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The kidneys play a key role in maintaining systemic pH near 7.4. The renal tubular acidoses (RTAs) are a group of disorders in which systemic acidosis occurs because the kidneys are unable either to excrete acid or to conserve bicarbonate. In either case, the result is a variable degree of normal anion gap metabolic acidosis accompanied by an abnormal serum potassium concentration. The RTA subtypes are classified as proximal or distal (pRTA, dRTA) based on which nephron segment is malfunctioning.

The proximal tubule reabsorbs 80% of the filtered bicarbonate (see Plate 3-21). Proximal tubular cells also metabolize glutamine, a process that yields bicarbonate, which is reabsorbed, and NH4+, which is secreted into the nascent urine.
Proximal RTA (pRTA), in which these processes fail, usually occurs as a component of generalized proximal tubular dysfunction (renal Fanconi syndrome). Most cases are acquired, reflecting exposure to substances that interfere with proximal tubular function, such as myeloma proteins or drugs (e.g., cytotoxic drugs or sodium valproate). In rarer cases, generalized proximal dysfunction may result from inherited diseases, such as cystinosis (see Plate 4-64). In even rarer cases, pRTA may be an isolated phenomenon (i.e., otherwise normal proximal function), as seen in individuals with recessively inherited defects in the basolateral NBC Na+/ HCO3- transporter.
Because the distal nephron can recapture some of the bicarbonate that is not reabsorbed in the proximal tubule, pRTA generally features a milder acidosis than dRTA. Indeed, once serum bicarbonate levels decline to 15 mEq/L, reabsorption in the distal nephron can fully compensate for the proximal dysfunction. At this point, bicarbonate wasting ceases, urine pH decreases (often becoming acidic), and serum bicarbonate concentrations stabilize. If patients are given an intravenous infusion of sodium bicarbonate, however, bicarbonate wasting resumes (with a fractional excretion of 15%) and the urine pH increases. This sequence of events is diagnostic of proximal RTA.
In addition to acidosis, pRTA features hypokalemia because the nonreabsorbed bicarbonate produces a negative charge in the collecting duct lumen, promoting K+ secretion through ROM-K channels. If there is generalized proximal tubule dysfunction, the increased distal Na+ load that reaches the cortical collecting duct also produces a negative intraluminal charge as it is reabsorbed. In addition, the increased urine flow through the distal tubule, which results from proximal salt wasting, stimulates K+ secretion through flow- sensitive maxi-K channels.
Although acidosis and hypokalemia are the hallmarks of pRTA, several additional abnormalities are often seen. Patients with generalized proximal tubular dysfunction, for example, exhibit salt wasting, polyuria, phosphaturia (and hypophosphatemia), glucosuria, uricosuria (and hypouricemia), aminoaciduria, microalbuminuria, and low molecular weight proteinuria (e.g., retinol binding protein or β2-microglobulin). Moreover, patients often develop rickets or osteomalacia cia (depending on age) because of inefficient renal activation of vitamin D. Meanwhile, patients with isolated pRTA, like those with NBC transporter mutations, often have aberrant calcification within the eyes (band keratopathy), cataracts, and mental retardation.
Proximal RTA is often difficult to treat because the marked bicarbonaturia mandates that large quantities of alkali be provided on a regular basis. Extensive bicarbonate supplementation, however, often causes worsening hypokalemia, and thus potassium supplements are often required as well. If there is generalized proximal tubular dysfunction, vitamin D and phosphate supplements are also helpful.

The collecting duct contains principal cells and intercalated cells (ICs), with the latter responsible for acid base handling. Within the IC population, at least two subtypes of cells have been described: type A and type
B. Type A cells secrete protons and reabsorb bicarbonate, whereas type B cells do the reverse. It is unclear if type A and B cells are molecular mirror images or separate cell types; however, the acid load in the average human diet dictates that the great majority of ICs be type A.
Classic distal RTA (i.e., hypokalemic dRTA) reflects type A cell dysfunction. Because there is inadequate secretion of protons, the kidneys are unable to appropriately acidify urine in the setting of systemic metabolic acidosis or following an acid load (e.g., with ammonium chloride). The urine anion gap (urine Na+ + K+ - Cl-) is a useful tool for confirming this defect; it will be positive in patients with metabolic acidosis if there are low levels of urine NH4+, the major unmeasured cation, secondary to impaired urine acidification.
In most cases classic dRTA is acquired. Major causes include immunologic diseases (e.g., Sjögren syndrome) and drugs (e.g., lithium, amphotericin). Rarely, classic distal RTA can occur during pregnancy, although it typically resolves after delivery. Genetic causes have also been reported, such as autosomal dominant (and, rarely, autosomal recessive) mutations in the gene encoding AE1, as well as autosomal recessive mutations in subunits of the apical proton pump.
No matter the cause, classic dRTA generally features hypokalemia, at least in part because the lack of proton secretion in the collecting duct increases the gradient for potassium secretion. Nephrolithiasis and/or nephrocalcinosis are also common, since calcium precipitation is favored by urine alkalinity, which results from failure of proton secretion, and hypocitraturia, which results from the increased citrate reabsorption that occurs in response to acidosis. Metabolic bone disease (osteomalacia or rickets) may occur because of the effects of acidosis on bone, even though calcium and phosphate levels are usually normal. In patients with autosomal recessive dRTA, progressive and irreversible bilateral sensorineural hearing loss is common, reflecting the functional significance of the H+ pump in the cochlea.
Classic dRTA is treated with alkali replacement. If treatment is not instituted early on, however, chronic kidney disease may occur secondary to nephrocalcinosis or uncontrolled nephrolithiasis with consequent obstruction. Of note, alkali treatment does not improve deafness in patients with autosomal recessive disease because orally administered alkali cannot access the inner ear compartment.
Hyperkalemic dRTA is chiefly a by-product of distal nephron dysfunction secondary to aldosterone resistance or deficiency. Acidosis reflects both the absence of aldosterone-induced proton secretion and the inhibitory effects of hyperkalemia on ammoniagenesis.
Most cases are related to drugs or to hyporeninemic hypoaldosteronism. The most commonly implicated drugs include trimethoprim, cyclosporine, and ACE inhibitors. Trimethoprim acts as an antagonist of the ENaC, whereas cyclosporine inhibits the basolateral Na+/K+ ATPase. Hyporeninemic hypoaldosteronism is most often found in the context of renal insufficiency, especially that caused by diabetes mellitus.
Hyperkalemic dRTA is treated by withdrawing precipitating drugs and providing sodium bicarbonate. Fludrocortisone and/or potassium-lowering drugs, such as oral resins, are also helpful, since reducing serum potassium concentrations increases renal ammo- niagenesis and ammonia excretion.

The entity of transient mixed proximal/distal RTA arising just after birth is thought to mark a developmental hiatus in distal nephron function, which normally continues to mature after birth. Nontransient RTA with both proximal and distal tubular dysfunction does, however, accompany one form of autosomal recessive osteopetrosis (Guibaud-Vainsel syndrome or marble brain disease). Investigators have identified loss of carbonic anhydrase 2, an enzyme expressed both throughout the nephron and in osteoclasts, as the biochemical defect. The disease presents in infancy, with major signs including thickened but brittle bones, short stature, mental retardation, dental malocclusion, and visual impairment from optic nerve com ression. Calcification of the basal ganglia may occur.

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