Clinical Note

Aldosteronism and Liddle's Syndrome

Bilateral hyperplasia or a discrete tumor of the adrenal cortex (adrenal adenoma) can result in the secretion of aldosterone at high and unregulated rates. In such patients, an elevated stimulus is observed in Na+ reabsorption and K+ secretion by CNT and principal cells, and in H+ secretion by the intercalated cells (see later discussion). The resulting increases in K+ and H+ secretion lead to hypokalemia and alkalosis, whereas the decreased excretion of Na+ leads to extracellular volume expansion. The resulting syndrome, referred to as primary aldosteronism, is characterized by mild to moderate hypertension from the expanded vascular volume and by muscle weakness, cramping, and cardiac arrhythmias from the hypokalemia and alkalosis. In diagnosing this condition, it is important to rule out diuretic use as a cause (see the preceding Clinical Note). Then, typically, the serum renin level is measured.

If the renin level is low, it indicates that the plasma angiotensin II level is also low, and the physician can rule out excessive aldosterone production being driven by excessive renin production, as might occur with atherosclerotic blockage of blood flow to one or both renal arteries. The physician can then order a measurement of the aldosterone level in a plasma sample taken after the patient is given intravenous saline to be sure that extracellular fluid volume contraction is not driving aldosterone production. If plasma aldosterone is high in this setting, it confirms a diagnosis of aldosteronism because all of the stimuli for aldosterone release are either absent or working in an opposing direction: Extracellular fluid volume is normal or expanded, the plasma Na+ concentration is normal or slightly elevated, the plasma K+ concentration is low, and angiotensin II levels are low. At this point, a computed tomography scan or adrenal venous catheterization can demonstrate the presence of a renal adenoma or may indicate bilateral adrenal hyperplasia. The syndrome can then be treated surgically or, if less severe, by administering the aldosterone renal receptor blocker spironolactone.

In the early 1960s, the endocrinologist Grant Liddle described a patient with all of the symptoms of aldosteronism but with a low plasma aldosterone. Treatment of this patient with spironolactone, a competitive inhibitor for aldosterone receptors, was ineffective, but the hypertension and hypokalemia were diminished by the Na+ channel blocker triamterene, leading Liddle to suggest that the cause was abnormally stimulated Na+ reabsorption in the distal tubule and collecting duct. This turned out to be a prescient hypothesis.

This condition, which came to be known as Liddle's syndrome or pseudoaldosteronism, was found to be due to an autosomal dominant genetic disorder. More than 30 years after the first patient was described, the genetic messages coding the proteins of the Na+ channel were cloned and sequenced. Three similar proteins called subunits (for epithelial Na+ channel) ENaC were found to make up the channel and all affected members of the kindred had a mutation in one of these three proteins. This mutation prevents normal regulation of the channel so it remains in a permanently active state in the luminal membranes of CNT and principal cells, regardless of the aldosterone level. It is interesting to note that the resulting syndrome is an example of hypertension caused by a renal defect. In fact, the original patient later in her life underwent a kidney transplant because of end-stage renal disease and experienced a subsequent abatement of her hypertension.

Apparent mineralocorticoid excess is a syndrome similar to Liddle's syndrome and includes hypertension, hyperkalemia, and alkalo-sis in the presence of low plasma aldosterone. In this case, the defect is caused by a variety of mutations in the gene for 11 ^-hydroxysteroid dehydrogenase, which lead to a loss in its activity. The enzyme is also inhibited by some exogenous agents including licorice!

to the plasma. The primary difference between the proximal and the distal tubule is the large gradient of protons that can be developed across the epithelium by the intercalated cells in the distal nephron, which can produce urine with a pH as low as 4.5. This is equal to a hydrogen ion concentration of 31.6 mM, compared with a concentration of 40 nM in the plasma—almost an 800fold increase! Obviously, a high-energy active transport

FIGURE 8 Scanning electron micrographs of epithelial cells in the cortical portion of the collecting duct. (Top) A collecting duct has been fractured along its axis to reveal the luminal surface of several cells. This segment of the nephron possesses two distinct cell types, principal (P) and intercalated (I) cells. The principal cell has only a few short microvilli on its luminal surface and a single cilium; the apical membrane of the intercalated cell is folded in numerous ridge-like microplicae. (Bottom) A higher magnification scanning electron micrograph showing the microplicae of an intercalated cell. This intercalated cell is surrounded by several principal cells. (Micrographs courtesy of Dr. Andrew P. Evan, Indiana University Medical Center, Indianapolis, IN.)

FIGURE 8 Scanning electron micrographs of epithelial cells in the cortical portion of the collecting duct. (Top) A collecting duct has been fractured along its axis to reveal the luminal surface of several cells. This segment of the nephron possesses two distinct cell types, principal (P) and intercalated (I) cells. The principal cell has only a few short microvilli on its luminal surface and a single cilium; the apical membrane of the intercalated cell is folded in numerous ridge-like microplicae. (Bottom) A higher magnification scanning electron micrograph showing the microplicae of an intercalated cell. This intercalated cell is surrounded by several principal cells. (Micrographs courtesy of Dr. Andrew P. Evan, Indiana University Medical Center, Indianapolis, IN.)

process is required to transport protons up such a steep electrochemical potential gradient. Furthermore, the epithelium of the distal nephron segments must be relatively impermeant to the back-leak of protons from the lumen to the plasma, which would dissipate the luminal acidity.

The mechanism used for active proton secretion across the luminal membrane of the proximal tubule is Na+-H+ exchange. However, the amount of energy available in the Na+ electrochemical potential gradient is not sufficient to generate the steep proton

FIGURE 9 H+ secretion by intercalated cells. H+ is actively secreted from the cell into the lumen by an H+-ATPase located in the luminal membrane. HCO3— exits across the basolateral membrane down its electrochemical potential gradient into the interstitium via an antiport mechanism in exchange for Cl—.

FIGURE 9 H+ secretion by intercalated cells. H+ is actively secreted from the cell into the lumen by an H+-ATPase located in the luminal membrane. HCO3— exits across the basolateral membrane down its electrochemical potential gradient into the interstitium via an antiport mechanism in exchange for Cl—.

concentration gradient observed in the distal nephron. As shown in Fig. 9, proton secretion by intercalated cells is directly coupled to ATP hydrolysis by the proton-activated H+-ATPase in the luminal membrane.

As protons are secreted into the lumen, the proton concentration within the cells falls and drives the production of additional HCO—. Therefore, just as in the proximal tubule cell, the secretion of H+ results in a higher HCO3— concentration in the cells that favors the diffusion of HCO3— out of the cell down its electrochemical potential gradient. As in the proximal tubule, the efflux of HCO— must be mediated across the cell membrane, and the only transporter available is located in the basolateral membrane. However, in contrast with the proximal tubule, this transporter is an anion exchanger. HCO— movement out of the cell occurs in exchange for Cl— movement into the cell, as shown in Fig. 9. The net result is that H+ is secreted actively into the lumen and HCO— diffuses passively into the plasma.

H+ secretion by the intercalated cell is also sensitive to aldosterone. Aldosterone increases H+ secretion, particularly in the outer medullary regions of the collecting duct, but the mechanisms involved in this stimulation are not yet fully understood.

The H+-ATPase in the luminal membrane of the intercalated cell is of a type referred to as a vacuolar ATP that is also found in some intracellular organelles.

FIGURE 10 In severe chronic alkalosis, H+ is actively transported across the basolateral membrane of the intercalated cell toward the interstitium, resulting in HCO3~ secretion across the luminal membrane.

In severe acidosis or hypokalemia, the intercalated cell also expresses another proton pump that is identical to that responsible for acid secretion in the stomach (see Chapter 34). This pump is the electroneutral H+,K+-ATPase that secretes H+ into the lumen while actively transporting K+ into the cell. Thus, this ATPase not only acidifies the lumen but also reduces K+ secretion. In fact, during chronic potassium depletion the expression of the H+,K+-ATPase is enhanced sufficiently to produce net K+ reabsorption in the distal nephron, thus conserving body K+.

Up until this point, we have spoken primarily of H+ secretion in the distal nephron, and this process normally occurs in omnivores including the human. However, it is also possible for the distal tubule and collecting duct to reverse the net direction of H+ transport. In severe chronic alkalosis, the urine is not acidified in the distal nephron; instead, HCO^ is secreted. This conversion occurs primarily in the intercalated cells of the cortical collecting duct, in which the normal arrangement of the H+-ATPase and the HCO^/CP exchanger is reversed as shown in Fig. 10. This reversal of the transporters causes H+ to be actively extruded toward the plasma while HCO^ is secreted into the lumen. Both the H+ and the HCO^ secreting types of intercalated cells may differentiate from a common precursor cell, or individual intercalated cells may reorganize the location of their transporters.

Suggested Reading

Edwards A, Delong MJ, Pallone TL. Interstitial water and solute recovery by inner medullary vasa recta. Am J Physiol 2000;278:F257-F269.

Hamm LL, Alpern RJ. Cellular mechanisms of renal tubular acidification. In Seldin DW, Giebisch G, eds. The kidney: Physiology and pathophysiology, Vol 2, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000, pp 1935-1980.

Malnic G, Muto S, Giebisch G. Regulation of potassium secretion. In Seldin DW, Giebisch G, eds. The kidney: Physiology and pathophysiology, Vol 2, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000, pp 1575-1614.

Muto S. Potassium transport in the mammalian collecting duct. Physiol Rev 2001;81:85-116.

Reeves WB, Winters CJ, Andreoli TE. Chloride channels in the loop of Henle. Annu Rev Physiol 2001;63:631-641.

Reilly RF, Ellison DH. Mammalian distal tubule: Physiology, pathophysiology, and molecular anatomy. Physiol Rev 2000;80:277-313.

Schafer JA. Abnormal regulation of ENaC: Syndromes of salt retention and salt wasting by the collecting duct. Am J Physiol 2002;283:F221-F235.

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