A new perspective on metabolic alkalosis

A New Perspective on Metabolic alkalosis

Taipei Veterans General Hospital, Hsin-Chu branch

Director of Nephrology

Steve Chen

HCO3-

Analysis of Acid-Base Disorders

Na+

NHE-3

H+ HCO3-

Na+

NBC

H2O CO2+

CA-2

Na+

K+

Na/K ATPase

PCT: ↓ Re-absorption of HCO3-

H+HCO3-

H+ATPase

H+

H2O

OH- CO2

HCO3-

+Cl-

CA

CCD: ↓ H+ secretion

AE-1

α - intercalated cell

CCD: ↑ HCO3- secretion generation

Pendrin

β intercalated cell

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

Shift of hydrogen ions into the intracellular space

Hypokalemia

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-

H+ATPase

H+

H2O

OH- CO2

HCO3-

+Cl-

CA

Hypokalemia ► ↑H+ ATPase in CCD

AE-1

Hypokalemia ►↓ Cl re-absorption in DCN

TSCNaCl

V2R

Inactive TSC dimer TSC

monomer

AT1R

MRSPAK

TSC: Thiazide Sensitive Co-transporter

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

Cortisone excessCushing syndrome

Aldosterone ►Hypokalemia in CCD

E Na C

ROMK

Na K ATP aseDepolarize

+

Aldosterone+

Na

K

H

Principal cell

Competitive affinity for MR Cortisol >> Aldosterone > cortisone

E Na C

ROMK

Na K ATP aseDepolarize

Na

K

H

Aldosterone

MR: Mineralocorticoid receptor

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

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

KMg

Hypokalemia in magnesium deficiencyHuang et al: JASN 2007 (University of Texas Medical Center)

• CCT

E Na C

ROMK

Na K ATP ase

Urine Blood

Na

K

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

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 ).

Chloride sensor in macula densa

Renin ↑

Bartter’s syndrome in THAL

NKCC

ROMK

Na K ATP aseNa/K

K

2Cl

CaSRNegative

Positive

ClC-Kb

ClC-KB

Variants of Bartter’s syndromeIsrael 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

Gitelman’s syndrome in DCT

TSCNaCl

V2R

Inactive TSC dimer TSC

monomer

AT1R

MRSPAK

FE-Cl > 0.5%Hypocalciuria: Ca/Cr < 0.07 (mg/mg)

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 thriveMimicked by Thiazides Loop diuretics

Plasma Mg ↓ ↓

D.D. Hypocalciuria HypercalciuriaUosm ↓

Check urine Cl-

Low urine chloride ( < 20 meq/L)

High urine chloride (> 20 meq/L)

Chloride responsiveRemote diureticVomiting/NG suction Congenital chloridorrhea: ARVillous 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

HTN

11β-HSD2D

11-beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2): cortisolcortisone

allow  Aldosterone free access to MR in CCD

E Na C

ROMK

Na K ATP aseDepolarize

Na

K

H

Aldosterone

MR: Mineralocorticoid receptor

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

HTN

GRH

Glucocorticoid-remediable aldosteronism an autosomal dominant disorder, in which ectopic production of aldosterone in the

zona fasciculata of the adrenal cortex occurs

Simple or mixed ?Conditions Primary event Secondary responseMetabolic 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

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

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