Type 4 RTA

Type 4 RTA, also known as hyperkalemic renal tubular acidosis, is a distinct variety of RTA characterized primarily by impaired aldosterone action. It is distinguished from other RTAs by the presence of hyperkalemia. This type is less common in children compared to Type 1 (Distal) and Type 2 (Proximal) RTA.

Pathophysiology and Mechanism

Type 4 RTA is fundamentally a disorder of tubular salt handling.

1. Impaired Aldosterone Action: Type 4 RTA results from either impaired aldosterone production (hypoaldosteronism) or impaired renal responsiveness to aldosterone (pseudohypoaldosteronism).
2. Hyperkalemia and Acidosis: The lack of effective aldosterone leads to hyperkalemia. Aldosterone is a potent stimulant for potassium secretion in the collecting tubule, and its absence results in the retention of potassium. Hyperkalemia then further exacerbates the acid-base imbalance by inhibiting ammoniagenesis, thus impairing ${\text{H}}^{+}$ excretion.
3. Distal Acidification Defect (Voltage Defect): Although Type 4 RTA is described as a form of distal RTA, the primary defect is a failure to reabsorb sodium in the collecting duct (making it a salt-wasting disorder). This failure causes a secondary defect in distal acidification known as a "voltage defect". Aldosterone is also noted to have a direct effect on the ${\text{H}}^{+}/\text{ATPase}$ responsible for hydrogen secretion.

Etiology

Type 4 RTA can be inherited or acquired (secondary).

Acquired Causes

Acquired forms are often associated with underlying kidney damage or medications:

• Tubulointerstitial Damage: Acquired aldosterone deficiency is often associated with obstructive uropathy and interstitial kidney disease (such as pyelonephritis or tubulointerstitial nephritis).
• Systemic Diseases/Structural Issues: Other conditions associated with acquired Type 4 RTA include Lupus nephritis, Sickle cell disease, and kidney transplant rejection. Chronic obstructive uropathy often results in acquired RTA and hyperkalemia.
• Drugs: Medications that interfere with aldosterone production or action can cause Type 4 RTA. These include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and potassium-sparing diuretics (e.g., spironolactone, eplerenone, or the ENaC blocker amiloride). Drugs like cyclosporine and tacrolimus are also listed among agents causing mineralocorticoid resistance or interfering with tubular function.

Inherited Causes

• Aldosterone Unresponsiveness (Pseudohypoaldosteronism, PHA): In children, aldosterone unresponsiveness is a common cause of Type 4 RTA. Rare inherited forms of Type 4 RTA, particularly pseudohypoaldosteronism type 2 (PHA II), are linked to mutations in WNK1, WNK4, KLHL3, and CUL3 genes. Variants in CUL3 are typically de novo and are associated with extrarenal manifestations, especially growth failure.
• Aldosterone Deficiency: This typically results from adrenal gland disorders such as Addison disease or some forms of congenital adrenal hyperplasia.

Clinical Manifestations and Diagnosis

Patients present with hyperkalemic non–anion gap metabolic acidosis. Patients with chronic obstructive uropathies may have significant hyperkalemia even when renal function is normal or only mildly impaired.

Clinical features can include growth failure in the first few years of life, polyuria, and dehydration resulting from salt wasting. Rarely, patients (especially those with pseudohypoaldosteronism type 1) may present with life-threatening hyperkalemia.

Key diagnostic features differentiating Type 4 RTA from other RTA types are summarized below:

Treatment

The treatment for Type 4 RTA focuses on managing the primary electrolyte abnormality, hyperkalemia, and correcting the acidosis.

Patients may require chronic treatment for hyperkalemia using a sodium-potassium exchange resin (e.g., sodium polystyrene sulfonate or patiromer).