Molecular mechanisms of renal phosphate transport in human health and disease
I hypothesize that urinary levels of NaPi-2a, NaPi-2c, and Pit-2 are accurate surrogates of the levels of these proteins in the proximal tubule brush border membrane, and provide an invaluable window into the physiology and pathophysiology of renal phosphate transport.
Two aims are proposed to test this hypothesis:
Aim 1. Assay validation and study of phosphate transporter physiology in normal individuals.
Volunteers will receive an oral phosphate binder or a phosphate load to elicit renal phosphate conservation or excretion. A time course of the urinary levels of the three phosphate transporters will be recorded and compared to serum phosphate, phosphaturic hormones, and renal fractional excretion of phosphate. This will provide for the first time data on how these transporters are normally regulated in humans.
Aim 2. Pathophysiology of phosphate transporters in disorders of deranged renal phosphate handling.
Phosphate pathophysiology will be studied in representative patients with classic disorders of deranged proximal tubule handling. I will study patients with post-transplant idiopathic phosphate wasting, primary hyperparathyroidism, chronic kidney disease, X-linked hypophosphatemic rickets, and hypophosphatemia secondary to tumor-induced osteomalacia. The molecular mechanisms of dysregulated renal phosphate transport in these conditions are not known. These studies will provide preliminary but novel and illuminating data in the field.
Aim 1: Men or premenopausal women between 21 and 60 years of age, free of acute or chronic illness, with body mass index (BMI) greater than 18.5 kg/m2 and less than 29.5 kg/m2.
Aim 2: Adult patients with CKD, primary hyperparathyroidism, post-transplant idiopathic phosphate wasting or TIO, or children with XLHR.