三浦 裕

BACKGROUND: Progression of aortic calcification is associated with all-cause and cardiovascular mortality in hemodialysis patients. Blood calciprotein particle (CPP) levels are associated with coronary artery calcification and were reported to be inhibited when using citric acid-based bicarbonate dialysate (CD). Therefore, this study aimed to examine the effect of CD on the progression of the aortic arch calcification score (AoACS) and blood CPP levels in hemodialysis patients. METHODS: A 12-month retrospective observational study of 262 hemodialysis patients was conducted. AoACS was evaluated by calculating the number of calcifications in 16 segments of the aortic arch on chest X-ray (minimum score is 0; maximum score is 16 points). The patients were divided into the following groups according to their baseline AoACS: grade 0, AoACS = 0 points; grade 1, AoACS 1-4 points; grade 2, AoACS 5-8 points; grade 3, AoACS 9 points or higher. Patients on bisphosphonates or warfarin or with AoACS grade 3 were excluded. Progression, defined as ΔAoACS (12-month score - baseline score) > 0 points, was compared between the CD and acetic acid-based bicarbonate dialysate (AD) groups before and after adjusting the background using propensity score matching. RESULTS: The AoACS progression rate was significantly lower in the CD group than in the AD group (before matching: P = 0.020, after matching: P = 0.002). Multivariate logistic regression analysis showed that CD was significantly associated with AoACS progression (odds ratio 0.52, 95% confidence interval 0.29‒0.92, P = 0.025). CONCLUSION: CD may slow the progression of vascular calcification in hemodialysis patients.

Calcium phosphate forms particles under excessive urinary excretion of phosphate in the kidney. While the formation of calcium phosphate particles (CaPs) has been implicated in the damage to renal tubular cells and renal dysfunction, clarifying the ultrastructural information and the elemental composition of the small CaPs in the wide areas of kidney tissue has been technically difficult. This study introduces correlative and sequential light as well as electron microscopic CaP observation in the kidney tissue by combining fluorescent staining for CaPs and energy-dispersive X-ray spectroscopy (EDS) in scanning electron microscopy (SEM) on resin sections prepared using high-pressure freezing and freeze substitution. CaPs formed in mouse kidneys under long-term feeding of a high-phosphate diet were clearly visualized on resin sections by fluorescence-conjugated alendronate derivatives and toluidine blue metachromasia. These CaPs were verified by correlative observation with EDS. Furthermore, small CaPs formed in the kidney under short-term feeding were detected using fluorescent probes. The elemental composition of the particles, including calcium and magnesium, was identified following EDS analyses. These results suggest that the correlative microscopy approach is helpful for observing in situ distribution and elemental composition of CaPs in the kidney and contributing to studies regarding CaP formation-associated pathophysiology.

Calciprotein particles (CPPs) are mineral-protein complexes containing solid-phase calcium-phosphate and the serum protein fetuin-A. CPPs are dispersed in the blood as colloids. Previous clinical studies revealed that circulating levels of CPPs were correlated with inflammation and vascular calcification/stiffness in patients with chronic kidney disease (CKD). Measurement of blood CPP levels is challenging because CPPs are unstable and change their physical and chemical properties spontaneously over time in vitro. Several different methods have been developed for quantification of blood CPP levels with different advantages and limitations. We have developed a simple and sensitive assay using a fluorescent probe that bound to calcium-phosphate crystals. This assay may be useful as a clinical test to evaluate the cardiovascular risk and prognosis in CKD patients.

Calciprotein particles (CPPs) are colloids composed of solid-phase calcium-phosphate and serum protein fetuin-A. CPPs form a polydispersed system with different particle size and density. CPPs with specific physical properties can induce calcification and innate immune responses in cultured cells. In hemodialysis patients, blood CPP levels were reported to correlate with vascular calcification and inflammation. However, little is known about relation between these disorders and physical properties of CPPs. Here, we show that the association between physical properties of plasma CPPs and serum levels of inflammatory cytokines/chemokines in 78 hemodialysis out-patients by cross-sectional study. Patients with cardiovascular disease (CVD) had significantly higher high density CPP (H-CPP) levels than patients without CVD but not low density CPP (L-CPP). Seven cytokines/chemokines (EGF, eotaxin, IL-8, IP-10, MCP-1, MIP-1, MIP-1β and TNFα) were detectable in the serum samples from > 95% of the patients. In multivariate regression analysis, H-CPP was positively associated with eotaxin after adjusting for age, gender, smoking, serum phosphate and FGF23. L-CPP was negatively associated with IL-8 after adjusting for age, gender, serum albumin, phosphate and FGF23. High H-CPP levels were associated with pro-inflammatory response, whereas L-CPPs were associated with anti-inflammatory response. CPPs with different physical properties may impact differently on pathophysiology in HD patients.

AIM: Recently, we demonstrated the efficacy of etelcalcetide in the control of secondary hyperparathyroidism (SHPT). This post hoc analysis aimed to evaluate changes in fibroblast growth factor-23 (FGF23) and calciprotein particles (CPPs) after treatment with calcimimetics. METHODS: The DUET trial was a 12-week multicenter, open-label, parallel-group, randomized (1:1:1) study with patients treated with etelcalcetide plus active vitamin D (E + D group; n = 41), etelcalcetide plus oral calcium (E + Ca group; n = 41), or control (C group; n = 42) under maintenance haemodialysis. Serum levels of FGF23 and CPPs were measured at baseline, and 6 and 12 weeks after the start. RESULTS: In the linear mixed model, serum levels of FGF23 in etelcalcetide users were significantly lower than those in non-users at week 6 (p < .001) and week 12 (p < .001). When compared the difference between the E + Ca group and the E + D group, serum levels of FGF23 in the E + Ca group were significantly lower than those in the E + D group at week 12 (p = .017). There were no significant differences in the serum levels of CPPs between etelcalcetide users and non-users at week 6 and week 12, while CPPs in the E + Ca group were significantly lower than those in the E + D group (p < .001) at week 12. CONCLUSION: Etelcalcetide may be useful through suppression of FGF23 levels among haemodialysis patients with SHPT. When correcting hypocalcaemia, loading oral calcium preparations could be more advantageous than active vitamin D for the suppression of both FGF23 and CPPs.