Fanconi syndrome - Etiology, Clinical Features, Pathology, Diagnosis and Treatment

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Fanconi syndrome - Etiology, Clinical Features, Pathology, Pathophysiology, Diagnosis and Treatment

Introduction
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Fanconi syndrome is categorized under Type 2 renal tubular acidosis in which the Inability of the proximal convoluted tubule cells to reabsorb HCO3-

Fanconi syndrome "not to be confused with Fanconi anemia" which is a defect in the proximal convoluted tubule in which amino acids, glucose, HCO3-, and PO43- are excreted rather than reabsorbed.

Fanconi anemia
• Hereditary autosomal recessive disorder due to a DNA crosslink repair defect resulting in bone marrow failure

Unlike other renal tubular defects e.g. Barrter, Gitleman, and Liddle syndromes, Fanconi syndrome is not a defect of a specific transporter, rather, it is a global defect in the PCT.

Causes of Fanconi syndrome include
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• Hereditary e.g. cystinosis, Wilson disease, tyrosinemia, glycogen storage disease type 1, Galactosemia
• Ischemia
• Heavy metals e.g. lead poisoning
• Multiple myeloma due to PCT light chain reabsorption
• Drugs e.g. expired tetracyclines, tenofovir, ifosfamide, cisplatin
• Light chain nephropathy e.g., multiple myeloma
• Amyloidosis
• Vitamin D deficiency
• Paroxysmal nocturnal hemoglobinuria
• Drugs: ifosfamide, tenofovir, expired tetracyclines, aminoglycosides
• Heavy metal poisoning e.g., lead, cadmium, mercury

Clinical Presentation
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The presentation of patients with Fanconi syndrome may be associated with a deficiency of any of the excreted solutes:
• Polyuria → polydipsia, hypovolemia
Polyuria
The production of an abnormally large amount of urine. Quantitatively defined as the passage of greater than 3 liters of urine in 24 hours.
Polydipsia
A condition of excessive thirst. It can be caused by organic e.g., dehydration, hypovolemia, hyperglycemia, diabetes insipidus, or non-organic conditions e.g., psychogenic polydipsia.
• Hypophosphatemic rickets in children; osteomalacia in adults due to loss of potassium
Due to phosphaturia and hypophosphatemia; vitamin D resistant rickets and osteomalacia are more severe among patients with Fanconi syndrome.

• Growth failure, due to acidosis and hypophosphatemia
• Nephrocalcinosis - Calcium stones are formed because calcium tends to precipitate in an alkaline solution. Calcium stones may be seen bilaterally.
• Calcium stones are formed because calcium tends to precipitate in an alkaline solution. Calcium stones may be seen bilaterally.

Failure of the PCT to reabsorb HCO3- can result in a proximal renal tubular acidosis "Type II RTA" in patients with Fanconi syndrome.

Diagnostics
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Serum
• Hyperchloremic metabolic acidosis,i.e., normal anion gap
• Hypokalemia that worsens with alkaline therapy
The degree of hypokalemia is usually mild when compared to type 1 RTA. However, hypokalemia worsens with the initiation of alkaline therapy. Severe hypokalemia may also be present in the case of Fanconi syndrome.

• Hypouricemia
• Hypophosphatemia

Urine
• Urine pH less than 5.5 Urine pH may be greater than 5.5 before acidosis sets in
• Bicarbonate infusion test: Urine pH rises above 7.5, and the fractional excretion of bicarbonate is less than 15% following IV sodium chloride administration.
Supplemental potassium should be given during the infusion because sodium chloride may induce hypokalemia.
• Negative urine anion gap
Fanconi syndrome
• Aminoaciduria
• Glucosuria despite normal or low serum glucose
• Phosphaturia

Treatment
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Alkali therapy with orally administered potassium citrate
• Potassium citrate is required in order to correct the hypokalemia that occurs with the initiation of alkali therapy.

Thiazide diuretics if alkali are not tolerated or effective
• Thiazide diuretics result in volume depletion and enhanced bicarbonate reabsorption.