ACCUMULATION OF CARBOXY-TERMINAL FRAGMENTS OF PARATHYROID HORMONE-RELATED PROTEIN IN RENAL-FAILURE

We have recently demonstrated elevations of separate amino- and carbox y-terminal parathyroid hormone-related protein (PTHrP) fragments in pa tients with humoral hypercalcemia of malignancy (HHM) using both a two -site immunoradiometric assay (IRMA) with amino-terminal specificity f or PTHrP, and with a carboxy-terminal radioimmunoassay (RIA) for PTHrP (109-138). PTHrP(109-138) immunoactivity from plasma of patients with HHM could not be extracted using an amino-terminal PTHrP immunoaffinit y column, indicating that the carboxy-terminal region circulates as a discrete peptide. Carboxy-terminal immunoreactive (i) PTHrP levels wer e also elevated in normocalcemic patients with chronic renal failure ( without cancer), whereas amino-terminal iPTHrP levels were normal in p atients with renal failure. In order to further define the renal handl ing of carboxy-terminal PTHrP peptides, we have evaluated circulating iPTHrP(109-138) concentrations in patients with a wide range of renal function. We studied 25 patients with abnormal renal function of diver se etiologies whose creatinine clearances ranged from 66 ml/min to les s than 5 ml/min. All patients had undetectable or low (less-than-or-eq ual-to 2 pmol/liter) concentrations of iPTHrP(1-74). iPTHrP(109-138) c oncentrations were undetectable in patients with creatinine clearances greater-than-or-equal-to 20 ml/min, but became elevated in patients w ith creatinine clearances <20 ml/min. The log of iPTHrP(109-138) corre lated negatively with the log of creatinine clearance (r = 0.88, P = 0 .0001). Mean iPTHrP(109-138) levels were slightly higher for patients on hemodialysis (32.7 +/- 3.1 pm) than for those on chronic ambulatory peritoneal dialysis (22.1 +/- 3.4 pm; P < 0.05), suggesting that some carboxy-terminal PTHrP fragments may be cleared to a greater extent b y the peritoneal membrane. Gel filtration chromatography was performed using Sephadex G-50 and Sephacryl S-200 columns to further characteri ze the carboxy-terminal PTHrP fragments. Plasma immunoactivity from no rmo-calcemic dialysis patients eluted largely as a single peak on both columns in a position similar to that for plasma from patients with H HM. However, because of anomalous elution of the PTHrP(109-138) standa rd, an accurate assessment of the molecular weight of this fragment co uld not be performed. We conclude that carboxy-terminal iPTHrPs are pr esent in the plasma of patients with renal failure but without cancer, and that these carboxy-terminal fragments depend on glomerular filtra tion for clearance. Gel filtration chromatography indicates that the c arboxy-terminal iPTHrP fragment circulating in patients with renal ins ufficiency appears to be similar or identical to the carboxy-terminal fragment which circulates in patients with humoral hypercalcemia of ma lignancy.