In normal individuals, amino acids gain access to the proximal nephron cells (left-hand arrows) 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 brush 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 also can be metabolized (metab) in the renal tubular cells. In the distal tubule (right-hand 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. 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 exceeds 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 that 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 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 (see Fig. 196-6). An integrative hypothesis that may 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. Lum lumen; Cap, capillary; AA, amino acids. Source: The Renal Fanconi Syndrome, The Online Metabolic and Molecular Bases of Inherited Disease Citation: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G. The Online Metabolic and Molecular Bases of Inherited Disease; 2014 Available at: https://ommbid.mhmedical.com/DownloadImage.aspx?image=/data/books/971/ch196fg2.png&sec=62654872&BookID=971&ChapterSecID=62654792&imagename= Accessed: October 30, 2017 Copyright © 2017 McGraw-Hill Education. All rights reserved