Renal Fanconi Syndrome (REFS)

Synonyms: Fanconi renotubular syndrome

Fanconi syndrome is a generalised inherited or acquired disturbance of renal tubular transport leading to aminoaciduria, glycosuria, phosphaturia, renal tubular acidosis type 2 (proximal), hypophosphataemic rickets (children) or osteomalacia (adults), and renal glycosuria.¹ Cystinosis is one of the most common causes of Fanconi syndrome in children.² Fanconi syndrome may occur at any age and is caused by a variety of predominantly rare causes.

• Inherited :
  • Primary idiopathic: sporadic or familial (autosomal dominant - chromosome 15). Occurs in the absence of any identifiable cause, and most cases are sporadic. Some cases are inherited, but the mode of inheritance appears to be variable (autosomal dominant, autosomal recessive, X-linked).
  • Secondary: cystinosis, tyrosinaemia, Wilsons disease, Lowe's syndrome (oculocerebrorenal syndrome: bilateral congenital cataracts, glaucoma, general hypotonia, hyporeflexia, severe mental retardation and Fanconi syndrome), galactosaemia, fructose intolerance, glycogen storage disorders and mitochondrial cytopathies.
• Acquired:
  • Intrinsic renal disease: acute tubular necrosis, interstitial nephritis, hypokalaemic nephropathy, myeloma, amyloidosis, Sjogrens syndrome, rejected transplant
  • Hyperparathyroidism
  • Drugs: cisplatin, ifosfamide, gentamicin, valproate³
  • Toxins: glue sniffing, heavy metals

• Polyuria, polydipsia and episodes of dehydration (sometimes associated with fever).
• Bone deformities: rickets in children or osteomalacia in adults. Results from excessive urinary losses of calcium and phosphate and of a defect in the hydroxylation of 25-hydroxyvitamin D3 into 1,25-dihydroxyvitamin D3.
• Impaired growth and failure to thrive.

• Other causes of polyuria and polydipsia, e.g. diabetes mellitus, diabetes insipidus
• Other causes rickets, osteomalacia and impaired growth

• The diagnosis is based on excessive loss of substances in the urine (e.g. amino acids, glucose, phosphate, bicarbonate) in the absence of high plasma concentrations.
• Further investigations are required to identify the cause.
• Proteinuria: but usually only in small quantities.
• Hypokalaemia, hypophosphataemia and hyperchloraemic metabolic acidosis.

• Management mainly consists of the replacement of substances lost in the urine and specific treatment for the underlying cause.
• Treat underlying cause if present. Alkali and potassium for RTA, phosphate and calcitriol for phosphate wasting.
• Dehydration due to polyuria: prevent by ensuring adequate fluid intake; episodes of dehydration require either oral or intravenous fluid replacement.
• Metabolic acidosis due to the loss of bicarbonate: corrected by the administration of alkali, usually sodium bicarbonate.
• Thiazide diuretic: may be necessary to avoid volume expansion, which increases the excretion of bicarbonate by lowering the renal threshold. However the diuretic increases potassium loss.
• Correction of metabolic acidosis is insufficient to treat bone disease and phosphate and vitamin D supplementation is also required.
• Phosphate supplements.
• Vitamin D, given as 1,25-dihydroxyvitamin D3 or 1a-hydroxyvitamin D3, as liver and/or renal hydroxylation may be impaired in patients with Fanconi syndrome.
• Renal losses of glucose, amino acids, and uric acid are not usually symptomatic and do not require replacement.

• Morbidity and complications are secondary to the underlying and resulting metabolic abnormalities.
• Most abnormalities, e.g. acidosis, calciuria, and phosphaturia, affect bone development and therefore growth.
• Some forms of Fanconi syndrome, e.g. cystinosis, lead to renal failure.

Prognosis depends on the cause of the syndrome and the severity of renal and extrarenal manifestations.

• Avoiding exposure to potential toxins, e.g. outdated tetracyclines and aminoglycosides.
• Effective management of underlying metabolic disorder, e.g. galactosaemia, tyrosinaemia.