title: Dynamics of skeletal resistance to parathyroid hormone in the rat: effect of renal failure and dietary phosphorus.
abstract: Secondary hyperparathyroidism develops in renal failure and is generally ascribed to factors directly affecting parathyroid hormone (PTH) production and/or secretion. These include hypocalcemia, phosphorus retention, and a calcitriol deficiency. However, not often emphasized is that skeletal resistance to PTH is an important factor. Our study evaluated: (1) the relative effects of uremia and dietary phosphorus on the skeletal resistance to PTH; and (2) how, during a PTH infusion, the dynamics of skeletal resistance to PTH were affected by renal failure. Renal failure was surgically induced and, based on serum creatinine, rats were divided into normal, moderate renal failure, and advanced renal failure. In each group, three diets with the same calcium (0.6%) but different phosphorus contents were used: high (1.2%, HPD); moderate (0.6%, MPD); and low (0.2%, LPD) phosphorus. The study diet was given for 14-16 days followed by a 48 h infusion of rat PTH(1-34) (0.11 microg/100 g per hour), a dose five times greater than the normal replacement dose. During the PTH infusion, rats received a calcium-free, low phosphorus (0.2%) diet. In both moderate and advanced renal failure, the PTH level was greatest in the HPD group (p < 0.05) and, despite normal serum calcium values, PTH was greater in the MPD than the LPD group (p < 0.05). Despite phosphorus restriction and normal serum calcium and calcitriol levels in the azotemic LPD groups, the PTH level was greater (p < 0.05) in the LPD group with advanced rather than moderate renal failure. During PTH infusion, the increase in serum calcium was progressively less (p < 0.05) in all groups as renal function declined. Furthermore, despite normal and similar serum phosphorus values at the end of PTH infusion, the serum calcium concentration was less (p < 0.05) in the HPD group than the other two groups and similar in the LPD and MPD groups.
  
  
  CONCLUSIONS
  (1) uremia and phosphorus each had separate and major effects on skeletal resistance to PTH; (2) skeletal resistance to PTH was an important cause of secondary hyperparathyroidism, even in moderate renal failure; (3) during PTH infusion, the dynamics of skeletal resistance to PTH changed because all groups received a low phosphorus diet, and the adaptation to a new steady state was delayed by the degree of renal failure and the previous dietary phosphorus burden; and (4) normal serum phosphorus may not be indicative of body phosphorus stores during states of disequilibrium.
authors.affiliation: Department of Medicine, West Los Angeles VA Medical Center, CA 90073, USA.
authors.forename: J
authors.initials: J
authors.lastname: Bover
authors.forename: A
authors.initials: A
authors.lastname: Jara
authors.forename: P
authors.initials: P
authors.lastname: Trinidad
authors.forename: M
authors.initials: M
authors.lastname: Rodriguez
authors.forename: A J
authors.initials: AJ
authors.lastname: Felsenfeld
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D002113:Calcification, Physiologic / Q000187:drug effects*; D002117:Calcitriol / Q000097:blood; D002118:Calcium / Q000097:blood; D003404:Creatinine / Q000652:urine; D006962:Hyperparathyroidism, Secondary / Q000097:blood / Q000209:etiology*; D007676:Kidney Failure, Chronic / Q000097:blood / Q000150:complications*; D008297:Male; D009392:Nephrectomy; D010281:Parathyroid Hormone / Q000097:blood / Q000494:pharmacology*; D016226:Phosphorus, Dietary / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D014511:Uremia / Q000150:complications
chemical_list: D010281:Parathyroid Hormone; D016226:Phosphorus, Dietary; D003404:Creatinine; D002117:Calcitriol; D002118:Calcium