Functional profile of the isolated uremic nephron: intrinsic adaptation of phosphate transport in the rabbit proximal tubule.

The maintenance of phosphate homeostasis in uremia appears to be governed both by parathyroid hormone (PTH) and by PTH-independent adaptations in renal tubular function. The relative contributions of these two mechanisms that control phosphate excretion by the diseased kidney have been difficult to define in intact animals. The present study was designed to examine the nature of the adaptation of phosphate handling by the proximal tubule of subtotally nephrectomized, uremic rabbits in vitro. Euparathyroid and hyperparathyroid uremic rabbits were studied. Tubular sensitivity to PTH was examined in vitro. The dose-response relationship between bath PTH concentration and inhibition of lumen-to-bath phosphate flux (Jp-lb) in isolated perfused proximal straight tubules (PSTs) revealed that PTH sensitivity was increased in the euparathyroid uremic rabbits and was decreased in hyperparathyroid uremic rabbits. The dose-response to dibutyryl cAMP was the same as normal in both uremic groups. These data strongly suggest the existence of a receptor-mediated adaptation in the effects of PTH on the uremic proximal tubule. In addition to an altered PTH-sensitivity the uremic PST also exhibited an alteration in the basal rate of phosphate transport studied in the presence of normal rabbit serum. Although net volume flux across the PST increased in both uremic groups as a possible consequence of hypertrophy, net phosphate flux per unit length was unchanged. Considering the increase of luminal area in these tubules, net phosphate flux per unit reabsorptive surface area was actually decreased. This dissociation is supportive of the existence of an intrinsic tubular adaptation which is independent of the size of the tubule per se. These studies indicate that there is an intrinsic adaptation of the basal rate of phosphate transport by the uremic rabbit proximal tubule and that the sensitivity of the tubule to PTH is altered. The data are strongly suggestive of an increase in the number of PTH receptors in the proximal tubule of the euparathyroid uremic rabbit and suggest that "down regulation" or persistent occupancy of these receptors occurs when hyperparathyroidism supervenes.