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doi:10.1093/qjmed/hci046
Masterclasses in medicine
An approach to the patient with severe hypokalaemia:
the potassium quiz
J.H.M. GROENEVELD1, Y.W.J. SIJPKENS1, S.-H. LIN2, M.R. DAVIDS3
and M.L. HALPERIN4
From the 1Department of Nephrology, Leiden University Medical Center, The Netherlands,
2
Renal division, Tri-Service General Hospital, National Defense Medical Center, Taipei,
Taiwan (ROC), 3Nephrology Unit and Department of Internal Medicine,
Stellenbosch University, Cape Town, South Africa, and 4Division of Nephrology,
St. Michaels Hospital, University of Toronto, Toronto, Canada
Introduction
In this clinical teaching exercise, the central figure is
Professor McCance, an imaginary consultant who
practiced medicine 70 years ago. The overall
objective is to demonstrate how applying principles
of integrative physiology at the bedside can be
extremely helpful in revealing the pathophysiology
of disease, making more accurate clinical diagnoses, and to plan optimal therapy.
The consultation
When the medical registrar received the first referral
of the day, she was surprised that it was another
Address correspondence to Professor M.L. Halperin, University of Toronto, St Michaels Hospital Annex, Lab #1,
Research Wing, 38 Shuter Street, Toronto, Ontario, M5B 1A6, Canada. email: mitchell.halperin@utoronto.ca
! The Author 2005. Published by Oxford University Press on behalf of the Association of Physicians.
All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Summary
306
Unit
Admission
Day 9
Na
K
Cl
HCO
3
pH
PaCO2
Albumin
Magnesium
Creatinine
Urea
mmol/l
mmol/l
mmol/l
mmol/l
148
1.7
43
7.54
50
33 (3.3)
0.79 (1.9)
84 (1.0)
8.6 (24)
146
3.2
104
30
7.44
38
35 (3.5)
58 (0.7)
mmHg
g/l (g/dl)
mmol/l (mg/dl)
mmol/l (mg/dl)
mmol/l (mg/dl)
Age
Gender
BP (mmHg)
Heart rate (bpm)
28
F
160/80
124
26
M
130/70
72
28
F
110/80
72
58
F
120/70
80
21
M
110/70
64
78
M
180/100
74
Plasma
K (mmol/l)
HCO
3 (mmol/l)
Mg2 (mmol/l)
Inorganic P (mmol/l)
1.8
24
0.7
0.6
1.8
24
0.8
0.9
1.8
15
0.9
0.8
1.8
31
0.7
0.8
1.8
31
0.5
0.8
1.8
31
0.8
0.9
Urine
Na (mmol/l)
K (mmol/l)
Cl (mmol/l)
Creatinine (mmol/l)
Osmolality (mOsm/kg)
UCa /UCreat (mmol/mmol)
UMg /UCreat (mmol/mmol)
UPi /UCreat (mmol/mmol)
UOsm /UCreat (mOsm/mmol)
102
10
98
10
680
0.63
0.2
0.1
68
84
8
90
11
586
0.18
0.25
0.9
53
44
11
46
3
201
0.39
0.24
3.3
67
72
22
78
4
314
0.56
0.81
1.3
78
146
12
188
4.3
660
0.06
0.66
1.5
77
120
14
117
5
348
0.26
0.4
1.6
67
List of diagnoses: (a) Bartter-like syndrome; (b) Chronic liquorice ingestion; (c) Gitelmans syndrome (GS); (d) Renal tubular
acidosis (RTA); (e) Sporadic periodic paralysis (SPP); (f) Thyrotoxic periodic paralysis (TPP).
Plasma
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307
Flow Chart 1. Initial steps in the patient with a very low PK.
A second issue for an extreme degree of hypokalaemia is weakness of the respiratory muscles,
especially if there is a need for increased ventilation
(e.g. metabolic acidosis).
308
Figure 1. Creation of a more negative voltage in cells. The circle depicts the cell membrane. The Na-K-ATPase pumps
positive voltage out of cells, causing a large inside negative voltage (60 to 90 mV). This ion pump is activated by
b2-adrenergics. Insulin, by activating the Na/H exchanger (NHE), causes the electroneutral entry of Na into cells, and
thereby more positive voltage exit from cells via the Na-K-ATPase. K exits cells through ion channels that are in a
sufficiently open configuration to approach, but not reach, the electrochemical equilibrium for K.
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ratio, said Professor McCance. Patients with a very
low K excretion rate (1015 mmol/day8) and a
creatinine excretion rate of 1015 mmol/day should
have a UK/UCreatinine that is 51.5 in mmol terms,
Table 3 Features in patients with hypokalaemic periodic
paralysis
Patient
Race
Age (years)
Gender
History
Provoked by high
carbohydrate
Provoked by
vigorous exercise
Symptoms of
hyperthyroidism
Family history of
paralysis
Laboratory data
Low K excretion
Acid-base disorder
Hypophosphataemia
Hypophosphaturia
High urine Ca
EKG
Specific therapy
FPP or SPP
Asian
2040
Male4female
All
520
Male4female
Often
Often
Often
Often
Often (50%)
No
No
Often
Often
Often
Rare
Rare
Yes
No
Often
Often
Yes
LVH,
tachycardia
b-blocker
Yes
No
Less often
Less often
No
Normal
Acetazolamide
Physical examination
Wide pulse pressure
Tachycardia
TPP
309
310
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311
Both high
Malignant High BP
Renovascular High BP
Renin-secreting tumor
High
Ectopic ACTH
Cushing's syndrome
Exogenous cortisol
Both low
P
Cortisol?
Low
11 -hydroxylase
17 -hydroxylase
Low P Renin
High PAldosterone
Hyperadrenal state
Exogenous aldosterone
Normal
More open ENaC
AME-like
Other
Figure 3. Plasma renin and aldosterone in the syndromes of mineralocorticoid excess. For details, see text. AME, apparent
mineralocorticoid excess syndrome; BP, blood pressure; ENaC, epithelial Na channel.
Figure 2. Components of K excretion in the terminal CCD. The barrel shaped structures represent the terminal CCD.
Reabsorbing Na faster than Cl in the CCD creates the lumen negative voltage that drives the net secretion of K.
This occurs when aldosterone (or cortisol) activates ENaC (upper right). Lower left, Na can be reabsorbed faster than Cl
if there is little Cl delivery and Na is accompanied by a non-Cl anion. Lower right, luminal HCO
3 can slow the
reabsorption of Cl. ENaC, epithelial Na channel.
312
of ammonium (NH
4 ) excretion. Those with a high
rate of NH
4 excretion have a non-renal, direct loss
of NaHCO3 (e.g. diarrhoea14) or an indirect loss of
NaHCO3 where there is production of an acid such
as hippuric acid, followed by the excretion of some
hippurate anions with Na or K instead of NH
4,
Figure 4).15 The group of patients with a low rate of
excretion of NH
4 has a renal defect that leads to a
low rate of excretion of NH
4 (called distal renal
tubular acidosis or RTA).16 Professor McCance
added one more clinical pearl. NH
4 in the urine
can be detected by its charge (urine net charge17) or
as a urinary particle (urine osmolal gap18).
Returning to the K quiz, Professor McCance
pointed out that patient 3 had a UK/UCreatinine 41.5,
and a urine that appeared to have a low NH
4
concentration, as judged from the urine electrolyte
concentrations (Na K 4 Cl). Because Uosm
was not appreciably higher than 2(UNa UK)
urine urea (not shown, but inferred), her urine flow
rate was not high, so the NH
4 excretion rate should
not be appropriately elevated.
The nephrology consultant added that the two
lesions to suspect are distal RTA due to impaired H
secretion in the distal nephron,19 or the secretion
of HCO
3 in this nephron segment as occurs in
certain patients with an abnormal Cl/HCO3 anion
exchanger.20 None of the patients had evidence suggesting a high rate of NH
4 excretion (e.g. patients
with diarrhoea or others who sniff glue producing
hippuric acid15).
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concentrating ability (unless there is a second
lesion) and a low rate of excretion of Ca.9 This
nephron segment is the last one that regulates the
excretion of magnesium (Mg) and hypokalaemia is
often accompanied by hypomagnesemia, especially
later in the disease.
Based on the above, patient 5 with a modestly
high Uosm (not tested after dDAVP), a low UCa/
Ucreatinine, and a low PMg fits a DCT lesion.9 Patient 4
would best fit a loop of Henle lesion, if the Uosm
failed to rise after dDAVP was administered. Given
the age of the patient, the most likely lesion in the
loop of Henle is an acquired problem such as the
presence of a cation that occupies the calciumsensing receptor (Ca-SR) on the basolateral membrane of the medullary thick ascending limb of
the loop of Henle.22 Ligands that may bind to this
receptor include Ca2 (hypercalcaemia), cationic
drugs such as aminoglycosides, and cationic proteins (globulins) as might be present in multiple
myeloma.
313
no effect on ENaC
blocks ENaC
Current consultation
314
Figure 5. Non-invasive estimate of the flow rate in the terminal CCD. The barrel-shaped structure represents the CCD.
When ADH acts, the Posm and the osmolality in the luminal fluid of the CCD are equal (represented as 300 mOsm/kg
H2O for easy calculation). For example, if 600 mOsm are excreted in a given time, the minimum flow rate in the terminal
CCD is 2 l.
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loss, the presence of a low K intake would lead to
larger K deficit and thereby, a lower PK. While this
was one factor the medical team had considered,
they were unable to describe a second one that
could have caused such a severe degree of
hypokalaemia. Therefore Professor McCance asked
his question in a more direct fashion. What could
cause the PK to be lower in one of two patients, if
both patients had the same total body K deficit and
identical factors influencing the distribution of K
across cell membranes?
Concluding remarks
Professor McCance said that he enjoyed participating in the K-quiz. What he found even more
rewarding was the opportunity to introduce his
younger colleagues to the application of principles
of integrative physiology (Table 4), to permit
them to deduce answers that may be correct.
He also emphasized the importance of a quantitative analysis. After considerable thought, he
developed Flow Charts 13 to illustrate an
approach to accurate diagnosis and therefore
logical therapy for patients with a severe degree of
hypokalaemia.
Regarding the new consultation, his message
was that more than one mechanism is likely to be
involved to produce such a severe abnormality.
Adding to this diuretic-induced K loss, were a low
intake of K, a shift of K into cells (hormone actions
and metabolic alkalosis), and an ability to amputate the renal effects of a K-sparing diuretic. The
latter could be explained when he considered
both the numerator and denominator of the concentration of this drug in the lumen of the CCD.
Comments
1.
2.
3.
4.
5.
With a low UNH4 V, look next at the urine pH. Those with high
UNH4 V have direct or indirect non-renal NaHCO3 loss
6.
Drug concentration in the CCD will fall with high flow rates to
the CCD
7.
The major osmoles delivered to the CCD are urea and Na Cl
8.
9.
The [K]CCDUK/(U/P)osm
315
316
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