This document discusses the approach to hypokalemia. It begins by distinguishing between renal and extrarenal causes of hypokalemia based on urinary potassium levels and the transtubular potassium gradient. It then reviews various endocrine causes of hypokalemia related to the renin-angiotensin-aldosterone system. Primary aldosteronism is discussed in more detail, including criteria for diagnosis, screening methods such as the aldosterone-renin ratio, and distinctions between forms with and without an adrenal tumor. Tests for evaluating renal tubular function like the urine anion gap and methods for diagnosing renal tubular acidosis are also summarized.

1. Approach to Hypokalemia
Ranjita Pallavi
Internal Medicine
PGY-2

3. Renal Vs Extra renal loss
 Urinary K+: > 20 mEq/L – Renal loss
 Urinary K + : < 20 mEq/L – Extrarenal loss
 TTKG :Transtubular Potassium Gradient
( Urine K+ / Plasma K+ )
( Urine Osm / Plasma Osm )
 TTKG : Renal loss : > 4
Extra renal loss : < 4

5. RENIN HIGH
ALD HIGH
RENIN LOW
ALD HIGH
LOW RENIN
LOW ALD
RAS Primary Hyperaldosteronism NORMALCORTISOL :
Malignant HTN Glucorticoid remediable HTN Apparent mineralocorticoid
excess
Renin SecretingTumor Liddles syndrome
Licorice
DOC
LOW CORTISOL :
Adrenogenital syndrome
11 beta hydroxylase
deficiency
17 alpha hydroxylase
deficiency
HIGH CORTISOL :
Familial Glucocorticoid
Resistance
EctopicACTH
Severe Cushings Syndrome

6. PRIMARY ALDOSTERONISM
 Primary Aldosteronism with an Adrenal
Tumor
 Primary Aldosteronism without an Adrenal
Tumor

7. WHEN TO SCREEN?
Recommended in Hypertensive Patients with
one of the following:
 Hypokalemia
 Severe, resistant or relatively acute
hypertension
 Adrenal incidentaloma

8. PRIMARY ALDOSTERONISM WITH AN
ADRENAL TUMOUR
 Aldosterone producing adrenal adenoma(
rarely adrenal carcinoma)
 Also known as Conn’s Syndrome
 Usually unilateral
 M:F: 1:2
 Commonly seen between 30-50 years
 ~1% patients present with hypertension

9. PRIMARY ALDOSTERONISM WITHOUT
AN ADRENAL TUMOUR
 Idiopathic hyperaldosteronism and/or
nodular hyperplasia
 The adrenal are either normal in appearance
or more commonly reveal Bilateral(10%) or
rarely, unilateral(<1%) micro- or
macronodular adrenal hyperplasia

10. THE CRITERIA FOR DIAGNOSIS OF
PRIMARY ALDOSTERONISM
 Diastolic hypertension without edema
 Renin hyposecretion that fails to increase
appropriately during volume depletion
 Aldosterone hypersecretion that does not
suppress appropriately to volume expansion

11. METHOD OF SCREENING
 Aldosterone conc/Renin activity ratio
 Considered positive if ratio > 20, usually > 30
 In addition, the aldosterone conc. Should be >
15 ng/dL

12. DIAGNOSIS
 Aldosterone > 15ng/dL
 Aldosterone/renin ratio > 30
 Confirmation with Na+ suppression test
 Imaging of the adrenal glands
 AdrenalVein sampling
 18-OH Corticosterone levels may help
differentiate hyperplasia from adenoma

13. Aldosterone Suppression Tests
IV Saline suppression
 500 ml 0.9% NaCl/hr for 4 hours OR 500 ml 0.9% over 30
mimutes, then 500ml/hr for 2 hours
 Draw PAC at time 0, 120 and 150 minutes
 Suppression if PAC< 8.5 ng/dL(<6 normal> 10 PA)
Oral sodium chloride suppression test
 10 gms NaCl dily for 4 days
 On Day 4, collect 24 hour urine aldosterone, sodium
Suppression if aldosterone< 14 mcg and sodium > 200 eEq/24 hours
Fludrocortisone suppression test
 High salt diet and large doses of fludrocortisone over a 4 day hospitalization

14. ADRENAL VEIN SAMPLING
 Considered gold standard to distinguish
adenoma and hyperplasia
 Usually done under ACTH infusion
 Looking for localization of aldosterone
increase
 Very useful when no abnormalities seen on
imaging or bilateral nodules

15. LIDDLE’S SYNDROME
 Clinical features include:
 Hypertension
 Hypokalemia with renal K+ wasting
 Metbolic alkalosis and
 Suppressed plasma renin activity
 Autosomal Dominant

16.  Primary abnormality in renal tubule that
enhances Na+ reabsorption: a defect in the
cyutoplasmic domain of the epithelial Na+
channel that results in gain of fuction
activating mutation of the channel
 Amiloride andTriamterene are specific
inhibitors of this channel, treatment with
these agents corrects the electrolyte
abnormalities and ameliorates the
hypertension.

17. Mechanism of action
Cortisol Aldosterone
Cortisone
(inactive)
11B-Hydroxysteroid
dehydrogenase (11β-
HSD)
Mineralocorticoid
Receptor (MR)
Glycyrrhetinic
Acid
11β-HSD
Cortisol
Cortisol nmol/L
Aldosterone pmol/L

21. Bartter and Gitelman Syndromes

22. Bartter syndrome genotype-
phenotype correlations
Genetic Type Defective Gene Clinical Type
Bartter type I NKCC2 Neonatal
Bartter type II ROMK Neonatal
Bartter type III CLCNKB Classic
Bartter type IV BSND Neonatal with deafness
Bartter typeV CLCNKB and CLCNKA Neonatal with deafness
Gitelman syndrome NCCT Gitelman syndrome

23. Indirect loss of NaHCO3 in glue sniffing.
Groeneveld J et al. QJM 2005;98:305-316
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

24. Functional evaluation of proximal bicarbonate
absorption
Fractional excretion of bicarbonate
 Urine ph monitoring during IV administration
of sodium bicarbonate.
 FEHCO3 is increased in proximal RTA >15%
and is low in other forms of RTA.

25. Functional Evaluation of Distal Urinary
Acidification and Potassium Secretion
 Urine ph
 Urine anion gap
 Urine osmolal gap
 Urine Pco2
 TTKG
 Urinary citrate

26. Urine ph
 In humans, the minimum urine pH that can be
achieved is 4.5 to 5.0.
 Ideally urine ph should be measured in a fresh
morning urine sample.
 A low urine ph does not ensure normal distal
acidification and vice versa.
 The urine pH must always be evaluated in
conjunction with the urinary NH4+ content to
assess the distal acidification process
adequately .
 Urine sodium should be known and urine
should not be infected.

27. Urine anion gap (UAG)
Urine anion gap = [Na+] + [K+] – [Cl-]
 Normal: zero or positive
 Metabolic acidosis: NH4+ excretion increases (which is excreted with
Cl-) if renal acidification is intact
 GI causes: “neGUTive” UAG
 Impaired renal acid excretion (RTA): positive or zero
 Often not necessary b/c clinically obvious (diarrhea)

28. Urine anion gap
 There are, however, two settings in which the
urineAG cannot be used.
 When the patient is volume depleted with a
urine sodium concentration below 25 meq/L.
 When there is increased excretion of
unmeasured anions

29. Urine osmolal gap
 When the urine AG is positive and it is unclear
whether increased excretion of unmeasured
anions is responsible, the urine ammonium
concentration can be estimated from
calculation of the urine osmolal gap.
 UOG=Uosm - 2 x ([Na + K]) + [urea
nitrogen]/2.8 + [glucose]/18.
 UOG of >100 represents intact NH4 secretion.

30. Urine Pco2
 Measure of distal acid secretion.
 In pRTA, unabsorbed HCO3 reacts with
secreted H+ ions to form H2CO3 that
dissociate slowly to form CO2 in MCT.
 Urine-to-blood pCO2 is <20 in pRTA.
 Urine-to-blood pCO2 is >20 in distal RTA
reflecting impaired ammonium secretion.

31. TTKG
 TTKG is a concentration gradient between the
tubular fluid at the end of the cortical collecting
tubule and the plasma.
 TTKG = [Urine K ÷ (Urine osmolality / Plasma
osmolality)] ÷ Plasma K.
 Normal value is 8 and above.
 Value <7 in a hyperkalemic patient indicates
hypoaldosteronism.
 This formula is relatively accurate as long as the
urine osmolality exceeds that of the plasma urine
sodium concentration is above 25 meq/L

32. Urine citrate
 The proximal tubule reabsorbs most (70-90%)
of the filtered citrate.
 Acid-base status plays the most significant
role in citrate excretion.
 Alkalosis enhances citrate excretion, while
acidosis decreases it.
 Citrate excretion is impaired by acidosis,
hypokalemia,high–animal protein diet and
UTI.

33. Renal Tubular Acidosis
 First described clinically in
1935
 Confirmed as a renal
tubular disorder in 1946
 Designated as RTA in
1951
 Refers to disorders
affecting the overall
ability of the renal tubules
either to secrete
hydrogen
ions or to retain
bicarbonate ions
 All types produce
hyperchloremic metabolic
acidosis
with a normal anion gap.

34. Proximal RTA
Proximal RTA (Type 2)
 Caused by an
impairment of
HCO3- reabsorption
in the proximal
tubules
 Most cases occur in
the context of
Fanconi’s syndrome
 Isolated proximal
RTA is rare.

36. DISTAL RTA
 Impairment of distal
acidification
 Inability to lower urine pH
maximally below 6.0 under
acid load
 Pathomechanism is
inability to secrete H+
adequately (secretory
defect or classic distal RTA)
 Gradient defect
 Voltage dependent defect
 In children mainly a genetic
defect of the H+ pump

38. Adolsterone
Water
K+
Na
Na+
H+
Cl-
RTA IV:
Hypoaldosteronism or
pseudohypoaldosteronis
m
H20

39. Proximal RTA Distal RTA RTA IV
Type of
Acidosis
Hyperchloremi
c metabolic
acidosis
Hyperchloremi
c metabolic
acidosis
Hyperchloremic
metabolic
acidosis
Serum
Potassium
low low high
Urine pH < 5.5 >5.5 < 5.5
Urine
bicarbonat
e loss