Clinical Syndromes of Metabolic Acidosis

Abstract

Metabolic acidosis is the acid–base disturbance that is initiated by a primary decrease in the plasma [HCO ₃⁻]. The acidemia leads to a time-dependent and quantitatively predictable ventilatory response, i.e., a secondary decrease in CO ₂tension which is taken as the basis for the diagnostic criteria of this disorder. Under certain circumstances, this secondary hypocapnia may elicit a maladaptive renal response characterized by worsening of acidosis. The clinical setting of the patient and the calculation of plasma and urine anion gaps as well as the associated electrolyte changes complement the relation among HCO ₃⁻and PaCO ₂for the identification of the underlying cause of metabolic acidosis. Metabolic acidosis can manifest as a hyperchloremic variety (mostly the result of HCO ₃⁻losses by the gut or renal proton retention as in the tubular acidosis) or as the normo-or hypochloremic variety (high plasma anion gap) that results from accumulation of organic acids such as lactic and keto acids.

Many clinical sequelae are the consequence of metabolic acidosis and include, besides hyperventilation, effects on sodium, potassium and divalent ion metabolism. Metabolic acidosis also results in negative nitrogen balance and exerts complex effects on bone metabolism with, among others, a negative impact on bone mass and bone quality.

Treatment of the disorder is mainly guided by the elimination of the initiating cause and provision of alkali in the chronic setting. In acute metabolic acidosis, alkali treatment should probably be limited to the most severe forms where remaining blood buffer capacity is very low and further acid loads will result in large pH changes (i.e. plasma [HCO ₃⁻] around 10 mmol/L or below).

Introduction

The maintenance of normal systemic acid–base regulation requires the subtle integration of a number of organ functions and physiologic mechanisms such as extracellular and cellular buffering processes and integrated responses of the kidney, lung, liver, gastrointestinal tract, and skeleton. Disturbances of acid–base homeostasis are the predictable consequences of many pathophysiological processes. Their recognition may lead the clinician to the diagnosis of specific diseases and/or complications thereof. In addition, it has become increasingly clear that adaptation to acid–base disturbances is characterized by a number of important metabolic and endocrine derangements. Thus, whereas there is no evidence that there is any defense of extracellular pH to any homeostatic value or “set-point,” there is evidence for homeostatic regulation of intracellular pH. Such regulation of intracellular pH affords unimpaired function of a multitude of cellular, enzymatic, and molecular processes. However, many adverse and clinically important effects of systemic acid–base disturbances in vivo have been recognized that might be viewed as maladaptive or constituting a “trade-off” for the maintenance of acid–base homeostasis.

In this chapter, we review the renal and systemic response to acidosis or acid load. Next, special emphasis is placed on the clinical consequences of acidosis such as on protein, divalent ion, and bone metabolism, and sodium and potassium balance as well as secondary endocrine disturbances. Finally, the various clinical entities of metabolic acidosis and their diagnostic recognition are described. The number of cited references had to be reduced for this edition. Therefore, not all important work of all authors that have contributed to the knowledge of the field could be cited. The reader will find additional references in the second to fourth editions of this book.

Definition of Metabolic Acidosis

Metabolic acidosis is the acid–base disturbance initiated by a primary decrease in plasma bicarbonate concentration. The resultant acidification of neural chemoreceptors stimulates ventilation and leads to a predictable secondary hypocapnia. The primary hypobicarbonatemia causing metabolic acidosis can occur due to: (1) loss of bicarbonate salts from the gastrointestinal tract or kidney, (2) excess of noncarbonic acid presented to body buffers from endogenous or exogenous sources, and/or (3) a decrease in the kidney’s set-point for regulation of plasma bicarbonate concentration. The latter circumstance might or might not be associated with a decrease in the kidney’s ability to excrete acid.

Metabolic acidosis is defined as acute on the basis of the characterization of an early steady-state period in which stable acid–base and electrolyte composition is observed during at least the initial six hours after an acid load. Within 120 minutes after an acid load and following a large net retention of administered acid, renal net acid excretion is significantly increased and is fully augmented within 72 hours. Net acid excretion is increased to values whereby the rate of acid excretion approaches the rate of endogenous acid production. Daily acid balance is again essentially achieved and the steady state of chronic metabolic acidosis has occurred. In chronic metabolic acidosis, the occurrence of an approach to daily acid balance permits the maintenance of stable but depressed plasma bicarbonate concentrations. The resulting decrease in plasma bicarbonate concentration in such conditions of extrarenal metabolic acidosis reflects the magnitude and anionic character of the acid load/production as well as the potency of the acid excretory response. Large variations in naturally occurring diet-induced acid production from 0 to 150 mmol protons/day correlate inversely and significantly with ambient plasma bicarbonate concentration, and lower bicarbonate concentrations are associated with higher blood acidity. Thus, normal subjects ingesting higher acid loads occupy the lower domains of the normal range of plasma bicarbonate concentration, whereas those that self-select smaller acid loads exhibit bicarbonate values within the upper domain of the normal range of values. The observation that higher acid-generating diets produce relatively small decrements in plasma bicarbonate and small increments in blood acidity reflects the potency of renal acid excretory mechanisms to adjust to changes in acid load as well as other factors such as primary or secondary changes in PaCO ₂as discussed in subsequent sections. Thus, plasma bicarbonate concentrations within the clinically normal range do not signify the rigorous absence of an acidotic process.

Systemic and Renal Acid–Base Homeostasis

Systemic acid–base homeostasis requires the coordinated and integrated action of the lung, kidney, liver, skeleton, and gastrointestinal tract ( Fig. 59.1 ). Cellular metabolism produces about 15,000 mmol of CO ₂daily that, if received as a nonvolatile acid or a volatile acid in a closed system would constitute a major acid load according to the following relationship:

CO2+?2?→?2CO3→HCO−3+?+

CO2+H2O→H2CO3→HCO3−+H+

CO 2 + H 2 O → H 2 CO 3 → HCO 3 − + H +

Although equimolar quantities of acid and base are produced by the dissociation of carbonic acid, the produced protons would be expected to have a much greater influence on acid–base equilibrium due to the basal concentration of H ⁺being six orders of magnitude lower than the corresponding value for bicarbonate (40 nmol/liter vs 25`mmol/liter).

However, under steady-state circumstances the HCO−3
HCO 3 −
/H ₂CO ₃buffer system behaves as an “open” buffer system, whereby CO ₂/H ₂CO ₃is eliminated at a rate necessary to maintain PaCO ₂at the level dictated by alveolar ventilation, the rate of that is, in turn, controlled by neural chemoreceptors. Accordingly, when regulation of alveolar ventilation is undisturbed, only noncarbonic acids normally contribute to net acid production or to appreciable acid retention.

In the healthy individual, the primary source and magnitude of an acid load results from hepatic metabolism of dietary protein. Neutral amino acids are metabolized without net proton consumption or production, and metabolism of dicarboxylic amino acids consumes protons, while sulfur-containing as well as cationic amino acid catabolism results in net hepatic proton production. Due to the prevalence of sulfur-containing amino acids in the animal protein-rich nutrients typical of the “Western diet,” endogenous acid production is around 1 mmol per kilogram of body weight per day.

Endogenous acid production is also influenced by organic acid production from neutral precursors and alkali lost through stool. Many of the clinical syndromes of metabolic acidosis are characterized by an increase in organic acid production and/or organic acid metabolism (such as ketoacidosis, lactic acidosis) and will be discussed in subsequent sections.

Hepatorenal Interactions

As illustrated in Fig. 59.1 , the proton load produced by hepatic amino acid metabolism will titrate extracellular bicarbonate resulting in production of CO ₂that is eliminated by the lungs. To maintain plasma bicarbonate constant, the kidney has two pivotal tasks. First, it must reclaim the bicarbonate present in the glomerular ultrafiltrate (filtered load of bicarbonate) and, second, it must regenerate bicarbonate to replete the bicarbonate consumed during endogenous acid production. The first task is accomplished by virtually complete tubular reabsorption or reclamation of the filtered bicarbonate along the nephron (predominantly in the proximal tubule). The kidney regenerates bicarbonate (bicarbonate neogenesis) by excretion of protons either as ammonium ( NH+4
NH 4 +
) or as titratable acid (TA) in amounts sufficient to offset those protons produced daily by oxidation of dietary foodstuffs. The amount of renal proton excretion or, equivalently, bicarbonate neogenesis/regeneration is measured as net acid excretion (NAE), which reflects the sum of NH+4
NH 4 +
and titratable acid excretion minus any urinary bicarbonate excreted (that which escapes tubular reabsorption):

Net acid excretion=NH+4?+TAU−HCO−3?

Net acid excretion=NH4+U+TAU−HCO3−U

Net acid excretion = NH 4 + U + TAU − HCO 3 − U

The rate of renal hydrogen ion secretion is thus expressed as the sum of excreted hydrogen ions (NAE) and filtered bicarbonate reabsorbed:

Renal H+secretion=HCO−3reabsorption+NH4+?+TAU

Renal H+secretion=HCO3−reabsorption+NH4+U+TAU

Renal H + secretion = HCO 3 − reabsorption + NH 4 + U + TAU

where

HCO−3reabsorption=(GFR×[HCO−3]plasma)−HCO−3?

HCO3−reabsorption=(GFR×[HCO3−]plasma)−HCO3−U

HCO 3 − reabsorption = ( GFR × [ HCO 3 − ] plasma ) − HCO 3 − U

Excretion of NH+4
NH 4 +
requires the interaction of hepatic and renal glutamine metabolism and intact renal ammoniagenesis. Urea synthesis in peripheral hepatocytes consumes equal amounts of bicarbonate and NH+4
NH 4 +
and thus is without impact on acid–base balance. However, a small fraction of NH+4
NH 4 +
is diverted to glutamine synthesis in hepatocytes located in the center of the hepatic lobule and such hepatic production of glutamine has been argued to be an important homeostatic substrate for renal NH+4
NH 4 +
/net acid excretion. Acidemia stimulates and alkalemia inhibits glutamine synthesis. Under certain conditions, acidemia has been demonstrated to be associated with decreased urea synthesis thereby increasing the supply of NH+4
NH 4 +
for glutamine synthesis, raising the question that the liver might control the renal acid excretory response to metabolic acidosis. Nevertheless, a significant role for acute metabolic acidosis in altering urea production rate in vivo has not been found when tested robustly in rats. In addition, in humans, a negative correlation between ureagenesis and plasma HCO−3
HCO 3 −
concentration was observed over a wide range of HCO−3
HCO 3 −
concentrations that were altered both chronically and acutely ( Fig. 59.2 ). Thus, the ureageneic process per se may even be maladaptive for acid–base regulation in humans and does not appear to have a discernible homeostatic effect on acid–base equilibrium. It is likely that other metabolic pathways operate in metabolic acidosis to offset the accelerated HCO−3
HCO 3 −
consumption of ureagenesis (e.g., oxidation of glutamate or other alkali generating reactions), but this issue has not been addressed experimentally either in animals or humans.

Glutamine supply to the kidneys is also increased by enhanced release of glutamine from skeletal muscle and increased intestinal glutamine absorption, thus providing higher levels of glutamine in the splanchnic circulation. In aggregate, acidemia increases glutamine synthesis or release and delivery of glutamine to the kidney.

In the proximal tubule, two deamidation/deamination steps, both positively regulated by low pH (glutamine deaminase, glutamate dehydrogenase) yield two NH+4
NH 4 +
and two HCO−3
HCO 3 −
molecules. NH+4
NH 4 +
and HCO−3
HCO 3 −
are then separated, NH+4
NH 4 +
is excreted in the urine and HCO−3
HCO 3 −
is added to the extracellular fluid. Therefore, glutamine catabolism in the kidney leads to excretion of protons (as NH+4
NH 4 +
) and reabsorption of equal amounts of HCO−3
HCO 3 −
. Excess glutamine, not taken up by the kidney, is returned to the liver and deamidated/deaminated, a process that stimulates ureagenesis, inhibits further glutamine synthesis and thus constitutes a feed-back loop regulating glutamine (and thus potential NH+4
NH 4 +
and bicarbonate) supply to the kidney. In contrast to the kidney, HCO−3
HCO 3 −
and NH+4
NH 4 +
are not physically partitioned or differentially excreted in the liver, but metabolized with a stoichiometry of 1:1 during ureagenesis. It is thus renal control of NH+4
NH 4 +
excretion, not hepatic control of glutamine vs. urea synthesis that relates changes in plasma acid–base composition to changes in NH+4
NH 4 +
metabolism and thus to possible effects on acid–base balance.

Role of the Gut

The gut affects acid–base homeostasis not only by absorbing sulfur-containing amino acids, but also by absorbing potential base. Organic anions in the gut are intrinsic to a whole food diet and are also derived in situ from dietary carbohydrates, protein and fat. They are absorbed (constituting potential base), or excreted in feces (around 10 to 60 mmol/day) or intestinally metabolized to organic acids by bacteria with subsequent reaction with HCO−3
HCO 3 −
in ileum and colon. The amount of enterally absorbed base from a human whole food diet has been estimated to be about 50% of the magnitude of endogenous acid production.

The amount of base absorbed can be estimated as the difference between diet and stool anion gaps. In both diet and feces, alkali content is estimated as the sum of noncombustible cations (Na ⁺+K ⁺+Ca ²⁺+Mg ²⁺) minus the sum of noncombustible anions (Cl ⁻+1.8 P), where 1.8 represents the average valence of phosphate at pH 7.4.

The same arithmetic version of the urinary anion gap ([Na ⁺+K ⁺+Ca ²⁺+Mg ²⁺]−[Cl ⁻+1.8 P]) has also been shown to be correlated directly and positively with the diet-stool anion gap in metabolically controlled human subjects. This would allow an estimate of gastrointestinal alkali absorption without measuring stool composition. However, the urinary anion gap cannot reliably estimate gut base absorption under conditions in which net systemic organic acid production is altered or in which net bone accretion or dissolution prevails (i.e., typical clinically encountered conditions) as this construct of the urinary anion gap reflects the combined effects of cellular and bone buffering, endogenous organic acid production as well as gastrointestinal base absorption.

There is only weak evidence that intestinal absorption might adapt to acidosis. An insignificant decrement in the stool anion gap of 7 mEq/day was noted during the first six days of acid loading (potential secondary systemic gain of alkali) in human subjects, but this decrement subsequently decreased to only 2.5 mEq/day during prolonged acidosis. The measured 2.5 mEq/day increment in gut base absorption in metabolic acidosis is a very small response in comparison to the simultaneous increment in renal net acid excretion (from 44 to 247 mEq/day). Thus, quantitative considerations and the fact that the estimation of the stool anion gap rests completely on an unknown valence for phosphate, and that only 5% of the fecal phosphate is dialyzable (suggesting that most of stool phosphate is either intracellular or sequestered in calcium/magnesium salts) are the most important arguments against an adaptive role of the gut in acidosis.

Role of Bone

Bone is a large reservoir of exchangeable base as calcium carbonate and dibasic phosphate. Exogenous and endogenous metabolic acid loads, both acute and chronic, liberate calcium and base (carbonate) from bone. Calcium is subsequently lost in the urine.

There is evidence from human studies (reviewed in Lemann et al. ) that when acid production is increased experimentally, renal net acid excretion does not increase as much as acid production. The difference in acid neutralization (i.e., the positive acid balance) is attributed to bone buffering of retained protons (or liberation of bone base) ( Fig. 59.3 ). Similarly, renal net acid excretion does not decrease as much as acid production when base (KHCO ₃) is administered. Under these experimental conditions, subjects are likely in small negative acid or positive base balance, with incorporation of base into bone. Positive acid balance is accompanied by equivalent cation loss (loss of Ca ⁺⁺and possibly K and/or Na from bone), negative acid balance by equivalently positive cation balance (incorporation of Ca ⁺⁺and K and/or Na). Scanning ion microprobe analysis indicates that bone buffer content (i.e., HCO−3
HCO 3 −
and phosphate) is decreased significantly in mouse calvariae in in vitro models of both acute and chronic metabolic acidosis. This consumption of proton buffers may attenuate the severity of both acute and chronic metabolic acidosis, but does so at the expense of a decrease in bone mineral content.

Based on these and other observations that acidotic normal subjects and patients with renal failure that were shown to be in positive acid balance and yet were able to maintain stable plasma bicarbonate concentrations, it is assumed that bone contributes in a quantitative important way to proton buffering in response to acid loads. However, in the chronic acidosis of renal failure, quantitative considerations of the required large magnitude of bone alkali have raised the possibility that available bone alkali content is insufficient to offset a possible underexcretion of acid relative to that needed for daily acid balance. While it has been argued that increased gut organic anion absorption may account for this needed base, such a conclusion is not a compelling one when based on a computation of acid balance that depends on a constant and assumed phosphate valence for whole food diets and stool (see Role of Gut section).

Renal Regulation of Acid–Base Equilibrium

As discussed, the kidney maintains a stable [ HCO−3
HCO 3 −
]p through two processes: (1) HCO−3
HCO 3 −
reclamation, the reabsorption of filtered HCO−3
HCO 3 −
, and (2) HCO−3
HCO 3 −
regeneration, the neogenesis of HCO−3
HCO 3 −
that has been decomposed by the invasion of fixed acids into the extracellular fluid or HCO−3
HCO 3 −
lost from the body through extrarenal or renal routes.

The relationship between the [ HCO−3
HCO 3 −
]p and renal HCO−3
HCO 3 −
reclamation is shown in Fig. 59.4 . When the [ HCO−3
HCO 3 −
]p is reduced below the normal range, about 25 mEq/liter, the kidney reclaims all filtered HCO−3
HCO 3 −
. As the [ HCO−3
HCO 3 −
]p increases toward normal, complete HCO−3
HCO 3 −
reclamation continues until a critical HCO−3
HCO 3 −
concentration is reached. This concentration is about 25 mmol/liter in normal humans’ “bicarbonate threshold,” and thus explains that normal subjects excrete only trivial quantities of bicarbonate in their urine (usually less than 5 mmol/day). Above the bicarbonate threshold, some filtered bicarbonate escapes reclamation and is excreted in the urine. As the [ HCO−3
HCO 3 −
]p increases further, HCO−3
HCO 3 −
reclamation also increases, but not in proportion to the increment in the filtered HCO−3
HCO 3 −
load. Therefore, despite greater reclamation, increasing quantities of HCO−3
HCO 3 −
enter the urine. Finally, a [ HCO−3
HCO 3 −
]p is reached beyond which further increases elicit no greater HCO−3
HCO 3 −
reclamation. At this [ HCO−3
HCO 3 −
]p (about 28 mEq/liter in normal humans), an apparent maximal reabsorptive rate, or apparent T _maxfor HCO−3
HCO 3 −
, has been achieved. When the [ HCO−3
HCO 3 −
]p increases above the apparent T _max, the resultant increment in the filtered HCO−3
HCO 3 −
load is entirely excreted into the urine.

In addition to HCO−3
HCO 3 −
reclamation (reabsorption), the kidney must also regenerate the HCO−3
HCO 3 −
, that has been decomposed by the entry of fixed acids into the extracellular fluid (ECF) or lost in urine or stool. The kidney regenerates HCO−3
HCO 3 −
by excreting acid. The vast majority of protons are excreted in the form of NH+4
NH 4 +
or titratable acid as the free proton concentration at the minimal urinary pH of 4.5 is less than 0.1 mmol/liter. The net effect of renal acidification can be measured as net acid excretion.

Net Acid excretion= NH+4
NH 4 +
+Titratable Acid− HCO−3
HCO 3 −

Quantitatively, changes in renal NH+4
NH 4 +
excretion account for most of the changes in renal acid excretion both in response to changes in endogenous acid production and in the adaptation to acid–base disturbances. In adaptation to changes in acid load, NH+4
NH 4 +
excretion is regulated at multiple levels including glutamine supply to the kidney, production of NH ₃in the proximal tubule (ammoniagenesis), secretion of NH ₃into the tubular lumen and various transport processes of NH ₃/ NH+4
NH 4 +
along the nephron. (For a discussion of these mechanisms, see Chapter 54 , Chapter 56 )

Phosphate and organic anions such as citrate, acetate, beta-hydroxybutyrate and creatinine contribute as filtered buffers to titratable acid excretion. Amongst these substances, the buffer pair di- and mono-basic phosphate ( HPO−4/?2PO−4
HPO 4 − / H 2 PO 4 −
) ₂is the most important buffer due to its pKa of 6.8 and urinary excretion values on the order of 20 to 50 mmol/day. Titration of the other potentially titratable species is severely limited due to their pKa values residing below 5.0. The importance of phosphate as a urinary proton buffer is illustrated by the effects of both neutral phosphate loading and depletion. Increases in neutral phosphate load significantly enhance net acid excretion and are able to generate as well as maintain metabolic alkalosis even without a concomitant increase in renal cation resorption or sodium avidity. Although phosphate delivery to distal acidification sites has been demonstrated to be rate limiting for renal acid secretion in acidotic dogs, under phosphate loading conditions, the generation of phosphate-induced secondary hyperparathyroidism appears to provide the major stimulus to enhanced renal acid excretion. Phosphate depletion reduces both phosphate and titratable acid excretion and induces positive hydrogen balance. It is unclear whether these changes are best explained by a rate-limiting role of luminal phosphate for renal acid excretion or by the observed renal HCO−3
HCO 3 −
wasting.

Determination of Net Acid Excretion

Although enzymatic ammonium assays in serum are widely performed in clinical medicine and this assay method is valid in urine, ammonium values are seldom requested in urine for reasons that have not been reported. As an alternative to requesting an ammonium value in urine, a simplified version of the urinary anion gap is frequently used as an indirect index of ammonium excretion:

Urinary anion gap=Na+?−?+?−Cl−?

Urinary anion gap=Na+u−K+u−Cl−u

Urinary anion gap = Na + u − K + u − Cl − u

The rationale is that in chronic metabolic acidosis, ammonium excretion is elevated, is a cation, and balances part of the negative charge of the major urinary cation, chloride. Thus, the urinary anion gap should become progressively negative as the rate of ammonium excretion increases in response to acidosis or to acid loads. However, the urinary anion gap is not a quantitative index of ammonium excretion. Its potential role in the clinical differential diagnosis of hyperchloremic metabolic acidosis will be discussed in subsequent sections.

Calculation of titratable acid requires determination of urinary pH (UpH), blood pH (BbpH), urine phosphate, estimation of the pKa (near 6.8) and an arithmetic computation:

TAexc=[[Pexc/antilog(UpH−pK‘)]+1]]−[[Pexc/antilog(BpH−pK‘)]+1]]

TAexc=[[Pexc/antilog(UpH−pK’)]+1]]−[[Pexc/antilog(BpH−pK’)]+1]]

TAexc = [ [ Pexc / antilog ( UpH − pK ‘ ) ] + 1 ] ] − [ [ Pexc / antilog ( BpH − pK ‘ ) ] + 1 ] ]

Although use of a pKa phosphate value of 6.8 is sufficient for most clinical purposes, the pK’ of phosphate can be corrected for ionic strength and pH for improved accuracy.

Clinical Consequences

Ventilatory Response to Acidosis: Homeostatic and/or Maladaptive?

The most characteristic clinical manifestation of metabolic acidosis is hyperventilation. Because the depth of ventilation increases to a much greater degree than the respiratory rate, hyperventilation may not be clinically apparent until acidemia becomes severe. Then, patients may experience labored breathing and their chief complaint is dyspnea.

Metabolic acidosis rapidly causes secondary hyperventilation, which reduces the PaCO ₂and tends to increase the blood pH toward normal. This secondary respiratory response is usually fully developed in 12–24 hours. Peripheral chemoreceptors in the carotid and aortic bodies and central chemoreceptors on the ventral surface of the medulla trigger the respiratory response to metabolic acidosis. Some controversy still exists as to which chemoreceptors are more important.

During acute metabolic acidosis (initial six hours after an acid load) PaCO ₂falls by 0.85 mm Hg for every millimole-per-liter decrease in [ HCO−3
HCO 3 −
]p ( Fig. 59.5 ). In response to sustained acidosis, the respiratory response is further stimulated and is maximal by 24 hours. Then, PaCO ₂is decreased by about 1.1 mm Hg for each millimole-per-liter fall in [ HCO−3
HCO 3 −
]p in acidotic human subjects. Several other helpful guides can be used at the bed side to determine whether respiratory compensation is appropriate: (1) metabolic acidosis should reduce the PaCO ₂so that it approximates the decimal digits of the pH. For example, when metabolic acidosis reduces the pH to 7.30, the pCO ₂should be about 30 mm Hg. Maximal hyperventilation in patients with extreme acidemia will reduce the PaCO ₂to about 10 mm Hg. (2) Another useful rule is that the PaCO ₂should approximate the [ HCO−3
HCO 3 −
]p+15. 9. (3) In uncomplicated metabolic acidosis the decrease in PaCO ₂after full adaptation may also be calculated as follows:

PaCO2=1.5[HCO−3]+8±2

PaCO2=1.5[HCO3−]+8±2

PaCO 2 = 1 . 5 [ HCO 3 − ] + 8 ± 2

The respiratory response to metabolic acidosis may be slightly different in patients with different forms of metabolic acidosis. For example, it has been suggested that lactic acidosis generates greater hyperventilation and a lower PaCO ₂than equally severe ketoacidosis. This could be the result of a lower intracellular pH in the patients with lactic acidosis. However, others find that secondary hyperventilation in lactic acidosis is not different from other metabolic acidoses.

A chronically low PaCO ₂(hypocapnia) lowers the [ HCO−3
HCO 3 −
]p as a result of transient bicarbonaturia or decreased renal net acid excretion. In dogs, experimental hypocapnia caused the kidney to decrease [ HCO−3
HCO 3 −
]p (transient renal acid retention) even in the context of metabolic acidosis with preexisting hypobicarbonatemia. The decrease in [ HCO−3
HCO 3 −
] was strictly proportional to the induced hypocapnia over a wide range of PaCO ₂values and [ HCO−3
HCO 3 −
]p (fall in [ HCO−3
HCO 3 −
]p of 0.54 mmol/liter per 1-mm Hg fall in PaCO ₂). The hypocapnia-induced decrement in [ HCO−3
HCO 3 −
]p was sufficient to increase blood acidity. These findings demonstrated that the renal response to metabolic acidosis is not primarily geared at the defense of pH and that secondary hypocapnia elicits a maladaptive renal response. In contrast to dogs, however, humans exhibit an alkalemic response to hypocapnia (increase in blood pH) ( Fig. 59.6 ) irrespective of the presence or absence of preexisting metabolic acidosis ([ HCO−3
HCO 3 −
]p between 25 and 10 mmol/liter), despite the finding that hypocapnia also caused transient renal acid retention. The reason for this species difference is that the inhibitory effect of hypocapnia on renal acid excretion (decrease of [ HCO−3
HCO 3 −
]p by 0.41 mmol/liter per 1-mm Hg fall in PaCO ₂) is too small in humans to offset the direct alkalemic effect of the decrease in PaCO ₂as dictated by the HCO−3
HCO 3 −
Henderson-Hasselbalch equation. However, if the slope of line for the relation of the [ HCO−3
HCO 3 −
]p on PaCO ₂extends to [ HCO−3
HCO 3 −
]p below 10 mmol/liter, it can be predicted that at the lowest end of the range of values for [ HCO−3
HCO 3 −
]p, hypocapnia might worsen acidemia in humans as well as dogs. Figure 59.7 illustrates these differences in the prediction of blood [H ⁺] when chronic hypocapnia is superimposed on chronic metabolic acidosis when a [ HCO−3
HCO 3 −
]/PaCO ₂slope of 0.54 is used (as reported for dogs; dashed lines) or when a [ HCO−3
HCO 3 −
]/PaCO ₂slope of 0.41 is used as reported for normal human subjects.

Metabolic and Endocrine Consequences of Metabolic Acidosis

Effects of Acidosis on Nitrogen Balance and Protein Metabolism

Metabolic acidosis results in reversible growth failure in children with tubular acidosis and in rats. It affects protein metabolism both by accelerating proteolysis (resulting in negative nitrogen balance) and amino acid oxidation and by decreasing protein synthesis. Quantitatively, metabolic acidosis may be the most important factor in the wasting syndrome associated with many illnesses—that is, uremia, sepsis, trauma, and chronic diarrhea—and thus may affect adversely the prognosis of these conditions.

Among the different proteolytic pathways, metabolic acidosis activates the ATP-dependent ubiquitin-26S proteasome pathway, which mediates muscle proteolysis. The balance between glucocorticoids and insulin regulates mRNA expression of ubiquitin-proteasome genes and thus muscle proteolysis. Glucocorticoid activity is stimulated in acidosis and, both in vitro and in vivo , the acidosis-induced stimulation of skeletal muscle proteolysis as well as the induction of ubiquitin-26S proteasome gene expression was shown to be glucocorticoid-dependent. Insulin is the chief counterregulatory factor opposing the catabolic effects of glucocorticoids via the ubiquitin-proteasome pathway. Since there is evidence for insulin resistance in metabolic acidosis, and acidosis was shown to impair insulin signaling via insulin-receptor substrate-1, associated phosphoinositide 3-kinase (PI3K) in muscle cells, both increased glucocorticoid activity and impaired insulin signaling might mediate increased rates of proteolysis in response to acidosis. In addition, decreased concentrations of free IGF-1, an inhibitor of ubiquitin gene expression, and altered thyroid function (mild primary hypothyroidism) have been reported in metabolic acidosis and constitute additional potential mechanisms for increased proteolysis.

Protein synthesis is also affected by metabolic acidosis. Muscle protein synthesis and albumin synthesis (the latter only after several days of metabolic acidosis) are inhibited in humans, but not in rats. Correction of acidosis has been effective in both increasing free IGF-1 and albumin serum concentrations as well as in conserving muscle mass and protein homeostasis in patients with chronic renal failure and metabolic acidosis (cited in Kleger et al. ).

Effects of Metabolic Acidosis on Sodium Homeostasis

It is well known that both acute and chronic metabolic acidosis are associated with natriuresis. Both proximal and distal tubular sodium reabsorption appear to be inhibited. The proximal effect is the result of downregulated organic-anion stimulated NaCl absorption, while HCO−3
HCO 3 −
reabsorption is enhanced as a consequence of increased expression and activity of Na ⁺/H ⁺exchange (sodium–hydrogen exchanger isoform 3, NHE-3). The natriuresis of acidosis induces extracellular volume depletion and increased renin-angiotensin-aldosterone activity, which significantly counteracts and limits the acidosis-induced negative sodium balance and weight loss. Inhibition of angiotensin II action by the AT-1 receptor antagonist losartan resulted in decreased renal net acid excretion in pre-existing metabolic acidosis. Therefore, distal nephron angiotensin II activity is a coregulator of the renal-tubular response to metabolic acidosis and, thereby, is important in determining the severity of acidosis. Increased aldosterone is also expected to limit the severity of metabolic acidosis by stimulation of distal nephron acidification. However, inhibition of aldosterone action by spironolactone exacerbated human metabolic acidosis by an extrarenal mechanism (increased endogenous acid production precluding an analysis of its effect on renal acidification. Thus, the quantitative role of acidosis-induced hyperaldosteronism in the tubular response to metabolic acidosis and the resultant severity of metabolic acidosis remain to be determined.

Effects of Metabolic Acidosis on Potassium Homeostasis

Both extrarenal cellular potassium shifts and the renal regulation of potassium transport have been examined in metabolic acidosis. Contrary to a widely expressed opinion, there is no compelling evidence—either in acute mineral or acute organic acidosis—for a demonstrable increase in plasma potassium in response to acidosis. Under carefully controlled conditions, arterialized venous plasma potassium increased nonsignificantly by only +0.02 mmol/liter per mmol/liter decrease in plasma [ HCO−3
HCO 3 −
] in acute, NH ₄Cl-induced metabolic acidosis in normal human subjects. Previous studies in dogs and humans (cited in Wiederseiner et al. ) had described both unchanged and increased plasma potassium concentrations albeit with unusually large variances. Failure to detect hyperkalemia in the most recent and some of the previous reports does not preclude, however, the existence of acidosis-induced net K ⁺/H ⁺exchange across cell membranes with efflux of K ⁺from cells. The finding of a hyperinsulinemic response (with concomitant decrease in glucagon concentration and unchanged catecholamine levels) in response to acidosis suggests that an insulin response counterregulates any acidemia-induced cellular potassium efflux, resulting in stable plasma potassium concentrations. This occurred despite an increase in the insulin/glucose ratio, suggesting the insulin resistance in acute acidosis may not involve transcellular potassium balance. A similar mechanism may operate in acute organic acidosis. In the case of organic acidosis, organic anions may enter cells along with protons thus obviating exit of potassium. In conclusion, acidosis-induced hyperinsulinemia seems to prevent acidosis-induced hyperkalemia. The plasma potassium response in acutely acidotic subjects with insulin deficiency or preexisting insulin resistance needs further investigation. In the clinical setting, therefore, the plasma potassium response must always be interpreted with a diligent analysis of the presence of factors in addition to acidemia that are known to influence potassium distribution between intra- and extracellular spaces such as changes in osmolality, sympathoadrenergic activity, aldosterone, and the activity of glucoregulatory hormones (insulin and glucagon).

Acute metabolic acidosis (less than two hours) initially reduces renal potassium excretion, based in large part on effects in the CCT. Experimental reduction of luminal pH in the isolated perfused CCT results in diminished K secretion. The effect of acute acidification of CCT principal cells is believed to be mediated by the effect of cellular acidity to decrease the open probability of potassium channels in the apical membrane. Metabolic acidosis of longer duration is a potent stimulus of renal K excretion and may lead chronically to significant hypokalemia and substantial potassium depletion. This increase in potassium excretion is probably the consequence of increased volume/sodium delivery to the distal tubule and collecting duct and hyperaldosteronism.

Effect of Metabolic Acidosis on Divalent Ion, PTH, and 1,25 (OH) ₂D Metabolism

Metabolic acidosis profoundly affects calcium and phosphate metabolism resulting in calcium loss from bone in association with hypercalciuria. Hypercalciuria is the result of an increase in filtered load and decreased tubular reabsorption of calcium, the cellular mechanisms of which are poorly understood although calcium reabsorption is correlated with luminal [ HCO−3
HCO 3 −
] in the distal tubule. Important clinical sequelae of the resultant negative calcium balance are a metabolic bone disease with poorly characterized features of osteomalacia/low formation rate/high resorption rate and calcium nephrolithiasis. Metabolic acidosis induces hypophosphatemia in association with increased renal phosphate clearance and increased fractional excretion of phosphate; in brief, metabolic acidosis induces renal phosphate depletion. The mechanism of decreased tubular phosphate reabsorption in the proximal tubule is likely to be complex. High ambient proton concentration was shown to stimulate phosphate transport by a glucocorticoid-dependent, posttranslational mechanism. Isohydric decreases in [ HCO−3
HCO 3 −
]/PaCO ₂, on the other hand, stimulated phosphate transport in OK-cells via a transcriptional effect. In addition, metabolic acidosis has been shown to decrease [IGF-1]s in humans, providing a plausible mechanism for decreased renal phosphate reabsorption. Thus, metabolic acidosis seems to affect renal regulation of phosphate reabsorption both directly (via effects of acid–base changes on phosphate transport) and indirectly via endocrine changes (increased glucocorticoid activity, decreased IGF-1 levels). The relative importance of these mechanisms remains to be elucidated.

Acute and chronic metabolic acidosis was demonstrated to induce renal magnesium wasting and hypomagnesemia. The cellular mechanisms of acidosis-induced renal magnesium wasting are largely unknown, although extracellular acidity has been shown to decrease magnesium uptake in mouse distal tubular cells.

In animals, metabolic acidosis was found to decrease [1,25(OH) ₂D]s, an effect generally attributed to decreased activity of renal 1-alpha-hydroxylase. However, chronic metabolic acidosis was demonstrated repeatedly to increase [1,25(OH) ₂D]s (by stimulation of its production rate) and to concomitantly decrease [PTH]s in humans. The effects of metabolic acidosis on ionized calcium concentration (hypercalcemia not observed or very mild in humans, but prevalent in rats) and on the severity of phosphate depletion/hypophosphatemia seem to differ among species. Thus, it is likely that the changes in [1,25(OH) ₂D]s and [PTH]s observed are primarily determined by the occurrence or the severity of acidosis-induced hypercalcemia, which has been shown to override other potent stimuli of 1,25(OH) ₂D production including phosphate depletion unless the latter is quite severe.

It is interesting to speculate that the elevated [1,25(OH) ₂D]s in response to metabolic acidosis could serve a homeostatic role, or, that elevated [1,25(OH) ₂D]s could contribute to the normal acid excretory response to an acid load/acidosis. This question merits investigation in as much as vitamin D deficiency was shown to result in metabolic acidosis in chicks and chronic 1,25(OH) ₂D administration results in metabolic alkalosis (in part of renal origin) in thyroparathyroidectomized dogs.

In summary, metabolic acidosis in humans induces (1) hypercalciuria due to release of calcium from bone and decreased renal tubular calcium reabsorption, (2) renal phosphate depletion and hypophosphatemia, (3) renal magnesium wasting, and (4) increases [1,25(OH)2D]s and decreases in intact [PTH]s.

Effect of Metabolic Acidosis on Bone

The effects of metabolic acidosis on bone mineral content—that is, reduced levels of mineral sodium, potassium, carbonate, calcium, and phosphate—are consistent with the role of bone as a proton buffer. In mouse calvariae in vitro , exposure to acid media (low HCO−3
HCO 3 −
) induces initial physicochemical mineral dissolution. Cell-mediated bone resorption follows and is characterized by both increased osteoclastic and inhibited osteoblastic activities paralleled by alterations in the expression of a number of osteoclastic and osteoblastic genes. In particular, increased osteoblastic RNA expression of the osteoclast activator RANK-ligand with unchanged expression of its soluble decoy receptor, osteoprotegerin, may provide a central mechanism by which metabolic acidosis enhances osteoclastogenesis and osteoclast activity. The effect is mediated—at least in part—by acidosis-induced enhancement of osteoblastic prostaglandin E2 (PGE2) secretion. Both RANK-L expression and cell-mediated calcium efflux from bone are inhibited by cyclooxygenase inhibition, confirming the central role of acidosis-induced PGE2 stimulation.

Since glucocorticoid activity is increased in metabolic acidosis and glucocorticoids are known to dramatically decrease bone mineral content, it is possible that acidosis-induced hyperglucocorticoidism might contribute to calcium efflux from bone. Surprisingly, however, in vitro cortisol inhibited rather than stimulated acid-induced, cell-mediated osteoclastic bone resorption through a decrease in osteoblastic PGE2 production.

Other Endocrine Effects of Metabolic Acidosis

Endothelin

Metabolic acidosis induces renal endothelial cells to release endothelin-1, which was demonstrated to play a key role in the renal defense to an acid load. Both proximal acidification (by activation of the proximal tubule Na/H antiporter, NHE-3) and collecting duct acidification are stimulated involving signaling via the endothelin receptor B (ETB). In the distal tubule, both direct (endothelin-induced activation of Na ⁺/H ⁺exchange) and indirect (stimulation of H ⁺-ATPase via endothelin-induced increases in aldosterone) effects may be operative to stimulate proton secretion. When ETB is inhibited by the unselective ET-receptor antagonist bosentan (Tracleer) in rats or ETB is knocked out in mice, the metabolic acidosis resulting from a given acid load is more severe. The mechanisms of acid-induced increased endothelin expression and endothelin-1/ETB signaling are complex, but quite well characterized and involve activation of a putative acid-sensor, a proline rich tyrosine kinase 2, Pyk2. Interpretation of the effects of bosentan in rats to decrease distal H ⁺secretion has been difficult since bosentan has also induced a decrease in chronic net acid excretion/endogenous acid production, which in itself, dictates lower tubular acidification rates along the nephron. In summary, renal endothelin-1 acting via ETB receptor is quantitatively important in the renal defense against an acid load in mice and rats. The importance of the acid-induced renal endothelin response has not yet been investigated in humans.

Growth Hormone (GH)/IGF-1 Axis

Important effects of metabolic acidosis on the GH/IGF-1 endocrine axis were suggested by the observation that growth retardation in children with renal-tubular acidosis was reversible upon administration of alkali. In humans, IGF-1 serum concentrations are decreased in response to metabolic acidosis. The primary abnormality in humans and rats is most likely due to peripheral insensitivity to GH action with GH secretion rates presumably elevated based on the demonstration of an exaggerated increase in GH in response to stimulation by GH releasing hormone. The recent observations that administration of GH both partially corrected metabolic acidosis by a renal mechanism (primarily by an increase in ammonium excretion) and corrected acidosis-induced negative nitrogen balance, corrected renal phosphate depletion as well as hypophosphatemia and attenuated renal magnesium wasting is evidence for the notion that acidosis-induced changes in the GH/IGF1 endocrine axis may be important in the mediation of some important metabolic effects of metabolic acidosis.

Thyroid Hormones

Chronic metabolic acidosis in humans mildly decreases freeT3 and freeT4 and significantly increases TSH serum concentrations with no change in reverse T3, findings consistent with a primary thyroidal decrease in thyroid hormone secretion, that is, mild primary hypothyroidism. The quantitative importance of these changes in thyroid function with respect to acidosis-induced negative nitrogen balance and to renal acidification is presently unknown.

Catecholamines

Acidosis induces release of catecholamines, which attenuate both the negative inotropic effect of acidosis on cardiac contractility and the peripheral vasodilatory effect of acidemia. With severe acidosis, catecholamine responsiveness decreases and cardiac collapse may result. Acidosis can also decrease the ventricular fibrillation threshold. Peripheral arterial vasodilatation is a direct effect of acidosis but is also offset by catecholamine release, so that peripheral vascular resistance remains relatively constant. However, in the venous system, the direct effect of acidosis is vasoconstriction, which is further enhanced by catecholamine release. Peripheral venoconstriction can shift blood from the peripheral vascular system to the pulmonary vascular bed. In patients with severe acidosis, this may contribute to pulmonary edema. Therapeutic administration of NaHCO ₃constitutes an important additional risk factor.

It is not known whether the catecholamine response affects the renal response to acidosis in humans, although alpha-adrenergic stimulation has been shown to enhance proximal tubule bicarbonate reabsorption in rats.

In moderately severe acute metabolic acidosis in humans (decrease of [ HCO−3
HCO 3 −
]p from 25 to about 19 mmol/liter), there was no significant effect on catecholamine levels. Thus, the effects described previously may be more applicable to severe forms of metabolic acidosis or to a pattern of sympathetic stimulation that does not result in overt systemic catecholamine spillover.

Glucocorticoids

Observations carried out in rats suggest that increased glucocorticoid activity in response to metabolic acidosis might modulate acidosis-induced increase in protein degradation, at least in part. It is also possible that increased glucocorticoid activity could co-determine the systemic and renal response to an acid load, given the effects of glucocorticoids on renal acidification and renal tubular acid–base transport mechanisms. Chronic metabolic acidosis in humans significantly increases glucocorticoid activity based on determination of the daily urinary excretion rates of cortisone and cortisol. In addition, neutralization of dietary acid production (decrease in renal acid excretion from ~80 to 10 mEq/day) significantly decreased urinary free-cortisol and THF excretion over 24 hours in normal humans. However, reports from another group indicated that chronic metabolic acidosis did not affect cortisol homeostasis in humans as analyzed by serum profile and urinary 17-OH-corticosteroid excretion rates. The reasons for this discrepancy are not clear.

Effects of Metabolic Acidosis on Renal Citrate Metabolism

The effects of metabolic acidosis on renal citrate metabolism have important clinical consequences and are, therefore, briefly discussed here. Citrate is derived from carbohydrate metabolism and contains three negatively charged carboxyl groups. Complete oxidation of citrate thus generates three HCO−3
HCO 3 −
ions per mole and thus increased renal reabsorption and metabolism of citrate would be expected to serve a homeostatic role in the adaptation to metabolic acidosis. Citrate is freely filtered at the glomerulus and reabsorbed and metabolized almost exclusively in the proximal tubules ( Fig. 59.8 ), with these processes determining the amount of urinary citrate excretion. In metabolic acidosis, tubular reabsorption is increased and urinary excretion decreased due to both increased protonation of trivalent to divalent citrate, the substrate for the sodium/citrate cotransporter in the proximal tubule and increased expression and activity of Na ⁺/citrate cotransporter NaDC1. In addition, cellular (i.e., cytoplasmic) metabolism of citrate ( Fig. 59.8 ) is increased in the proximal tubule. Enhanced cytoplasmic metabolism in response to metabolic acidosis is mediated by a specific increase in renal ATP citrate lyase activity and expression. Mitochondrial citrate metabolism is also stimulated in metabolic acidosis as shown by the increased activity of mitochondrial aconitase, the first step in mitochondrial citrate metabolism. These findings are clinically important because of citrate’s role in calcium complexation, inhibition of stone formation and prevention of nephrocalcinosis. Indeed, a high proportion of patients with nephrolithiasis have low urinary citrate levels. A high-protein intake (which increases endogenous acid production) decreases urinary citrate excretion in rats by renal mechanisms described previously.

Miscellaneous Clinical Effects of Metabolic Acidosis

Renal Growth

In contrast to the growth inhibitory effect in nonrenal tissue, metabolic acidosis leads to hyperplasia and hypertrophy in renal tissue with an apparent predilection for the renal tubules. Interestingly, acidosis induces metabolic effects in the kidney that also contrast with its systemic consequences: renal IGF1 levels are increased and renal protein degradation is decreased. Decreased protein degradation is a cell-cycle independent mechanism for renal hypertrophy. Whether cell-cycle dependent mechanisms (via cyclin kinases) are important in metabolic acidosis as they are in diabetic nephropathy or compensatory renal hypertrophy remains to be investigated.

Based on the hypothesis that renal hypertrophy is associated with progression of renal disease, it is possible that acidosis might accelerate the rate of decline of renal function in renal insufficiency. The following evidence from animal studies suggests that such an effect of acidosis may be present: (1) ammonia has been proposed to be responsible for tissue injury, possibly by acting as a convertase for the alternate pathway of complement activation. (2) The remnant kidney model in the rat is associated with increased ammoniagenesis by residual nephrons. (3) Systemic alkalinization has been shown to reduce ammoniagenesis and to mitigate proteinuria and the histological damage typically seen in this model.

Acidosis-induced promotion of growth may be most relevant in polycystic kidney disease. Patients with hyperaldosteronism and potassium depletion (which leads to intracellular acidosis and stimulation of ammoniagenesis) were shown to have a greatly increased incidence of renal cysts. Furthermore, in Han:SPRD rats, a rat model for polycystic kidney disease, induction of acidosis by NH ₄Cl enhances, while systemic alkalinization by HCO−3
HCO 3 −
slows the rate of cyst formation. Thus, correction of acidosis may be most important in patients with polycystic kidney diseases. However, no human studies have yet been performed to evaluate the effect of complete correction of acidosis on the progressive decline in renal function both in cystic and non-cystic kidney diseases.

O ₂and CO ₂Dissociation Curves

Metabolic acidosis, as mediated by an increase in hydrogen ion concentration, shifts the hemoglobin saturation curve to the right, that is, less oxygen is bound to hemoglobin for a given PO ₂. This circumstance provides for acute acidosis-enhanced oxygen release in tissues. Quantitatively, this effect is quite small; however, at least for the pH changes observed in vivo and can be estimated using the Bohr factor (BF):

BF=?log P50/?pH

BF=Δlog P50/ΔpH

BF = Δ log P5 0 / Δ pH

where P50 is the half-saturation PO ₂, normally around 27 mm Hg (3.6 kPa). Since the Bohr factor in human blood is about 0.5, it can be calculated that a change in blood pH of 0.1 U will shift the half-saturation of hemoglobin by about 1 mm Hg. When metabolic acidosis persists beyond 6–8 hours, the dissociation curve is shifted back toward its normal position (leftward) due to the more prolonged effect of acidosis to decrease erythrocyte 2,3-diphosphoglycerate. It is not known with certainty which of these effects is predominant during sustained metabolic acidosis in vivo .

Hemoglobin displays a higher affinity for hydrogen ion in the reduced form (Haldane effect) and roughly half of acute buffering of an acid load is due to nonbicarbonate buffers including Hb. The decrease in oxygen saturation (or increase in reduced hemoglobin) for a given PO ₂associated with acute acidosis could therefore increase the hemoglobin buffering capacity of an acute systemic acid load and thus limit the fall in [ HCO−3
HCO 3 −
]p. At the same time, the Haldane effect increases the CO ₂transport capacity of blood at the low pCO ₂values of metabolic acidosis. The quantitative in vivo contribution of the Haldane effect to the early plasma bicarbonate response to acid loads remains to be determined.

The Trade-Off Hypothesis

As was described earlier and shown in Fig. 59.9A , normal acid–base balance is achieved and maintained when renal net acid excretion equals endogenous acid production at normal [ HCO−3
HCO 3 −
]p. As illustrated in Fig. 59.9B , an increase in endogenous acid production leads to renal and extrarenal cellular adaptations, ultimately increasing net acid excretion to again balance endogenous acid production. While it was demonstrated that increases in dietary-induced acid production correlate inversely and significantly with HCO−3
HCO 3 −
]p during metabolic balance studies, [ HCO−3
HCO 3 −
]p generally does not fall out of the wide normal range when determined in clinical practice. Thus, an ongoing acidotic process may be present albeit not recognized due to the efficient adaptation of acid excretory mechanisms and the imperfections of routine laboratory analysis. The term eubicarbonatemic metabolic acidosis ( Table 59.1 ) circumscribes this entity. It is instructive to review, therefore, to which extent some of the metabolic and endocrine effects of metabolic acidosis discussed previously also occur during normal dietary variation of acid production and/or during physiologic declines in acid excretion such as during the aging process.

Abdominal Key

Fastest Abdominal Insight Engine

Clinical Syndromes of Metabolic Acidosis

Introduction

Definition of Metabolic Acidosis

Systemic and Renal Acid–Base Homeostasis

Hepatorenal Interactions

Role of the Gut

Role of Bone

Renal Regulation of Acid–Base Equilibrium

Determination of Net Acid Excretion

Clinical Consequences

Ventilatory Response to Acidosis: Homeostatic and/or Maladaptive?

Metabolic and Endocrine Consequences of Metabolic Acidosis

Effects of Acidosis on Nitrogen Balance and Protein Metabolism

Effects of Metabolic Acidosis on Sodium Homeostasis

Effects of Metabolic Acidosis on Potassium Homeostasis

Effect of Metabolic Acidosis on Divalent Ion, PTH, and 1,25 (OH) ₂D Metabolism

Effect of Metabolic Acidosis on Bone

Other Endocrine Effects of Metabolic Acidosis

Endothelin

Growth Hormone (GH)/IGF-1 Axis

Thyroid Hormones

Catecholamines

Glucocorticoids

Effects of Metabolic Acidosis on Renal Citrate Metabolism

Miscellaneous Clinical Effects of Metabolic Acidosis

Renal Growth

O ₂and CO ₂Dissociation Curves

The Trade-Off Hypothesis

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Abdominal Key

Fastest Abdominal Insight Engine

Clinical Syndromes of Metabolic Acidosis

Introduction

Definition of Metabolic Acidosis

Systemic and Renal Acid–Base Homeostasis

Hepatorenal Interactions

Role of the Gut

Role of Bone

Renal Regulation of Acid–Base Equilibrium

Determination of Net Acid Excretion

Clinical Consequences

Ventilatory Response to Acidosis: Homeostatic and/or Maladaptive?

Metabolic and Endocrine Consequences of Metabolic Acidosis

Effects of Acidosis on Nitrogen Balance and Protein Metabolism

Effects of Metabolic Acidosis on Sodium Homeostasis

Effects of Metabolic Acidosis on Potassium Homeostasis

Effect of Metabolic Acidosis on Divalent Ion, PTH, and 1,25 (OH) 2 D Metabolism

Effect of Metabolic Acidosis on Bone

Other Endocrine Effects of Metabolic Acidosis

Endothelin

Growth Hormone (GH)/IGF-1 Axis

Thyroid Hormones

Catecholamines

Glucocorticoids

Effects of Metabolic Acidosis on Renal Citrate Metabolism

Miscellaneous Clinical Effects of Metabolic Acidosis

Renal Growth

O 2 and CO 2 Dissociation Curves

The Trade-Off Hypothesis

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Effect of Metabolic Acidosis on Divalent Ion, PTH, and 1,25 (OH) ₂D Metabolism

O ₂and CO ₂Dissociation Curves