The above mentioned roles of relative or absolute deficiency states of calcium and vitamin D are steadily gaining importance with the progression of CRF, and phosphate becomes a major player.

The role of hyperphosphatemia. In advanced stages of CRF hyperphosphatemia is a nearly constant feature, due to phosphate retention caused by the progressive loss of functioning nephrons characterized by an increasing difficulty to augment the filtered load of phosphate and to further reduce its tubular reabsorption when it is already maximally inhibited. A high extracellular phosphate concentration stimulates PTH secretion both directly and indirectly (see below).

The uremic syndrome itself could also play a role. Thus several uremic toxins, that is substances which accumulate in the uremic state, have been shown to interfere with vitamin D metabolism and action.