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1999 Resident Poster Competition

Hatim A. Hassan M.D.
ST. LOUIS UNIVERSITY
Uremic Plasma Ultrafiltrate Blunts the Response to PTH in UMR-106-01 Osteoblast-like Cells

First Place!
Research Division

Hatim A. Hassan M.D.: Uremic Plasma Ultrafiltrate Blunts the Response to PTH in UMR-106-01 Osteoblast-like Cells

Secondary hyperparathyroidism is a frequent complication of chronic renal failure. Pathogenetic factors for secondary hyperparathyroidism are phosphate retention, decreased levels of calcitriol, hypocalcemia, abnormalities of parathyroid function and skeletal resistance to the actions of PTH. Homologous down regulation/desensitization of the PTH/PTHrP receptor-adenylate cyclase system could contribute to PTH resistance; however, recent studies have revealed that while the levels of PTH/PTHrP receptor mRNA were reduced in renal failure, this abnormality was not corrected by parathyroidectomy. These observations suggest that factors other than high levels of PTH contribute to the skeletal resistance. The present studies were designed to test the hypothesis that factors circulating in the uremic environment contribute to decreased response of target cells to PTH. To this end, ultrafiltrate of uremic plasma was collected at the initiation of hemodialysis, and the influence of this on PTH stimulated cAMP generation was evaluated in UMR-106-01 osteoblast-like cells. Experiments were performed by incubating confluent cultures of UMR 106-01 cells in medium containing up to 50% of the uremic ultrafiltrate for periods of up to 72 hours. Control experiments were performed using a buffered salt solution containing a comparable ionic composition to that of the uremic ultrafiltrate. Following these incubations the cultures were tested for PTH stimulated cAMP production. In control cultures, PTH stimulated cAMP averaged 1992 pmol of cAMP per culture. In contrast, following exposure to uremic ultrafiltrate, PTH stimulated cAMP generation averaged 1023 pmol of cAMP per culture. Thus, the response to PTH was blunted by 48.7% in the presence of uremic ultrafiltrate. The clearance of biologically active PTH peptides by hemodialysis is expected to be negligible due to their large molecular weight; therefore, the decreased response to PTH is unlikely to represent homologous desensitization/downregulation of the PTH/PTHrP receptor. These data suggest that factors circulating in the uremic environment which are present in the low-molecular weight ultrafiltrate decrease the response of the PTH/PTHrP receptor adenylate cyclase system, thus contributing in the skeletal resistance to PTH seen in chronic renal failure.

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