1. An Unusual Case of Metabolic Alkalosis: A Window Into the Pathophysiology and Diagnosis of This Common Acid-Base Disturbance 
F. John Gennari, MD, Sarah Hussain-Khan, MBBS, Alan Segal, MD 
American Journal of Kidney Diseases 
Volume 55, Issue 6, Pages (June 2010)
DOI: /j.ajkd
Copyright © 2010 National Kidney Foundation, Inc. Terms and Conditions

2. Figure 1
Diagnostic approach to a patient with increased serum total carbon dioxide concentration. Clinical judgment is required to determine whether arterial blood gas analysis is needed for diagnosis and in what settings urine chloride concentration ([Cl−]) be measured. Urine chloride concentration of mEq/L is an indeterminate finding. Abbreviations and definitions: BP, blood pressure; ECF, extracellular fluid; [HCO3−], bicarbonate concentration; NG, nasogastric; Pco2, partial pressure of carbon dioxide; [total CO2], total carbon dioxide concentration.
American Journal of Kidney Diseases  , DOI: ( /j.ajkd )
Copyright © 2010 National Kidney Foundation, Inc. Terms and Conditions

3. Figure 2
Schematics of the collecting duct under various conditions. By convention, the blood side or basolateral membrane of the epithelium is defined as bioelectrical ground (), and the transepithelial voltage in this part of the nephron is lumen negative. Principal and α-intercalated cells both contain the intracellular mineralocorticoid receptor (MR), which can be activated endogenously by either aldosterone or cortisol. 11β-Hydroxysteroid dehydrogenase type 2 (11βHSD2) converts cortisol to cortisone, preventing the former from acting as a mineralocorticoid. The epithelial sodium (ENaC) and renal outer medullary potassium (ROMK) channels are in the apical membrane of principal cells; the Na+-K+-ATPase pump is in the basolateral membrane (for clarity, the K conductance of the basolateral membrane is not shown). H+-ATPase (and, when active, H+-K+-ATPase) is in the apical membrane of α-intercalated cells, and the AE1 (anion exchanger 1) Cl−-HCO3− antiporter is in the basolateral membrane. The relative size of channels corresponds to variations in total membrane conductance, and relative thickness of arrows indicates variations in ion flux. (A) Normal physiology. The rate-limiting step for Na+ reabsorption in the collecting duct is apical entry through ENaC. An increase in Na+ conductance depolarizes the apical membrane; also, by stimulating the Na+-K+-ATPase pump and in turn K+channels in the basolateral membrane (not shown), hyperpolarizes the basolateral membrane. This provides the driving force for K+secretion via ROMK and facilitates H+ secretion through H+-ATPase. An increase in total ENaC activity (eg, due to increases in flow rate, Na+ delivery, and/or aldosterone) increases the driving force for K+ and H+ secretion. Aldosterone binds to the intracellular MR, resulting in genomic and nongenomic stimulating effects on ENaC, Na+-K+-ATPase, and H+-ATPase. Normally, the enzymatic action of 11βHSD2 prevents cortisol from acting as a mineralocorticoid. (B) Primary hyperaldosteronism and chloride depletion states promote increased ENaC activity and Na+ reabsorption across the apical membrane by increasing distal Na+ delivery and/or increasing aldosterone secretion, which increases lumen electronegativity and the driving force for K+ secretion through ROMK channels and H+ secretion via H+-ATPase pumps. The increase in Na+ delivery is consequent to either hypervolemia or decreased Na+ reabsorption in the thick ascending limb of the loop of Henle or early distal tubule (eg, due to loop or thiazide diuretics, respectively). Whether aldosterone secretion continues at a normal or increased rate depends on the clinical setting. In either case, changes in electrogenic ion transport induced by the loss of the normal inverse relationship between Na+ delivery and aldosterone secretion, along with the resultant K+ depletion that induces insertion of H+-K+-ATPase pumps into the apical membrane of α-intercalated cells, generates and sustains metabolic alkalosis. (C) In Liddle syndrome, the rate-limiting step for Na+ reabsorption in the collecting duct becomes dysregulated when a gain-of-function mutation occurs in ENaC, resulting in a decrease in endocytic removal of ENaC from the apical membrane and an increase in the open probability of the channels in the membrane. The resulting Na+ hyper-reabsorption suppresses renin and aldosterone secretion, and the increased apical Na+ conductance increases lumen electronegativity, which promotes K+ and H+ secretion. This results in the triad of hypertension, hypokalemia, and metabolic alkalosis despite negligible plasma aldosterone levels. (D) Genetic 11βHSD2 deficiency or habitual ingestion of substances that inhibit the enzyme (eg, carbenoxolone or black licorice) allow cortisol to accumulate within collecting duct cells. Intracellular accumulation of cortisol activates the MR and its downstream signaling, producing hypertension, hypokalemia, and metabolic alkalosis with suppressed plasma aldosterone levels.
American Journal of Kidney Diseases  , DOI: ( /j.ajkd )
Copyright © 2010 National Kidney Foundation, Inc. Terms and Conditions