12.11 A physiological approach to acid– base disor

12.11 A physiological approach to acid– base disorders: The roles of ion transport and body fluid compartments 2182

ESSENTIALS The normal pH of human extracellular fluid is maintained within the range of 7.35 to 7.45. The four main types of acid–​base disorders can be defined by the relationship between the three variables, pH, Pco2, and HCO3 –​. Respiratory disturbances begin with an increase or decrease in pulmonary carbon dioxide clearance which—​through a shift in the equilibrium between CO2, H2O, and HCO3 –​—​favours a
decreased hydrogen ion concentration (respiratory alkalosis) or an increased hydrogen ion concentration (respiratory acidosis) respectively. Metabolic acidosis may result when hydrogen ions are added with a nonbicarbonate anion, A−, in the form of HA, in which case bicarbonate is consumed, or when bicarbonate is removed as the sodium or potassium salt, increasing hydrogen ion concentration. Metabolic alkalosis is caused by removal of hydrogen ions or add- ition of bicarbonate. Laboratory tests usually performed in pursuit of diagnosis, aside from arterial blood gas analysis, include a basic metabolic profile with electrolytes (sodium, potassium, chloride, bicarbonate), blood urea nitrogen, and creatinine. Calculation of the serum anion gap, which is determined by subtracting the sum of chloride and bicar- bonate from the serum sodium concentration, is useful. The normal value is 10 to 12 mEq/​litre. An elevated value is diagnostic of meta- bolic acidosis, helpful in the differential diagnosis of the specific metabolic acidosis, and useful in determining the presence of a mixed metabolic disturbance. Acid–​base disorders can be associated with (1) transport pro- cesses across epithelial cells lining transcellular spaces in the kidney (e.g. renal tubular acidosis), gastrointestinal tract (e.g. vomiting), and skin (e.g. cystic fibrosis); (2) transport of acid anions from intracel- lular to extracellular spaces—​anion gap acidosis (e.g. diabetic keto- acidosis, lactic acidosis); and (3)  intake (e.g. infusions with high chloride content). Introduction The normal pH of human extracellular fluid (ECF) is maintained within the range of 7.35 to 7.45. Though intracellular pH regula- tion may be more critical to processes such as protein synthesis, cell growth, and reproduction, it is generally assumed that cell pH, which is more difficult to measure, is reflected in the readily accessible ECF. The usual approach taken to understand how acid–​base disturb- ances are generated starts with the principle of LeChâtellier:  the tendency for chemical reactions thrown out of equilibrium to move in the direction that restores the equilibrium state. This is apparent in the overall equation relating concentrations of carbon dioxide to hydrogen ion and bicarbonate ion in the following expression CO +H O H CO H +HCO 2 2 2 3 + 3 CO ↔ ↔ ←↑ − P 2

(Equation 1) The four main types of acid–​base disorders can be defined by the relationship between the three variables, pH, Pco2, and HCO3–​ (Table 12.11.1). Respiratory disturbances begin with an increase or decrease in pulmonary carbon dioxide clearance which through a shift in the equilibrium favours a decreased hydrogen ion concentration (respiratory alkalosis) or an increased hydrogen ion concentration 12.11 A physiological approach to acid–​base disorders: The roles of ion transport and body fluid compartments Julian Seifter Table 12.11.1  Features of the four main types of primary acid–​base disorder pH Pco2/​HCO3 − Primary disorder Acidaemia Low HCO3 − Metabolic acidosis High Pco2 Respiratory acidosis Alkalaemia High HCO3 − Metabolic alkalosis Low Pco2 Respiratory alkalosis

12.11  A physiological approach to acid–base disorders 2183 (respiratory acidosis) respectively. Metabolic acidosis may result when hydrogen ions are added with a nonbicarbonate anion, A−, in the form of HA, in which case bicarbonate is consumed as the re- action shifts left. Alternatively, bicarbonate may be removed as the sodium or potassium salt, shifting the reaction to the right, increasing hydrogen ion concentration. Metabolic alkalosis is caused by the removal of hydrogen ion or the addition of bicarbonate. In the case of adding acids such as HCl, acid phosphates, and sulphates, or organic acids such as lactic or ketoacids, there would be a decrease in bicarbonate proportional to the increase in A−. The bicarbonate lost due to HA appearance is renewed by net renal ex- cretion of hydrogen and the anion in order to restore acid–​base balance. Since the kidney initially filters large quantities of bicar- bonate from the ECF, all of the filtered bicarbonate must first be reabsorbed just to stay even. Once that process is accomplished, nonbicarbonate buffers, usually ammonium and acid phosphate, remove hydrogen in the urine accompanied by A− and in the pro- cess generate ‘new’ bicarbonate. The metabolic acids that require urinary excretion are usually in the range of 1 to 2 mEq of H+ per kg of body weight. By comparison, the volatile carbon dioxide produc- tion per day is about 20 moles. The diagnostic approach to identifying acid–​base disorders The key questions to ask when attempting to diagnose the cause of an acid–​base disorder are shown in Box 12.11.1. The usual diagnostic approach to an acid–​base disorder begins with a complete history and physical examination. When taking a history, it is important to understand the quantity, contents, and source of fluid losses or gains from the body; ingested substances; and certain diseases known to be associated with acid–​base disorders. Examples include vomiting (metabolic alkalosis), diarrhoea (metabolic acidosis), chronic ob- structive lung disease (respiratory acidosis), pneumonia (respira- tory alkalosis), and so on. Laboratory tests usually performed, aside from arterial blood gas analysis, include a basic metabolic profile with electrolytes (so- dium, potassium, chloride, bicarbonate), blood urea nitrogen, and creatinine. Disturbance of the bicarbonate concentration alone does not prove a metabolic disturbance because there are two other variables in equilibrium with bicarbonate: carbon dioxide and the hydrogen ion concentration. Characterization of the type of acid–​base disturbance A low bicarbonate is consistent with either metabolic acidosis or re- spiratory alkalosis. If blood gases reveal low pH (acidaemia) and low bicarbonate (metabolic acidaemia), the dominant process is a meta- bolic acidosis. The response to metabolic acidosis is through stimu- lation of carotid body and central nervous system chemosensors, which stimulate an increase in alveolar ventilation, so the Pco2 is expected to drop. Normal compensation for metabolic acidosis is predicted based on an expected range of Pco2 established by ob- servation of subjects with simple metabolic acidosis. Should the actual Pco2 be lower than the predicted value, the diagnosis of re- spiratory alkalosis as a second primary disturbance can be made. If the actual Pco2 is higher than predicted, then a simultaneous re- spiratory acidosis is present. It is apparent that metabolic acidosis and its hyperventilatory compensation cause HCO3− and Pco2 to fall. The ratio of HCO3−/​Pco2 is proportional to the pH, as dem- onstrated in the Henderson–​Hasselbalch relationship expressing equation 1 in logarithmic terms, where the pK is 6.1 and the con- centration of carbon dioxide in water is 0.03 mmol/​litre per mmHg of equilibrated gas. pH = p

• log[HCO ]/[0.03 ] 3 2 CO K P − ×

(Equation 2) The finding of a metabolic acidosis does not rule out multiple processes simultaneously present. There are many findings that help diagnose mixed disturbances. In each of the primary disturb- ances, once the dominant process is identified, it is necessary to infer the degree of compensation by looking at empirical data (see Box 12.11.2 for a range of normal compensations). Determining whether the respiratory response to a metabolic acidosis is as expected for a mixed disorder allows the recognition or exclusion of an additional primary respiratory disorder, but a mixed metabolic disturbance is still possible. For example, Winters’ equation—​which gives the expected value for the patient’s Pco2 if there is adequate respiratory compensation for a metabolic acidosis (Box 12.11.2)—​is still valid when metabolic acidosis and alkalosis coexist if the predominant process is acidosis. In the case where a high-​chloride acidosis and a low-​chloride alkalosis coexist, it is not possible to differentiate this double disturbance from a simple meta- bolic acidosis. Box 12.11.1  The key questions for diagnosis of the cause of an acid–​base disorder Approach to acid–​base disorders 1 Is there acidaemia (pH <7.35) or alkalaemia (pH >7.45)? 2 What is the primary process (metabolic or respiratory, acidosis or alkalosis)? 3 Is there an appropriate compensatory response? 4 If this is an anion gap acidosis, are there other clues to a second pri- mary process? Box 12.11.2  Compensations for acid–​base disturbances Pco2 is measured in mmHg and HCO3 − in mEq/​litre. The direction of compensatory response in Pco2 or HCO3 − is the same as the ini- tial change in HCO3 − or Pco2, but compensation is almost never complete Expected values if simple disturbance Metabolic acidosis (Winters’ formula): Pco2 = (1.5 × HCO3 −) + 8 ± 2 Metabolic alkalosis: Pco2 = 0.7[HCO3 −] + 20 ± 5 Acute respiratory acidosis: [HCO3 −] = 24 + [(Pco2 − 40)/​10] Chronic respiratory acidosis: [HCO3 −] = 24 + 4[(Pco2 − 40)/​10] Acute respiratory alkalosis: [HCO3 −] = 24 –​ 2[(Pco2 − 40)/​10] Chronic respiratory alkalosis: [HCO3 −] = 24 − 5[(Pco2 − 40)/​10]

section 12  Metabolic disorders 2184 The serum anion gap It is useful to calculate the serum anion gap, which is determined by subtracting the sum of chloride and bicarbonate from the serum sodium concentration (the measured ions). The normal value is approximately 10 to 12 mEq per litre, the amount of charge asso- ciated with a normal albumin concentration. The relationship is as follows: Na (Cl + HCO ) = (albumin ) + unmeasured A = anion gap + 3 − − − − − (Equation 3) An elevated anion gap is diagnostic for a metabolic acidosis. Not only is the presence of an anion gap helpful in the differential diagnosis of the specific metabolic acidosis (Box 12.11.3), but it is also useful in determining the presence of a mixed metabolic disturbance. A  calculation of the increment in anion gap (ob- served anion gap minus normal anion gap of 10 mEq per litre) can be compared to a calculation of the decrease in bicarbonate concentration (normal bicarbonate of 25 mEq per litre minus the observed bicarbonate concentration). If this relationship is ap- proximately 1:1, then it is likely that the acidotic disorder is due to an unmeasured acid anion. However, if the rise in anion gap is greater than the fall in bicarbonate, a process raising the bicar- bonate concentration such as a metabolic alkalosis coexists. This combination might be seen in a patient who is vomiting and has diabetic ketoacidosis. If the fall in bicarbonate concentration ex- ceeds the rise in anion gap, then the second process is most likely a hyperchloraemic acidosis. Metabolic acidosis In diagnosing the cause of metabolic acidosis, calculation of the serum anion gap can distinguish hyperchloraemic acidosis (Box 12.11.4) from common organic anion acidosis (Box 12.11.3), some overproduced in the body, others caused by ingestion of toxic substances. These conditions are discussed later in this chapter. Metabolic alkalosis Metabolic alkalosis is generally divided into two categories based on its responsiveness to chloride. Chloride-​responsive metabolic alkal- osis is associated with ECF and chloride depletion and is seen in cases of gastric fluid loss and diuretic use. As is the case of hyperchloraemia versus anion gap acidosis, a diagnostic clue in metabolic alkalosis comes from the serum electrolytes. Bicarbonate is increased with a corresponding fall in serum chloride (hypochloraemic alkalosis, Box 12.11.5). Chloride-​unresponsive metabolic alkalosis is seen in patients with ECF expansion in conditions such as primary aldos- teronism and hypokalaemia. These conditions are discussed later in this chapter. Acid–​base disorders as disturbances of chemistry of the extracellular fluid That the normal H+ concentration is in the range of 40 nM, while the bicarbonate concentration is in the 25 mM range, is an indication that protons are involved in many reactions within the body, including with water and many buffers such as phosphate, haemoglobin, and the amino groups on many proteins (carbamino compounds). Use Box 12.11.3  Causes of high anion gap metabolic acidosis • Lactic acidosis:

—​ Severe illness

—​ Sepsis

—​ Shock

—​ Seizures

—​ Malignancy

—​ Drugs

—​ Metformin

—​ Nucleoside reverse transcriptase inhibitors • Uraemia • Rhabdomyolysis • Ketoacidosis:

—​ Diabetes

—​ Ethanol (alcohol)

—​ Starvation • Poisoning:

—​ Methanol

—​ Ethylene glycol

—​ Propylene glycol

—​ Toluene (glue sniffer) hippurates • Drugs:

—​ Salicylates

—​ Iron

—​ Isoniazid •​ Pyroglutamic acid (5-​oxoprolinuria)

—​ Acetaminophen (paracetamol) •​ d-​Lactic acid Box 12.11.4  Causes of hyperchloraemic acidosis and their diagnosis Chloride poor losses Renal losses • Diuretics with high cation content:

—​ Acetazolamide

—​ Potassium-​sparing • Renal tubular acidosis:

—​ Early only in proximal

—​ Chronic in distal • Nonbicarbonate anion:

—​ Ketoacidosis

—​ Hippurate anion Gastrointestinal losses • Small bowel losses • Most diarrhoea Chloride rich gains • 0.9%, 0.45% saline • Ringer’s lactate Urinary electrolytes • Suggest renal cause of acidosis:

—​ UNa + UK –​ UCl is positive

—​ Low urinary NH4Cl • Suggest nonrenal cause of acidosis:

—​ UNa + UK –​ UCl is negative

—​ High urinary NH4Cl

12.11  A physiological approach to acid–base disorders 2185 of the standard bicarbonate approach relying on the HCO3−/​Pco2 system to describe acid–​base phenomena depends on the isohydric principle: that a single H+ concentration is in equilibrium with mul- tiple other buffer pairs. Alternative approaches involve consider- ation of electrostatic forces requiring electroneutrality between all cations and anions in the ECF giving dependency of HCO3− and H+ to concentrations of strong electrolytes such as sodium, potassium, and chloride. Pertinent to the approach taken in this chapter, one could apply either theory because all that is required is disturbance of ionic species within the ECF. Since clinical acid–​base disorders are defined in terms of blood chemistry, and because plasma volume is part of the total ECF volume, the approach taken here is to describe the ways by which electrolytes including hydrogen and bicarbonate ions can be intro- duced into or removed from the ECF. As shown in Fig. 12.11.1, the boundaries of the ECF are cell membranes at the interface of intracellular water and the interstitial fluid compartment of the ECF or specialized epithelial cells that line compartments known as transcellular spaces. The transcellular spaces are outside cell water, so fall into a special category of ECF, and their contents reflect solute exchanges with the interstitial space. This chapter will approach acid–​base disorders through understanding these cell membrane boundaries and their transport functions. We start with mechanisms by which acid–​base disturbances ori- ginate through transfer of electrolytes such as sodium, potassium, chloride, hydrogen, and bicarbonate across epithelial cell mem- branes that line transcellular spaces within the ECF. Transcellular fluids include the lumina of the entire gastrointestinal tract, the kidney tubules, and sweat gland ducts. These particular epithe- lial lined spaces have a common feature in having an outlet to the external world. Other transcellular spaces are the pleural and peri- toneal space and cerebrospinal fluid. These spaces reflect systemic acid–​base conditions through equilibration rather than cause them because they are not in continuity with the external environment. A second mechanism for introduction of acids or bases into or out of the ECF involves movement of ions between cells and the extracellular space. Organic acid anions (HA) such as ketoacids and lactic acids produced in the liver, muscle, or other tissues, and metabolites of toxins absorbed from the gastrointestinal tract, undergo such internal transfers across cell plasma membranes as they enter the ECF. These examples constitute the anion gap acidoses because the anion (A−) entering the ECF is not chloride. When the same anions, such as lactate and citrate, are ingested as the sodium or potassium salt, taken up by liver cells, and oxi- dized, it is bicarbonate that is transported to the ECF, which may cause metabolic alkalosis if production exceeds clearance. It should be noted that respiratory disorders also involve trans- port of carbon dioxide into or out of the ECF. Carbon dioxide generated by cell respiration diffuses into venous plasma before entering red blood cells en route to the lungs, where the process is reversed as carbon dioxide diffuses from red cell to plasma to lung interstitium to cells lining the airspaces prior to alveolar ventilation. Acid–​base disorders associated with transport across epithelial cells lining transcellular spaces The following discussion emphasizes ion transport processes of the plasma membranes of epithelia in various organs. The first to be examined are renal tubular epithelial cells. The reason be- hind starting with the kidney is that the same cell transporters that regulate acid–​base in normal physiology may initiate acid–​base disturbances and compensate for disturbances that are generated elsewhere in the body. Primary renal disorders as well as the com- pensations for respiratory and metabolic disturbances can be con- sidered together. Box 12.11.5  Causes of hypochloraemic alkalosis and their diagnosis Renal causes of hypochloraemia Diuretics and renal channelopathies • NKCC:

—​ Furosemide, bumetanide

—​ Bartter’s syndrome • NaCl:

—​ Thiazides

—​ Gitelman’s syndrome Nonrenal causes of hypochloraemia • Gastrointestinal:

—​ Gastric

—​ Congenital chloridorrhoea

—​ Infection • Skin:

—​ Cystic fibrosis Urinary electrolytes • Suggest renal cause of alkalosis:

—​ Urinary electrolytes reveal Cl− loss

—​ UNa + UK –​ UCl is low or negative • Suggest nonrenal cause of alkalosis:

—​ Urinary electrolytes reveal low Cl−

—​ UNa + UK –​ UCl is high Transcellular fluids Extracellular fluid Interstitial fluid Components of total body water Intracellular fluid P l a s m a Fig. 12.11.1  Body fluid compartments.

section 12  Metabolic disorders 2186 Acid–​base disorders and the kidney Glomerular filtration utilizes mechanical energy of the cardiac-​ generated blood pressure to form a glomerular ultrafiltrate that requires modification by the renal tubules before being excreted as urine. The role of the tubules is primarily to reclaim necessary fluids, electrolytes, and solutes while allowing the elimination of ap- propriate quantities of waste substances. The process accounts for as much as 15% of the body’s energy expenditure in the form of high-​ energy phosphates. Oxygen consumption is high, particularly in the renal cortex, and is related to these transport functions. In normal circumstances, glomerular filtration rate (GFR) is in the order of 180 litres/​day and the amount of freely filtered solutes can be calculated as the product of GFR and the concentration of the solute in the arterial plasma. For bicarbonate, the quantity might be more than 4500 mEq/​day. The uncontrolled excretion of even a small quantity of this filtrate could prove fatal. The proximal tubule The first tubular segment to confront this large filtrate is the prox- imal tubule (Fig. 12.11.2). The early proximal tubule has abundant brush-​border membranes on the apical surface allowing for a large surface area for reabsorption. As shown in Fig. 12.11.2a, the luminal fluid remains isosmotic to plasma and accounts for approximately 50% of sodium and water reabsorption, but 85% of filtered bicar- bonate is reclaimed by the proximal tubule. The normal process of fluid resorption involves many steps, as shown in Fig. 12.11.2b. There must be adequate ATP production by proximal tubule mitochondria to fuel the sodium potassium ATPase which pumps sodium into the extracellular space in exchange for potassium. The consequence is a low intracellular sodium con- centration and a cell-​negative electrical potential difference across the plasma membranes. A  sodium electrochemical gradient thus formed favours entry of sodium from the lumen into the cell. Many transporters utilize the energy of the sodium gradient to cotransport important solutes such as glucose and amino acids back into the cell. The luminal secretion of protons from the cell occurs by exchange with sodium entering the cell (sodium–​hydrogen ex- change). Once the proton is in the lumen of the proximal tubule it can combine with a filtered bicarbonate ion, forming carbonic acid. The dehydration of carbonic acid to water and carbon dioxide is kinetically favoured by carbonic anhydrase IV in the brush-​border membrane. Carbon dioxide can then re-​enter the cell where it com- bines with hydroxyl ions left in excess in the cell with the secretion of hydrogen into the lumen. This reaction of hydroxyl and carbon dioxide to form bicarbonate is catalysed by intracellular carbonic anhydrase II. The bicarbonate thus formed, representing filtered bicarbonate, can then pass across the basolateral membrane to the extracellular space via a sodium bicarbonate cotransporter (NBC) with a 1:3 stoichiometry. This electrogenic ratio of sodium to bicar- bonate provides enough driving force for completing proximal bi- carbonate reabsorption. Another way of viewing NBC function is that it protects against cellular alkalinization. Bicarbonate reabsorp- tion would be decreased as interstitial fluid bicarbonate concentra- tion is elevated when bicarbonate is ingested and the gradient for bicarbonate to exit the cell diminished. This is one mechanism by which bicarbonaturia is achieved when serum bicarbonate levels go up, even minimally. The net result of proximal bicarbonate reabsorption is a luminal pH decrease by the end of the proximal tubule to approximately 6.5. The reduced delivery of bicarbonate to the more distal segments of the tubule, which have lower capacity for bicarbonate absorption, al- lows completion of the process of reabsorption in regulated fashion. Proximal tubular reabsorption of sodium and HCO3− is regulated by hormones such as angiotensin II and catecholamines (which in- crease) and by parathyroid hormone (which decreases) the exchange of sodium and hydrogen. Other factors that regulate the activity of sodium–​hydrogen exchange and sodium bicarbonate cotransport include hypokalaemia and hypercapnia, which increase the process. Hypocapnia has the opposite effect, decreasing proximal sodium bi- carbonate reabsorption. Another important function of the proximal tubule in acid–​base balance is the mitochondrial production of ammonia from glu- tamine and glutamate. The ammonia formed can get into the urine by diffusion into the lumen or by counter-​transport with sodium via the sodium–​hydrogen exchanger. Basolateral glutamine uptake and ammonia production by glutaminase activity is increased in both respiratory and metabolic acidosis and will increase urinary net acid excretion as ammonium chloride. While ammonia is pro- duced in the proximal tubule, regulation of how much is ‘trapped’ and excreted as ammonium is a function of the distal nephron where urine pH falls to a value as low as 5. Hypokalaemia also increases ammonia production. Role of the proximal tubule in metabolic acidosis Considering the many steps involved in proximal HCO3− reabsorp- tion, it is understandable that an abnormality at any one of the steps could result in delivering an amount of bicarbonate exceeding the capacity for distal nephron reabsorption. Bicarbonaturia and an alkaline urine would then result and metabolic acidosis develop. Because the excretion of bicarbonate is with sodium and potassium and less chloride, the ECF will express hyperchloraemic metabolic acidosis. These syndromes are known collectively as proximal renal tubular acidoses. Proximal renal tubular acidosis (type 2)  Proximal renal tubular acidosis (type 2)  is characterized by a decreased threshold for Fig. 12.11.2  The early proximal tubule: (a) luminal content; (b) cellular transport mechanism. CA, carbonic anhydrase.

12.11  A physiological approach to acid–base disorders 2187 bicarbonate reabsorption. HCO3–​ wasting and concomitant urinary losses of potassium occur until a lower level of serum bicarbonate re- duces the filtered HCO3–​ to a level at which the combined remaining function of the abnormal proximal tubule and low capacity distal nephron can completely reabsorb filtered bicarbonate. At that point, the urine becomes acid (pH <5.3) and net acid production equals net acid excretion, with a steady-​state low plasma HCO3−. Attempts to raise the plasma bicarbonate to normal may be difficult because the added bicarbonate will promptly enter the urine (high fractional excretion of bicarbonate), unnecessary because once the low bicar- bonate is achieved, a balance of acid produced and excreted occurs, and risky because the more bicarbonate excreted in the urine, the greater is potassium loss. However, correcting acidosis with bicar- bonate replacement is especially necessary in growing children. Isolated proximal renal tubular acidosis may result from muta- tions of specific transporters of the proximal tubule, such as the sodium–​hydrogen exchanger 3 (NHE3) or NBC, or from hereditary deficiency of carbonic anhydrase isoforms or carbonic anhydrase inhibitors. More commonly, proximal renal tubular acidosis is as- sociated with Fanconi’s syndrome or generalized proximal tubule dysfunction. Causes include genetic diseases such as glucose-​6-​ phosphatase deficiency, cystinosis, hereditary fructose intolerance, and Wilson’s disease. Acquired conditions such as multiple myeloma and Sjögren’s syndrome should be considered in an adult patient. For further discussion see Chapter 21.15. Primary hyperparathyroidism results in proximal renal tubular acidosis and hypophosphataemia secondary to inhibition of Na/​H exchange (NHE3) and sodium phosphate cotransport in the prox- imal tubule by parathyroid hormone through cyclic AMP. The Cl−/​ phosphate ratio in plasma may be elevated. Hyperparathyroidism is one of the few causes of metabolic acidosis and hypercalcaemia. Drug toxicity with aminoglycosides, cisplatin, and ifosfamide may cause proximal tubule dysfunction. The antiretroviral drug tenofovir, a nucleotide analogue reverse transcriptase inhibitor used in the treatment of human immunodeficiency virus-​1 (HIV-​1) and hepatitis B, is a cause of Fanconi’s syndrome. The syndrome also may be seen after kidney transplantation. As shown in Fig. 12.11.3, the late proximal tubule receives fluid that is low in bicarbonate and high in chloride due to preferential sodium bicarbonate reabsorption earlier. Chloride may then enter the proximal tubule cell in exchange for base, or chloride—​favoured by its high luminal to interstitial fluid concentration gradient—​ may pass through the paracellular route creating a positive luminal voltage that would increase paracellular sodium absorption. When filtered chloride is high at the outset (filtrate of plasma and ECF), and bicarbonate low, no such chloride gradient develops. A clinical corollary is that carbonic anhydrase inhibitors and hyperchloraemic acidoses per se decrease the lumen to interstitial fluid chloride gra- dient and therefore result in diuresis of sodium chloride. The metabolic acidosis that develops in chronic kidney disease is related to the failure to produce ammonia, thereby limiting the amount of net acid that can be excreted in the urine. If that amount is smaller than acid production within the body, then metabolic acidosis will develop. Many organic and inorganic anions, such as phosphate and sulphates, are retained at GFRs of less than 25 ml/​ min and constitute an increased anion gap in association with the metabolic acidosis. Patients with chronic kidney disease will not normally compensate for respiratory acidosis or nonrenal metabolic acidosis because they do not have the ability to further increase am- monia production. Role of the proximal tubule in metabolic alkalosis An increase in proximal sodium bicarbonate reabsorption allows less bicarbonate to flow distally and will maintain the existing level of plasma bicarbonate. In the case of volume (sodium) depletion with increased angiotensin II, or during hypokalaemia, it becomes diffi- cult to excrete an increased bicarbonate load. In order to eliminate any excess of filtered bicarbonate, there must be normal sodium and potassium balance. Metabolic alkalosis, if present, is therefore main- tained until replacement of potassium and extracellular volume is achieved (discussed later in this chapter). Role of the proximal tubule in compensation for respiratory disorders In respiratory acidosis, increased ammonium excretion allows for a rise in plasma bicarbonate because elimination of hydrogen ions that does not result in bicarbonate reabsorption instead results in ‘new’ bicarbonate. Though the final formation of ‘new’ bicarbonate is a distal function involving hydrogen secretion, the ammonia ne- cessary for the process is made in the proximal tubule and stimu- lated by hypercapnia. The role of a high Pco2 in respiratory acidosis to increase sodium bicarbonate reabsorption in the proximal tubule is the basis of the maintenance of high bicarbonate concentrations in compensated respiratory acidosis. In patients with compensated chronic respiratory acidosis who are acutely ventilated to normal Pco2, high bicarbonate levels remain until chloride is replaced (posthypercapnic alkalosis). Taken together the compensation for respiratory acidosis re- quires the generation of new bicarbonate and increased proximal reabsorption of filtered sodium bicarbonate. By contrast, the renal compensatory mechanism in respiratory alkalosis is decreased so- dium bicarbonate reabsorption in the proximal tubule causing alka- line urine and a low plasma bicarbonate concentration. Thick ascending limb of Henle’s loop As the tubular fluid leaves the proximal tubule and enters the loop of Henle, the process of bicarbonate reabsorption continues in the Late proximal tubule Fig. 12.11.3  Late proximal tubule. (a) Luminal content; (b) cellular transport mechanism.

section 12  Metabolic disorders 2188 thick ascending limb. Luminal sodium hydrogen exchangers and basolateral sodium bicarbonate cotransporters reabsorb approxi- mately 5% of the bicarbonate filtered. As shown in Fig. 12.11.4, the thick ascending limb has a major role in sodium chloride reabsorp- tion for maintenance of extracellular volume, osmoregulation (both concentrating and diluting mechanisms), and divalent cation re- absorption (calcium and magnesium). Role of the thick ascending limb in hypochloraemic alkalosis The sodium, potassium, two-​chloride cotransporter, NKCC, can be inhibited by drugs such as furosemide and bumetanide and by hypercalcaemia through a unique mechanism of the basolateral calcium receptor. Patients with hypercalcaemia lose salt in the urine. The effect of hypercalcaemia is to inhibit the NKCC trans- porter, much like furosemide. This provides a mechanism for the frequently observed association between hypercalcaemia and al- kalosis. Inhibition of chloride reabsorption in this segment leads to hypochloraemic metabolic alkalosis. Bartter’s syndrome is an autosomal recessive disorder associated with extracellular volume depletion and excessive urinary chloride loss that results in hypokalaemia and hypochloraemic metabolic alkalosis. Secondary increases of plasma renin and aldosterone occur, as does renal juxtaglomerular cell hyperplasia. The syndrome resembles the effects of furosemide on the thick ascending limb of Henle. Gene mutations in the NKCC cotransporter, the renal outer medullary K+ channel (ROMK), and Cl–​ channels (Bartin) have been described. Because calcium reabsorption occurs in the thick ascending limb of Henle, Bartter’s syndrome, like furosemide, causes hypercalciuria and nephrocalcinosis, as well as polyuria due to decreased urinary concentrating ability. For further discussion see Chapters 21.2.2 and 21.16. Distal tubule As shown in Fig. 12.11.5, the distal tubule receives input from the loop of Henle and plays an important role in continued salt re- absorption to maintain extracellular volume and in urinary dilution by separating salt from water in the absence of antidiuretic hormone. Furthermore, the segment is responsive to parathyroid hormone which increases calcium absorption in the distal tubule. Calcium reabsorption is increased when the sodium chloride cotransporter (NCC) is inhibited. NCC is often referred to as the thiazide-​sensitive sodium chloride transporter because of its inhibition by thiazide diuretics. Role of the distal tubule in hypochloraemic alkalosis Like furosemide, thiazide diuretics cause hypochloraemic alkal- osis due to urinary chloride loss. Gitelman’s syndrome is an auto- somal recessive cause of extracellular volume depletion, urinary chloride wasting, and hypokalaemic metabolic alkalosis. It is due to inactivating mutations in the SLC12A3 gene encoding the thiazide-​ sensitive NCC cotransporter of the renal distal tubule. Urinary con- centrating ability is preserved because the cortical distal tubule has no effect on the interstitial concentrating gradient of the medulla, and patients are hypocalciuric because decreased sodium chloride reabsorption in the distal tubule is associated with a decrease in calcium excretion (hence its usefulness in hypercalciuric states). Hypomagnesaemia may also be severe. Patients who present with hypokalaemic metabolic alkalosis with normal or low blood pressure and have urinary chloride concen- trations greater than 25 mEq/​litre may be taking diuretics such as furosemide or thiazides surreptitiously; a diuretic screen can docu- ment the presence of the drug. If the screen is negative, Bartter’s or Gitelman’s syndrome should be considered. Bartter’s syndrome is less common, usually more severe, and presents in young patients. The presence of hypercalciuria favours Bartter’s syndrome, whereas hypocalciuria and hypomagnesaemia suggest Gitelman’s syndrome. The hypokalaemia in both syndromes is due to increased sodium delivery to more distal collecting tubule segments where K+ se- cretion occurs and depends on delivered sodium, and secondary hyperaldosteronism. For further discussion, see Chapter 21.2.2. Role of the distal tubule in hyperchloraemic acidosis In Gordon’s syndrome (pseudohypoaldosteronism type 1), in- creases in Na+ and Cl–​ reabsorption through increased activity of the distal thiazide-​sensitive NCC transporter leads to hypertension and hyperkalaemic, hyperchloraemic acidosis, volume expansion, and (consequently) low renin and aldosterone. The hyperkalaemia is due to decreased sodium delivery to more distal collecting tubule segments where K+ secretion occurs and depends on delivered so- dium, and aldosterone. For further discussion see Chapter 21.15. Thick ascending limb of Henle Fig. 12.11.4  Thick ascending limb of Henle. (a) Luminal content; (b) cellular transport mechanism. CaR, calcium receptor Distal convoluted tubule Fig. 12.11.5  Distal tubule. (a) Luminal content; (b) cellular transport mechanism.

12.11  A physiological approach to acid–base disorders 2189 Collecting duct The final 10% of filtered bicarbonate reabsorption occurs in the renal collecting duct. The mechanism by which this occurs involves the coordinated effort of two types of cells: the principal cell and the intercalated cell (Figs. 12.11.6 and 12.11.7). As in other nephron segments, principal cell basolateral sodium–​potassium ATPase lowers intracellular sodium and provides a gradient for inwardly directed sodium movement. In this cell type, sodium enters through the epithelial sodium channel known as ENaC. The process of so- dium reabsorption renders the lumen of the collecting duct elec- tronegative. If no other ion transport occurred, the lumen-​negative charge would increase to a degree that would shut down further so- dium reabsorption. However, if either a cation enters the lumen or an anion leaves the lumen, the negative charge would be neutralized or ‘compensated’ allowing more sodium to be reabsorbed. Charge compensation for the negative lumen occurs by potassium secretion through luminal potassium channels or by selective anion reabsorp- tion. Another mechanism for charge compensation is proton secre- tion by the electrogenic proton ATPase of adjacent α-​intercalated cells shown in Fig. 12.11.7. The secreted protons can combine with the small amount of re- maining filtered bicarbonate delivered from proximal sites to re- form luminal carbon dioxide which then enters the intercalated cell where—​in the presence of intracellular carbonic anhydrase—​it re- forms bicarbonate for return to the ECF by a chloride–​bicarbonate exchanger. To the extent that the secreted proton combines instead with ammonia or phosphate in the lumen, the hydroxyl left over within the cell (as the proton is secreted), combines with ambient carbon dioxide to recreate bicarbonate which returns to the ECF as ‘new’ bicarbonate to replace the extracellular bicarbonate initially lost by acid produced within the body. In other circumstances, particularly on an alkaline ash diet (con- sisting mainly of fruit, vegetables, and milk) where bicarbonate needs to be eliminated, the β-​intercalated cell (with reversed polarity of proton pump and chloride–​bicarbonate exchange) predominates, allowing for bicarbonate secretion into the lumen in exchange for chloride (Fig. 12.11.8). Coordinated function of the principal and intercalated cells involves sodium reabsorption by ENaC, lumen negativity, and increased distal acidification of the urine. ENaC is regulated by aldosterone through the intracellular mineralocorticoid re- ceptor (MR) in the principal cell. That receptor can be activated by either aldosterone or cortisol. Cortisol is prevented from nor- mally activating the MR by virtue of 11 β-​hydroxysteroid de- hydrogenase type 2, which degrades cortisol to inactive cortisone. Aldosterone production is increased independently by adrenal se- cretion due to angiotensin II and hyperkalaemia. The dual mech- anism for aldosterone production allows for potassium secretion in volume expanded states and potassium conservation in hypo- volaemia. The so-​called aldosterone paradox, which refers to the ability of the kidney to retain sodium and chloride with minimal potassium secretion in the presence of volume depletion and yet to maximize potassium excretion without sodium retention in hyperkalaemia, may be mediated by decreased activity of potas- sium channels in the collecting duct when angiotensin II is pre- sent and increased activity when angiotensin II is low. When AII is high, more sodium is reabsorbed upstream from the potassium-​ secreting principal cells, decreasing net sodium for potassium exchange. Cortical collecting duct Fig. 12.11.6  Collecting duct principal cell. (a) Luminal content; (b) cellular transport mechanism. 11β OHSD, 11β hydroxysteroid dehydrogenase; AldoR, aldosterone receptor; ENaC, epithelial
sodium channel. Cortical and medullary collecting duct: α-intercalated cell Fig. 12.11.7  Collecting duct α-​intercalated cell. (a) Luminal content; (b) cellular transport mechanism. CA, carbonic anhydrase. Cortical collecting duct: β-intercalated cell Fig. 12.11.8  Collecting duct β-​intercalated cell. (a) Luminal content; (b) cellular transport mechanism. CA, carbonic anhydrase.

section 12  Metabolic disorders 2190 From this analysis, it is apparent that renal acidification can be- come abnormal at many different steps within either the principal or intercalated cells of the collecting duct. If the disease results in decreased hydrogen excretion, the abnormalities are collect- ively known as distal renal tubular acidoses. If the disease instead leads to increased acid excretion, then metabolic alkalosis ensues. Disorders of the principal cell typically cause hyperkalaemia with acidosis or hypokalaemia with alkalosis because of the similar direction of potassium and hydrogen ion secretion. However, in- creased ENaC activity syndromes can cause extracellular volume expansion or be the appropriate response to extracellular volume depletion. Similarly, decreased ENaC activity can be the cause of extracellular volume depletion or the appropriate response to extra- cellular volume expansion. Role of the collecting duct principal cell in hyperkalaemic, hyperchloraemic acidosis (distal/​type 4 renal tubular acidosis) This combination of abnormalities suggests dysfunction of the cor- tical collecting duct, where acidification of urine and disorders in potassium secretion may occur. Some patients with high blood po- tassium and hyperchloraemic acidosis can lower urinary pH below 5.3, whereas others appear to have defects in both potassium balance and urinary acidification. Hyperkalaemia itself may worsen meta- bolic acidosis since the high potassium outcompetes ammonia reabsorption at the K-​site of NKCC in the thick limb, thereby decreasing NH3 accumulation by countercurrent multiplication in the medullary interstitium. Causes include hyporeninaemic hypoaldosteronism, as seen in diabetic renal disease; other tubulointerstitial diseases, usually with some renal impairment; sickle cell anaemia; or the use of drugs such as renin inhibitors, β-​blockers, and nonsteroidal anti-​inflammatory drugs, where cyclooxygenase-​2 inhibition of the cells of the macula densa result in decreased renin secretion. Low renin and aldosterone levels can be found in cases of volume expansion with hypertension. Ciclosporin and tacrolimus may lead to decreased electrical driving forces for K+ and H+ secretion. Hyperkalaemic acidosis with elevated renin and low aldosterone is found in adrenal insufficiency, isolated hypoaldosteronism, and the use of angiotensin-​converting enzyme inhibitors, and angio- tensin II receptor blockers. High renin and aldosterone levels are anticipated when the renal collecting duct cell is insensitive to aldos- terone, as with urinary tract obstruction, sickle cell anaemia, amyl- oidosis, and systemic lupus erythematosus. Inhibition of aldosterone action with spironolactone, eplerenone, or new nonsteroidal MR receptor antagonists may cause hyperkalaemic acidosis, as does ENaC inhibition by amiloride, triamterene, tri- methoprim, and lithium. Pseudohypoaldosteronism type 1 is due to autosomal recessive, inactivating mutations of the Na+ channel ENaC, whereas autosomal dominant pseudohypoaldosteronism type 1 is due to mutations of the MR. Both cause hypovolaemia, metabolic acidosis, and hyperkalaemia with secondary increases in renin and aldosterone. Hyperchloraemic metabolic acidoses with a normal or ele- vated potassium concentration can develop as a result of the addition of chloride salts such as NaCl, KCl, CaCl2, NH4Cl, ar- ginine and lysine hydrochlorides, or HCl itself. If the quantity of Cl–​ introduced exceeds the ability of the kidney to eliminate NH4Cl in urine, hyperchloraemia will develop. Electroneutrality is maintained by a decrease in the serum HCO3–​ concentration, and a hyperchloraemic acidosis ensues. Renal production of NH3 increases in an attempt to improve HCl (NH4 Cl) excretion. Hyperkalaemia can occur because the acidaemia favours the exit of K+ from cells within the body. Acidaemia also inhibits K+ secretion in the renal collecting duct. Role of the collecting duct principal cell in hypokalaemic, hypochloraemic alkalosis with extracellular volume
expansion (hypertension) The renal conditions that cause metabolic alkalosis and volume expansion are due to a proportionately greater increase in Na+ re- absorption above that required to maintain a steady state of Na+ balance, rather than primary loss of the Cl–​ anion. As Na+ is reab- sorbed, electroneutrality is maintained by an increase in plasma HCO3–​. The extracellular volume and plasma Na+ concentration may be increased, Cl–​ appears in urine, and hypochloraemia is not present. In the kidney, the loss of net acid as NH4Cl in excess of the acid produced generates a metabolic alkalosis in which the ‘new’ bicarbonate is due to proton secretion by the distal nephron H+-​ ATPases. The H+ combines with NH3 to form NH4+ in urine. The increased plasma HCO3–​ will be filtered, but in the absence of a stimulus to increase proximal HCO3–​ reabsorption, the HCO3–​ will flow distally to be reabsorbed by the increased H+ secretion of the collecting duct. At first, the alkalosis is mild, but increased cor- tical collecting duct Na+ reabsorption leads to increased K+ secretion and hypokalaemia. Hypokalaemia increases the capacity for prox- imal HCO3–​ reabsorption, thereby opposing the effect of volume expansion, so that distal delivery of HCO3–​ decreases. The higher than normal distal H+ secretion titrates urinary buffers so further ‘new’ HCO3–​ is formed and the alkalosis worsens. Metabolic alkal- oses of this type are sustained by hypokalaemia and the alkalosis can be treated by potassium replacement. Specific causes of renal alkalosis with hypokalaemia, volume ex- pansion, and hypertension can be classified according to levels of renin and aldosterone. Primary increases in renin with secondary increases in aldosterone can be seen in patients with unilateral renal artery stenosis, renin-​secreting tumours of the kidney, and malig- nant hypertension. Low renin and elevated aldosterone levels are characteristic of primary hyperaldosteronism from adrenal adenoma or hyperplasia. If the aldosterone secretion is autonomous, a high salt intake will worsen the hypokalaemia and the alkalosis because more sodium will be delivered distally because of the volume expansion, and al- dosterone, usually shut off in such circumstances, remains active causing increased potassium secretion. Low renin and low aldosterone are seen when volume expan- sion is due to a high cortisol level in Cushing’s syndrome and the hypercortisolism of adrenocorticotropic hormone-​secreting tu- mours. Inhibition of the intracellular enzyme 11β-​hydroxysteroid dehydrogenase, which normally inactivates cortisol to form cor- tisone in the principal cell, will also result in low renin levels and low aldosterone levels, as endogenous cortisol generates the hypokalaemic alkalosis. Both genetic mutations (the ap- parent mineralocorticoid excess syndrome) and an excess con- sumption of glycyrrhizic acid (found in liquorice or anisette) are causes of this enzyme block. Another cause of hypertension with hypokalaemic alkalosis but with low renin and aldosterone

12.11  A physiological approach to acid–base disorders 2191 levels is Liddle’s syndrome, in which an activating mutation in the cortical collecting duct Na+ channel (ENaC) leads to increased Na+ reabsorption. Hypokalaemic metabolic alkalosis may also develop without volume expansion when a nonreabsorbable anion is presented to the cortical collecting duct lumen. Nitrates, sulphates, and certain anti- biotics such as nafcillin, carbenicillin, and ticarcillin may obligate K+ and H+ secretion as Na+ is reabsorbed. Topical administration of silver nitrate to burn victims may result in alkalosis. Secondary hyperaldosteronism associated with high levels of renin contributes to the hypochloraemic alkalosis associated with chloride losses from diuretics or other states of chloride and extra- cellular volume depletion. When the secondary hyperaldosteronism is due to volume depletion in a setting of metabolic acidosis (such as proximal tubular acidosis), hypokalaemia but not metabolic alkal- osis is observed. Role of the collecting duct intercalated cell in hypokalaemic, hyperchloraemic acidosis (distal/​type 1 renal tubular acidosis) In distal renal tubular acidosis (type 1), failure to excrete NH4Cl leads to an inability to excrete adequate net acid, thereby leading to continuous retention of acid in the body. The degree of acidaemia is often severe, with pH reaching values as low as 7.2, whereas urine pH usually exceeds 5.3. Kindreds have been described in which mutations in genes for the distal vacuolar H+-​ATPase cause an autosomal recessive distal renal tubular acidosis with deafness. Mutations resulting in defective Cl/​ HCO3 exchange protein (AE1) have been linked to an autosomal dominant form of distal renal tubular acidosis. Distal renal tubular acidosis is also associated with autoimmune disorders, including systemic lupus erythematosus and Sjögren’s syndrome, and genetic diseases, including sickle cell anaemia, Wilson’s disease, Fabry’s disease, cystic kidney diseases, and her- editary elliptocytosis. Hypercalciuria and hyperoxaluria may cause distal renal tubular acidosis; nephrocalcinosis and nephrolithiasis may be present. Increased proximal tubular citrate reabsorption as a consequence of the chronic acidosis leads to hypocitraturia, a risk factor for calcium nephrolithiasis. A chronically alkaline urine is a risk for pure CaHPO4 stones, and when the latter are found distal renal tubular acidosis should be suspected. Amyloidosis may be manifested as severe acidaemia and other tubular dysfunction, including nephrogenic diabetes insipidus. Chronic tubulointerstitial diseases of the kidney, including reflux nephropathy and urinary ob- struction, may result in renal tubular acidosis with hypokalaemia or hyperkalaemia. Acute tubulointerstitial nephritis may also result in renal tubular acidosis. Drugs such as amphotericin B can cause hypokalaemic distal renal tubular acidosis. Topiramax, used for migraines, is a carbonic anhydrase inhibitor that may cause mixed proximal and distal renal tubular acidosis. Distinguishing proximal and distal renal tubular acidosis  In contrast to proximal renal tubular acidosis, distal renal tubular acidosis (type 1) is generally a more severe metabolic disorder that may be accompanied by hypercalciuria, nephrocalcinosis, calcium phosphate kidney stones, and bone disease that includes rickets in children and osteomalacia in adults. It is necessary to treat distal acidosis because of relentless acid retention, and—​compared to proximal renal tubular acidosis—​easier to treat with enough bicar- bonate to cover the usual production rate of acids, and safer to treat because potassium improves with return to normal pH. Proximal and distal renal tubular acidoses usually can be dis- tinguished by clinical evaluation (Table 12.11.2). Helpful find- ings include the presence of a urine pH greater than 5.3 in distal but not proximal renal tubular acidosis during acidaemia; a frac- tional excretion of bicarbonate as high as 10 to 15% during bicar- bonate loading in proximal renal tubular acidosis; and the lowering of serum potassium upon correction of proximal but not distal tubular acidosis. In order to know what the kidney is doing with respect to elec- trolyte excretion, it is necessary to evaluate the urine chemistry. Considering sodium, potassium, and chloride in the urine, sodium and potassium concentrations relative to chloride that are dispro- portionate to that which exists in the ECF can predict whether the loss of that urine will have an acidifying or alkalizing effect on the ECF. For example, if the sum of the sodium and potassium concen- trations greatly exceeds the chloride concentration in urine, there will be a tendency to acidify the body fluids. If there is a meta- bolic acidosis in the blood, then such an excretion pattern by the kidney suggests that the kidney is the culprit in the generation of the acidosis. The diagnosis would then be called renal tubular acidosis and the unmeasured anion accompanying sodium and Table 12.11.2  Comparison of renal tubular acidoses Proximal (type 2) Classic distal (type 1) Hyporeninaemic hypoaldosteronism (type 4) Common causes Ifosfamide NRTI (tenofovir, adefovir, cidofovir) Myeloma Sjögren’s syndrome SLE Amphotericin CKD plus: • DM, amyloid • obstruction • sickle cell • SLE NSAIDs Treatment Bicarbonate (large dose) Bicarbonate (1 mEq/​kg per day) K+-​lowering treatment: • Diuretics • Kayexalate • Low K diet • Mineralocorticoid CKD, chronic kidney disease; DM, diabetes mellitus; SLE, systemic lupus erythematosus; NSAIDs, nonsteroidal anti-​inflammatory drugs; NRTI, nucleoside reverse transcriptase inhibitors.

section 12  Metabolic disorders 2192 potassium might be bicarbonate. If, by contrast, chloride was ex- creted in concentrations disproportionately high to the sum of so- dium and potassium concentrations, then an alkalinizing effect on plasma would be predicted. If a systemic acidaemia were present, then this urinary pattern would be considered appropriate and compensatory, favouring a search for an extrarenal cause of meta- bolic acidosis such as diarrhoea or respiratory acidaemia. From the urinary point of view, the extra chloride in the urine would need be accompanied by an unmeasured cation, which we know would be ammonium. Role of the collecting duct in compensation for nonrenal metabolic and respiratory disorders Although the proximal tubule plays a major role in compensation for these disorders, intracellular acidification of intercalated cells by both metabolic and respiratory acidosis leads to increased exo- cytotic expression of proton ATPase on the luminal membrane, increasing urinary acidification. A maximally acid urine will trap more ammonia in the form of ammonium. Alkalinization of cells in metabolic and respiratory alkalosis has the opposite effect. Renal compensations for respiratory disturbances can also be in- ferred from urinary chemistry. For example, the renal compensation for respiratory acidosis should be the loss of urinary electrolytes in the pattern that would alkalinize the extracellular space, that is, loss of high chloride concentration relative to sodium and potassium. As pre- viously discussed, the cation accompanying chloride is ammonium. Acid–​base disorders and the gastrointestinal tract The organs of the gastrointestinal tract produce secretions that en- able the absorption of fluid, electrolytes, and organic solutes derived from the metabolism of protein, carbohydrate, and fat. Excessive production or loss of these secretions will disturb the economy of electrolytes and acid–​base equivalents in the ECF because the source of these secretions is the ECF. Acid–​base disturbances also develop when ingested quantities of chloride or bicarbonate salts exceed the ability of the kidney or in some cases liver to clear them from the circulation. Stomach In Fig. 12.11.9a, the gastric lumen is shown to contain HCl as well as sodium and potassium. The volume of gastric fluid produced per day is usually about 2 litres, but in disease states, particularly with bowel obstruction, the volume can increase markedly. Normally the fluid flows distally into the upper small intestine where hydrogen and pan- creatic bicarbonate combine to form carbon dioxide and water, while the sodium and chloride are absorbed along the small intestine. In that way, there is internal balance of acid–​base. However, a transient postprandial sequestration of HCl in the gastrointestinal tract leads to a phenomenon known as the alkaline tide, a transient alkalinization of the body fluids and the urine. Shown in Fig. 12.11.7b, the acid-​ secreting parietal cell of the stomach has potassium-​hydrogen ATPase on the apical side, which is responsible for the secretion of hydrogen ion into the stomach against its chemical gradient. Stomach pH may reach values as low as 1 to 2. Chloride is secreted by chloride channels. Role of the stomach in hypochloraemic metabolic alkalosis If gastric fluid is removed by a nasogastric tube or by vomiting, then the loss of chloride and the gain of bicarbonate within the extracellular space would result in hypochloraemia and metabolic alkalosis. With vomiting, the initiating or generating event is loss of HCl. As shown in Fig. 12.11.9b, secretion of HCl into the stomach lumen by the parietal cell is coupled to the absorption of HCO3–​ in exchange for chloride at the basolateral membrane. With vomiting, initial increases in serum HCO3–​ are filtered by the renal glomeruli and excreted in urine accompanied by Na+ and K+; volume depletion begins to develop as sodium is lost in the urine and chloride in the vomitus. Thus, extracellular volume depletion is not accompanied by low sodium excretion in metabolic alkalosis. As vomiting continues, extracellular volume depletion worsens, glom- erular filtration falls, and HCO3–​ filtration is limited. The volume depletion activates the renin–​angiotensin II–​aldosterone system and proximal tubule fluid and NaHCO3 reabsorption increase as a consequence. Distal nephron Na+ reabsorption increases under the influence of aldosterone, and that results in greater H+ secretion, thereby enhancing HCO3–​ reabsorption. These effects reduce renal Na+ loss but at the expense of maintaining the metabolic alkalosis. Significant K+ losses, which occur as a result of the bicarbonaturia and hyperaldosteronism, lead to hypokalaemia, which is due to renal, not gastrointestinal, losses as a consequence of attempts to maintain extracellular volume. Similar to initiating events in prox- imal renal tubular acidosis, the hypokalaemia during generation of gastric alkalosis is of distal nephron aetiology as bicarbonate leaves the proximal tubule in a volume-​depleted state of high aldoster- onism, thereby enhancing potassium secretion. The hypokalaemia further increases proximal NaHCO3 reabsorp- tion, distal H+ secretion, and K+ reabsorption via the proton-​potassium ATPase of the intercalated cell of the collecting duct, all at the ex- pense of further reabsorption of HCO3–​. At the new steady state after vomiting or nasogastric suctioning ceases, the paradoxical aciduria of metabolic alkalosis develops as HCO3–​ reabsorption is complete and the urine contains low levels of Na+, K+, and Cl–​. The patient may be hypovolaemic, hypokalaemic, and alkalaemic, but because Na+, K+, and acid–​base balance are intrinsically linked, life-​threatening volume depletion, K+ depletion, and alkalaemia are usually avoided. Small intestine As shown in Fig. 12.11.10a, the fluid delivered from the upper small bowel is alkaline and contains iso-​osmotic sodium, chloride, and Stomach Fig. 12.11.9  Stomach and gastric parietal cell. (a) Luminal content; (b) cellular transport mechanism. CA, carbonic anhydrase.

12.11  A physiological approach to acid–base disorders 2193 bicarbonate. Most ingested nutrients such as glucose and amino acids and much of the bicarbonate are absorbed in more proximal bowel, such as duodenum and jejunum, and water is absorbed os- motically. The bicarbonate comes predominately from pancreatic secretions, with some contribution of biliary secretion, while the chloride is primarily dietary and that remaining from gastric acid secretion. In Fig. 12.11.11a, the luminal contents of fluid in the ileum and proximal colon are shown. An important role of these late small in- testinal and early colonic segments is to absorb sodium, chloride, bicarbonate, and water. In Fig. 12.11.11b, a cell is shown dem- onstrating the mechanism by which this absorption takes place. The luminal membrane contains both sodium–​hydrogen exchan- gers and chloride–​bicarbonate exchangers oriented in such a way to allow entry of sodium and chloride into the cell in exchange for secreted hydrogen and bicarbonate: thus the mechanism for sodium chloride absorption is by ‘double exchange’. In jejunal cells that favour sodium bicarbonate absorption, the sodium–​ hydrogen exchanger functions without a chloride–​bicarbonate antiporter, while in some villous cells of ileum and large intestine, chloride–​bicarbonate exchange without accompanying sodium–​ hydrogen exchange is the mechanism for chloride absorption and bicarbonate secretion. Role of the small intestine in hyperchloraemic acidosis In patients who have small bowel malabsorption, as in inflamma- tory bowel disease, pancreatitis, or with an infectious gastroenteritis, large volumes of small intestinal losses result in high bicarbonate-​ containing diarrhoea. Patients with an ileostomy can lose large quantities of pancreatic secretions rich in bicarbonate resulting in hyperchloraemic metabolic acidosis because the large amounts of bi- carbonate present in the lumen being delivered from upstream seg- ments are greater than the chloride anion in a relative comparison to ECF sodium and chloride. In some situations where bowel motility is poor, large quantities of pancreatic secretions accumulate in the intestine creating a hyperchloraemic metabolic acidosis. On occa- sion, acidaemia will result from vomiting small bowel contents or by duodenal or jejunal drainage. Ileal segments are used as urinary diversion conduits to replace bladder function. In such a situation, particularly when there is obstruction to flow, the ileal segment maintaining its ‘double exchange’ properties can lead to the reabsorption of excessive quantities of chloride by the loop, resulting in hyperchloraemic acidosis. Diabetic patients receiving pancreas and renal transplantation in which the exocrine pancreas drains into the urinary bladder can develop severe metabolic acidosis with hyperchloraemia, and this is one of the reasons why bowel drainage of the exocrine pancreas is now the preferred surgical technique in pancreatic transplantation. Secretagogues such as vasoactive intestinal peptide (VIP), which is associated with neoplasms of the pancreas or sympathetic chain, cause large losses of HCO3–​ in stool, with a resulting hypokalaemic, hyperchloraemic acidosis. Role of the small intestine in hypochloraemic alkalosis From the previous discussion, one could predict the following: if double exchange is dysfunctional as would be the case in a mutation of the chloride–​bicarbonate exchanger, then the luminal fluid would contain large quantities of chloride. If that chloride was unable to be absorbed by the downstream large intestine, then stool chloride would be increased. In Zollinger–​Ellison syndrome, excessive gastrin-​induced gastric acid secretion may result in large volumes of acidic stool with high chloride content resulting in hypochloraemic alkalosis. Congenital chloridorrhoea (chloride-​losing diarrhoea) is an autosomal reces- sive disorder of defective intestinal, apical Cl/​HCO3 exchange asso- ciated with the downregulated adenoma (DRA) gene, so-​named for its decreased expression in some patients with villous adenomas or adenocarcinomas. Intestinal crypt cells secrete chloride across the apical mem- brane in association with the cystic fibrosis transmembrane con- ductance regulator (CFTR) and this process may be activated by secretogogues including neurohumoral substances, cyclic AMP, and certain toxins in infectious diarrhoea. Most diarrhoeal illnesses, including the secretory diarrhoeas, result in metabolic acidosis ra- ther than alkalosis, but the acid–​base disorder is determined by the electrolyte content of the stool. Diarrhoea does not cause metabolic Duodenum and proximal jejunum Fig. 12.11.10  Upper small intestine. (a) Luminal content; (b) cellular transport mechanism. Ileum and proximal colon Lumen Fig. 12.11.11  Lower small intestine and early colon. (a) Luminal content; (b) cellular transport mechanism. CA, carbonic anhydrase; ClC, chloride channel.

section 12  Metabolic disorders 2194 alkalosis unless the stool electrolyte relationship [Na+ + K+− Cl–​] is less than plasma HCO3−. Colon Fig.  12.11.12a represents the diminishing amounts of water and electrolytes in the distal colon. In Fig. 12.11.12b a colonic cell is shown in which, as in the renal collecting duct, aldosterone increases sodium absorption via the epithelial sodium channel and potassium is secreted into the lumen. Role of colonic diarrhoea and hyperchloraemic acidosis Diarrhoeal disorders affecting these areas usually cause hyper­ chloraemic acidosis as unabsorbed sodium and potassium are lost with organic anions of bacterial origin. Chloride and bicarbonate concentrations may be low. Hypokalaemic, hyperchloraemic acid- osis results from loss of body fluids low in Cl–​ relative to Na+ and K+ when compared with the ratio of Cl–​ to Na+ in ECF. It is not always the case that metabolic acidosis caused by diarrhoea is due to bicar- bonate loss. Stool losses of Na+, K+, and HCO3–​ characterize most small bowel diarrhoea, while organic acid anions such as butyrate and acetate of bacterial origin are often the lost anions in colonic diarrhoea. Role of colonic diarrhoea in hypochloraemic alkalosis Rarely, villous adenomas or adenocarcinomas of the rectosigmoid secrete excessive quantities of sodium, potassium, and chloride, re- sulting in severe hypokalaemic, hypochloraemic metabolic alkal- osis. Some infectious diarrhoeas may result in alkalosis. From this discussion of the gastrointestinal tract, it should be noted that functions of the early small intestine, where bicarbonate from pancreatic and biliary secretions is absorbed along with glu- cose, amino acids, and water of dietary source, are analogous with the situation in the proximal tubule, where bicarbonate, glucose, amino acids, and water are reabsorbed from a filtrate of plasma. Likewise, the large intestine absorbs sodium and water and se- cretes potassium in an aldosterone regulated fashion, much like the collecting duct of the kidney. As emphasized in this discus- sion, the abnormal function of intestinal epithelial cells can result in volume depletion in association with either acidosis or alkal- osis, depending on the balance of losses of sodium and potassium compared to chloride. The term contraction alkalosis is therefore misleading. Acid–​base disorders and the skin Sweat gland ducts The sweat gland ducts (Fig. 12.11.13), like the principal cells in the kidney and the cells of the colon, contain aldosterone-​sensitive ENaC. Na+ absorption from the glandular duct renders the lumen electronegative. Normally the negative lumen drives chloride absorption through the CFTR, leading to limited volumes of hypotonic sweat. Cystic fibrosis and metabolic alkalosis Patients with cystic fibrosis may develop hypochloraemic alkalosis as a consequence of excessive sweat chloride content related to their CFTR gene mutation. When Cl− absorption is decreased in cystic fibrosis, the lumen becomes more negative, decreasing Na+, Cl−, and fluid absorption, leading to ‘salty’ sweat; the proportionally large Cl− loss may generate hypochloraemic metabolic alkalosis. Acid–​base disorders associated with transport of acid anions from intracellular to extracellular spaces: anion gap acidosis Several organic acid anions are produced metabolically in one cell type and carried by the blood to another cell type where they can be used as a fuel for further metabolism. For example, the Cori cycle involves the production of lactate in skeletal muscle, where it en- ters the interstitial fluid through monocarboxylic acid transporters (MCTs) on the plasma membrane, driven by solute gradients (Fig. 12.11.14). The lactate is then transported by similar MCTs into hepatic cells where it enters gluconeogenic pathways to form glucose. Thus, when considering the plasma as part of the ECF, the steady-​state lactate concentration is equal to the ratio of production to clearance. Excessive levels may occur with overproduction or de- creased clearance. The reason that plasma does not accumulate pyruvate in the same way is that the MCT has greater specificity for lactate. Pyruvate ­remains in the cell as a potential energy source through acetyl co- enzyme A. The ketoacids acetoacetate and β-​hydroxy butyrate are made in liver mitochondria and transported out of the liver cells by Distal colon Fig. 12.11.12  Distal colon. (a) Luminal content; (b) cellular transport mechanism. AldoR, aldosterone receptor; ENaC, epithelial sodium channel. Sweat gland duct Fig. 12.11.13  Sweat gland duct. (a) Luminal content; (b) cellular transport mechanism. AldoR, aldosterone receptor; CFTR, cystic fibrosis transmembrane conductance regulator.

12.11  A physiological approach to acid–base disorders 2195 MCTs, circulate, and are then cleared by brain and heart tissue (via MCTs) to be used as fuel when glucose is low, as in starvation. As with lactate, the plasma level of ketoacids represents the production to clearance ratio. Because these anions are filtered by the kidney, they can enter the urine (by renal clearance), obligating cations sodium and potassium for electroneutrality. The urinary excretion of sodium with a nonchloride anion leaves behind a relatively greater amount of extracellular chloride than sodium (hyperchloraemic acidosis). Thus, with lactic acidosis and ketoacidosis there are two mechanisms for acidosis; one an anion gap due to anion production greater than total clearance, and a hyperchloraemic component that involves the production of HA entering plasma and loss of NaA in the urine. In such a case, the decrease in HCO3–​ will exceed the increased anion gap, especially if the GFR and the filtered load of the anion are high. Box 12.11.3 lists causes of high anion gap metabolic acidosis, some of which are now discussed further. Diabetic ketoacidosis Diabetic ketoacidosis is defined as hyperglycaemia with meta- bolic acidosis resulting from generation of the acid anions β-​hydroxybutyrate and acetoacetate in response to insulin defi- ciency and elevated counter-​regulatory hormones such as epineph- rine and glucagon. Most commonly seen in cases of type 1 diabetes mellitus, severe stress can occasionally bring on ketoacidosis in type 2 diabetes mellitus diabetics. The lack of insulin increases lipolysis in adipose tissue; free fatty acids are transported to the liver, where hepatic mitochondria pro- duce ketone bodies, including acetoacetate, from acetyl coenzyme A. In the presence of a high NADH/​NAD ratio, the more reduced form of β-​hydroxybutyrate is produced. Ketoacids produced within hepatocytes are secreted into the ECF by the monocarboxylate-​ proton cotransporter, thereby causing acidaemia (Fig. 12.11.15). Ketoacidosis is also seen in cases of starvation, in which it is gen- erally mild and not associated with hyperglycaemia. The urinary dipstick nitroprusside test for ketones may underestimate the degree of ketosis because it does not detect β-​hydroxybutyrate, and the ketone test may become more positive as treatment helps metabolize β-​hydroxybutyrate to acetoacetate. This problem can be addressed by direct measurement of serum β-​hydroxybutyrate. Treatment of diabetic ketoacidosis consists of volume repletion, insulin administration (with dextrose if necessary to avoid hypogly- caemia), and potassium replacement. Bicarbonate administration should be considered only if ketoacidosis is accompanied by shock in conjunction with arterial pH of less than 7.0. Alcoholic ketoacidosis Alcoholic ketosis occurs in a patient who has been drinking very heavily without eating. The pathophysiology is based on the over- production of β-​hydroxybutyrate and (to a lesser extent) acetoacetate because of an increased production of free fatty acids from adipose tissue. Alcohol inhibits the conversion of lactate to glucose in the liver, favouring hypoglycaemia with fasting. The oxidation of ethanol in- creases the ratio of NADH to NAD+ and favours the production of β-​hydroxybutyrate from acetoacetate. Damage to mitochondria by al- cohol can further elevate the ratio of β-​hydroxybutyrate to acetoacetate by preventing reoxidation of NADH to NAD. The oxidative metab- olism of ethanol favours the reaction of dehydrogenase enzymes to form β-​hydroxybutyrate and lactate (opposing glucose production). Alcoholic ketoacidosis usually follows binge drinking and may be associated with withdrawal symptoms and the associ- ated hyperadrenergic state. It is associated with abdominal pain, vomiting, starvation, and volume depletion. In contrast to diabetic ketoacidosis, coma is rare. The blood glucose level is generally low or normal, and the insulin level is frequently low. The blood alcohol level may be unrecordable (absent) or elevated on initial evaluation. The osmolar gap, if secondary to ethanol, should be equal to the ethanol concentration in milligrams per decilitre divided by 4.6. If this calculation does not yield the expected gap based on the ethanol concentration, ingestion of another alcohol such as methanol, iso- propanol, or ethylene glycol should be suspected. Acetone, the product of acetoacetate metabolism, is seen during recovery and may register as an unmeasured osmol. By contrast, isopropanol me- tabolizes directly to acetone and causes ketosis without acidosis. Liver Fat Lipogenesis Lactate Heart, brain Skeletal muscle Monocarboxylic acid transporters (MCTs) Ketoacids Ketoacids Oxidation Glucose Lactate Lactate Glycolysis Fig. 12.11.14  Monocarboxylic acid transporters (MCTs) in lactate and ketoacid transport. During exercise glucose is broken down to lactate in skeletal muscle. Outwardly directed lactate gradients drive lactate into the extracellular fluid via an MCT. The liver takes up that lactate, also via an MCT, and converts it to glucose, which is available for export to the muscle cells for completion of the Cori cycle. Ketoacids are produced in the liver from fatty acids. They are then transported via an MCT, particularly in diabetes and hypoglycemic conditions, and the ketoacids are then transported via MCTS into brain and heart muscle cells as a source of energy through oxidation. Monocarboxylate transporters (MCTs) Hepatocyte Lactate Acetoacetate β-hydroxybutyrate Interstitial fluid (SLC)16 solute carrier family Fig. 12.11.15  An example of an MCT transporter in a hepatic cell shows coupling to hydrogen ion as well as the substrates that are transported through the (SLC) solute carrier family.

section 12  Metabolic disorders 2196 Treatment of alcoholic acidosis consists of volume repletion with 0.9% saline, administration of thiamine (50 to 100 mg intravenously), and enough glucose to treat hypoglycaemia, and the correction of any hypophosphataemia, hypokalaemia, and hypomagnesaemia that may be present. The acid–​base disturbance usually resolves after several hours. Both hypophosphataemia and thiamine deficiency, which may not be apparent until 12 to 24 h after the initiation of treatment in an undernourished patient, are exacerbated by glucose administration and may contribute to an associated lactic acidosis. Lactic acidosis Lactate, the final product in the anaerobic pathway of glucose me- tabolism, is produced from pyruvate by the following reaction cata- lysed by lactate dehydrogenase: NADH +pyruvate +H lactate +NAD

• →

(Equation 4) Lactic acidosis is caused by an imbalance in the rates of lactate pro- duction and clearance, primarily in the liver. Lactic acidosis, which increases the anion gap, is most often due to impaired lactate clear- ance due to circulatory failure, hypoxia, and mitochondrial dysfunc- tion that increase anaerobic glycolysis and the rate of reduction of pyruvate to lactate. Lactate, once formed, results in acidaemia after transport into the ECF by the organic acid anion transporter, MCT1. Other causes of lactic acidosis are thiamine deficiency, hypo­ phosphataemia, isoniazid toxicity, and hypoglycaemic states. Metformin may cause lactic acidosis, particularly in elderly patients with cardiac, hepatic, or renal dysfunction. Nucleoside antivirals, including zidovudine, may cause lactic acidosis and abnormal liver function as a result of toxic mitochondrial effects. Abnormal mito- chondrial function is also a feature of aspirin overdose. The anti- biotic linezolid is another cause of lactic acidosis. Many tumours utilize glycolysis for energy and produce large quantities of lactate. Treatment of lactic acidosis is aimed at correcting the underlying cause. Tissue perfusion and ventilation need to be restored. If the arterial pH is 7.0 or less, or when shock or cardiac failure has de- veloped, sodium bicarbonate therapy should be considered. This is usually given as an isotonic infusion (1.26% sodium bicarbonate, or 5% dextrose with added bicarbonate). Treatment carries risks of pul- monary oedema and hypernatraemia. In patients with intestinal bacterial overgrowth, disorientation, and ataxia, an anion gap metabolic acidosis may develop after a carbohydrate meal because of lactobacilli production of d-​lactate. This isomer of the mammalian l-​lactate can be measured only by a specific d-​lactate assay. The condition is treated with oral antibiotics and appropriate diet. Ethylene glycol Ethylene glycol is a constituent of antifreeze and also used as an in- dustrial solvent. It has a sweet taste and patients occasionally ingest it as a substitute for ethanol. Although ethylene glycol itself is not par- ticularly damaging, its highly toxic metabolites include glyoxylate, glycolate, oxalic acid, and ketoaldehydes. These acidic products are formed by metabolism within cells catalysed by alcohol and alde- hyde dehydrogenase and then transported into the ECF by MCTs. Oxalate is transported across cells by anion exchangers in the SLC26 gene family. Glycolic acid appears to be primarily responsible for the metabolic acidosis observed. Intoxication is characterized by profound central nervous system symptoms, including diplopia, seizures and coma, severe metabolic acidosis, and cardiac, pulmonary, and renal failure. Patients are often dehydrated and hypernatraemic because of os- motic diuresis from the renal clearance of the alcohol. Calcium oxalate crystals in the urine may cause intratubular obstruction and acute kidney injury. Patients typically have a high osmolal gap, initially defined as the difference between the measured and the calculated serum osmolality: S 2(Na )+ glucose [mg/dl] 18

• bloodureanitrogen[mg/dl]

osm + − ÷ ÷ 8     (Equation 5) Table 12.11.3 shows the differential diagnosis of patients with anion gap metabolic acidosis and high osmolar gaps. The serum osmolality should be measured by a freezing point depression technique and compared with the calculated osmo- lality. If possible, ethanol, ethylene glycol, propylene glycol, and methanol levels should be measured directly; each is associated with a metabolic acidosis. An increased anion gap is attributable to ethylene glycol metab- olites. A high osmolar gap will also be present because of the un- charged alcohol, but an osmolar gap may not be present if all of the alcohol has been converted to the toxic anionic forms. Treatment is aimed at rehydration with 0.9% saline and correc- tion of acidosis with NaHCO3 based on an estimate of the bicar- bonate deficit. When there is an osmolal gap, competitive inhibition of alcohol dehydrogenase should be initiated with fomepizole at a loading dose of 15 to 20 mg/​kg intravenously in 100 ml 0.9% sa- line over 30 min to 1 h, followed by a maintenance dose of 10 mg/​ kg every 12 h. An alternative is to use ethanol itself, in which case a solution of 10% ethanol in 5% dextrose can be given as a loading dose of 0.6 g/​kg intravenously, followed by a maintenance dose of 150 mg/​kg per h in alcoholic patients, or 65 mg/​kg per h in non- alcoholic patients. The blood ethanol level should be maintained at 100 to 200 mg/​dl. The goal of therapy is to prevent metabolism of the uncharged glycol to acidic products. Haemodialysis is required in severe cases. Some automotive fluids now contain the less toxic propylene glycol. Propylene glycol, a 3-​carbon glycol, is used as a diluent in some intravenous medications such as lorazepam. It metabolizes to lac- tate. Treatment consists of early recognition, fluid replacement (es- pecially if associated with an osmotic diuresis), and withdrawal of the offending agent. Table 12.11.3  Anion and osmolal gap in diagnosis of intoxications Anion gap acidosis Osmolal gap Diagnosis + Normal Salicylates + High Ethanol Ethylene glycol Propylene glycol Methanol − High Isopropanol

12.11  A physiological approach to acid–base disorders 2197 Methanol Methanol (wood alcohol) is a component of shellac and windshield wiper fluid and is highly toxic to the central nervous system after metabolism by alcohol and aldehyde dehydrogenase to formalde- hyde and formic acid. Optic papillitis may cause blindness. Treatment consists of competitive inhibitors for alcohol dehydro- genase, including ethanol or fomepizole, in similar amounts as for ethylene glycol poisoning, to reduce the formation of acid anions and the anion gap while maintaining a higher level of methanol in the blood. Haemodialysis may be necessary to increase elimination. 5-​Oxoprolinuria 5-​Oxoprolinuria is detected in debilitated patients with depleted intracellular glutathione (GSH) who are taking paracetamol (acet- aminophen). The accumulation of 5-​oxoproline (pyroglutamic acid) is caused by further drug-​induced depletion of GSH through interference with the γ-​glutamyl transpeptidase pathway respon- sible for creating GSH for shuttling amino acids into the cytosol. Normal glutathione levels are necessary for feedback inhibition of γ-​glutamylcysteine synthase, which regulates the activity of the cycle and is metabolized to 5-​oxoproline. As shown in Fig. 12.11.16, 5-​oxoproline leaves cells through plasma membrane H+-​coupled SLC16A1/​MCT1 transporter. Salicylate intoxication Salicylate intoxication can be caused by accidental overdose, thera- peutic overdose, or in a parasuicide or suicide attempt. Salicylates may cross cell membranes through nonionic diffusion, anion ex- change, and organic anion transporters (OAT1). Salicylate functions as an uncoupler of oxidative phosphorylation and consequently results in increased oxygen consumption and CO2 production. However, the increase in alveolar ventilation resulting from stimu- lation of central chemoreceptors overcomes this increase in CO2. The most common clinical manifestation is a combined anion gap metabolic acidosis and respiratory alkalosis, although the condition also can be manifested as either one or the other only. Children are often seen with metabolic acidosis, whereas adults often have pre- dominant respiratory alkalosis. Hypoglycaemia, ketoacidosis, and lactic acidosis may result. Other manifestations of intoxication include haemorrhage, fever, nausea and vomiting, hyperventilation, diaphoresis, tinnitus, and occasionally polyuria followed by oliguria. Severe cases may lead to seizures, respiratory depression, and coma. Noncardiogenic pul- monary oedema is sometimes seen in adults. Respiratory alkalosis is the result of a direct stimulatory effect of salicylate on the medullary respiratory control centre. Salicylate in- toxication also increases the metabolic rate. Diagnosis is suspected by the clinical presentation and confirmed by the salicylate level. Treatment is aimed at correcting the meta- bolic acidosis and removing salicylate. Bicarbonate as a sodium salt should be administered according to an estimated calculation of the deficit if metabolic acidosis predominates. Salicylates are removed by alkaline diuresis because the less reabsorbable salicylate anion will predominate when the urine pH increases. In severe poisoning, or when renal failure is present, dialysis may be required. Acid–​base disorders associated with intake The ECF contains approximately 140 mM sodium and 100 mM chloride. Sodium concentration is critically important in osmotic regulation, hence if sodium salts are ingested, then water will be taken in and conserved in order to maintain a constant plasma so- dium concentration. By contrast, plasma chloride concentration is determined by fluid balance and acid–​base requirements. The in- take of sodium and chloride in equivalent concentrations therefore requires a greater clearance of the chloride ion than of the sodium ion, and this clearance is primarily urinary. In order to eliminate chloride without sodium, and without necessitating potassium ex- cretion, there must be a cation to accompany chloride to achieve electroneutrality. Ammonium serves that purpose, and yet we think of ammonium excretion as a mechanism for acid elimination in the urine. That the intake of sodium chloride requires the loss of ammo- nium chloride (having an alkalinizing effect on the ECF) suggests that sodium chloride is an acidifying salt. If the intake of sodium chloride required the production of ammonium that exceeded the maximal ability of the kidney to do so, then the amount of acid ex- creted would be limited and hyperchloraemic metabolic acidosis should follow. Intravenous fluids may cause metabolic disorders by direct access to the ECF. Acidosis may be caused by infusions of high chloride salts including saline. Alkalosis may result from the addition of intravenous alkali salts of metabolizable organic anions. The normal response to NaHCO3 is rapid urinary alkalinization because of an unaltered threshold for HCO3–​ reabsorption. However, a marked ex- cess of HCO3–​, as may be administered in an attempt to alkalinize a patient’s urine, expands volume and causes an alkalaemia, especially in the presence of volume depletion or low glomerular filtration. Milk-​alkali syndrome, usually seen when patients in chronic kidney disease ingest milk or calcium antacids, is associated with hypercalcaemia, alkalaemia, and normal Cl–​. Other situations in which intake of alkali salts results in metabolic alkalosis include infusion of large quantities of sodium salts of acetate, citrate, lac- tate, or bicarbonate; hyperalimentation with acetate salts; peritoneal dialysis with acetate or lactate dialysate; or excessive transfusions or plasmapheresis in which large quantities of citrate, used as an anti- coagulant, are delivered. Entry of hydrogen ions into cells can also lead to metabolic al- kalosis in patients with hypokalaemia. If an alkalotic patient is not hypochloraemic, electroneutrality must be maintained either by depletion of an alternative anion or by an excessive concentration of a cation. An example of a metabolic alkalosis associated with MCT1 transports 5-oxoproline, as does SLC5A8 5-Oxoproline H+ Fig. 12.11.16  MCT1 transport of 5-​oxoproline (pyroglutamate).

section 12  Metabolic disorders 2198 depletion of a nonchloride anion is hypoproteinaemic alkalosis, with hypoalbuminaemia and a small anion gap. Chloride balance is normal and chloride appears in urine. Symptoms of acid–​base disorders Mild metabolic alkalosis up to a pH of 7.50 is usually asymptomatic. When the pH exceeds 7.55, however, the alkalosis itself and the com- pensatory hypoventilation are frequently associated with metabolic encephalopathy. Symptoms include confusion, obtundation, de- lirium, and coma. The seizure threshold is lowered, and tetany, par- aesthesias, muscular cramping, and other symptoms of low ionized calcium are seen. In patients with hypocalcaemia, these signs may be seen at pH values above 7.45, hence extreme caution should be taken if a decision is made to alkalinize a hypocalcaemic patient with acidaemia and this should only be done if there is a very pressing need for rapid correction of acidosis. Other findings include cardiac tachyarrhythmias and hypotension. Lactate production increases as a result of increased anaerobic glycolysis. Healthy, trained athletes may develop severe acidaemia (pH <7.0), but in acutely ill patients, blood pH as low as 7.2 may cause shock, and cardiac arrhythmia. Symptoms of chronic metabolic acidosis include nausea, vomiting, anorexia, and dyspnoea on exertion. Acutely, patients often exhibit Kussmaul respirations and volume depletion. Neurological symptoms include fatigue and lethargy with depression of the sensorium. Treatment of acid–​base disorders Metabolic acidosis Aside from treatment of the underlying condition, patients whose pH is less than 7.2 are typically treated with infusions of sodium bicarbonate, guided by the estimated bicarbonate deficit, calculated using the serum HCO3–​ concentration in mEq per litre: Amount of HCO = (25 [HCO ]) wt(kg)/2 3 3 − − − ×   (Equation 6) In general, the correction of metabolic acidaemia should be based on a calculated amount, with not more than 50% of the estimate given before re-​measurement of electrolyte and bicarbonate concen- trations and recalculation. It should be noted that this equation is used for deficit correction only; the ongoing losses of 1 to 2 mEq/​ kg per day, equivalent to the daily acid load, should be replaced in distal renal tubular acidosis with NaHCO3, KHCO3, or citrate salts in divided doses. Citrate should be avoided as an alkalinizing salt in patients with low GFR. Metabolic alkalosis The treatment of metabolic alkalosis rarely depends on giving back HCl. In chloride responsive alkalosis, replacement with 0.9% saline is indicated, but can be complicated by worsening of hypokalaemia if the bicarbonate is promptly excreted, mandating simultaneous treatment with potassium chloride. Expansion in patients with hypovolaemic hyponatraemia may correct the low sodium concen- tration faster than a safe rate, in which case the clinician must be prepared to replace with hypotonic fluids or add an antidiuretic hor- mone analogue to control water loss. The derivation of equation 6 is important in that it suggests the volume of distribution of bicarbonate to be 50% body weight. In fact, the bicarbonate volume of distribution is closer to 20% body weight, or the ECF volume. At pH 7.40, the fraction of total body buffer capacity for the bicarbonate system approximates 0.4, thus 0.2/​0.4 is the derivation of 0.5 × body weight. Due to the isohydric relation- ship being nonlinear, at acid pH the denominator of 0.2 decreases, meaning that bicarbonate becomes a less important buffer and con- sequently the bicarbonate amount calculated as replacement using equation 6 will be an underestimate. Further, in an acidaemic con- dition the change in chloride added to the ECF may differ from the amount of bicarbonate leaving the ECF, the latter being more. That the change in chloride equals the change in bicarbonate concentra- tion is evidence that the bicarbonate concentration is dependent on the balance of strong ions like sodium and chloride. FURTHER READING Adrogué HJ, et al. (2009). Assessing acid-​base disorders. Kidney Int, 76, 1239–​47. Batlle DC, et al. (1988). The use of the urinary anion gap in the diagnosis of hyperchloremic metabolic acidosis. N Engl J Med, 318, 594–​9. Chadha V, Alon US (2009). Hereditary renal tubular disorders. Semin Nephrol, 29, 399–​411. De Backer D (2003). Lactic acidosis. Intensive Care Med, 29, 699–​702 Emmett M, Narins RG (1977). Clinical use of the anion gap. Medicine (Baltimore), 56, 38–​54. Fordtran JS (1971). Organic anions in fecal contents. N Engl J Med, 284, 329–​30. Gennari FJ, Weise WJ (2008). Acid-​base disturbances in gastrointes- tinal disease. Clin J Am Soc Nephrol, 3, 1861–​8. Gennari FJ (2011). Pathophysiology of metabolic alkalosis: a new clas- sification based on the centrality of stimulated collecting duct ion transport. Am J Kidney Dis, 58, 626–​36. Halestrap AP, Wilson MC (2012). The monocarboxylate transporter family—​role and regulation. IUBMB Life, 64, 109–​19. Koeppen BM (2009). The kidney and acid-​base regulation. Adv Physiol Educ, 33, 275–​81. Kraut JA, Madias NE (2007). Serum anion gap: its uses and limitations in clinical medicine. Clin J Am Soc Nephrol, 2, 162. Luke RG, Galla JH (2012). It is chloride depletion alkalosis, not con- traction alkalosis. J Am Soc Nephrol, 23, 204–​7. Oh MS, Carroll HJ (1977). The anion gap. N Engl J Med, 297, 814–​17. Seldin DW, Rector FC Jr (1972). Symposium on acid-​basis homeo- stasis:  the generation and maintenance of metabolic alkalosis. Kidney Int, 1, 306–​21.