Clinical Syndromes of Metabolic Alkalosis

Homeostatic control of acid–base parameters within discreet limits is vital to all living organisms. Acid–base disturbances are conditions that reflect abnormal underlying physiologic processes that can stem from a broad range of etiologies. In humans with a filtration-reabsorption nephron design, more than 4000 mEq of HCO ₃ ⁻ is filtered daily at the glomerulus and virtually all of it is reabsorbed by the tubules.Two points are noteworthy. Since HCO ₃ ⁻ absorption is an active process, in defense of elevated plasma [HCO ₃ ⁻ ], the renal tubule simply has to do less work and bicarbonaturia invariably ensues. Given the relative magnitudes of filtered and reabsorbed versus excreted HCO ₃ ⁻ , bicarbonaturia can be massive, which translates to rapid correction of excess extracellular fluid HCO ₃ ⁻ . Within such context, one wonders why metabolic alkalosis would even be encountered. In contrast to metabolic acidosis, where the pathophysiology reflects increased acid production, reduced acid excretion, or both, the maintenance of metabolic alkalosis is a quintessential renal disease of altered HCO ₃ ⁻ absorption.Alkalosis is the condition in which there is an excess of base in total body fluids. By contrast, alkalemia refers to a state of decreased H ⁺ activity in the plasma (reduced plasma pH). Alkalosis can exist without alkalemia because alkalosis might be part of a mixed acid–base disturbance. Conversely, alkalemia can be present without total body alkalosis. The adjective metabolic denotes that the disturbance is caused by a primary gain of base (e.g., HCO ₃ ⁻ ) or loss of H ⁺ from the body.

Introduction

Homeostatic control of acid–base parameters within discreet limits is vital to all living organisms. Acid–base disturbances are conditions that reflect underlying pathophysiology, which can stem from a broad range of etiologies. In humans with a filtration-reabsorption nephron, >4,000 mEq of HCO ₃ ⁻ is filtered daily at the glomerulus and virtually all of it is reabsorbed by the tubules ( Figure 58.1 ).

Figure 58.1, Filtration-absorption mechanism of bicarbonate handling by the nephron.

HCO ₃ ⁻ absorption is an energy-requiring process. Under normal circumstances with a more or less fixed capacity to reabsorb elevated filtered [HCO ₃ ⁻ ], the renal tubule does not commensurately increase energy consumption or bicarbonate reabsorption therefore bicarbonaturia invariably ensues. Given this background, one wonders why metabolic alkalosis should supervene. In contrast to metabolic acidosis where the pathophysiology reflects increased acid production, reduced acid excretion, or both, the maintenance of metabolic alkalosis is a quintessential disease of altered renal HCO ₃ ⁻ handling. Even though extrarenal factors contribute, the final effectors of maintaining a high plasma [HCO ₃ ⁻ ] reside in the kidney. Metabolic alkalosis is a tubulopathy.

A few definitions are necessary. Alkalosis denotes an excess of base in total body fluids. Alkalemia refers to a state of decreased H ⁺ activity in the plasma (increased plasma pH). Alkalosis can exist with little alkalemia due to respiratory compensation and without alkalemia because alkalosis might be part of a mixed acid–base disturbance. Conversely, alkalemia can be present without total body alkalosis. The adjective metabolic denotes that the disturbance is caused by a primary gain of base (e.g., HCO ₃ ⁻ ) or loss of H ⁺ from the body; as opposed to primary disturbances in carbon dioxide excretion.

The only compartment that is accessible to clinical testing is the ECF; hence ECF composition has defined most clinical acid–base disorders. Note that the direction of alterations in intracellular fluid (ICF) H ⁺ activity might differ from ECF. The pathogenesis of metabolic alkalosis involves two distinct derangements— generation and maintenance . The increased ECF [HCO ₃ ⁻ ] that characterizes metabolic alkalosis is usually due to excessive ECF HCO ₃ ⁻ content with noted exceptions such as massive contraction of ECFV around a constant amount of HCO ₃ ⁻ , or shift of H ⁺ into cells with intracellular K ⁺ depletion. ECF HCO ₃ ⁻ addition might occur through oral or intravenous routes. Of equal importance is H ⁺ removal from ECF which is tantamount to HCO ₃ ⁻ addition.

H ⁺ can leave the body (external H ⁺ loss) through the gastrointestinal tract by vomiting or the kidney through stimulated urinary H ⁺ excretion. In either case, H ⁺ loss is synonymous with formation of HCO ₃ ⁻ from the gastric or renal cell, respectively, which then enters the ECF. Alternatively, H ⁺ can move from the ECF into the ICF (internal H ⁺ loss) as seen in K ⁺ depletion. The phase of metabolic alkalosis in which addition to the ECF exceeds HCO ₃ ⁻ exit from ECF thus raising ECF [HCO ₃ ⁻ ], is called the generation phase . Normally, excess ECF HCO ₃ ⁻ is readily and rapidly excreted by the kidneys. Persistent excess ECF HCO ₃ ⁻ content and concentration is usually due to inhibition of the ability of the kidney to excrete HCO ₃ ⁻ . This is referred to as the maintenance phase .

Metabolic alkalosis is the most common acid–base disorder in hospitalized patients. The magnitude of metabolic alkalosis correlates with morbidity, mostly as a marker of severe underlying conditions but also a direct contributor to adverse events. A careful approach guided by the known pathophysiology of this order can direct diagnosis and management of the underlying disorders.

In this chapter, we will cover how one normal copes with the defense against high extracellular fluid HCO ₃ ⁻ concentration, the systemic factors that act on the kidney to “reset” the plasma HCO ₃ concentration, the proximal and distal tubular mechanisms responsible for this feat and finally, the clinical syndromes of metabolic alkalosis.

Defense Against Excess Extracellular Fluid (ECF) HCO ₃

As with any acid–base disturbance, one can envision three fronts of defense ( Figure 58.2 ). First, the excess base confronts constituents of the fluid compartments, which harbors chemical components of defense. Second, the ventilatory system adjusts one determinant of ECFV pH, namely the CO ₂ tension, to minimize the pH deviation. Third and the most important of all is the definite correction by the kidney with external elimination of the excessive base.

Figure 58.2, Three lines of defense against a HCO 3 − load: 1. Redistribution and buffer. 2. Hypoventilation to increase pCO 2 . 3. Renal excretion of HCO 3 − .

Systemic Response to ECF HCO ₃ ⁻ Addition

Distribution of HCO ₃ ⁻ Added to ECFV

Unlike a non-decomposable anion such as sulfate, HCO ₃ ⁻ is partially dissipated by body buffers, so its distribution does not fit into a single body compartment. The apparent distribution space of added HCO ₃ ⁻ has been partitioned into anatomic and non-anatomic divisions ( Figure 58.3 ).

Figure 58.3, Apparent HCO 3 − space. This entity is theoretically partitioned into anatomic ECF volume and a non-anatomic space whose size is dependent on existing plasma [HCO 3 − ].

The “anatomic” division refers to mainly the ECF compartment where added HCO ₃ ⁻ is freely distributed. The “non-anatomic” division refers to the theoretical volume that accommodates the added HCO ₃ ⁻ which cannot be accounted for by the anatomic space (ECF). This presumably represents some HCO ₃ ⁻ that has entered cells and some that has been titrated by H ⁺ released from non-HCO ₃ ⁻ buffers (such as hemoglobin and phosphate) thus constituting a virtual “space.” At normal pH, these two divisions are approximately equal and together yield a total apparent HCO ₃ ⁻ space of about 40 to 50% of total body weight. Apparent HCO ₃ ⁻ space is inversely related to preexisting ECF [HCO ₃ ⁻ ], with the non-anatomic fraction decreasing in size as the ECF [HCO ₃ ⁻ ] increases. Decreasing size of the non-anatomic division with increasing ECF [HCO ₃ ⁻ ] is due to progressive narrowing of the titration range for non-HCO ₃ ⁻ buffers at higher ECF [HCO ₃ ⁻ ]. Thus, a higher preexisting ECF [HCO ₃ ⁻ ] indicates greater titration of non-HCO ₃ ⁻ buffers, causing a greater rise in ECF [HCO ₃ ⁻ ] in response to a given quantity of added HCO ₃ ⁻ . As with H ⁺ , HCO ₃ ⁻ added to ECF is buffered by cellular and extracellular processes. Compared to acid, a smaller fraction of added base is buffered in the cell, so a greater fraction of added HCO ₃ ⁻ is retained in the ECF. In addition, there is less stabilization of intracellular pH in the alkaline range compared to the acid range. This highlights the importance of rapid renal HCO ₃ ⁻ removal in the systemic defense against excess ECF HCO ₃ ⁻ .

Respiratory Response to a Primary Increase in ECF [HCO ₃ ⁻ ]

Respiratory mechanisms alleviate but do not fully correct the elevated plasma pH ( Figure 58.2 ). The pH increase from added ECF HCO ₃ ⁻ is attenuated by a concomitant rise in pCO ₂ . The acute component begins within seconds of HCO ₃ ^- addition due to neutralization of added HCO ₃ ⁻ by H ⁺ derived from titrated non-HCO ₃ ⁻ buffers as follows:

{NaHCO}_{3} + H Buffer \to NaBuffer + H_{2} {CO}_{3} \to {CO}_{2} + H_{2} O

${NaHCO}_{3} + H Buffer \to NaBuffer + H_{2} {CO}_{3} \to {CO}_{2} + H_{2} O$

The CO ₂ generated by this reaction stimulates ventilation, returning pCO ₂ toward but not precisely to normal. This acute response is followed by a more chronic one commencing at about 1 hour in which the alkalemia suppresses ventilation, leading to a sustained increase in pCO ₂ . This effect on the central ventilatory centers is probably mediated through alkalinization of cerebral interstitial fluid. The hypercapneic response to metabolic alkalosis takes several hours to complete and attenuates the rise in body fluid pH (but does not return pH to normal). In general, the pCO ₂ increase in metabolic alkalosis is about 0.74 mm Hg for every 1 mEq/L increase in ECF [HCO ₃ ⁻ ]. The compensatory fall in alveolar ventilation is limited by hypoventilatory hypoxemia which can override the pH effect.

Renal Excretion of HCO ₃ ⁻

Despite the importance of buffering and respiratory responses which provides transient amelioration, the kidney has the ultimate responsibility for disposal of excess ECF HCO ₃ ⁻ . Although its usual task is to completely recover filtered HCO ₃ ⁻ and excrete a nearly HCO ₃ ⁻ -free urine, the normal kidney has an extraordinary capacity to excrete HCO ₃ ⁻ . The normal kidney excretes ingested HCO ₃ ⁻ more rapidly than it excretes ingested H ⁺ .

The classic experiment of Pitts and Lotspeich ( Figure 58.4 ) demonstrated that renal HCO ₃ ⁻ reabsorption does not increase after plasma [HCO ₃ ⁻ ] is beyond about 24 mM- a “threshold” at the whole organism level. Bicarbonaturia commence beyond the threshold which is when the tubular reabsorptive capacity is reach ( Figure 58.4 ). The inflection point does not have a sharp angle but rather has a splay ( Figure 58.4 ). Chronic oral NaHCO ₃ ⁻ loads as large as 24 mEq/kg/day are readily excreted in humans with minimal changes in ECF [HCO ₃ ⁻ ], and acute intravenous loads are excreted entirely within 24 hours. The kidney also increases excretion of organic anions (e.g. citrate) which are HCO ₃ ⁻ equivalents (metabolism of which produces HCO ₃ ⁻ ) in response to ingested HCO ₃ ^- , contributing to the defense against metabolic alkalosis. Urine HCO ₃ ⁻ excretion in response to administered HCO ₃ ⁻ might theoretically be mediated by increased glomerular filtration rate (GFR), reduced tubule HCO ₃ ⁻ reabsorption, or a combination of both. Intravenous isotonic NaHCO ₃ ⁻ induces massive urinary HCO ₃ ⁻ excretion with minimal or no change in GFR highlighting the importance of the renal tubule in mediating bicarbonaturia. Acute HCO ₃ ⁻ infusion reduces fractional HCO ₃ ⁻ reabsorption in the proximal and distal nephron. In addition, juxtamedullary nephrons excrete proportionally more HCO ₃ ⁻ than do superficial ones in response to an acute intravenous HCO ₃ ⁻ load. Thus, the fixed or even suppressed capacity of HCO ₃ ⁻ reabsorption is the predominant mechanism that mediates bicarbonaturia in response to an acute HCO ₃ ⁻ load.

Figure 58.4, Whole kidney HCO 3 − absorption as a function of plasma [HCO 3 − ]. HCO 3 − reabsorption increases as plasma [HCO 3 − ] increases (assuming constant glomerular filtration rate) up to a point which is the plasma [HCO 3 − ] threshold beyond which bicarbonaturia ensues. The inflection point is not sharp in the sense that there is a slight splay. Above the threshold the maximal capacity of renal HCO 3 − reabsorption is reached.

Acute HCO ₃ ⁻ infusion tests the nephron’s response to extreme HCO ₃ ⁻ loads and massive bicarbonaturia is the usual response. However, mammals are rarely exposed to such massive alkali insults in their natural habitats and more subtle means of base excretion are utilized such as reduced net acid excretion and citraturia. More physiologic alkali challenges have been modeled using dietary NaHCO ₃ . Chronic oral NaHCO ₃ ⁻ reduces urine net acid excretion (urine ammonium + titratable acid − urine base) by decreasing excretion of ammonium and titratable acid as well as by increasing organic anion (primarily citrate) and HCO ₃ ⁻ excretion. Decreased ammonium and titratable acid excretion with maintained GFR is caused by decreased distal nephron acidification.

The inference from clearance studies was confirmed by direct measurements showing reduced acidification in distal and collecting tubules in animals ingesting NaHCO ₃ . Because HCO ₃ ⁻ is both reabsorbed (mediated largely through H ⁺ secretion) and secreted in the distal and collecting tubule, decreased acidification in these distal segments can actually be mediated by increased HCO ₃ ⁻ secretion and/or decreased H ⁺ secretion. Animals chronically ingesting NaHCO ₃ have increased HCO ₃ ⁻ secretion in the distal and collecting tubule while distal tubule H ⁺ secretion is less affected. H ⁺ ingestion increases H ⁺ -ATPase staining activity in collecting ducts. Thus, stimulated HCO ₃ ⁻ secretion is more prominent than reduced H ⁺ secretion as the predominant mechanism by which dietary HCO ₃ ⁻ decreases distal nephron acidification.

Renal Disposal of Excess ECF HCO ₃ ⁻

Peritubular and Luminal Acid–Base Composition

Because increased ECF [HCO ₃ ⁻ ] is accompanied by simultaneous increase in [HCO ₃ ⁻ ] in the proximal tubule luminal fluid in vivo , it is difficult to separate the effects of peritubular from luminal acid−base changes on tubular HCO ₃ ⁻ reabsorption in response to ECF [HCO ₃ ⁻ ] addition. This is best studied by measuring renal tubule HCO ₃ ⁻ reabsorption in response to unilateral changes of acid–base composition in a renal tubule or its adjacent peritubular capillary in vivo.

In the proximal tubule, increased peritubular [HCO ₃ ⁻ ] and pH decrease net HCO ₃ ⁻ reabsorption and increased luminal [HCO ₃ ⁻ ] increases it ( Figures 58.5 and 58.6 ). When H ⁺ secretion (transcellular active transport) is measured with varying luminal [HCO ₃ ⁻ ] at two levels of constant plasma [HCO ₃ ⁻ ], two features are evident. First, the proximal HCO ₃ ⁻ threshold is not 25 mM but rather 40-50 mM. The threshold depicted in Figure 58.4 of 24 mM is a whole animal phenomenon. Second, increase in peritubular [HCO ₃ ⁻ ] reduces the HCO ₃ ⁻ transport capacity of the proximal tubule ( Figure 58.6 ). Acute increases in plasma [HCO ₃ ⁻ ] and pH (peritubular) also decrease distal tubule HCO ₃ ⁻ reabsorption in vivo . On the other hand, increases in luminal [HCO ₃ ⁻ ] increases HCO ₃ ⁻ reabsorption in both proximal and distal tubules. Acute HCO ₃ ⁻ addition to ECF will inhibit both proximal and distal HCO ₃ ⁻ reabsorption by increasing peritubular [HCO ₃ ⁻ ] but the concurrent increase in luminal [HCO ₃ ⁻ ] will stimulate proximal absorption and depending on whether the increased luminal [HCO ₃ ⁻ ] is translated axially down the nephron, it may offset the distal effect of increased peritubular [HCO ₃ ⁻ ].

Figure 58.5, Regulation of proximal tubule transcellular HCO 3 − absorption (H + secretion). Transcellular bicarbonate reabsorption is regulated by both luminal and plasma [HCO 3 − ] and pH, and ECF volume while paracellular HCO 3 − back-leak is regulated by extracellular fluid volume.

Figure 58.6, Interaction of luminal and plasma [HCO 3 − ] on rate of transcellular H + secretion in rat proximal tubule . At each level of luminal [HCO 3 − ], plasma [HCO 3 − ] influences proximal acidification.

ECF Volume and Dietary NaCl

Classic clearance studies showed increasing bicarbonaturia as ECF [HCO ₃ ⁻ ] (and HCO ₃ ⁻ filtered load) rises above baseline in response to isotonic NaHCO ₃ ⁻ infusion suggesting that the kidney ordinarily operates near its maximal capacity for HCO ₃ ⁻ reabsorption. Renal HCO ₃ ⁻ reabsorption can be dramatically enhanced above control levels when ECF [HCO ₃ ⁻ ] and filtered HCO ₃ ⁻ load are increased with hypertonic NaHCO ₃ ⁻ infusion with minimal concomitant volume expansion. In the absence of volume expansion, proximal tubule HCO ₃ ⁻ reabsorption increases robustly in response to increasing luminal [HCO ₃ ]; showing partial saturation at a luminal [HCO ₃ ] that is nearly twice that of plasma. These studies highlight the kidneys’ large intrinsic capacity for HCO ₃ ⁻ reabsorption—an ability that is important in maintaining metabolic alkalosis.

Renal HCO ₃ ⁻ reabsorption is inversely related to the state of effective ECF volume ( Figure 58.5 ). Volume expansion decreases fractional HCO ₃ ⁻ reabsorption in the proximal convoluted tubule whether it is achieved with isotonic Ringers solution or with salt-poor hyperoncotic albumin. Decreased proximal tubule HCO ₃ ⁻ reabsorption induced by volume expansion is due to increased HCO ₃ ⁻ permeability from peritubular blood to the tubule lumen, which likely increase “back-leak” of HCO ₃ ⁻ into the tubule lumen and reducing net HCO ₃ ⁻ reabsorption; volume expansion induced no changes in proximal tubule H ⁺ secretion. Thus, adequate ECF volume is an important permissive factor for renal excretion of excess ECF HCO ₃ ⁻ . Dietary restriction or excess of NaCl yields subtle changes in ECF volume and influence steady-state ECF [HCO ₃ ⁻ ] via modulation of renal HCO ₃ ⁻ excretion. Animals ingesting a NaCl-restricted diet have higher plasma [HCO ₃ ⁻ ] and lower urinary HCO ₃ ⁻ excretion. Furthermore, humans given NaHCO ₃ increase their ECF [HCO ₃ ⁻ ] when they concomitantly ingest an NaCl-restricted diet. Dietary NaCl restriction also increases ECF [HCO ₃ ⁻ ] in animals and humans with uremic acidosis. Dietary NaCl also induce distal HCO ₃ ⁻ secretion. Thus, supplemental dietary NaCl facilitates excretion of HCO ₃ ⁻ added to ECF.

Potassium Status

K ⁺ deficiency is associated with intracellular acidosis independent of the extracellular pH. To a renal epithelial cell, this likely provides a signal that calls for augmentation of HCO ₃ ⁻ absorption. K ⁺ depletion causes metabolic alkalosis in rats and humans by multiple mechanisms, some of which are not fully clarified. Because K ⁺ depletion causes renal Cl ⁻ wasting, the effects of K ⁺ depletion with respect to renal HCO ₃ ⁻ handling might be due in part to KCl depletion. Renal HCO ₃ ⁻ reabsorption is greater in K ⁺ -deplete compared to K ⁺ -replete animals, and K ⁺ loading augments urinary HCO ₃ ⁻ excretion in response to HCO ₃ ⁻ infusion at all levels of ECF volume. Acute NaHCO ₃ infusion induces less renal HCO ₃ ⁻ excretion and higher ECF [HCO ₃ ⁻ ] in KCl-deplete animals compared to K ⁺ -replete ones. Thus, KCl depletion reduces renal ability to excrete excess ECF HCO ₃ ⁻ and helps to maintain metabolic alkalosis. There is a very modest increase in the mRNAs for the subunits of H,K-ATPases in the outer medulla; the physiologic significance of this finding is not known.

Hormones Affecting Renal HCO ₃ ⁻ Excretion

Addition of HCO ₃ ⁻ to the ECF may modulate renal HCO ₃ ⁻ excretion. ECF volume expansion due to NaHCO ₃ administration decreases angiotensin II and aldosterone levels, both being stimulatory hormones for renal tubule HCO ₃ ⁻ reabsorption. More importantly, euvolemic increases in ECF [HCO ₃ ⁻ ] and pH generated by dialysis decrease plasma aldosterone concentration. Vasoactive intestinal peptide which increases after meals, increases distal tubule HCO ₃ ⁻ secretion, possibly facilitating postprandial urinary HCO ₃ ⁻ excretion. Dietary NaHCO ₃ increases urinary prostacyclin, which also augments distal tubule HCO ₃ ⁻ secretion. Altered actions of these and other agonists induced by ECF HCO ₃ ⁻ addition might contribute to urinary HCO ₃ ⁻ excretion. In contrast, disturbances in such responses might contribute to the persistence of excess ECF HCO ₃ ⁻ and maintenance of metabolic alkalosis.

Mechanisms of Metabolic Alkalosis

When the rate of HCO ₃ ⁻ generation or administration exceeds the capacity of regulatory mechanisms to immediately correct it, transient disequilibrium metabolic alkalosis can occur. Most commonly, the generation of excess ECF HCO ₃ ⁻ is not sustained and ECF acid–base composition is returned to normal. Sustained metabolic alkalosis is hard to achieve with normal renal HCO ₃ ⁻ excretory ability and invariably involves compromised renal ability to excrete HCO ₃ ⁻ and/or failure to reduce net acid excretion.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here

Introduction

Defense Against Excess Extracellular Fluid (ECF) HCO 3

Systemic Response to ECF HCO 3 − Addition

Distribution of HCO 3 − Added to ECFV

Respiratory Response to a Primary Increase in ECF [HCO 3 − ]

Renal Excretion of HCO 3 −

Renal Disposal of Excess ECF HCO 3 −