Renal Tubular Disorders and Fanconi Syndrome

Question 1

Fanconi Syndrome

Answer 1

Proximal tubular dysfunction causing excessive renal wasting of low molecular weight (LMW) proteins, glucose, bicarbonate, phosphate, uric acid, carnitine, and others.

Question 2

Clinical Manifestations of Fanconi Syndrome

Answer 2

Polyuria, polydipsia, tendency for volume depletion

Question 3

Clinical Manifestations of Fanconi Syndrome

LMW Proteinuria

Answer 3

LMW proteinuria (non-albumin proteinuria): LMW proteinuria reflects proximal tubular injury and reduced proximal tubular endocytosis and reabsorption of filtered proteins. LMW proteins that may be excreted with proximal tubular injury include amino acids, β2-microglobulin, cystatin C, α1-macroglobulin.

Question 4

Clinical Manifestations of Fanconi Syndrome

Glucose

Answer 4

Glucosuria in the absence of hyperglycemia

Question 5

Clinical Manifestations of Fanconi Syndrome

RTA

Answer 5

Proximal renal tubular acidosis (RTA) due to reduced bicarbonate reabsorption (ammoniagenesis appears to be normal)

Question 6

Clinical Manifestations of Fanconi Syndrome

Hypophosphatemia

Answer 6

Hypophosphatemia (phosphaturia is typically only seen in early disease; once new steady state has been achieved, phosphate loss in urine matches intake).

Question 7

Clinical Manifestations of Fanconi Syndrome

Hypokalemia

Answer 7

Hypokalemia (likely due to distal potassium loss due to high distal sodium delivery to the epithelial sodium channel (ENaC); high filtered load of K+ associated with acidemia).

Acidosis (exchange of extracellular H+ for intracellular K+)

Alkalosis (exchange of intracellular H+ for extracellular K+)

Question 8

Clinical Manifestations of Fanconi Syndrome

Uric Acid

Answer 8

Hypouricemia due to hyperuricosuria

Question 9

Clinical Manifestations of Fanconi Syndrome

Carnitine deficiency:

Answer 9

Carnitine is required for the transport of fatty acids from cytosol into mitochondria during the breakdown of lipids for the generation of metabolic energy. Carnitine deficiency has been implicated in poor fatty acid metabolism, reduced antioxidant activities, poor glucose control, and osteoporosis.

Question 10

Clinical Manifestations of Fanconi Syndrome

Rickets, osteomalacia, growth failure:

Answer 10

likely due to hypophosphatemia, decreased 1,25 vitamin D production in proximal tubule (due to reduced renal 1-α hydroxylase activity), and chronic metabolic acidosis.

Question 11

Conditions Associated with Fanconi Syndrome Inherited:

Cystinosis:

Answer 11

Most common inherited condition associated with Fanconi syndrome; associated with defective tubular reabsorption of Cystine, Ornithine, Lysine, and Asparagine, known as COLA. Unlike the other three amino acids, cystine has low solubility, thus easily crystallizes in tubular lumen to form cystine stones.

Question 12

Conditions Associated with Fanconi Syndrome Inherited:

Others:

Answer 12

galactosemia, hereditary fructose intolerance, tyrosinemia type 1, glycogenosis, Wilson disease (inherited disorder involving copper metabolism), oculocerebrorenal syndrome (Lowe syndrome), mitochondrial cytopathies

Question 13

Conditions Associated with Fanconi Syndrome Acquired:

Heavy metals:

Answer 13

lead, cadmium, mercury, platinum.

Question 14

Conditions Associated with Fanconi Syndrome Acquired:

Drugs:

Answer 14

cisplatin, ifosfamide, imatinib (Gleevac), gentamicin, rifampin, expired tetracycline, tenofovir, didanosine, adefovir, azathioprine (AZA), valproic acid, suramin, streptozocin, ranitidine.

Question 15

Conditions Associated with Fanconi Syndrome Acquired:

Other exogenous agents:

Answer 15

glue sniffing, diachrome, some herbal medicines.

Question 16

Conditions Associated with Fanconi Syndrome Acquired:

Dysproteinemias:

Answer 16

multiple myeloma/light chain nephropathy (most common condition associated with Fanconi syndrome in adults), amyloidosis, Sjogren’s.

Question 17

Conditions Associated with Fanconi Syndrome Acquired:

Answer 17

Others: acute tubular necrosis, nephrotic syndrome.