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Normal Control of Acid–Base Balance
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The plasma bicarbonate concentration is normally maintained at a constant level of 24–25 mEq/L in males and 22–23 mEq/L in nonpregnant females. Plasma bicarbonate concentration is maintained at these levels, despite ongoing H+ production resulting from metabolism of dietary constituents, because of compensatory equimolar generation of bicarbonate by the kidney (˜70 mmol/day). In addition, since the kidney filters a large quantity of bicarbonate each day, ˜4500 mEq, it must reclaim most of this bicarbonate to maintain a normal plasma bicarbonate concentration.
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Approximately 85% of filtered bicarbonate is reclaimed in the proximal tubule. As depicted in Figure 5–1, this bicarbonate is reabsorbed indirectly via the apical sodium–hydrogen exchanger NHE3, and exits the cell via the sodium–bicarbonate cotransporter kNBC1. Membrane-bound carbonic anhydrase IV in the apical and basolateral membranes and cytoplasmic carbonic anhydrase II are necessary for efficient absorption of filtered bicarbonate from the tubular fluid to the systemic circulation.
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In addition to absorbing the filtered bicarbonate load, the kidney needs to generate new bicarbonate to match the loss of HCO3 resulting from neutralization of acid generated in the liver from the daily metabolism of dietary protein. The proximal tubule in the kidney generates the new HCO3 primarily from the metabolism of glutamine. In addition to HCO3, NH4+ is also produced. The HCO3 is transported across the basolateral membrane of the proximal tubule cell to the systemic circulation. Were all the NH4+ produced in the proximal tubule transferred along with HCO3 to the systemic circulation, the HCO3 produced in the proximal tubule would be converted to urea in the liver and therefore would be unavailable to buffer the dietary H+ load. As depicted in Figure 5–1, this futile cycle is prevented by intrarenal transport mechanisms that ensure that a portion of the NH4+ is trapped in the lumen of the collecting duct as the result of proton transport by an apically located vacuolar H+-ATPase and possibly H+-K+-ATPase. Luminal proton transport by the H+-ATPase is coupled to basolateral bicarbonate exit via the anion exchanger AE1, with the NH4+ subsequently excreted in the urine.
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Collecting duct proton secretion by the H+-ATPase (the primary proton transporter) is modulated by the action of aldosterone, in part by enhancing sodium reabsorption via the epithelial sodium channel (ENaC) to produce a favorable electrical gradient. The kidney generates the remaining new HCO3 by a process called titratable acid (TA) formation/excretion. In this process, secreted H+ (via the proximal tubule NHE3, collecting duct H+-ATPase, and possibly H+-K+-ATPase transporters) bind to HPO42− in the tubule lumen and generates intracellular HCO3 that is transported to the systemic circulation. Clinically, the total effective new bicarbonate generated by the kidney can be quantified by measuring a parameter called net acid excretion, which is equal to the urinary excretion of NH4+ + TA − HCO3−. Under normal acid–base conditions, 40 mEq NH4 and 30 mEq TA are excreted daily while HCO3− excretion is negligible.
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Physiologic Response to an Increment in Acid Load or Extrarenal Bicarbonate Loss
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The normal response of the body to an H+ load or HCO3− loss involves four processes: (1) Extracellular buffering, (2) intracellular buffering, (3) respiratory compensation, and (4) enhanced renal HCO3− generation. Immediately upon an increase in an acid load, H+ is buffered by plasma HCO3− followed by H+ influx into cells (intracellular buffering). The latter process occurs more slowly, and is completed in 2–4 hours. Approximately 60% of an H+ load is buffered intracellularly, but this can increase dramatically with more severe degrees of metabolic acidosis as bicarbonate buffers are depleted. The degree of intracellular buffering can be indirectly determined by the quantity of bicarbonate required to raise plasma bicarbonate concentration to a certain level (bicarbonate deficit × bicarbonate space). The bicarbonate space is the apparent volume of distribution of administered bicarbonate and is calculated according to the following equation: Bicarbonate space = [0.4 + (2.6/plasma bicarbonate) × lean body weight]. The bicarbonate space can increase from 50% body weight with mild to moderate metabolic acidosis (12–23 mEq/L) to more than 100% body weight with severe metabolic acidosis (plasma bicarbonate concentration <5 mEq/L).
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The kidney plays the dominant role in regulating acid–base balance by increasing the quantity of new HCO3− generated. New HCO3− generation increases immediately and achieves a maximal level in approximately 4 days. The quantity of HCO3− generated can increase several fold and is due primarily to enhanced glutamine metabolism.
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Respiratory Compensation
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A fall in plasma bicarbonate concentration and blood pH stimulates receptors in the periphery and central respiratory center increasing alveolar ventilation. The increase in alveolar ventilation creates an inequality between mitochondrial CO2 production and pulmonary CO2 excretion. Pco2 decreases until a new steady state is reached, a process that requires approximately 12–24 hours. The magnitude of the decrease in Pco2 for any given level of sustained metabolic acidosis has been empirically determined and is given by the following relationship: For a given decrease in HCO3 of 10 mEq/L, the Pco2 decreases by approximately 12 mm Hg. When the Pco2 decreases appropriately, the metabolic acidosis is called “compensated” and a simple metabolic acidosis is said to be present. If the Pco2 is above the predicted value, the patient has a coexisting defect in ventilation and a mixed acid–base disturbance, ie, respiratory acidosis and a metabolic acidosis. Conversely, if Paco2 falls below the expected value, the patient has a mixed metabolic acidosis and respiratory alkalosis.
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Metabolic acidosis is subdivided into those disorders in which the serum anion gap is normal and those in which it is elevated. The serum anion gap represents the concentration of unmeasured anions minus unmeasured cations: Na+ + K+ + unmeasured cations = Cl− + HCO3− + unmeasured anions. Since the concentration of serum K+ is low, it is not considered in the calculation of the serum anion gap, which is then calculated as Na+ − (Cl− + HCO3). The normal serum anion gap ranges between 8 and 18 mEq/L, with an average of 10–12 mEq/L. However, introduction of a new autoanalyzer method for measuring serum chloride in some clinical laboratories has resulted in a higher value of serum chloride and therefore a lower value for the mean serum anion gap (average of 6–8 mEq/L).
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An increase in the serum anion gap is usually the result of retention of unmeasured anions in the blood, although rarely a decrease in the concentration of unmeasured cations can also be the cause. A decrease in the anion gap may be due to a decrease in the concentration of unmeasured anions (primarily negative charges on albumin) or an increase in unmeasured cations. An important cause of the latter is overproduction of cationic proteins seen in some cases of myeloma.
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The differential diagnosis of metabolic acidosis is facilitated by examination of the serum anion gap. In certain forms of metabolic acidosis (eg, lactic acidosis, ketoacidosis) H+ is infused into the circulation with a non-Cl− anion such as lactate or β-hydroxybutyrate (see Table 5–2). The increase in the anion gap reflects the increase in the concentration of lactate or β-hydroxybutyrate. By contrast, in patients in whom HCO3− is lost from the body (eg, small bowel diarrhea, proximal RTA), the serum anion gap remains stable because the fall in plasma HCO3 concentration is matched by an equivalent rise in serum Cl−. C8 Metabolic acidosis associated with a high anion gap is called an elevated or high anion gap metabolic acidosis. Metabolic acidosis associated with a normal anion gap is also called hyperchloremic metabolic acidosis.
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The disorders producing a high anion gap metabolic acidosis are shown in Table 5–2. They include renal failure, ketoacidosis, either diabetic or alcoholic, lactic acidosis, salicylate intoxication, and methanol and ethylene glycol intoxication.
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A high anion gap metabolic acidosis can be observed with acute or chronic renal failure. With chronic renal failure, the acidosis is generally mild to moderate in degree, with plasma bicarbonate concentrations ranging from 12 to 22 mEq/L. Values below 12 mEq/L should raise the suspicion of superimposition of other acid–base disorders. Epidemiologic studies have indicated that the acidosis can first be detected when glomerular filtration rate (GFR) falls below 20–30 mL/minute of normal. Therefore, the presence of metabolic acidosis at higher levels of GFR should alert the physician to potential additional renal tubular disorders such as hyporeninemic hypoaldosteronism (Type IV RTA) that can cause a non-anion gap metabolic acidosis. The metabolic acidosis of chronic kidney disease remains the most common cause of chronic metabolic acidosis, ie, metabolic acidosis lasting for more than several days or weeks. Although chronic renal disease is often considered a paradigm of high anion gap metabolic acidosis, various studies have indicated that these patients can manifest a wide range of anion gap levels.
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Metabolic acidosis is also frequent in oliguric acute renal failure. The severity of the metabolic acidosis in acute renal failure is dependent upon the level of residual renal function, duration of renal failure, and catabolic state of the patient. Thus, the acidosis will be more severe in catabolic patients with minimal residual renal function that has been present for several days.
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Ketoacidosis either due to diabetes or alcohol intoxication is one of the most common causes of acute metabolic acidosis, ie, metabolic acidosis lasting a few hours to days. Diabetic ketoacidosis is detected by noting increased urinary and/or blood concentrations of ketoacids. The nitroprusside reaction detects acetoacetate and will be positive in the majority of cases of diabetic ketoacidosis. However, if diabetic ketoacidosis is complicated by lactic acidosis, or if there is alcoholic ketoacidosis, the reaction may be trace positive or even negative reflecting the predominance of β-hydroxybutyrate over acetoacetate in the body fluids. Therefore, a negative nitroprusside reaction does not exclude ketoacidosis. Most cases of diabetic ketoacidosis are associated with marked hyperglycemia. In contrast, alcoholic ketoacidosis is often characterized by a normal or low blood sugar, reflecting impaired glucose release from the liver. Another clue to the presence of alcoholic ketoacidosis is an elevated serum osmolal gap (see below). As noted with chronic renal failure, it has been recognized that patients with ketoacidosis can have a wide range of anion gap levels. However, patients with higher serum anion gap values are usually volume depleted, reflecting a decreased ability of the kidney to excrete the ketone bodies.
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Lactic acidosis, another common cause of acute metabolic acidosis and possibly the most frequent cause of severe metabolic acidosis, is indicated by a blood pH <7.1 and plasma bicarbonate concentration <8–10 mEq/L. Indeed, ketoacidosis and lactic acidosis together account for more than 90% of the cases of metabolic acidosis in which the anion gap is >30 mEq/L. Type A lactic acidosis associated with tissue hypoxia is the most frequent type and can be readily suspected by the presence of hypotension and reduced tissue perfusion. The diagnosis of lactic acidosis is confirmed by a serum lactate concentration greater than 5 mEq/L.
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Salicylate intoxication can cause both metabolic acidosis and respiratory alkalosis. Therefore, a high anion gap metabolic acidosis in association with respiratory alkalosis could indicate the presence of this disorder. Ketoacids accumulate and can be detected with the nitroprusside reaction. Although this acid–base disturbance has frequently been encountered in young adults trying to commit suicide, recent studies have found it in adults taking salicylates for treatment of rheumatic conditions. Another clue to its presence includes a prolonged prothrombin time. Treatment includes forced diuresis to increase urinary excretion of the salicylates and hemodialysis. The latter procedure is indicated when the serum levels of salicylates are extremely high or the patient has marked central nervous system (CNS) abnormalities.
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Methanol (wood alcohol) and ethylene glycol (antifreeze) are rare, but serious causes of metabolic acidosis. Since both disorders can be rapidly lethal, it is critical to recognize their presence. Both substances are low-molecular-weight moieties and can increase serum osmolality. Therefore, measurement of serum osmolality and comparison of this value to the estimate of serum osmolality derived from consideration of the usual, osmotically active substances in blood can be of great value. Quantitatively the most important moieties contributing to serum osmolality are sodium (and its counterbalancing anions chloride and bicarbonate), glucose, and urea. Serum osmolality can rapidly be estimated using the following formula: 2 × [Na+] + [glucose]/18 + [BUN]/2.8, where [glucose] and [BUN] (blood urea nitrogen) are expressed in mg/dL. An osmolal gap (defined as the difference between the measured and estimated serum osmolality) greater than 10 mOsm/kg H2O indicates the presence in serum of additional osmotically active particles.
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Alchoholic ketoacidosis is the most common cause of a high anion gap metabolic acidosis associated with an increased osmolal gap, but methanol and ethylene glycol intoxication are other important causes. A slight increase in the osmolal gap ˜10 mOsm/kg H2O has been reported with lactic acidosis or chronic renal failure and might confound the diagnosis in some instances. If methanol and ethylene glycol are metabolized completely to their toxic byproducts, formic acid and glycolic acid, respectively, little or no increment in the osmolal gap might be detected. Other clues to the diagnosis of these disorders include optic papillitis in methanol intoxication and renal failure with oxalate crystals in the urine in patients with ethylene glycol intoxication. Treatments of methanol and ethylene glycol intoxication include infusion of alcohol to retard their metabolism and/or hemodialysis, which is very effective in removing these substances from the body.
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In summary, rapid diagnosis of the cause of high anion gap metabolic acidosis can be facilitated by measuring serum creatinine, urine and blood ketones, serum osmolality, serum sodium, glucose, and urea nitrogen necessary for calculation of the serum osmolal gap, and serum salicylate levels. If an elevated osmolal gap is found, then measurement of methanol, ethylene glycol, and alcohol levels is warranted to detect one of these intoxications.
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Normal Anion Gap (Hyperchloremic)
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As shown in Table 5–3, disorders causing a normal anion metabolic acidosis are often subdivided into those in which serum potassium concentration is low and those in which serum potassium concentration is normal or elevated to facilitate diagnosis of the underlying cause. Alternatively, the disorders causing a normal anion gap acidosis can be categorized based on the predominant organ involved in their pathogenesis as discussed below.
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Gastrointestinal Causes
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The most common cause of a normal anion gap metabolic acidosis associated with hypokalemia is diarrhea. Some studies have indicated this is more common with diarrhea emanating from the distal bowel. Other causes of gastrointestinal bicarbonate wasting include intestinal or pancreatic fistulas in which the bicarbonate-rich fluids are lost from the body. Construction of a conduit from the ureter to the sigmoid or ileal segments of the bowel is often done after removal of the bladder in patients with bladder cancer. The former procedure is regularly accompanied by the development of hypokalemic metabolic acidosis, whereas with the latter procedure this disorder usually indicates blockage of the ileal conduit.
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Administration of solutions containing amino acids that are metabolized in the liver to produce hydrochloric acid (arginine, lysine) or sulfuric acid (cysteine, methionine) can also produce a normal anion gap acidosis with hyperkalemia. In this regard, the administration of total parenteral nutrition solutions containing cationic and sulfur-containing amino acids causes a metabolic acidosis. Addition of sufficient organic anions, such as acetate, that are metabolized into HCO3− has eliminated or reduced the severity of this problem.
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Proximal Renal Tubular Acidosis (Type 2)
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Proximal RTA (Table 5–4) is the result of impaired reabsorption of filtered HCO3 leading to urinary bicarbonate wasting. This can be due to selective dysfunction of proteins present in the proximal tubule essential for bicarbonate absorption such as the basolateral Na–HCO3 cotransporter (kNBC1), defective cytoplasmic carbonic anhydrase (CAII) activity, or metabolic abnormalities that alter cellular adenosine triphosphate (ATP) production. The causes of proximal RTA are either genetic or acquired as shown in Table 5–4. When generalized proximal tubule malabsorption is present, bicarbonate wasting may be accompanied by glycosuria, phosphaturia, aminoaciduria, and hyperuricosuria (Fanconi's syndrome).
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During the generation phase of proximal RTA, an excessive amount of HCO3 is delivered to the distal nephron (which is incapable of reclaiming it), resulting in a net renal excretion of bicarbonate. The excretion of bicarbonate causes the plasma HCO3 to decrease, resulting in a metabolic acidosis. The decrease in plasma HCO3 lowers the filtered load of HCO3 (GFR × plasma bicarbonate). Once the plasma HCO3 concentration falls below the reabsorptive threshold for the patient, the proximal tubule will again be able to reclaim the majority of the luminal HCO3 and the excessive excretion of bicarbonate will no longer occur. A new steady state is achieved, albeit at a plasma HCO3 concentration lower than normal.
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The reabsorptive threshold in proximal RTA can vary, resulting in a steady-state plasma HCO3 concentration ranging from 15 mEq/L to 22 mEq/L. Urinary bicarbonate wastage will also occur as bicarbonate is administered to patients to raise the plasma HCO3 concentration. Urine pH is elevated during both the generation phase and reparative phases of proximal RTA, but is appropriately acidic during the steady state.
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Proximal RTA is diagnosed by measuring the fractional excretion of HCO3 (FEHCO3) when the plasma HCO3 concentration has been normalized using the following formula:
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A value greater than 20% is diagnostic of proximal RTA. The defect in proximal tubule HCO3 bicarbonate absorption may be mild. In this case, the FEHCO3 will be less than 20%. Since the nephron segments distal to the proximal tubule normally absorb ˜20% of the filtered HCO3 load, an FEHCO3− less than 20% does not necessarily implicate the proximal tubule as the site of defective HCO3 absorption. Hypokalemia is prominent in proximal RTA, although it is often less severe than in distal RTA. Urinary K+ losses are in large part associated with urinary HCO3 and Na+ losses, and therefore are most severe during generation and treatment of proximal RTA.
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Distal Renal Tubular Acidosis
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Distal RTA has traditionally been divided into two types: Type I (hypokalemic) and Type IV (hyperkalemic) (Table 5–4). In both forms, there is decreased collecting duct net H+ secretion and consequent reduced titratable acid (H2PO42−) excretion and NH4+ excretion leading to decreased new renal bicarbonate generation. Defective net proton transport can be due to (1) impaired hydrogen secretion from a dysfunction of one of the subunits of the H+-ATPase and possibly the H+-K+-ATPase (Figure 5-1), (2) increased luminal H+ efflux into the cells because of increased apical cellular permeability (occurring with exposure to amphotericin B), or (3) impaired hydrogen secretion because of a less favorable electrical gradient due to the abnormal function of aldosterone, decreased sodium absorption via ENaC (sodium channel), or augmented chloride entry (chloride shunt).
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Type I RTA can result from genetic diseases affecting the transporters that play a role in collecting duct proton secretion or from diseases that damage the collecting duct. Genetic causes have been ascribed to mutations in the apical H+-ATPase and basolateral Cl–HCO3 exchanger, AE1, and carbonic anhydrase II, which is expressed in collecting duct intercalated cells. Although many features are shared among these disorders, the clinical phenotype differs somewhat depending upon the transporter that is affected. Thus, patients with mutations in AE1 sometimes have red cell abnormalities. Type I RTA due to AE1 mutations is either autosomal dominant or autosomal negative. Some patients with mutations in specific H+-ATPase subunits have concomitant sensorineural deafness, since the proton pump is expressed in the inner ear. Patients with carbonic anhydrase II mutations can have a combined proximal and distal RTA and bony abnormalities.
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Many patients with distal RTA in addition to metabolic acidosis have hypercalciuria, nephrocalcinosis, and hypokalemia. In some patients osteomalacic bone disease can also be detected.
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Although the hypercalciuria is often attributed to the metabolic acidosis and the buffering of H+ by bone, this explanation is likely incomplete, given that many patients with Type IV RTA or patients with extrarenal causes of metabolic acidosis do not have hypercalciuria. The hypokalemia has been attributed to impaired collecting duct H+-K+-ATPase rather than impaired vacuolar H+-ATPase function. This explanation may not be correct, since patients with distal RTA due to genetic defects in the vacuolar H+-ATPase also have hypokalemia. An alternate explanation is that Na+ wasting results in volume depletion and enhanced aldosterone secretion with subsequent increased collecting duct K+ secretion and renal K+ excretion. Importantly, since these disorders often appear in childhood and metabolic acidosis affects bone metabolism, stunted growth may be present.
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Acquired disorders such as systemic lupus erythematosus (SLE), interstitial nephritis, and Sjögren's syndrome can injure the collecting duct and produce Type I RTA. Immunohistochemical staining of some patients with SLE have documented a decrease in H+-ATPase pumps in the collecting duct.
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Patients with distal RTA are often recognized by documenting an elevated urine pH (>5.5) in the presence of a normal anion gap metabolic acidosis in the absence of diarrhea (see below). More sophisticated studies of collecting duct proton secretion such as a urine minus blood Pco2 difference after bicarbonate infusion or urinary acidification with sodium sulfate administration can be helpful in determining the precise mechanism of the disease, but are often not required in clinical practice.
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Hyperkalemic Distal Renal Tubular Acidosis
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Hyperkalemia associated with distal RTA was first recognized in patients with hyporeninemic hypoaldosteronism, and was designated Type IV RTA to distinguish the syndrome from Types I, II, and III RTA associated with hypokalemia. Subsequently, other causes of distal RTA associated with hyperkalemia were recognized in which a low serum aldosterone concentration was not the pathogenic mechanism. The term Type IV RTA is used when referring to patients with hyperkalemic distal RTA due to an abnormality in the renin–aldosterone axis resulting in aldosterone deficiency or aldosterone resistance (pseudohypoaldosteronism). Importantly, these patients are able to acidify their urine appropriately. Patients with distal RTA and hyperkalemia where aldosterone does not play a role (Table 5–4) are diagnosed as having hyperkalemic distal RTA (HDRTA). These patients are unable to acidify their urine appropriately.
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The causes of Type IV RTA are listed in Table 5–5. It is important to realize that not all patients with Type IV RTA have hyporeninemic hypoaldosteronism. Depending on the cause, patients with Type IV RTA can have elevated aldosterone and renin levels as, for example, in genetic or acquired syndromes resulting in aldosterone resistance (Table 5–5). Furthermore, some patients with Type IV RTA have high renin and low aldosterone levels [angiotensin-converting enzyme (ACE) inhibition, adrenal abnormalities, heparin].
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As shown in Table 5–6, based on the pathogenesis of the disorder patients with HDRTA are further subcategorized into those with genetic or acquired diseases that decrease ENaC activity and those with a genetic disease called Gordon's syndrome, also referred to as a chloride shunt defect. Acquired causes of decreased ENaC activity include treatment with amiloride, pentamidine, trimethoprim, or triamterene, which all bind to and block sodium absorption via ENaC. Patients with Gordon's syndrome have hypercalciuria and hypertension, distinguishing them clinically from patients with HDRTA due to decreased ENaC activity. Gordon's syndrome has recently been shown to be due to mutations in WNK1 and WNK4 kinases.
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Diagnosis of the cause of normal anion gap metabolic acidosis can often be made with the use of clinical information and routine laboratory studies. However, since defects in renal acidification are often prominent causes, measurement or estimates of urine NH4+ excretion can be helpful. In general, in patients with extrarenal metabolic acidosis, the urine NH4+ excretion is increased several fold. Failure to detect an appropriate increase in urine NH4+ excretion will implicate the kidney as the cause of the metabolic acidosis. The urine NH4+ concentration can be estimated from calculation of either the urine anion or osmolal gap. The former is calculated from [Na+] − (Cl− + HCO3−) in a urine with a pH <6.5, which is free of nonreabsorbable anions such as ketones. In an acidemic patient, the urine anion gap should be negative (˜ −30 mEq/L). A positive urine anion gap indicates a low NH4+ concentration. In patients in whom there is increased excretion of unmeasured anions, such as ketones or hippurate, the urine anion gap can be positive despite ample quantities of NH4+ in the urine. In these rare cases, the urine osmolal gap can be calculated from the measured osmolality − (2[Na+ + K+] + [urea nitrogen]/2.8 + [glucose]/18), where [urea nitrogen] and [glucose] are measured in mg/dL. An appropriate urine osmolal gap in an acidemic patient is greater than 150–200 mOsm/kg H2O (the NH4+ concentration is half this value), whereas in patients with a decreased urine NH4+ concentration as in renal failure or distal RTA, the osmolal gap is usually less than 50–100 mOsm/kg H2O.
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Measurement of urine pH in patients with normal anion gap metabolic acidosis can complement the estimation of urinary ammonium excretion for further characterization of metabolic acidosis resulting from defects in renal acidification. For optimal measurement of urine pH and ammonium, a sample of urine should be obtained under oil (to prevent CO2 loss) when the patient is acidemic. If the urine pH is below 5.5, bicarbonate is administered until the urine becomes alkaline or the serum bicarbonate returns to normal. The development of an alkaline urine (pH >6.5) prior to normalization of serum bicarbonate indicates that proximal RTA (defective proximal tubule bicarbonate absorption) is present. If urine pH is high (>6.0) and remains relatively constant despite bicarbonate administration, distal RTA is potentially present. It is necessary to be cautious in making a diagnosis of distal RTA without initially ruling out diarrhea as a cause of a non-gap acidosis and an elevated urine pH. Importantly, hypokalemia due to diarrhea can result in an inappropriately elevated urine pH that is due to a decrease in collecting duct H+ secretion (distal RTA), but results from the fact that hypokalemia is a potent stimulus of renal NH3 production. The excess NH3 in the urine binds to secreted H+, thereby elevating the urine pH despite normal tubular H+ secretion. Importantly, when the hypokalemia is treated, NH3 production by the kidney decreases, and the urine pH decreases appropriately. In contrast, in Type I distal RTA, correction of hypokalemia has no effect on the urine pH.
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The classification of metabolic acidosis into high anion gap and normal anion gap forms is extremely useful in determining the cause of the acidosis. The reciprocal fall in serum bicarbonate, termed the (delta) ΔHCO3, and the rise in the anion gap, termed the Δ anion gap, have also been useful in the identification of mixed forms of metabolic acidosis. It has been suggested that there is a strict 1:1 relationship between the rise in the serum anion gap and fall in serum bicarbonate concentration in patients with high anion gap metabolic acidosis. However, the ratio between the Δ anion gap and ΔHCO3 can range between 1 and 2 and may differ with different acid–base disorders. Thus, with lactic acidosis the rise in the serum anion gap exceeds the fall in bicarbonate concentration, reflecting in part differences in the volume of distribution of H+ and lactate ions (H+ is buffered in intracellular and extracellular compartments, whereas lactate anion is confined to the extracellular space). By contrast, the Δ anion gap to ΔHCO3 ratio in diabetic ketoacidosis is ˜1:1. However, irrespective of the precise nature of the relationship between the ΔHCO3 and the Δ anion gap, the sum of the value for the Δ anion gap and the prevailing blood HCO3 concentration allows an approximation of the basal value of the blood HCO3 concentration existing prior to the development of the high anion gap metabolic acidosis. This concept is important both for distinguishing between a high anion gap metabolic acidosis and a mixed high and normal anion gap metabolic acidosis, and for detecting the presence of a mixed high anion gap metabolic acidosis and metabolic alkalosis.
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The clinical findings associated with metabolic acidosis are relatively limited and primarily related to the underlying cause. Hyperventilation reflecting the respiratory response to the metabolic acidosis might be observed. With severe degrees of metabolic acidosis organ dysfunction such as impaired cardiac output and hypotension might be apparent. With chronic metabolic acidosis, bone disease and muscle wasting may be present, which produce clinical abnormalities.
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The nature of the adverse effects of metabolic acidosis depends on both the duration of the metabolic acidosis and its severity. It is valuable to consider the effects of acute and chronic metabolic acidosis separately.
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Adverse Effects of Acute Metabolic Acidosis
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The adverse effects of acute metabolic acidosis include decreased cardiac output and hypotension, impaired glucose control, decreased tissue perfusion, reduced oxygen delivery, and induction of an inflammatory state. There is a direct relationship between the severity of the acidemia and the appearance of these changes, with most appearing when the blood pH is less than 7.1–7.2. Although not definitively proven, there is a correlation between the severity of acidemia and mortality, increasing at lower values of blood pH. These findings have an important bearing on the approach to treatment taken by most clinicians (see below).
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Adverse Effects of Chronic Metabolic Acidosis
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The adverse effects of chronic metabolic acidosis are distinctly different from those of acute metabolic acidosis. Chronic metabolic acidosis has been shown to impair bone metabolism contributing to the genesis of osteomalacia and/or osteitis fibrosa and might also play a role in the genesis of osteoporosis. Muscle wasting has been demonstrated in both experimental and clinical studies of chronic metabolic acidosis, which improves with correction of the acidosis. Similarly, chronic metabolic acidosis can contribute to the genesis of hypoalbuminemia. Insulin resistance due to impaired ligand binding may contribute to abnormal glucose tolerance. In experimental studies in animals, metabolic acidosis can exacerbate renal disease, but this remains to be shown in humans. Cardiac disease so prominent in acute metabolic acidosis has not been shown to be present by chronic metabolic acidosis, although mortality in dialysis patients was increased in the presence of acidosis. Of interest, many of these abnormalities can be seen with even mild metabolic acidosis, a finding that has important implications for treatment.
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Treatment of acute metabolic acidosis remains one of the more controversial issues in clinical medicine. Although severe acidemia (blood pH <7.1 to 7.2) has been shown to have important adverse effects on organ function, base administration to raise blood pH has not been demonstrated to improve the outcome of lactic acidosis or ketoacidosis, the two disorders in which this issue has been examined. Moreover, in some studies, when bicarbonate is given, a decrease in cardiac output has been found in patients with lactic acidosis and exacerbation of cerebral edema has been noted in children with diabetic ketoacidosis. Benefits and possible adverse effects of treatment of normal anion gap metabolic acidosis have not been examined in a prospective way. These adverse effects of bicarbonate administration have been attributed in part to a bicarbonate-induced reduction in the intracellular pH rise in cellular sodium and fall in ionized calcium. We presently recommend administration of bicarbonate when blood pH is less than 7.1 as a constant infusion rather than a bolus. A calcium infusion might be indicated if ionized calcium falls. Moreover, we target a blood pH ˜7.2 but not higher initially. We also recommend considering alternative bases such as tris (hydroxymethyl) aminomethane (THAM) or the use of continuous renal replacement therapy.
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Treatment of chronic metabolic acidosis is less controversial because the side effects of treatment are less severe. Since even mild metabolic acidosis can contribute to abnormalities of bone and muscle metabolism, we recommend complete normalization of acid–base balance. This can be achieved with administration of either oral bicarbonate or other bases that are metabolized to produce bicarbonate, such as Shohl's solution (sodium citrate). The latter is preferred because oral bicarbonate can produce gas that patients do not tolerate well. Possible consequences of base administration include potentiation of vascular calcifications and volume excess and exacerbation of hypertension (from accompanying sodium).