A small circulating miRNAs signature predicts mortality and adverse cardiovascular outcomes in chronic hemodialysis patients.

Background: Chronic hemodialysis (HD) patients exhibit severe morpho-functional cardiac alterations, putting them at a high risk of death and adverse cardiovascular (CV) outcomes. Despite the fact that an unbalanced expression of various microRNAs (miRNAs) has been related to pathological cardiac remodeling and worse CV outcomes, scarce evidence exists on their role in this setting. Methods: We evaluated circulating levels of a selected miRNAs panel (30a-5p, 23a-3p, 451a and let7d-5p) in 74 chronic HD patients together with a thorough clinical and echocardiography assessment. Individuals were then prospectively followed (median 22 months). The primary endpoint was a composite of all-cause and CV mortality and non-fatal CV events. Results: Circulating levels of all miRNAs were lower in HD patients as compared with healthy controls and independently correlated to the severity of cardiac dysfunction. miRNA 30a-5p, 23a-3p and 451a expression was even lower in 30 subjects (40.5%) reaching the composite endpoint (P < .001), while no differences were reported for let7d-5p. The predictive value of these miRNAs was supported by univariate followed by multivariate Cox regression analyses [hazard ratio (HR) ranging from 0.943 to 0.995; P = .05 to .02] while Kaplan-Meier analyses confirmed a faster progression to the endpoint in individuals displaying miRNA levels below an optimal receiver operating characteristic-derived cut-off value (P ranging from .001 to <.0001; crude HRs 7.95 to 8.61). Conclusions: Lower circulating levels of miRNA 30-5p, 23a-3p and 451a in HD patients may reflect cardiac abnormalities and predict a higher risk of worse clinical outcomes in the short mid-term. Future studies on larger HD populations are needed to generalize these findings.

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 (ß = 0.37; p < 0.001), PTH (ß = 0.30; p = 0.02) and C-reactive protein (ß = 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.

Cathepsin-K is a potential cardiovascular risk biomarker in prevalent hemodialysis patients.

PURPOSE: Cardiovascular (CV) disease remains the leading cause of mortality among end-stage kidney disease (ESKD) patients. Cathepsin-K (CatK), a small cysteine protease involved in bone and extracellular matrix remodeling, has recently emerged as a key-factor in the pathogenesis of various conditions predisposing to CV disease, including atherosclerosis, obesity, diabetes, and vascular calcification. In this pilot prospective study, we aimed at evaluating the clinical significance and the predictive power of CatK in a small cohort of hemodialysis (HD) patients. METHODS: Cathepsin-K was measured in 54 prevalent HD patients and in 30 controls together with routine parameters. Patients were then followed up to 26 months and the time of cardiovascular death (endpoint of the study prospective phase) recorded. RESULTS: CatK levels were increased in the HD cohort as compared with controls (p < 0.001). In HD patients, CatK was also independently correlated to PTH (ß = 0.368; p = 0.001), alkaline phosphatase (ß = 0.383; p < 0.001), C-reactive protein (ß = 0.260; p = 0.01), and white cell count (ß = - 0.219; p = 0.02). After baseline assessment, patients were followed for CV death (mean follow-up 24.8 ± 3.1 months). Kaplan-Meier analysis showed a worsen survival (log-rank p = 0.04) in HD patients with CatK levels > 440 pg/mL (best ROC-derived cut-off with 69.6% sensitivity and 79.8% specificity) with a crude HR (Mantel-Haenszel) of CV death of 3.46 (95% CI 1.89-13.44). CONCLUSIONS: In prevalent HD patients, altered CatK levels may reflect mineral dysmetabolism and inflammation, and predict CV death in the mid-term. These preliminary findings prompt the rationale for further investigations on larger cohorts to validate CatK as a biomarker for improving CV risk stratification in ESKD.