The document discusses metabolic alkalosis, outlining the mechanisms that can cause increased bicarbonate levels including hypokalemia, hypomagnesemia, corticosteroid excess, and gastrointestinal or renal losses of hydrogen ions. It examines these mechanisms in detail through their effects on ion transporters in the kidney, and explores related conditions like Bartter syndrome, Gitelman syndrome, and mineralocorticoid excess. General principles for treatment focus on increasing renal bicarbonate excretion and addressing underlying causes of potassium depletion or reduced effective arterial blood volume.

1. A New Perspective on
Metabolic alkalosis
Taipei Veterans General Hospital, Hsin-Chu branch
Director of Nephrology
Steve Chen
HCO3-

3. Analysis of Acid-Base Disorders

5. Na+
NHE-3
H+ HCO3-
Na+
NBC
H2O CO2+
CA-2
Na+
K+
Na/K
ATPase
PCT: ↓ Re-absorption of HCO3-
H+HCO3-

6. H+
ATP
ase
H+
H2O
OH- CO2
HCO3-
+
Cl-
CA
CCD: ↓ H+ secretion
AE-1
α - intercalated cell

7. CCD: ↑ HCO3- secretion  generation
Pendrin
β intercalated cell

9. TYPES OF ACID-BASE DISTURBANCES
Depression of the central
nervous system, as evidenced
by disorientation followed by
coma
Excitability of the nervous
system; muscles may go
into a state of tetany and
convulsions

13. Shift of hydrogen ions into the intracellular space
Hypokalemia

14. Na+
NHE-3
H+ HCO3-
Na+
NBC
H2O CO2+
CA-2
Na+
K+
Na/K
ATPase
Intracellular acidosis ► ↑ Re-absorption of
HCO3- in PCT
H+HCO3-

15. H+
ATP
ase
H+
H2O
OH- CO2
HCO3-
+
Cl-
CA
Hypokalemia ► ↑H+ ATPase
in CCD
AE-1

16. Hypokalemia ►↓ Cl re-absorption
in DCN
TSCNa
Cl
V2R
Inactive
TSC dimer TSC
monomer
AT1R
MR
SPAK
TSC: Thiazide Sensitive Co-transporter

17. Hypokalemia  Metabolic alkalosis
• Hypokalemia results in the shift of hydrogen ions
intracellularly. The resulting intracellular acidosis enhances
bicarbonate re-absorption in the collecting duct
• Hypokalemia stimulates the apical H+/K+ ATPase in the
collecting duct
• Hypokalemia stimulates renal ammonia genesis and alpha-
ketoglutarate is produced, the metabolism of which
generates bicarbonate that is returned to the systemic
circulation
• It leads to impaired chloride ion re-absorption in the distal
nephron. This results in an increase in luminal electro-
negativity, with subsequent enhancement of hydrogen ion
secretion

18. Cortisone excess
Cushing syndrome

19. Aldosterone ►Hypokalemia in CCD
E Na C
ROMK
Na K ATP ase
Depolarize
+
Aldosterone
+
Na
K
H
Principal cell

20. Competitive affinity for MR
Cortisol >> Aldosterone > cortisone
E Na C
ROMK
Na K ATP ase
Depolarize
Na
K
H
Aldosterone
MR: Mineralocorticoid receptor

22. Gastrointestinal H+ loss
Vomiting or NG suction
Antacids in advanced renal failure
Renal H+ loss
Primary mineralocorticoid excess
Post-hypercapnic alkalosis
Hypercalcemia (milk-alkali syndrome)
Intracellular shift of H+
Hypokalemia / Hypomagnesemia
Alkali administration
Excess CPR (Ringer lactate)
Excess transfusion(citrate blood)
Contraction alkalosis (Loss of bicarbonate-poor, chloride-rich extracellular fluid)
Loop or thiazide diuretics
Bartter or Gitelman syndrome
Sweat loss in cystic fibrosis
Villous adenoma(Chronic chloride diarrhea )or factitious diarrhea(Laxative abuse)
∆HCO3- < 2~4 meq/L

23. ROMK - intracellular magnesium
Huang et al: JASN 2007 (University of Texas Medical Center)
• CCT
E Na C
ROMK
Na K ATP ase
UK 5mM CK 143mM
Na
K
Mg

24. Hypokalemia in magnesium deficiency
Huang et al: JASN 2007 (University of Texas Medical Center)
• CCT
E Na C
ROMK
Na K ATP ase
Urine Blood
Na
K

25. Gastrointestinal H+ loss
Vomiting or NG suction
Antacids in advanced renal failure
Renal H+ loss
Primary mineralocorticoid excess
Post-hypercapnic alkalosis
Hypercalcemia (milk-alkali syndrome)
Intracellular shift of H+
Hypokalemia / Hypomagnesemia
Alkali administration
Excess CPR (Ringer lactate)
Excess transfusion(citrate blood)
Contraction alkalosis
(Loss of bicarbonate-poor, chloride-rich extracellular fluid)
Loop or thiazide diuretics
Bartter or Gitelman syndrome
Sweat loss in cystic fibrosis
Chronic chloride diarrhea (AR)
∆HCO3- < 2~4 meq/L

26. Chloride depletion, even without volume
depletion, enhances bicarbonate re-absorption
• In the late thick ascending limb (THAL) and early
distal tubule, specialized cells called the macula
densa are present
• Na+/K+/2Cl- cotransporter in the apical membrane,
which is mainly regulated by chloride ions
• When fewer chloride ions reach this transporter
(eg, chloride depletion), the macula densa signals
the juxtaglomerular apparatus (ie, specialized
cells in the wall of the adjacent afferent arteriole) to
secrete renin, which increases aldosterone
secretion via angiotensin II ( ↑RAA ).

27. Chloride sensor
in macula densa
Renin ↑

29. Bartter’s syndrome in THAL
NKCC
ROMK
Na K ATP ase
Na/K
K
2Cl
CaSR
Negative
Positive
ClC-Kb
ClC-KB

30. Variants of Bartter’s syndrome
Israel Zelikovic, NDT 18: 1696-1700, 2003
Defective
transporter/protein
Clinical Locus
Type I NKCC2 (TAL) Antenatal 15q
Type II ROMK (TAL/CD) Antenatal 11q
Type III ClC-Kb (TAL,DCT) Classic 1p36
Type IV Barttin (β of CIC-
Ka/CIC-Kb)
BSND
(Deafness)
1p31
AD
Hypercalciuria
CaSR
(PT/TAL/DCT/CD)
Hypocalcemia 3q

31. Gitelman’s syndrome in DCT
TSC
Na
Cl
V2R
Inactive
TSC dimer TSC
monomer
AT1R
MR
SPAK
FE-Cl > 0.5%
Hypocalciuria:
Ca/Cr < 0.07
(mg/mg)

32. Gitelman’s / Bartter’s syndrome
Gitelman’s Bartter’s
Molecular level ↓TSC in DCT ↓NKCC, ROMK, or
Cl
Age at onset Teenage Children
Clinical Tetany Failure to thrive
Mimicked by Thiazides Loop diuretics
Plasma Mg ↓ ↓
D.D. Hypocalciuria Hypercalciuria
Uosm ↓

34. Check urine
Cl-

35. Low urine chloride
( < 20 meq/L)
High urine chloride
(> 20 meq/L)
Chloride responsive
Remote diuretic
Vomiting/NG suction
Congenital chloridorrhea: AR
Villous adenoma (rare)
Cystic fibrosis
S/P Chronic hypercaria
Chloride unresponsive
Recent diuretic
Severe K depletion
High BP
Primary hyperaldosteronism
Cushing’s disease
Ectopic ACTH production
Exogenous mineralocorticoids
Mineralocorticoid like substance
Liddle’s syndrome
Low BP
Bartter’s syndrome
Gitelman’s syndrome

36. HTN
11β-
HSD2D

37. 11-beta-hydroxysteroid dehydrogenase type 2
(11β-HSD2): cortisolcortisone
allow Aldosterone free access to MR in CCD
E Na C
ROMK
Na K ATP ase
Depolarize
Na
K
H
Aldosterone
MR: Mineralocorticoid receptor

38. 11-beta-hydroxysteroid dehydrogenase
type 2 (11B-HSD2) deficiency
• AR
• Syndrome of apparent mineralocorticoid excess
(AME)
• Hypertension with low renin and low aldosterone,
hypokalemia, and metabolic alkalosis
• Serum cortisol is within the reference range
because the negative feedback of cortisol on
adrenocorticotropic hormone (ACTH) is intact.
• The enzyme may be inhibited by glycyrrhizic acid,
which is found in licorice and chewing tobacco, or
carbenoxolone, which is a synthetic derivative of
glycyrrhizinic acid

39. HTN
GRH

40. Glucocorticoid-remediable aldosteronism
an autosomal dominant disorder, in which ectopic production of aldosterone in the
zona fasciculata of the adrenal cortex occurs

42. Simple or mixed ?
Conditions Primary event Secondary response
Metabolic acidosis
(30 minutes onset,
12-24H completion)
HCO3 ↓ 1 meq/L pCO2 ↓ 1.2 mmHg
Metabolic alkalosis
(30 minutes onset,
12-24H completion)
HCO3 ↑ 1 meq/L pCO2 ↑ 0.7 mmHg
Respiratory acidosis
Acute
Chronic > 3-5days
pCO2 ↑ 10 mmHg HCO3
↑ 1 meq/L
↑ 3.5-4 meq/L
Respiratory alkalosis
Acute
Chronic >3-5 days
pCO2 ↓ 10 mmHg HCO3
↓ 2 meq/L
↓ 4-5 meq/L

44. General Principles of Treatment
 ↑ Renal bicarbonate excretion ( urine pH>7 )
A reduced effective arterial blood volume (EABV)
Chloride depletion (hypochloremia)
Potassium depletion (hypokalemia)  K supply
 All exogenous sources of alkali should be
discontinued: Citrate/Ketones/Lactate
 Drugs that reduce gastric HCl secretion.
H2 blockers
PPI
NS

45. General Principles of Treatment
 Acetazolamide(250-500mg/D) is a carbonic
anhydrase inhibitor that preferentially
inhibits proximal sodium bicarbonate
reabsorption
 Potassium-sparing diuretics
 NH4Cl ( 100 meq/L/ 20 mL vial)
1-2 vials in 1000 mL of NS