Plasma levels of parathyroid hormone (1-84) whole molecule and parathyroid hormone (7-84)-like fragments in pseudohypoparathyroidism type I.

PTH (7-84) has antagonistic effects on the calcemic and phosphaturic actions of PTH (1-84) whole molecule (bioPTH). Human plasma contains bioPTH and PTH (7-84)-like fragments. Using bioPTH-specific and nonspecific assays, we found that the patients with pseudohypoparathyroidism (PHP) type I with PTH-resistant hypocalcemia and hyperphosphatemia had the increased plasma levels of bioPTH and PTH (7-84)-like fragments than normal subjects (26.8 +/- 13.2 vs. 2.37 +/- 0.75 pmol/liter, P < 0.01 and 16.2 +/- 8.8 vs. 0.82 +/- 0.47 pmol/liter, P < 0.01, respectively). Calcitriol treatment increased phosphaturic response to PTH (1-34) (P < 0.05), and there was a negative correlation between phosphaturic response and the PTH levels (P < 0.05). These results suggested that the increased bioPTH and PTH (7-84)-like fragment levels may be related to the impaired phosphaturic response to PTH (1-34) in PHP type I. We also examined bioPTH-calcium dynamics in PHP type Ib patients and found that set-point calcium was 0.928 +/- 0.045 mmol/liter and the baseline to maximal ratio of bioPTH was 0.96 +/- 0.04. Calcitriol treatment increased set-point calcium to 1.129 +/- 0.028 mmol/liter (P < 0.01) and suppressed baseline to maximal ratio of bioPTH to 0.35 +/- 0.21 (P < 0.01). These bio-PTH calcium dynamics studies revealed the maximally stimulated baseline PTH secretion in PHP type Ib and demonstrated the effects of calcitriol on PTH-calcium curve shift and the degree of relative stimulation of baseline secretion.

Decreased sensitivity of distal nephron and collecting duct to parathyroid hormone in pseudohypoparathyroidism type I.

Parathyroid hormone (PTH) transiently increases urinary excretion of the lysosomal enzyme, N-acetyl-beta-D-glucosaminidase, which is distributed mainly in proximal tubules. The response is reduced in pseudohypoparathyroidism (PHP) type I, which is characterized by target-organ resistance to PTH. Evidenced by normal calcium resorption, distal tubule sensitivity to PTH has been believed to be normal in this disorder. This hypothesis was tested through a search for another marker of distal nephron sensitivity to PTH. In the human kidney, cathepsin D was expressed predominantly in distal segments of the nephron, cortical and medullary thick ascending limbs of Henle's loop, distal convoluted tubules, and connecting tubules and in cortical collecting ducts and medullary collecting ducts. PTH infusion transiently increased cathepsin D excretion in normal subjects. The cathepsin D response to PTH was reduced in the patients with PHP type I. The decrease in cathepsin D response in PHP type I indicates a resistance to PTH in the distal nephron (cortical thick ascending limbs of Henle's loop, distal convoluted tubules, and connecting tubules) and cortical collecting ducts. These observations suggest that the preservation of renal tubular sensitivity to PTH in this disorder may be confined to PTH-dependent calcium resorption in distal tubules.