THE EFFECT OF UNINEPHRECTOMY ON OSTEOCALCIN METABOLISM IN SHEEP - A DIRECT EVALUATION OF RENAL OSTEOCALCIN CLEARANCE

Indirect evidence has suggested that the kidney is a major organ of clearance for osteocalcin, a circulating marker of osteoblast function. The objectives of the present study were (1) to confirm the role of the kidney in osteocalcin clearance (2) to quantify the contribution of extrarenal sites and (3) to investigate the renal mechanism(s) of osteocalcin clearance. Plasma osteocalcin levels, osteocalcin plasma clearance rate (PCR) and plasma production rate (PPR) were determined in oophorectomized (OX) and uninephrectomized oophorectomized (UOX) sheep. The osteocalcin renal extraction efficiency (REE) and the effective renal plasma flow (ERPF) were measured, and the osteocalcin renal clearance rate (RCR) was calculated. The osteocalcin PCR was reduced significantly in UOX compared with OX sheep (2.0 +/- 0.1 (n = 9) vs 2.5 +/- 0.1 litres/h (n = 44); P < 0.0005). In UOX sheep with plasma creatinine levels less-than-or-equal-to 130-mu-mol/l, the osteocalcin REE was 9 +/- 1.3% and the osteocalcin RCR was 50-91% of osteocalcin PCR (n = 4). In UOX sheep with plasma creatinine levels in the range 100-440-mu-mol/l, there was a linear relationship between osteocalcin PCR and ERPF; the osteocalcin RCR was related to the osteocalcin PCR (RCR = 0.9 x PCR - 0.50). Intravenous infusion of the synthetic glucocorticoid triamcinolone acetonide (TA) in UOX sheep led to marked decrements in plasma osteocalcin levels and the osteocalcin PPR, and a significant increase in the osteocalcin PCR. These changes were accompanied by a 44% increase in ERPF. During i.v. infusion of I-125-labelled osteocalcin in three UOX sheep, the urinary excretion of trichloroacetic acid-precipitable radioactivity represented 27% (range 22-31%) of the amount cleared by the kidney. Bio-Gel P6 chromatography of urine suggested the presence of intact I-125-labelled osteocalcin and at least one radiolabelled osteocalcin fragment. These findings confirm that the kidney is the major site of osteocalcin clearance and show that extrarenal sites also make an appreciable contribution. ERPF is an important determinant of the osteocalcin PCR. Augmentation of the ERPF by TA may mediate the induction of osteocalcin clearance by this glucocorticoid. In the UOX sheep, urinary excretion of intact osteocalcin may account for up to 30% of renal osteocalcin clearance.