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INTRODUCTION

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There are approximately 1 million glomeruli in each kidney, which filter blood and generate an ultrafiltrate of plasma. With a glomerular filtration rate of 120 mL/min/1.73 m2, the kidneys of an adult generate approximately 170 L of an ultrafiltrate of plasma daily, which is delivered to the renal tubules. The renal tubules reabsorb organic solutes, salts, and water to maintain a constant extracellular fluid volume and composition. In addition, organic anions and cations, which are protein bound and not filtered by the glomerulus, are secreted by the proximal tubule. The final urine contains about one hundredth of the volume and sodium as that in the original glomerular filtrate, but contains waste products. There are 12 nephron segments, which have different transport properties to perform the task of modifying the glomerular ultrafiltrate so that we maintain a constant volume and composition of the extracellular fluid. Disorders of tubular function can be due to inherited defects in transporters, result from mutations in factors that regulate transport, or result from inherited or acquired disorders that cause tubular injury. Renal transport disorders can be mild, with little or no clinical consequences, or life-threatening depending on the transporters and nephron segments affected.

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THE FANCONI SYNDROME

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The Fanconi syndrome is a generalized proximal tubule transport disorder. The proximal tubule is responsible for the reabsorption of two-thirds of the glomerular ultrafiltrate including all of the filtered glucose, amino acids, 80% of the filtered bicarbonate, and 90% of the filtered phosphate. Thus, patients with the Fanconi syndrome have hypophosphatemia, hypokalemia, and a hyperchloremic metabolic acidosis. Evaluation of the urine reveals glucosuria, generalized aminoaciduria, and hyperphosphaturia despite the hypophosphatemia.

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The luminal fluid entering the proximal tubule is an ultrafiltrate of plasma. Most solutes are transported across the apical membrane in conjunction with sodium. The driving force for solute transport is the low intracellular sodium generated by the basolateral Na+/K+-ATPase. A generalized decrease in proximal tubular transport could result from a primary injury to the Na+/K+-ATPase pump or a decrease in intracellular adenosine triphosphate (ATP) that fuels the pump. Theoretically, an increase in the permeability of the proximal tubule paracellular pathway could result in the Fanconi syndrome, but this theory has been discounted. While the cellular basis for most causes of the Fanconi syndrome has not been determined, most studies have demonstrated that the proximal tubular transport defect in the Fanconi syndrome is the result of a decrease in intracellular ATP.

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The causes of the Fanconi syndrome are listed in Table 470-1. Cystinosis is the most common inherited cause of the Fanconi syndrome in children. Cystinosis is an autosomal recessive disorder where cystine accumulates predominantly in lysosomes due to an inactivating mutation in cystinosin, the carrier-mediated transporter for cystine from the lysosome into the cytoplasm. Eventually the intracellular cystine burden increases to the point that there is impairment ...

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