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A new perspective on metabolic alkalosis
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.
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A new perspective on metabolic alkalosis
- 1. A New Perspectiveon Metabolic alkalosis Taipei Veterans General Hospital, Hsin-Chu branch Director of Nephrology Steve Chen HCO3-
- 3. Analysis of Acid-BaseDisorders
- 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-BASEDISTURBANCES 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 hydrogenions into the intracellular space Hypokalemia
- 14. Na+ NHE-3 H+ HCO3- Na+ NBC H2O CO2+ CA-2 Na+ K+ Na/K ATPase Intracellularacidosis ► ↑ 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 ►↓ Clre-absorption in DCN TSCNa Cl V2R Inactive TSC dimer TSC monomer AT1R MR SPAK TSC: Thiazide Sensitive Co-transporter
- 17. Hypokalemia Metabolicalkalosis • 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.
- 19. Aldosterone ►Hypokalemia inCCD E Na C ROMK Na K ATP ase Depolarize + Aldosterone + Na K H Principal cell
- 20. Competitive affinity forMR Cortisol >> Aldosterone > cortisone E Na C ROMK Na K ATP ase Depolarize Na K H Aldosterone MR: Mineralocorticoid receptor
- 22. Gastrointestinal H+ loss Vomitingor 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 - intracellularmagnesium 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 magnesiumdeficiency 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 Vomitingor 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, evenwithout 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 maculadensa Renin ↑
- 29. Bartter’s syndrome inTHAL NKCC ROMK Na K ATP ase Na/K K 2Cl CaSR Negative Positive ClC-Kb ClC-KB
- 30. Variants of Bartter’ssyndrome 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 inDCT 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’ssyndrome 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.
- 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.
- 37. 11-beta-hydroxysteroid dehydrogenase type2 (11β-HSD2): cortisolcortisone 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.
- 40. Glucocorticoid-remediable aldosteronism an autosomaldominant 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 ofTreatment ↑ 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 ofTreatment 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