Clinical Review & Education

JAMA Diagnostic Test Interpretation

Evaluation of Hypokalemia
Morgan E. Grams, MD, PhD; Melanie P. Hoenig, MD; Ewout J. Hoorn, MD, PhD

A 52-year-old woman presented to an outpatient clinic with palpitations and was found
to have hypokalemia (Table). She was diagnosed with hypertension at age 40 years, at which WHAT WOULD YOU DO NEXT?
time a thiazide diuretic was prescribed. However, at age 49 years, the patient was hospi-
talized for palpitations and found to have a serum potassium level of 2.6 mEq/L, and the A. Normalize serum potassium and
diuretic was discontinued. At the current outpatient visit, her blood pressure was 159/94 test plasma aldosterone-renin
mm Hg; other physical examination findings were unremarkable. She had no recent his- ratio (ARR)
tory of gastrointestinal symptoms and no longer used any antihypertensive medications.
B. Obtain a computed tomography
Table. Patient’s Blood and Urine Laboratory Results on Presentation
scan of the abdomen
Test Patient’s value Reference range
Blood
C. Prescribe spironolactone
Sodium, mEq/L 142 136-145
Potassium, mEq/L 3.2 3.5-5.0
D. Screen for surreptitious
Magnesium, mEq/L 2.07 1.70-2.55
diuretic use
Total CO2, mEq/L 26.6 21.0-27.0
Blood urea nitrogen, mg/dL 9.5 6-20
Creatinine, mg/dL 0.76 0.60-1.10 Quiz at jamacmelookup.com
Estimated glomerular filtration rate, mL/min/1.73 m2 93 >60
Glucose, mg/dL 95.5 60-99
Hemoglobin, g/dL 14.2 12-16
Urine
Potassium, mEq/L 24 Varies
Creatinine, mg/dL 45 Varies

SI conversion factors: To convert urea nitrogen to mmol/L, multiply values by 0.357; serum creatinine
to μmol/L, multiply by 76.25; and glucose to mmol/L, multiply by 0.0555.

Answer
A. Normalize serum potassium and test plasma ARR.
Test Characteristics
Hypokalemia, defined as a serum potassium concentration less than
3.5 mEq/L, is detected in 2% to 3% of outpatient encounters.1 In con-
trast with hyperkalemia, in which potassium levels can be falsely el-
evated in a variety of settings, a falsely low potassium level, or pseu-
dohypokalemia, is uncommon and usually due to prolonged time
before specimen processing.2,3 Severe hypokalemia (serum potas-
sium<2.5mEq/L)cancausepalpitations,musclecramps,muscleweak-
ness, and paralysis. Even mild (serum potassium of 2.5-3.4 mEq/L)
asymptomatic hypokalemia has been associated with increased rates
of cardiovascular events and all-cause mortality.1
Potassium homeostasis is tightly regulated to maintain serum
potassium, intracellular potassium, and total body potassium.4 In-
gested potassium must be matched by potassium excretion, most
of which occurs in the urine. In the kidney, potassium secretion is
coupled to sodium reabsorption in the principal cells of the connect-
ing tubule and cortical collecting duct. Therefore, the primary regu-
lators of urinary potassium excretion are sodium delivery to the dis-
tal nephron and the adrenal hormone aldosterone, which facilitates
sodium-potassium exchange. In the setting of hypokalemia, the so-
dium-chloride cotransporter in the distal convoluted tubule is acti-
vated, reducing sodium delivery to the principal cells, and aldoste-
rone is suppressed, reducing sodium-potassium exchange.4
Hypokalemia may generally be categorized as urinary potas-
sium loss, stool potassium loss, or a shift of potassium into cells. Low
dietary potassium intake and loss of potassium in perspiration alone
are relatively uncommon precipitants. A careful clinical history in a
patient with hypokalemia should identify obvious etiologies, such
as gastrointestinal losses and medication use. Thiazide and loop di-
uretics are common causes of excessive urinary potassium loss. How-
ever, hypokalemia that occurs after initiation of a diuretic may also
represent primary aldosteronism, a common and manageable cause
of urinary potassium loss that is often missed in patients with hy-
pokalemia and hypertension.5,6
Other causes of hypokalemia include tubulopathies (eg, rare, in-
herited disorders of the kidney tubule, such as Bartter syndrome or
Gitelman syndrome); surreptitious vomiting or medication use; and
severe hypomagnesemia, which occurs in approximately 20% of
people using proton pump inhibitors.7,8 Urinary potassium loss as a
cause of hypokalemia is supported by a ratio of urine potassium to
urine creatinine greater than 22 mEq/g creatinine in a spot urine
sample.9 Urine sodium and urine chloride measures may distinguish
between vomiting, surreptitious diuretic or laxative use, and tubu-
lopathies (Figure).2,9,10 Calculation of the transtubular potassium gra-
dient,anestimateofpotassiumsecretion,isnolongerrecommended.9

1216 JAMA March 23/30, 2021 Volume 325, Number 12 (Reprinted) jama.com

© 2021 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a Universidad Libre de Colombia User on 09/13/2021

 JAMA Diagnostic Test Interpretation Clinical Review & Education

Patient presents with hypokalemia adrenal glands, causing sodium retention and extracellular volume ex-
Serum potassium <3.5 mEq/L pansion and, in turn, suppression of plasma renin. Laboratory tests and
standards for both aldosterone and renin vary (eg, direct renin concen-
Is there a readily identifiable cause? Yes tration,plasmareninactivity),butthethresholdforprimaryaldosteron-
Treat underlying cause;
Loop or thiazide diuretica potassium supplementation ism is generally an ARR greater than 750 pmol/L per ng/mL/h (27 ng/
Gastrointestinal losses (eg, diarrhea) as needed dL per ng/mL/h) when renin is measured as plasma renin activity.5
Use of cisplatin, amphotericin, or licorice
Potassium levels should be repleted prior to measurement of
Acute intracellular potassium shift
(eg, effect of insulin) the ARR, because hypokalemia may suppress plasma aldosterone.
No Mineralocorticoid receptor antagonists, such as spironolactone and
Are there risk factors for primary eplerenone, must be stopped 4 weeks before measuring ARR, but
aldosteronism?
Yes
Check plasma aldosterone-
angiotensin-converting enzyme inhibitors and angiotensin recep-
Hypertension renin ratio after repleting tor blockers may be continued.2 Although adrenalectomy is typi-
Diuretic therapy with resistant potassium
hypertension or recurrent hypokalemia cally recommended for unilateral adenomas, mineralocorticoid re-
No ceptor antagonists may be used to treat patients who are not
Is there urinary potassium loss? Low urine chloride and urine candidates for surgery or who have bilateral disease.
Yes sodium-chloride ratio >1.6
Check urine sodium, chloride, potassium, Evaluate for vomitingb
and creatinine Patient Outcome
Urine sodium-chloride ratio
Check serum magnesium and bicarbonate
approximately 1 After correction of the hypokalemia with oral potassium supplemen-
Urine potassium-creatinine ratio >22 mEq/g Evaluate for diuretic use
suggests urine loss tation, the patient’s ARR was greater than 1000 pmol/L per ng/mL/h.
Evaluate for tubulopathy and
No renal tubular acidosisc Anadrenalcomputedtomographyscanwithadrenalveinsamplingsug-
High urine chloride and urine Low serum magnesium gested a unilateral adenoma. She underwent a laparoscopic adrenal-
sodim-chloride ratio <0.7 Evaluate for culprit medications ectomy. Seventeen months after treatment, the patient no longer had
Evaluate for laxative use (eg, proton pump inhibitors)
palpitations. Her blood pressure was 120/75 mm Hg without antihy-
Evaluate for tubulopathy
pertensive medications, her potassium level was 4.1 mEq/L, and her
Figure. Algorithm for investigating the cause of hypokalemia. Adapted from the ARR level was 47 pmol/L per ng/mL/h (1.7 ng/dL per ng/mL/h).
algorithm presented in the study by Clase et al.2
a
Hypokalemia that is disproportionately severe for the dose of diuretic may
represent aldosterone excess.
b
Clinical Bottom Line
Metabolic alkalosis or urine pH of 7 or higher also suggests vomiting.
c
A metabolic acidosis will distinguish a renal tubular acidosis from most • The most common causes of hypokalemia are diuretic use and
other causes. gastrointestinal loss.
• Primary aldosteronism is an underrecognized cause of
hypokalemia and hypertension.6
Application of the Test Result to This Patient
• Management of hypokalemia should focus on correcting the
Because of the patient’s hypokalemia and hypertension, a workup for underlying cause and may include dietary changes, potassium
primary aldosteronism was initiated by testing the plasma aldosterone supplementation, or the use of potassium-sparing diuretics or
and renin and calculating the ARR. The ARR is elevated in primary aldo- mineralocorticoid receptor antagonists.
steronism because of unregulated aldosterone secretion by 1 or both

ARTICLE INFORMATION
Author Affiliations: Division of Nephrology,
Department of Medicine, Johns Hopkins University,
Baltimore, Maryland (Grams); Division of
Nephrology, Department of Medicine, Beth Israel
Deaconess Medical Center, Boston, Massachusetts
(Hoenig); Division of Nephrology and
Transplantation, Department of Internal Medicine,
Erasmus Medical Center, University Medical Center
Rotterdam, Rotterdam, the Netherlands (Hoorn).
Corresponding Author: Morgan E. Grams, MD,
PhD, Welch Center for Prevention, Epidemiology,
and Clinical Research, Johns Hopkins University,
2024 E Monument St, Ste 2-638, Baltimore, MD
21205 (mgrams2@jhmi.edu).
Section Editor: Mary McGrae McDermott, MD,
Deputy Editor.
Correction: This article was corrected on May 11, 2021,
to correct an error in the Figure that included acute in-
tracellular sodium shift as a potential readily identifiable
cause of hypokalemia. This was corrected to instead in-
clude acute intracellular potassium shift as a potential
readily identifiable cause of hypokalemia.
Conflict of Interest Disclosures: Dr Grams reported
receiving grants from the National Kidney Foundation
outside the submitted work and receiving funding
from the National Institute of Diabetes and Digestive
and Kidney Diseases and travel support from Dialysis
Clinic Inc to speak on risk calculators at an annual
director’s meeting in May 2019. Dr Hoorn reported
receiving grants from the Dutch Kidney Foundation
outside the submitted work. All authors reported
participating in a KDIGO meeting on potassium
management in October 2018.
Additional Contributions: We thank the patient for
granting permission to publish this information.
REFERENCES
1. Kovesdy CP, Matsushita K, Sang Y, et al; CKD
Prognosis Consortium. Serum potassium and
adverse outcomes across the range of kidney
function. Eur Heart J. 2018;39(17):1535-1542.
2. Clase CM, Carrero JJ, Ellison DH, et al;
ConferenceParticipants. Potassium homeostasis
and management of dyskalemia in kidney diseases:
conclusions from a Kidney Disease: Improving
Global Outcomes (KDIGO) Controversies
Conference. Kidney Int. 2020;97(1):42-61.
3. Sodi R, Davison AS, Holmes E, Hine TJ, Roberts NB.
The phenomenon of seasonal pseudohypokalemia:
effects of ambient temperature, plasma glucose and
role for sodium-potassium-exchanging-ATPase. Clin
Biochem. 2009;42(9):813-818.
4. Palmer BF, Clegg DJ. Physiology and
pathophysiology of potassium homeostasis. Am J
Kidney Dis. 2019;74(5):682-695.
5. Funder JW, Carey RM, Mantero F, et al. The
management of primary aldosteronism: case
detection, diagnosis, and treatment. J Clin
Endocrinol Metab. 2016;101(5):1889-1916.
6. Brown JM, Siddiqui M, Calhoun DA, et al. The
unrecognized prevalence of primary aldosteronism.
Ann Intern Med. 2020;173(1):10-20.
7. Kieboom BC, Kiefte-de Jong JC, Eijgelsheim M,
et al. Proton pump inhibitors and hypomagnesemia
in the general population: a population-based
cohort study. Am J Kidney Dis. 2015;66(5):775-782.
8. Srinutta T, Chewcharat A, Takkavatakarn K, et al.
Proton pump inhibitors and hypomagnesemia.
Medicine (Baltimore). 2019;98(44):e17788.
9. Palmer BF, Clegg DJ. The use of selected urine
chemistries in the diagnosis of kidney disorders.
Clin J Am Soc Nephrol. 2019;14(2):306-316.
10. Wu KL, Cheng CJ, Sung CC, et al. Identification
of the causes for chronic hypokalemia. Am J Med.
2017;130(7):846-855.

jama.com (Reprinted) JAMA March 23/30, 2021 Volume 325, Number 12 1217

© 2021 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a Universidad Libre de Colombia User on 09/13/2021