RTA traditionally is classified as proximal or distal, based on the nephron segment that is thought to have an abnormal function (Table 333.1). A rare type 3 RTA has been described in infants with features of both distal (type 1) and proximal (type 2) RTA. This autosomal recessive syndrome (gene locus chromosome 8q22) is characterized by the additional findings of osteopetrosis and mental retardation, and it is caused by carbonic anhydrase II deficiency. Proximal RTA (often called RTA type 2) is a defect in the proximal tubular reabsorption of filtered bicarbonate. Ordinarily, approximately 85% (somewhat less in infants) of filtered bicarbonate is reabsorbed in the proximal tubule primarily by sodium-hydrogen ion exchange. In comparison, 15% is reabsorbed in the distal nephron primarily via hydrogen secretion by a proton pump (H-ATPase). In proximal
RTA, the renal threshold for bicarbonate reabsorption is abnormally low, so that at normal plasma levels of bicarbonate, more than 15% of filtered bicarbonate is delivered to the distal nephron for reabsorption, resulting in bicarbonate wasting and metabolic acidosis. Possible pathogenetic causes for proximal RTA include a defective sodium-potassium adenosinetriphosphatase (ATPase) activity in the basolateral membrane, which provides the energy for the luminal sodium-hydrogen antiporter by maintaining a low cell sodium concentration, hence a favorable gradient for passive sodium entry into the cell; a defect in the sodium-hydrogen antiporter itself; deficiency or inhibition of carbonic anhydrase activity; or impairment of the basolateral sodium bicarbonate cotransporter responsible for returning the reabsorbed bicarbonate into the systemic circulation.

Distal RTA (see Table 333.1) is seen in two major forms: type 1, usually associated with hypokalemia or normokalemia and rarely hyperkalemia, and type 4, always associated with hyperkalemia. Distal RTA type 1 results from a reduced rate of hydrogen ion secretion that normally occurs in the intercalated cells in the collecting tubules where luminal H-ATPase pumps are located. The most common cause of distal type 1 RTA is diminished H-ATPase pump (classic distal RTA). Mutations have been described in the genes encoding the B1 and alpha 4 subunits of the H-ATPase pump. In addition to metabolic acidosis, sensorineural deafness is seen in the B1 subunit mutation, suggesting that the pump is required for normal function of the inner ear. Other causes of distal type 1 RTA include increased luminal membrane permeability leading to back-leak of secreted hydrogen ions from lumen to cell (gradient defect). Amphoterium B causes RTA via this mechanism and impaired distal sodium transport, leading to reduced luminal electronegativity, and thereby inhibiting potassium and hydrogen ion secretion (voltage-dependent defect). The associated impairment of secretion of potassium leads to hyperkalemia, which renders it difficult to distinguish this type of distal type 1 RTA from that of hyperkalemic type 4 RTA.

Distal RTA type 1 may occur in an incomplete form. Patients with incomplete distal RTA type 1 have a persistent high urine pH and hypocitraturia, but in contrast to those with the complete form, they are able to maintain net acid excretion, and the plasma bicarbonate concentration remains in the normal range. Untreated, it can lead to recurrent urolithiasis or nephrocalcinosis.

In hyperkalemic RTA type 4, the acidification defect is caused mainly by impaired renal ammoniagenesis. Patients with this type cannot excrete the necessary amounts of hydrogen ion in urinary buffers to avoid a metabolic acidosis and cannot excrete potassium normally. However, the ability to lower urinary pH in response to systemic acidosis is maintained. RTA type 4 is observed most frequently in conditions associated with aldosterone deficiency or resistance.

RTA can be caused by a variety of disorders, most of which are rare (Boxes 333.1, 333.2, and 333.3). Hereditary RTA occurs most commonly in children. Recent advances in the molecular biology of acid-base transporters have allowed researchers to gain a better understanding of the different inherited forms. Proximal RTA can occur as an isolated abnormality; however, much more commonly, proximal RTA is seen as part of the Fanconi syndrome, with associated glycosuria, aminoaciduria, and phosphaturia.

RTA usually is suspected during the workup of patients with failure to thrive or unexplained acidosis. Children may have
histories of repeated episodes of dehydration and anorexia. Others may present with clinical manifestations of hypokalemia, such as polyuria, constipation, and profound weakness. In distal RTA type 1, the signs and symptoms of kidney stones may precede the establishment of the diagnosis of RTA. The physical examination may reveal only growth retardation or signs of dehydration. In some cases, the physical examination may suggest a secondary cause of proximal RTA, such as the finding of cystine crystals in cystinosis, mental retardation in Lowe syndrome, or evidence of liver involvement in Wilson disease. The presence of sensorineural deafness suggests the diagnosis of the autosomal recessive form of distal RTA type 1.