Hyperchloremic acidosis is a group of pathophysiologic states characterized by metabolic acidosis in which the blood's concentration of chloride ions and acid is increased (ie, there is low arterial blood pH).
This article covers the pathophysiology, causes, workup, and management of hyperchloremic metabolic acidoses, in particular renal tubular acidosis (RTA).[1, 2, 3, 4] Hyperchloremic acidosis is often due to renal diseases, gastrointestinal diseases, and iatrogenic causes (excessive chloride relative to other anions in IV fluid or parenteral nutrition). Acute (lasting up to several days) and chronic (lasting up to lifelong) types hyperchloremic acidosis can result from different causes.
A low plasma bicarbonate (HCO3-) concentration represents, by definition, metabolic acidosis, which may be primary or secondary to a respiratory alkalosis. Loss of bicarbonate stores through diarrhea or renal tubular wasting leads to a metabolic acidosis state characterized by increased plasma chloride concentration and decreased plasma bicarbonate concentration. In contrast, primary metabolic acidoses that occur as a result of a marked increase in endogenous acid production (eg, lactic or keto acids) or progressive accumulation of endogenous acids when excretion is impaired by renal insufficiency are characterized by decreased plasma bicarbonate concentration and increased anion gap (AG) without hyperchloremia.
The initial differentiation of metabolic acidosis should involve a determination of the plasma AG. This is usually defined as AG = (Na+) - [(HCO3- + Cl-)], in which Na+ is the plasma sodium concentration, HCO3- is the bicarbonate concentration, and Cl- is the chloride concentration; all concentrations in this formula are in mmol/L (see also the Anion Gap calculator). The AG value represents the difference between unmeasured cations and anions, that is, the presence of anions in the plasma that are not routinely measured.
An increased AG is associated with renal failure, ketoacidosis, lactic acidosis, and ingestion of certain toxins. It can usually be easily identified by evaluating routine plasma chemistry results and from the clinical picture.
A normal AG acidosis is characterized by a lowered bicarbonate concentration, which is counterbalanced by an equivalent increase in plasma chloride concentration (in other words, bicarbonate is effectively replaced by plasma Cl-). For this reason, the condition is also known as hyperchloremic metabolic acidosis. Hyperchloremic metabolic acidosis arises from one of the following conditions[5, 6] :
Go to the Medscape Drugs & Diseases articles Metabolic Acidosis, Pediatric Metabolic Acidosis, and Metabolic Acidosis in Emergency Medicine for complete information on these topics.
Conditions associated with hyperchloremic acidosis include the following:
If the acidosis is marked and/or of acute onset, the patient may report headache, lack of energy, nausea, and vomiting.
An increase in minute ventilation of up to four- to- eight-fold may occur in persons with respiratory compensation.
Effects on the cardiovascular system include direct impairment of myocardial contraction (especially at a pH < 7.2), tachycardia, and increased risk of ventricular fibrillation or heart failure with pulmonary edema. Patients may report dyspnea upon exertion or, in severe cases, at rest.
Chronic acidemia, as is observed in RTA, can lead to a variety of skeletal problems. Clinical consequences include osteomalacia (leading to impaired growth in children), osteitis fibrosa (from secondary hyperparathyroidism), rickets (in children), and osteomalacia or osteopenia (in adults).
Important complications of chronic RTA (mainly distal, type I) are nephrocalcinosis and urolithiasis.
If the cause of a patient’s acidosis is not apparent from the history and physical examination findings, the next step is to determine whether hyperchloremic acidosis is present. Tests include the following:
Proximal RTA
In cases of proximal RTA (pRTA), multitherapy with large quantities of alkali, vitamin D, and potassium supplementation is required. The usual range of bicarbonate administration is 5-15 mEq/kg/d; the administration must be accompanied or preceded by the administration of large amounts of potassium.
Hypokalemic distal RTA
In hypokalemic distal RTA (dRTA), treatment consists of long-term alkali administration in amounts sufficient to counterbalance endogenous acid production and any bicarbonaturia that may be present. Potassium supplements are indicated in the presence of hypokalemia.
Hyperkalemic dRTA
With hyperkalemic dRTA, entities amenable to intervention, such as obstructive uropathy, must be identified. In general, distal sodium delivery is increased if patients increase their ingestion of dietary salt, taking into account that many of these patients have concomitant cardiorenal compromise.
Fluid overload can be overcome with the addition of furosemide to a high-salt diet. This combination encourages distal delivery of sodium by rendering the collecting tubule impermeable to chloride, and it increases the exchange of sodium for hydrogen and potassium.
The kidneys maintain acid-base balance by bicarbonate reclamation and acid excretion. Most conditions that affect the kidneys cause a proportionate simultaneous loss of glomerular and tubular function. Loss of glomerular function (associated with a decreased glomerular filtration rate [GRF]) results in the retention of many end products of metabolism, including the anions of various organic and inorganic acids and urea. Loss of tubular function prevents the kidneys from excreting hydrogen cations (H+) and thereby causes metabolic acidosis. The development of azotemia, anion retention, and acidosis is defined as uremic acidosis, which is not hyperchloremic.
The term hyperchloremic acidosis (ie, RTA) refers to a diverse group of tubular disorders, uncoupled from glomerular damage, characterized by impairment of urinary acidification without urea and anion retention. Consequently, RTA typically is unaccompanied by significant decreases in GFR. These disorders can be divided into two general categories, proximal (type II) and distal (types I and IV).
The proximal convoluted tubule (PCT) is the major site for reabsorption of filtered bicarbonate. In proximal RTA (pRTA), bicarbonate reabsorption is defective. Proximal RTA rarely occurs as an isolated defect of bicarbonate transport and is usually associated with multiple PCT transport defects; therefore, urinary loss of glucose, amino acids, phosphate, uric acid, and other organic anions, such as citrate, can also occur (Fanconi syndrome).
A distinctive feature of type II pRTA is that it is nonprogressing, and when the serum bicarbonate is reduced to approximately 15 mEq/L, a new transport maximum for bicarbonate is established, and the proximal tubule is able to reabsorb all of the filtered bicarbonate. A fractional excretion of bicarbonate (FE[HCO3-]) greater than 15% when the plasma bicarbonate is normal after bicarbonate loading is diagnostic of pRTA. In contrast, the fractional excretion of bicarbonate in low and normal bicarbonate levels is always less than 5% in distal RTA (dRTA). Another feature of pRTA is that the urine pH can be lowered to less than 5.5 with acid loading.
The pathogenic mechanisms responsible for the tubular defect in persons with pRTA are not completely understood. Defective pump secretion or function, namely aberrations in the function of the proton pump ([H+ adenosine triphosphatase [ATPase]),[7] the Na+/H+ antiporter, and the basolateral membrane Na+/K+ ATPase, impair bicarbonate reabsorption. Deficiency of carbonic anhydrase (CA) in the brush-border membrane or its inhibition also results in bicarbonate wasting. Finally, structural damage to the luminal membrane with increased bicarbonate influx or a failure of generated bicarbonate to exit is a proposed mechanism that does not currently have strong experimental backing.
Genetics
Loss-of-function mutations in SLC4A4 (also called NBCe1), impacting a cotransporter on the basolateral membrane, result in recessive pRTA with ocular and central nervous system abnormalities.[8] Other genes, such as EHHADH, CLCN5, and SLC2A2, can cause generalized proximal tubule dysfunction with bicarbonate wasting and decreased ammonia production, resulting in pRTA.[9] Mutations in CA2 affect several nephron segments, leading to a mixed phenotype of both proximal and distal RTA.[9]
The distal nephron, primarily the collecting duct (CD), is the site at which urine pH reaches its lowest values. Inadequate acid secretion and excretion produce a systemic acidosis. A metabolic acidosis occurring secondary to decreased renal acid secretion in the absence of marked decreases in GFR and characterized by a normal AG is due to diseases that are usually grouped under the term dRTA. These are further classified into hypokalemic (type I) and hyperkalemic (type IV) RTA.
Until the 1970s, dRTA was thought to be a single disorder caused by an inability to maintain a steep H+ gradient across the distal nephron, either as a failure to excrete H+ or as a result of increased back-diffusion of H+ through an abnormally permeable distal nephron. Structural damage to the nephron from a variety of sources has been shown to result in different pathogenic mechanisms.
Excretion of urinary ammonium (NH4+) accounts for the largest portion of the kidneys' response to the accumulation of metabolic acids. Patients with dRTA are unable to excrete ammonium in amounts adequate to keep pace with a normal rate of acid production in the body. In some forms of the syndrome, maximally acidic urine can be formed, indicating the ability to establish a maximal H+ gradient. However, despite the maximally acidic urine, the total amount of ammonium excretion is low. In other forms, urine pH cannot reach maximal acidity despite systemic acidemia, indicating low H+ secretion capacity in the collecting duct.
In the presence of systemic acidemia, a low rate of urinary ammonium secretion is related either to decreased production of ammonia by the cells of the PCT or to failure to accumulate ammonium in the distal convoluted tubule (DCT) and excrete it in the urine. Decreased ammonium production is observed in hyperkalemic types of dRTA, also known as type IV RTA, because hyperkalemia causes an intracellular alkalosis with resultant impairment of ammonium generation and excretion by renal tubular cells. Acid secretion is thus reduced because of the deficiency of urinary buffers. This type of acidosis is also observed in early renal failure, due to a reduction in renal mass and decreased ammonium production in the remaining proximal tubular cells.
Genetics
Distal RTA type I results from mutations in the a4 subunit of the V0 transmembrane pore complex of ATPase (from gene ATP6V0A4), B1 subunit of the V1 cytoplasmic ATPase complex (from gene ATP6V1B1), anion exchanger 1 (from gene SLC4A1), and forkhead transcription factor (from gene FOXI1).[9] Loss-of-function mutations in either of the two subunits of vacuolar H+-ATPase (V-ATPase) in intercalated cells will cause recessive dRTA with deafness.[8]
In addition, another gene, SLC4A1, may also be involved,[10] with Alonso-Varela et al reporting that dRTA presented later in patients with SLC4A1 mutations than in cases associated with ATP6V0A4 or ATP6V1B1 mutations. Serum potassium levels tended to be normal or less depressed in patients with SLC4A1 defects. In addition, most patients with ATP6V1B1 mutations had hearing loss at diagnosis, compared with 17% and 0% of the patients with ATP6V0A4 or SLC4A1 defects, respectively.[11] In recessive cases of primary dRTA, mutations in ATP6V0A4 occurred as frequently as mutations in ATP6V1B1.[10]
The carbonic acid and bicarbonate buffering system is essential for acid-base homeostasis in the body. Hyperchloremic acidosis can occur if either a high chloride load or a loss of bicarbonate overwhelms the mechanisms of acid-base homeostasis, or when renal acid-base regulation is compromised.[12] On average, net acid production in adults is 1 mmol/kg/day, and in children or infants, 1-3 mmol/kg/day. In order to maintain acid-base homeostasis, the renal tubules need to reabsorb about 4.5 mol/day of HCO3- from glomerular filtrate and synthesize enough HCO3- to neutralize endogenously generated acids.
Bicarbonate in glomerular filtrate is mainly reabsorbed in the proximal convoluted tubule (PCT), primarily (90%) through the Na+/H+ exchanger (from gene SLC9A3). In the PCT, mutations of SLC4A4, NBCe1, CLCN5, SLC2A2, or EHHADH cause PCT dysfunction, with bicarbonate wasting and decreased ammonia production, resulting in pRTA.[9]
Carbonic anhydrase II (from gene CA2) catalyzes the dissociation of cytosolic H2CO3 into H+ and HCO3−; the HCO3− exits the cell via the Na+/HCO3- cotransporter (from gene SLC4A4) on the basolateral plasma membrane, and luminally situated CA4 catalyzes the dissociation of H2CO3 into CO2 and H2O to prevent accumulation of H+. HCO3− reabsorption is mainly regulated by peritubular pCO2, luminal and peritubular concentrations of angiotensin II, luminal flow rate, luminal HCO3− concentration, and luminal pH. Loss of CA2 or CA4 activities or mutations of SLC4A4 will lead to impaired HCO3− reabsorption pRTA. In the thick ascending limb of the loop of Henle, HCO3− is reabsorbed via the Na+/H+ exchanger; in the collecting duct, via H+-ATPase and H+/K+-ATPase. Therefore, little HCO3− is excreted in the urine, and urine pH is usually below 6.0 in persons in normal health.
HCO3− is also formed de novo in both the PCT and collecting duct by catabolization of glutamine via glutaminase to produce NH3 and HCO3−. HCO3− exits the cell via the Na+/HCO3– cotransporter, and NH3 diffuses into the lumen and is also secreted as NH4+ via the Na+/H+ exchanger, perhaps regulated by angiotensin II. In the medullary thick ascending limb of the loop of Henle, NH4+ is reabsorbed via the Na+/K+/Cl– symporter (from gene SLC12A2), increasing the medullary concentration of NH4+ and NH3 such that a concentration gradient is present to drive entry of NH3 into the collecting duct.
NH3 is predominantly transported on an NH4+ transporter (from gene RHCG) in the collecting duct. Luminal H+ ions combine with HPO42 to form H2PO4−. The amount of HCO3− returned to the circulation by this mechanism is limited by the urine pH (lowest pH achievable is 4.5-5.0) and the amount of urinary phosphate. The amount of phosphate excreted in the urine is dependent on the phosphate load in glomerular filtrate and the fractional reabsorption of phosphate by the renal tubules. Therefore, this process does not have a lot of influence in altering HCO3− generation.
The rate of acid excretion is affected by the quantity of Na+ reaching the collecting duct and by aldosterone activity. It is also regulated by angiotensin II, urine pH, pCO2, extracellular Ca2+ concentration, and calcium-sensing receptors. Dysfunction of H+-ATPases (from gene s ATP6V1 and ATPV0A4), SLC4A1, and FOXI1, and decreased aldosterone levels or resistance to aldosterone's action, can reduce net acid excretion, causing RTA. However, a reduction in net acid excretion is more commonly caused by decreased NH3 production in chronic renal insufficiency.
A study by Toyonaga and Kikura of 206 patients indicated that hyperchloremic acidosis is a precursor to the development of acute kidney injury (AKI) following abdominal surgery. The study found that a postoperative base excess–chloride level of less than -7 mEq/L was an independent risk factor for AKI and suggested that the AKI risk can be reduced by decreasing the intraoperative chloride ion load in fluids.[13]
Inform patients about the dietary issues related to hyperchloremic acidoses.
Metabolic acidosis, per se, has no specific symptoms and signs, unless it is extremely severe or of acute onset; however, it can produce symptoms and signs from changes in pulmonary, cardiovascular, neurologic, and musculoskeletal function.
If the acidosis is marked and/or of acute onset, the patient may report headache, lack of energy, nausea, and vomiting.
Neurologic abnormalities such as mental confusion progressing to stupor, when observed, are not usually secondary to the acidosis but are the cause of the acidosis itself.
In general, neurologic abnormalities are less common in persons with metabolic acidosis than in persons with respiratory acidosis.
An increase in minute ventilation of up to four- to- eight-fold may occur in persons with respiratory compensation.
Persistent tachypnea or hyperpnea (affecting the depth more than the rate of ventilation) may be the only clinical clue to an underlying acidotic state. This type of tachypnea/hyperpnea characteristically persists in sleep or interferes with sleep.
Effects on the cardiovascular system include direct impairment of myocardial contraction (especially at pH < 7.2), tachycardia, and increased risk of ventricular fibrillation or heart failure with pulmonary edema. Patients may report dyspnea upon exertion or, in severe cases, at rest.
In advanced stages, overt cardiovascular collapse may occur from impaired catecholamine release.
Chronic acidemia, as is observed in RTA, can lead to a variety of skeletal problems. This is probably due in part to the release of calcium and phosphate during bone buffering of the excess protons. Decreased tubular absorption of calcium secondary to acidemia, especially in dRTA, leads to a negative calcium balance.
Clinical consequences include osteomalacia (leading to impaired growth in children), osteitis fibrosa (from secondary hyperparathyroidism), rickets (in children), and osteomalacia or osteopenia (in adults).
Important complications of chronic RTA (mainly distal, type I) are nephrocalcinosis and urolithiasis. A number of pathophysiologic alterations contribute to stone formation:
A study by Guimerà et al found that of 54 patients with calcium phosphate stones and a urinary pH of over 6.0, dRTA was present in 19 (35.2%). The report indicated that the occurrence of dRTA in these patients was associated with young age, bilateral stones, stone recurrence, hypercalciuria, hypocitraturia, and plasma hypokalemia.[14]
In contrast, stone disease is rare with type II RTA because of the difference in its pathogenesis. Since the fall in plasma HCO3- is nonprogressing, after the renal HCO3- threshold is reached (transport maximum not exceeded) there is complete absorption of luminal HCO3-. At this point, the urine pH is acid, since urine is devoid of HCO3- and there is no defect in distal proton secretion. The daily acid load is thus excreted by the collecting duct, obviating the need for bone buffering. Also, citrate usually escapes proximal reabsorption (along with other solutes) and promotes calcium phosphate solubility.
An increase in minute ventilation of up to four- to- eight-fold may occur in persons with respiratory compensation.
Tachypnea or hyperpnea (affecting the depth more than the rate of ventilation) may be the only clinical clue to an underlying acidotic state.
Chronic acidemia, as is observed in RTA, can lead to a variety of musculoskeletal problems. Muscle protein catabolism is increased and muscle protein synthesis is inhibited. Skeletal problems are probably due in part to phosphate homeostasis and the release of calcium and phosphate during bone buffering of the excess protons. Decreased tubular absorption of calcium secondary to acidemia, especially in dRTA, leads to a negative calcium balance.
Clinical consequences include osteomalacia (leading to impaired growth in children), osteitis fibrosa (from secondary hyperparathyroidism), rickets (in children), and osteomalacia or osteopenia (in adults).
Metabolic acidosis due to loss of intestinal secretions, medications, or exogenous acid intake is usually apparent from the history. An exception is diarrhea due to laxative abuse, for which the history is difficult to obtain. When this condition is suggested because of hypokalemia and a normal AG metabolic acidosis, it may be confirmed by findings of low sodium concentration in the urine from volume contraction, positive test results for stool phenolphthalein, or high fecal magnesium levels.
Loss of intestinal secretions as the cause of acidosis may be confirmed by measuring the pH and the estimated non-chloride anion concentration ([Na+] + [K+] - [Cl–]) of the volume lost; an alkaline pH and elevated estimated non-chloride anion concentration suggest bicarbonate loss.
If the cause of acidosis is not apparent from the history and physical examination findings, the next step is to determine whether hyperchloremic acidosis is present. Urinary ammonium excretion and urine pH can be used to define the etiology of the disorder.
Urinary ammonium excretion (urinary AG; urinary net charge) is inferred from the urinary AG, also known as the urinary net charge, when direct measurement of ammonium is not possible.
The urinary net charge is defined as follows: UNA+ + UK+ - UCl-. In this equation, UNA+ is the urinary concentration of sodium, UK+ is the urinary concentration of potassium, and UCl- is the urinary concentration of chloride. The urinary net charge and ammonium excretion have a linear relationship. When excretion of Cl– exceeds that of Na+ and K+, the urinary net charge is negative, and the assumption is that a substantial concentration of ammonium is present in the urine, which would be the case in metabolic acidosis of nonrenal origin.
Conversely, in hypokalemic and hyperkalemic dRTA, the urinary concentration of ammonium is insufficient, excretion of Na+ and K+ exceed that of Cl–, and the urinary net charge is positive.
This method of analysis has potential pitfalls. A negative urinary AG is also observed in patients whose acidosis is due to nonrenal causes but in whom maximal acidification fails because of decreased presentation of sodium to the distal nephron. In these cases, the urinary sodium concentration is very low. Urinary excretion of ketoanions secondary to systemic ketoacidosis can cause a positive AG despite adequate ammonium excretion. Thus, ketonuria should also be excluded in cases of metabolic acidosis in which the etiology is uncertain enough to warrant calculation of the urinary AG.
The urinary net charge is also less useful when large amounts of bicarbonate are present in the urine (pH >6).
Urinary pH tends to be increased in the presence of large amounts of ammonia in the urine.
An inability to lower the urinary pH to less than 5.5 despite systemic acidemia was formerly considered the hallmark of dRTA. Given that a lower pH implies increased excretion of acid if the concentration of urinary buffers stays constant, an inability to decrease urinary pH was interpreted as signifying decreased excretion of urinary acid. Although this is true in many cases, it is not in all cases.
The presence of large amounts of ammonia in the urine, which typically occurs with chronic metabolic acidosis, tends to increase the urinary pH. In hyperkalemic dRTA, urine pH can be maximally acidic. Decreased acid excretion is due to other concurrent defects, mainly decreased production of ammonia.
In patients with normal AG acidosis due to diarrhea, the pH can be greater than 5.5. This is because volume contraction results in decreased availability of Na+ for reabsorption in the collecting duct, lessening the negative intratubular electrochemical potential and, thus, the rate of proton secretion.
Infection with urea-splitting organisms (eg, Proteus species) can also cause elevated urinary pH and may lead to an incorrect diagnosis of RTA.
The urinary AG is calculated using the following formula: UAG = UNA+ + UK+ - UCl-.
Na+ + K+ + unmeasured cations = Cl- + unmeasured anions. In the absence of ketonuria and bicarbonaturia, there are no significant unmeasured anions in the urine. The principal unmeasured cation is NH4+ and when present in substantial concentration is evident by a negative AG. UAG is thus a measure of the urinary concentration of NH4+.
Urinary pH and UAG values in patients with RTA are as follows:
The most common acid-loading test uses ammonium chloride (NH4Cl). This test consists of the oral administration of 0.1 g/kg (1.9 mEq/kg) of ammonium chloride to induce metabolic acidosis. Urine is collected hourly 2-8 hours after administration, and urinary pH is tested. Failure to acidify urine below a pH of 5.5 supports the diagnosis of dRTA or incomplete dRTA (with systemic acidosis being absent in incomplete dRTA).
Urinary pH would decrease normally in pRTA and hypoaldosteronism. In the setting of a preexisting acidosis, administration of an acidifying agent is unnecessary and potentially harmful.
Calcium chloride and arginine hydrochloride can also be used to induce systemic acidosis, with interpretation of results the same as for the ammonium chloride test.
The urinary pCO2 during alkaline diuresis reflects the rate of proton secretion in the distal tubule. In an alkaline diuresis induced by infusions of NaHCO3, the intratubular pH is high, and this results in a high rate of proton secretion. Because of the high concentration of bicarbonate in the urine, large quantities of carbonic acid (H2CO3) form. The carbonic acid dehydrates and forms water and carbon dioxide, thus raising the urinary pCO2.
In healthy individuals undergoing a bicarbonate diuresis, the urinary pCO2 should rise to above 70 mm Hg. In patients with secretory defects (ie, the inability to secrete protons in the collecting duct), the urine pCO2 fails to rise above 55 mm Hg. In patients with permeability defects, the CO2 tension rises normally because of the normal proton-pump function and because the H+ gradient does not favor the back-diffusion of protons under conditions of alkaline diuresis. Normal results are also observed in hypoaldosteronism RTA and reversible voltage-dependent defects.
The urinary pCO2 test is performed by infusing a quantity of NaHCO3 sufficient to raise plasma bicarbonate to greater than 30 mEq/L and urine pH to higher than 7. This can be accomplished with intravenous or oral NaHCO3. With the intravenous route, 7.5% NaHCO3 is infused at a rate of 1-2 mL/min for 2 hours, with hourly samples taken for the duration of the test. The infusion is stopped when the pH from at least 3 urine collections is greater than 7.8. With the oral route, 200 mEq of NaHCO3 is given in divided doses the evening prior to testing, and overnight dehydration is necessary.
An important disadvantage of this test is that false-positive results can occur in persons with concentration defects, because urine bicarbonate concentrations are lower and lead to less carbon dioxide generated. This is significant because concentration defects are common in persons with dRTA and are a consistent finding in persons with chronic renal failure.
Contraindications to the test are other sodium-retaining states and congestive heart failure.
In healthy individuals, administering a sodium salt of a non-reabsorbable anion in the presence of a sodium-avid state results in negative intratubular potential and thus in increased proton and potassium secretion. In patients with either secretory or voltage defects, the urine will not become maximally acidic.
The sodium sulfate test is performed by restricting salt to less than 1 g/d Na+ for 3 days and orally administering 1 mg of fludrocortisone in the evening, 12 hours before the sodium sulfate infusion, in order to ensure a sodium-avid state. The following morning, 500 mL of 4% sodium sulfate is administered intravenously over 1 hour. Urine pH, potassium excretion, and net acid excretion should be obtained.
A normal response does not necessarily rule out an acidification defect, because a normal response can be observed in patients with hyperkalemic dRTA and in those with reversible voltage-dependent defects, as with lithium.
False-positive results can occur when the infusion is too rapid or when sodium avidity is absent because inadequate preparation or aldosterone resistance causes a bicarbonate-losing osmotic diuresis, thus raising the urine pH.
Because sodium sulfate is not commercially available, this method is largely limited to research settings. A more practical method involves orally administering 1 mg fludrocortisone the evening before testing and then giving 1 mg/kg of oral or intravenous furosemide the following morning. Evidence suggests that furosemide enhances distal acidification by increasing distal sodium delivery, and results should be interpreted in the same manner as for the sodium sulfate test.
Treatment of GI causes of hyperchloremic acidosis is aimed at the underlying cause and includes (1) administration of saline solutions to repair the volume losses and (2) early administration of potassium.
Treatment of acidosis with bicarbonate-containing solutions is accompanied by potassium replacement to avoid severe hypokalemia, with its possible associated cardiac arrhythmias and muscular paralysis due to the rapid introduction of potassium into the cells.
Patients with chronic acidosis secondary to diarrhea benefit from long-term therapy with sodium and potassium citrate solutions.
Once the underlying disease entity behind hyperchloremic acidosis has been identified, specific therapy is needed to control the primary problem. However, therapy for the hyperchloremic acidosis itself is still needed. Depending on the type of RTA, the goals of therapy are to decrease the rate of progressive renal insufficiency by preventing nephrocalcinosis and nephrolithiasis, to neutralize metabolic bone disease, and, in children, to improve growth.
Go to the Medscape Drugs & Diseases articles Metabolic Acidosis, Pediatric Metabolic Acidosis, and Metabolic Acidosis in Emergency Medicine for complete information on these topics.
In cases of pRTA, multitherapy with large quantities of alkali, vitamin D, and potassium supplementation is required. (Depending on the degree of renal dysfunction, renal activation of vitamin D to the active calcitriol metabolite may be impaired, and administration of calcitriol may be preferred over other vitamin D preparations.)
The usual range of bicarbonate administration is 5-15 mEq/kg/d, and the administration must be accompanied or preceded by the administration of large amounts of potassium.
Proximal RTA can be difficult to treat, because alkali administration results in prompt and marked bicarbonaturia and potassium wasting.
The use of diuretics to induce extracellular volume depletion that enhances proximal tubular bicarbonate reabsorption can be effective but is usually accompanied by worsening of the hypokalemia. Thus, diuretics must be used with caution, and they require additional potassium or the addition of potassium-sparing agents.
In hypokalemic dRTA, treatment consists of long-term alkali administration in amounts sufficient to counterbalance endogenous acid production and any bicarbonaturia that may be present.
Fortunately, the alkali requirements of these patients are minimal compared with the requirements needed to treat patients with pRTA. A daily dose of 1-2 mEq/kg of NaHCO3 is usually sufficient in most cases and can be provided in the form of citrate solutions (eg, Shohl solution), which is well tolerated because it causes less abdominal distention and aerophagia than does sodium bicarbonate (tablet or solution).
Providing bicarbonate via citrate salts that are metabolized to bicarbonate in the liver provides the additional advantage of exogenous citrate from the portion escaping hepatic metabolism.
Potassium supplements are indicated in the presence of hypokalemia. Hypokalemia can be severe, and patients can be symptomatic. Spironolactone can be used to maintain normokalemia.
Corrective alkali therapy results in normal growth in children with dRTA if therapy is started early.
Hypercalciuria, nephrolithiasis, and nephrocalcinosis are also prevented when alkali therapy is started in the early stages of dRTA.
With hyperkalemic dRTA, entities amenable to intervention, such as obstructive uropathy, must be identified.
In general, distal sodium delivery is increased if patients increase their ingestion of dietary salt, taking into account that many of these patients have concomitant cardiorenal compromise.
Fluid overload can be overcome with the addition of furosemide to a high-salt diet. This combination encourages distal delivery of sodium by rendering the collecting tubule impermeable to chloride, and it increases the exchange of sodium for hydrogen and potassium.
Mineralocorticoid therapy (ie, fludrocortisone in daily doses of 0.1-0.2 mg) is sometimes useful for aldosterone deficiency, but care needs to be taken when combining mineralocorticoid therapy with diuretics (in order to prevent precipitation of heart failure).
Foods with a high potassium content and drugs that may aggravate hyperkalemia (eg, angiotensin-converting enzyme [ACE] inhibitors, potassium-sparing diuretics, beta blockers) must be avoided.
Cation-exchange resins (eg, sodium polystyrene sulfonate [Kayexalate], alkalinizing salts) can be helpful in controlling hyperkalemia.
In many instances, careful evaluation of iatrogenic offenders (eg, beta blockers, ACE inhibitors) can explain persistently high potassium levels in the absence of moderate to severe renal failure.
A variety of drugs can aggravate or cause hyperchloremic acidosis. Drugs that increase GI bicarbonate loss include calcium chloride, magnesium sulfate, and cholestyramine.
Drugs or toxins that can induce pRTA include streptozotocin, lead, mercury, arginine, valproic acid, gentamicin, ifosfamide, and outdated tetracycline.
Drugs or toxins that can cause dRTA include amphotericin B, toluene, nonsteroidal anti-inflammatory drugs (NSAIDs), lithium[15] , and cyclamate.
The French Intensive Care Society and the French Society of Emergency Medicine have published guidelines for the diagnosis and management of metabolic acidosis. Recommendations that are relevant to hyperchloremic acidosis include the following[16] :
The goals of pharmacotherapy are to correct the acidosis, to reduce morbidity, and to prevent complications. Alkalinizing agents, electrolytes, diuretics, mineralocorticoids, and vitamin D supplements can be used against acidosis.
Clinical Context: Sodium bicarbonate is indicated for the treatment of metabolic acidosis. It increases renal clearance of acidic drugs.
Clinical Context: Sodium citrate treats metabolic acidosis and is used as an alkalinizing agent when long-term maintenance of alkaline urine is desirable.
These are used as gastric, systemic, and urinary alkalinizers and have been employed in the treatment of acidosis resulting from metabolic and respiratory causes, including diarrhea, kidney disturbances, shock, and diabetic coma.
Clinical Context: Potassium chloride is essential for the transmission of nerve impulses, the contraction of cardiac muscle, the maintenance of intracellular tonicity, skeletal and smooth muscle function, and the maintenance of normal renal function.
Gradual potassium depletion occurs via renal excretion, through GI loss, or because of low intake. Depletion usually results from diuretic therapy, primary or secondary hyperaldosteronism, diabetic ketoacidosis, severe diarrhea (if associated with vomiting), or inadequate replacement during prolonged parenteral nutrition.
Potassium depletion sufficient to cause a 1-mEq/L decrease in serum potassium requires the loss of approximately 100-200 mEq of potassium from total body stores.
Electrolytes are used to correct disturbances in fluid and electrolyte homoeostasis or acid-base balance and to reestablish the osmotic equilibrium of specific ions.
Clinical Context: This agent increases water excretion by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule. The dose must be individualized to the patient.
Clinical Context: Bumetanide increases the excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium, potassium, and chloride reabsorption in the ascending loop of Henle. These effects increase urinary excretion of sodium, chloride, and water, resulting in profound diuresis. Renal vasodilation occurs following administration, renal vascular resistance decreases, and renal blood flow is enhanced. Bumetanide is roughly four times as potent as furosemide on a milligram basis. Depending on the response, administer bumetanide at small dose increments (0.5-5 mg) until the desired diuresis occurs.
Clinical Context: Torsemide acts from within the lumen of the thick ascending portion of the loop of Henle, where it inhibits the sodium, potassium, and chloride carrier system. It increases urinary excretion of sodium, chloride, and water but does not significantly alter the glomerular filtration rate, renal plasma flow, or acid-base balance. Torsemide is roughly twice as potent as furosemide on a milligram basis. Depending on the response, administer furosemide at small dose increments (10-100 mg) until the desired diuresis occurs.
Diuretics are used to overcome fluid overload. They increase the distal delivery of sodium by rendering the collecting tubule impermeable to chloride and increase the exchange of sodium for hydrogen and potassium.
Clinical Context: Fludrocortisone promotes increased sodium reabsorption and potassium loss in renal distal tubules.
Mineralocorticoids may be useful for aldosterone deficiency. Combine mineralocorticoid therapy with sodium loading and diuretics to prevent heart failure.
Clinical Context: This is the active form of vitamin D. It is used in pRTA as multitherapy, with large quantities of alkali and potassium supplementation.
Vitamin D is a fat-soluble vitamin that promotes the absorption of calcium and phosphorus in the small intestine. It also promotes renal tubule phosphate resorption.