Panproximal Tubular Dysfunction (Fanconi Syndrome)

Panproximal Tubular Dysfunction (Fanconi Syndrome)

Eileen D. Brewer

Fanconi syndrome (FS) is the result of generalized transport dysfunction of the proximal renal tubule. It is characterized classically by excessive urinary losses of amino acids, glucose, bicarbonate, and phosphate but also by losses of calcium, magnesium, uric acid, and other organic acids, low-molecular-weight (tubular) proteins, sodium, potassium, and water. The urinary losses can result in metabolic acidosis, dehydration, hypokalemia, hypophosphatemia, rickets, and growth retardation in children. Many inherited and acquired disorders can lead to FS in adults and children (Box 334.1). When FS occurs in children, the cause usually is hereditary and is related to an inborn error of metabolism.


Basic abnormalities underlying renal tubular transport dysfunction in FS are incompletely understood. Because a variety of inherited, acquired, and experimentally induced conditions can cause FS, specific pathologic mechanisms operative in one disorder may not be present necessarily in another, although each could lead to a final common pathway that results in the expression of FS. Suggested possibilities for a final common pathway include defective generation of energy to drive the transport processes, increased backleak of reabsorbed solutes across the cell membrane into the tubular lumen, and abnormal action or location of carriers that normally transport solutes across the cell membrane from the tubular lumen into the intracellular space. Recent advances in molecular genetics with identification of specific gene defects and their gene products are laying the foundation for a better understanding of the underlying pathophysiology of FS in each disorder.


The general clinical manifestations of FS depend on the patient’s age and on the type and chronicity of the underlying disease. Infants and children most often present with failure to thrive. Many features of FS, including chronic acidosis, volume contraction, hypokalemia, hypophosphatemia, and abnormal vitamin D metabolism, contribute to impaired linear growth. However, in some cases, especially in patients with cystinosis, these factors alone are not sufficient to explain the severity of the growth retardation. Rachitic bone changes may be a presenting or accompanying clinical sign in some children with FS. If the child has been walking, bowing deformities of the legs may be noticed first. A child who does not yet bear weight may have straight legs but noticeable metaphyseal widening at the wrists, knees, or ankles and radiographic changes classic for rickets at these sites. Infants younger than 5 months old rarely have the clinical findings of rickets.

Episodic vomiting, anorexia, polydipsia and polyuria, chronic constipation, and unexplained fevers are nonspecific symptoms of chronic FS. Constipation probably results from chronic depletion of volume associated with the polyuria, hypokalemia, and chronic metabolic acidosis of untreated FS. Unexplained fevers, which occur especially frequently in infants and young children with cystinosis, may reflect episodic dehydration.

The laboratory findings of FS reflect mostly abnormal proximal renal tubular function. In physiologically normal children, more than 98% of the filtered amino acids are reabsorbed in the proximal renal tubule. In FS, hyperaminoaciduria occurs in the presence of normal plasma amino acid levels and is an exaggeration of the normal excretory pattern of each amino acid, with the percentage of tubular reabsorption of each amino acid decreased below normal. Because urinary losses are trivial compared with intake, hyperaminoaciduria is not clinically significant, but it is an important clinical marker for FS. Plasma and urinary amino acids should be sampled simultaneously as part of the clinical evaluation of patients with FS.

Urinalysis often reveals characteristic abnormalities, including the following: glucosuria in the presence of a normal blood glucose concentration; abnormally high urine pH (greater than 5.5) in the presence of mild to moderate hyperchloremic metabolic acidosis but appropriately low pH with
severe acidosis (type 2 renal tubular acidosis); specific gravity 1.010 to 1.015, even in the presence of dehydration; and mild albuminuria (1 to 2+, or 30 to 100 mg/dL) with normal serum protein and albumin.

Glucosuria, which often is intermittent, rarely exceeds 2+ (500 mg/dL) on the dipstick and is clinically insignificant except as a marker of FS, except in the Fanconi-Bickel syndrome, in which glucosuria and galactosuria are quite prominent as a result of the underlying genetic defect. Patients who present with severe hyperchloremic metabolic acidosis (plasma bicarbonate level 10 to 15 mEq/L) usually have a urinary pH less than 5.5, characteristic of type 2 (proximal) renal tubular acidosis. When their acidosis is treated and the plasma bicarbonate concentration is kept in the normal range by supplemental alkali therapy, the excretion of bicarbonate exceeds 15% of the bicarbonate filtered by the glomerulus, a value typical of proximal renal tubular acidosis. The urinary pH usually exceeds 7.0. Fractional excretions of bicarbonate as high as 30% have been reported. If a patient has severe depletion of volume, paradoxical metabolic alkalosis actually can occur, but it changes to metabolic acidosis after volume expansion occurs. Depletion of volume in affected patients is the result of obligatory polyuria, which is caused mainly by the wasting of sodium, amino acids, glucose, and other osmotically active solutes from the proximal tubule. Polyuria may be worse in the presence of chronic hypokalemia, which can impair urinary concentration in the distal renal tubule and can stimulate thirst and polydipsia. In patients with FS, the urine specific gravity rarely exceeds 1.015 to 1.020, even in the presence of severe dehydration; thus, urine specific gravity should not be used as an indicator of the status of hydration.

Mild albuminuria (2+ or less, or 100 mg/dL or less by urinalysis dipstick) usually indicates tubular proteinuria. Tubular proteinuria is characterized not only by the predominance of low-molecular-weight species such as lysozyme (molecular weight 15,000 daltons) and beta-2-microglobulin (molecular weight 11,800 daltons) but also by albumin (molecular weight 40,000 daltons). Proteins of approximately 40,000 daltons or less, including a small amount of albumin, normally are filtered by the glomerulus and then are reabsorbed and catabolized in the proximal tubule. A receptor-mediated endocytic process in the first part of the proximal tubule normally reabsorbs these tubular proteins. In FS, dysfunction of proximal tubular transport results in tubular proteinuria. Like glucosuria and generalized aminoaciduria, tubular proteinuria appears to be of no clinical significance except as a marker of FS. Proteinuria may be more pronounced in the oculorenal syndrome of Lowe (OCRL), often exceeding 1 g/m2/day, without causing nephrotic syndrome.

Serum chemistry studies often are abnormal in fully expressed FS. Besides having hyperchloremic metabolic acidosis with a normal anion gap, patients may have hyponatremia, hypokalemia, hypophosphatemia, and, in some cases, hypouricemia. Serum calcium and magnesium concentrations usually are normal, despite increased losses of calcium and magnesium in the urine. Excessive loss of sodium in the urine without sufficient sodium intake eventually can result in hyponatremia, although increased delivery of sodium to the distal renal tubule and high levels of renin and aldosterone caused by depletion of volume increase distal tubular sodium reabsorption to avoid hyponatremia. The preferential distal reabsorption of sodium worsens hypokalemia, especially in the presence of the proximal renal tubular acidosis of FS and delivery of excess bicarbonate to the distal nephron. During distal tubular reabsorption of sodium, sodium is exchanged for potassium, and potassium is secreted into the urine to become the primary cation to be excreted with the excess bicarbonate. The combination of excessive distal tubular secretion of potassium and increased proximal tubular rejection of potassium creates obligatory loss of large amounts of potassium in the urine, usually leading to hypokalemia and severe depletion of total body potassium. This depletion can cause weakness, poor growth, paralysis, and fatal cardiac arrhythmias. Treatment of acidosis with sodium bicarbonate without supplementation of potassium can result in death.

Hypophosphatemia results from excessive urinary wasting of phosphate and reduced tubular reabsorption of phosphate, even at low concentrations of serum phosphate. Serum parathyroid hormone concentration usually is normal. Serum levels of 1,25-dihydroxyvitamin D, Which is made in the proximal
renal tubule by 1-hydroxylation of 25-hydroxyvitamin D, often are reduced or are lower than expected for the degree of hypophosphatemia, which is a major stimulus for production of 1,25-dihydroxyvitamin D. Hypophosphatemia, impaired metabolism of vitamin D in the renal tubule, excessive urinary excretion of calcium, and chronic acidosis all contribute to the chronic bone disease (i.e., rickets and osteomalacia) of patients with FS.

Most patients with FS waste uric acid in the urine and have hypouricemia. Patients with hereditary fructose intolerance who are exposed to fructose have transient hyperuricemia instead because of the abnormal biochemical pathways underlying this disease.

Some affected patients, especially those with cystinosis and some with OCRL, may have decreased carnitine reabsorption in the proximal tubule and may be deficient in carnitine. Carnitine is required to transport free fatty acids into mitochondria for subsequent energy production. Deficiency in carnitine may contribute to muscle weakness and delayed development.


As previously stated, FS has many causes (see Box 334.1). Most of these disorders are discussed elsewhere in this text. This section focuses on diseases associated with FS that occur in children and lead to progressive chronic renal failure.

Cystinosis (Nephropathic Cystinosis)

Cystinosis is a rare lysosomal transport disorder in which intracellular accumulation of cystine is associated with FS, chronic renal failure, growth failure, corneal opacities, photophobia, and hypothyroidism. It is not related to the disease cystinuria, which is a genetically transmitted defect for transport of the dibasic amino acids in the renal tubule and intestine, resulting in massive urinary cystine and cystine nephrolithiasis. In cystinosis, plasma cystine concentration is normal, and urinary cystine concentration is elevated only to a degree consistent with the generalized hyperaminoaciduria of FS.

Three types of cystinosis are recognized based on age at onset and severity of symptoms: infantile nephropathic (MIM 219800), juvenile (MIM 219900), and ocular nonnephropathic (MIM 219750). All are autosomal recessive and monogenic, resulting from different mutations in the cystinosis gene CTNS, which is located on chromosome 17p13. Ocular nonnephropathic cystinosis is characterized by adult onset of mild photophobia without FS, glomerular disease, or retinal depigmentation; only cornea, bone marrow, and peripheral leukocytes exhibit significant cystine crystals. Intracellular cystine is increased only moderately (30 to 50 times normal, compared with 100 to 1,000 times normal for infantile nephropathic cystinosis). Juvenile cystinosis is similar to the infantile nephropathic form, except for a later age of onset in adolescence, usually between 12 and 15 years, and the absence of FS but the presence of proteinuria from glomerular injury, slower progression to end-stage renal disease, normal stature, photophobia, and late development of pigmentary retinopathy. Both the juvenile and ocular nonnephropathic forms of cystinosis are extremely rare and likely result from the combination of a severe nephropathic mutation of one allele and a mild mutation of the other allele for the CTNS gene. This discussion focuses on infantile nephropathic cystinosis, the most common and most severe presentation of this disease.

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Jul 24, 2016 | Posted by in ORTHOPEDIC | Comments Off on Panproximal Tubular Dysfunction (Fanconi Syndrome)
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