Renal Tubular Acidosis for the ABIM

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Renal Tubular Acidosis for the American Board of Internal Medicine Exam

Renal tubular acidosis (RTA) refers to a group of disorders characterized by an inability of the renal tubules to appropriately manage acid-base balance, leading to hyperchloremic metabolic acidosis. Unlike other causes of metabolic acidosis, RTA occurs without an elevated anion gap. There are four main types of RTA, each associated with defects at different sites along the nephron.

Type 1 (Distal RTA):
Defect in hydrogen ion secretion in the distal nephron, leading to an inability to acidify the urine (urine pH >5.5) despite systemic acidosis.
Etiology:
Idiopathic, autoimmune diseases (e.g., Sjögren's syndrome, systemic lupus erythematosus), genetic mutations, hypercalciuria, or medications (e.g., amphotericin B, lithium).
Pathophysiology:
Impaired H⁺ secretion in the distal nephron leads to acid retention in the body, resulting in metabolic acidosis. Inadequate H⁺ secretion also decreases the reabsorption of filtered bicarbonate (HCO₃⁻), worsening acidosis.
Clinical Features:
Hypokalemia, hypercalciuria, nephrolithiasis, nephrocalcinosis, failure to thrive in children, bone demineralization (rickets/osteomalacia).
Complications:
Chronic metabolic acidosis may result in calcium phosphate kidney stones due to increased urinary calcium and alkaline urine.

Type 2 (Proximal RTA):
Defect in bicarbonate reabsorption in the proximal tubule, leading to excessive bicarbonate loss.
Etiology:
Hereditary disorders (e.g., Fanconi syndrome), multiple myeloma, carbonic anhydrase inhibitors (e.g., acetazolamide), heavy metals (e.g., lead), vitamin D deficiency.
Pathophysiology:
The proximal tubule is unable to reabsorb filtered bicarbonate, leading to bicarbonaturia and systemic acidosis. As the filtered bicarbonate drops, urinary pH initially increases but later becomes acidic (<5.5) as distal acidification compensates.
Clinical Features:
Hypokalemia, bone demineralization, glucosuria (Fanconi syndrome), phosphaturia, aminoaciduria.
Complications:
Bone disease (rickets in children, osteomalacia in adults), growth retardation, metabolic bone disease.

Type 4 (Hyperkalemic RTA):
Impaired aldosterone secretion or resistance leads to defective potassium (K⁺) and hydrogen (H⁺) excretion, causing hyperkalemia and metabolic acidosis.
Etiology:
Hypoaldosteronism (primary or secondary), diabetic nephropathy, interstitial nephritis, medications (e.g., ACE inhibitors, ARBs, NSAIDs, heparin, cyclosporine), Addison’s disease.
Pathophysiology:
Decreased aldosterone activity impairs both K⁺ and H⁺ excretion in the distal nephron, leading to hyperkalemia and a mild acidosis.
Clinical Features:
Hyperkalemia, mild metabolic acidosis, usually no nephrolithiasis, but associated with progressive kidney dysfunction in chronic kidney disease (CKD).
Complications:
Arrhythmias from hyperkalemia, worsening kidney function, progressive CKD.

Type 3 RTA:
Rare and largely obsolete classification. It involves a combination of features of both distal and proximal RTA, seen in inherited disorders such as carbonic anhydrase deficiency. This type is no longer commonly used clinically.

In RTA, defects in renal tubular function prevent normal acid excretion and bicarbonate reabsorption, resulting in a non-anion gap hyperchloremic metabolic acidosis. Depending on the location of the defect in the nephron (proximal vs. distal), other associated findings such as electrolyte abnormalities (hypokalemia or hyperkalemia), nephrolithiasis, and bone disease (due to chronic acidosis) may be present.
Hypokalemia: Common in types 1 and 2 due to increased urinary potassium excretion, as potassium is exchanged for retained hydrogen ions.
Hyperkalemia: Seen in type 4 RTA due to aldosterone deficiency or resistance, leading to impaired potassium excretion.
Bone Disease: Chronic acidosis can result in bone demineralization due to buffering of excess hydrogen ions by bone calcium, which leaches calcium and phosphate from bones, increasing the risk of rickets and osteomalacia.

Blood Tests:
Hyperchloremic metabolic acidosis with a normal anion gap (typically 8–12 mEq/L), low bicarbonate, hyperkalemia in type 4, hypokalemia in types 1 and 2.
Urine pH:
In distal RTA (type 1), the urine pH is inappropriately high (>5.5) despite acidosis. In proximal RTA (type 2), urine pH is initially high but becomes acidic once the filtered bicarbonate load decreases.
Serum Potassium:
Low in types 1 and 2, high in type 4.
Fractional Excretion of Bicarbonate (FeHCO₃⁻):
In proximal RTA, FeHCO₃⁻ is elevated (>15%), indicating bicarbonate wasting.
Ammonium Chloride Challenge Test:
In type 1 RTA, an oral ammonium chloride load fails to lower urine pH <5.5.
Urinary Anion Gap:
Helps differentiate between RTA and other causes of metabolic acidosis. A positive urinary anion gap (urine Na⁺ + K⁺ - Cl⁻) suggests impaired ammonium excretion, as seen in RTA.

Type 1 RTA:
Alkali therapy (oral sodium bicarbonate or potassium citrate) to correct acidosis, and potassium supplementation if needed. In some cases, thiazide diuretics may be used to reduce hypercalciuria.
Type 2 RTA:
High doses of alkali (sodium bicarbonate or potassium citrate) to compensate for bicarbonate losses. Potassium supplements are usually necessary due to urinary potassium wasting.
Type 4 RTA:
Treatment of hyperkalemia with potassium-binding agents (e.g., sodium polystyrene sulfonate) and correction of acidosis with bicarbonate or fludrocortisone in cases of hypoaldosteronism. Managing the underlying disease (e.g., diabetes, adrenal insufficiency) is also crucial.

Nephrolithiasis: Particularly common in type 1 RTA due to hypercalciuria and alkaline urine, leading to calcium phosphate stone formation.
Bone Disease: Chronic acidosis contributes to bone demineralization, causing rickets in children and osteomalacia in adults.
Chronic Kidney Disease (CKD): Prolonged acidosis, hyperkalemia, and nephrocalcinosis can contribute to progressive renal dysfunction, particularly in type 4 RTA.

Key Points

Renal tubular acidosis is a disorder of acid-base regulation due to defects in renal tubular function, leading to non-anion gap hyperchloremic metabolic acidosis.
Type 1 (distal RTA) is characterized by impaired H⁺ secretion, causing hypokalemia, hypercalciuria, nephrolithiasis, and an inability to acidify the urine.
Type 2 (proximal RTA) involves defective bicarbonate reabsorption, resulting in bicarbonate wasting, bone disease, and hypokalemia.
Type 4 (hyperkalemic RTA) is caused by aldosterone deficiency or resistance, leading to hyperkalemia and mild acidosis.
Diagnosis involves identifying hyperchloremic metabolic acidosis, assessing urine pH, and measuring serum potassium.
Treatment includes alkali therapy (sodium bicarbonate or potassium citrate), potassium supplements, and addressing underlying causes such as autoimmune disease or medications.