Distal RTA

Definition and Pathophysiology

Distal RTA (Type 1) is defined by a selective defect in the secretion of hydrogen ions (${\text{H}}^{+}$) in the distal tubule (specifically the cortical collecting duct), resulting in hyperchloremic metabolic acidosis. This occurs in the absence of significant impairment of the glomerular filtration rate (GFR).

The underlying molecular defect involves impaired function of key transporters and proteins necessary for the acidification process:

1. H${}^{+}$-ATPase and H${}^{+}$/K${}^{+}$ ATPase: These pumps, located in the $\alpha$-intercalated cells of the cortical collecting ducts, secrete ${\text{H}}^{+}$ into the tubular lumen.
2. Anion Exchanger 1 (AE1 or ${\text{HCO}}_3^{-}$/${\text{Cl}}^{-}$ exchanger): This protein, located on the basolateral membrane of the $\alpha$-intercalated cells, mediates the exit of bicarbonate (${\text{HCO}}_3^{-}$) generated within the cell into the systemic circulation.

A defect in these mechanisms means the kidney cannot adequately excrete the daily acid load. For instance, retention of bicarbonate in the cytosol due to AE1 variants increases intracellular pH, impairing proton secretion.

Clinical and Pathophysiological Consequences

The failure of the distal tubule to excrete protons leads to several characteristic findings:

Acidosis and Urine pH

In the presence of systemic acidemia, patients with dRTA are unable to maximally decrease the urine pH; thus, the urine pH typically remains above 5.3 (or $>5.5$). This contrasts sharply with Proximal RTA (Type 2), where the distal acidification mechanism is intact, allowing the urine pH to fall below 5.3 during acidosis.

Electrolyte Abnormalities (Hypokalemia)

Hypokalemia is a classical, though variable, finding in dRTA. The mechanisms leading to potassium (${\text{K}}^{+}$) wasting include:

• Increased urinary losses of ${\text{K}}^{+}$ and aldosterone stimulation due to urinary ${\text{Na}}^{+}$ loss and volume contraction.
• Failure of distal acid secretion, which creates an electrochemical gradient favoring potassium secretion.
• Compensatory overactivity of the ${\text{H}}^{+}$/${\text{K}}^{+}$-ATPase in the collecting tubule.
• Impaired urinary concentrating ability and increased urinary flow rate activating ${\text{K}}^{+}$-secretion via BK-channels.

Severe hypokalemia can cause life-threatening complications, such as rhabdomyolysis and muscle paralysis, which may be a presenting sign of dRTA. Furthermore, ${\text{Na}}^{+}$ reabsorption may be impaired, resulting in salt wasting.

Bone Disease, Hypercalciuria, and Nephrocalcinosis

Chronic metabolic acidosis in dRTA is buffered by hydroxyapatite in the bone, leading to its dissolution. This process releases calcium, causing hypercalciuria and a negative calcium balance. The chronic acidosis impairs growth and can lead to rickets or osteomalacia.

Hypercalciuria, combined with hypocitraturia and an alkaline urine, creates a favorable environment for calcium-phosphate precipitation.

• Hypocitraturia (decreased urinary citrate) results from systemic acidosis increasing the proximal reabsorption of citrate, thereby reducing its concentration in the urine. Citrate is crucial as an antilithogenic agent and calcium chelator.
• This combination leads to nephrocalcinosis (medullary) (seen in almost all patients) and/or urolithiasis (renal stones), which is common, particularly in adulthood.

General Clinical Features

Patients usually present with failure to thrive or stunting. Other symptoms include polyuria, polydipsia, and, occasionally, hypokalemic muscle weakness. Patients with dominant inherited dRTA may present later in childhood or adolescence with urolithiasis. Non-specific symptoms like nausea, vomiting, and fatigue are also recognized.

Etiology and Genetics

dRTA can be inherited (primary) or acquired (secondary).

Inherited (Primary) Disorders

Genetic defects typically affect the AE1 exchanger or the ${\text{H}}^{+}$-ATPase pump subunits:

• Autosomal Dominant (AD) dRTA: Associated with mutations in the SLC4A1 gene (encoding AE1). This form can be associated with hemolytic anemia.
• Autosomal Recessive (AR) dRTA: Linked to mutations in the ${\text{H}}^{+}$-ATPase subunits, specifically the ATP6V1B1 or ATP6V0A4 genes.
• dRTA with Deafness: Associated with mutations in ATP6V1B1.
• dRTA with Amelogenesis Imperfecta (AI): Associated with recessive variants in the WDR72 gene.

Acquired (Secondary) Disorders

dRTA can be associated with systemic diseases or tubular damage:

• Autoimmune Disorders: Such as Sjögren syndrome or systemic lupus erythematosus.
• Tubulointerstitial Diseases/Structural Issues: Chronic pyelonephritis, kidney transplantation (rejection), or obstructive uropathy. Partial bilateral urinary tract obstruction often results in acquired dRTA and hyperkalemia.
• Toxins/Drugs: Amphotericin B, toluene, lithium, or calcineurin inhibitors.
• Other Conditions: Sickle cell disease (due to ischemic damage), Wilson disease, or hypercalciuria/nephrocalcinosis.

Diagnosis and Evaluation

The diagnosis usually follows the finding of hyperchloremic metabolic acidosis with a normal plasma anion gap (8–12 mEq/L). Key diagnostic evaluations include:

Incomplete Distal RTA is a variant where patients do not have overt systemic acidosis but exhibit impaired renal tubular acidification (failure to lower urine $\text{pH}$ below 5.3 after an acid load). This form is often identified during investigations for recurrent kidney stone disease and is associated with hypercalciuria and hypocitraturia.

Treatment

The goal of treatment is to correct the acidosis, which also reduces potassium losses and promotes growth and healing of rickets.

1. Treat Hypokalemia: Hypokalemia should be corrected before addressing the acidosis.
2. Alkali Supplementation: Acidosis is treated by administering sodium bicarbonate or sodium citrate (Shohl solution), with doses titrated to blood bicarbonate levels.
   • The base requirement is typically in the range of $\mathbf{2}\mathbf{-}\mathbf{4}\mathbf{mEq}\mathbf{/}\mathbf{kg}\mathbf{/}\mathbf{24}\mathbf{hr}$.
   • Alkali requirements generally decrease beyond 5 years of age.
   • Prolonged potassium replacement may be necessary for some patients.
   • Vitamin D supplements are not required because the bone disorder resolves upon correction of the metabolic acidosis.
3. Managing Hypercalciuria: Patients with symptomatic hypercalciuria, nephrocalcinosis, or nephrolithiasis may require thiazide diuretics to decrease urinary calcium excretion.

The prognosis is generally favorable for isolated dRTA when treated, leading to improved growth, provided serum bicarbonate levels are maintained in the normal range.