Kidney Case Conference:
Nephrology Quiz and Questionnaire
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Hypertension with Hypokalemic Metabolic Alkalosis:
The Diagnosis Is Apparent
WnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 01/06/2024
Roger Rodby
CJASN 18: 965–968, 2023. doi: https://doi.org/10.2215/CJN.0000000000000166
An 84-year-old woman was admitted for fatigue and
weakness. The medical history was significant for lung
cancer. There was no history of diabetes or hyperten-
sion, and the patient was not taking diuretics. On
physical exam, BP was 160/90 mm Hg, heart rate
was 80, and respiration rate was 16. There was no
edema. Laboratory test results on admission were as
follows: blood glucose was 400 mg/dl; the basic met-
abolic panel showed Na1 136 mmol/L, K1 2.1 mmol/L,
Cl2 88 mmol/L, HCO32 32 mmol/L, BUN 12 mg/dl,
and creatinine 0.7 mg/dl; and an arterial blood
gas showed pH 7.52, PCO2 40 mm Hg, HCO32
32 mmol/L, and PO2 96 mm Hg.
Question 1
How would you characterize this acid-
base disorder?
A. Uncompensated metabolic alkalosis
B. Compensated metabolic alkalosis and anion gap
metabolic acidosis
C. Anion gap metabolic acidosis, metabolic alkalosis,
and respiratory alkalosis
D. Uncompensated anion gap metabolic acidosis
Discussion of Question 1
The approach to these data can be simplified as
follows: The correct answer is C. The elevated arterial
blood gas pH at 7.52 represents an alkalemia. With a
HCO32 of 32 mmol/L, this is a metabolic alkalosis. The
normal response to metabolic alkalosis is to decrease
ventilation and raise PCO2, the amount ranging from
0.253 to 1.03 the change in HCO32. In this patient,
there is an increase of 8 mmol/L from a normal HCO32
of 24 mmol/L. Thus, you would expect the PCO2 to
increase from the normal value of 40 mm Hg by
2–8 mm Hg (resultant [PCO2] of 42–48 mm Hg).
This patient’s PCO2 is 40 mm Hg and demonstrates
a lack of appropriate respiratory compensation,
indicating a simultaneous primary respiratory alkalo-
sis. Finally, we calculate the anion gap because the
presence of a metabolic alkalosis does not exclude the
presence of a simultaneous hidden metabolic acidosis.
In fact, the anion gap is elevated at 16, which defines
www.cjasn.org Vol 18 July, 2023
Rush University
the third (triple) acid-base finding in this case, a hidden Medical Center,
Chicago, Illinois
anion gap metabolic acidosis.1
Correspondence:
Dr. Roger Rodby, Rush
Case Continued University University
The serum lactate was normal, but the serum b-OH- Medical Center,
butyrate was elevated at 6 mmol/L consistent with Division of
diabetic ketoacidosis. The patient was treated with Nephrology,1426 W
intravenous fluid and insulin, and the blood glucose Washington
Boulevard, Chicago, IL
and anion gap normalized; her respiratory alkalosis 60607. Email:
resolved, but the hypokalemic metabolic alkalosis rogerrodby@mac.com
(now a single acid-base disorder) persisted; and the
patient remained hypertensive. There was no history of
licorice use.
Her basic metabolic panel showed the following
results: Na1 140 mmol/L, K1 2.4 mmol/L, Cl2
94 mmol/L, and HCO32 36 mmol/L; arterial blood
gas showed pH 7.51, PCO2 46 mm Hg, HCO32
36 mmol/L, and PO2 96 mm Hg. Urine studies
showed a spot urine K1 of 43 mmol/L, urine cre-
atinine of 51 mg/dl, and urine Cl2 of 105 mmol/L.
Both plasma renin activity (PRA) and plasma
aldosterone concentration were suppressed (PRA
0.3 ng/ml per hour, plasma aldosterone concentra-
tion 1.1 ng/dl).
Question 2
Which of the following tests would most likely pro-
vide the diagnosis?
A. 24-hour urine for cortisol, cortisone, and aldosterone
B. 24-hour urine for free cortisol-to-cortisone ratio
C. Genetic testing for Liddle syndrome
D. Serum 11-b-hydroxysteroid dehydrogenase type
2 levels
E. 24-hour urine for glycyrrhizic acid
Discussion of Question 2
The evaluation of hypokalemic metabolic alkalosis
with hypertension covers a vast differential diagnosis
that encompasses several genetic, acquired, and even
iatrogenic disorders.
We can approach these three findings indepen-
dently, but there is considerable overlap. Hypokalemia
Copyright © 2023 by the American Society of Nephrology 965
 966 CJASN
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Figure 1. Factors that prevent or allow cortisol’s conversion to cortisone by 11-b-hydroxysteroid dehydrogenase (11-b-HSD). (A) In
normal individuals, 11-b-HSD in the kidney converts cortisol (with mineralocorticoid activity) to cortisone (that lacks mineralocorticoid
activity). (B) This cortisol to cortisone conversion by 11-b-HSD can be impaired by two mechanisms: (1) a congenital lack of 11-b-HSD or
(2) if the enzyme is blocked by glycyrrhizic acid (found in licorice products) or the antifungal agents posaconazole and itraconazole. The
excessive cortisol effect in the kidney then leads to hypertension with hypokalemia, metabolic alkalosis with suppressed renin and
aldosterone. (C) In Cushing’s disease, excessive ACTH can cause the production of so much cortisol that it overwhelms 11-b-HSD’s
ability to convert it adequately to cortisone. This renal hypercortisolism results in an uncontrolled mineralocorticoid effect on the kidney,
again causing hypertension with hypokalemia, metabolic alkalosis with suppressed renin and aldosterone. ACTH, adrenocorticotrophic
hormone; DOC, deoxycorticosterone.

can occur from renal or extrarenal losses. A urine K1-to-
urine creatinine (K1/Cr) ratio of .13 mmol/g (or .1.5
mmol/mmol) indicates renal K1 loss as the etiology for
hypokalemia, which is the case here with a urine K1/Cr of
84 mmol/g.2 Metabolic alkalosis can be divided into chlo-
ride (Cl2)-responsive or Cl2-unresponsive as determined
by a urine Cl2 of ,20 mmol/L (responsive) or .20 mmol/L
(unresponsive).3 With this patient’s urine Cl2 of 105 mmol/
L, this is a Cl2-unresponsive metabolic alkalosis. The pres-
ence of hypertension takes this case out of the Gitelman/
Bartter spectrum. The next approach to this patient with
hypertension, hypokalemic metabolic alkalosis with both
 CJASN 18: 965–968, July, 2023
high urine K1 and Cl2, is to assess renin and aldosterone
levels. Doing so will produce one of three patterns4:
1. High renin and high aldosterone seen in
a. Renovascular hypertension
b. Reninoma—an extremely rare renin-producing tumor
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c. During episodes of malignant hypertension
2. Suppressed renin with high aldosterone seen in
a. Autonomous adrenal aldosterone production from
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either an adenoma or bilateral hyperplasia
b. Glucocorticoid-remediable aldosteronism
And finally,
3. Suppression of both renin and aldosterone seen in
a. Liddle syndrome
b. Geller syndrome
c. Apparent mineralocorticoid excess (AME) syndromes:
i. Hereditary
ii. Iatrogenic from licorice (glycyrrhizic acid), pos-
aconazole, or itraconazole
iii. Cushing syndrome
iv. A DOC (deoxycorticosterone)-producing tumor
This patient’s renin and aldosterone were suppressed,
putting her into the third diagnostic category listed
above. Liddle syndrome is a rare autosomal dominant
disease of an overactive epithelial sodium channel in the
collecting tubule. The hypertension in this disease can be
severe with a strong family history of hypertension and
strokes and would not present in the ninth decade of life.
Liddle syndrome is typically treated with amiloride.
Aldosterone antagonists will not be effective because
the defect of the sodium channel is not dependent
on aldosterone.5 Geller syndrome is a rare autosomal
dominant gain-of-function mutation of the aldosterone
receptor. In addition, in Geller syndrome, normal aldo-
sterone antagonists, e.g., progesterone and spironolac-
tone, become aldosterone agonists. This is particularly
problematic if misdiagnosed and the patient receives
spironolactone or is in pregnancy when progesterone
levels get quite high. Geller syndrome is also best treated
with amiloride.6 This disease similarly does not first
appear in an 84-year-old postmenopausal woman.
Both Liddle and Geller syndromes would require genetic
testing for diagnosis.
We are thus left with the syndromes of AME.7 Cortisol
is the body’s major glucocorticoid produced by the ad-
renal gland. It also has activity on the aldosterone re-
ceptor (mineralocorticoid activity). However, the kidney
possesses the enzyme 11-b-hydroxysteroid dehydroge-
nase 2 (11-b-HSD), which converts cortisol to cortisone;
cortisone lacks mineralocorticoid activity (Figure 1A).
There are three ways that this physiologic enzymatic
inactivation can go wrong, allowing cortisol to act as a
mineralocorticoid (causing hypertension with hypokale-
mia, metabolic alkalosis, and suppression of renin and
aldosterone).
1. Mutations in 11-b-HSD, making it ineffective. These are
rare autosomal recessive conditions that present in
childhood (Figure 1B).
Hypertension with Metabolic Alkalosis and Hypokalemia, Rodby 967
2. Inhibition of 11-b-HSD, making it ineffective. This is
typically described from excessive ingestion of glycyr-
rhizic acid, found in licorice, anise-flavored liquors, and
chewing tobacco. The antifungal agents posaconazole
and itraconazole have also been shown to inhibit
11-b-HSD (Figure 1B).
3. Overwhelming 11-b-HSD in the presence of extremely
high levels of cortisol so that cortisol is not sufficiently
converted to inactive cortisone (Figure 1C).
Finally, there are very rare adrenal tumors that produce
DOC. These tumors are typically very large and malignant.
DOC is a mineralocorticoid agonist (1/20th of the Na re-
taining effect of aldosterone) and a glucocorticoid antago-
nist (Figure 1A).
In this case, endocrinology was consulted to diagnose
the possibility of an ectopic adrenocorticotrophic hormone
(ACTH) syndrome as evidenced by new-onset diabetes,
worsening hypertension in the setting of a chloride non-
responsive hypokalemic metabolic alkalosis with sup-
pressed renin and aldosterone.
c An evening salivary cortisol level was .1000 mg/dl
(normal ,0.13).
c A dexamethasone suppression test was administered
with the following results:
○ Serum cortisol was 83 mg/dl (normal ,1.8).
○ ACTH was 232 pg/ml (no suppression).
The patient’s tumor was a metastatic lung carcinoid
tumor. Carcinoid tumors have been known to produce
various neuroendocrine hormones, such as ACTH.8 Ec-
topic ACTH-related Cushing syndrome will have ACTH
(and thus cortisol) levels much higher than that in Cushing
disease from ACTH-producing pituitary adenomas. As
demonstrated in Figure 1C, the amount of cortisol
produced by the adrenal gland in response to the high
ACTH overwhelms 11-b-HSD’s ability to adequately con-
vert cortisol to mineralocorticoid-inactive cortisone. The
diagnosis of AME can thus be made by a 24-hour urine
collection to determine the ratio of free cortisol to free
cortisone. This ratio is typically ,1.0, and it was extremely
elevated at 12 in this patient. The correct answer for
Question 2 is B.
The treatment of this disorder in addition to treating the
tumor directly with chemotherapy is to use a mineralocor-
ticoid antagonist to block the excessive cortisol from acti-
vating the mineralocorticoid receptor. Ketoconazole can
also used because it has been shown to inhibit adrenal
steroidogenesis.9
Disclosures
R. Rodby reports an advisory or leadership role for the NXStage
Scientific Advisory Board.
Funding
None.
Acknowledgments
For most American Society of Nephrology (ASN) Kidney
Week attendees, case-based clinical nephrology talks are one
of the most exciting venues. The Nephrology Quiz and Ques-
tionnaire is the essence of clinical nephrology and represents
 968 CJASN
what drew all of us into the field of nephrology. The expert
discussants prepared vignettes of puzzling cases, which illus-
trated some topical, challenging, or controversial aspect of the
diagnosis or management of key clinical areas of nephrology.
These cases were presented and eloquently discussed by our four
expert ASN faculty. Subsequently, each discussant prepared a man-
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uscript summarizing his or her case discussions, which serves as the
main text of this article (Melanie P. Hoenig and Michael J. Ross,
comoderators).
Author Contributions
WnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 01/06/2024
Writing – original draft: Roger Rodby.
Writing – review & editing: Roger Rodby.
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Published Online Ahead of Print: April 7, 2023