The Generation and Maintenance of Metabolic Alkalosis

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Kidney International, Vol. 1 (1972), p. 306—321

The generation and maintenance of metabolic alkalosis

DONALD W. SELDIN and FLOYD C. RECTOR JR.

Department ofInternal Medicine,The University of Texas Southwestern Medical School atDallas, Dallas, Texas

The pathogenesis of chronic metabolic alkalosis involves of hydrogen ions, both in the proximal and distal portions two distinct physiologic derangements. First, there must of the nephron [1, 2]. According to this model, hydrogen be a loss of acid or gain of alkali in order to generate the ions are secreted into the tubular lumen in exchange for alkalosis. Renal or extra-renal factors may be responsible. filtered sodium. It is not clear whether hydrogen secretion If the alkalosis is generated by the kidney, the net excretion and sodium reabsorption are tightly coupled in an ob- of acid in the form of titratable acid and ammonia must be ligatory fashion or only loosely coupled through electrical increased, at least transiently, to a level greater than the forces. Malnic and de Mello-Aires [3] have recently presum of the acid load originating from both dietary and sented evidence that in the absence of sodium in luminal metabolic acid production and from alkali loss into the fluid, the secretion of hydrogen continues at a near normal feces. For each mEq of excess net acid excretion by the rate. Presumably under these conditions (tubular fluid kidney, one mEq of new bicarbonate will be generated and containing principally choline bicarbonate) the secretion of added to the blood. The kidney is not the only source for hydrogen would be accompanied by the inward movement the generation of metabolic alkalosis. Extra-renal factors, of chloride along its electrochemical gradient. Their results, such as vomiting, special types of diarrhea, and the like, therefore, would suggest that under normal physiologic may be the source of the alkali load. conditions, the reabsorption of sodium and the secretion The generation of alkali by either renal or extra-renal of hydrogen are only very loosely coupled. mechanisms may not be sufficient to produce sustained The process of hydrogen secretion by the tubule may metabolic alkalosis. Under normal circumstances the kidney involve a number of reduced substrates in oxidation- has an enormous capacity to excrete NaHCO3. In conse- reduction reactions, but ultimately the hydrogen must be quence, increased amounts of NaHCO3 which gain access derived from the splitting of water with the liberation of to the blood may be promptly excreted into the urine. hydroxyl ions into the cell. The hydroxyl ions subsequently Clearly, then, in order to maintain metabolic alkalosis, the react with C02, under the catalytic impact of the enzyme increased amounts of bicarbonate in the glomerular filtrate carbonic anhydrase, to form bicarbonate. In this respect, must be reclaimed by a commensurate rise in tubular it is of interest that recent evidence indicates that the reabsorption. During chronic stable metabolic alkalosis, hydroxyl ion, not water or carbonic acid, is the primary the tubular reabsorption of bicarbonate will be persistently substrate for carbonic anhydrase [4]. The bicarbonate ions elevated, while the net excretion of acid will have returned formed by this process leave the cell, presumably by passive to a level equal to the net acid load. The present paper will diffusion down their clectrochemical gradient, along with be concerned with the factors involved in the generation the reabsorbed sodium. Thus for each hydrogen secreted, and maintenance of metabolic alkalosis. Physiologic deter- one sodium bicarbonate is added to renal venous blood, minants will be explored. Clinical derangements will then The fate of the secreted hydrogen depends upon the be examined. composition of the tubular fluid. As long as bicarbonate is present in the luminal fluid, it will preferentially react with the hydrogen to form H2O and CO2. However, as the The Maintenance of Metabolic Alkalosis by the Kidney removal of bicarbonate nears completion, the pH of the There is now abundant evidence that both the reabsorp- tubular fluid will begin to fall and the secreted hydrogen tion of bicarbonate and the excretion of titratable acid and will react with filtered buffers to form titratable acid, and ammonium are mediated primarily by the tubular secretion with ammonia to form ammonium. From a quantitative standpoint, the formation of titratable acid and ammonium © 1972, by the International Society of Nephrology ions normally accounts for only 2 to 3 % of total hydrogen

306 Metabolic alkalosis 307 secretion, while the remainder is consumed in the con- or threshold level, reabsorption is complete, and no bi- servation of filtered bicarbonate. carbonate is lost into the urine. Below this critical plasma The level at which the plasma bicarbonate concentration concentration, reabsorption is a linear function of the will be maintained is dependent in some manner on the filtered load. However, as the plasma concentration is total or maximal hydrogen secretory capacity of the kidney. raised above this threshold level, reabsorption does not Since the rate of hydrogen secretion is influenced by the pH increase proportionately and excretion of bicarbonate into of the tubular fluid, the maximal capacity of the system can the urine begins. Further increases in plasma concentration only be assessed when the tubular fluid is maintained produce only slight changes in reabsorption and the system relatively alkaline. This requires that the plasma bicarbonate exhibits an apparent transport maximum. concentration be progressively elevated by infusions of There is, however, no true transport maximum for sodium bicarbonate solutions, and, as a consequence, a bicarbonate reabsorption (via hydrogen secretion). Pitts highly distorted physiologic state is induced: alkaline blood and Lotspeich [5] found the maximum rate of bicarbonate pH, elevated P02, hypernatremia, expanded extracellular reabsorption is not constant, but varies proportionately to fluid volume, variable glomerular filtration rate. The spontaneous or chronically induced changes in GFR. method of measuring the maximal rate of hydrogen secre- Bicarbonate reabsorption, expressed as mEq/liter GFR, tion, therefore, introduces a number of variables which however, appeared to be constant. Thompson and Barrett could independently influence the rate of secretion and [6], on the other hand, observed that acutely reducing GFR obscure the true capacity of the system. by partial obstruction of the aorta above the renal arteries The hydrogen secretory system operates in such a manner did not change the absolute rate of bicarbonate reabsorp- that when the plasma bicarbonate is below a certain critical tion, but reabsorption expressed as mEq/liter GFR rose.

5 .

S 0 S • • • S S. •.. S .

0. 0 E 03 0. 0 Mean concentration of bicarbonate in -c glomerular filtrate during control period C)

C) 0C2 -D

0 10 20 30 40 50 60 70 Concentration of bicarbonate in glomerular filtrate in mEcj]liter

Fig. 1. Maximum bicarbonate reabsorptive capacity in normal ruts. 308 Seldin/Rector

Lemieux et al [7] have recently reexamined the relation ate concentration would stabilize at a concentration be- between bicarbonate reabsorption and GFR by constricting tween the threshold level and the maximal capacity, even either one or both renal arteries acutely and chronically. in the face of fairly large loads of sodium bicarbonate. In both the acute and chronic experiments, absolute reab- This assumption, however, is clearly an over-simplifica- sorption paralleled the changes in GFR and reabsorption tion, particularly with respect to the rat. Fig. 1, based on expressed as mEq/liter GFR remained constant. Thus, unpublished data from our laboratory, shows a bicarbonate with the exception of the studies of Thompson and Barrett titration study in a group of normal rats. As bicarbonate [6], the observed relation between bicarbonate reabsorption concentration in the glomerular filtrate is progressively and GFR is similar to that observed between total sodium raised, reabsorption is complete until the concentration reabsorption and GFR, and indicates that the mechanisms exceeds 35 mEq/liter. The maximal capacity in these animals responsible for glomerulotubular balance involve not only was approximately 42 mEq/liter. It would be predicted, sodium reabsorption, but also the secretion of hydrogen therefore, that rats given chronic sodium bicarbonate loads ions. would stabilize their plasma bicarbonate concentration The participation of hydrogen secretion in glomerulo- somewhere between 35 and 42 mEq/liter. tubular balance has much the same physiologic significance To examine this question, awake rats were placed in as does the participation of total sodium reabsorption. The restraining cages and infused continuously with sodium roughly proportionate changes between the rate of hydro- bicarbonate at a rate of 1.46 mEq/l0 hr. As shown in gen secretion and GFR serve to prevent both marked Fig. 2, the bicarbonate concentration in glomerular filtrate augmentation of titrable acid and ammonium excretion, was approximately 30 mEq/liter (comparable to a plasma with the subsequent production of metabolic alkalosis when bicarbonate of 27 mEq/liter) at the beginning of the in- GFR is reduced, and bicarbonate wastage and metabolic fusion and rose to 36 mEq/liter during the next 20 hours. acidosis when GFR is elevated. Thereafter, the bicarbonate concentration fell progressively, It has become common practice, therefore, to express reaching control levels within 60 to 70 hours after starting bicarbonate reabsorption and its maximal capacity in the infusion. In part, the administered bicarbonate is terms of mEq/liter GFR. The maximal rate of bicarbonate consumed in neutralizing the net acid load; the remainder, reabsorption, measured as described above, varies among however, is excreted into the urine at a steady state rate of different species and is approximately 28 mEq/liter GFR 0.75 mEq/10 hr. These results suggest that, associated with in man, 25 mEg/liter GFR in dogs and 45 mEq/Iiter GFR the chronic administration of sodium bicarbonate, there is in rats. In bicarbonate titration studies, the plasma concen- a compensatory readjustment of the renal threshold in a tration (threshold) at which excretion begins is approxi- downward direction. mately 75 % of the maximal reabsorptive rate. It has This readjustment of the threshold level can better be generally been assumed, therefore, that the plasma bicarbon- seen in comparison of the effects of chronic sodium a 0 mEq/Iiter concentration La Ln / GFR in / 0 Bicarbonate — 0 mEq - - — C in C — a C' C CC . o am o 0 bicarbonate -- - Urinary Fig. 2.Relationship of filtered bicarbonate

C to urinary bicarbonate daring prolonged intravenous sodium bicarbonate infusion. Metabolic alkalosis 309 bicarbonate and ammonium chloride loads. As shown in was elevated by dialyzing dogs with a low-chloride, high- Fig. 3, when bicarbonate concentration was progressively bicarbonate fluid, bicarbonate reabsorption was much raised by intravenous infusions, the rats pretreated chroni- greater (approximately 40 mEq/Iiter GFR) than when cally with sodium bicarbonate excreted bicarbonate into plasma bicarbonate concentration was raised by infusions the urine at bicarbonate concentrations as low as 26 mEq/ of hypertonic sodium bicarbonate solutions. Both sets of liter GFR, whereas bicarbonate excretion in the rats observations were originally attributed to competitive ef- chronically pre-treated with ammonium chloride did not fects of chloride concentration on bicarbonate reabsorp- begin until the bicarbonate concentration exceeded 40 mEq/ tion: hyperchioremia inhibiting and hypochioremia en- literGFR. hancing bicarbonate reabsorption. It is not clear whether the alteration in the threshold for An alternative and more likely explanation of the above bicarbonate excretion is due to effects of the chronic acid results is that the differences in bicarbonate reabsorption or alkali load per Se, or perhaps to some other factor such were due to differences in extracellular volume. Dialysis of as alteration of the volume of extracellular fluid. The rats dogs against a low-chloride, high-bicarbonate fluid would given sodium bicarbonate chronically might become slight- raise plasma bicarbonate concentration without expanding ly over-expanded, whereas the rats given ammonium extracellular volume, whereas similar increments in plasma chloride would be expected to become slightly salt-depleted, bicarbonate concentration achieved by infusions of hyper- and thus have some contraction of their extracellular tonic sodium bicarbonate would be associated with signi- volume. ficant expansion of extracellular volume. Addition of an There is accumulating evidence that changes in func- infusion of hypertonic saline in dogs already made alkalotic tional extracellular fluid volume have profound effects on by hypertonic sodium bicarbonate infusions would further the rate of bicarbonate reabsorption. In 1946, Pitts and expand extracellular volume and greatly exaggerate any Lotspeich [5] observed that infusions of hypertonic saline effects volume might have on bicarbonate reabsorption. depressed bicarbonate reabsorption in normal dogs. In Kunau et al [9], utilizing micropuncture techniques, contrast, Toussaint, Telerman, and Vereerstraeten [8] in were the first to observe a direct effect of extracellular 1958 found that when plasma bicarbonate concentration volume expansion on tubular reabsorption of bicarbonate.

• 5 mEq ammonium chloride per day 0 5 mEq sodium bicarbonate per day 0 40 - 0 a 0 . S o0 •• S 0 •• 0 0 0 30- 00 000 •••••0 0a 0 0 00 S Ce .. 0 S C- 20 0a 0

>C Ce • 10 - 0 •t•. •' 0 •.•0 ••• ocP • 0 S Qc • 00 00 5 8 . (C

I I I I I 20 30 40 50 60 70 80 90 Concentration of bicarbonate in glomerular filtrate in mEq/liter

Fig. 3. The effect of chronic sodium bicarbonate and ammonium chloride loads on bicarbonate threshold. 310 Se/din/Rector

The results from their studies are shown in Fig. 4. They observed that isohydric expansion of extracellular volume with Ringer's-bicarbonate solution suppressed reabsorp- 40 tion, not only of sodium and water, but also of bicarbonate in the proximal convoluted tubule. This effect on proximal bicarbonate concentration could not be reversed by lower- 30 ing GFR by aortic constriction. Whether a similar effect C I-0.20 occurs in the more distal portions of the nephron is not C known. .0 CS Subsequently, others have shown that the volume of Maximal Expansion— extracellular fluid has a profound effect on maximal 0tn Isotonic NaHCO3 bicarbonate reabsorption. Purkerson et al [10] found that L)x when plasma bicarbonate concentration in rats was raised 10 20 30 40 50 60 by infusions of hypertonic sodium bicarbonate to minimize Plasma HCO3 concentration (mEq/liter) expansion of extracellular fluid, bicarbonate reabsorption rose progressively to levels as high as 57 mEq/liter GFR, Fig.5. Theeffect of extracellular volume on bicarbonate reabsorp- and did not reach a maximum or plateau. On the other tion, hand, when plasma bicarbonate concentration was raised by infusions of isotonic sodium bicarbonate in order to lattereffect was exaggerated by simultaneous infusions of exaggerate expansion of extracellular volume, reabsorption both isotonic sodium bicarbonate and sodium chloride achieved a stable maximal value of 45mEq/literGFR. solutions. In some animals, bicarbonate reabsorption fell In recent studies by Kurtzman [11], bicarbonate reab- from as high as 28 mEq/liter GFR to as low as 9 mEq/liter sorption in the dog appears to be even more sensitive to GFR as extracellular volume was progressively expanded. changes of extracellular volume than in the rat. In dogs If, however, the effect of extracellular volume expansion whose plasma bicarbonate concentration was raised by was blunted by either controlled hemorrhage or partial injections of hypertonic sodium bicarbonate, tubular reab- obstruction of the thoracic vena cava, bicarbonate reabsorption reached a stable plateau of 23 to 25mEq/liter sorption was not depressed, but instead remained at higher GFR. In contrast, in dogs expanded with isotonic sodium than normal levels. bicarbonate, reabsorption rose as plasma bicarbonate con- The results of several different studies in the dog are centration was elevated, until a level was achieved at which summarized in Fig. 5.Anapparent reabsorptive maximum point further elevation in plasma bicarbonate reabsorption (approximately 25 mEq/liter GFR) is achieved only when resulted in progressive reductions in reabsorption. This plasma bicarbonate concentration is raised by an infusion of hypertonic sodium bicarbonate, and there is only a 12 - modest associated expansion of extracellular volume. When plasma bicarbonate concentration is raised without expansion of extracellular volume by means of dialysis 10 against a low-chloride, high-bicarbonate fluid, or when volume is contracted by controlled hemorrhage or partial vena caval obstruction, then bicarbonate reabsorption pro- LU 8- gressively increases and does not reach a maximum or E plateau level. On the other hand, when expansion of extra- a . cellular fluid is exaggerated either by isotonic NaHCO3 or . NaCI infusions, bicarbonate reabsorption can be pro- L) I gressively reduced to very low levels. In the rat, there is also an effect of extracellular volume on bicarbonate reabsorption, but the rat appears less sensitive to the effects of volume expansion than the dog : and the pattern is somewhat different. Hypertonic infusions : with modest expansion result in progressively rising reabsorption without achieving a maximal value, while greater expansion with isotonic sodium bicarbonate infusions gives Control ECV expansion ECV expansion an apparent reabsorptive maximum of approximately + 45 mEq/liter GFR. There is undoubtedly also an effect of Aortic constriction extracellular volume on bicarbonate reabsorption in man, Fig. 4. Effectof expansion ofextracellularvolume (ECV) and but the exact pattern is not clear. With infusions of both aortic constriction on proximal bicarbonate concentration. hypertonic and isotonic sodium bicarbonate solutions, Metabolic alkalosis 311 bicarbonate reabsorption has been reported to achieve a these two ions compete for a common secretory pathway stable maximal level of 25 to 28 mEq/liter GFR. [20]. These studies in the aggregate, therefore, indicate that The extent to which potassium deficiency can accelerate there is no true reabsorptive maximum, or Tm, for bi- hydrogen secretion has been difficult to ascertain because carbonate. The apparent Tm reported by many investigators of the frequent association of extracellular volume contrac- is simply a fortuitous artifact arising from the counter- tion and/or excess mineralocorticoid activity. Schwartz and balancing effects of augmentation of reabsorption asso- his associates [16—18] have found that the metabolic ciated with increasing plasma bicarbonate concentrations alkalosis associated with moderate potassium deficiency and suppression of reabsorption caused by progressive can be corrected by the administration of sodium chloride expansion of extracellular volume. despite persistence of the potassium deficit. However, Most investigators exploring the influence of effective Kassirer, Lowance, and Schwartz [21] have recently ob- extracellular volume on bicarbonate reabsorption have served in man that the alkalosis associated with more focussed attention on the maximal rate of bicarbonate severe potassium depletion can be partially, but not reabsorption. From a physiologic point of view, however, completely, corrected by the administration of sodium the more important regulatory role of extracellular volume chloride, as long as administration of aldosterone is on bicarbonate reabsorption stems from its effects on the maintained. bicarbonate threshold and the level at which plasma We have obtained similar results in rats. As shown in bicarbonate concentrations can be stabilized. It is on the Table I, rats fed an electrolyte-deficient diet containing basis of this effect that contraction of extracellular volume one mM Na2504 per day and given 0.5 mg DOCA daily plays a major role in the maintenance of metabolic alkalosis. for 10 days developed severe hypokalemic alkalosis. When The many studies of Schwartz and his associates [12—181 rats prepared in similar fashion were continued on DOCA illustrate this important point. They have shown that under and given an infusion of two mM Na2SO4 daily for two a variety of circumstances (gastric aspiration, exposure to days, both the hypokalemia and the alkalosis worsened. and then removal from high CO2 tensions, administration In contrast, when the hypokalemic rats were continued on of NaNO3) both man and dog will maintain a mild DOCA, but infused with four mM NaCI daily for 4 days, metabolic alkalosis while on a chloride-free diet. The the plasma bicarbonate concentration fell from 42.1 mEq/ kidneys will not accelerate bicarbonate excretion until liter to 30.6 mEq/liter, where it stabilized in the presence chloride is added to the diet; administration of either KCJ of persistent hypokalemia. The plasma bicarbonate con- or NaC1 results in prompt excretion of bicarbonate into centration, however, did not return completely to normal, the urine and correction of the metabolic alkalosis. but remained approximately five mEq/liter above the nor- The unique role of dietary chloride in this process arises mal value. These observations suggest that, in part, the alka- from the fact that sodium chloride and sodium bicarbonate losis associated with hypokalemia may be the consequence are the only two physiologically important salts that can be easily reabsorbed by the tubule and participate in main- Table 1. Effect of sodium chloride on the metabolic alkalosis tenance of extracellular volume. Sodium chloride, therefore, in Potassium-deficient ratsa is the only means of correcting a contraction of extracellular volume in salt-depleted subjects without generating and Group Treatment Plasma Plasma maintaining a metabolic alkalosis. Cohen [19] has clearly potassiumbicarbonate shown that in selective chloride depletion, it is the con- mEq/liter mEq/liter tracted extracellular volume rather than the low plasma I (N= 12) Normal diet 4.9±0.2 25.9+ 0.4 chloride concentration that is responsible for maintaining ha (N= 18) Electrolyte-deficient 2.4±0.2 42.1±0.7 the relatively high rate of hydrogen secretion. He found diet + DOCA + that expansion of extracellular volume of chloride-depleted Na2SO4 alkalotic dogs with a solution containing sodium chloride for 10 days and sodium bicarbonate in the same ratio as existed in the 11 b (N= 6) Potassium-deficient 2.10.5 47.2± 0.8 animal's plasma resulted in prompt excretion of bicarbonate rats (IlA)+ and correction of the alkalosis. DOCA+ In addition to contraction of extracellular volume there infusion of 2 mM Na2SO4 per day for are other factors, such as potassium deficiency and adrenal 4 days steroids, which can augment hydrogen secretion and thus lic (N= 10) Potassium-deficient 2.3± 0.3 30.6± 0.8 participate in the maintenance of metabolic alkalosis. rats (IIA)+ Hypokalemia, with or without associated excess mineralo- DOCA+ corticoid steroids, is frequently accompanied by hypo- infusion of 4 mM chloremic alkalosis. On the basis of this and other observa- NaCI per day for 4 days tions in which the secretion of hydrogen and potassium appear to be reciprocally related, it has been suggested that a Valuesrepresent means± si. 312 Se/din/Rector of contraction of extracellular volume and can be corrected same degree and equally alkalotic (Group III), had end- by administration of saline. However, in the presence of proximal bicarbonate concentrations of only eight mEqJ more severe deficits there appears to be an additional effect liter. Massive expansion (0.5 mI/mm) of the hypokalemic related to the potassium deficiency per Se. rats (Group IV) increased proximal bicarbonate concen- Excessive mineralocorticoid activity may also participate tration slightly to 14.3 mEq/liter, but not to the level of in the maintenance of hypokalemic alkalosis. Both Seldin, either the modestly expanded (Group 1) or massively ex- Welt, and Cort [221 and Luke and Levitin [23] have shown panded (Group II) normokalemic rats. Whether there are in rats with hypokalemic alkalosis that omission of mm- similar effects of extracellular volume and potassium eralocorticoids and administration of NaCI will not com- deficiency on distal hydrogen secretion has not been pletely correct the alkalosis, clearly indicating an effect of determined at the present time. potassium deficiency per se independent of any excess There have been no micropuncture studies to examine adrenal steroid activity. On the other hand, Luke and the specific effects of adrenal steroids on the rate of hydro- Levitin [23] found that administration of NaC1 to hypo- gen secretion in the proximal and distal tubules. However, kalemic alkalotic rats maintained on adrenal steroids had recent clearance studies in adrenalectomized dogs by Kurtz- less of a corrective effect than in the absence of adrenal man, White and Rogers [25] indicate that mineralocorticoid steroids. This suggests that in addition to contraction of activity is necessary for attaining the minimal urine pH. extracellular volume and potassium deficiency, adrenal This stimulation of hydrogen secretion against a pH gra- steroids can also augment hydrogen secretion. This effect dient is most likely due to an effect in the more distal of adrenal steroids, however, is not a simple straight- portions of the nephron. forward action, since the administration of excess steroid All of these studies, therefore, suggest a complex inter- plus sodium salts produces an alkalosis only if hypokalemia action among extracellular volume, potassium and adrenal is permitted to occur; if potassium deficiency is prevented steroids in the control of bicarbonate reabsorption. Under by administration of supplemental potassium salts then the conditions where potassium deficiency is modest, the excess steroids do not augment hydrogen secretion. metabolic alkalosis is readily corrected by saline, suggesting Micropuncture studies show that both alterations in that contracted extracellular volume, not potassium defi- extracellular volume [9] and potassium deficiency [24] in- ciency, is responsible for the elevated bicarbonate reab- fluence bicarbonate reabsorption in the proximal con- sorption. However, when potassium deficiency is severe, voluted tubule. As shown in Table 2, there is clearly an the metabolic alkalosis is only partially corrected by NaCl, effect of potassium deficiency on bicarbonate concentra- indicating a role for potassium deficiency per se. Excess tions at the end of the accessible portion of the proximal adrenal steroids, either exogenous or endogenous, will tubule that cannot be attributed to contracted extracellular produce hypokalemic metabolic alkalosis despite adequate volume. The normokalemic rats made alkalotic by an in- dietary NaCI and overexpansion of extracellular volume. fusion of 0.15 MNaHCO3at 0.1 mI/mm for two hours Several studies suggest that there is a specific effect of (Group I) had an end-proximal bicarbonate concentration adrenal steroids in maintaining a high rate of bicarbonate of 22 mEq/liter, while hypokalemic rats, expanded to the reabsorption, probably by stimulating sodium-hydrogen

Table 2. Effect of potassium defeciency on proximal tubular bicarbonate concentrationsa

Group Infusion Plasma Plasma Tubular fluid potassium bicarbonate bicarbonate mEq/lifer mEqi/iter mEq/Iiter

I (N=4) 0.15 MNaHCO3 4.01±0.32 35.4± 1.6 22.0±4.5 (Normokalemic— at 0.1 mI/mm modest expansion) for 2 hrs II (N=4) 0.075 at NaHCO3 3.49± 0.28 34.4± 1.8 25.1±4.1 (Normokalemic— 0.050 M NaCl massive expansion) 0.004 MKc! at 0.5 mI/mm for 2 hrs III (N=4) 0.0375 at NaHCO3 2.42±0.55 35.1±2.4 8.2±5.1 (Hypokalemic— 0.0875 M NaCI modest expansion) at 0.1 mI/mm for 2 hrs TV (N=4) 0.0375 M NaHCO3 1.90±0.25 34.6± 2.3 14.3± 5.5 (Hypokalemic— 0.0875 at NaCI massive expansion) at 0.5 mI/mm for 2 hrs

a Valuesrepresent means SD Metabolic alkalosis 313 exchange in the distal nephron. However, excess adrenal other hand, increasing the distal delivery of sodium salts steroids appear to be capable of stimulating hydrogen by infusions or dietary supplements, without a concomitant secretion mainly if there is concomitant potassium defi- stimulus to sodium-hydrogen exchange, will not augment ciency. net acid excretion, but will simply result in excretion of the administered sodium salt into the urine. The Generation of Metabolic Alkalosis by the Kidney The acceleration of net acid excretion and generation of a metabolic alkalosis, therefore, requires the combination In the discussions above, consideration was given only of stimulation of the distal sodium-hydrogen process and to those factors influencing total hydrogen secretion as it an adequate supply of distal sodium salts which are not relates to bicarbonate reabsorption and the maintenance of derived from dietary and metabolic acids. One circum- a steady state metabolic alkalosis. Under certain circumstance in which this combination might occur is in salt- stances, however, the kidney can increase its excretion of depleted subjects given sodium salts of poorly reabsorbable net acid (titratable acid plus ammonium minus bicarbonate) anions (sulfate, phosphate, nitrate). A clinically and physio- above the net acid load arising from diet, metabolism and logically more important circumstance, however, arises fecal losses of alkali, and thus participate in the generation from the existence of persistent excessive mineralocorticoid of a metabolic alkalosis. In general, the ability of the activity in the presence of a plentiful supply of dietary kidney to increase its excretion of net acid will depend sodium chloride or other sodium salts. Under these condi- upon the complete reabsorption of bicarbonate in the tions, the distal sodium-hydrogen secretary mechanism can proximal portions of the nephron, the nature and quantity be stimulated in a manner that does not concomitantly of sodium salts reaching the distal nephron, the intensity diminish the distal delivery of sodium salts. When the of the distal sodium—hydrogen exchange process, and the predominant sodium salt is phosphate, then titratable acid capacity to add ammonia to tubular fluid. will be selectively augmented. On the other hand, when the Under normal circumstances, the distal tubular fluid, predominant salt in distal fluid is either sodium sulfate or after reabsorption of sodium bicarbonate becomes nearly sodium chloride, the increment in net acid excretion will be complete, contains primarily sodium chloride and the entirely as ammonium. sodium salts of the acids arising from diet and metabolism The stimulation of distal sodium reabsorption by excess (sulfate, phosphate, creatinate, organic acid anions). From adrenal steroids has as its primary and predominant conse- this tubular fluid sodium will be reabsorbed and hydrogen quence acceleration of potassium, rather than hydrogen, secreted; as pH of the tubular fluid falls the buffer anions secretion. Only as potassium deficiency develops and are titrated and NH3 which diffuses into the urine is potassium secretion becomes limited will accelerated hydro- trapped as NH. Thus, the sum of sulfate, phosphate, gen secretion become apparent. The development of po- creatinate and organic acid anions excreted as titratable tassium deficiency is also essential for the adaptive increase acid and ammonium salts will be equal to the net acid load. in ammonia production by the renal tubular cells, which is in addition, there will be some sodium reabsorbed distally necessary if any significant augmentation of net acid ex- as sodium chloride or in exchange for potassium which cretion from sodium chloride and sulfate is to occur [261. will not contribute to net acid balance. Thus, if adrenal steroids are administered along with ade- Simply increasing total hydrogen secretory capacity, quate dietary sodium chloride, but the development of although it will permit a high rate of bicarbonate reabsorp- potassium deficiency is prevented by supplemental po- tion, will not necessarily result in an increase in net acid tassium chloride, neither the increased rate of ammonia excretion. If, for example, a subject receiving a normal acid production nor the accelerated rate of hydrogen secretion load is salt-depleted and maintained on a low salt diet will occur [221. without changing the net acid load, his potential capacity to reabsorb bicarbonate will be increased, but net acid excretion will remain the same. The sequence of events in Clinical Derangements this circumstance is probably as follows: as a consequence In Table 3 the factors responsible for the generation and of the salt depletion, the capacity of both the proximal and maintenance of metabolic alkalosis are summarized. The distal nephron to reabsorb sodium and secrete hydrogen is factors responsible for generating alkalosis may act per- sharply augmented. The quantity of sodium salts of poorly sistently or transiently. reabsorbed anions (sulfate, phosphate, creatinate and or- Persistent generation of alkali may occur under such ganic anions) reaching the distal nephron will be main- circumstances, for example, as unrelenting vomiting, the tained at a normal level, whereas enhanced proximal reab- ingestion of salt in the presence of persistent non-suppres- sorption will drastically curtail the distal delivery of sodium sible hyperaldosteronism, and the like. In this context, chloride. Although the distal nephron has the capacity to chronic metabolic alkalosis may be an expression of both increase net acid excretion, this will not occur because of persistent bicarbonate generation as well as the activation the limited supply of sodium salts in the distal nephron, of factors serving to enhance renal bicarbonate reabsorp- which will he roughly equal to the net acid load. On the tion. However, under certain circumstances, the addition of 314 Se/din/Rector

Table 3. The generation and maintenance of metabolic alkalosis

Generation Maintenance

I. Loss of acid from extracellular space I.effective arterial volume A. Loss of acid into gastric juice: vomiting; gastric suction or fistula B. Loss of acid into urine: increased distal Na delivery in presence of hyperaldosteronism. C. Loss of acid into cells: K deficiency D. Loss of acid into stool: congenital alkalosis with diarrhea II. Excessive 11C03 loads II. Potassium deficiency A. Absolute 1. Oral or parenteral loads of NaHCO3 or alkalinizing Na salts 2. Metabolic conversion of endogenous acid anions (e.g. ketones, lactate) to HCO3 B. Relative 1. Alkaline loads in renal failure III. Contraction of extracellular space 111. Renal failure A. Diuretic loss of NaCI without commensurate loss of NaHCO3 IV. Post-hypercapneic state IV. Persistent mineralo-corticoid excess

bicarbonate to the blood may be so great that chronic plasma; negligible amounts of chloride (0.6 to 4.0 mEq/ alkalosis may exist even when the internal regulatory fac- day), but amounts of sodium equal to or greater than tors responsible for the maintenance of metabolic alkalosis potassium. These patients have very severe systemic alka- do not seem to be activated. In the studies by Sanderson losis. In other patients [29], urine pH is normal and the and his associates [27, 281, massive sodium bicarbonate urinary excretion of potassium, sodium and chloride very loads (up to 140 g/day) given continuously through a low. These patients also had severe hypokalemia, elevated gastric tube for periods up to three weeks could produce a plasma concentrations of renin and aldosterone, and alka- mild chronic metabolic alkalosis. Potassium deficiency did losis (less severe than in the former group). not occur; the balances of sodium, bicarbonate, and chlo- The factors responsible for the changes in plasma com- ride were positive; glomerular filtration rate rose. Presum- position and the diverse urinary findings are exceedingly ably, the alkalosis was principally the consequence of the difficult to unravel, since complete balance data during massive alkali loads. the period of development as well as maintenance of On the other hand, the factors responsible for the alkalosis are usually not available. Such data have been generation of alkalosis may act only transiently: vomiting provided in meticulous balance studies in dogs [32] and may stop after several days; diuretics may be discontinued. man [33] by Schwartz and his associates. Selective hydro- Nevertheless, the alkalosis may continue because bicarbon- chloric acid depletion was accomplished by gastric drainage ate has been generated in a setting where there is a con- in which the amount of KC1 and NaC1 removed by drainage tinuous stimulus to enhanced bicarbonate reabsorption. was returned the following day. The diets contained ade- This is the usual circumstance. In the evaluation of meta- quate amounts of potassium but were essentially free of bolic alkalosis, therefore, it is critical to identify the factors NaCl. The following findings are noteworthy: 1) during responsible for its maintenance, since alkalosis may remain the period of drainage (when alkalosis was developing long after the factors responsible for its generation have rapidly), the urine pH rose (in association with increased disappeared. urinary bicarbonate excretion) and the urinary excretion of Vomiting, gastric suction and fistula. Vomiting and gastric sodium and potassium also increased, while urinary chloride drainage involve the loss of hydrochloric acid, sodium excretion remained negligible; 2) during the postdrainage chloride, and potassium chloride from the body. In conse- period (when the diet was maintained but gastric aspiration quence, metabolic alkalosis, potassium deficiency, contrac- discontinued), urine pH and electrolyte excretion fell to tion of extracellular volume, and activation of the renin- control values. The excretion of bicarbonate was negligible; angiotensin-aldosterone system ensue [29, 30]. Associated sodium and chloride excretion were very low, as in the with these changes in the volume and composition of the control period, in keeping with the salt-free diet; urine extracellular fluid, two patterns of urinary electrolyte ex- potassium excretion decreased approximately to control cretion have been described. In some patients [30, 31], the values. Nevertheless, hypokalemia and systemic alkalosis urine displays the following findings: it is intensely alkaline persisted relatively unchanged; 3) extracellular volume was (pH 7.60 to 8.25), containing large amounts of bicarbonate diminished in both the drainage and post-drainage periods, (39 to 102 mEq/day); large amounts of potassium (39 to presumably the consequence of an intracellular transfer of 102 mEq/day) despite concomitant hypokalemia in the sodium in exchange for potassium, as well as urinary losses Metabolic alkalosis 315 of NaHCO3 during the drainage period; 4) provision of [32, 33]. In addition, hydrogen may shift into tissue cells as sodium chloride in the diet was associated with a retention potassium deficiency develops. Although buffer [35, 36] of large amounts of the administered salt, the excretion of and glass electrode [37] measurements of muscle pH have, an alkaline urine containing increased amounts of sodium in general, failed to disclose a fall with potassium defi- bicarbonate, and a marked retention of potassium as ciency, this may well be the result of the capacity of intra- potassium chloride. In consequence, the alkalosis and cellular buffering to blunt any fall in intracellular pH which potassium deficit was corrected. can be measured by these methods. On the basis of these clinical and experimental observa- In addition to alkalosis, there is severe contraction of tions, a tentative reconstruction of the pattern of metabolic extracellular volume. This is principally the consequence of alkalosis associated with loss of gastric juice may be loss of sodium chloride in gastric juice. Two additional ventured (Fig. 6). The primary factor generating alkalosis factors contribute: 1) loss of sodium into cells with the is loss of hydrochloric acid. Even with profound alkalosis development of potassium depletion; and, 2) loss of sodium, and hypochioremia of the order of 65 mEq/liter, hydro- as sodium bicarbonate, into the urine if vomiting is severe. chloric acid secretion by the stomach continues at a normal The contraction of extracellular volume is doutbless respon- rate [34]. Two other factors contribute to the generation of sible for activation of the renin-angiotensin-aldosterone alkalosis. Contraction of extracellular volume, as a result system [29, 30]. of loss of sodium into vomitus and cells, without pro- The third feature associated with vomiting is potassium portionate losses of bicarbonate, will have the effect of deficiency. Starvation and loss of potassium chloride in increasing the concentration of the remaining bicarbonate gastric juice doubtless contribute, but it should be em- in the extracellular fluid. Even when gastric drainage has phasized that the potassium concentration of gastric juice been accomplished during rigid dietary restriction of is low and potassium deficiency develops even when the sodium chloride, contraction of volume, presumably the potassium chloride, lost in gastric drainage, is replenished consequence of intracellular shift of sodium as potassium [32, 33]. The principal cause of the deficit, as Burnett et al deficiency develops, was responsible for a significant frac- [38] originally pointed out, is urinary losses, a fact amply tion of the elevation of plasma bicarbonate concentration confirmed in several studies [3 1—33]. VOMITING

Decreased Loss of KC1 Loss of HCI Loss of NaCI food intake in vomitus in vomitus in vomitus

I Nadeficiency - 1

Jr Diminished r — -- KDeficiency Alkalosis i ExtracellularVolume

I .1 H+shiftsinto ce Ifplasma [HCO] I Renin-Angiotension I ¶ renal HCO Tm11s;exceeds renal HCO Tm

1 ' 1NaHCO3 I Aldosicrone /(andNaCI) % / deliveredto / distaltubule / / $ INa-K' / S // exchange S // S

IUrine lUrine K I UrineNa Urine C1 I HCO (urine pH 7-8) I I

Fig.6. _J L_ —— — — — — -j 316 Se/din/Rector

This sequence of events does not explain why vomiting is carbonate reabsorptive capacity commensurate with the associated in some patients with an alkaline urine contain- elevation in serum bicarbonate. As a result, distal delivery ing appreciable amounts of bicarbonate, potassium and of sodium salts is sharply curtailed. Although the stimulus sodium, but very little chloride, while in other patients the for distal sodium reabsorption is still very intense, owing urine pH is normal and contains little bicarbonate, potas- to secondary hyperaldosteronism, the reduced delivery of sium, sodium, and chloride. On the basis of the data avail- sodium salts results in greatly reduced potassium secretion. able, the most attractive hypothesis would attribute the As a result, therefore, of the more complete proximal difference in urinary patterns to the varied capacity of the reabsorption of sodium bicarbonate, the urine pH is now kidney to reabsorb the increased filtered bicarbonate. A normal and the excretion of potassium, sodium and chloride disequilibrium state exists if serum bicarbonate rises more very low. This is the pattern in the post-drainage state in than reabsorptive capacity; a steady state exists when the the studies of Schwartz and his associates. bicarbonate reabsorptive capacity can reclaim the filtered The provision of sodium chloride, by expanding extra- load more or less completely. cellular volume, reduces both the intense stimulus to The disequilibrium state is indicated in Fig. 6 by the proximal reabsorption and, by suppressing the renin- interrupted lines. If vomiting or drainage is continuous, angiotensin-aldosterone system, the stimulus to distal reab- rapid and severe, the concentration of serum bicarbonate sorption as well. The correction of alkalosis is associated may rise faster than the reabsorptive capacity. The con- with the excretion of sodium bicarbonate into the urine. traction of extracellular volume will stimulate intense It is likely that in many clinical circumstances the inter- reabsorption of filtrate in the proximal tubule. There- mittancy of vomiting will result in pulse-like rises in serum fore, distal delivery of sodium chloride will be mark- bicarbonate. There may then be a more or less continuous edly reduced. However, the reabsorptive capacity for shuttling between the pattern characteristic of disequilib- bicarbonate may well be exceeded by the high concentra- rium and steady state. On the other hand, if vomiting has tions in the glomerular filtrate. In consequence, the distal stopped without the deficits having been replaced, the nephron will be presented with excessive sodium bicarbonate pattern of the steady state will predominate. and diminished sodium chloride. Some of the sodium bicarbonate (in the presence of secondary hyperaldosteron- Generation of metabolic alkalosis by the kidney. It has ism) will be reabsorbed in exchange for potassium, augment- previously been pointed out that the kidney can generate ing urinary excretion; the remainder of the sodium bi- a metabolic alkalosis if there is a stimulation of the distal carbonate will be excreted into the urine, thereby raising sodium-hydrogen process coupled with an adequate deli- urine pH and augmenting urinary sodium excretion. How- very of sodium salts which are not derived from dietary ever, urinary chloride remains very low, furnishing evidence and metabolic acids. Persistent excessive mineralo-corticoid for contraction of extracellular volume and enhanced activity is the mechanism usually responsible for stimulating proximal reabsorption of filtrate. In the balance studies of distal sodium reabsorption. The sources for delivery of Schwartz and associates [32, 33] it is during the period of sodium salts are: 1) dietary sodium chloride; 2) inhibition of active drainage of gastric juice that the urine is alkaline sodium reabsorption in the more proximal segments of the and contains increased amounts of sodium and potassium. nephron (as by diuretics); 3) administration of sodium salts The disequilibrium state of vomiting is one of the few of poorly reabsorbable anions (nitrate, sulfate, phosphate). circumstances in clinical medicine where the criteria to Fig. 7 illustrates the pathogenesis of metabolic alkalosis distinguish extrarenal from renal losses of sodium and in a patient maintained on a diet of constant composition potassium break down. Salt depletion is ordinarily asso- containing 10 grams daily of sodium chloride and given ciated with markedly reduced urinary sodium excretion. large amounts of hydrocortisone. After a control period The salt depletion of vomiting, during the disequilibrium (not plotted) of two weeks on diet and salt, the hydro- period, is characterized by increased sodium excretion; the cortisone was begun. The upper panel charts the serum depletion of extracellular volume is best indicated by the concentrations of electrolytes at intervals as variations low chloride excretion. The high urinary potassium ex- from the mean of the control values, indicated by the cretion (in excess of 30 mEq/day), in the presence of horizontal lines. The middle panel charts the cumulative hypokalemia, is usually taken as evidence of primary renal positive balances of sodium and chloride, and the cumula- potassium wastage [39]. Once again, however, the active negative balances of potassium and potassium in excess celerated distal delivery of sodium bicarbonate provides of nitrogen. The values for urine pH are plotted up or the sodium which would ordinarily be very low during salt down from a mean control value of 6.21. In the bottom depletion. Accelerated urinary potassium excretion results panel, the cumulative excretion of NH plus titratable because secondary hyperaldosteronism is coupled with in- acid in excess of the control excretion rate is plotted. creased distal sodium bicarbonate delivery. For the first four days of hydrocortisone administration, If vomiting stops or is not very severe, a steady state there was about a two liter expansion of extracellular supervenes where contraction of extracellular volume and volume, indicated by the gain in body weight and the to a lesser extent potassium deficiency augment the bi- positive balances of sodium and chloride. Thereafter, de- Metabolic alkalosis 317

145 145 140

f[Na]110 [CIJ & 100 S 35 fHCO3]30 25J 5 4 3 2 600 /?:.::.:ff:::....' 500- .::::::::::::::::::::::: Na . ::::: : :::: :: :: 400 "

300 50.4

200 49.4

100 0 a -100 IP

E —200

pH 621 :60c. —

5— 15

4- 400-

300 NH4 plus titratable acid

200 E3z E 100

Fig. 7.Parhogenesis of metabolic alkalosis. See text. 318 Seldin/Rector spite the continued daily administration of hydrocortisone consequence the alkalosis is maintained. The combination and sodium chloride, extracellular volume did not expand of potassium deficiency and mineralo-corticoid excess does further. This is the escape phenomenon. it has been not completely obliterate the effects of volume expansion. suggested by micropuncture as well as free-water studies The progressive rise in urine pH (see Fig. 7) with marked to be the consequence of increased delivery of filtrate volume expansion doubtless indicates a small bicarbonate out of the proximal tubule (presumably caused by the leak into the urine probably resulting from inability of the expanded extracellular volume) which exactly counter- distal nephron to reabsorb all of the augmented bicarbonate balances the enhanced distal sodium reabsorption produced load delivered to it. The continued generation of new by the mineralo-corticoid action of hydrocortisone. The bicarbonate, as indicated by the high excretion rates of increased delivery of filtrate out of the proximal tubule ammonium, prevents this small loss from lowering the presumably results from inhibition of absolute reabsorption concentration of serum bicarbonate. and increased filtration rate. Chronic hypokalemic alkalosis caused by excessive Simultaneously with the retention of sodium chloride, mineralocorticoid action combined with a plentiful supply there is a loss of potassium and acid from the body. The of sodium chloride to the distal nephron has been recognized loss of potassium is largely in excess of nitrogen and there- as a feature of a variety of clinical syndromes. Cushing's fore indicates a depletion of stores of intracellular potas- syndrome, due to exogenous administration of hydro- sium. Accelerated acid excretion (as NH plus titratable cortisone or ACTH or to such endogenous disorders as an acid) is in part the consequence of increased tissue break- adrenal adenoma, bilateral adrenal hyperplasia and espe- down caused by the anti-anabolic action of hydrocortisone, cially extra-adrenal tumors producing ACTH-like sub- but principially a result of the enhanced reabsorption' of stances, is a well-recognized cause. So too is primary sodium in exchange for hydrogen as increased amounts of aldosteronism associated with an adrenal adenoma [41]. sodium chloride are delivered distally. Accelerated or malignant hypertension [42] and renal These events are best explained by assuming that mineralo- artery stenosis [43] can be associated with a persistent corticoid steroids accelerate sodium reabsorption in the hyper-secretion of aldosterone, and at times, hypokalemic distal nephron. Part of the sodium is reabsorbed as sodium alkalosis. In addition, two syndromes have been described chloride, expanding extracellular volume, suppressing in which relatively non-suppressible hyperaldosteronism proximal reabsorption, and thereby ensuring continued may occur in the absence of tumors: non-adenomatous distal supply of sodium salts. Part of the sodium is reab- bilateral adrenal hyperplasia [44—48]; and dexamethasone- sorbed for potassium, generating potassium deficiency, and suppressible hyperaldosteronism [49—5 1], apparently due part for hydrogen, generating hypochloremic alkalosis [201. to a partial 17-hydroxylase deficiency. Bartter's syndrome None of these events transpire if mineralocorticoids are [52], consisting of juxtaglomerular hyperplasia, high plasma given with a rigid sodium-free diet [221. This is because the renin with normal blood pressure and high aldosterone, absence of dietary salt does not allow for the expansion of may be a peculiar form of renal salt wastage [53, 54], in extracellular volume which by suppressing proximal reab- which extracellular volume is chronically contracted, sorption ensures a plentiful supply of sodium salts distally. thereby activating the renin-angiotensin-aldosterone sys- According to this model, then, the alkalosis is generated tem. The most frequent cause of persistent aldosteronism by a loss of acid into the urine. In addition, some of the associated with adequate distal sodium delivery is the use alkalosis may result from a loss of acid into cells in ex- of diuretics in edematous patients, where chronic contrac- change for cellular potassium which is ultimately excreted tion of effective arterial volume elicits secondary aldo- into the urine [40]. steronism, and in non-edematous patients, where the How is the alkalosis maintained? Contraction of effec- diuretic-induced salt loss is responsible for both secondary tive extracellular volume which, by enhancing proximal aldosteronism and increased distal sodium delivery. tubular reabsorption, is the principal factor ordinarily Finally, there are three syndromes in which the avid responsible for maintaining metabolic alkalosis, cannot be distal sodium reabsorption is mediated by some mechanism invoked here. Quite the contrary, the expansion of volume other than hyperaldosteronism. The adrenogenital syn- should serve to dissipate the generated bicarbonate by drome caused by complete absence of the enzyme 17- augmenting urinary excretion. It seems most reasonable to c-hydroxylase [55, 56] is associated with high levels of attribute the maintenance of alkalosis to the effects of corticosterone and desoxycorticosterone which can exert potassium deficiency and mineralo-corticoid excess. In the marked mineralo-corticoid activity and therefore produce proximal tubule, potassium deficiency can enhance bi- the same effects as hyperaldosteronism. Another form of carbonate reabsorption even when the fractional reabsorp- the adrenogenital syndrome, absence of the enzyme 11- lion of filtrate has been sharply reduced by volume ex- hydroxylase [57], is characterized by excessive mineralo- pansion [24]. This has the effect of reducing the distal load corticoid activity due to desoxycorticosterone alone. Second, of sodium bicarbonate. In the distal nephron, mineralo- Liddle, Bledsoe, and Coppage [58] have reported a familial corticoid excess in the presence of potassium deficiency disturbance in which there is a primary increase in distal accelerates the reabsorption of sodium bicarbonate. In sodium reabsorption. In consequence, hypokalemic alka- Metabolic alkalosis 319 losis, hypertension, and negligible secretion of aldosterone tors. First, the reabsorption of bicarbonate, unlike chloride, eventuate. Finally, licorice [59] ingestion is associated with seems to be limited and displays in man an "apparent" Tm. hypokalemic alkalosis because of an aldosteronelike action. Since the steady state concentration of serum bicarbonate Potassium deficiency. Whatever the cause of metabolic is very close to the apparent Tm in man (unlike the rat), alkalosis, it will often be corrected by expansion of effective minor elevations in the serum concentration quickly exceed arterial blood volume. In non-edematous patients, infusion the reabsorptive capacity and are excreted. Second, the of saline will expand volume, suppress bicarbonate reab- administration of sodium bicarbonate, by expanding extra- sorption, and correct alkalosis by augmenting bicarbonate cellular volume, suppresses fractional reabsorption in the excretion. However, in the presence of nonsuppressible proximal tubule, and may lead to diminished aldosterone mineralo-corticoid excess, such as primary aldosteronism secretion, and therefore, reduced reabsorption, distally. The or Cushing's syndrome, infusion of saline may not correct net effect would be reduced sodium bicarbonate reabsorp- the alkalosis. Such states, in which chloride is present in tion. the urine (usually in concentrations greater than 10 mEq/ In renal failure, the capacity to excrete bicarbonate loads liter) and which do not respond to saline, have been called is still striking. We have repeatedly observed that patients saline-resistant. Such a syndrome has been described in with advanced renal disease who tend to form edema will become edema-free if sodium chloride in the diet is sharply patients with profound potassium deficiency resulting from diarrhea and starvation, and without evidence of primary reduced and sodium bicarbonate substituted. In general, hypersecretion of adrenal steroids [60]. The urinary ex- alkalosis does not develop because bicarbonate excretion cretion of large amounts of chloride without correction of rises sharply as the serum concentration begins to exceed alkalosis is strong evidence that profound potassium def i- the normal value. However, excessive bicarbonate loads in ciency can augment the bicarbonate reabsorptive capacity, a setting of renal failure can produce alkalosis with or and thereby maintain a metabolic alkalosis, even when without edema. This results not only because so few volume expansion would tend to suppress proximal reab- nephrons are functioning, but also because in these re- sorption and endogenous aldosterone secretion. maining nephrons fractional reabsorption of filtrate is already greatly reduced. Congenital alkalosis and diarrhea. This syndrome begins at birth and is characterized by metabolic alkalosis, watery Contraction alkalosis. It has been pointed out by several diarrhea in which stool chloride is higher than the sum of observers [65, 66] that diuretics given to edematous patients stool sodium plus potassium, and absence of chloride in may accelerate the excretion of sodium chloride without the urine [61, 62]. Evanson and Stanbury [63] suggested commensurate losses of sodium bicarbonate. Under such that the primary disturbance was a defective gastro- circumstances, metabolic alkalosis will eventuate without intestinal absorption of chloride, which then acted as an loss of acid or gain of alkali. The elevated serum bicarbon- osmotic cathartic, causing diarrhea. They therefore termed ate will be maintained because of accelerated reabsorption the disorder congenital chloridorrhea. The diarrhea, in of filtrate characteristic of circumstances where there is a turn, would tend to produce potassium deficiency and salt stimulus for edema formation. depletion. Post-hypercapneic state. Schwartz et al [12] demon- Recent studies by Bieberdorf, Gorden, and Fordtran [64] strated that the serum bicarbonate of dogs, removed from indicate that the primary defect is an inability of the ileum a high CO2 atmosphere, did not return to normal if they actively to absorb chloride. Sodium absorption from the were on a salt-free diet. Access to dietary salt promptly lumen in exchange for hydrogen proceeds normally, and corrected the metabolic alkalosis. This suggests that the the secreted hydrogen reacts with luminal bicarbonate, contracted extracellular volume, incident to dietary salt forming CO2 and H20, thereby accomplishing net sodium restriction, was responsible for the maintenance of the bicarbonate reabsorption. The failure of active chloride for elevated serum bicarbonate. bicarbonate exchange means that the ileum is losing sodium and potassium chloride into the stool and adding sodium Reprintrequests to Dr. Donald W. Se/din, Department of bicarbonate to the blood. The alkalosis, thus generated, is Internal Medicine, University of Texas Southwestern Medical maintained by contracted extracellular volume and potas- School, 5323 Harry Hines Blvd., Dallas, Texas 75235, U.S.A. sium deficiency. Excessive bicarbonate loads. Normally, the kidney has an References enormous ability to excrete administered loads of bicarbonate. In the studies of Sanderson and his associates I. Rector, F. C., Jr., Carter, N. W., and Seldin, D. W.: The mechanism of bicarbonate reabsorption in the proximal and [27, 28], massive bicarbonate loads, up to 140 grams daily, distal tubules of the kidney. J. Clin. Invest. 44: 278—290, often produced only minor elevations (in one instance no 1965. more than about one mEq/liter) in the serum concentration. 2. Vieira, F. L., and Malnic, G.: Hydrogen ion secretion by This remarkable capacity to eliminate administered sodium rat renal cortical tubules as studied by an antimony micro- bicarbonate appears to be the consequence of several fac- electrode. Am. J. Physiol. 2/4: 710—718, 1968. 320 Se/din! Rector

3. Malnic, G., and de Mello-Aires, M.: Kinetic study of bi- 19. Cohen, J. J.: Correction of metabolic alkalosis by the kidney carbonate reabsorption in proximal tubule of the rat. Am. after isometric expansion of extracellular fluid. J. Clin. J. Physiol. 220: 1759—1767, 1971. Invest. 47.' 1181—1192, 1968. 4. Pocker, Y., and Stone, J. T.: The catalytic versatility of 20. Berliner, R. W., Kennedy, T. J., Jr., and Orloff, J.: Rela- enythrocyte carbonic anhydrase. The enzyme catalyzed tionship between acidification of the urine and potassium hydrolysis of p-nitro phenyl acetate. J. Am. Chem. Soc. 87: metabolism. Am. J. Med. 1]: 274—282, 1951. 5497—5498, 1965. 21. Kassirer, J. P., Lowance, D. C., and Schwartz, W. B.: 5.Pitts, R. F., and Lotspeich, W. D.: Bicarbonate and the Aldosterone-induced metabolic alkalosis in man. Proc. Am. renal regulation of acid-base balance, Am, J. Physiol. 147: Soc. Neph. (abstracts), 1971, p. 36. 138—154, 1946. 22. Seldin, D. W., Welt, L. G., and Cort, J. 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