Ultrastructural analysis of vascular calcifications in uremia.
Accelerated intimal and medial calcification and sclerosis accompany the increased cardiovascular mortality of dialysis patients, but the pathomechanisms initiating microcalcifications of the media are largely unknown. In this study, we systematically investigated the ultrastructural properties of medial calcifications from patients with uremia. We collected iliac artery segments from 30 dialysis patients before kidney transplantation and studied them by radiography, microcomputed tomography, light microscopy, and transmission electron microscopy including electron energy loss spectrometry, energy dispersive spectroscopy, and electron diffraction. In addition, we performed synchrotron x-ray analyses and immunogold labeling to detect inhibitors of calcification. Von Kossa staining revealed calcification of 53% of the arteries. The diameter of these microcalcifications ranged from 20 to 500 nm, with a core-shell structure consisting of up to three layers (subshells). Many of the calcifications consisted of 2- to 10-nm nanocrystals and showed a hydroxyapatite and whitlockite crystalline structure and mineral phase. Immunogold labeling of calcification foci revealed the calcification inhibitors fetuin-A, osteopontin, and matrix gla protein. These observations suggest that uremic microcalcifications originate from nanocrystals, are chemically diverse, and intimately associate with proteinaceous inhibitors of calcification. Furthermore, considering the core-shell structure of the calcifications, apoptotic bodies or matrix vesicles may serve as a calcification nidus.
Schlieper
Georg
G
Department of Nephrology and Clinical Immunology, Rheinisch-Westfälische Technische Hochschule Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany. gschlieper@ukaachen.de
Aretz
Anke
A
Verberckmoes
Steven C
SC
Krüger
Thilo
T
Behets
Geert J
GJ
Ghadimi
Reza
R
Weirich
Thomas E
TE
Rohrmann
Dorothea
D
Langer
Stephan
S
Tordoir
Jan H
JH
Amann
Kerstin
K
Westenfeld
Ralf
R
Brandenburg
Vincent M
VM
D'Haese
Patrick C
PC
Mayer
Joachim
J
Ketteler
Markus
M
McKee
Marc D
MD
Floege
Jürgen
J
D002114:Calcinosis / Q000209:etiology* / Q000473:pathology*; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications*; D008297:Male; D008875:Middle Aged; D017540:Tunica Media / Q000648:ultrastructure*; D014511:Uremia / Q000150:complications*; D014652:Vascular Diseases / Q000209:etiology* / Q000473:pathology*