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Abstract

Abstract 

  1. The renal Fanconi syndrome consists of two components: (a) a generalized dysfunction of the proximal renal tubule leading to impaired proximal reabsorption of amino acids, glucose, phosphate, urate, and bicarbonate and therefore increased urinary excretion of all these solutes, and (b) a vitamin D–resistant metabolic bone disease—either rickets in growing children or osteomalacia in adults.

  2. The renal Fanconi syndrome is either associated with various inborn errors of metabolism or acquired through exposure to various toxic agents. The inherited form may be idiopathic (in the absence of any recognizable metabolic disease) or secondary to various primary Mendelian diseases. Cystinosis is the most common cause of a secondary hereditary Fanconi syndrome in children. The degree of cystine accumulation determines three clinical forms of cystinosis: infantile, adolescent, and adult. The secondary Fanconi syndrome disappears in patients with hereditary fructose intolerance, galactosemia, tyrosinemia, and Wilson disease when these disorders are treated by restriction of fructose, galactose, tyrosine, or copper, respectively. Other metabolic diseases also can be associated with the Fanconi syndrome: vitamin D dependency, glycogen storage disease, and oculocerebrorenal (Lowe) syndrome.

  3. A wide variety of toxic and immunologic tubular injuries may produce the generalized renal dysfunction characteristic of the Fanconi syndrome. Heavy metals (cadmium, uranium, mercury, lead, and platinum), various drugs (especially antibiotics), the glomerular filtration of abnormal proteins observed in dysproteinemias, and immunologic disorders are all known to induce a Fanconi syndrome. Maleate and cadmium were used to produce experimental models in animals. Finally, the Basenji dog can have a spontaneous Fanconi syndrome.

  4. The renal Fanconi syndrome theoretically may result either from multiple transport dysfunctions restricted to the proximal tubule or from concomitant proximal and distal tubular dysfunctions. Recent data obtained from the experimental Fanconi syndrome indicate that the initial deleterious effect of maleate (and other toxins) in the proximal cells could be via megalin, a membrane glycoprotein that is a receptor for many ligands. Blockade at any point along the recycling pathway will modify luminal membrane function of the proximal tubular cells by trapping transport proteins and other constituents in endosomes. Some experimental data suggest that in addition to the proximal disturbance, a distal nephron involvement may play a role in the final production of the aminoaciduria, glycosuria, and phosphaturia observed in the Fanconi syndrome; all these transport defects could result from a decreased entry of molecules into the cell, an increased backflux at its luminal pole, or a combination of both. An impaired mitochondrial production of ATP and a reduced activity of the basolateral membrane Na+, K+-ATPase also have been suggested as pathogenetic mechanisms. The presence of physiologic intracellular gradients of Na+, ATP, and ADP may amplify a minor decrease in mitochondrial phosphorylation and translate a modest defect in energy production into a major transport dysfunction.

  5. In children, the clinical features of the renal Fanconi syndrome are not specific and result from the renal loss of fluid and electrolytes and the characteristic vitamin D–resistant metabolic bone disease. The most frequent manifestations are polyuria, polydipsia, dehydration, hypokalemia, acidosis, impaired growth, and rickets. In the absence of a specific treatment, fluids and electrolytes lost have to be replaced. The metabolic bone disease resulting from Fanconi syndrome must be treated, and renal transplantation can be performed for severely uremic children with nephropathic cystinosis.

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