A novel mechanism for skeletal resistance in uremia

Background. In treating secondary hyperparathyroidism, the target level of serum intact parathyroid hormone (I-PTH) should be three to five times norm al to prevent adynamic bone disease. In circulation, there is a non-(1-84) PTH-truncated fragment, likely 7-84, which, in addition to PTH 1-84, is mea sured by most I-PTH immunoradiometric (IRMA) assays, giving erroneously hig h I-PTH values. We have developed a new IRMA assay in which the labeled ant ibody recognizes only the first six amino acids of the PTH molecule. Thus, this new IRMA assay (Whole PTH) measures only the biologically active 1-84 PTH molecule. Methods. Using this new IRMA assay (Whole PTH) and the Nichols "intact" PTH assay, we compared the ability of each assay to recognize human PTH (hPTH) 1-84 and hPTH 7-84 and examined the percentage of non-1-84 PTH in circulat ion and in parathyroid glands. Possible antagonistic effects of the 7-84 PT H fragment on the biological activity of 1-84 PTH in rats were also tested. Results. In 28 uremic patients, PTH values measured with the Nichols assay, representing a combined measurement of both hPTH 1-84 and hPTH 7-84, were 34% higher than with the Whole assay (hPTH 1-84 only); the median PTH was 5 23 versus 318 pg/mL (P < 0.001). Similar results were found in 14 renal tra nsplant patients. In osteoblast-like cells, ROS 17.2, 1-84 PTH (10(-8) mol/ L) increased cAMP from 18.1 +/- 1.25 to 738 +/- 4.13 mmol/well. Conversely, the same concentration of 7-84 PTH had no effect. In parathyroidectomized rats fed a calcium-deficient diet, 7-84 PTH was not only biologically inact ive, but had antagonistic effects on 1-84 PTH in bone. Plasma calcium was i ncreased (0.65 mg/dL) two hours after 1-84 PTH treatment, while 7-84 PTH ha d no effect. When 1-84 PTH and 7-84 PTH were given simultaneously in a 1:1 molar ratio, the calcemic response to 1-84 PTH was decreased by 94%. In nor mal rats, the administration of 1-84 PTH increased renal fractional excreti on of phosphate (11.9 to 27.7%, P < 0.001). However, when 1-84 PTH and 7-84 PTH were given simultaneously, the 7-84 PTH decreased the phosphaturic res ponse by 50.2% (P < 0.005). Finally, in surgically excised parathyroid glan ds from six uremic patients, we found that 44.1% of the total intracellular PTH was the non-PTH (1-84), most likely PTH 7-84. Conclusion. In patients with chronic renal failure, the presence of high ci rculating levels of non-1-84 PTH fragments (most likely 7-84 PTH) detected by the "intact" assay and the antagonistic effects of 7-84 PTH on the biolo gical activity of 1-84 PTH explain the need of higher levels of "intact" PT H to prevent adynamic bone disease.