Fanconi's Syndrome ⁝ Proximal RTA

I. Definition and Pathophysiology

Fanconi Syndrome is classified under Type 2 Renal Tubular Acidosis (RTA).

  1. Proximal Tubule Defect: Type 2 RTA is defined by a problem in the proximal convoluted tubule (PCT) reabsorption of bicarbonate.
  2. Global Defect: FS is characterized as a complete inactivation or global defect of the PCT. Unlike other renal tubular defects (e.g., Bartter’s or Gitelman’s) which involve a defect in a specific transporter, FS affects the PCT function globally.
  3. Solute Loss (Mechanism): The PCT is normally responsible for maximum absorption, including 67% of sodium and water, and 100% of glucose and amino acids, along with potassium and phosphate. In FS, solutes normally reabsorbed by the PCT are excreted in the urine.
  4. Specific Losses: Along with defective bicarbonate reabsorption, FS results in the excretion of amino acids, glucose, and phosphate.

II. Etiology (Causes of Fanconi Syndrome)

Causes are broadly categorized into hereditary and acquired forms.

Category Specific Causes Details
Hereditary (Most common cause in children: Cystinosis) Cystinosis, Wilson's disease, Tyrosinemia, Type 1 glycogen storage disease, Galactosemia, and Dent disease. These are important hereditary causes.
Acquired Drugs: Expired tetracyclines, Tenofovir, Ifosfamide, and Cisplatin. Drugs play a major role.
Ischemia. A recognized acquired cause.
Multiple Myeloma. Light chains are reabsorbed by the PCT, causing complete damage to PCT cells.
Heavy Metal Poisoning Cadmium, Lead, and Mercury. Cadmium is often the answer of choice if both Cadmium and Lead are available in options.
Other Conditions Amyloidosis, Renal transplantation (less common), Vitamin D deficiency, Paroxysmal nocturnal hemoglobinuria (PNH), and Jochran syndrome (though this more commonly causes distal RTA).

III. Clinical Presentation

Clinical features arise from the loss of key compounds that the PCT fails to reabsorb.

  1. Fluid and Electrolyte Imbalance:

    • Polyuria (production of urine greater than 3 liters per day) is the most important clinical feature due to the excretion of large amounts of sodium and water.
    • Polyuria leads to polydipsia (excessive thirst) and hypovolemia.
    • Hypokalemia: Prolonged loss of potassium in the urine leads to decreased serum potassium. Significant hypokalemia (less than 3 mEq/L) causes muscle wasting and muscle weakness.

  2. Skeletal and Growth Issues:

    • Phosphate Excretion: Loss of phosphate leads to decreased phosphate concentration in the blood (Hypophosphatemia).
    • This results in hypophosphatemic rickets in children. Phosphate is essential, along with calcium, for forming the bone matrix (hydroxyapatite).
    • In adults, phosphate loss leads to osteomalacia.
    • Growth Failure (Stunted Growth): This is the most common clinical finding in children with FS, often caused by hereditary factors. Growth failure is linked to chronic hypokalemia, rickets, volume depletion, and persistent acidosis (acidosis decreases blood pH, inhibiting enzyme function necessary for growth metabolism).

  3. Metabolic Acidosis: FS causes metabolic acidosis due to the loss of bicarbonate in the urine, increasing hydrogen ion concentration in the blood.

  4. Nephrocalcinosis (Calcium Stones):

    • The development of bilateral nephrocalcinosis (calcium stones) depends heavily on urinary pH.
    • Golden Rule: Calcium precipitates only in an alkaline solution.
    • Typically, distal acidification is normal, keeping the urinary pH acidic (around 4.5 to 5 or less than 6), meaning stones usually do not form.
    • However, if a high bicarbonate load reaches the collecting ducts and hydrogen ion secretion cannot compensate, the urine pH becomes high (alkaline, e.g., greater than 6.5 or 7), leading to calcium stone precipitation.
    • In advanced, long-standing cases, if distal acidification also becomes impaired, alkaline urine forms, and nephrocalcinosis will develop.

IV. Diagnosis

Diagnosis relies on serum and urine findings.

  1. Serum Findings:

    • Normal anion gap hyperchloremic metabolic acidosis.
    • Hypokalemia.
    • Hypouricemia.
    • Hypophosphatemia.

  2. Urine Findings:

    • Glucosuria.
    • Aminoaciduria.
    • Urinary pH: Generally less than 5.5 (4.5 to 5) because distal acidification is normal.

  3. Specific Diagnostic Test:

    • Bicarbonate infusion test is performed. Since the PCT cannot reabsorb the bicarbonate, the infused bicarbonate goes to the collecting duct, causing the urinary pH to rise above 7.5.

V. Treatment

Treatment primarily focuses on replacing lost alkali and electrolytes.

  1. Initial Therapy: Clinicians prescribe 10 to 15 mEq/kg/day of alkali in divided doses to overcome bicarbonate losses and raise serum levels.
  2. Hypokalemia Warning: The initiation of alkali therapy stimulates potassium secretion in the distal tubule and increases urinary potassium losses, causing hypokalemia to worsen.
  3. Combination Treatment: Due to the worsening hypokalemia, the treatment must be a combination of Alkali plus Potassium citrate to replace lost potassium.
  4. Second Line: Thiazide diuretics are administered if alkali is not well tolerated or effective. Thiazide diuretics cause volume depletion and enhance bicarbonate reabsorption.