Review Article

A Practical and Pathophysiologic Approach to Hypokalemia

Shih-Hua Lin

Hypokalemia is not an isolated disease but an associated finding in a vast number of different diseases; it poses
a great challenge in correct diagnosis and proper management. Hypokalemia usually arises from a shift of
potassium (K +) into cells and/or a net loss of K + . Besides a detailed history and physical examination,
measurement of K+ excretion rate with freshly-voided and/or 24-hour urine and assessment of blood acid-base
status can help discriminate between the various causes of hypokalemia. In patients with a low rate of K+
excretion, hypokalemia can be due to an acute shift of K + into cells, intestinal/sweating K + loss, or prior renal
K+ excretion. In patients with a high rate of K + excretion, there may be either increased flow rate or increased
K+ secretion, seen with fast sodium (Na +) or slow chloride (Cl ) disorders, in the cortical collecting ducts
(CCD). An increased flow rate in the CCD arises from increased osmole excretion (whether solutes or
electrolytes). Patients with fast Na+ disorders have a high extracellular fluid (ECF) volume and thus high blood
pressure associated with a state of high mineralocorticoid activity. Measurement of renin activity, aldosterone,
and cortisol levels in plasma helps distinguish between the causes. Patients with slow Cl disorders usually
have low to normal ECF volume and blood pressure and are usually associated with abnormal acid-base states.
In patients with metabolic alkalosis, urine Na + and Cl excretion rate reveal the basis for renal Na+ wasting and
distinguish it from non-renal Na + loss. In patients with hyperchloremic metabolic acidosis, an assessment of
the ammonium excretion rate (NH4+) separates those with renal tubular acidosis (low NH4+ excretion) from
those with other causes. The treatment of hypokalemia depends on the degree and timing of hypokalemia,
clinical manifestations, underlying causes, and potential risks from associated conditions. [Hong Kong J Nephrol
2008;10(1):1426]

Key words: acid-base, aldosterone, ammonium, blood pressure, hypokalemia, renin, urine electrolyte

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Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei,
Taiwan.
Correspondence to: Dr. Shih-Hua Lin, Division of Nephrology, Department of Medicine, Tri-Service General Hospital,
No. 325, Section 2, Cheng-Kung Road, Taipei 114, Taiwan.
Fax: (+886) 2-87927134; E-mail: shihhualin@yahoo.com

14 Hong Kong J Nephrol April 2008 Vol 10 No 1

 Practical and pathophysiologic approach to hypokalemia

INTRODUCTION I discuss a more practical and pathophysiologic

Potassium (K+), a major intracellular cation, functions
in critically maintaining the osmotic equilibrium of the
cell and the electrical gradient across the cell membrane.
Most of the cellular K+ in the body (~50 mmol/kg, 98%)
resides primarily in the skeletal muscles (3,000 mmol),
red blood cells (300 mmol), and liver (200 mmol). In
contrast, the total K+ content in the extracellular fluid
(ECF) is very low (< 1 mmol/kg, approximately 2%)
and similar to the daily dietary K+ intake and renal
excretion of K+. Plasma K+ concentration represents a
function of total body K+ and the distribution between
intracellular fluid (ICF) and ECF stores. Hypokalemia
usually arises from redistribution of K+ from ECF to
ICF stores and/or a consequence of total body K +
depletion. The most significant effects of hypokalemia
are on the cardiovascular, neuromuscular, renal and
metabolic functions (Table 1) [16]. In addition,
hypokalemia is also associated with increased mortality,
likely due to the profound effects on arrhythmogenesis,
blood pressure, and cardiovascular morbidity.
Hypokalemia is the most common electrolyte
abnormality encountered in clinical practice. One
should understand that hypokalemia per se is not a
specific disease but an associated finding in a large
number of different diseases. The rapid identification
of its underlying causes with appropriate management
is still challenging. Although several articles about
hypokalemia have been extensively reviewed [712],
approach to hypokalemia and introduce some important
concepts in managing hypokalemia in this review.
K+ HOMEOSTASIS
K+ concentration in the ICF is close to 35-fold greater
than that in the ECF. Renal excretion in response to a
K+ load is relatively slow (approximately 50% within
the first 4 hours). To avoid retained K+ in the ECF and
the ensuing hyperkalemia, there must be sensitive
regulatory mechanisms to dampen plasma K +
concentration before complete renal K+ excretion. The
mechanisms regulating the distribution of K+ between
the ICF and ECF are known as the internal K+ balance
in contrast to the external balance of renal K+ excretion.
Derangements in either the internal balance (e.g. K+
shift) or external balance (e.g. K+ wasting) can result
in hypokalemia [13,14].
Regulation of K+ between ICF and ECF
The movement of K+ ions across cell membranes has
two requirements: (1) a driving force; (2) a K+ ion
channel in that membrane (Figure 1).
Driving force: The force driving K+ shift into cells
is the more negative voltage in cells. This is created by
Na-K-ATPase. Na-K-ATPase extrudes three sodium
ions (Na+) for every two K+ ions that enter cells, thus
producing a net export of positively charged ions [15].

Table 1. Clinical signs and symptoms of hypokalemia

Cardiovascular
ECG changes: flattened or inverted T waves, prominent U wave, depressed, prolonged QT interval
Arrhythmias: atrial tachycardia with or without block, premature ventricular contraction, ventricular tachycardia and/or fibrillation,
torsades de pointes, atrioventricular block or dissociation
Hypertension

Neurologic/neuromuscular
Neurologic: paresthesia, decreased deep tendon reflexes
Skeletal muscle: cramp, myalgia, rhabdomyolysis, weakness, paralysis
Gastrointestinal tract: reduced gastrointestinal motility (nausea, vomiting, constipation, paralytic ileus)
Genitourinary tract: hypomotility with dilatation of bladder (hypotonic bladder)

Renal
Metabolic alkalosis due to increased HCO reabsorption and ammoniagenesis in the proximal tubule, decreased urinary citrate excretion,
3
increased H+ secretion in the cortical collecting duct
Impaired medullar concentration
Renal cystic disease, interstitial scarring, and renal insufficiency
Increased renal stone formation

Metabolic
Decreased insulin release with hyperglycemia
Impaired end-organ sensitivity to insulin with carbohydrate intolerance
Inhibited aldosterone secretion, but stimulated renin secretion
Worsened hepatic encephalopathy

Hong Kong J Nephrol April 2008 Vol 10 No 1 15

S.H. Lin
Because impermeable ICF anions (macromolecular
phosphates such as RNA, DNA, phospholipids) cannot
follow the Na+ movement, a negative intracellular
voltage is generated. The main hormones that increase
the activity of Na-K-ATPase include `2-adrenergic
agonists, insulin and thyroid hormone [15,16]. Increases
in the concentration of Na+ inside cells can also activate
Na-K-ATPase. For instance, insulin stimulates a
membrane Na+/H+ exchanger (NHE) [17], thus helping
prevent hyperkalemia when K + is ingested in
carbohydrate-rich food. Metabolic alkalosis also affects
the NHE and causes K+ shift into cells.
K + channels: K + channels are a diverse and
ubiquitous family of membrane-spanning proteins that
selectively conduct K+ ions across the cell membrane
along its electrochemical gradient in both excitable and
non-excitable cells [18]. There are several different
types of K + channels. These K + channels share the
common features of a water-filled permeation pore
allowing K+ ions to flow across the cell membrane, a
selectivity filter that specifies K+ as the permeant ion
species, and a gating mechanism that serves to switch
between open and closed channel conformations [19].
Some of these channels are regulated by voltage, others
by ligands such as calcium ions (Ca2+) and metabolites
such as adenosine triphosphate (ATP). Because K+ ions
do not reach diffusion equilibrium, control of the open-
probability of K+ channel regulates the transmembrane
voltage. K+ channels are inhibited by barium and other
drugs [20]. Closure or opening of them may not only
Figure 1. K+ homeostasis: the internal balance of K+. The circle
depicts the cell membrane. Na+/K+-ATPase, NHE, and K+ channels
are three major elements controlling K+ shift. The Na+/K+-ATPase
pumping Na+ out of cells in exchange for two K + entering cells
causes a large internal negative voltage and is activated by `2-
adrenergics, insulin and thyroid hormone. Also, insulin, by
activating NHE, causes the electroneutral entry of Na+ into cells,
and thereby the net exit of positive voltage via the Na+-K+-ATPase.
K+ exiting cells through K+ channels is responsible for generating
the majority of the resting membrane potential.
16
alter the membrane potential but also acutely affect the
plasma K+ concentration.
Renal handling of K+
K+ is freely filtered in the glomerulus. Most of the
filtered K+ is reabsorbed by the proximal tubule and
the loop of Henle. The final amount of K+ excreted in
the urine is primarily controlled by the late distal
convoluted tubule, the connecting tubule, and the
cortical collecting duct (CCD) [14,21]. Two factors
influence the rate of excretion of K+: the flow rate in
the terminal CCD and the net secretion of K + by
principal cells in the CCD which raises the luminal
concentration of K+ ([K+]CCD) (Figure 2). There is an
interplay between the magnitudes of the flow rate in
the CCD and the [K+]CCD that permits the kidney to
excrete all the K+ that is ingested in steady state [22].
The flow rate in the CCD: The flow rate in the CCD
is directly proportional to the rate of excretion of
osmoles and can be expressed as the urine osmole
excretion rate divided by plasma osmolality (Uosm
volume/plasma osm) because urine osmolality in the
terminal CCD is equal to the plasma osmolality when
antidiuretic hormone (ADH) is present [23]. While the
rate of flow in the CCD is high during a water diuresis,
the rate of K+ excretion need not be elevated, even with
mineralocorticoid effects, because ADH must be
present to have high rates of K+ secretion [24]. Using
spot urine, the flow rate in the CCD can be indirectly
represented by Uosm/Ucreatinine (see below).
Figure 2. Fast Na + and slow Cl in CCD. The barrel-shaped
structures represent the terminal CCD. The reabsorption of Na+
faster than Cl (right panel) or Cl slower than Na + (left) in the
CCD creates the lumen negative voltage that drives the net secretion
of K+. Fast Na+ disorders cause ECF volume expansion and high
blood pressure whereas slow Cl disorders lead to diminished ECF
volume and low to normal blood pressure.
Hong Kong J Nephrol April 2008 Vol 10 No 1

[K+]CCD: K+ secretion in the CCD depends on the K+
channel conductance of the apical membrane (primarily
renal outer-medullary K [ROMK]) driven by the
electrogenic reabsorption of Na+ (a lumen-negative
transepithelial voltage) via epithelial Na+ channels
(ENaC) [10,14]. Blood aldosterone and luminal
bicarbonate are two major factors enhancing K +
secretion in the CCD [22,25]. Aldosterone action leads
to an increase in the activity of ENaC by activating
various serum and glucocorticoid-regulated kinases
(SGK) which phosphorylate the ubiquitin ligase Nedd-
4-2 and reduce its interaction with ENaC as well as
channel-activating proteases (CAP 1-3) which activate
ENaC by increasing its open-probability [26]. The
concentration of HCO3 and/or an alkaline luminal pH
appear to exert a decrease in the apparent permeability
of Cl and/or an increase in ROMK open probability in
the CCD, although the mechanism has not been fully
validated. There are two ways to generate more
negativity in the lumen of the CCD and thus drive K+
secretion via the ROMK channel. When Na + is
reabsorbed faster than Cl (fast Na+ disorders) or Cl is
reabsorbed slower than Na+ (fast Na+ disorders), the
lumen of the CCD becomes more negatively charged
(electrogenic) and drives K+ secretion via the ROMK
channel [24]. The [K+] in the CCD can be estimated by
calculating the transtubular potassium gradient (TTKG)
as {(urine/plasma [K+])/(urine/plasma osmolality)} [27,
28]. The TTKG is a semiquantitative index that reflects
the driving force of K+ secretion in the CCD because it
adjusts for plasma K + concentration and for water
reabsorption in the medullary collecting ducts [27]. A
TTKG that is greater than 3 in the presence of
hypokalemia indicates fast Na+ or slow Cl disorders
(electrogenic), whereas a TTKG that is less than 3
indicates that Na + is not reabsorbed faster than Cl
(electroneutral) as seen with extrarenal or former renal
K+ loss. Of note, TTKG cannot be calculated if the urine
osmolality is appreciably less than the plasma
osmolality.
Opening of K+ channels are crucial for K+ secretion
in the CCD. Although many types of K+ channels have
been identified in renal tubules, the ROMK channel
Table 2. Tests used to assess the K+ excretion rate for hypokalemia
Test Unit Expected
24-hr urine mmol/d < 15
Spot urine
Random urine [K+] mmol/L None
Fractional excretion of K+ % < 3%
K+ to creatinine ratio mmol/mmol < 1.5
TTKG <3
Osmolality to creatinine ratio mosm/mmol 120150
Hong Kong J Nephrol April 2008 Vol 10 No 1
Practical and pathophysiologic approach to hypokalemia
(Kir 1.1; secretory K+, small K+, or SK channel) (a low-
conductance 35 pS) and large-conductance (140 pS),
Ca2+-activated K+ channels (BK, maxi-K+ channels) are
two particularly important channels [29,30]. Opening
of ROMK is primarily driven by a lumen-negative
transepithelial voltage. Maxi-K+ channels are stimulated
as a result of increased intracellular Ca2+ when flow
rate to the CCD is increased. The importance of maxi-
K+ channels in renal K+ secretion is further supported
by the finding that patients with Bartters syndrome,
due to inactivation mutations of ROMK in the ascending
limb of Henles loop and distal tubules, do not have
hyperkalemia but hypokalemia [31]. Mutations of
ROMK decrease NaCl and flow reabsorption in the
thick ascending limb, resulting in increased distal
delivery of NaCl and fluid to the CCD which increases
flow-stimulated K+ secretion via maxi-K + channels
despite the loss of functional ROMK in the CCD [32].
ASSESSMENT OF URINE K+ EXCRETION RATE
A major branch point in hypokalemic pathophysiology
is the renal K+ excretion response during hypokalemia.
The 24-hour urine and/or spot urine have been used to
assess renal K+ excretion rate. However, 24-hour urine
collection can be cumbersome to the patient and is
frequently erroneous because of inaccurate timing,
collection and calculation. More importantly, it is
implausible to collect urine for 24 hours during
emergency situations and in states of acute K+ shift into
cells. Furthermore, KCl, volume expansion, or drugs
affecting K+ excretion (e.g. diuretics) may interfere with
the validity of the 24-hour urinary K+ collection. We
prefer a spot (timed) urine collection prior to therapy
as a fast and practical alternative. Nevertheless, 24-hour
urine, if collected properly, can provide additional
information such as how much K+ is needed to replace
a K+ deficit and the state of K+ balance from calculation
of K+ input and output. Five spot urine indices of renal
response to hypokalemia have been used: urine K+
concentration, fractional excretion of K+, TTKG, K+/
Cr ratio and Uosm/Cr (Table 2) [3338].
Pitfalls
Inaccurate or incomplete collections, K+ shift, drugs
Polyuria or oligouria
Need nomogram if renal function impairment
Renal failure, muscle mass, volume depletion, severe rhabdomyolysis
Low urine osmolality
As in K+/Cr ratio
17
S.H. Lin
CAUSES OF HYPOKALEMIA
Based on the urinary K+ excretion rate in response to
hypokalemia, the etiology of hypokalemia can be
simply divided into two groups: those with a low K+
excretion rate and those with a high K+ excretion rate.
Disorders with a low urine K+ excretion rate
Low urine K+ excretion can be caused by an increased
transcellular shift of K+ or excessive loss of K+ from
the intestinal tract or sweat glands. In contrast to either
metabolic acidosis or alkalosis commonly found in
gastrointestinal or sweat K + loss as a result of a
concomitant bicarbonate (HCO3) or chloride (Cl) loss,
an acid-base imbalance is usually not prominent in
patients with increased intracellular shift of K+ [35,39].
This is because ECF K+ content is relatively small and
every K+ entering cells is exchanged for H+ or Na+ out
of cells to maintain electroneutrality. However, the
amount of H+ that enters the ECF compartment and is
buffered by HCO3 is minute compared to the ECF
HCO 3 content. Accordingly, the simultaneous
assessments of blood acid-base state also helps
discriminate the causes of hypokalemia with low urine
K+ excretion rate (Figure 3).
As a whole, increased shift of extracellular K+ into
cells can occur acutely in a number of highly stressful
conditions associated with increased catecholamines
or hyperinsulinemia via the activation of membrane
Na-K-ATPase or NHE activity [40,41]. Barium
intoxication and chloroquine overdose cause
hypokalemia via the direct closure of cellular
membrane K+ channels [42,43]. We would like to
18
clarify the clinical definition of hypokalemic periodic
paralysis (HPP) which has been used with confusion
in many causes of hypokalemia with paralysis. HPP
is specifically used for any hypokalemic disorders
caused by an acute shift of K+ into cells in contrast to
non-HPP where there is a large total body deficit of
K+ [44]. Within the HPP subgroups, the most common
are thyrotoxic periodic paralysis (TPP) in Asia [45,
46] and familial periodic paralysis (FPP) due to gene
mutations encoding the dihydropyridine-sensitive
voltage-gated Ca2+ channel _1-subunit (CACNA1S)
and tetradoxin-sensitive voltage-gated Na+ channel
_-subunit (SCN4A) of skeletal muscle in Western
countries [47,48].
Any cause of gastrointestinal K+ loss and excessive
sweating can lead to hypokalemia with low urinary K+
excretion. Of note, metabolic alkalosis and/or acidosis
is usually present as mentioned above. Furthermore,
other electrolyte excretion rates, such as Na+, Cl,
divalent ions, and osmoles, are frequently low prior to
therapy [35]. However, sometimes, patients with
gastrointestinal or sweat loss may have high urine K+
excretion because concomitant Na+ loss with secondary
hyperaldosteronism, metabolic alkalosis with
bicarbonaturia, hypomagnesemia, and coexisting
intrinsic renal disorders all contribute to renal K+
wasting [49,50].
Disorders with a high urine K+ excretion rate
Hypokalemia due to renal K+ wasting is chronic and
usually related to disorders with either increased flow
rate to the CCD or increased K+ in the CCD (fast Na+
or slow Cl).
Figure 3. Algorithm for the
approach to hypokalemia with
a low urine K+ excretion.
Hong Kong J Nephrol April 2008 Vol 10 No 1
 Practical and pathophysiologic approach to hypokalemia

Figure 4. Algorithm for the approach to hypokalemia with a high urine K+ excretion.

Hong Kong J Nephrol April 2008 Vol 10 No 1 19

S.H. Lin
Increased urine flow rate to CCD
Flow rate to the CCD is enhanced when osmole
excretion rate is increased. Increased osmole excretion
rate can be caused by increased excretion of electrolytes
(diuretics or tubular defects) or non-electrolytes
(mannitol, glucose, urea) [27,28] (Figure 4).
Increased [K+] in the CCD
Fast Na+ disorders: Because Na+ reabsorption in the
CCD is augmented, ECF volume is usually expanded
and thus blood pressure is high, as in states of
mineralocorticoid excess [51]. In this setting,
measurement of plasma renin activity, aldosterone and
cortisol concentration helps narrow the differential
diagnosis of fast Na+ disorders [12,28,52] (Figure 4).
Plasma renin activity and aldosterone levels are high
in patients with a renin-secreting tumor, renal vascular
stenosis, malignant hypertension, and
pheochromocytoma. High plasma aldosterone levels but
low plasma renin activity indicates primary
hyperaldosteronism which can be caused by bilateral
adrenal hyperplasia, adrenal adenoma/carcinoma,
glucocorticoid-remediable aldosteronism or others [53].
In contrast, low plasma aldosterone level and renin
activity represents pseudohyperaldosteronism [54].
Based on the plasma cortisol concentration, three
subgroups can be readily divided. Patients with high
plasma cortisol concentrations may have ectopic
adrenocorticotropic hormone, Cushings syndrome or
exogenous hydrocortisone administration [55,56]. Low
plasma cortisol concentration suggests the diagnosis
of congenital adrenal hyperplasia due to either 17_-
hydrolyase or 11`-hydroxylase deficiency [57]. A
normal plasma cortisol level has been found in the
following causes: 11-deoxycorticosterone (DOC)
producing adenoma, autosomal dominant Liddles
syndrome due to a gain of function mutation in the
C-terminal part of the ` or a subunit of ENaC, and
failure of the 11`-hydroxysteroid dehydrogenase-2
(11`-HSDH-2) to remove cortisol resulting in apparent
mineralocorticoid excess from either a hereditary defect
due to a homozygous deficiency of 11`-HSDH-2 or
licorice ingestion (inhibition) [51,5860].
Because aldosterone synthesis and secretion can be
inhibited by hypokalemia itself, the effect of
hypokalemia should be taken into consideration when
interpreting plasma aldosterone concentration [61]. One
must also be concerned about the effect of
antihypertensive drugs such as angiotensin-converting
enzyme inhibitors (ACEIs), angiotensin II (AII)
antagonists, and beta-blockers which may influence
plasma renin activity and aldosterone concentrations.
Diuretics (thiazides or loop diuretics) prescribed to
hypertensive patients can cause or aggravate
hypokalemia and metabolic alkalosis while mimicking
the clinical and laboratory finding of mineralocorticoid
20
excess. To differentiate a diuretic-induced hypokalemia
from a true mineralocorticoid excess state, withdrawal
of diuretics coupled with replacement of the K+ deficit
can be employed. Once plasma K+ level is normal, stop
K+ supplementation. If hypokalemia recurs, excess
mineralocorticoid state is more likely than a diuretic-
induced hypokalemia.
Slow Cl disorders: Because Cl reabsorption in the
CCD is diminished, ECF volume is usually contracted
and thus blood pressure is relatively low to normal.
Because intracellular K+ loss is often accompanied by
ECF HCO3 or Cl loss, slow Cl disorders can have
either hyperchloremic metabolic acidosis or
hypochloremic metabolic alkalosis (Figure 4).
H y p e rch l o re m i c m e t a b o l i c a c i d o s i s :
Hyperchloremic metabolic acidosis provides an
important diagnostic clue for the presence of a
pathophysiologic process involving both K+ depletion
and direct or indirect loss of HCO3. Estimating the
urine NH4+ concentration unveils the basis of metabolic
acidosis associated with K + depletion [62]. The
excretion of NH4+ is low in patients with renal tubular
acidosis (RTA), whereas this excretion is not depressed
in simple gastrointestinal loss of NaHCO3 [63]. Because
direct measurement of urine NH4+ concentration is
usually unavailable in most laboratories, an indirect
estimate of NH4+ can be obtained from the urine anion
gap (Na + + K+ Cl ) or osmolar gap (measured
calculated urine osmolality/2). Positive urine net charge
and osmolar gap < 100 mosm/kgH2O are indicative of
low urine NH4+ excretion, pointing to the diagnosis of
RTA [64]. RTA can be proximal or distal in origin.
Intravenous NaHCO3 loading at a rate of 23 mmol/
kg/hr can be administered to separate proximal from
distal RTA. Fractional excretion of bicarbonate
(FEHCO3) as an index of proximal tubule H+ secretion
at plasma bicarbonate close to 24 mmol/L is > 15% in
proximal RTA, whereas urine-blood carbon dioxide
gradient (6U-B PCO2), an index of distal renal tubule
H+ secretion in the alkaline urine (pH > 7.4) is less than
25 mmHg in distal RTA [65]. The causes for patients
who do not have a low NH4+ excretion rate include
gastrointestinal loss of HCO3, chronic toluene abuse,
treatment of diabetic acidosis with insulin, and ureteral
diversion [66,67].
Hypochloremic metabolic alkalosis: Metabolic
alkalosis is diagnostically useful in patients with severe
KCl depletion. An assessment of urine Na+ and Cl may
reveal the basis for renal tubular electrolyte disorders
and distinguish it from non-renal Na + loss. Low
excretion of Na+ and Cl indicate remote vomiting,
remote or yesterdays diuretics, Cl-losing diarrhea (e.g.
congenital chloridorrhea), or excessive sweating [68].
Low urine Na+ but high Cl excretion in the presence
of hypokalemia and metabolic alkalosis suggests
laxative abuse or some chronic diarrhea states with
Hong Kong J Nephrol April 2008 Vol 10 No 1
 Practical and pathophysiologic approach to hypokalemia

chronic stimulation of renal NH4+ excretion. Conditions
of high Na+ excretion but low Cl suggests the presence
of an anion that is not reabsorbed. If the urine is alkaline
(pH > 7), vomiting and/or ingestion of bases is the likely
cause. If the urine is not alkaline, intake or generation
of anions that are poorly reabsorbed by the kidney is
likely [69]. A high urine Na+ and Cl excretion in the
presence of ECF volume depletion is indicative of the
recent use of diuretics, intrinsic renal disease or the
lack of signaling to stimulate NaCl reabsorption.
Inherited or acquired renal tubular disorders such as
Gitelmans syndrome, Bartters syndrome, and related
medication-induced disorders, such as from
aminoglycosides, cisplatin, diuretics, and foscarnet, are
often the diagnosis [7072]. The evaluation of urine
divalent Mg2+ and Ca2+ excretion helps to localize the
exact tubular defect. A high urine Ca 2+ and Mg2+
excretion is universally present in lesions of the loop
of Henle, whereas low urine Ca 2+ and high Mg 2+
excretion is invariably found in lesions of the distal
convoluted tubule [7375]. A differential diagnosis of
Gitelmans syndrome and different subtypes of Bartters
syndrome is shown in Table 3. It is important to
discriminate Gitelmans syndrome from Bartters
syndrome because nonsteroidal anti-inflammatory drugs
are usually ineffective and not needed in treating patients
with Gitelmans syndrome based on the relatively normal
urinary prostaglandin E2 excretion [76], unlike Bartters
syndrome with abnormally higher prostaglandin E2
excretion, especially in antenatal type [77].
MANAGEMENT
The management of hypokalemia incorporates the
acuity of illness, magnitude of K + deficit, K +
preparations, risks of therapy, and special associated
conditions.
Medical emergency
The major emergencies include cardiac arrhythmias and
respiratory failure. There are two notes of caution when
treating patients with profound hypokalemia in a
medical emergency. First, the aim of therapy is to get

Table 3. Differential diagnosis of Gitelmans syndrome (GS) or Bartters syndrome (BS)-like inherited renal electrolyte disorders

GS aBS/HPS cBS BSND ADH

OMIM 263800 241200 602023 602522 601189

602023 600359

Inheritance AR AR AR AR AD
AR

Gene locus 16q 15q15-21 1p36 1p31 3q13.3-21

1p36 11q24

Gene SLC12A3 SLC12A1 CLCNKB BSND CASR

CLCNKB KCNJ1

Protein NCC Na+-K+-2Cl CLC-Kb Barttin CASR

CLC-Kb ROMK

Clinical
Age at onset Variable Neonatal Variable Neonatal Infancy
Nephrocalcinosis No Yes Rare No Yes
Renal stones No Yes or no No No Yes

Laboratory
Blood pH B B B B B
Plasma K+ ? to ?? ? to ?? ? to ?? ?? ?
Plasma Mg2+ ? N or ? N or ? N ?
Plasma Ca2+ N N N N ?
Urine Mg2+ B N or B N or B N B
Urine Ca2+ ? BB Variable N or B BtoBB

OMIM = online Mendelian Inheritance in Man; aBS/HPS = antenatal Bartters syndrome/hyperprostaglandin E syndrome; cBS = classic
Bartters syndrome; BSND = antenatal Bartters syndrome with sensorineural deafness; ADH = autosomal dominant hypoparathyroidism;
AR = autosomal recessive; AD = autosomal dominant; CASR = calcium sensing receptor.

Hong Kong J Nephrol April 2008 Vol 10 No 1 21

S.H. Lin
the patient out of danger, not to immediately correct
the entire K+ deficit. Enough K+ must be given to raise
the plasma K+ quickly to a safe range (~3.0 mmol/L)
and the total body K+ deficit should then be replaced
more slowly [78]. Since large doses and high
concentrations of K+ might be needed, a central venous
catheter and cardiac monitor are essential for aggressive
treatment. Second, the infusion should not contain
glucose or HCO3 because this might aggravate the
degree of hypokalemia by increasing redistribution of
K+ from ECF into ICF space [79].
Magnitude of K+ deficit
Balance studies in K+-deprived normal subjects show
that when plasma K+ concentration decreases from 4
to 3 mmol/L, there is a mean K+ deficit of 350 mmol. A
further reduction in plasma K+ concentration from 3 to
2 mmol/L is associated with an additional 400 mmol
K+ deficit [13]. Given the degree of K+ loss, an estimated
amount of K+ supplement should be provided. The oral
route is preferred if bowel sounds are present. When a
peripheral intravenous route is used, the K +
concentration should not be > 40 mmol/L. The rate of
K+ administration should not be > 60 mmol/hr in all
but emergency settings. However, one must know that
there is no useful quantitative relationship between
plasma K+ and total body K+ deficit because there may
also be shift of K+ into cells such as in the presence of
coexisting volume depletion, metabolic alkalosis, and
increased `-adrenergic activity.
K+ preparations
Three kinds of K+ salts are available to replace body
K+ deficit: KCl, KHCO3 (K+ citrate or organic anion),
and K + phosphate. KCl is needed in hypokalemic
patients with K+ deficit and hypochloremic metabolic
alkalosis, whereas KHCO3 or K+ citrate is preferred in
patients with K+ deficit and hyperchloremic metabolic
acidosis. KHCO3 or K+ citrate also has the significant
effect of reducing calcium excretion in patients with
metabolic acidosis. Because the administration of
HCO3 may lead to a shift of K+ into cells, KCl should
be given initially and alkali should be withheld unless
there are ongoing and large losses of HCO 3. K +
phosphate may be needed when there is concomitant
deficit of K+ and phosphate such as in the condition of
rapid anabolism, little oral intake, gastrointestinal
disorders, and preexisting cellular K+ phosphate loss
(e.g. diabetic or alcoholic ketoacidosis) [80].
Risks of therapy
In hypokalemic patients with acute increased shift K+
into cells, body K+ stores are normal. Aggressive KCl
therapy may be associated with a potential risk of
rebound hyperkalemia, due to K+ rapidly released from
cells when the K + shift resolves [38,44,45]. With
22
prolonged hypokalemia, the CCD may become
temporarily hyporesponsive to the kaliuretic effect of
aldosterone [81]. Hyperkalemia may develop,
especially when K+ supplementation is given with K+-
sparing diuretics and if other conditions compromising
K+ excretion are present. These conditions include renal
failure, diabetes mellitus and the simultaneous use of
ACEIs, AII receptor blockers, beta-blockers or
nonsteroidal anti-inflammatory drugs [82]. However,
a recent retrospective study reported that total parenteral
nutrition as a source of K+, magnesium supplementation
which may reduce kaliuresis, and hematologic
malignancy causing cell lysis contribute to subsequent
hyperkalemia in one of every six patients with
hypokalemia [83].
Special associated settings
HPP due to transcellular shift of K+: In patients with
HPP, acute intravenous or oral KCl administration can
hasten recovery and prevent cardiac arrhythmia and
respiratory arrest. However, caution must be exercised
because KCl therapy is associated with the development
of rebound hyperkalemia on recovery. One interesting
but still less-appreciated finding is a further fall in
plasma K+ concentration in some patients with TPP
during KCl therapy. This paradoxical hypokalemia may
trigger physicians to administer more K+
supplementation to correct the hypokalemia, leading
to marked rebound hyperkalemia. From retrospective
and case-controlled studies, rebound hyperkalemia
(> 5.0 mmol/L) has been reported to occur in close to
3070% of patients with TPP if > 90 mmol KCl was
given within 24 hours or at a rate of 10 mmol/hr [84,
85]. We suggest that KCl supplementation be kept low
(< 10 mmol/hr) unless there are cardiopulmonary
complications. An alternative therapeutic option in TPP
is high-dose nonselective beta-blockers to suppress
adrenergic activity and inhibit insulin secretion, based
on the implication of hyperadrenergic activity and
hyperinsulinemia in the pathogenesis of TPP [86,87].
Nonselective beta-blockers may not only reverse an
acute episode of TPP without the development of
rebound hyperkalemia but also prevent or ameliorate
future paralytic attacks [88].
Associated with chronic hyponatremia: K+ may be
important in cerebral recovery following hyponatremia
because the cellular uptake of K+ is a critical response
to increasing extracellular tonicity. Hypokalemia is a
paramount risk factor for osmotic demyelination
syndrome (ODS) following the correction of chronic
hyponatremia [89]. It has been reported that 89% of
patients who developed ODS presented with initial
hypokalemia and that their K+ level did not normalize
with serum Na + correction [90]. Normalizing the
hypokalemia either before, or at least concomitant with
the plasma Na+ correction would be a prudent and
Hong Kong J Nephrol April 2008 Vol 10 No 1

logical approach. There are many benefits of KCl
supplementation over NaCl, including the reduction of
arrhythmia related to hypokalemia, the Na+ gain in the
ECF and volume expansion if K+ enters the cells, and
reduced risk of ODS during correction of chronic
hyponatremia [89]. Nevertheless, the administration of
desmopressin is warranted to prevent or reduce a larger
water diuresis with a rapid and unwanted rise in plasma
Na+ concentration if aggressive KCl or NaCl therapy
causes ECF volume expansion with the resultant
inhibition of ADH release [91].
Associated with volume depletion: Because volume
depletion can cause an increase in _-adrenergic activity
and reduce the extracellular K+ shift into cells, plasma
K+ concentration is often misleadingly high [92]. When
volume status is restored in parallel with a reduction in
_-adrenergic activity, there will be a further fall in
plasma K + concentration, leading to a paradoxical
wo r s e n i n g o f hy p o k a l e m i a eve n w i t h K C l
supplementation, similar to that found during K +
supplementation in the acute phase of HPP.
A s s o c i a t e d w i t h m a g n e s i u m d e fi c i e n c y :
Hypokalemia is frequently associated with magnesium
deficiency. It is estimated that > 50% of clinically
significant hypokalemia has concomitant magnesium
deficiency. Concomitant magnesium deficiency
exacerbates hypokalemia and renders it refractory to
treatment with K+ supplementation [93]. Micropuncture
studies have shown that magnesium decreases distal
K+ secretion [94]. In patch clamp studies, a decrease in
intracellular magnesium caused by magnesium
deficiency may release the magnesium-mediated
inhibition of ROMK channels and thus increase K+
secretion [95]. However, an increased Na+ delivery to
CCD or elevated aldosterone may be required for
aggravating K+ wasting in magnesium deficiency due
to the fact that magnesium deficiency alone does not
necessarily cause hypokalemia [96]. Correction of
magnesium deficiency may help in the correction of
hypokalemia and prevention of cardiac arrhythmia [97].
Associated with severe metabolic acidosis: Because
inorganic rather than organic acidosis causes the efflux
of intracellular K+ in exchange with extracellular H+
and thus raises plasma K+ concentration, the degree of
K+ deficit is underestimated in hypokalemic patients
with severe hyperchloremic metabolic acidosis [98].
One may be misled to correct the plasma HCO3 first
because the low HCO3 concentration appears more
dramatic than the K + concentration in this setting.
Actually, the risk of profound hypokalemia is much
greater than severe metabolic acidosis and should be
corrected first. In fact, there have been case reports of
catastrophic acute respiratory failure and ventricular
arrhythmia from exacerbation of hypokalemia as a
result of aggressive alkali therapy before K +
supplementation.
Hong Kong J Nephrol April 2008 Vol 10 No 1
Practical and pathophysiologic approach to hypokalemia
Hypokalemia associated with hereditary renal
tubular defects: A common clinical observation is that
hypokalemia is difficult to correct in patients with
hereditary renal tubular disorders such as Gitelmans
syndrome or Bartters syndrome, even with large K+
supplements. Because of chronic hypokalemia, luminal
K+ channels in the CCD might be downregulated [99].
KCl supplements transiently raise the plasma K +
concentration, which may not only augment the
insertion of K+ channels into the luminal membrane of
the CCD but also exert a loop diuretic-like effect, thus
inducing a prompt kaliuresis [100]. While maintaining
in a subnormal plasma K+ concentration, to administer
KCl in multiple small doses instead of infrequent large
doses may be a better way to avoid raising the plasma
K+ concentration to the normal range for even transient
periods.
Associated with a low lean mass: Because cellular
K+ primarily resides in the skeletal muscle, total body
K+ depends upon the lean muscle mass. For the same
degree of hypokalemia, K+ supplementation should be
relatively less in patients with low lean mass. If the
same amount of K+ replacement is given to patients
with low lean mass as to those with normal/high lean
mass, iatrogenic hyperkalemia may develop.
CONCLUSION
Hypokalemia caused by a multitude of etiologies is
often associated with cardiovascular, neuromuscular,
renal and metabolic disturbances. It usually arises from
derangements of internal K+ shift or external K+ balance.
Apart from detailed history and careful physical
examination, the measurement of urine K+ excretion
rate by spot and/or 24-hour urine, and assessment of
blood acid-base status will help to discriminate the
causes of hypokalemia. The treatment of hypokalemia
involves weighing the degree and timing of
hypokalemia with clinical manifestations, underlying
causes, associated conditions and risks during therapy.
Prompt diagnosis with appropriate management of
hypokalemia avoids unnecessary examination and dire
complications related to hypokalemia.
ACKNOWLEDGMENTS
This work was supported by a grant from the Chen-
Han Foundation for Education.
REFERENCES
1. Halfant RH. Hypokalemia and arrhythmias. Am J Med 1986;80:
1322.
23
S.H. Lin
2. Coca SG, Perazella MA, Buller GK. The cardiovascular
implications of hypokalemia. Am J Kidney Dis 2005;45:23347.
3. Lin YF, Lin SH, Tsai WS, Davis MR, Halperin ML. Severe
hypokalemia in a Chinese male. QJM 2002;95:695704.
4. Schwartz WB, Relman AS. Effects of electrolyte disorders on renal
structure and function. N Engl J Med 1967;276:3839.
5. Schwartz WB, Relman AS. Metabolic and renal studies in chronic
potassium depletion resulting from overdose of laxatives. J Clin
Invest 1953;32:25871.
6. Cremer W, Bock CW. Symptoms and course of chronic
hypokalemic nephropathy in man. Clin Nephrol 1977;17:6547.
7. Brown RS. Potassium homeostasis and clinical implications. Am
J Med 1984;77:310.
8. Mandal AK. Hypokalemia and hyperkalemia. Med Clin North Am
1997;81:61139.
9. Weiner ID, Wingo CS. Hypokalemiaconsequences, causes, and
correction. J Am Soc Nephrol 1997;8:117988.
10. Halperin ML, Kamel KS. Potassium. Lancet 1998;352:13540.
11. Gennari FJ. Hypokalemia. N Engl J Med 1998;339:4518.
12. Lin SH, Halperin ML. Hypokalemia: a practical approach to
diagnosis and its genetic basis. Curr Med Chem 2007;14:155165.
13. Sterns RH, Cox M, Feig PU, Singer I. Internal potassium balance
and the control of the plasma potassium concentration. Medicine
1981;60:33954.
14. Giebisch G, Krapf R, Wagner C. Renal and extrarenal regulation
of potassium. Kidney Int 2007;72:397410.
15. Clausen T. Clinical and therapeutic significance of the Na+, K +
pump. Clin Sci 1998;95:317.
16. Rosic NK, Standaert ML, Pollet RJ. The mechanism of insulin
stimulation of (Na+,K+)-ATPase. J Biol Chem 1985;260:620612.
17. Klip A, Ramlal T, Cragoe EJ Jr. Insulin-induced cytoplasmic
alkalinization and glucose transport in muscle cells. Am J Physiol
1986;250:C7208.
18. Shieh CC, Coghlan M, Sullivan JP, Gopalakrishnan M. Potassium
channels: molecular defects, diseases, and therapeutic
opportunities. Pharmacol Rev 2000;52:55794.
19. Hebert SC, Desir G, Giebisch G, Wang W. Molecular diversity
and regulation of renal potassium channels. Physiol Rev 2005;85:
31971.
20. Antes LM, Kujubu DA, Fernandez PC. Hypokalemia and the
pathology of ion transport molecules. Semin Nephrol 1998;18:
3145.
21. Giebisch G. Renal potassium transport: mechanisms and
regulation. Am J Physiol 1998;274:F81733.
22. Steele A, deVeber H, Quaggin SE, Scheich A, Ethier J, Halperin
ML. What is responsible for the diurnal variation in potassium
excretion? Am J Physiol 1994;267:R55460.
23. Fernandez-Repollet E, Maldonado MM, Opava-Stitzer S. The
effects of antidiuretic hormone and state of potassium balance on
the renin-angiotensin system in rats with diabetes insipidus.
J Physiol 1982;323:51931.
24. Rutecki GW, Cox JW, Robertson GW, Francisco LL, Ferris TF.
Urinary concentrating ability and antidiuretic hormone
responsiveness in the potassium-depleted dog. J Lab Clin Med
1982;100:5360.
25. Lin SH, Cheema-Dhadli S, Gowrishankar M, Marliss EB, Kamel
KS, Halperin ML. Control of excretion of potassium: lessons from
studies during prolonged total fasting in human subjects. Am J
Physiol 1997;273:796800.
26. Garty H. Regulation of the epithelial Na + channel by aldosterone:
open questions and emerging answers. Kidney Int 2000;57:12706.
24
27. West ML, Bendz O, Chen CB, Singer GG, Richardson RM,
Sonnenberg H, et al. Development of a test to evaluate the
transtubular potassium concentration gradient in the cortical
collecting duct in vivo. Miner Electrolyte Metab 1986;12:22633.
28. Kamel KS, Quaggin S, Scheich A, Halperin ML. Disorders of
potassium homeostasis: an approach based on pathophysiology.
Am J Kidney Dis 1994;24:597613.
29. Wang WH. Regulation of ROMK (Kir1.1) channels: new
mechanisms and aspects. Am J Physiol 2006;290:F149.
30. Pluznick JL, Sansom SC. BK channels in the kidney: role in K +
secretion and localization of molecular components. Am J Physiol
2006;291:F51729.
31. Finer G, Shalev H, Birk OS, Galron D, Jeck N, Sinai-Treiman L,
et al. Transient neonatal hyperkalemia in the antenatal (ROMK
defective) Bartter syndrome. J Pediatr 2003;142:31823.
32. Bailey MA, Cantone A, Yan Q, MacGregor GG, Leng Q, Amorim
JB, et al. Maxi-K + channels contribute to urinary potassium
excretion in the ROMK-deficient mouse model of Type II Bartters
syndrome and in adaptation to a high-K + diet. Kidney Int 2006;
70:519.
33. Narins RG, Jones ER, Stom MC, Rudnick MR, Bastl CP.
Diagnostic strategies in disorders of fluid, electrolyte and acid-
base homeostasis. Am J Med 1982;72:496520.
34. Kamel KS, Ethier JH, Richardson RM, Bear RA, Halperin ML.
Urine electrolytes and osmolality: when and how to use them. Am
J Nephrol 1990;10:89102.
35. Groeneveld JHM, Sijpkens YWJ, Lin SH, Davis MR, Halperin
ML. Approach to the patients with a severe degree of hypokalemia:
the potassium quiz. QJM 2005;98:30516.
36. Elisaf M, Siamopoulos KC. Fractional excretion of potassium in
normal subjects and in patients with hypokalemia. Postgrad Med
J 1995;71:2112.
37. Gagnnon RF, Halperin ML. Possible mechanisms to explain the
absence of hyperkalemia in Addisons disease. Nephrol Dial
Transplant 2001;16:12804.
38. Lin SH, Lin YF, Chen DT, Chu P, Hsu CW, Halperin ML.
Laboratory tests to determine the causes for hypokalemia and
paralysis. Arch Intern Med 2004;164:15616.
39. Groeneveld JH, Sijpkens YW, Lin SH, Davids MR, Halperin ML.
An approach to the patient with severe hypokalemia. QJM 2005;
98:30516.
40. Brown MJ, Brown DC, Murphy MB. Hypokalemia from beta2-
receptor stimulation by circulating epinephrine. N Engl J Med
1983;309:14149.
41. Alazami M, Lin SH, Cheng CJ, Davids MR, Halperin ML. Unusual
cases of hypokalemia and paralysis. QJM 2006;99:18192.
42. Wells JA, Wood KE. Acute barium poisoning treated with
hemodialysis. Am J Emerg Med 2001;19:1757.
43. Clemessy JL, Favier C, Borron SW, Hantson PE, Vicaut E, Baud
FJ. Hypokalemia related to acute chloroquine ingestion. Lancet
1995;346:87780.
44. Lin SH, Lin YF, Halperin ML. Hypokalemia and paralysis. QJM
2001;94:1339.
45. Lin SH. Thyrotoxic periodic paralysis. Mayo Clin Proc 2005;80:
99105.
46. Kung AW. Thyrotoxic periodic paralysis: a diagnostic challenge.
J Clin Endocrinol Metab 2006;91:24905.
47. Lin SH, Hsu YD, Cheng NL, Kao MC. Sk eletal muscle
dihydropyridine-sensitive calcium channel gene mutations in
Chinese patients with hypokalemic periodic paralysis. Am J Med
Sci 2005;329:6670.
Hong Kong J Nephrol April 2008 Vol 10 No 1

48. Venance SL, Cannon SC, Fialho D, Fontaine B, Hanna MG, Ptacek
LJ, et al; CINCH investigators. The primary periodic paralyses:
diagnosis, pathogenesis and treatment. Brain 2006;129:817.
49. Agarwal R, Afzalpurkar R, Fordtran JS. Pathophysiology of
potassium absorption and secretion by the human intestine.
Gastroenterology 1994;107:54871.
50. Kim HJ, Yoon YM, Park KN. The change in electrolytes and acid-
base after artificially induced acute diarrhea by laxatives. J Korean
Med Sci 1994;9:38893.
51. Lin SH, Chau T. A puzzling cause of hypokalemia. Lancet 2002;
360:224.
52. Lin SH, Chiu JS, Hsu CW, Chau T. A simple and rapid approach
to hypokalemic paralysis. Am J Emerg Med 2003;21:48791.
53. Young WF. Primary aldosteronism: renaissance of a syndrome.
Clin Endocrinol 2007;66:60718.
54. Cheng CJ, Chen YH, Chau T, Lin SH. A hidden cause of
hypokalemic paralysis in a patient with prostate cancer. Support
Care Cancer 2004;12:8102.
55. Tsai WS, Wu CP, Hsu YJ, Lin SH. Life-threatening hypokalemia
in an asthmatic patient treated with high-dose hydrocortisone. Am
J Med Sci 2004;327:1525.
56. Lin CS, Yao NS, Cheng MF, Lin SH. Ectopic ACTH syndrome
associated with large cell neuroendocrine carcinoma of lung. Am
J Med Sci 2007;334:4879.
57. New MI. Diagnosis and management of congenital adrenal
hyperplasia. Ann Rev Med 1998;49:31128.
58. Palmer BF, Alpern RJ. Liddles syndrome. Am J Med 1998;104:
3019.
59. Mune T, Rogerson FM, Nikkil H, Agarwal AK, White PC. Human
hypertension caused by mutations in the kidney isozyme of 11
beta-hydroxysteroid dehydrogenase. Nat Genet 1995;10:3949.
60. Lin SH, Yang SS, Chau T, Halperin ML. An unusual cause of
hypokalemic paralysis: chronic licorice ingestion. Am J Med Sci
2003;325:1536.
61. Saruta T, Fujimaki M, Senba S, Saito I, Konishi K. Aldosterone
and other mineralocorticoids in Bartters syndrome. J Lab Clin
Med 1984;103:84853.
62. Simpson DP. Control of hydrogen ion homeostasis and renal
acidosis. Medicine 1971;50:50341.
63. Kamel KS, Briceno LF, Sanchez MI, Brenes L, Yorgin P, Kooh
SW, et al. A new classification for renal defects in net acid
excretion. Am J Kidney Dis 1997;29:13646.
64. Carlisle EJ, Donnelly SM, Vasuvattakul S, Kamel KS, Tobe S,
Halperin ML. Glue-sniffing and distal renal tubular acidosis:
sticking to the facts. J Am Soc Nephrol 1991;1:101927.
65. Cheng CJ, Chu P, Huang GS, Lin SH. Diffuse bone pain in a
young women. Lancet 2004;364:1910.
66. Orman RA, Lewia JB Jr. Flaccid quadriparesis with Yersinia
enterocolitis-induced hypokalemia. Arch Intern Med 1989;149:
11934.
67. Murakami K, Tomita M, Kawamura N, Hasegawa M, Nabeshima
K, Hiki Y, et al. Severe metabolic acidosis and hypokalemia in a
patient with enterovesical fistula. Clin Exp Nephrol 2007;11:
2259.
68. Bates CM, Baum M, Quigley R. Cystic fibrosis presenting with
hypokalemia and metabolic alkalosis in a previously healthy
adolescent. J Am Soc Nephrol 1997;8:3525.
69. Kamel KS, Ethier J, Levin A, Halperin ML. Hypokalemia in the
beautiful people. Am J Med 1990;88:5346.
70. Peters M, Jeck N, Reinalter SS, Leonhardt A, Tonshoff B, Klaus
GG, et al. Clinical presentation of genetically defined patients
Hong Kong J Nephrol April 2008 Vol 10 No 1
Practical and pathophysiologic approach to hypokalemia
with hypokalemic salt-losing tubulopathies. Am J Med 2002;112:
18390.
71. Lin SH, Shiang JC, Huang CC, Yang SS, Hsu YJ, Cheng CJ.
Phenotype and genotype analysis in Chinese patients with
Gitelmans syndrome. J Clin Endocrinol Metab 2005;90:25007.
72. Chou CL, Chen YH, Chau T, Lin SH. Acquired Bartter-like
syndrome associated with gentamicin administration. Am J Med
Sci 2005;329:1449.
73. Lin SH, Cheng NL, Hsu YJ, Halperin ML. Intrafamilial phenotype
variability in patients with Gitelman syndrome having the same
mutations in their thiazide-sensitive sodium/chloride cotransporter.
Am J Kidney Dis 2004;443:30412.
74. Bettinelli A, Bianchetti MG, Girardin E, Caringella A, Cecconi M,
Appiani AC, et al. Use of calcium excretion values to distinguish
two forms of primary renal tubular hypokalemic alkalosis: Bartter
and Gitelman syndromes. J Pediatr 1992;120:3843.
75. Lin SH. Gitelmans syndrome: from clinic to gene. Acta
Nephrologica 2003;17:11320.
76. Luthy C, Bettinelli A, Iselin S, Metta MG, Basilico E, Oetliker
OH, et al. Normal prostaglandinuria E 2 in Gitelmans syndrome,
the hypocalciuric variant of Bartters syndrome. Am J Kidney Dis
1995;25:8248.
77. Reinalter SC, Jeck N, Brochhausen C, Watzer B, Nusing RM,
S ey b e r t h H W, e t a l . R o l e o f c y c l o o x y g e n a s e - 2 i n
hyperprostaglandin E syndrome/antenatal Bartter syndrome.
Kidney Int 2002;62:25360.
78. Cohn JN, Kowey PR, Whelton PK, Prisant LM. New guidelines
for potassium replacement in clinical practice: a contemporary
review by the National Council on Potassium in Clinical Practice.
Arch Intern Med 2000;160:242936.
79. Kunin AS, Surawicz B, Sims EAH. Decrease in serum potassium
concentration and appearance of cardiac arrhythmia during
infusion of potassium with glucose in potassium depleted patients.
N Engl J Med 1962;266:28896.
80. Casteels K, Mathieu C. Diabetic ketoacidosis. Rev Endocr Metab
Disord 2003;4:15966.
81. Wang WH. Regulation of renal K + transport by dietary K intake.
Annu Rev Physiol 2004;66:54769.
82. Perazella MA, Mahnensmith RL. Hyperkalemia in the elderly:
drugs exacerbate impaired potassium homeostasis. J Gen Intern
Med 1997;12:64656.
83. Crop MJ, Hoorn EJ, Lindemans J, Zietse R. Hypokalemia and
subsequent hyperkalemia in hospitalized patients. Nephrol Dial
Transplant 2007;22:34717.
84. Lu KC, Hsu YJ, Chiu JS, Hsu YD, Lin SH. Effects of potassium
supplementation on the recovery of thyrotoxic periodic paralysis.
Am J Emerg Med 2004;22:5447.
85. Manoukain MA, Foote JA, Crapo LM. Clinical and metabolic
features of thyrotoxic periodic paralysis in 24 episodes. Arch Intern
Med 1999;159:6016.
86. Lin SH, Lin YF. Propranolol rapidly terminates the hypokalemia,
hypophosphatemia and paralysis in thyrotoxic periodic paralysis.
Am J Kidney Dis 2001;37:6203.
87. Shayne P, Hart A. Thyrotoxic periodic paralysis terminated with
intravenous propranolol. Ann Emerg Med 1994;24:73640.
88. Conway MJ, Seibel JA, Eaton RP. Thyrotoxicosis and periodic
paralysis: improvement with beta blockade. Ann Intern Med 1974;
81:3326.
89. Lin SH, Chau T, Wu CC, Yang SS. Osmotic demyelination
syndrome following correction of chronic hyponatremia with
normal saline. Am J Med Sci 2002;323:25962.
25
S.H. Lin
90. Lohr JW. Osmotic demyelination syndrome following correction
of hyponatremia: association with hypokalemia. Am J Med 1994;
96:40813.
91. Lin SH, Hsu YJ, Chiu JS, Chau T, Hsu CW, Davids MR, et al.
Osmotic demyelination syndrome: a potentially avoidable disaster.
QJM 2003;96:93547.
92. Knochel JP. Diuretic-induced hypokalemia. Am J Med 1984;77:
1827.
93. Whang R, Flink EB, Dyckner T, Wester PO, Alkawa JK, Rayn
MP. Magnesium depletion as a cause of refractory potassium
repletion. Arch Intern Med 1985;149:1869.
94. Francisco LL, Sawin LL, DiBona GF. Mechanism of negative
potassium balance in the magnesium-deficient rat. Proc Soc Exp
Biol Med 1981;168:3828.
95. Lu Z, MacKinnon R. Electrostatic tuning of Mg 2+ affinity in an
26
inward-rectifier K+ channel. Science 1994;371:2435.
96. Huang CL, Kuo E. Mechanism of hypokalemia in magnesium
deficiency. J Am Soc Nephrol 2007;18:264952.
97. Ruml LA, Pak CY. Effect of potassium magnesium citrate on
thiazide-induced hypokalemia and magnesium loss. Am J Kidney
Dis 1999;34:10713.
98. Magner PO, Robinson L, Halperin RM, Zettle R, Halperin ML.
The plasma potassium concentration in metabolic acidosis; a re-
evaluation. Am J Kidney Dis 1988;11:2204.
99. Palmer L, Frindt G. Regulation of the apical K + channels in the
rat cortical collecting tubule during changes in K + intake. Am J
Physiol 1999;277:F80512.
100.Cheema-Dhadli S, Lin SH, Chee KC, Kamel KS, Halperin ML.
Requirement for a high rate of potassium excretion in rats
consuming a low electrolyte diet. J Physiol 2006;572:493501.
Hong Kong J Nephrol April 2008 Vol 10 No 1