It Is Chloride Depletion Alkalosis, Not Contraction Alkalosis

Abstract

Maintenance of metabolic alkalosis generated by chloride depletion is often attributed to volume contraction. In balance and clearance studies in rats and humans, we showed that chloride repletion in the face of persisting alkali loading, volume contraction, and potassium and sodium depletion completely corrects alkalosis by a renal mechanism. Nephron segment studies strongly suggest the corrective response is orchestrated in the collecting duct, which has several transporters integral to acid-base regulation, the most important of which is pendrin, a luminal Cl/HCO₃⁻ exchanger. Chloride depletion alkalosis should replace the notion of contraction alkalosis.

Chloride depletion is the commonest of the three major causes of metabolic alkalosis; the others relate to potassium depletion/mineralocorticoid excess and to very low or absent glomerular filtration with base loading and are not further discussed in detail. Metabolic alkalosis has generation, maintenance, and recovery phases.¹ This article focuses on the factors that affect the latter two phases.

In a seminal paper published in 1965, contraction alkalosis produced by ethacrynic acid was described in humans that gave rise to the hypothesis that extracellular fluid (ECF) volume contraction produces alkalosis.² The authors concluded that abrupt change in ECF volume was the primary event, while acknowledging that chloride depletion might influence renal bicarbonate retention.

In an effort to separate the correction of volume depletion from that of chloride depletion, Cohen maintained alkalosis for 5 days in dogs treated with ethacrynic acid and a NaCl-deficient diet, and then expanded ECF volume with a fluid containing chloride and bicarbonate in concentrations identical to that in the plasma of the dogs with stable alkalemia.³ These isometric infusions completely corrected alkalosis by 24 hours without an increase in GFR, despite increasing potassium depletion; chloride repletion was acknowledged. On the basis of the known characteristics of fluid and electrolyte handling in the various nephron segments at that time, the volume hypothesis in which the intranephronal redistribution of fluid reabsorption plays the central role was expounded. ECF volume depletion accompanying alkalosis augments fluid reabsorption in the proximal tubule where bicarbonate is preferentially reabsorbed compared with chloride; the increased bicarbonate reabsorption in this segment thus maintains the alkalosis. During correction, volume expansion decreases proximal tubule fluid reabsorption, thereby delivering more bicarbonate to the distal nephron, which has a limited capacity to reabsorb bicarbonate; bicarbonaturia ensues and the alkalosis corrects.⁴

Schwartz et al. studied the pathogenesis of alkalosis produced by chloride depletion (CDA) in men and dogs.⁵ Gastric aspiration, chloruretic diuretics, NaNO₃ infusion (an effect of un-reabsorbable anions), and prior hypercapnia (posthypercapnic CDA) were all used to generate CDA. These studies establish that Cl⁻ repletion by NaCl or KCl—but not replacement of Na⁺ and K⁺ losses without Cl⁻—fully corrects CDA in the maintenance phase. The issue of the specific role of ECF volume depletion was not resolved at this time.

To separate chloride from volume repletion, we first studied rats with selective CDA produced by peritoneal dialysis against NaHCO₃ and a normal serum potassium concentration. In rats given a 70 mEq/L Cl⁻ drink with either Na⁺ or choline, CDA was completely corrected despite negative Na⁺ and K⁺ balances, decreased body weight, and obligatory sodium or choline bicarbonate loading.⁶ Acid-base status in choline-receiving controls was not altered. Rats treated in like manner with CDA maintained for 7–10 days responded in the same manner.⁷ The corrective response occurs by a renal mechanism.⁸

To more rigorously exclude a role for volume expansion, CDA rats were infused with 5% dextrose with either 6% albumin or an isometric Cl⁻ solution. CDA persisted in rats infused with albumin despite 15% ECF volume expansion, but was corrected by the Cl^--containing solution despite persistent volume depletion and decreased GFR.⁹ Delivery of chloride to the collecting duct was not statistically different between the groups but was absolutely greater in rats that corrected. Urinary bicarbonate excretion increased as chloride was infused, whereas it decreased further in the volume-expanded rats. The magnitude of bicarbonaturia approximated the estimated amount of chloride delivered to the collecting ducts. Renal chloride conservation persisted until plasma chloride concentration returned to normal.¹⁰

In normal human participants, we turned to diuretic-induced CDA. Furosemide, Na⁺, K⁺ citrate supplementation, and dietary Cl⁻ restriction produced stably maintained CDA for 5 days that was completely corrected thereafter by oral KCl, despite the presence of maintained negative Na⁺ balance and plasma volume contraction (measured by the ¹³¹I albumin space and plasma albumin concentrations) and persistently lowered GFR and estimated renal plasma flow.¹¹ During correction, net acid excretion decreased with HCO₃⁻ diuresis. In contrast, neutral sodium phosphate given in lieu of KCl was associated with increased serum HCO₃⁻ concentration despite increased plasma volume. In control participants, furosemide administration without Cl⁻ restriction did not cause CDA and serum electrolyte concentrations and net acid excretion did not change with the same amount of KCl administration. Thus, in both rats and humans, chloride repletion in the face of persistent volume depletion corrects CDA, whereas volume expansion without chloride does not.

The contraction alkalosis viewpoint was consistent with then-current views of the mechanism of renal bicarbonate reabsorption by sodium-proton exchange. Aldosterone was regarded as necessary to increase the sodium avidity of ECF volume contraction. Chloride was regarded as the mendicant anion, allowing for sodium reabsorption without obligating proton secretion. Knowledge about specialized cells in the distal nephron capable of secreting protons or bicarbonate and of chloride bicarbonate exchange independent of sodium was yet to come.

The site at which this renal maintenance and correction of CDA occurs was addressed in micropuncture and microperfusion studies in our peritoneal dialysis rat model. First, GFR was inversely correlated with the degree of CDA by tubuloglomerular feedback.¹² Although intact function of the proximal tubule and the loop of Henle are essential to the renal response, these segments have no identifiable adaptive role in the corrective response to chloride repletion in that glomerulotubular balance is maintained whether CDA is being corrected.^8,9 Delivery of chloride and bicarbonate out of the loop of Henle was not different whether rats were maintaining or correcting CDA.^9,13 In the distal convoluted tubule, alkalosis can induce HCO₃ secretion, which is inhibited by the removal of luminal chloride; it is likely that such effects emanate from the connecting tubule.¹⁴

In perfused cortical collecting ducts, HCO₃⁻ is secreted in tubules from CDA rats and is dependent on luminal chloride, whereas it is reabsorbed in normal rats.¹⁵ The magnitude and direction of HCO₃⁻ transport is dependent upon the degree of alkalosis and chloride repletion in vivo at the time of tubule harvesting.¹⁶

Thus, our studies in rats and humans suggest that the single and necessary correction effect for CDA is an increase in distal nephron chloride; the B-type intercalated cells along the cortical collecting duct were poised to secrete bicarbonate in exchange for administered chloride (Figure 1). H⁺-ATPase activity was increased at the basolateral membrane of B-type cells,¹⁷ but pendrin (the chloride bicarbonate exchanger) was not yet identified as the luminal anion exchanger.

Figure 1.

In the CCD during reduced Cl⁻ delivery to that segment in CDA, pendrin activity is increased but secretion of HCO₃⁻ is inhibited by insufficient Cl^- for anion exchange. HCO₃⁻ reabsorption may be partly maintained by Na⁺/H⁺ exchange by the electrical coupling between the principal cell and the H⁺-secreting A cell (although it is morphologically less active than normal¹⁷) and by the remainder of the collecting duct in the medulla. Coupled Na⁺/K⁺ exchange causes kaliuresis. After Cl⁻ delivery to the cortical collecting ducts increases, HCO₃⁻ secretion occurs and medullary HCO₃⁻ reabsorption diminishes,³² allowing correction of the hypochloremic alkalosis. In our rat studies, bicarbonaturia occurred within minutes of Cl⁻ administration intravenously and Cl⁻ did not increase in the urine until correction of serum [Cl⁻] was nearly complete. (Both H⁺ and HCO₃⁻ are produced in the A- and B-type cells by carbonic anhydrase, and during acute acid-base changes, pendrin and H⁺ ATPase shuttle back and forth from cytosol to the luminal or basolateral membrane¹⁸).

Abundant evidence now supports pendrin as an important regulatory transporter in the cortical collecting ducts, which responds briskly¹⁸ in vivo and in vitro¹⁶ to alterations in chloride intake¹⁹ and to acid-base perturbations including metabolic alkalosis and acidosis²⁰ and respiratory acidosis²¹ (Table 1). The main stimuli seem to be distal chloride delivery²² and intracellular pH.²³ In CDA, pendrin is stimulated both by low chloride distal delivery²² and by metabolic alkalosis,²⁰ including intracellular alkalosis. In potassium depletion metabolic alkalosis, a high serum bicarbonate is maintained by intracellular acidosis in the renal tubular cells with resulting increased bicarbonate reabsorption at several sites along the nephron. Pendrin is reduced in potassium depletion²⁴; this suggests that the signal for increased activity for the luminal anion exchanger is related to changes in intracellular pH, rather than extracellular pH or urine pH. Pendrin has been studied in mice, rats, rabbits, and the gills of rays²² (where it responds to changes in acid-base status on moving from sea to fresh water).

Table 1.

Responses of CCD luminal B cell pendrin to changes in dietary chloride and acid-base perturbations

Condition	B Cell Pendrin Expression/Activity
Low chloride diet	↑
High chloride diet	↓
Chloride depletion alkalosis	↑
Metabolic acidosis	↓
Respiratory acidosis	↓
Potassium depletion alkalosisa	↓

^aAssociated with intracellular acidosis.

In renal pendrin null mice, serum HCO₃⁻ concentration is higher and urine is less acidic than in controls.²⁵ Humans with Pendred syndrome (hypothyroid goiter and deafness) seem to have normal acid-base status. However, two recent descriptions of a severe metabolic alkalosis in a child, given thiazide for excess endolymph²⁶ and severe alkalosis and potassium depletion in response to vomiting,²⁷ suggest that an intact functioning of B-type intercalated cells are important for defense against chloride depletion.

The role of aldosterone, if any, in regulating pendrin’s response to changes in dietary chloride and to acid-base changes is not clear. We showed that angiotensin II was not regulatory in maintenance or correction of CDA.²⁸ High aldosterone levels are also not necessary for maintenance of CDA²⁹ and correction by chloride occurs despite rising levels.¹⁰ Aldosterone, within its physiologic range of levels, is not important for direct pendrin regulation.^20,21 Adrenalectomized rats ingesting a low chloride diet and drinking isotonic neutral sodium phosphate excrete extremely low concentrations of chloride and maintain chloride balance.³⁰ Again, this suggests that chloride conservation in the distal nephron is not aldosterone dependent.

Recently, a new mechanism of electroneutral sodium chloride absorption, which is not inhibited by amiloride but is by thiazides, has been shown in the mouse cortical collecting duct.³¹ It is dependent on pendrin and another sodium-dependent anion exchanger. Thus, reduced chloride delivery to the cortical collecting ducts causes sodium conservation to be more dependent on ENaC and may explain the high losses of urinary potassium in CDA.

Our conceptual model of maintenance and correction of CDA is shown (Figure 1). In the rat model, bicarbonate secretion in exchange for administered chloride in the cortical collecting duct can account for correction of CDA. Clearly there must be a coordinated response in more distal sites to allow secreted bicarbonate to pass into the final urine. We have shown in medullary collecting duct segments that bicarbonate reabsorption is decreased in tubules obtained from rats with correcting CDA³² and chloride is intensely conserved along the collecting ducts on a low chloride diet.³³

In summary, CDA can be corrected by selective chloride repletion despite maintained or increasingly negative sodium or potassium balance, continued bicarbonate loading, and continuing high levels of angiotensin II or aldosterone, and is not corrected by sodium or potassium repletion without chloride repletion, by chloride repletion in the absence of renal function, by plasma volume expansion by as much as 15%, or by restoring baseline GFR without chloride repletion. In addition, we have demonstrated in vitro and in vivo correction mechanisms by anion exchange along the collecting duct, which are consistent with current physiology. The more proximal nephron segments do not contribute to the adaptive response for the correction of CDA by administered chloride.

Chloride administration without volume expansion is necessary and sufficient to correct CDA. Volume deficits, whether associated with metabolic acidosis or alkalosis, should be corrected. We suggest that the term chloride depletion alkalosis is clinically valuable because it indicates the correct pathophysiology and focuses on the ion in the blood and urine that is fundamental to that mechanism.

DISCLOSURES

None.