PTH metabolism is greatly disturbed in CRF. Normally, most of intact PTH1-84 is transformed in the liver into the biologically active N-terminal PTH1-34 fragment and several other, inactive C-terminal fragments. The latter are mainly catabolized in the kidney and the degradation process involves solely glomerular filtration and tubular reabsorption, whereas the N-terminal PTH1-34 fragment undergoes both tubular reabsorption and peritubular uptake, as does the intact PTH1-84 molecule . Tubular reabsorption involves the multifunctional receptor megalin.

In CRF, both pathways of renal PTH degradation are progressively impaired. This leads to a markedly prolonged half-life of C-terminal PTH fragments in the circulation and their accumulation in the extracellular space. Moreover, there is no peritubular metabolism of intact PTH1-84 in uremic non-filtering kidneys, in contrast to peritubular uptake by normal, filtering kidneys. Hepatic PTH catabolism appears however to be unchanged in CRF. Thus uremic livers released equal amounts of immunoreactive C-terminal PTH fragments as control livers.

A decreased response to the action of PTH may be another factor involved in the stimulation of the parathyroid glands in CRF. A diminished calcemic response to the infusion of PTH has long been reported, suggesting that PTH oversecretion was necessary to maintain eucalcemia. The skeletal resistance to PTH is probably due to several different factors, including impaired vitamin D action in association with hyperphosphatemia overestimation of true PTH(1-84) (see below), accumulation of inhibitory PTH fragments, increase in circulating osteoprotegerin levels, and changes in PTH-R1 expression . Concerning the latter mechanism, studies suggest the presence of PTH receptor isoforms in various organs of normal rats. Moreover, downregulation of PTH-R1 mRNA was observed in various tissues in uremic rats and also in osteoblasts of bones from patients with end-stage renal disease . However, the issue of PTH-R1 expression in bone tissue remains a matter of controversy since another group actually found it to be upregulated in patients with moderate to severe renal hyperparathyroid bone disease.