Renal Tubular Acidosis (RTA)
The term renal tubular acidosis (RTA) is applied to a group of transport defects in the reabsorption of bicarbonate (HCO3−), the excretion of hydrogen ion (H+), or both.
The RTA syndromes are characterized by a relatively normal GFR and a metabolic acidosis accompanied by hyperchloremia and a normal plasma anion gap.
RTA occurs due to tubular defects leading to systemic acidosis with preserved GFR.
The degree of acidosis varies with the type of RTA:
In distal (type 1) RTA, there is hydrogen ion retention and fall of plasma bicarbonate to even less than 10 mEq/L. The urine pH is 5.5 or higher, while patients with metabolic acidosis not due to RTA have a urine pH that is 5.3 or less. Distal (type 1) RTA is characterized by an impaired capacity for hydrogen ion excretion. Hence, there is a decrease in ammonium secretion in the collecting tubules. There is a high urine pH (5.3 or higher) even during systemic acidosis with plasma bicarbonate <15 mEq/l. DRTA results from one of several defects in distal hydrogen ion secretion. Decreased proton pump (H-ATPase) activity causes: (i) Increased luminal membrane permeability with back leak of hydrogen ions, (ii) voltage defect, and (iii) rate defect. Voltage defect is often associated with hyperkalemia.
In proximal (type 2) RTA, whenever the plasma bicarbonate is above the threshold, that is, 15 mEq/l there is bicarbonate wasting. The distal segments can absorb up to 15% bicarbonate, hence some bicarbonate which is not absorbed in the proximal tubule in PRTA is absorbed by the distal tubule; however, if plasma bicarbonate is above the threshold, that is, 15 mEq/l there is bicarbonaturia. Plasma bicarbonate concentration is usually between 15 ± 3 meq/L in untreated patients. The urine pH is appropriately low (5.3 or less) in untreated patients. Proximal (type 2) RTA occurs as an isolated defect or along with generalized dysfunction of the proximal tubule (Fanconi syndrome). It is characterized by bicarbonaturia, glucosuria, phosphaturia, uricosuria aminoaciduria, and tubular proteinuria. Hypophosphatemia and hypouricemia are seen.
Type 3 is combined proximal and distal RTA.
Type 4 is hyperkalemic RTA.
Distal (type 1) RTA – The most common causes of DRTA in adults are autoimmune disorders and other conditions associated with chronic hyperglobulinemia. In children, DRTA is most often a primary, hereditary condition.
Proximal (type 2) RTA – The most common cause of PRTA with or without Fanconi syndrome in adults is monoclonal gammopathy. In children, inherited diseases are most often responsible for PRTA. Isolated RTA is rare in children and Fanconi’s is the commonest presentation.
Hyperkalemic RTA accompanies a large number of hyperkalemic states and is most frequently observed in states of hypo- or pseudohypoaldosteronism, either isolated or appearing in the context of chronic renal parenchymal damage. Nephrocalcinosis and urolithiasis are absent in this disorder, and bone lesions are seen only in uremic subjects.
Distal RTA (Type 1) –
Distal RTA shares features with those of pRTA, including non–anion gap metabolic acidosis and growth failure; distinguishing features of distal RTA include nephrocalcinosis and hypercalciuria.
The phosphate and massive bicarbonate wasting characteristic of pRTA is generally absent.
Proximal RTA (Type 2) –
Patients with isolated, sporadic, or inherited pRTA present with growth failure in the 1st year of life. Additional symptoms can include polyuria, dehydration (from sodium loss), anorexia, vomiting, constipation, and hypotonia.
Patients with primary Fanconi syndrome have additional symptoms, secondary to phosphate wasting, such as rickets.
Type IV RTA –
Patients with type IV RTA can present with growth failure in the 1st few years of life.
Polyuria and dehydration (from salt wasting) are common.
Rarely, patients (especially those with pseudohypoaldosteronism type 1) present with life-threatening hyperkalemia.
Patients with obstructive uropathies can present acutely with signs and symptoms of pyelonephritis, such as fever, vomiting, and foul-smelling urine.
For DRTA, the immediate step in the diagnostic workup is to measure plasma K+ concentration. If the value pf plasma K+ is normal or decreased, the demonstration of an inability to lower urine pH below 5.5, either after NH4Cl loading or after furosemide administration, establishes the diagnosis of distal RTA.
The definitive diagnosis of proximal RTA is accomplished by the demonstration of a low urine pH at low plasma HCO3− concentration and by the presence of normal urine Pco2 and a high urine HCO3− excretion at normal plasma HCO3− concentration. Patients with PRTA should be evaluated for renal glycosuria, hypophosphatemia, and hypouricemia to rule out Fanconi’s syndrome.
Diagnostic work-up should always include the search for nephrocalcinosis by ultrasonography and the measurement of urinary excretion of calcium and citrate.
DRTA – The daily bicarbonate requirement is only 1-2 mEq/kg per day to replace the daily acid load. If detected early in life, therapeutic correction of the acidosis by continuous alkali administration may induce resumption of normal growth, the arrest of nephrocalcinosis, and preservation of renal function.
PRTA – Most children require 10-15 mEq/kg of bicarbonate per day to maintain a normal pH.
Type IV RTA – Patients with type IV RTA can require chronic treatment for hyperkalemia with sodium-potassium exchange resin (i.e., sodium polystyrene sulfonate).
Primary distal RTA is a permanent disease, and therapy should be maintained throughout life. Nevertheless, the prognosis is excellent if the diagnosis has been performed early in life and appropriate amounts of alkali supplements are continuously administered. Alkali therapy restores growth in children and prevents the progression of nephrocalcinosis at all ages. However, if therapy is delayed to late childhood or adulthood progression to end-stage renal insufficiency may not be avoided.
Prognosis of proximal RTA depends on the underlying etiology, especially in cases observed in the context of the Fanconi syndrome. However, in children with sporadic isolated proximal RTA, the tubular defect improves over time, and therapy can be generally discontinued at about 3 to 5 yr of age.