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Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance

Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance
Literature review current through: Jan 2024.
This topic last updated: Sep 28, 2023.

INTRODUCTION — The lungs and the kidneys are responsible for the maintenance of acid-base balance within the body. Alveolar ventilation removes carbon dioxide, while the kidneys reclaim filtered bicarbonate and excrete hydrogen ions produced by the metabolism of dietary protein (or bicarbonate when the diet generates more base than acid).

The term "renal tubular acidosis" (RTA) refers to a group of disorders in which, despite a relatively well-preserved glomerular filtration rate, metabolic acidosis develops because of defects in the ability of the renal tubules to perform the normal functions required to maintain acid-base balance [1]. All forms of RTA are characterized by a normal anion gap (hyperchloremic) metabolic acidosis. This form of metabolic acidosis usually results from either the net retention of hydrogen chloride or a salt that is metabolized to hydrogen chloride (such as ammonium chloride) or the net loss of sodium bicarbonate or its equivalent [2]. The most common cause of a normal anion gap acidosis in patients without a significant impairment in kidney function is diarrhea. (See "Approach to the adult with metabolic acidosis".)

This topic will review the classification and pathophysiology of the different forms of RTA and the impact these disorders have on potassium balance. The major causes, diagnosis, and treatment of RTA are discussed separately:

(See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis".)

(See "Treatment of distal (type 1) and proximal (type 2) renal tubular acidosis".)

(See "Causes and evaluation of hyperkalemia in adults".)

(See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)".)

ROLE OF THE KIDNEY IN ACID-BASE AND POTASSIUM BALANCE — Prior to discussing renal tubular acidosis (RTA), it is helpful to briefly review the kidneys' role in the maintenance of acid-base and potassium balance and how disturbances in tubular function can result in metabolic acidosis and an abnormal serum potassium.

To maintain acid-base balance in individuals ingesting a typical (acid generating) Western diet, the kidneys reclaim the filtered bicarbonate and excrete the daily acid load, which is primarily derived from the metabolism of sulfur-containing amino acids.

Reclaiming filtered bicarbonate — The bicarbonate that is filtered by the glomeruli returns to the circulation, predominately as a result of sodium-hydrogen exchange by the proximal tubules (figure 1). Approximately 80 to 85 percent of the filtered load is reclaimed at this site. The remaining 15 to 20 percent is reclaimed in the thick ascending limb of Henle and the collecting tubules via sodium-hydrogen exchange and hydrogen secretion by proton pumps (H-ATPase and H-K ATPase). Under normal conditions, when a typical Western diet is ingested, there is virtually no bicarbonate in the final urine.

Acid excretion — The excretion of the daily hydrogen ion load is primarily a function of the connecting and collecting tubules. The average daily acid load generated by a typical Western diet is approximately 1 mEq/kg of body weight. Excretion of this acid load in the urine requires urinary buffers to bind hydrogen ions. If hydrogen ions were free and not buffered in the urine, the daily excretion of 50 to 70 mEq of acid in 1 liter of urine would require a urine pH of less than 2.5, which represents a pH gradient between the cell interior and the tubular lumen of 100,000 to 1. Such a gradient cannot be achieved by the tubular cell. The minimum urine pH in humans is 4.5 to 5.

The principal conjugate buffering pairs in the urine are ammonia-ammonium (NH3 and NH4+) and phosphate (HPO4-2 and H2PO4-1); phosphate is the major component of "titratable acid." Ammonium excretion requires the renal synthesis of ammonia, which diffuses and is secreted into the lumen, and the secretion of hydrogen ions into the tubular lumen, where they are "trapped" as ammonium (NH3 + H+ → NH4+). Uncharged ammonia can diffuse freely across membranes, while the positively charged ammonium ion is relatively impermeant [3].

The renal tubular production of ammonia is stimulated by intracellular acidosis. When the systemic acid load is modestly increased, near-normal balance is maintained by increases in ammonium production and excretion (figure 2). Failure to excrete sufficient ammonium often leads to the net retention of hydrogen ions and the development of metabolic acidosis.

POTASSIUM METABOLISM BY THE KIDNEY — Almost all of the filtered potassium is reabsorbed passively in the proximal tubule and loop of Henle. Most potassium excreted in the urine is derived from potassium secretion into the tubular lumen by cells in the distal nephron, particularly the connecting tubule and the principal cells in the cortical collecting tubule [4].

Distal potassium secretion is primarily influenced by two factors, both of which promote sodium reabsorption: aldosterone and the distal delivery of sodium and water (figure 3) [5-7].

Aldosterone acts, in part, by increasing the number of open sodium channels in the luminal membrane of the distal tubule. Because the luminal sodium concentration is usually much higher than the intracellular sodium concentration, an increased density of open sodium channels results in increased sodium reabsorption from the tubular lumen into the tubular cell; absorbed sodium is then transported out of the cell into the peritubular capillaries in exchange for potassium by sodium-potassium ATPase located on the cell's basolateral membrane.

Distal tubule reabsorption of sodium is more rapid than chloride reabsorption, which results in a relatively electronegative lumen. This relative negative charge provides a favorable gradient for secretion of positively charged ions (potassium and hydrogen ions) from the tubular cell into the lumen through potassium channels in the luminal membrane.

Although these mechanisms are of major importance in potassium balance, a number of other molecular regulatory mechanisms that contribute to potassium homeostasis have been subsequently described [8].

Alterations in potassium excretion are common in patients with renal tubular acidosis (RTA) and, depending upon the site of the defect and the mechanism responsible for the various forms of RTA, can result in hypokalemia or hyperkalemia. As will be discussed, hyperkalemia can also contribute to the development of metabolic acidosis.

All forms of RTA produce hyperchloremic (normal anion gap) metabolic acidosis. Some forms of RTA cause potassium wasting and hypokalemia; other forms are associated with positive potassium balance and hyperkalemia. The treatment of RTA also has variable effects on potassium balance and serum potassium.

CLASSIFICATION OF RTA — There are four major forms of renal tubular acidosis (RTA). Two are hypokalemic, and two are hyperkalemic. The two hypokalemic RTAs are classic distal (type 1) and proximal (type 2). The hyperkalemic RTAs are hypoaldosteronism (type 4) and voltage-dependent RTA, which some consider a subtype of distal RTA. These major forms of RTA differ in their pathophysiology and clinical manifestations (table 1):

Distal (type 1) RTA is caused by defects in distal hydrogen ion excretion (table 2). (See 'Distal (type 1) RTA' below.)

Proximal (type 2) RTA is caused by defects that reduce the capacity to reclaim filtered bicarbonate in the proximal tubule (table 3). (See 'Proximal (type 2) RTA' below.)

Hypoaldosteronism (type 4 RTA) is caused by reductions in aldosterone secretion or responsiveness (table 4). (See 'Hypoaldosteronism' below.)

Voltage-dependent RTA is caused by defects in distal sodium reabsorption, which affect the negative electric potential difference normally generated in the distal tubule. (See 'Voltage-dependent RTA' below.)

DISTAL (TYPE 1) RTA — Distal (type 1) renal tubular acidosis (RTA) is characterized by impaired hydrogen ion secretion in the distal nephron, which reduces the kidney's ability to excrete the daily acid load (50 to 100 mEq on a typical Western diet). This results in progressive hydrogen ion retention and a normal anion gap (or hyperchloremic) metabolic acidosis. If untreated, the plasma bicarbonate concentration can fall below 10 mEq/L. Patients with distal RTA almost always have hypocitraturia and frequently develop kidney calcifications and calcium-containing (frequently calcium phosphate) kidney stones. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis" and "Kidney stones in adults: Epidemiology and risk factors", section on 'Low urine citrate'.)

Distal RTA is commonly associated with hypokalemia due to renal potassium wasting [9,10]. Occasionally, the hypokalemia is so severe (ie, serum potassium below 2 mEq/L) that it results in muscle paralysis or respiratory arrest [11].

The secretion of hydrogen ions into the lumen of the distal tubule is mainly accomplished by type A (alpha) intercalated cells in the connecting and collecting tubules via a luminal H-ATPase pump and, to a lesser degree, via an H-K-ATPase pump that secretes hydrogen ions and reabsorbs potassium (figure 4). By contrast, the site of distal tubule potassium secretion is primarily the principal cells in the connecting and collecting tubules (figure 3) [12,13].

The general underlying pathophysiology of distal RTA is either:

Decreased net activity of the proton pumps – the most common mechanism (see 'Decreased net activity of proton pumps and HCO3 exchangers' below)

Increased hydrogen ion permeability of the luminal membrane – which is much less common (see 'Increased luminal membrane permeability' below)

Decreased net activity of proton pumps and HCO3 exchangers — Diminished H-ATPase activity (figure 4) can be due to a variety of mutations in genes encoding different subunits of this pump; most follow an autosomal recessive inheritance pattern [14]. In addition, both autosomal dominant and recessive mutations of the SLC4A1/anion exchanger 1, which exchanges serum bicarbonate (HCO3) for chloride on the basolateral side of the alpha intercalated cells, have been described [14]. These defects impair the ability to maximally acidify the urine, and in most patients with distal RTA, the urine pH cannot be reduced below 5.5 despite systemic acidemia (individuals without this disorder can reduce the urine pH to 5 or lower).

However, occasional patients with genetic forms of distal RTA can reduce their urine pH slightly below 5.5. As an example, 2 of 17 patients with distal RTA due to decreased expression of the proton pump were able to reduce their urine pH to 5.24 and 5.38 [15]. In such patients, distal RTA should still be suspected if other causes of a hyperchloremic or normal anion gap metabolic acidosis have been excluded (table 5). Specialized diagnostic techniques, such as measurement of the urine-to-blood partial pressure of carbon dioxide gradient, can establish a diagnosis of distal RTA in such patients [15,16]. Genetic testing for these mutations is also available. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Urine pH'.)

When distal RTA is suspected and other, more common causes of normal anion gap metabolic acidosis are not present, the simplest diagnostic approach is to measure the urine pH several times to see whether values below 5.5 can be documented. If the urine pH is persistently 5.5 or higher, despite systemic acidemia, a renal acidification defect may exist (although other causes of an inappropriately high urine pH, such as urinary tract infection, should be considered). If the urine pH is between 5.2 and 5.5, a subtle acidification defect may still be present.

It is important to note that the urine pH must be measured with a pH electrode; pH measurements using color indicators or dipsticks are not adequate.

A number of different genetic and acquired defects can directly or indirectly decrease the net activity of the distal tubule proton pump [17]:

Sjögren's disease – Immunocytochemical analyses of kidney biopsies obtained from some patients with Sjögren's disease have shown complete absence of H-ATPase pumps in the intercalated cells (figure 4) [18,19]. How immunologic injury leads to this change is not known.

High titers of an autoantibody directed against carbonic anhydrase II have also been identified in some patients with Sjögren's disease [20]. Inhibition of carbonic anhydrase II probably impairs intracellular generation of hydrogen ions, which would diminish the capacity for hydrogen ion secretion by the proton pump (figure 4). (See "Kidney disease in primary Sjögren's disease".)

kAE1 (SLC4A1/anion exchanger 1) mutations – The kidney chloride-bicarbonate exchanger (kAE1), located on the basolateral cell membrane in the distal tubule, is necessary to efficiently transport intracellular bicarbonate, generated by the luminal secretion of hydrogen ions, into the peritubular blood in exchange for chloride (figure 4). Mutations in the gene (SLC4A1) that codes for this exchanger have been identified in some families with autosomal dominant (more common) and autosomal recessive (less common) forms of distal RTA [21-31].

The mutations of the chloride-bicarbonate exchanger gene can generate distal RTA through at least two distinct pathophysiologic mechanisms that impair hydrogen ion secretion:

A malfunction of kAE1, which prevents bicarbonate exit from the cell. The resulting rise in cell pH impedes hydrogen ion generation and secretion.

Aberrant trafficking of an otherwise normal basolateral kAE1 to the luminal, rather than basolateral, membrane. This results in bicarbonate secretion into the lumen, which neutralizes the hydrogen ions secreted into the lumen [31-34].

A different splice form of the chloride-bicarbonate exchanger (eAE1 or band 3 protein) is present in the red cell membrane, and some mutations of this exchanger cause hereditary spherocytosis and Southeast Asian ovalocytosis. Sometimes, mutations result in both the hematologic disorders and distal RTA [35-37]. (See "Hereditary spherocytosis" and "Southeast Asian ovalocytosis (SAO)", section on 'Specific SLC4A1 deletion'.)

H-ATPase mutations – Mutations in the genes that encode either the B1 or A4 subunits of the H-ATPase pump (ATP6V1B1 and ATP6V0A4) can impair the function of the proton pump [26]. Defects in either subunit may also be associated with sensorineural deafness, suggesting that the proton pump is required for normal function of the inner ear [14,38,39].

Untreated patients with a proton pump defect tend to waste potassium and become hypokalemic [10,40]. The potassium wasting is linked to the reduction in distal hydrogen ion secretion via several mechanisms:

Sodium that is reabsorbed in the collecting tubules must, in order to maintain electroneutrality, be reabsorbed with an anion, such as chloride or bicarbonate, or in exchange for a cation, such as potassium (figure 3) or hydrogen (figure 4). If hydrogen ion secretion is impaired, potassium secretion generally increases.

Defective intercalated cell H-ATPase generates some sodium wasting [40], and this stimulates the renin-angiotensin-aldosterone system.

Metabolic acidosis inhibits a component of proximal tubule sodium reabsorption [41]. Diminished proximal reabsorption delivers more sodium to the distal tubule sites where aldosterone acts; sodium reabsorption by the distal nephron is generally associated with potassium secretion.

Potassium wasting generated by these mechanisms can be largely reversed by adequate oral alkali therapy (eg, sodium bicarbonate or sodium citrate), which reduces potassium secretion by one or both of the following changes:

Increased sodium bicarbonate delivery to the distal nephron raises the tubule fluid pH and allows more hydrogen (instead of potassium) to be secreted before a limiting pH gradient is reached.

The administered sodium load expands the extracellular fluid volume. This reduces the drive for sodium reabsorption and also reduces aldosterone secretion. As a result, collecting tubule sodium reabsorption and potassium secretion both fall.

Thus, hypokalemia generally resolves with adequate treatment of the acidemia in patients with distal RTA.

The acid-secreting type A intercalated cells in the cortical and outer medullary collecting tubules have two different proton-secreting pumps in their luminal membranes: an H-ATPase pump that electrogenically secretes hydrogen ions and an electrically neutral H-K-ATPase pump that secretes hydrogen ions and reabsorbs potassium ions (figure 4) [42,43]. In most patients with hypokalemia and potassium depletion, the activity of the H-K-ATPase pump is appropriately increased. However, inhibition of, or a defect in, this exchange pump would reduce hydrogen ion secretion and increase net potassium excretion by decreasing potassium reabsorption [43,44].

Increased luminal membrane permeability — The ability to generate and maintain a highly acidic urine requires the luminal membrane of the distal nephron to be relatively impermeable to hydrogen ions and carbonic acid. As an example, when the urine pH is 5, the urine hydrogen ion concentration is 250 times the hydrogen ion concentration in the extracellular fluid (pH of 7.4). Increased luminal membrane permeability results in back-leak of secreted hydrogen ions from the urine into the extracellular fluid. This reduces urine acid excretion. Increased luminal membrane permeability to hydrogen ions may also be associated with increased apical cell membrane permeability for potassium and magnesium; these ions then leak from the cell cytoplasm into the urine, causing renal potassium and magnesium wasting.

Amphotericin B therapy is the most common cause of distal RTA generated by this mechanism. This drug's antifungal action is linked to the creation of pores in the fungal cell membrane. To a lesser degree, amphotericin B creates similar pores in the luminal membrane of distal nephron tubule cells. The resulting increase in membrane permeability allows secreted hydrogen ions to diffuse from the urine back into the tubule cells and then into the extracellular fluid. In addition, the pores allow potassium and magnesium to leak from the tubule cells into the urine. The clinical presentation is a normal anion gap metabolic acidosis that is usually accompanied by hypokalemia and, less frequently, hypomagnesemia [45-47]. (See "Amphotericin B nephrotoxicity", section on 'Electrolyte and acid-base disorders'.)

Treatment is similar to the other forms of RTA due to proton pump defects. Alkali therapy allows more hydrogen to be secreted before reaching the limiting pH gradient. Although this may decrease potassium losses, it would not be expected to reduce the component of potassium (and magnesium) wasting related to increased membrane permeability to these ions.

Incomplete distal RTA — Patients with incomplete distal renal tubular acidosis (RTA) cannot normally acidify their urine, resulting in a urine pH that is persistently 5.5 or higher, as in the complete forms of distal RTA. However, despite this abnormality, normal net acid excretion is maintained, and the plasma bicarbonate concentration remains in the normal range [5,48]. Maintenance of a normal rate of acid excretion is achieved by an increase in ammonium excretion, which offsets the reduction in titratable acid excretion related to the high urine pH. The increased ammonium excretion in this disorder is in contradistinction to the very low urine ammonium excretion in the other forms of distal RTA.

An important clinical feature of incomplete distal RTA (similar to classic type I RTA) is persistent hypocitraturia, which contributes to urinary and kidney calcification. (See "Kidney stones in adults: Epidemiology and risk factors", section on 'Low urine citrate'.)

The pathogenesis of incomplete distal RTA is not well understood, but in one large family with autosomal recessive distal RTA due to a V-ATPase B1 subunit truncation mutation, some heterozygous carriers manifested incomplete distal RTA [49]. In general, all patients with incomplete distal RTA have a low rate of citrate excretion and a relatively high rate of ammonium excretion, which correlate with a reduction in proximal tubule intracellular pH [50]. The proximal tubule cell generates ammonia and reabsorbs most of the filtered citrate [51].

The development of an abnormally low pH within proximal tubule cells could generate the following sequence [50]:

Proximal tubule ammonium and hydrogen ion secretion into the lumen is increased. This is similar to the normal proximal tubule response to metabolic acidosis, which is mediated, at least in part, by a low intracellular pH.

Normal plasma citrate concentration is in the 0.1 to 0.5 mm range, and it is >95 percent completely ionized (ie, in the trivalent [-3]) form. Plasma citrate is freely filtered and largely reabsorbed by the proximal tubule. Normally, between 10 to 30 percent of the filtered load is excreted in the urine. Trivalent citrate is poorly reabsorbed, while the divalent form of citrate (-2) is more efficiently reabsorbed via a sodium-citrate cotransporter. The concentration of citrate (-2) in the tubule lumen increases markedly when the tubule fluid pH falls. The pH of the proximal tubular lumen fluid falls with all forms of metabolic acidosis, including RTA. This increases intraluminal divalent citrate (-2), accelerates citrate reabsorption, and reduces citrate excretion [51]. The reduction in intracellular pH of the proximal tubule cells also accelerates citrate metabolism, reducing the intracellular citrate concentration, further enhancing citrate entry from the tubular lumen into the cell [51]. Low urine citrate concentration increases the risk of kidney calcification and calcium-containing kidney stones.

Much of the ammonium (NH4+) that is secreted in the proximal tubule is reabsorbed in the loop of Henle. The ammonia (NH3) is then recycled within the medulla and secreted into the medullary collecting tubule where it combines with hydrogen ions (H+) and drives the following reaction to the right, raising the urine pH:

 NH3 + H+  ↔  NH4+

Two pathogenic mechanisms have been proposed to explain the reduction in proximal tubule intracellular pH in incomplete distal RTA:

A subtle distal acidification defect reduces the plasma bicarbonate concentration into the low-normal range, resulting in intermittent, short-lived episodes of overt metabolic acidosis [52,53]. This causes intracellular acidosis within the proximal tubule cells that leads to increased ammonia synthesis and excretion as well as reduced urinary citrate excretion. Early in the course, the increase in ammonium excretion can almost entirely compensate for the distal acidification defect, resulting in maintenance of a near-normal or normal serum bicarbonate concentration.

A pathologic process generates intracellular acidosis in the proximal tubule cells [50]. This will initiate a sequence similar to that described above. Ammonia synthesis increases and urinary citrate excretion falls. If this hypothesis is correct, then incomplete RTA is not initially a distal form of RTA.

Over a period of time, some patients with incomplete distal RTA progress to the complete form of distal RTA. Both the toxic effect of high interstitial ammonia concentrations and calcium phosphate precipitation (due to both the high urine pH and the low urine citrate concentration) may contribute to the distal nephron injury. (See "Kidney stones in adults: Epidemiology and risk factors", section on 'Low urine citrate'.)

PROXIMAL (TYPE 2) RTA — Proximal (type 2) renal tubular acidosis (RTA) is characterized by a decrease in proximal bicarbonate reabsorptive capacity, resulting initially in bicarbonate wasting and a fall in the serum bicarbonate concentration. A number of discrete transporters, pumps, and enzymes are required for the proximal tubule to reclaim most of the filtered bicarbonate (figure 1).

More than 4000 mEq of filtered bicarbonate are reclaimed daily, primarily by the proximal tubule transport processes described below (figure 1):

Hydrogen ions and bicarbonate are generated from carbonic acid within the proximal tubule cells. The reaction is accelerated by the kidney intracellular isoform of carbonic anhydrase (carbonic anhydrase II). The hydrogen ions are then secreted into the proximal tubule lumen, mainly (80 percent) via the sodium-hydrogen ion exchanger (NHE3) in the luminal membrane and, to a smaller extent (20 percent), by an electrogenic V-type H+ATPase. The movement of sodium down the large electrochemical concentration gradient from the lumen (where its concentration is similar to plasma) into the cell (where its concentration is much lower and the electrical charge is negative) drives hydrogen ions in the opposite direction (from the cytoplasm into the lumen). The Na-K-ATPase pump in the basolateral membrane of proximal tubule cells indirectly "drives" this exchange by maintaining the low intracellular sodium concentration.

Hydrogen ions that enter the proximal tubule lumen react with filtered bicarbonate to generate carbonic acid, which is rapidly dehydrated to water and carbon dioxide. This dehydration reaction is catalyzed by the membrane-bound luminal enzyme, carbonic anhydrase IV. The carbon dioxide formed in the lumen rapidly enters proximal tubule cells via the aquaporin 1 channel in the luminal membrane.

Within proximal tubule cells, the carbon dioxide is hydrated with water to form carbonic acid. The carbonic acid dissociates into hydrogen and bicarbonate ions. For every hydrogen ion secreted from the cell into the lumen, an intracellular bicarbonate exits the cell across the peritubular membrane. The bicarbonate exit step occurs via a sodium-bicarbonate cotransporter. The net effect of this process is that, for every hydrogen ion molecule secreted into the lumen, a bicarbonate molecule enters the peritubular capillary. Because each hydrogen ion that enters the lumen combines with one bicarbonate ion to form carbonic acid, the net effect of this process is the disappearance of one bicarbonate ion and one sodium ion from the lumen and the appearance of one bicarbonate ion and one sodium ion in the peritubular capillary. This process of sodium bicarbonate reclamation is equivalent to sodium bicarbonate reabsorption.

Abnormalities of one or more of the multiple proximal tubule transporters, pumps, or enzymes can impair sodium bicarbonate reabsorption and cause the bicarbonate wasting found in proximal RTA (figure 1).

Several genetic forms of proximal RTA have been well defined:

NHE3 mutations – Autosomal dominant mutations of the gene that encodes for the luminal membrane sodium-hydrogen exchanger (NHE3) [54].

NBCe1 mutations – Mutations (usually autosomal recessive) in the gene coding for the sodium-bicarbonate cotransporter (NBCe1). This mutation is also often associated with ocular abnormalities and short stature [54,55].

Carbonic anhydrase II mutations – Mutations (usually autosomal recessive) in the gene coding for carbonic anhydrase II. This enzyme is important for both proximal and distal tubule proton generation and secretion. Consequently, these patients usually have both proximal and distal acidification defects. Carbonic anhydrase II is also involved in skeletal metabolism and systemic calcium balance. Consequently, this form of RTA may be associated with osteopetrosis, cerebral calcification, and often, intellectual disability [56-58].

Genetic Fanconi syndrome – Some forms of proximal RTA are accompanied by defective reabsorption of other ions and molecules that are also normally reabsorbed by the proximal tubule. These include phosphate, uric acid, glucose, and low-molecular-weight proteins such as beta-2 microglobulin. Generalized proximal tubule dysfunction is called Fanconi syndrome. A number of inherited enzymatic disorders are associated with Fanconi syndrome in infants. They include cystinosis, tyrosinemia, and glycogen storage disease (table 3) [59].

When acquired, proximal RTA is usually associated with generalized proximal tubular dysfunction (ie, Fanconi syndrome) (see "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Proximal (type 2) RTA'):

Drug nephrotoxicity – Acquired proximal RTA with Fanconi syndrome is often a toxic side effect of a drug, such as ifosfamide, valproic acid, tenofovir, and other reverse transcriptase inhibitors including drugs in both nucleoside and nucleotide classes [60].

Monoclonal gammopathy – Another important cause of acquired proximal RTA with Fanconi syndrome in adults is a monoclonal gammopathy [61].

Carbonic anhydrase inhibitors – Isolated proximal RTA (ie, without Fanconi syndrome) may be caused by medications that inhibit carbonic anhydrase. However, as noted above, this enzyme is also required for normal distal tubule acidification, so the defect generally affects the distal tubule as well (figure 4). Drugs inhibiting carbonic anhydrase include acetazolamide, methazolamide, dorzolamide, and topiramate.

Regardless of the specific etiology or mechanism, the degree of acidosis is usually self-limited in proximal RTA, and the serum bicarbonate concentration usually stabilizes between 14 and 20 mEq/L. The severity of the acidosis depends upon the severity of the proximal defect and the ability of the distal nephron to reabsorb the increased bicarbonate load delivered by the proximal tubule [62]. As the serum bicarbonate concentration falls, less bicarbonate is filtered, less escapes into the distal nephron, and less is excreted into the urine. Eventually, the serum bicarbonate concentration, and the filtered load, falls to levels that can be "normally" reclaimed by the affected proximal tubule. At this point, a "normal" bicarbonate load is delivered to the distal nephron, which is functioning normally. When the plasma bicarbonate concentration stabilizes at a reduced level (usually between 14 and 20 mEq/L), the collecting tubules function normally, the urine pH can be reduced to 5.3 or less, and daily dietary acid load can be excreted in the form of ammonium and titratable acid.

The ability of distal tubular bicarbonate reabsorption to compensate for the proximal tubule disorder was illustrated in a child with no demonstrable proximal tubular function in whom the serum bicarbonate concentration did not fall below 11 to 12 mEq/L [63].

Hypokalemia often develops in patients with proximal RTA. However, in contrast to the hypokalemia of distal RTA, which is improved by alkali therapy, hypokalemia in proximal RTA is typically generated or exacerbated by alkali therapy. Thiazide diuretics, which are sometimes used in patients with proximal RTA to generate mild volume contraction and thereby increase proximal bicarbonate reabsorption, may also generate or exacerbate hypokalemia.

As noted above, in the absence of alkali therapy, the plasma bicarbonate concentration will fall to a level that results in a filtered bicarbonate load that permits all of the filtered bicarbonate to be reabsorbed in the proximal, connecting, and collecting tubules. Once this occurs, the plasma bicarbonate concentration stabilizes at a reduced level (usually between 14 and 20 mEq/L), the collecting tubules then function normally, the urine pH can be reduced to 5.3 or less, and daily dietary acid load can be excreted in the form of ammonium and titratable acid.

Under these conditions, there may be a modest degree of urinary potassium wasting [10] since all forms of metabolic acidosis diminish proximal sodium reabsorption [64]. The ensuing sodium losses may be sufficient to cause subtle hypovolemia and secondary hyperaldosteronism. The combination of high levels of aldosterone and increased distal sodium delivery will promote sodium reabsorption and potassium secretion in the cortical collecting tubule (figure 3). However, this is a generally modest effect, and the plasma potassium concentration is usually relatively normal in patients with untreated proximal RTA.

However, this situation changes when alkali is administered (eg, as sodium bicarbonate or sodium citrate). This raises the plasma bicarbonate concentration, increasing the filtered bicarbonate load to a level that exceeds the bicarbonate reabsorptive capacity of the proximal tubule. The increased distal tubule delivery of sodium, bicarbonate, and water combines with hyperaldosteronism generated by the modest hypovolemia and markedly stimulates potassium secretion in the cortical collecting tubule (figure 3) [10,65]. Thus, most patients with proximal RTA who are treated with alkali will develop hypokalemia and require potassium supplements.

Thiazide diuretics are frequently used to treat patients with proximal RTA because they contract extracellular fluid volume, which increases proximal tubule sodium and bicarbonate reabsorption. However, thiazide diuretics will also accelerate renal potassium secretion and losses. (See "Treatment of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Proximal (type 2) renal tubular acidosis'.)

HYPERKALEMIC FORMS OF RTA — Normally, sodium reabsorption by the principal cells of the connecting segment and cortical collecting tubule (figure 3) has a major impact on both potassium and hydrogen ion secretion at these sites (figure 4). These effects occur via the following mechanisms:

Sodium reabsorption by the principal cells is more rapid than chloride reabsorption. This creates a negative electrical field within the lumen.

The luminal electronegativity promotes secretion of positively charged potassium ions from the principal cells (figure 3) and hydrogen ions from the intercalated cells into the tubular lumen (figure 4).

Thus, any defect or physiologic alteration that impairs or reduces sodium reabsorption in the connecting segment and cortical collecting tubule will tend to produce both metabolic acidosis and hyperkalemia [66,67].

The principal causes of hyperchloremic, hyperkalemic acidosis due to impaired distal tubule sodium reabsorption include the following:

Voltage-dependent renal tubular acidosis (RTA):

Markedly reduced distal sodium delivery as a result of either reduced sodium intake and/or increased proximal tubule sodium reabsorption

An inherited or acquired defect in the sodium transport mechanisms in the principal cells

Hypoaldosteronism:

Aldosterone is the most important hormone regulating distal tubule sodium reabsorption. Hypoaldosteronism can be due either to inadequate synthesis of the hormone or resistance to its effect in the kidney.

Diminished aldosterone synthesis may be due to an acquired or inherited defect in adrenal synthesis or to reduced renin and/or angiotensin II levels.

Resistance to the action of aldosterone, which can result from structural or molecular defects in principal cells or drugs that antagonize aldosterone or inhibit its effect via other mechanisms.

The hyperkalemia in these forms of RTA is a major contributor to the development of metabolic acidosis. Hyperkalemia inhibits ammoniagenesis and reduces urine ammonium excretion. The mechanisms responsible for this inhibition are discussed in detail elsewhere (see "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)", section on 'Metabolic acidosis' and "Potassium balance in acid-base disorders", section on 'Metabolic acidosis'). In many patients with hyperkalemic forms of RTA, correction of the hyperkalemia reduces the severity of the metabolic acidosis or, if there are no other contributing factors (such as chronic kidney disease), completely reverses the metabolic acidosis [68,69].

Voltage-dependent RTA — Voltage-dependent (also called "voltage-defect") renal tubular acidoses (RTAs) can occur with markedly reduced distal sodium delivery or with inherited or acquired defects in sodium reabsorption by the principal cells [70]. Sometimes, these disorders are classified as a subtype of distal RTA. However, most experts place both voltage-dependent RTA and hypoaldosteronism in the category of "hyperkalemic RTA" [70-72].

Voltage-dependent distal RTA has been described in a number of clinical settings; many of these disorders can also generate other distal tubule acidification pathology including classic distal RTA and various forms of hypoaldosteronism.

Severe hypovolemia – Some patients with severe volume contraction due, for example, to long-term laxative abuse may develop a pure voltage-dependent RTA [73].

Urinary tract obstruction – Urinary tract obstruction can injure tubule cells and reduce the activity of the cellular Na-K-ATPase pump [74]. This may diminish sodium reabsorption [75]. However, urinary obstruction can also generate a wide spectrum of other acidification disorders including hypoaldosteronism (related to hyporeninemia), tubule resistance to aldosterone, and other forms of distal tubule voltage defects [74]. (See "Clinical manifestations and diagnosis of urinary tract obstruction (UTO) and hydronephrosis".)

Lupus nephritis – Lupus nephritis can be associated with voltage-dependent RTA, although intercalated cell H-ATPase activity usually appears to be intact (figure 4) [71,76]. (See "Lupus nephritis: Diagnosis and classification".)

Sickle cell disease – Sickle cell disease can produce both voltage-dependent RTA and hypoaldosteronism [77].

Drugs – Drugs including amiloride and lithium salts, which produce voltage defects in a number of experimental models, may also have other effects on renal tubule acidification [66].

Hypoaldosteronism — Aldosterone deficiency or resistance produces a hyperkalemic RTA that is often called "type 4 RTA." Compared with voltage-dependent RTA, the hyperkalemia and metabolic acidosis associated with hypoaldosteronism is milder. The serum bicarbonate is usually greater than 15 mEq/L [78], and the urine pH can usually be reduced below 5.5 [79].

The acidification defect in most patients with aldosterone deficiency or resistance is thought to be primarily due to a reduced rate of proton secretion rather than an intrinsic defect in the tubule's capacity to generate a normal pH gradient [80,81]. Thus, when very little buffer (ammonia and/or phosphate) is present in the renal tubule lumen, the pH can be reduced below pH 5.5 (but the quantity of excreted acid is relatively low). By contrast, when greater amounts of buffer are present in the distal tubule, the impaired rate of hydrogen ion secretion is unable to normally protonate the buffer load and the urine pH increases above 5.5. In either case, the reduction in net acid excretion results in metabolic acidosis.

Hyperkalemia itself will reduce renal ammonia generation and excretion. This may be related to relative alkalization of renal tubule cells (hyperkalemia will shift potassium ions into cells in exchange for hydrogen ions). The metabolic acidosis in many such patients will improve, or resolve entirely, when serum potassium levels are reduced (ie, with potassium-binding medications).

These disorders, including rare forms of aldosterone resistance such as pseudohypoaldosteronism type 2, or Gordon's syndrome, are presented elsewhere in detail. (See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)".)

Distinguishing voltage-dependent RTA from hypoaldosteronism — If a patient has hyperchloremic (normal anion gap) metabolic acidosis and hyperkalemia, and both the measured serum aldosterone and renin levels are reduced, then a diagnosis of hyporeninemic hypoaldosteronism can be established. This is probably the commonest form of hyperkalemic RTA. If the aldosterone level is reduced but the renin level is elevated, then an adrenal aldosterone synthetic defect may exist. However, if the aldosterone level is elevated, it is difficult to distinguish between aldosterone resistance and a voltage-dependent form of RTA. Sometimes, multiple pathologies coexist [70], and H-ATPase defects have also been identified in some patients with hyperkalemic forms of RTA [82].

However, while the various forms of hyperkalemic RTA have a variety of underlying pathophysiologic etiologies that may be difficult to distinguish from one another, from the practical clinical and therapeutic perspective, it is usually not important to differentiate these disorders. Most patients will improve with correction of the patient's volume status and hyperkalemia.

TYPE 3 RTA — The term type 3 renal tubular acidosis (RTA) is not a well-defined diagnosis and is rarely used. When it is used, this term refers to patients with both proximal and distal acidification defects. Thus, patients with genetic or drug-related carbonic anhydrase disorders could be classified as a form of "type 3 RTA."

SUMMARY

Classification of renal tubular acidosis – There are three major forms of RTA: distal (type 1), proximal (type 2), and hyperkalemic. Hyperkalemic RTAs include hypoaldosteronism (type 4) and voltage-dependent RTA, which is sometimes considered a subtype of distal RTA. These major forms of RTA differ in their pathophysiology and clinical manifestations (table 1) (see 'Potassium metabolism by the kidney' above):

Distal (type 1) RTA is characterized by impaired hydrogen ion secretion in the distal nephron resulting either from decreased net activity of the proton pump (see 'Decreased net activity of proton pumps and HCO3 exchangers' above) or from increased luminal membrane hydrogen ion permeability (see 'Increased luminal membrane permeability' above). The plasma bicarbonate concentration can fall below 10 mEq/L in the absence of treatment with exogenous alkali. Patients with distal RTA almost always have hypocitraturia and frequently develop kidney calcifications and calcium-containing kidney stones. (See 'Distal (type 1) RTA' above.)

Proximal RTA is caused by proximal tubule defects that reduce the capacity to reclaim filtered bicarbonate (table 3). Proximal RTA is often associated with Fanconi syndrome, which is characterized by defective reabsorption of other substances that are normally reabsorbed in the proximal tubule, such as phosphate, uric acid, glucose, and amino acids. (See 'Proximal (type 2) RTA' above.)

Hypoaldosteronism is caused by reductions in aldosterone secretion or responsiveness (table 4). (See 'Hyperkalemic forms of RTA' above and 'Hypoaldosteronism' above.)

Voltage-dependent RTA is caused by defects in distal sodium reabsorption. (See 'Hyperkalemic forms of RTA' above and 'Voltage-dependent RTA' above.)

Effect of RTA on potassium balance – Potassium balance is frequently abnormal in patients with RTA:

Hypokalemia, due to renal potassium wasting, frequently develops in patients with distal RTA and usually improves with alkali therapy. (See 'Distal (type 1) RTA' above.)

Hypokalemia may also develop in patients with proximal RTA. However, in contrast to distal RTA, alkali therapy usually generates or exacerbates hypokalemia in patients with proximal RTA. (See 'Proximal (type 2) RTA' above.)

Hyperkalemia occurs frequently in patients with hypoaldosteronism (type 4 RTA) and in patients with other defects in sodium reabsorption in their distal nephron (voltage-dependent RTA). (See 'Hyperkalemic forms of RTA' above.)

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Topic 2327 Version 23.0

References

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