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April 12, 2019

Art of Medicine: Fanconi Syndrome

This painting shows the transition between a proximal tubule and the thick descending limb of the loop of Henle.  The proximal tubule has numerous functions, including transport of sodium chloride, bicarbonate, glucose, amino acids, organic cations, organic anions, and phosphate.  Disruption of proximal tubule function manifests clinically as Fanconi syndrome.   Development of polyuria, osteomalacia, muscle weakness, and growth failure can result if it is unrecognized and untreated.

Fanconi syndrome can be diagnosed by clinical chemistry tests, including urine sodium, potassium, calcium, phosphate, glucose, amino acids, and uric acid levels, as well as urine pH.   In Fanconi syndrome, there is glycosuria (despite normal plasma glucose levels), aminoaciduria, uricosuria, sodium and potassium wasting, hyperphosphaturia (despite presence of hypophosphatemia), and renal tubular acidosis.   Renal tubular acidosis occurs secondary to a defect in resorption of bicarbonate at the proximal tubule, consistent with type 2 renal tubular acidosis. 

The differential diagnosis for Fanconi syndrome is very broad.  It includes inherited conditions, including hereditary fructose intolerance, galactosemia, cystinosis, Lowe syndrome, mitochondrial disorders, tyrosinemia, glycogen storage disease, and Wilson’s disease.  Medications can also induce Fanconi syndrome, including adefovir, aminoglycosides, cisplatin, gentamicin, tenofovir, and valproate.  Additional exogenous causes include heavy metal exposure (cadmium, lead, mercury, and platinum) or maleic acid.  It can also be caused by monoclonal gammopathies of renal significance (MGRS). 

Monoclonal gammopathies of renal significance show renal injury due to effects of nephrotoxic light chains.  While the nephrotoxicity of the monoclonal paraprotein is clear in some cases of MGRS, such as in light chain deposition disease, light chain cast nephropathy, amyloidosis, and in light chain proximal tubulopathy with crystals, it is more difficult to determine in casts of light chain proximal tubulopathy without crystals.  This is because in the presence of a circulating monoclonal paraprotein, there will be increased light chain resorbed by proximal tubules as part of normal physiologic trafficking.  Evaluation for Fanconi syndrome in this setting is very helpful, as it can establish the presence of proximal tubular dysfunction and injury.   In the absence of tubular injury, presence of a dominant light chain within tubular epithelium in itself may not require clone-directed therapy, as end-organ damage by a MGRS is not established.