Accumulation of carboxy-terminal fragments of parathyroid hormone-related protein in renal failure.

We have recently demonstrated elevations of separate amino- and carboxy-terminal parathyroid hormone-related protein (PTHrP) fragments in patients with humoral hypercalcemia of malignancy (HHM) using both a two-site immunoradiometric assay (IRMA) with amino-terminal specificity for 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 immunoaffinity column, indicating that the carboxy-terminal region circulates as a discrete peptide. Carboxy-terminal immunoreactive (i) PTHrP levels were also elevated in normocalcemic patients with chronic renal failure (without cancer), whereas amino-terminal iPTHrP levels were normal in patients with renal failure. In order to further define the renal handling 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 diverse etiologies whose creatinine clearances ranged from 66 ml/min to less than 5 ml/min. All patients had undetectable or low (< or = 2 pmol/liter) concentrations of iPTHrP(1-74). iPTHrP(109-138) concentrations were undetectable in patients with creatinine clearances > or = 20 ml/min, but became elevated in patients with creatinine clearances < 20 ml/min. The log of iPTHrP(109-138) correlated 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 by the peritoneal membrane.(ABSTRACT TRUNCATED AT 250 WORDS)