Practice Essentials
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] :
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Bicarbonate loss from body fluids through the GI tract (eg, via severe diarrhea, pancreatic fistula, chronic laxative abuse) or kidneys (eg, through prolonged use of a carbonic anhydrase inhibitor [acetazolamide]), with subsequent chloride retention
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Defective renal acidification, with failure to excrete normal quantities of metabolically produced acid (whereby the conjugate base is excreted as the sodium salt and sodium chloride is retained)
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Addition of hydrochloric acid to body fluids
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Addition or generation of another acid, with rapid titration of bicarbonate and rapid renal excretion of the accompanying anion and replacement by chloride
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Rapid dilution of the plasma bicarbonate by intravenous (IV) saline (sodium chloride) (eg, in the setting of intravascular volume resuscitation with 3-4 L of normal saline)
Go to the Medscape Drugs & Diseases articles Metabolic Acidosis, Pediatric Metabolic Acidosis, and Metabolic Acidosis in Emergency Medicine for complete information on these topics.
Associated disorders in hyperchloremic acidosis
Conditions associated with hyperchloremic acidosis include the following:
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Underlying gastrointestinal (GI), renal, or autoimmune conditions
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Hereditary disorders
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Effects of agents used in treatment (eg, cardiac complications)
Signs and symptoms of hyperchloremic acidosis
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.
Workup in hyperchloremic acidosis
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:
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Urinary ammonium excretion (urinary AG; urinary net charge) - This is inferred from the urinary AG, also known as the urinary net charge, when direct measurement of ammonium is not possible
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Urinary pH - This tends to be increased in the presence of large amounts of ammonia in the urine
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Acid-loading tests - The most common acid-loading test uses ammonium chloride (NH4Cl)
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Urinary partial pressure of CO2 (pCO2) test - The urinary pCO2 during alkaline diuresis reflects the rate of proton secretion in the distal tubule
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Sodium sulfate test - 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
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Furosemide test - Evidence suggests that furosemide enhances distal acidification by increasing distal sodium delivery; results should be interpreted in the same manner as for the sodium sulfate test
Management of hyperchloremic acidosis
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.
Etiology
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).
Proximal renal tubular acidosis (type II [bicarbonate-wasting acidosis]; pRTA)
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]
Distal renal tubular acidosis (dRTA)
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]
Pathophysiology
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.
Prognosis
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]
Patient Education
Inform patients about the dietary issues related to hyperchloremic acidoses.