[GENETIC DISORDERS OF RENAL PHOSPHATE HANDLING]

Hereditary disorders of renal phosphate handling comprise a diverse group of genetic diseases, usually characterized by excessive urinary phosphate wasting and a negative phosphate balance. In the minority of cases, perturbations of renal phosphate handling are associated with excessive urinary phosphate reabsorption, leading to pathological hyperphosphatemia. Inorganic phosphate is an essential mineral in the human body, playing a crucial role in cellular metabolism and skeletal mineralization. Whole body phosphate balance is maintained by a highly controlled equilibrium between intestinal uptake, skeletal deposition and renal excretion. The human kidney plays a crucial role in phosphate homeostasis. The bulk filtered phosphate is reabsorbed in the renal proximal tubule by two specialized phosphate transporters, NaPi-IIa and NaPi-IIc. Phosphate balance is regulated by dietary phosphate intake, and by the action of the parathyroid hormone, vitamin D3 and fibroblast growth factor-23 (FGF-23). All these regulators exert their effect by modulating the activity of the proximal-tubular phosphate transporters, NaPi-IIa and NaPi-IIc. Based on the versatile molecular mechanism underlying various renal phosphate wasting disorders, these diseases can be divided into three main subgroups: (1) primary impairment of proximal tubular phosphate transporters; (2) disorders of FGF-23 metabolism; (3) generalized dysfunction of the proximal tubule, also known as renal Fanconi syndrome. The clinical similarity between various renal phosphate wasting disorders, combined with their rarity, pose a diagnostic and therapeutic challenge. Recent advancement in molecular biology has led to the identification of the genetic basis of many disorders in this group, has improved our understanding of underlying disease mechanisms, and enables accurate genetic diagnosis. Nevertheless, the current therapy of most renal phosphate wasting disorders is mainly supportive, with limited capacity to change their natural course.