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. 2019 Jun 1;34(6):992-1000.
doi: 10.1093/ndt/gfy117.

Patients with advanced chronic kidney disease and vascular calcification have a large hydrodynamic radius of secondary calciprotein particles

Wei Chen  1 , Viktoriya Anokhina  2 , Gregory Dieudonne  3 , Matthew K Abramowitz  4 , Randeep Kashyap  5 , Chen Yan  1 , Tong Tong Wu  6 , Karen L de Mesy Bentley  7 , Benjamin L Miller  2   8   9 , David A Bushinsky  1
Affiliations

Patients with advanced chronic kidney disease and vascular calcification have a large hydrodynamic radius of secondary calciprotein particles

Wei Chen et al. Nephrol Dial Transplant. .

Abstract

Background: The size of secondary calciprotein particles (CPP2) and the speed of transformation (T50) from primary calciprotein particles (CPP1) to CPP2 in serum may be associated with vascular calcification (VC) in patients with chronic kidney disease (CKD).

Methods: We developed a high throughput, microplate-based assay using dynamic light scattering (DLS) to measure the transformation of CPP1 to CPP2, hydrodynamic radius (Rh) of CPP1 and CPP2, T50 and aggregation of CPP2. We used this DLS assay to test the hypothesis that a large Rh of CPP2 and/or a fast T50 are associated with VC in 45 participants with CKD Stages 4-5 (22 without VC and 23 with VC) and 17 healthy volunteers (HV). VC was defined as a Kauppila score >6 or an Adragao score ≥3.

Results: CKD participants with VC had larger cumulants Rh of CPP2 {370 nm [interquartile range (IQR) 272-566]} compared with CKD participants without VC [212 nm (IQR 169-315)] and compared with HV [168 nm (IQR 145-352), P < 0.01 for each]. More CPP2 were in aggregates in CKD participants with VC than those without VC (70% versus 36%). The odds of having VC increased by 9% with every 10 nm increase in the Rh of CPP2, after adjusting for age, diabetes, serum calcium and phosphate [odds ratio 1.09, 95% confidence interval (CI) 1.03, 1.16, P = 0.005]. The area under the receiver operating characteristic curve for VC of CPP2 size was 0.75 (95% CI 0.60, 0.90). T50 was similar in CKD participants with and without VC, although both groups had a lower T50 than HV.

Conclusions: Rh of CPP2, but not T50, is independently associated with VC in patients with CKD Stages 4-5.

Keywords: calcification propensity; calciprotein particle; chronic kidney disease; mineral metabolism; vascular calcification.

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Figures

FIGURE 1
FIGURE 1
CPP transformation and size distribution of CCPs. (A) CPP transformation measured by DLS in 10 representative participants with CKD (5 with VC, solid squares; 5 without VC, hollow circles); (B–D) TEM of serum (magnification: 150 000×) showing (B) CPP1 and a few other nanoparticles (solid arrow indicates the other nanoparticle) in Phase 1; (C) radial growth of CPP1 into crystalline CPP2 (solid arrow indicates CPP1 in transition; hollow arrow indicates the center of radial growth) in Phase 2 and (D) CPP2 in Phase 3 (solid arrow indicates the other nanoparticle seen in B); (E–G) size distribution of nanoparticles in serum measured by DLS with the percentage of total light scattered in the parenthesis (X-axis is in log scale) in each phase.
FIGURE 2
FIGURE 2
TEM of CPP2 aggregates in Phase 3 (magnification: 50 000×).
FIGURE 3
FIGURE 3
Boxplots of (A) cumulants Rh of CPP2 and (B) T50 in HV (white), CKD participants without VC (light gray) and CKD participants with VC (dark gray); (C–E) size distribution curves of CPP2 in HV and CKD participants with and without VC, as indicated by Peak 3 in Phase 3. Vertical dash line is the reference line at Rh of 150 nm, which is the calculated size of a CPP2 spindle based on TEM measurements. T50, time for half-maximal transformation of CCPs. *P < 0.05 versus HV. #P < 0.05 versus CKD participants without VC.
FIGURE 4
FIGURE 4
ROC curves for VC in participants with CKD (n = 45). Multiple logistic regression models for VC were adjusted for age, diabetes, serum calcium, phosphate, with and without CPP2. AUC, area under the curve.
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