Renal Fanconi Syndrome

Abstract

Renal Fanconi syndrome is a tubular dysfunction increasing the urinary excretion of glucose, amino acids, phosphate and bicarbonate and inducing rickets in children and osteomalacia in adults.

Keywords: aminoaciduria; cadmium; cystinosis; glucosuria; maleate; megalin; phosphaturia; renal tubular acidosis; rickets; osteomalacia

Figure 1.

Schematic view of the cells of kidney tubules. The tubules form the renal functional unit, known as the nephron. Immediately after being filtered through the glomerulus, molecules (e.g. amino acids, glucose, sodium) and water are reabsorbed by the early part of the tubule, defined as the proximal nephron. The last part of the nephron is known as the distal and is comprised of tubular cells with different properties. In normal individuals, amino acids gain access to the proximal nephron cells (wide blue arrow) through the apical microvilli or through the infoldings of the antiluminal membrane. Intracellular accumulation of amino acids (∗) can occur against a concentration gradient. At the luminal border, uptake is a carrier‐mediated process and, when coupled to a sodium gradient (Na+ out > Na+ in), is ‘secondary active’ transport. Exit can occur at all membranes. Amino acids (AA) can also be metabolized (metab) in the renal tubular cells. In the distal nephron (thin blue arrows), similar amino acid movements occur except that there is no luminal entry of amino acids and little, if any, luminal entry of glucose and phosphate. (b) In the maleate model of Fanconi syndrome, there is a marked backleak of amino acids and sugar into the tubular lumen. As a consequence, intracellular amino acid levels fall significantly (pool). In proximal tubular cells, luminal amino acid uptake mechanisms are also disturbed, but residual luminal uptake still exceed backleak, allowing at least some net amino acid reabsorption. However, in the distal tubule where luminal uptake systems are absent, maleate‐induced exit of amino acids into the lumen is completely uncompensated, allowing net amino acid ‘secretion’ into the urine. Other forms of renal Fanconi syndrome have been ascribed to numerous complex mechanisms which might disturb luminal membrane function. These include: (1) a defect in some aspect of transport critical to all luminal carrier mechanisms (of note, most solutes lost in urine are coupled to luminal reabsorption of sodium); (2) a disturbance of luminal membrane organization affecting both uptake and backleak of solutes as in the maleate model above; (3) impaired production of metabolic energy or adenosine triphosphate (ATP) as in the example of human cytochrome c oxidase deficiency; (4) defective Na+–K+ATPase activity at basolateral membranes, affecting the sodium gradient at the luminal membrane; (5) reduced H+ATPase activity affecting the endocytotic recycling apparatus; (6) structural disorganization and dysfunction of organelles such as the endoplasmic reticulum or mitochondria; (7) defective megalin‐dependent recycling of transport proteins and transporters from endocytotic compartments to the luminal membrane. An integrative hypothesis that might link many forms of Fanconi syndrome is that they have in common a toxic effect or a primary cellular dysfunction that disrupts some critical element of endocytotic membrane recycling. Blockade at any point along the recycling pathway will modify luminal membrane function by trapping membrane transport proteins and other constituents in endosomes; depletion of these elements from the luminal membrane may limit reabsorptive transport and allow increased backleak of organic solutes.

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Bergeron, Michel, and Gougoux, André(Apr 2001) Renal Fanconi Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0002284]