Upload
stevechendoc
View
19
Download
1
Embed Size (px)
Citation preview
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