Abstract
Elevated concentrations of parathyroid hormone related peptide (PTHrP) may indicate hypercalcemia of malignancy and can prompt investigation into potential malignancy. Early studies using PTHrP radioimmunoassays suggested that PTHrP concentrations in normocalcemic renal failure patients were elevated due to assay cross-reactivity with C-terminal fragments present in this population [1]. At our institution, we developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for PTHrP targeting a peptide in the middle of the PTHrP sequence (to avoid measuring terminal fragments). Given the high specificity of LC-MS/MS, our objective was to revisit the earlier observation that PTHrP concentrations are elevated in renal failure patients. We used retrospective chart review to investigate 1) whether PTHrP concentrations differed between adult patients with and without renal impairment and 2) how PTHrP and calcium concentrations were related in these patients. We excluded patients with cancer; the participants (n=93, 20-90y, 56% female) were categorized based on eGFR using the 2009 CKD-EPI equation following KDIGO guidelines. We focused on patients with healthy kidney function (n=21, 20-73y, 43% female), stage 4 kidney disease (n=40, 23-90y, 63% female), and end stage renal disease (ESRD, n=19, 27-81y, 58% female), 7 of whom were on hemodialysis. When measured by LC-MS/MS, we observed higher PTHrP concentrations in ESRD and stage 4 patients compared to those with healthy kidney function (p<0.0001 for both). Overall, there was a strong negative correlation between eGFR and PTHrP (ρ=-0.768, p<0.0001). In contrast to the previous study documenting elevated C-terminal fragments of PTHrP in normocalcemic patients, we observed that 80% of patients with elevated PTHrP had hypercalcemia, in agreement with the positive association between concentrations of PTHrP and calcium (ρ=0.295, p=0.0178). No statistically significant difference was observed between distributions of PTHrP concentrations in stage 4 and ESRD patients with and without hypercalcemia. Among ESRD patients, higher PTHrP concentrations occurred in patients on dialysis compared to those not on dialysis (p=0.003). Our data suggest that elevated PTHrP concentrations are not solely due to decreased glomerular filtration; otherwise, patients on hemodialysis would have decreased PTHrP concentrations due to clearance. Considering the specificity of the LC-MS/MS method for the central portion of PTHrP, we conclude that elevated PTHrP concentrations may occur in patients with severe renal dysfunction; PTHrP elevations correlate with hypercalcemia in the majority of these patients. Clinicians should be cognizant of the method used to measure PTHrP when evaluating hypercalcemia, particularly in patients with renal insufficiency. 1) Orloff et al., Kidney International. 1993;43:1371-76.