Etiology

Classical distal RTA (type I)

  1. Primary (inherited):[3][5][27][28]

    1. Autosomal dominant: mutations of the SLC4A1 and AE1 genes, which code for chloride/bicarbonate exchanger proteins. SLC4A1 mutations can occur with either autosomal dominant or autosomal recessive transmission.

    2. Autosomal recessive: mutation of the ATP6V1B1, ATP6V0A4, FOXI1, or WDR72 genes.

  2. Acquired:[3][4][29][30][31]

    1. Systemic diseases: autoimmune disease including Sjogren syndrome, primary biliary cirrhosis, and systemic lupus erythematosus

    2. Drugs: amphotericin B, lithium, immunotherapy, and high doses of ibuprofen

    3. Tubulointerstitial disease: obstructive nephropathy

    4. Nephrocalcinosis: medullary sponge kidney, hyperthyroidism, milk-alkali syndrome, and vitamin D.

Proximal RTA (type II)[2][7]

  1. Primary (inherited):

    1. Autosomal recessive: mutation in SLC4A4, the gene encoding electrogenic NBCe1

    2. Lowe syndrome: X-linked disorder characterized by cataract, intellectual disability, and Fanconi-like proximal RTA, results from a mutation in the OCRL gene

    3. Fanconi-Bickel syndrome: an autosomal recessive disorder characterized by proximal RTA and impaired utilization of glucose and galactose

    4. Dent disease: X-linked recessive disorder characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, and nephrolithiasis, caused by mutations in either the chloride channel gene, CLCN5, or the OCRL gene.

  2. Familial:

    1. Cystinosis

    2. Wilson disease.

  3. Acquired:

    1. Light chain disorder

    2. Amyloidosis

    3. Multiple myeloma

    4. Toxins: lead and cadmium

    5. Drugs: tenofovir, ifosfamide, valproic acid, and carbonic anhydrase inhibitors (e.g., acetazolamide, methazolamide, and dichlorphenamide).

Mixed proximal and distal RTA (type III)[2][4][29][32][33][34]

  1. Inherited carbonic anhydrase II deficiency.

  2. Carbonic anhydrase inhibitors (e.g., topiramate, acetazolamide, methazolamide, and dichlorphenamide).

Hyperkalemic distal RTA (type IV)[19][20][29]

  1. Hereditary hyperkalemic RTA: inherited hypoaldosteronism due to congenital isolated hypoaldosteronism, pseudohypoaldosteronism type 2 (Gordon syndrome), or resistance to aldosterone action seen in type 1 pseudohypoaldosteronism.

  2. Acquired hyperkalemic RTA:

    1. Diabetic kidney disease or chronic interstitial nephritis

    2. Obstructive nephropathy

    3. Drugs: potassium-sparing diuretics, trimethoprim, pentamidine, nonsteroidal anti-inflammatory drugs (NSAIDs), calcineurin inhibitors, angiotensin inhibitors, and heparin.

Pathophysiology

Classic distal RTA (type I)

  • Classic distal RTA is characterized by impaired distal nephron proton secretion or failure to reabsorb bicarbonate by intercalated cells in the collecting duct.[3][15][35] Mutations of the B1 subunit of the renal H+-ATPase gene (ATP6V1B1) cause autosomal recessive distal RTA and sensorineural hearing loss in the majority of cases.[14][15][27][36][37] Studies in mice have shown that mutation of the B1 subunit can disrupt H+-ATPase driven acidification of proximal tubule vacuoles, suggesting that B1 subunit mutation can cause Fanconi syndrome in addition to distal RTA, as occasionally observed in clinical reports.[38] Mutations of the gene coding the A4 subunit of the proton pump (ATP6V0A4) also cause autosomal recessive distal RTA. Patients with this mutation may also have sensorineural hearing loss.[14][27] Mutations of the AE1 gene have more recently also been associated with autosomal recessive distal RTA.[39]

  • Autosomal dominant distal RTA is due to mutation of the chloride bicarbonate exchanger (AE1) that transports bicarbonate to the blood from acid-secreting intercalated cells.[14][15][27][40] The inability of these cells to export bicarbonate raises intracellular pH, limiting their ability to secrete protons.

Proximal RTA (type II)

  • Proximal RTA is characterized by the failure of proximal tubule cells to normally reabsorb filtered bicarbonate.[2][4][41] The defective bicarbonate reabsorption can result from a defect in proton secretion by NH₃ or H+-ATPase, impairment in the exit of bicarbonate by the Na+/3HCO₃-cotransporter, and a defect of luminal or cytosolic carbonic anhydrase. Autosomal recessive proximal RTA results from mutations of SLC4A4, the gene for the sodium bicarbonate cotransporter (NBC1) at the basolateral membrane of proximal tubular cells.[42][43]

  • Proximal RTA can also present as a component of Fanconi syndrome secondary to generalized proximal tubular dysfunction as a result of inherited or acquired disorders.[7] Idiopathic Fanconi syndrome has been shown to be a consequence of the mutation of the proximal tubule NaPi-IIa transporter in a well studied kindred.[44] In others, Fanconi syndrome may be a result of abnormalities affecting recycling of apical membrane vesicles in the renal proximal tubule. People from families with Dent disease and Lowe syndrome have been shown to have absence of urinary megalin. The genetic defect in Dent disease relates to the CLC-5 chloride channel, and the defect in Lowe syndrome affects an enzyme in lipid metabolism; the changes in urinary megalin appear to be secondary.[45][46][47] Autosomal dominant Fanconi syndrome resulting from a mutation of EHHADH, an enzyme involved in peroxisomal fatty acid metabolism, has been studied. The mistargeting of the mutant enzyme to the mitochondria disrupts oxidative phosphorylation causing defective proximal tubule transport in affected individuals.[48]

Mixed proximal and distal RTA (type III)

  • Hereditary carbonic anhydrase deficiency inhibits acid secretion in both the proximal and distal nephron.[33][34] This occurs because the enzyme carbonic anhydrase is critical for generating and breaking down carbonic acid from water and carbon dioxide, and for making bicarbonate from carbon dioxide and hydroxyl ions. Both of these reactions are critical intracellular events in acid excretion. Carbonic anhydrase inhibitors can produce the same effect.[49]

Hyperkalemic distal RTA (type IV)

  • Hyperkalemic distal RTA develops when sodium absorption, which generates a lumen negative electrical potential in the distal nephron, is inhibited. A number of drugs, and aldosterone deficiency or aldosterone resistance (most often due to urinary tract obstruction), alter sodium transport in the distal nephron and can be considered significant risk factors for development of hyperkalemic distal RTA. Hyperkalemia develops because potassium secretion depends upon the normal lumen negative potential.[50] Hyperkalemia inhibits production of ammonia, and decreased ammonium production reduces urine buffering capacity and thus impairs acid excretion.[51] Because the H+-ATPase in the distal nephron is electrogenic, proton secretion is also affected by the loss of the lumen negative potential generated by sodium reabsorption in the distal nephron. Classic physiology studies in the turtle bladder have shown that loss of lumen negative potential slows the rate of the proton pump in that membrane.[52] The impaired pump rate results in decreased proton secretion, but because there is less ammonia buffering the protons, the final urine pH may be normal, as is observed in type IV distal RTA. Treatment of hyperkalemia improves ammonium excretion and improves the acid-base status and the serum potassium level.

Classification

Clinical classification

Classic distal RTA (type I)

  • Impairment of proton secretion in the distal nephron to a degree beyond that expected for the patient's renal function.[3]

  • Hyperchloremic metabolic acidosis with a normal serum anion gap and hypokalemia.

  • The urine pH is abnormally elevated (>5.5) despite systemic acidosis.[4]

  • Mutation of ATP6V1B1, ATP6V0A4, FOXI1, WDR72, or SLC4A1 gene.[3][5]

  • Seen with or without sensorineural hearing loss.[4]

  • May be primary (inherited) or acquired.

  • May present with evidence of partial Fanconi syndrome in untreated patients.

  • Incomplete distal RTA:[3][4][6]

    • Likely to be part of a distal RTA spectrum.

    • In the steady state the serum bicarbonate and pH are normal.

    • Inadequate urinary acidification when under acid-base stress.

    • Inadequate urinary acidification when given ammonium chloride load.

    • Usually presents with nephrocalcinosis or nephrolithiasis.

Proximal RTA (type II)

  • Proximal RTA may occur as a primary and isolated entity, however it is most often accompanied by other proximal tubular defects (Fanconi syndrome).[2]

  • Characterized by the inability of the proximal tubule to normally reabsorb filtered bicarbonate.

  • Hyperchloremic metabolic acidosis with a normal serum anion gap and hypokalemia.

  • Urine pH is appropriately low (<5.5) in the presence of acidemia.

  • If serum bicarbonate is restored to normal by bicarbonate infusion, the fractional excretion of bicarbonate exceeds 15%.

  • Fanconi syndrome:[2][7] 

    • Global dysfunction of the proximal tubule characterized by the inability of the proximal tubule to normally reabsorb filtered bicarbonate, along with excessive urinary excretion of amino acids, glucose, phosphate, uric acid, and other solutes.

    • Measurable urinary glucose excretion when serum glucose <5.5 mEq/L.

    • Phosphate wasting is characteristic.

    • Multiple etiologies, both hereditary and acquired.

Mixed proximal and distal RTA (type III)

  • Type III RTA is a rare combination of proximal and distal RTA caused by carbonic anhydrase II deficiency and carbonic anhydrase inhibitors blocking the metabolism of bicarbonate and carbonic acid.

  • Characterized by hyperchloremic metabolic acidosis with a normal serum anion gap and hypokalemia.

  • Urine pH is high during acidosis, and the fractional excretion of bicarbonate is greater than normal, indicating disordered urinary acidification in both proximal and distal nephrons.

Hyperkalemic distal RTA (type IV)[4]

  • Characterized by hyperchloremic metabolic acidosis with a normal serum anion gap and hyperkalemia.

  • Urine pH is low during acidosis (<5.5), but the urine anion gap is positive, indicating the absence of urinary ammonium.

  • Caused by aldosterone deficiency or aldosterone resistance.

Classification of Fanconi syndrome[7]

  • Primary (heritable) Fanconi syndrome

  • Idiopathic Fanconi syndrome

  • Fanconi syndrome in metabolic disease

    • Lowe syndrome

    • Dent disease (X-linked nephrolithiasis)

    • Cystinosis

    • Hereditary fructose intolerance

    • Galactosemia

    • Glycogenosis

    • Tyrosinemia

    • Wilson disease

    • Fanconi-Bickel syndrome

    • Inherited diseases affecting mitochondrial metabolism

  • Fanconi syndrome secondary to toxins or drugs

  • Fanconi syndrome in conditions characterized by proteinuria

  • Fanconi syndrome with Balkan nephropathy

  • Partial Fanconi syndrome in untreated distal RTA[8]

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