Figure 128

Fanconi's syndrome is characterized by two components: generalized dysfunction of the proximal tubule, leading to impaired net reabsorption of bicarbonate, phosphate, urate, glucose, and amino acids; and vitamin D-resistant metabolic bone disease [20]. The clinical manifestations in patients with either the hereditary or acquired form of Fanconi's syndrome include polyuria, dehydration, hypokalemia, acidosis, and osteomalacia (in adults) or impaired growth and rickets (in children). Inherited Fanconi's syndrome occurs either as an idiopathic disorder or in association with various inborn errors of metabolism.

with Fanconi's syndrome cause a global disruption in sodium-coupled transport systems rather than a disturbance in specific transporters. Bergeron and coworkers [20] have proposed a patho-physiologic model that involves the intracellular gradients of sodium, adenosine triphosphate (ATP), and adenosine diphosphate (ADP). A transepithelial sodium gradient is established in the proximal tubule cell by sodium (Na) entry through Na-solute cotransport systems (Na-S) (1) and Na exit through the sodium-potassium adenosine triphosphatase (Na-K ATPase) (2). This Na gradient drives the net uptake of cotransported solutes. A small decrease in the activity of the Na-K ATPase cotransporter may translate into a proportionally larger increment in the Na concentration close to the luminal membrane, thus decreasing the driving force that energizes all Na-solute cotransport systems. Concomitantly, reciprocal ATP and ADP gradients are established in the cell by the activity of membrane bound ATPases (Na-K ATPase (2) and hydrogen-ATPase (3)) and mitochondrial (4) ATP synthesis. A small reduction in mitochondrial rephosphorylation of ADP may result in a juxtamembranous accumulation of ADP and a reciprocal decrease in ATP, altering the ADP-ATP ratio and downregulating pump activities. Therefore, a relatively small mitochondrial defect may be amplified by the effects on the intracellular sodium gradients and ADP-ATP gradients and may lead to a global inhibition of Na-coupled transport. H+—hydrogen ion.

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