AKDH

Potassium Homeostasis
Niraj B. Desai and Melanie P. Hoenig

Potassium homeostasis is essential for maintaining the normal resting membrane potential of excitable cells. Yet daily dietary
potassium typically far exceeds total extracellular potassium, thus the body has elegant strategies to shift potassium into cells
promptly after a meal and then the kidneys efficiently excrete potassium. Potassium excretion depends on adequate kidney
perfusion and filtration, sodium delivery to the distal nephron and aldosterone action on the distal nephron. Both hypokalemia
and hyperkalemia have been associated with an increase in mortality. In this piece, we share 5 challenging cases to explore
normal potassium homeostasis and disorders that can lead to derangements in potassium balance or excretion.
Q 2024 by the National Kidney Foundation, Inc. All rights are reserved, including those for text and data mining, AI training, and
similar technologies.
Key Words: Cellular shift, Hyperkalemia, Hypokalemia, Potassium, Type IV RTA

P otassium is the major intracellular cation and the

difference between the concentration of K1 within cells
and the extracellular fluid plays a key role in the resting
What is the next best step in treating this patient’s hyper-
kalemia?
A. Sodium zirconium cyclosilicate 10 g once by
membrane potential of excitable cells. Dietary potassium mouth
far exceeds the total extracellular potassium, but after a B. Insulin infusion
meal, potassium promptly shifts into cells until the potas- C. Sodium bicarbonate infusion
sium can be excreted by the kidneys. Potassium excretion D. Initiation of CRRT
depends on ample kidney function, adequate distal deliv- E. 0.9% saline infusion
ery, and aldosterone action on the distal nephron. Both hy-
pokalemia and hyperkalemia have been associated with an The correct answer is B.
increase in mortality. The following 5 cases explore normal
potassium homeostasis and the processes that can go awry. Total body potassium (K1) balance is achieved by match-
ing dietary K1 intake primarily with renal (90%) and some
intestinal excretion. Average dietary potassium intake in
CASE 1 adults is approximately 60-80 mEq/d. Of the total body
A 78-year-old man with end-stage kidney disease (ESKD) K1 content, only 2% is found in the extracellular fluid, re-
on thrice weekly hemodialysis, insulin-dependent dia- sulting in a typical plasma K1 concentration ranging be-
betes and hypertension presents to the emergency depart- tween 3.5 and 5.3 mEq/L.1 Plasma K1 levels are
ment with fever, muscle weakness, right foot tenderness normally maintained in this narrow range initially by ex-
and erythema, headache, and lethargy. His last dialysis trarenal potassium homeostasis and the subsequent excre-
treatment was 2 days ago. His blood pressure is 110/ tion by the kidneys.
50 mmHg and pulse is 88 beats/min. At the cellular level, Na1/K1 ATPase activity promotes
Laboratory evaluation shows plasma sodium 126 mEq/ asymmetric distribution of potassium between intracel-
L, potassium 6.7 mEq/L, chloride 87mEq/L, total CO2 13 lular and extracellular compartments and in part, helps
mEq/L, BUN 18 mg/dL, creatinine 3.1 mg/dL, phosphorus to maintain the resting membrane potential. Na1/K1
4.2 mg/dL, calcium 9.1 mg/dL, and plasma glucose ATPase activity is regulated by multiple hormones, pri-
780 mg/dL. Arterial blood gas shows pH 7.3, PCO2 27. marily, insulin, catecholamines and to a lesser extent, min-
EKG shows a prolonged PR interval, prolonged QRS dura- eralocorticoids. Postprandial release or exogenous
tion, and ST depression. The emergency room physician administration of insulin, independent of its effect on
ordered 1 g intravenous calcium gluconate. cellular glucose uptake, stimulates Na1/K1 ATPase activ-
ity which facilitates transfer of Na1 out of cells and K1 into
cells in a 3:2 ratio.2
Hyperglycemia-induced hyperosmolality results in a
From the Division of Nephrology and Hypertension, Case Western Reserve
shift of potassium out of cells into the extracellular fluid
University School of Medicine, Cleveland, OH (N.B.D.); and Division of
Nephrology, Beth Israel Deaconess Medical Center, Harvard Medical School,
(Fig 1). Normally, endogenous insulin release moderates
Boston, MA (M.P.H.). this potassium shift, blunting a rise in serum glucose level
Financial Disclosure: The authors would like to thank The Burton Rose and facilitating potassium entry into cells. Moreover, in
Foundation for its generous educational grant to support the subscription to the setting of normal kidney function, patients with se-
Biorender.com vere hyperglycemia undergo glucose-driven osmotic
Address correspondence to Melanie P. Hoenig, MD, Beth Israel Deaconess diuresis, promoting urinary K1 loss by way of increased
Medical Center, 171 Pilgrim Road, Boston, MA 02215. E-mail: mhoenig@ tubular flow. However, in diabetic patients with ESKD,
bidmc.harvard.edu this stopgap does not occur, allowing hyperglycemia to
Ó 2024 by the National Kidney Foundation, Inc. All rights are reserved, worsen unchecked. Consequently, severe hyperglycemia
including those for text and data mining, AI training, and similar technologies.
significantly increases plasma osmolality with every
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180 mg/dL of plasma glucose contributing to an

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 Potassium Homeostasis 505

approximate 10 mOsm/dL rise in the osmolality.3 This Her father and older brother both take multiple antihy-
leads to movement of water from the intracellular space pertensive medications.
to the extracellular space. Cellular water loss results in Laboratory evaluation shows plasma sodium 141 mEq/
an increase in intracellular [K1], favoring K1 extrusion L, potassium 3.5 mEq/L, magnesium 2.1 mg/dL, calcium
(Fig 1). Additionally, water movement carries K1 with 8.8 mg/dL, bicarbonate 31 mEq/L, and creatinine
it, via solvent drag, through water channels in cell mem- 0.9 mg/dL.
branes, resulting in K1 movement into the extracellular Plasma renin activity was 0.9 ng/mL/h and serum aldo-
fluid.2 Generally, for every 10 mOsm/kg rise in plasma sterone level was 3 ng/dL and 4 ng/dL on subsequent visit
osmolality, K1 concentration increases by 0.3-0.8 mEq/ (reference range: 0.3-2.5 and # 10, respectively). The
L.4 Infusion of hypertonic solutions, including hypertonic serum cortisol level at 8 am was 12.5 mcg/dL, a 24-h urine
saline and mannitol, can also induce hyperosmolality, cortisol and cortisone level are normal (30.2 mg/24 h and
causing similar effects on K1 translocation. 118 mg/24 h, respectively) and 24-h urine potassium is 64
For this patient with severe hyperglycemia and hy- mEq/24 h.
perosmolality, insulin infusion is the best next step in A computed tomography scan showed normal sized kid-
managing the attendant hyperkalemia. Its effect is neys bilaterally and a left-sided 0.8-cm adrenal adenoma.
quick, readily available, and directly addresses the
pathophysiology underlying this patient’s electrolyte What is the most likely reason for hypokalemia and hy-
abnormalities. Insulin will stimulate cellular uptake of pertension in this patient?
glucose and reverse the osmolar forces promoting wa- A. Fibromuscular dysplasia of renal arteries
ter and potassium out B. Inhibition of 11-beta–hy-
of cells while directly droxysteroid dehydroge-
CLINICAL SUMMARY
stimulating Na1/K1 nase enzyme type 2
ATPase activity, allow- C. Genetic mutation of WNK-
 Potassium excretion depends on adequate kidney
ing for rapid intracel- 4, a serine/threonine kinase
perfusion and filtration, sodium delivery to the distal
lular buffering of D. Gain of function mutation of
nephron and aldosterone action.
serum K1.5 It will also the epithelial sodium chan-
improve the serum so-  When hypokalemia is present in the setting of low blood nel in the distal nephron
dium. Patients with se- pressure, the cause typically relates to body fluid losses E. Unilateral aldosterone pro-
vere hyperglycemia that include potassium, whereas when hypokalemia is ducing adenoma
associated with hypertension, action at the principal cells
with acute kidney
injury rather than
should be suspected. The correct answer is D.
ESKD, may develop hy-  Hyperkalemia is common in CKD, but when this occurs out of
pokalemia after treat- proportion to reduced kidney function, relative or functional This young patient has hypo-
ment because of aldosterone deficiency may play an important role. kalemia with urinary potassium
urinary potassium los- wasting, elevated serum bicar-
ses earlier in the clinical bonate, and uncontrolled hy-
course coincident with glycosuria. In contrast, in those pertension. This constellation is
with ESKD, insulin-induced resolution of hyperglyce- suggestive of a mineralocorticoid effect, yet the serum
mia and hyperosmolarity improves hyperkalemia but aldosterone is low. When screening for primary hyperal-
subsequent hypokalemia is uncommon. dosteronism, it is important to recognize that circulating
aldosterone levels can fluctuate but a value below 5 ng/dL
is generally considered a negative screening test.6 Here,
Key Reference
since the clinical syndrome suggests aldosterone excess
 Tzamaloukas AH, Ing TS, Siamopoulos KC, et al. Path-
but the aldosterone is suppressed, the presentation is
ophysiology and management of fluid and electrolyte
consistent with another cause or an “apparent mineralo-
disturbances in patients on chronic dialysis with se-
corticoid effect.” Apparent mineralocorticoid effect can
vere hyperglycemia. Semin Dial. 2008; 21(5):431-9.
be seen with deficiency or inhibition of 11b-hydroxyste-
https://doi.org/10.1111/j.1525-139X.2008.00464.x.
roid dehydrogenase, the enzyme that converts cortisol to
cortisone and normally prevents cortisol action on the
CASE 2 mineralocorticoid receptor.7 Glycyrrhizic acid, which is
A 21-year-old woman is referred for uncontrolled hyper- found in licorice, and several azole based antifungal
tension. Home blood pressure readings average agents (posaconazole and itraconazole but not flucona-
150/70 mmHg despite lifestyle interventions, dietary salt zole) can inhibit this enzyme, leading to high 24-h urine-
restriction, and pharmacologic therapy with amlodipine free cortisol–to–cortisone ratio. This patient had normal
10 mg daily, clonidine 0.2 mg thrice daily, and chlorthali- 24-h urine cortisone and cortisol levels which excludes
done 25 mg daily. She reports a history of lip and tongue this diagnosis.
swelling with lisinopril. Other medications include potas- This patient has early onset hypertension and a strong
sium chloride 40 mEq daily and fluconazole 300 mg family history of a significant hypertension. Taken
weekly for onychomycosis. together, the most likely diagnosis is Liddle Syndrome, a

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506 Desai and Hoenig

Figure 1. The effect of severe hyperglycemia on [K1]. In the setting of severe hyperglycemia associated with insulin resistance
or deficiency, water moves out of cells because of the osmotic gradient. Potassium leading to an increase in intracellular [K1]
which favors K1 movement out of the cells. When insulin is given (not shown), glucose can move into cells via the GLUT-4
transporter and water can return to cells. In addition, insulin activates the Na1/K1 ATPase activity which promotes movement
of K1 into cells against its electrochemical gradient. Created with BioRender.com. (For interpretation of the references to color
in this figure legend, the reader is referred to the Web version of this article.)

condition attributed to a gain of function mutation of the Sodium uptake via ENaC increases luminal negative
epithelial sodium channel (ENaC) in the distal nephron charge which is then counterbalanced by secretion of po-
(Fig 2). tassium into the tubular lumen via renal outer medullary
ENaC is a cation selective ion channel that is highly ex- potassium channel and maxi-K channels in the principal
pressed in the aldosterone-sensitive distal nephron cells and hydrogen ions by neighboring intercalated cells,
(ASDN). The ASDN includes the late portion of the distal accounting for the attendant hypokalemia and alkalemia
convoluted tubule, the connecting tubules, and collecting that may be seen in this condition.9
ducts. In the ASDN, electrogenic reabsorption of Na1 is Diagnosis of Liddle syndrome can be difficult, even in
coupled with K1 and H1 secretion through multiple apical the presence of the classic triad of early onset hyperten-
transporters and channels. The presence of aldosterone en- sion, alkalosis, and hypokalemia. Renin and aldosterone
hances sodium transport via ENaC by increasing transla- levels are suppressed. Family history is helpful, but there
tion and transcription of ENaC subunits, enhancing is variable penetrance and thus variable phenotype among
ENaC channel density on apical cell surfaces and promot- affected kindreds. Sporadic cases have also been
ing factors that increase the probability of keeping ENaC described.10 Genetic testing can provide confirmation of
channels open.8 a Liddle Syndrome diagnosis.
Liddle syndrome is a rare, autosomal dominant heredi- Treatment consists of dietary sodium restriction and
tary disorder characterized by a gain-of-function mutation direct ENaC blockade by potassium sparing diuretics
in genes that code for subunits of ENaC. These mutations such as amiloride or triamterene. Mineralocorticoid recep-
result in an inability to downregulate the number of apical tor antagonists are not effective.
channels in the absence of aldosterone and permit ENaC to Familial syndromes of hypertension have also been
remain in the open configuration.8 described with mutation of WNK-4, a serine/threonine ki-
The primary clinical and biochemical features of Liddle nase, but these individuals have hyperkalemia not hypo-
syndrome include early-onset hypertension and hypokale- kalemia.
mic metabolic alkalosis. Liddle syndrome pathophysi- Table 1 features hypertensive disorders that are associ-
ology is driven by the overactivity of ENaC, resulting in ated with hypokalemia.
unregulated distal tubular sodium reabsorption from the
tubular filtrate, expanded intravascular volume, and Key References
consequent arterial hypertension. Accordingly, plasma  Enslow BT, Stockand JD, Berman JM. Liddle’s syndrome
renin activity and aldosterone production are suppressed.9 mechanisms, diagnosis and management. Integr Blood

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 Potassium Homeostasis 507

Figure 2. The aldosterone sensitive distal nephron plays a key role in potassium secretion. Distal convoluted tubule (DCT)
cells play a role in potassium excretion by sensing the [K1] via the basolateral potassium channel Kir4/Kir5 heterodimer
(top cell). When extracellular potassium is low, this leads to an intracellular cascade that activates the sodium chloride co-
transporter (NCC) and limits distal delivery of sodium. In contrast, if extracellular potassium is increased, this leads to inhi-
bition of NCC to promote distal delivery. Aldosterone increases the number and activity of the Epithelial sodium channel
(ENaC) in the late DCT and in the principal cells in the connecting tubule (CT) and collecting duct (CD). Action of ENaC leads
to a lumen negative gradient which favors loss of K1 from renal outer medullary potassium (ROMK) and maxi-K channels in
the principal cells and H1 from the neighboring cells alpha intercalated cells. Created with BioRender.com. (For interpretation
of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Press Control. 2019; 12:13-22. https://doi.org/10.2147/ Laboratory data are notable for a leukocyte count of
IBPC.S188869. 3200 3 109/L, hemoglobin 11.8 g/dL, and platelet count
 Palmer BF. A physiologic-based approach to the evalua- 125,000 3 109/L. Sodium is 134 mEq/L, potassium 2.9
tion of a patient with hypokalemia. Am J Kidney Dis. Dec mEq/L, chloride 104 mEq/L, total CO2 18 mEq/L, BUN
2010; 56(6):1184-90. doi:10.1053/j.ajkd.2010.07.010. 24 mg/dL, and creatinine 1.9 mg/dL. Arterial blood gas
 Vaidya A, Carey RM. Evolution of the Primary Aldoste- shows pH 7.32 and pCO2 36. ALT is 83 IU/L and AST is
ronism Syndrome: Updating the Approach. J Clin Endo- 74 IU/L, total bilirubin is 6 mg/dL, with direct bilirubin
crinol Metab. Dec 01 2020; 105(12):3771-83. https://doi. level of 4.9 mg/dL. On urinalysis, pH is 6, 21 leukocyte
org/10.1210/clinem/dgaa606. esterase, negative nitrates, 11 heme, and 21 protein.
Urine microscopy shows a white blood cell cast and
several white and red blood cells. Random urine sodium
CASE 3 is 25 mEq/L, potassium 29 mEq/L, chloride 49 mEq/L,
A 38-year-old man presents with malaise and fever. He has and creatinine 102 mg/dL.
been generally healthy and takes no medications. Three
weeks ago, he traveled to South America and reported What is the most likely cause of hypokalemia in this pa-
bicycling through a pool of stagnant water which sprayed tient?
over his face and body. One week ago, he began to feel A. Infectious diarrhea
poorly, with fever, nausea, abdominal discomfort, and my- B. Decreased intake
algias. He reports that he vomited once and that bowel C. Vomiting
movements have been soft but formed. On examination, D. Interstitial nephritis
his temperature is 38.9 C, heart rate 102 beats/minute E. Cellular shift
and blood pressure 104/65 mmHg. He appears ill and
sclera is icteric. He has clear lungs, and the abdomen is
soft. There is no lower extremity edema. The correct answer is D.

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 508
Table 1. Hypertension With Hypokalemia and Metabolic Alkalosis
Features Diagnosis Treatment
Elevated renin and elevated aldosterone level
Renovascular hypertension Negative family history, acute Duplex doppler ultrasound, CT RASi, antihypertensive therapy,
rise in creatinine after RASi, angiography, Magnetic percutaneous angioplasty
renal size asymmetry, flash resonance angiography with or without stent
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pulmonary edema placement

Reninoma Young age of presentation, 2:1 Solid low density renal cortical Surgical resection
female-to-male mass on CT or MRI
predominance
Low renin and elevated aldosterone level
Primary hyperaldosteronism Subtypes: aldosterone Elevated PAC/PRA . 20, 24-h Mineralocorticoid receptor
producing adenoma, bilateral urine aldosterone level after antagonist
adrenal hyperplasia, or salt loading, Adrenal CT scan, Surgical removal of adenoma or
adrenal carcinoma adrenal vein sampling carcinoma
Glucocorticoid remediable Autosomal dominant, young CYP11B1/CYP11B2 chimeric Glucocorticoids or
hyperaldosteronism age of onset, early age stroke, gene mineralocorticoid receptor
ACTH sensitive aldosterone antagonist
production
Low renin and low aldosterone level

Desai and Hoenig

Liddle syndrome Autosomal dominant, gain of mutations of ENaC subunit ENaC blockade
function mutation in ENaC genes: SCNN1A, SCNN1B,
SCNN1G
Geller syndrome Autosomal dominant, gain of mutation of NR3C2 gene ENaC blockade
function mutation of the MR,
paradoxical activation of MR
by progesterone
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Syndromes of apparent mineralocorticoid excess (AME):

Inhibition of 11 b-HSDH2 Ingestion of glycyrrhizic acid Ingestion and medication Discontinue offending agents
(licorice, chewing tobacco) history
Posaconazole, Itraconazole
Deficiency of 11b-HSDH2 Autosomal recessive, Mutation in HSDH-11 B2 gene, Mineralocorticoid receptor
Childhood disease with low chromosome 16 antagonist, ENaC blockade,
birth weight, failure to thrive, high ratio of 24-h urine-free dexamethasone, kidney
hypercalciuria, cortisol to cortisone (normal transplant
nephrocalcinosis, ,0.5), suppressed ACTH
Cushing Syndrome and High cortisol level, Cushingoid Salivary cortisol level Treatment for underlying
ectopic ACTH syndrome features Dexamethasone suppression condition, Mineralocorticoid
test receptor antagonist,
ACTH level Ketoconazole
Markedly elevated 24-h urine
free cortisol
Congenital adrenal Autosomal recessive, Mutation in CYP11B1 or CYP17 Glucocorticoid replacement
hyperplasia Deficiency of 11b-HSD2 or
17a-hydroxylase, Virilization,
ambiguous genitalia, primary
amenorrhea

Abbreviations: 11b-HSD2, 11 b-hydroxysteroid dehydrogenase type 2; ACTH, adrenocorticotropic hormone; MR, mineralocorticoid receptor; PAC/PRA, plasma aldosterone con-
centration/plasma renin activity; RASi, renin angiotensin system inhibitors.
 Potassium Homeostasis 509

Figure 3. Approach to hypokalemia. In most instances, the cause of hypokalemia is evident from the clinical history, but it is
helpful to have a framework to approach this issue. After excluding dietary syndromes with extremely low intake and intra-
cellular shift, hypokalemia can be approached by considering whether hypertension is present. In setting of hypertension,
further consideration of the renin-angiotensin II-aldosterone axis is appropriate (see Table 1 for details). If hypertension is
not present, then the urine potassium creatinine ratio can help determine whether there are GI (diarrhea or laxative use) or
renal losses (Convert urine K1 in mmol/L and urine creatinine in mg/dl: Kurine X 1000/Crurine X 88). GI, gastrointestinal. Created
with BioRender.com. (For interpretation of the references to color in this figure legend, the reader is referred to the Web
version of this article.)

This patient has a systemic illness characterized by fever, bulointerstitial nephritis, and tubular dysfunction.
malaise, and gastrointestinal symptoms along with hepat- Although acute kidney injury is typically associated with
ic involvement given the icteric sclera and a hepatocellular hyperkalemia, hypokalemia is a common manifestation
pattern of injury on bloodwork. of tubulointerstitial nephritis from leptospiral infection
Laboratory data shows a nonanion gap metabolic and an important diagnostic clue in this case.
acidosis with appropriate respiratory compensation, hy- Injury to various segments of the nephron have been
pokalemia, and abnormal kidney function which, in the implicated in the pathogenesis of urinary K1 wasting in
absence of additional data, represents acute kidney injury. leptospiral infection including proximal tubulopathy
There is also pyuria and white blood cell casts. The urine with associated glycosuria or dysfunction of the Na1-
anion gap (Naurine 1 Kurine – Clurine) is 5 mEq/L, which sug- K1-Cl22 cotransporter (NKCC) in the thick ascending
gests decreased urinary ability to excrete ammonium (in a limb of the loop of Henle.15
nonanion gap metabolic acidosis, if renal tubular function When hypokalemia is present in the setting of low blood
is normal, the urine anion gap should be negative to reflect pressure, the cause of hypokalemia typically relates to
excretion of the unmeasured ammonium, excreted with body fluid losses that include potassium (Fig 3). The next
chloride).11 The urine potassium to creatinine ratio is step is to determine whether the potassium loss is of renal
3.2 mmol/mmol (Kurine X 1000/Crurine X 88), consistent or extrarenal origin. Normally, when the serum potassium
with renal potassium wasting (see below).12 is low, urinary potassium excretion is significantly
Taken together, the clinical syndrome is likely related to decreased. Although the kidney’s ability to limit potas-
leptospirosis, a zoonotic infection that can affect humans sium loss is not as robust as the ability to limit sodium
as accidental hosts. Although most of the global disease excretion, total urinary potassium excretion can still
burden relates to occupational exposure, there have also decrease to , 15 mmol/day.16
been many reports of infection during athletic endeavors Urinary potassium loss can be assessed by measuring the
such as a triathlon and other adventures both in domestic urinary potassium concentration on a random urine specimen
and tropical or remote destinations.13,14 Kidney involve- or from a 24-hour urine collection, though the latter is signifi-
ment in leptospirosis may range from a small increase in cantly more challenging and most appropriate for a chronic
serum creatinine to severe oliguric acute kidney injury, tu- situation. The appropriateness of urine potassium excretion

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510 Desai and Hoenig

relative to plasma potassium concentration can be assessed by Laboratory data are notable for hemoglobin 10.6 g/dL, so-
several strategies including the fractional excretion of potas- dium 133 mEq/L, potassium 2.2 mEq/L, chloride 101 mEq/
sium and the transtubular gradient. Currently, the most pop- L, total CO2 20 mEq/L, blood urea nitrogen 12 mg/dL, and
ular strategy is the urine potassium to creatinine ratio. When creatinine 0.5 mg/dL. Serum albumin is 3 g/dL. Urine
the ratio is . 2.5 mmol/mmol, renal potassium wasting is chemistry includes a sodium of 15 mEq/L, potassium 17
likely, whereas a value of ,2.5 mmol/mmol suggests renal mEq/L, chloride 40 mEq/L, and creatinine 112 mg/dL.
conservation of potassium.12,17,18
Urinary potassium excretion is dependent on the presence What is the most likely cause of hypokalemia in this pa-
of aldosterone, and distal tubule urinary flow rate and sodium tient?
delivery. In this case, renal potassium loss has occurred in A. Intracellular shift
setting of leptospirosis tubulointerstitial nephritis and tubular B. Stool losses
injury that affects distal tubular sodium delivery. Significantly C. Inadequate intake
more common causes of renal potassium loss include use of D. Pseudohypokalemia
loop and thiazide diuretics. In both cases, potassium loss is E. Dilutional hypokalemia
more profound if the diet is high in sodium due to significant
The correct answer is B.
distal delivery of sodium chloride. Genetic disorders of
tubular transporters that lead to Bartter and Gitelman syn-
This patient presents with chronic diarrhea and weak-
dromes are also associated with hypokalemia and metabolic
ness, the latter most likely related to severe hypokalemia.
alkalosis. When diabetes mellitus is poorly controlled, the
She has evidence of a chronic illness with a low body
ensuing osmotic diuresis is associated with significant potas-
mass index, anemia, and low serum albumin. She reports
sium loss and potassium depletion. Patients who have dia-
that symptoms may be exacerbated by intake of carbohy-
betic ketoacidosis may lose potassium with urinary ketones,
drates. Taken together, this may be related to celiac dis-
the latter as a “nonreabsorbable anion.” In the setting of
ease, but further investigation is warranted.
chronic vomiting, the ensuing metabolic alkalosis can lead
to urinary loss of potassium with bicarbonate serving as the In addition to hypokalemia, her serum chemistry is notable
for a low serum bicarbonate without an anion gap, this likely
“nonreabsorbable anion.” Proximal renal tubular acidosis
represents a metabolic acidosis consistent with diarrheal los-
(RTA) (type II) or proximal tubulopathy and the classic distal
(or type I) RTA are also associated with hypokalemia from ses. The urine K1/Cr ratio is 1.7 mmol/mmol (,2.5 suggests
renal conservation of potassium). Low potassium intake is
renal losses. Finally, hypomagnesemia can contribute to renal
an uncommon cause of hypokalemia without concomitant
potassium loss, particularly in states of increased distal
losses or significant distal delivery of sodium (as with infusion
tubular sodium delivery and increased mineralocorticoid ac-
of crystalloid without potassium). Shift of potassium out of
tivity. Normally, magnesium binds to a cytosolic component
skeletal muscle cells occurs in the setting of metabolic acidosis.
of the apical potassium channel responsible for voltage-
There is no direct H1-K1 exchange, but rather, functional
dependent K1 secretion and limits K1 secretion (Fig 2).19
coupling that leads to K1 movement out of cells and H1
Key References into cells,20 so treatment of the acidosis may identify even
 Clase CM, Carrero JJ, Ellison DH, et al. Potassium ho- more severe hypokalemia; this is particularly common in
meostasis and management of dyskalemia in kidney dis- the setting of diabetic ketoacidosis.
eases: conclusions from a Kidney Disease: Improving Of note, although pseudohyperkalemia is frequently
Global Outcomes (KDIGO) Controversies Conference. encountered because of mechanical trauma during veni-
Kidney Int. Jan 2020; 97(1):42-61. https://doi.org/10. puncture and in certain hematologic conditions, spurious
1016/j.kint.2019.09.018. hypokalemia is rare (though it has also been described
 Chancharoenthana W, Leelahavanichkul A, Schultz MJ, with myeloproliferative disorders when severe leukocy-
Dondorp AM. Going Micro in Leptospirosis Kidney Dis- tosis leads to intracellular shift of K1). The term dilutional
ease. Cells. Feb 16 2022; 11(4) https://doi.org/10.3390/ hyponatremia has been used to describe hypotonic hypo-
cells11040698. natremia but a parallel effect on hypokalemia is not
observed since movement of water into cells in hyponatre-
CASE 4 mia, is in part, counterbalanced by potassium movement
An 18-year-old girl presents with weakness of her lower out of cells to achieve a volume regulatory decrease.21
limbs. The weakness does not correlate with exercise or Significant gastrointestinal losses of potassium can occur
carbohydrate-rich meals, but the latter leads to bloating from decreased intestinal transit time and resultant
and abdominal discomfort. She has not vomited but decreased absorption. Infectious diarrhea, both secretory
does have frequent painless, watery, nongreasy mixed and exudative types, can lead to potassium losses. Simi-
loose stools. On physical examination, her blood pressure larly, osmotic diarrhea whether from a laxative, lactulose
is 98/60 mmHg, heart rate 98 beats/minute, and body mass or pancreatic insufficiency can lead to losses. Further,
index 17 kg/m2. Her oropharynx is clear with normal exudative diarrheal illnesses from compromised intestinal
dentition. Her abdomen is soft. Motor strength is only 4/ barrier such as celiac disease can cause hypokalemia.
5 for hip flexors but normal for ankle dorsiflexion and Rarely, this is so severe that “celiac crisis” can present
plantar flexion. Sensation is normal. ECG features diffuse with hypokalemia paralysis.22,23 Finally, several uncom-
T wave flattening. mon tumors including villous adenoma, medullary

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 Potassium Homeostasis 511

Figure 4. Approach to hyperkalemia. Hyperkalemia may occur because of preanalytic errors related to phlebotomy or spec-
imen handling. If this is excluded, then hyperkalemia may be from release or shift from cells or related to decreased excretion.
Created with BioRender.com. (For interpretation of the references to color in this figure legend, the reader is referred to the
Web version of this article.)

carcinoma, gastrinoma, and carcinoid syndrome can pro- but unremarkable urine sediment. Urine albumin-to-
duce diarrhea by stimulating colonic secretion. creatinine ratio is 2600 mg/g. Serologic workup is unre-
markable.
Key Reference
What is the next best step in management of this patient’s
 Palmer BF, Clegg DJ. Physiology and Pathophysiology
hyperkalemia?
of Potassium Homeostasis: Core Curriculum 2019. Am
A. Start fludrocortisone 0.1 mg daily
J Kidney Dis. 11 2019; 74(5):682-695. https://doi.org/10.
B. Prescribe sodium bicarbonate 650 mg twice daily
1053/j.ajkd.2019.03.427. C. Stop celecoxib
D. Hold carvedilol
CASE 5 E. Begin patiromer 8.4 g daily
A 72-year-old woman is seen in consultation for stage 3a CKD
The correct answer is C.
and hyperkalemia. She has a longstanding type 2 diabetes
mellitus, hypertension, hyperlipidemia, osteoarthritis, dia- This patient has a high serum [K1] and relatively low
betic retinopathy, and peripheral arterial disease. serum bicarbonate (which may represent a metabolic
Current medications include carvedilol 12.5 mg twice acidosis) in the setting of several chronic conditions
daily, amlodipine 10 mg daily, dapagliflozin 10 mg daily, including CKD and multiple medications. Certainly, hy-
atorvastatin 20 mg daily, and celecoxib 200 mg daily. perkalemia is common in CKD but when this issue occurs
Blood pressure is 130/78 mmHg in both arms, pulse rate out of proportion to the reduction in kidney function, rela-
72 beats/minute, and respiratory rate is 14 breaths/minute. tive or functional aldosterone deficiency may play an
Cardiac examination is normal. There is no elevation in ju- important role (Fig 4). This scenario has been called hypo-
gular venous pressure and no lower edema. reninemic hypoaldosteronism or a type 4 RTA. Type 4 RTA
Laboratory evaluation shows a plasma sodium of 140 is characterized by impaired K1 secretion; impaired H1
mEq/L, potassium 5.4 mEq/L, chloride 110 mEq/L, total may also be observed but is typically less pronounced
CO2 21 mEq/L, and creatinine 1.3 mg/dL. Estimated than the defect in K1 secretion such that the metabolic
glomerular filtration rate is 44 mL/min/1.73 m2. HgbA1c acidosis is typically very mild if present. Multiple mecha-
is 7.3%. On urinalysis, pH is 5.6 and there is 31 protein nisms have been described including either inherited or

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512 Desai and Hoenig

acquired aldosterone deficiency, impaired renin release rather than mineralocorticoid supplementation. Many of
from juxtaglomerular cells, or cortical collecting duct resis- these individuals have volume expansion and would
tance to the actions of aldosterone.24 benefit from potassium-wasting diuretics or addressing
Common forms of acquired hypoaldosteronism include medications that may contribute to hyporeninemic hypo-
long standing diabetes mellitus, angiotensin inhibition, use aldosteronism.27 This approach differs from treatment of
of potassium sparing diuretics, heparin, or nonsteroidal primary adrenal insufficiency which requires both gluco-
anti-inflammatory drugs (NSAIDs). Calcineurin inhibitors corticoid and mineralocorticoid replacement to avoid hy-
can contribute to hyperkalemia by several potential effects potension and sodium losses.
on the distal nephron including activation of the sodium chlo- In addition to the decreased H1 excretion, the mild non-
ride cotransporter in thiazide sensitive cells and inhibition of anion gap metabolic acidosis often seen in hypoaldoster-
renal outer medullary potassium channel and the Na1/K1 onism relates to increased serum potassium
ATPase in aldosterone sensitive cells. The trimethoprim concentration. Hyperkalemia decreases proximal tubular
component of trimethoprim/sulfamethoxazole and pentami- ammonia synthesis, affects ammonia reabsorption in the
dine are structurally similar to triamterene and can competi- thick ascending limb of the loop of Henle, and impairs
tively inhibit ENaC and cause hyperkalemia in patients excretion of ammonium into the collecting duct. The net
with reduced glomerular filtration. For this patient, the most result is abnormal urinary ammonium excretion and a
likely cause of hyperkalemia, mild acidemia and elevated metabolic acidosis.28
serum creatinine, is celecoxib, an NSAID that selectively in-
hibits cyclooxygenase-2. Cyclooxygenase enzymes catalyze Key References
the conversion of arachidonic acid to prostaglandin H2, the  Harris AN, Grimm PR, Lee HW, et al. Mechanism of
precursor to prostacyclin and prostaglandins which affect Hyperkalemia-Induced Metabolic Acidosis. J Am Soc
both vascular and tubular function in the kidney. Irrespective Nephrol. May 2018; 29(5):1411-1425. https://doi.org/10.
of cyclooxygenase isoform specificity, NSAIDs inhibit local 1681/ASN.2017111163.
production of prostaglandins that maintain afferent arteriolar  Palmer BF, Kelepouris E, Clegg DJ. Renal Tubular
vasodilatation, of particular importance in patients with Acidosis and Management Strategies: A Narrative Re-
chronic kidney disease, heart failure, cirrhosis, or in patients view. Adv Ther. Feb 2021; 38(2):949-968. https://doi.
using diuretics.25 This effect, compounded by the afferent arte- org/10.1007/s12325-020-01587-5.
riolar vasoconstriction mediated by SGLT2 inhibitor induced
tubuloglomerular feedback, can contribute to a decreased
SUMMARY
glomerular filtration in this patient. In addition, NSAIDs
Hyperkalemia is a common clinical problem, particularly
impair prostaglandin-mediated renin release from the macula
in patients with CKD. Presence of hyperkalemia increses
densa, reducing production of angiotensin II which is a major the risk of complications such as cardiac arrythmias and
stimulus for adrenal aldosterone release (hyporeninemic hy-
can increase the risk of mortality. Understanding the path-
poaldosteronism).25 For this patient, prior to considering
ophysiology of hyperkalemia is important in determining
additional pharmacologic therapy, celecoxib should be dis- the correct approach to management.
continued.
Urinary potassium excretion is dependent on sodium de-
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