Abstract

1. Renal tubular acidosis (RTA) is a clinical syndrome characterized by hyperchloremic metabolic acidosis secondary to an abnormality in renal acidification. The acidification defect may be manifested by an inappropriately high urine pH, bicarbonaturia, and, by definition, reduced net acid excretion. Classical distal renal tubular acidosis and proximal renal tubular acidosis are frequently associated with hypokalemia. Distal renal tubular acidosis can also result from a generalized dysfunction of the distal nephron, in which case it is usually accompanied by hyperkalemia and may be associated with either hypoaldosteronism or aldosterone resistance.

   
   

2. Proximal renal tubular acidosis may result from an isolated defect of acidification in the proximal nephron. The isolated defect in acidification could be the result of selective dysfunction of the Na⁺/H⁺ antiporter, the proximal tubule H⁺-ATPase or the Na⁺/HCO₃ ⁻/CO₃ ⁼ symporter.

   
   

3. More commonly, proximal renal tubular acidosis occurs as one manifestation of a generalized defect in proximal tubule function. Patients with this generalized abnormality, the Fanconi syndrome, usually have glycosuria, aminoaciduria, citraturia, and phosphaturia. The acidification defect associated with this generalized tubular dysfunction may be the result of (a) impairment of cellular ATP generation, (b) cellular phosphate depletion, or (c) a selective abnormality of the basolateral Na⁺, K⁺-ATPase.

   
   

4. Vitamin D deficiency is associated with the Fanconi lesion. The transport defect may be due to a combination of factors including reduction in 1,25-dihydroxy vitamin D₃ levels, elevated parathyroid hormone levels, hypocalcemia, and intracellular phosphate depletion.

   
   

5. The diagnosis of proximal renal tubular acidosis is based on the demonstration of a chronic hyperchloremic metabolic acidosis and an acid urine pH. Correction of the metabolic acidosis with alkali raises the plasma bicarbonate level above the renal threshold and results in prominent bicarbonaturia and an alkaline urine pH. The fractional excretion of bicarbonate may exceed 15 percent of the filtered load in such conditions, and hypokalemia is common. Bone disease, which commonly accompanies this disorder, is expressed as rickets in children and osteopenia in adults.

   
   

6. The goal of therapy in proximal renal tubular acidosis is to maintain a near normal serum bicarbonate concentration while avoiding potassium deficiency. Concomitant administration of thiazide diuretics to reduce intravascular volume, and secondarily to reduce the filtered load of bicarbonate, is often beneficial.

   
   

7. The mechanisms underlying hypokalemic classical distal renal tubular acidosis have not been fully elucidated. Nevertheless, important advances in our understanding of the molecular bases of this disorder have been made recently. Distal RTA may be inherited or acquired. The hypokalemia that is particularly prevalent in the acquired forms, suggests a lesion in the medullary collecting duct or a selective lesion in the cortical collecting tubule. Possible mechanisms include an abnormal leak pathway or “gradient” lesion or a “secretory” defect. An example of a leak defect is that induced by amphotericin B in which the urine minus the arterial blood PCO₂ (U−B PCO₂) is normal. Only two patients, both young children, have been reported in which a normal U−B PCO₂ was present in the absence of exposure to amphotericin B, suggesting a nonamphotericin-acquired “gradient” lesion. The observed low U-?B PCO₂ gradient in most patients with distal renal tubular acidosis studied thus far argues against a gradient lesion and suggests a rate or secretory defect as the underlying mechanism. The rate of distal H⁺ secretion could be impaired as a result of a defect in: (a) the apical H⁺-ATPase; (b) the apical H⁺,K⁺-ATPase; (c) the basolateral HCO₃ ⁻/Cl⁻ exchanger; or (d) the enzyme carbonic anhydrase present in the cytoplasm of kidney cells (CA II).

   
   

8. Most patients with classical hypokalemic distal renal tubular acidosis have the condition in association with a systemic illness (acquired). Most available evidence, derived from studies using renal biopsies in patients with acquired distal RTA, suggests that acquired distal RTA is a result of abnormal function of the H⁺-ATPase in the collecting tubule. Classical hypokalemic distal renal tubular acidosis also occurs as an isolated defect inherited as an autosomal dominant trait. Recent studies have demonstrated an association between a missense mutation in the HCO₃ ⁻/Cl⁻ exchanger or band 3 protein (AE1 gene) and autosomal dominant distal RTA in several families. It has been proposed that the HCO₃ ⁻/Cl⁻ exchanger is misdirected to the apical membrane of type A intercalated cells in patients with the inherited form of distal RTA. This hypothesis is not proven. An endemic form of distal RTA, common in northeastern Thailand, appears to be the result of abnormal function of the renal H⁺,K⁺-ATPase. This association is not proven. Finally, distal RTA is a component of the CA II deficiency syndrome: osteopetrosis, distal RTA, and mental retardation. Patients with this autosomal recessive defect have been demonstrated to have one of several abnormalities in CA II. Most patients, however, appear to have a mixed form of proximal and distal RTA. Therefore, acquired and inherited forms of distal RTA may have diverse etiologies, all of which impair distal acidification and net acid excretion.

   
   

9. Classical hypokalemic distal renal tubular acidosis (type I RTA) is characterized clinically by an inability to acidify the urine appropriately during metabolic acidosis. Most but not all patients have a low U−B PCO₂ gradient. Hypokalemia, hypercalciuria, and hypocitraturia frequently accompany this disorder, but proximal tubular reabsorptive function is preserved. Chronic metabolic acidosis results in calcium, magnesium, and phosphate wasting which may be associated with dissolution of bone and nephrocalcinosis.

   
   

10. Untreated classical distal renal tubular acidosis produces growth retardation in children and progressive renal and bone disease in adults. Correction of the acidosis by alkali administration leads to correction of the accompanying hypokalemia, sodium depletion, hypercalciuria, and results in an increase in citrate excretion, which decreases the frequency of nephrolithiasis. Restoration of normal growth and prevention of nephrocalcinosis are the major goals of therapy.

    
    

11. A generalized dysfunction of the distal nephron produces distal renal tubular acidosis in association with hyperkalemia. This type of distal RTA (type 4) is quite common, but may be of diverse etiologies.

    
    

12. Aldosterone deficiency results in hyperkalemia and metabolic acidosis by decreasing the activity of the apical epithelial sodium channel, the basolateral Na⁺,K⁺-ATPase, or the force of one of the proton pumps in the collecting tubule. The hyperkalemia has independent effects on net acid excretion by reducing renal ammoniogenesis and ammonium transport in the thick ascending limb of Henle's loop, thereby impairing ammonium excretion.

    
    

13. Mineralocorticoid resistance also causes hyperkalemic-hyperchloremic metabolic acidosis in children and adults. Pseudohypoaldosteronism type I (PHAI) in children is associated with hyperkalemia, salt wasting, and metabolic acidosis. It was recently reported that PHAI is the result of a loss-of-function mutation of the apical epithelial sodium channel in the cortical collecting tubule (ENaC). Children with PHAI respond to correction of the salt and fluid deficits. Conversely, in adults, pseudohypoaldosteronism type 2 (PHAII), or Gordon syndrome (familial hyperkalemia and hypertension), is associated with volume expansion, hypertension, and hyperkalemic metabolic acidosis. Because these patients respond to dietary salt restriction and thiazide diuretics, it has been suggested that this disorder occurs as a result of a gain-in-function mutation of the electroneutral Na⁺-Cl⁻ cotransporter in the distal convoluted tubule (NCC1). Although linkage analysis has failed to substantiate such an association, recent studies have demonstrated linkage of PHAII to chromosome 1q31-q42 and to chromosome 17p11-q21, a locus that is implicated in blood pressure regulation (QTL).

    
    

14. In some patients, this defect can be acquired as a result of a “voltage” defect that limits the rate of proton secretion by the cortical collecting tubule at any given luminal pH and impairs potassium secretion. In addition, however, this defect involves compromise in the function of the H⁺-ATPase and cannot be ascribed merely to inability to generate a negative transepithelial potential difference.

    
    

15. Renal insufficiency, especially in association with diabetes and tubulointerstitial disease, may be associated with hyperkalemia and evidence of compromise of distal acidification. The hyperkalemia is out of proportion to the reduction in glomerular filtration rate. Underlying this disorder is either mineralocorticoid deficiency or mineralocorticoid resistance. As in primary mineralocorticoid deficiency, metabolic acidosis is secondary, in part, to the hyperkalemia and to a compromise in the H⁺-ATPase or H⁺,K⁺-ATPase. Correction of the chronic hyperkalemia may result in improvement of the acidosis.

    
    

16. Patients with hyporeninemic hypoaldosteronism and chronic renal insufficiency may require cation exchange resins, alkali therapy, and a loop diuretic to enhance renal potassium and salt excretion. Mineralocorticoid therapy, which may be necessary in mineralocorticoid deficiency, should be administered in combination with a loop diuretic in edematous or hypertensive patients to avoid volume overexpansion and aggravation of hypertension.

    
    

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