefore, post-treatment monitoring, after either intrave-
nously or oral therapy, is advisable.
HYPERKALEMIA
Case
A 50-year-old female with a previous history of breast can-
cer and chemotherapy exposure was diagnosed with
therapy-related acute monocytic leukemia. Before antici-
pated treatment with cytarabine-based chemotherapy,
she was given hydroxyurea but developed lower extrem-
ity weakness. She was found to have hyperkalemia to
6.1 mmol/L. Her lab work showed a white blood cell 182,
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Ratanasrimetha et al
Hgb 9.8 g/dL, platelets 60 K/mL, creatine kinase 26 U/L,
SCa 8.8 mg/dL, P 7.1 mg/dL, SCr 1.1 mg/dL, and uric
acid 12.2 mg/dL.
Hyperkalemia is potentially deadly, and potassium regu-
lation is essential. Hyperkalemia is defined as a serum or
plasma potassium level typically greater than 5.0 mEq/L.
Disruption of the potassium gradient can impair cellular
function resulting in acute neurologic and cardiovascular
dysfunction and arrhythmia. Muscle weakness is a com-
mon feature of hyperkalemia, but the most lethal compli-
cation is cardiac arrhythmias that can lead to sudden
death. Patients with hyperkalemia experience significantly
higher emergency room visits, inpatient admission, hospi-
tal length of stay, readmission, and mortality.48 All-cause
mortality increases in hyperkalemia in a graded fashion.
In study an analysis of more than 900,000 patients with
various comorbidities, mortality was elevated for every
0.1-mEq/L change in potassium $5.0 mEq/L, and the pres-
ence of comorbidities increased mortality.49,50 Patients
with severe hyperkalemia experienced up to 7.5-fold
higher odds of death over an 18-month period.
Evaluation of Hyperkalemia. The approach to hyperkale-
mia should be informed by historical and laboratory clues,
and the general approach is summarized in Fig 4. If hyper-
kalemia is suspected, rapid assessments with use of iSTATor
chemistries from blood gas machine can be performed. The
most common cause of hyperkalemia is pseudohyperkale-
mia due to hemolysis of the sample measured due to disrup-
tion of cellular integrity resulting from the collection. Use of
tourniquets, fist-pumping, or increased negative pressure
from syringe aspiration can be factors that contribute to
this phenomenon. Cancer-specific causes in myeloprolifera-
tive disease with significant lymphocytosis, polycythemia,
or thrombocytosis can be associated with pseudohyperkale-
mia. In the case we describe, cell fragility is a concern, and
the method of exclusion would be to allow fibrin clot to
form before centrifugation and measurement of sK1.
Although diet is often invoked as a cause of hyperkale-
mia, it is not expected unless there is a disruption of ho-
meostatic mechanisms to maintain normal serum
potassium or in the event of acute or chronic kidney dis-
ease. The body can eliminate over 15 g (400 mEq) of potas-
sium in 24 hours, and in cases of potassium loading in
normal individuals, there may be only transient hyperka-
lemia.51 In hospitalized patients who receive a brisk
intravenous replacement, total parenteral nutrition, or
large-volume blood transfusions, the infusion can over-
come the kidneys’ ability to eliminate potassium, however.
CKD is the most common predisposing condition for hy-
perkalemia.52 AKI, common in patients receiving cancer
therapy, results in a rapid decrease in GFR and tubular
flow, accompanied by a hypercatabolic state, tissue injury,
and high acute potassium loads.
The primary route of eliminating potassium is kidneys
and is where the principle regulation based on feedback
mechanisms occurs. Aldosterone is the principal hormone
that regulates potassium excretion. Indeed, hyperkalemia
due to deficiency (hyporeninemic hypoaldosteronism) or
unresponsiveness is observed in patients with diabetes.
Adv Chronic Kidney Dis. 2022;29(2):171-179
 Sodium and Potassium Disorders in Cancer 177

Confirmation of true hyperkalemia

(Must exclude pseudohyperkalemia from hemolysis,

leukocytosis, polycythemia and thrombocytosis)

Detail history taking and physical examination to determine etiology

Tumor-related etiologies Non tumor-related etiologies

• Adrenal insufficiency from pituitary/adrenal tumor
• Adrenalitis/hypophysitis from ICI
• Rhabdomyolysis from electrolyte disorders,
chemotherapy or ICI
• Tumor lysis syndrome
• AKI/CKD who had blood transfusion
• Iatrogenic causes (e.g., excessive K replacement)
• Diabetes (e.g., hyperglycemia, type 4 RTA) Adrenal
insufficiency from abrupt cessation of steroids
• Use of medications that interfere with RAAS

Figure 4. Diagnostic algorithm for hyperkalemia. Pseudohyperkalemia is common in cancer and should be excluded before
the various etiologies are considered.

Furthermore, medications that disrupt the renin-
angiotensin-aldosterone axis are associated with the
development of hyperkalemia. The use of these agents in
patients with cancer reflects the general population, partic-
ularly if patients suffer from hypertension, diabetes, or
congestive heart failure. Hyperkalemia can be seen in ad-
renal insufficiency, which can occur due to steroid with-
drawal after a prolonged course, primary or metastatic
tumor involvement of adrenal or pituitary gland, and sur-
gical resection of the adrenal or pituitary gland.53,54 Adre-
nalitis or hypophysitis from immunotherapy can also
cause hyperkalemia.55
Significant tissue or widespread cellular injury will result
in hyperkalemia because of intracellular contents releasing
into the extracellular fluid space. Patients with cancer can
suffer from rhabdomyolysis from traditional chemo-
therapy as well as novel therapies. Rhabdomyolysis has
been described after treatment with cyclophosphamide,
5-azacytidine, interleukin-2, interferon, pemetrexed, and
cytarabine.56,57 The use of immune-checkpoint inhibitors
(ICIs) has expanded, and these patients can experience
immune-related adverse effects (irAEs) including
myositis.58,59 Although it appears to be rare, there have
Table 1. Diagnostic Criteria for Tumor Lysis Syndrome
Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome
Uric acid x $ 8 mg/dL or 25% increase from baseline
Potassium x $ 6 mEq/L or 25% increase from baseline
Phosphorous x $ 6.5 mg/dL (children), x $ 4.5 mg/dL
(adults) or 25% increase from baseline
Calcium x # 7 mg/dL or 25% decrease
from baseline
Cairo-Bishop Definition of Clinical Tumor Lysis Syndrome
1. Creatinine: x . 1.5 ULN (age . 12 years or age adjusted)
2. Cardiac arrhythmia/sudden death
3. Seizure
been several reports of rhabdomyolysis as a consequence
of the use of ICIs in cancer.
Tumor lysis syndrome (TLS) is entirely cancer-specific
and is the culprit in the case described. It occurs more
frequently in patients with a significant disease burden
or high replication rates, such as leukemia or
high-grade lymphomas or tumors responsive to therapy.
It can occur spontaneously or result from traditional
chemotherapy, targeted therapy, immunotherapy, or ra-
diation. TLS requires immediate recognition and man-
agement. TLS can lead to AKI, cardiac arrhythmias,
seizures, and significant mortality associated with the
disorder. Lysis of tumor cells results in an immediate
efflux of intracellular contents such as potassium, phos-
phorus, and uric acid into the bloodstream. The most
widely used diagnostic criteria are listed in Table 1, first
proposed by Cairo and colleagues.60 It should be noted
that hyperkalemia is typically the earliest laboratory
manifestation of TLS and that the syndrome can occur
without the presence of clinically evident features.
When clinical features such as oliguric AKI occur, it can
further contribute to hyperkalemia.
Management of Hyperkalemia. The approach to hyper-
kalemia management in patients with cancer is similar
to that in the general population. Hospitalized patients
with significant hyperkalemia should undergo electro-
cardiogram evaluation to risk stratify and identify pa-
tients who require emergency interventions to correct
hyperkalemia.61 Emergency management includes car-
diac protection, including intravenous calcium. Measures
to promote potassium uptake into cells, including intra-
venous insulin, dextrose solution, and beta-2 adrenergic
agents, should be considered. In cases where renal func-
tion is preserved or in instances of nonoliguric renal
injury, loop diuretics may enhance the elimination of po-
tassium. The use of GI cation exchangers, such as pa-
tiromer, or sodium zirconium cyclosilicate, can also be
considered. Finally, dialysis can be considered depending

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178 Ratanasrimetha et al
on the acuity, magnitude, and anticipated response to the
previously listed interventions or refractory cases.
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