Etiology and clinical manifestations of renal tubular acidosis in infants and children

INTRODUCTION — In children, renal tubular acidosis (RTA) is due to either an inherited or acquired defect that affects the kidney's ability to absorb filtered bicarbonate, or excrete ammonia or titratable acid. RTA is characterized by a normal anion gap (hyperchloremic) metabolic acidosis caused by the net retention of hydrogen or loss of bicarbonate.

The most common pediatric forms of RTA are distal (type 1) and proximal (type 2) (table 1). The two other types of RTA are mixed (type 3) and hypoaldosteronism (type 4)

The etiology and clinical manifestations of the different forms of RTA in infants and children will be reviewed here.

Other topics review the following aspects of RTA:

●Diagnosis (see "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis" and "Causes and evaluation of hyperkalemia in adults")

●Pathophysiology (see "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance")

●Treatment (see "Treatment of distal (type 1) and proximal (type 2) renal tubular acidosis" and "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)")

DISTAL (TYPE 1) RENAL TUBULAR ACIDOSIS

Pathogenesis — Type 1 (distal) RTA is due to impaired distal acid secretion that results in an inability to excrete the daily acid load. In the absence of alkali therapy, progressive hydrogen ion retention leads to a fall in plasma bicarbonate concentration that is accompanied by an abnormally high urine pH (greater than 5.5) (table 1).

Etiology — The etiology of distal RTA in children can be divided into genetic and acquired disorders (table 2).

Genetic causes — Genetic primary causes of distal RTA include mutations of genes that directly affect membrane transport proteins such as the chloride-bicarbonate exchanger (AE1) or subunits of the H-ATPase pump (table 3) and others that indirectly affect intracellular trafficking [1-3]. (See "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance".)

●Dominant distal RTA – Mutations of the SLC4A1 gene (MIM# 179800), located on chromosome 17q21-q22, which encodes the chloride-bicarbonate exchanger (AE1 or band 3), have been described in several families with autosomal dominant distal RTA [4-7]. Patients with dominant distal RTA generally have milder acidosis than those with recessive disease and present later in life, often in adolescence or adulthood [8]. Untreated patients have metabolic acidosis that is associated with hypercalciuria, nephrolithiasis or nephrocalcinosis, osteomalacia, and erythrocytosis. Mutations of the SLC4A1 gene also are reported in some patients with hereditary spherocytosis and Southeast Asian ovalocytosis, both of which can be associated with RTA. (See "Hereditary spherocytosis" and "Southeast Asian ovalocytosis (SAO)", section on 'Specific SLC4A1 deletion'.)

●Recessive distal RTA with deafness

•Patients with mutations in the gene ATP6V1B1 (MIM# 192132), which encodes the B1 subunit of H-ATPase, have distal RTA and sensorineural deafness [9,10]. This gene is expressed in the intercalated cells of the distal renal tubule, cochlea, and male genital tract, and is located on chromosome 2p13 [9-12]. Untreated patients develop severe metabolic acidosis with poor growth, rickets, and nephrocalcinosis during infancy and early childhood. Patients also may develop progressive bilateral sensorineural hearing loss (SNHL) that typically begins in infancy [13]. Treatment of acidosis prevents poor growth, rickets, and nephrocalcinosis but does not improve or prevent ongoing hearing loss.

•Missense mutations in the gene FOXI1 (MIM# 601093), which encodes the transcription factor FOXI1, have been reported in two consanguineous kindreds with autosomal recessive distal RTA and sensorineural deafness [14]. Affected individuals also had nephrocalcinosis and developed medullary cysts. In animal models, FOXI1 is a transcription factor that regulates expression of B1 and a4 subunits of the V-ATPase proton pump and the anion-exchange proteins AE1, AE4, and pendrin in the intercalated cells of the renal tubules and the endolymphatic duct and sac of the inner ear.

●Recessive distal RTA without deafness

•Patients with mutations in the gene ATP6V0A4 (MIM# 605239), located on chromosome 7q33-q34, which encodes the a4 subunit of H-ATPase, develop distal RTA without early hearing loss [15]. The severity of metabolic acidosis and its associated findings of failure to thrive, rickets, and nephrocalcinosis are similar to that seen in patients with mutations that affect the B1 subunit. This gene product is also expressed in the inner ear, although most children with ATP6V0A4 gene mutations have normal hearing based upon audiometric screening, there are cases with sensorineural hearing loss (SNHL) [2,16].

•In a report from Southeast Asia, a family with recessively transmitted distal RTA was associated with homozygosity for three mutations in SLC4AE1 [17].

•In another report, mutations in the gene WDR72 have been reported in two families with recessive distal RTA. The product of WDR72 is thought to be involved with endocytic vesicle trafficking [18]. Mutations of WDR72 have previously been identified as a cause of amelogenesis imperfecta (MIM # 613214) that affect tooth enamel formation. One of the individuals in this report had distal RTA and tooth enamel hypoplasia.

Acquired causes — The acquired causes of distal RTA in children include the following:

●Medications

•The administration of amphotericin B can result in reversible distal RTA. However, the use of lipid formulations of amphotericin B avoids tubular damage and RTA. (See "Amphotericin B nephrotoxicity", section on 'Electrolyte and acid-base disorders'.)

•Lithium can cause an incomplete distal RTA with impairment of urine acidification but typically does not cause metabolic acidosis. (See "Renal toxicity of lithium", section on 'Renal tubular acidosis'.)

●Autoimmune disorders – Although rare in children, reported autoimmune conditions associated with distal RTA include Sjögren's disease [19] and systemic lupus erythematosus [20,21]. (See "Kidney disease in primary Sjögren's disease", section on 'Distal renal tubular acidosis'.)

●Obstructive uropathy – Distal RTA with hyperkalemia may be present in patients with obstructive uropathy. It is caused by mineralocorticoid resistance with impaired distal Na resorption and loss of the lumen-negative potential difference due to reduced activities of transporter proteins, such as apical Na/K/2Cl cotransporters, sodium channels, and basolateral Na-K-ATPase. (See "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance".)

Clinical manifestations — The clinical manifestations of distal RTA vary depending upon the underlying etiology. The recessive genetic forms present in infancy, the dominant form later in life, and acquired distal RTA may occur at any age based upon the timing of renal tubular injury.

Recessive form — As discussed previously, the recessive genetic form of RTA usually presents during infancy and generally is associated with severe clinical manifestations [2,22]. These findings include:

●Severe hyperchloremic metabolic acidosis (serum bicarbonate levels may decrease below 10 mEq/L)

●Moderate to severe hypokalemia (serum potassium ≤ 3.0 mEq/L)

●Nephrocalcinosis

●Vomiting

●Dehydration

●Poor growth

●Rickets

●Bilateral SNHL in some cases with mutations of the gene that encodes B1 subunit of the H-ATPase pump (see 'Genetic causes' above)

Dominant form — In comparison with recessive distal RTA, dominant distal RTA is usually associated with milder disease, and presents later in life (often in adolescence and adulthood) [8]. The most common initial finding is renal stone or nephrocalcinosis. Patients typically have mild or no acidosis (referred to as incomplete RTA), mild to moderate hypokalemia, and less commonly, poor growth [2,4,22]. Bone disease is a rare finding. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Incomplete distal RTA'.)

Chronic kidney disease — Chronic kidney disease (CKD) with a glomerular filtration rate of <90 cc/min per 1.73 m², has been reported as a complication of hereditary distal RTA [2]. CKD presents after the pubertal growth spurt and is thought to be due to the combination of nephrocalcinosis, persistent hypokalemia, and repeated episodes of hypovolemia that results in progressive tubulointerstitial injury. In a retrospective long-term study of 16 patients, the prevalence of CKD at 20- and 40-year follow-up in patients was 41 and 71 percent, respectively [23].

PROXIMAL (TYPE 2) RENAL TUBULAR ACIDOSIS

Pathogenesis — Proximal RTA is caused by a reduction in proximal bicarbonate reabsorptive capacity resulting in a fall in the plasma bicarbonate. Depending on the renal bicarbonate excretion threshold and serum bicarbonate level, urine pH may be inappropriately high or normal. (See "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance", section on 'Proximal (type 2) RTA'.)

Etiology — Proximal RTA may present either as an isolated tubular defect or as a component of a generalized proximal tubular disorder called the Fanconi syndrome (table 4).

Isolated proximal renal tubular acidosis — In children, isolated proximal RTA is less common. It is usually due to a transient or inherited (table 3) disorder.

●Transient or sporadic proximal RTA – Infants with transient or sporadic proximal RTA have a decreased capacity to bind bicarbonate without any identifiable cause or evidence of renal abnormality. These infants who are beyond the newborn period are believed to have extended functional immaturity of the proximal sodium-hydrogen exchanger (or antiporter), resulting in an age-based decrease in bicarbonate reabsorption capacity. This reduced capacity, which is the same as that of a normal neonate, results in a persistently low serum bicarbonate level [24]. Patients usually present within the first year of life with symptoms of tachypnea, growth failure, recurrent vomiting, and feeding difficulties [25,26]. Bone disease, hypokalemia, and urinary concentration defects are uncommon, and hypercalciuria, nephrocalcinosis, and urolithiasis do not occur. Resolution of symptoms and a rapid increase in growth are seen with alkali therapy, which can be discontinued after several years without recurrence of RTA and its symptoms.

●Autosomal recessive proximal RTA – Mutations in the gene SLC4A4, which encodes the sodium bicarbonate cotransporter (NBC), are associated with isolated proximal RTA [27-29]. This rare disorder with reported cases from Europe and Japan presents with:

•Severe hypokalemic.

•Hyperchloremic metabolic acidosis.

•Growth retardation.

•Ocular abnormalities including glaucoma, cataracts, and band keratopathy. Ocular findings may progress with age [28,30].

•Additional features include enamel defects of the permanent teeth, impaired psychomotor and cognitive function, and opacification of the basal ganglia [31,32].

●Autosomal dominant proximal RTA – Case reports have described a rare autosomal dominant inheritance pattern of proximal RTA in two families with several affected members [33,34]. In both these families, clinical manifestations were limited to short stature and metabolic acidosis. There was no evidence of bone disease or hypercalciuria. No mutation was found in any of the nine tested candidate genes studied in the Israeli pedigree [34].

Studies using a knockout mouse model identified the gene SLC9A3 as a candidate gene for dominant proximal RTA [35]. It encodes one of the five plasma membrane sodium-hydrogen exchangers.

Fanconi syndrome — Generalized proximal tubular dysfunction, referred to as Fanconi syndrome, is characterized by proximal RTA, phosphaturia, renal glucosuria (with a normal plasma glucose concentration), aminoaciduria, and tubular proteinuria.

Etiology — The etiology of Fanconi syndrome includes inherited diseases or acquired causes:

●Genetic conditions associated with Fanconi syndrome include the following:

•Dent disease (see "Dent disease (X-linked recessive nephrolithiasis)", section on 'Proximal tubular reabsorptive failure and proteinuria')

•Cystinosis (see "Cystinosis", section on 'Renal manifestations')

•Tyrosinemia type 1 (see "Disorders of tyrosine metabolism", section on 'Hereditary tyrosinemia type 1')

•Galactosemia (see "Galactosemia: Clinical features and diagnosis", section on 'Clinical features')

•Wilson disease (see "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Other organs')

•Lowe oculocerebrorenal syndrome (MIM #309000), also referred to as Lowe syndrome (see "Dent disease (X-linked recessive nephrolithiasis)", section on 'Dent disease 2 versus Lowe syndrome')

•Hereditary fructose intolerance

•Mitochondrial myopathies

●Acquired causes

•Drugs – Medication associated with Fanconi syndrome include aminoglycosides, cisplatin, ifosfamide, valproic acid, and deferasirox [36-38] (see "Manifestations of and risk factors for aminoglycoside nephrotoxicity", section on 'Electrolyte abnormalities' and "Ifosfamide nephrotoxicity", section on 'Clinical manifestations' and "Cisplatin nephrotoxicity", section on 'Fanconi-like syndrome')

•Heavy metals – Heavy metals associated with Fanconi syndrome include lead, mercury, and cadmium (see "Lead nephropathy and lead-related nephrotoxicity", section on 'Clinical manifestations' and "Epidemiology and toxicity of cadmium", section on 'Kidney disease' and "Mercury toxicity", section on 'Tubular dysfunction')

•Vitamin D disorders – In patients with vitamin D deficiency or vitamin D resistance rickets, type 2 RTA can occur because of secondary hyperparathyroidism caused by chronic hypocalcemia

Clinical manifestations — In children, the most common clinical findings of Fanconi syndrome are growth failure, and episodes of hypovolemia due to polyuria caused by impaired concentrating ability. Poor growth may be due to hypophosphatemia, persistent acidosis, chronic hypokalemia, rickets, and volume depletion [39]. Other findings may include bony abnormalities, including rickets and osteomalacia due to hypophosphatemia and low levels of calcitriol (1,25 dihydroxy vitamin D), and constipation and muscle weakness caused by significant hypokalemia (serum potassium less than 3 mEq/L). (See "Clinical manifestations and treatment of hypokalemia in adults", section on 'Severe muscle weakness or rhabdomyolysis'.)

Laboratory evaluation demonstrates hyperchloremic metabolic acidosis, hypophosphatemia, moderate to severe hypokalemia (serum potassium levels less than 3 mEq/L), and proteinuria.

The age of presentation varies with the underlying etiology.

●Genetic causes

•Infancy – Several genetic causes of Fanconi appear during infancy, including Lowe oculocerebrorenal syndrome, the infantile form of cystinosis, and Dent disease. (See "Dent disease (X-linked recessive nephrolithiasis)", section on 'Proximal tubular reabsorptive failure and proteinuria' and "Cystinosis", section on 'Infantile form' and "Dent disease (X-linked recessive nephrolithiasis)", section on 'Dent disease 2 versus Lowe syndrome'.)

•Childhood and adolescence – Other genetic conditions, such as Wilson disease, late-onset forms of cystinosis, and galactosemia present with Fanconi syndrome later in life as accumulation of toxic material (eg, copper in Wilson disease) over time results in progressive proximal renal tubular damage. (See "Galactosemia: Clinical features and diagnosis", section on 'Clinical features' and "Cystinosis", section on 'Late-onset (juvenile) cystinosis' and "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Other organs'.)

●Acquired Fanconi may occur at any age depending upon the timing of exposure to noxious toxins and drugs, which injure the proximal tubule.

MIXED (TYPE 3) RENAL TUBULAR ACIDOSIS — Type 3 RTA, also referred to as mixed RTA, is a rare autosomal recessive disorder that affects mostly children of Arab, North African, and Middle Eastern descent. Patients have features of both distal and proximal RTA. These include a high fractional excretion of bicarbonate and increased urine citrate, which occur in type 2 RTA, in addition to the features of type 1 RTA, such as inappropriately high urine pH in presence of non-anion gap metabolic acidosis, positive urine anion gap, and a low urine-blood PCO₂ after urine alkalization with intravenous sodium bicarbonate or acetazolamide. It is due to an inherited carbonic anhydrase (CA) 2 deficiency.

Because CA2 is widely expressed, mutations of the CA2 gene (located on chromosome 8q22) result in a syndrome with multiple clinical findings, including mixed RTA, osteopetrosis, cerebral calcification, and intellectual disability [40-43]. This constellation of findings is also referred to as Guibaud-Vainsel syndrome or marble brain disease. Other clinical features include bone fractures (due to increased bone fragility) and growth failure [44]. Excessive facial bone growth leads to facial dysmorphism, and conductive hearing loss and blindness due to nerve compression. The majority of affected patients are of Arabic descent and live in North Africa and the Middle East.

In some patients with type 1 RTA, increased parathyroid hormone secretion due to hypocalcemia may induce bicarbonaturia in the proximal tubule mimicking type 3 RTA.

Based on the author's experience, patients with type 3 RTA generally require a lower dose of alkali to correct acidosis as compared with those with isolate type 2 RTA.

ALDOSTERONE DEFICIENCY OR RESISTANCE (TYPE 4 RENAL TUBULAR ACIDOSIS) — Hypoaldosteronism primarily results in a loss of NH₄ excretion. It is uncommon in children and is usually due to either aldosterone deficiency or tubular resistance to the action of aldosterone, also called pseudohypoaldosteronism (ie, mineralocorticoid deficiency). Hypoaldosteronism is typically characterized mild acidosis (serum bicarbonate above 17 mEq/L) due to the impairment of NH₄ excretion. Normally during acidosis, increased levels of aldosterone stimulate renal acid excretion by enhancing ammonia (NH₄) excretion and increasing H⁺ excretion either directly or indirectly by a voltage-dependent mechanism linked to increased sodium reabsorption. Hyperkalemia is also common because aldosterone is the major hormone that promotes potassium excretion. Other clinical features in children with hypoaldosteronism may include failure to thrive and hyponatremia because of sodium loss.

Unlike adults, in whom the most common causes for a lack of response to aldosterone are kidney damage due to diabetic nephropathy or chronic interstitial nephritis, hypoaldosteronism in children is more likely to be due to drugs that impair aldosterone release or function (table 5). These include heparin, nonsteroidal antiinflammatory agents, angiotensin inhibitors, trimethoprim, calcineurin inhibitors (cyclosporine and tacrolimus), and potassium sparing diuretics (eg, spironolactone). In addition, human immunodeficiency virus (HIV) infection is also associated with hypoaldosteronism [45]. (See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)", section on 'Etiology'.)

In children, hypoaldosteronism due to inherited disorders include the following rare disorders, which are discussed in greater detail separately (see "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)", section on 'Etiology' and "Causes of primary adrenal insufficiency in children", section on 'Disorders of steroidogenesis'):

●Congenital adrenal insufficiency

●Aldosterone synthase deficiency

●Pseudohypoaldosteronism distal and 2 (also known as Gordon syndrome)

SUMMARY

●Introduction – Renal tubular acidosis (RTA) is due to either an inherited or acquired renal tubular defect that affects the kidney's ability to absorb filtered bicarbonate, or excrete ammonia or titratable acid. It is characterized by a normal anion gap (hyperchloremic) metabolic acidosis caused by the net retention of hydrogen or the net loss of bicarbonate. There are several subgroups of RTA that include many genetic disorders (table 1 and table 3). The most common pediatric forms are distal (type 1) RTA and proximal (type 2) RTA (table 1). (See 'Introduction' above.)

●Distal RTA – Distal (type 1) RTA is due to impaired distal acid secretion that results in an inability to excrete the daily acid load. It is divided into genetic causes due to mutations of genes that encode the chloride-bicarbonate exchanger (AE1) or subunits of the H-ATPase pump, and acquired causes due to distal tubular injury from drugs, autoimmune disorders, or obstructive uropathy. (See 'Pathogenesis' above and 'Etiology' above.)

Clinical manifestations of distal RTA are dependent upon the underlying etiology (table 2). Recessive autosomal distal RTA due to several different gene variants generally presents in infancy and is associated with more severe disease than the dominant form, which presents later in life (table 3). (See 'Clinical manifestations' above.)

●Proximal RTA – Proximal (type 2) RTA is caused by a reduction in proximal renal tubular bicarbonate reabsorptive capacity, resulting in a fall in the plasma bicarbonate. Its etiology is divided into disorders with isolated RTA and those with generalized proximal tubular dysfunction, referred to as Fanconi syndrome. (See 'Etiology' above.)

•Isolated proximal RTA – In children, isolated proximal RTA is rare and is usually due to an inherited or transient disorder. Clinical features vary with the underlying etiology. (See 'Isolated proximal renal tubular acidosis' above.)

•Fanconi syndrome – Fanconi syndrome is the most common cause of proximal RTA in children and is caused by inherited diseases (eg, Dent disease and cystinosis) and acquired disorders (eg, heavy metal toxicity and drugs). It is characterized by phosphaturia resulting in hypophosphatemia, renal glucosuria, aminoaciduria, tubular proteinuria, and proximal RTA. The age of clinical presentation depends upon the underlying etiology . Clinical findings include growth failure, hypovolemia, bony abnormalities (eg, rickets and osteomalacia), and constipation and muscle weakness due to hypokalemia. (See 'Fanconi syndrome' above and 'Clinical manifestations' above.)

●Mixed RTA – Mixed (type 3) RTA is a rare autosomal recessive disorder that has features of both types 1 and 2 RTA. These include a high fractional excretion of bicarbonate and increased urine citrate, which occur in type 2 RTA, in addition to the features of type 1 RTA such as inappropriately high urine pH in presence of non-anion gap metabolic acidosis, positive urine anion gap, and a low urine-blood PCO₂ after urine alkalization. It is due to an inherited carbonic anhydrase (CA) 2 deficiency. (See 'Mixed (type 3) renal tubular acidosis' above.)

●Hypoaldosteronism – Aldosterone deficiency or resistance (type 4 RTA) is due to either aldosterone deficiency or tubular resistance to the action of aldosterone. It is uncommon in children and is generally characterized by hyperkalemia and mild acidosis (serum bicarbonate above 17 mEq/L). In children, the most common cause of hypoaldosteronism is drugs (eg, heparin, nonsteroidal antiinflammatory agents, angiotensin inhibitors, trimethoprim, calcineurin inhibitors, and potassium sparing diuretics) that impair aldosterone release or function. Human immunodeficiency virus (HIV) may also be associated with hypoaldosteronism. (See 'Aldosterone deficiency or resistance (type 4 renal tubular acidosis)' above.)