Renal tubular acidosis

Renal acid-base regulation in the developing kidney

A tight control of pH is relatively efficient since birth. However, it is well established that the renal bicarbonate threshold is lower in neonates compared with older infants and children. The plasma concentration of bicarbonate is within the range of 20–22 mmol/L in term healthy infants and in the range of 18–20 mmol/L in preterm infants. Bicarbonate concentrations as low as 14 mmol/L can be observed in extremely preterm infants. Adult values are achieved during the first year of life. This “physiological acidosis” observed in neonates can be explained by the immaturity of glomerular filtration rate (GFR) and tubular function during the transition from a fetal to an extrauterine environment.

Retracing the steps of the acidification process at different nephron levels, several mechanisms that reduce the kidneys’ ability to maintain acid-base homeostasis can be identified in neonates ( Table 13.1 ).

The postnatal maturation of tubular transporters is under hormonal control. Experimental studies show that prenatal glucocorticoids stimulate neonatal juxtamedullary proximal convoluted tubule acidification. The postnatal rise of thyroid hormones and glucocorticoids increases messenger RNA expression and the activity of NHE3 and Na ⁺ /K ⁺ -ATPase pumps.

In very preterm infants, the state of relative expansion of the extracellular fluid volume, the disparate maturity of nephrons, as well as some glomerulotubular imbalance during postnatal development are responsible for a greater difficulty to maintain high levels of plasma bicarbonate. The urinary excretion of titratable acids (mostly in the form of phosphates) and ammonia is lower in preterm infants compared with infants born at term and increases as a function of gestational age. This maturation process is quite abrupt and occurs by the age of 1 month, regardless of the gestational age at birth. Human studies showed that the renal mechanisms for preserving bicarbonate to compensate for the acid load delivered by milk intake are normally effective enough in preterm infants. However, considering the age-specific low capacity for renal acidification, attention has been given traditionally to reducing acid load of preterm formula, as this prevents the development of “incipient late metabolic acidosis” in formula-fed preterm babies. This entity, which is rare nowadays, was characterized by persistent maximum renal acid excretion (urinary pH < 5.4), with normal or almost normal systemic acid–base status, in premature infants receiving alimentation with cow milk–based formulas. As the development of late metabolic acidosis lasted several days, exposed infants exhibited compensating mechanisms (volume contraction, hyperventilation, increased renal bicarbonate threshold), ensuring that their acid-base status in the blood remained within the normal values. “Incipient late metabolic acidosis” was accompanied by increased phosphaturia, decreased nitrogen assimilation, and impaired weight gain. More recently, a randomized controlled trial in breast milk–fed preterm infants showed that the addition of a milk fortifier with an acidic composition created a high renal acid load and induced the occurrence of metabolic acidosis, with consequent effects on growth and bone mineralization.

Finally, several drugs administered in neonatal intensive care units may be responsible for RTA, as they can increase base loss or decrease renal acid excretion: (1) both dopamine and carbonic-anhydrase inhibitors (acetazolamide) lower the renal bicarbonate threshold by decreasing the apical sodium ion (Na ⁺ /H ⁺ ) exchanger activity; (2) K ⁺ -sparing diuretics reduce the excretion of H ⁺ into distal tubular fluid ; (3) gentamicin interferes with the conversion of ADP to ATP, thus inhibiting the Na ⁺ /K ⁺ -ATPase pump, and also inhibits NHE3 pump activity ; and (4) amphotericin B might lead to pores in collecting duct cell membranes. This results in K ⁺ waste and a back-flux of H ⁺ into the cells, which inhibits collecting duct urinary H ⁺ excretion.

Proximal renal tubular acidosis (type 2 and fanconi syndrome)

Proximal renal tubular acidosis (pRTA) (RTA type 2) is caused by a defect in tubular transport of bicarbonate and characterized by a low renal threshold of bicarbonate. The defect may present as a single dysfunction of the proximal tubule, which relates exclusively to the reabsorption of bicarbonate and occurs without alterations in the transport of other solutes. This form, called isolated pRTA, can be inherited or acquired. The acquired form is essentially due to the administration of carbonic-anhydrase inhibitors (acetazolamide). These diuretics are occasionally used in the treatment of posthemorrhagic hydrocephalus in newborn infants, but more often as a treatment of congenital glaucoma until surgery can be performed. Inherited, isolated pRTA is a very rare disease that can present at birth. The implicated gene is the SLC4A4 , encoding the membrane Na ⁺ /HCO ₃ ⁻ cotransporter (NBC1) ( Table 13.2 ). ^, The mutation can be autosomal recessive, autosomal dominant, or sporadic. The autosomal recessive trait should be suspected in the presence of severe failure to thrive and with ocular abnormalities such as band keratopathy, glaucoma, or cataracts, and it is associated with intellectual developmental disability. ^, The autosomal dominant form has been reported in two distinct families showing similar clinical features, but the involved gene has not yet been identified. The sporadic isolated pRTA has been reported as a transient disease in infants, affecting renal and intestinal bicarbonate reabsorption.

In pRTA there is a low renal threshold for bicarbonate, and bicarbonate begins to appear in the urine at serum concentration of 15 mEq/L. At the outset of the disease, when the serum HCO ₃ ⁻ concentration is within the normal range, the filtered load of bicarbonates escaping proximal reabsorption will reach the distal tubule and will be excreted into the urine, thus producing an alkaline urine. Once the serum bicarbonate level has lowered below the renal threshold, HCO3 ⁻ lost by the defective proximal tubule can be reabsorbed by the intact distal tubule, thus the urinary pH decreases to less than 6.2 and urinary pH can be as low as <5.5. In addition, the delivery of the bicarbonate to the collecting duct occurs in the form of sodium bicarbonate, where some of the sodium is exchanged for potassium. This leads to increase in serum aldosterone concentration, mild volume depletion, and enhanced potassium excretion, which is responsible for significant hypokalemia. Newborn and young infants with isolated pRTA can present with mild or severe disease. The clinical manifestations of mild disease are usually limited to growth failure and lethargy. Severe symptoms are often related to untreated hypokalemia and patients present with dehydration, vomiting, polyuria, and feeding difficulties.

pRTA can be part of a generalized proximal tubule dysfunction (Fanconi syndrome), which includes pRTA, phosphaturia, glycosuria, and aminoaciduria. Fanconi syndrome is usually due to hereditary disorders, such as cystinosis (the most common cause of congenital Fanconi), galactosemia, tyrosinemia, hereditary fructose intolerance, and mitochondrial cytopathies . A discussion of inherited causes of Fanconi syndrome is beyond the scope of this review. The reader is referred to Quigley and Wolf for a more detailed description. Drug-induced Fanconi syndrome is exceptionally rare in neonates.

The treatment of pRTA consists of the administration of large amounts of oral alkali in the form of sodium salts (bicarbonate, citrate, or lactate), correction of water depletion, and potassium supplementation. As above previously, when serum bicarbonate levels are normalized, bicarbonaturia occurs, and supplements of HCO ₃ ⁻ as high as 15 mEq/kg per day can be required. Thiazides can be used to create mild hypovolemia, which encourages salt and bicarbonate uptake by the proximal tubule and in the loop of Henle. This may allow for a reduction of daily intakes of bicarbonate. Hypokalemia can be aggravated by the combination of sodium bicarbonate and thiazides, as their administration increases the K ⁺ secretion in the collecting duct. Therefore, potassium supplementation should be given together with these treatments, and careful monitoring of K serum concentration is needed. With proper treatment the prognosis of pRTA is good, but associated extrarenal features impact on patient outcomes. The correction of chronic acidosis is critical to avoid failure to thrive, and this can be avoided with proper treatment. In Fanconi syndrome, the long-term outcome is affected by associated extrarenal manifestations and underlying disease.

Distal renal tubular acidosis (type 1)

Distal renal tubular acidosis (dRTA) (RTA type 1) is the most common form of RTA. The hallmark of dRTA is failure of proton (H ⁺ ) secretion by the α-intercalated cells of the cortical collecting duct, in the presence of moderate to severe metabolic acidosis. The primary, or inherited dRTA, may present in infancy, childhood, or young adulthood and is transmitted as a dominant or recessive trait. Progress in genetics has allowed identification of six pathogenic variants in genes encoding the basolateral membrane Cl ⁻ /HCO ₃ ⁻ exchanger (AE1) or proteins/subunits of the apical H ⁺ -ATPase pump of α-intercalated cells (see Table 13.2 ). ^, The clinical manifestations of dRTA are growth retardation, anorexia, vomiting, polyuria, polydipsia, dehydration, constipation, and other symptoms of hypokalemia. Different underlying genetic mutations causing dRTA are associated with nephrocalcinosis and extrarenal symptoms, such as early or late deafness (see Table 13.2 ). ^, The biochemical characteristic of dRTA is a metabolic hyperchloremic acidosis, with a urinary pH remaining always higher than 6.2. Hypokalemia (from mild to severe) is present, due to urinary potassium loss, as potassium is the only proton exchanged with sodium, when distal secretion of H ⁺ is diminished. Hypercalciuria and hypocitraturia are seen in the forms with nephrocalcinosis.

Acquired forms of dRTA are rare in pediatric patients but can occur secondary to obstructive uropathies, drugs or toxin exposures, and autoimmune diseases.

The goal of the treatment in dRTA is the early correction of metabolic acidosis, which should start from the first months of life to ensure normal growth, and the prevention of complications, such as nephrocalcinosis and chronic kidney disease (CKD). Treatment by alkali is advised, and the amount of bases is modulated according to patient’s weight and needs. In general, forms with defective H ⁺ -ATPase protein require more oral alkalizers than those with defective AE1. The control of hypercalciuria is strongly facilitated by the correction of metabolic acidosis, as this raises urinary citrate. Bases are given in the form of sodium and potassium salts. In case of hypercalciuria, potassium citrate is the preferred treatment, as it reduces calcium excretion. The described treatments may not be well tolerated, because they cause gastrointestinal discomfort. A recent multicenter, open-label trial in adult patients and infants with dRTA showed the noninferiority, better palatability, and gastrointestinal safety of a new prolonged-release formulation, called ADV7103, compared with standard-of-care oral alkalizers.