Increased circulating Cathepsin-K levels reflect PTH control in chronic hemodialysis patients

Background: Mineral bone disease (MBD) is remarkably frequent among chronic hemodialysis (HD) patients. In this setting, deranged PTH levels portend an adjunctive risk of worsen outcomes. Various evidence exists demonstrating that PTH strongly induces Cathepsin-K, a cysteine protease mainly found in lysosomes of osteoclasts and macrophages which promotes bone and extracellular matrix remodelling. Cathepsin-K levels are altered in various bone disorders, systemic inflammation and even in non-advanced CKD. In this study, we tested the hypothesis of an association between Cathepsin-K, uremic-MBD and circulating PTH levels in a cohort of chronic HD patients. Methods: We measured Cathepsin-K in 85 stable chronic HD patients and dialysis vintage > 6 months by a commercially available ELISA kit and we collected routine clinical parameters, including intact PTH. Patients were further stratified according to their “on- target” or “off-target” PTH status. Results: Cathepsin-K levels were significantly higher in HD patients than in healthy controls (p < 0.0001) and were independently associated with alkaline phosphatase (β = 0.37; p < 0.001), PTH (β = 0.30; p = 0.02) and C-reactive protein (β = 0.24; p = 0.008) levels. Cathepsin-K was also higher in patients with off-target PTH as compared to those with controlled PTH levels (230 [40–420] vs. 3250 [820–4205] pg/mL; p < 0.0001). At ROC analyses, Cathepsin-K levels were able to identify off-target PTH and parathyroidectomized patients (AUCs 0.85 [95% CI 0.71–0.98] and 0.97 [95% CI 0.92–0.99], respectively). Conclusion: In chronic HD patients, Cathepsin-K associates with PTH levels, raising the intriguing hypothesis that this protein represents a causal link between mineral and inflammatory complications and could be tested as a candidate biomarker of MBD severity and PTH balance.