You are on page 1of 4

VOL 55, NO 1, JANUARY 2010

Coronary Calcifications: Lessons From Histology in CKD Patients
between results of the present study, in which
Related Article, p. 21
arterial calcifications exclusively affect the in-
tima, and previous studies are discussed in greater
T he leading cause of mortality in patients
with chronic kidney disease (CKD) is car-
diovascular disease. In patients with kidney fail-
Coronary artery calcification, detected using
ure treated using dialysis or transplant, ⬎50% cardiac computed tomography, is very common
die as a result of myocardial infarction, left in dialysis patients, with studies of dialysis pa-
ventricular failure, or sudden cardiac death. More- tients showing markedly higher calcification
over, this high risk is present even in earlier scores of the coronary arteries than in nondialy-
stages of CKD, for which it is well appreciated sis patients.5 Interestingly, most of these studies
that most individuals with mild to moderately have shown that when coronary artery calcifica-
impaired kidney function will never reach kid- tion is present, its severity rapidly increases.
ney failure, but rather will die of cardiovascular Coronary arterial calcification seems to occur
disease before this time.1 This increased risk almost exclusively in atherosclerotic arteries and
may even be present in younger patients with appears to be a key facet for the development of
kidney disease, with Goodman et al2 showing a coronary atherosclerosis.6 However, although an
high prevalence of coronary calcification using association between degree of coronary calcium
electron-beam computed tomography in younger and luminal stenosis on angiography has been
adults (aged 20-30 years) receiving long-term reported,7 this has not been consistent across all
hemodialysis. Atherosclerosis, a primary intimal studies.8
disease characterized by the presence of plaques The pathogenesis of vascular calcification in
and occlusive lesions, is the most frequent under- patients with CKD likely is multifactorial and is
lying cause of these cardiovascular complica- incompletely understood, with even the localiza-
tions. This assertion is supported by autopsy tion of vascular calcification a matter of debate.
findings documenting that the prevalence of cor- Calcification may develop at 2 sites in the arterial
onary plaques is higher in individuals receiving wall: the intima and the media. Arterial intima
dialysis compared with matched nonuremic pa- calcification represents an advanced stage of
tients.3 atherosclerosis and is associated with the devel-
In this issue of the American Journal of Kid- opment of plaques and occlusive lesions. Arterial
ney Diseases, Nakano et al4 provide the first media calcification, or Monckeberg arteriosclero-
description of coronary artery histopathologic sis, is observed essentially in muscular arteries
characteristics in individuals with earlier stages
of CKD, clearly showing the relationship be-
tween decreased glomerular filtration rate (GFR) Address correspondence to Alain Guerin, MD, Hopital
and severity of coronary atherosclerosis. Further- Manhes, 8 Grande Rue, FR—91712, Fleury Merogis, France.
more, they show the importance of vascular © 2009 by the National Kidney Foundation, Inc.
calcifications in patients with CKD. Because this 0272-6386/09/5501-0002$36.00/0
particular point is a matter of debate, differences doi:10.1053/j.ajkd.2009.10.005

American Journal of Kidney Diseases, Vol 55, No 1 (January), 2010: pp 1-4 1

which can prevalence of calcified coronary lesions and thick- promote or inhibit mineralization depending on ened arterial intima. and upregulated activity of cause they studied an elderly population with a monocyte-macrophages. pre- of VSMCs to osteo/chondrocytic cells to occur. and cultured ciation of lower estimated GFR with a higher VSMCs elaborate matrix vesicles. ness was greater in patients with kidney failure. regardless of the gests that both intimal and medial calcification technique used.2 Alain Guerin and commonly is associated with aging. temic and/or local calcification inhibitors. lesions in autopsy specimens from 27 patients lar evidence for an osteogenic signaling mecha. ate between intimal and medial calcifications.73 m2). including oxidized lipids. Hypertension and diabetes were These include MGP (matrix gla [␥-carboxyglu.4 similar mesenchymal precursor cell. when used to explain the higher very similar to the process of skeletal mineraliza. In their sample of 126 patients. they were unable to local activation of vitamin D by these monocyte. the role of medial calcification as a with an osteoclast-like phenotype within the arte- marker of cardiovascular risk in individuals with rial wall.and sex-matched controls outer margins of coronary artery plaques at the showed that plaque area and volume did not calcification front. The The finding of Cbfa1 in both CKD-associated same problem and the same conclusion could be intimal and medial calcification and atheroscle.12 promote osteogenesis and ma. calcified lesion in subjects with estimated GFR ⬍ genic stimuli. presently is unable to differenti. may occur by similar processes.9 Prominent plaque was more calcified in patients with kid- factors involved in the calcification process in. calcification was observed in the study by encoded by the RUNX2 gene) believed to be the Schwarz et al3. (3) deficiency of sys. given that Nakano . In arterial cal- estimated GFR.10 Many athero. with chronic kidney failure (21 prevalent dialysis nism. Osteopontin was found primarily in the patients) and 27 age. ney failure. Unfortu. however.3 (VSMCs). (2) high calcium.13 Moreover. significantly different between groups. Limitations of this study trix calcification in vascular cell culture. tion was seen. rotic disease in individuals without CKD sug- nately. and Lumen diameter was significantly smaller in pa- (4) direct effects on vascular smooth muscle cells tients with end-stage renal disease. matrix vesicles are found in both me- dial and intimal calcium deposits. radiologic examination. they show an asso- cification. Be- matory cytokines. but also was present within differ between groups. inflam. cluding the ability to confirm the hypothesis of both VSMCs and osteoblasts are derived from a accelerated atherosclerosis. calcification with age. medial thick- phosphate product levels. preliminary data support the presence of cells Additionally. Support. including cell damage or death in- The study of Nakano et al4 sheds further light duced by mineral imbalances. no medial calcifica- their content of calcification inhibitory factors. The findings of bone morphogenic protein 2 CKD. Although intimal thickness was not clude: (1) hyperphosphatemia. are not entirely supported by in vivo studies.13 no medial transcription factor core binding factor ␣1 (Cbfa1. Notably. an active cellular process may be involved in the Converging evidence now suggests that vascu.73 m2 (⬍1 mL/s/1. lar calcification is an actively regulated process. include its cross-sectional design and the ab- ing the ability for the phenotypic transformation sence of an external comparison population. investigate the association of coronary artery macrophages. associated significantly with the increased risk of tamic acid] protein) and fetuin. typic transformation of VSMCs to osteo/chondro- Nakano et al4 report that the proportion of ad- cytic cells characterized by the upregulation of vanced atherosclerotic lesions is higher at a lower bone-specific transcription factors. as well as pheno- on these theories. with the As reviewed by Moe and Chen. 60 mL/min/1. Finally. these theories. this review emphasizes switch that turns this mesenchymal precursor that segments examined by Schwartz et al3 were cell into an osteoblast. but that atherosclerotic the central portion of each plaque. In addition. regression of vascular calcification. (BMP2) and osteopontin expression in human A comparative study of coronary atherosclerotic atherosclerotic plaque provided the first molecu. experimental data indicate that CKD is not well defined. selected based on severe obstructive lesions.11 potentially reflecting relatively narrow age range.14 However. observed in the present study. prevalence of atherosclerosis in individuals with tion.

but no controls. Nephrol Dial Transplant. and 6 controls. 4. kano et al. calcification. plaque area: a histopathologic correlative study. and and the diversity of the origins of VSMCs may medial calcification (58% vs 17%) compared be reflected in intrinsic differences in blood ves- with matched controls.351:1296- had mild/moderate calcification. Coronary artery calcium area by electron- was significantly higher in medium-sized arter.27:394-401. Pereira D.Editorial 3 et al4 specifically noted that there was no medial calcification. et al. renal failure. and hospitalization. of the coronary arterial ist among studies. In sayama Study. highlight the importance of controlling media- ing and x-ray microradiography. Electron beam com- dren with incident kidney failure. and 2 samples were inadequate for 2. Coronary artery calcification is related to coronary atherosclerosis in chronic renal disease patients: a elastic lamina. plant in 41 patients with end-stage renal disease. 38%). No. at autopsy. disease who are undergoing dialysis. REFERENCES patients were 45 ⫾ 13 years old and had been on dialysis therapy for 25 ⫾ 20 months. Am J Kidney Dis. were able to tors of vascular calcification. VSMCs tients had increased intimal thickness (97% vs have a pivotal role in the calcification process. 7 had severe 1305. had a 3. 1996.4 highlight the importance of vascular 2004. CKD.55(1):21-30. who had diabetes. Sumiyoshi S. Taken in conjunc- Nevertheless. location of arterial calcification. 1. Chronic kidney disease and the risk of death. Sheedy PF. et al. discrepancies that ex- well as in the media. Twenty. Similarly and also in heterogeneity in both techniques used to assess contrast to the findings of Schwartz et al. calcification artery calcification in young adults with end-stage renal was located exclusively in the medial layer.15:218-223. Hsu C.9 using the 2 additional techniques of stain. even in earlier detect areas of mineralization in the intima. Financial Disclosure: None. 5. with vessels in dialysis patients showing 7. Fleury Merogis. Covic AA. In all except 1 patient. Moshage W. . Nephrol Dial Transplant. Morphology of calcified intimal plaque. calcification puted tomography in the evaluation of cardiac calcification in was not detectable using von Kossa staining. Fitzpatrick LA. scores and coronary angiography. Kuizon BD. only 1 patient.92:2157-2162. Haydar AA. Nakano T. Ritz E. Hopital Manhes mately half the dialysis patients. Association dren of 24 prevalent dialysis patients. as stages of CKD. Coronary- examination. in patients without tion. intimal calcification (58% vs 17%). N Engl J Med.3 Ibels calcification and in sources of vessels studied to et al15 found that renal arteries of dialysis pa. chronic dialysis patients. Circulation. with Nakano et al4 elaborating on calcification in any specimen examined. Oldendorf M. tably. with these areas of calcifications extend. FanD. Goodman WG. 5 events. Goldsmith AJ. France In another study. et al.17 Finally. McCulloch CE. Am J Kidney Dis. Hujairi NM.18 study comparing EBCT-generated coronary artery calcium These data. as well as in the disparate re- similar observations in radial arteries: intimal sponses to common risk factors associated with and medial thickening were greater in dialysis vascular disease. Fitzpatrick vascular calcification accompanying dialysis and et al.4 in chil. with medial (6 of 15 participants) or intimal (2 of 15 partici. 2000. However. highlight the ing into the adventitia. Schwarz RS. 2010. cardiovascular seven vessels had no evidence of calcification. Schwarz U. Braun J. N Engl J Med.342: 1478-1483. beam computed tomography and coronary atherosclerotic ies of both incident and prevalent dialysis pa. 10 incident of kidney function with coronary atherosclerosis and calcifi- cation in autopsy samples from Japanese elders: the Hi- dialysis or transplant patients. the recently coronary atherosclerotic lesions in patients with end-stage published work of Shroff et al18 compares cal. tients compared with arteries in controls without 1995. Go AS. MD pants) calcification often present in approxi. Buzello M. ACKNOWLEDGEMENTS logic examination at the time of kidney trans. However. elderly individuals with CKD. Rubens calcification in the media and along the internal M. calcium load 6. the data suggest potential acceleration of CKD with known coronary disease. Finally. including that presented by Na. cium load in medium-sized arteries from chil. Goldin J. Simons DB. Ejerblad et al16 noted sels themselves. particularly with regard to the walls. contrast to the results of Nakano et al. Chertow GM. show vascular calcifications. measured quantitatively. 2004.19:2307-2312. the proximal portion of the inferior epigastric artery was removed for histo. Alain Guerin.19 patients compared with controls. Rumberger JA. Ninomyia T. 2000.

Ericsson JL. 17. Chen XN. 1597-1604. Kidney Int. Acta Chir Scand. 2002. the radial artery in uremic patients. Arterioscler Thromb Vasc Biol. 11. et al. 1979. Hsu J.73:384-390. 2008. of bone matrix proteins. 2008. 560-567.43:313-319. Coronary 14. 10. et al. Edwards WD. 790-796. Circ Res. Shroff RC. 1979. O’Neill KD. et al.95: smooth muscle diversity. McNair R. 2008. Developmental basis of vascular calcification in chronic kidney disease. Moe SM. 2007. Diffuse calcification in human coronary arteries: association Anderson JT. Demer L. Arterial calcification and pathology of osteopontin with atherosclerosis. Ka- artery calcification measured by electron-beam computerized mel S. Clin J Am Soc Nephrol. Alfrrey AC. Vitamin D and osteogenic accelerates medial vascular calcification in part by trigger- differentiation in the arterial wall. Aikawa E. 15. et al. Massy ZA. Am J Med. 18. Pathophysiology of vascular 19. osteoclast-like cells the missing link? Diabetes Metab. Tintut Y. Pereira D. 9. Ingram RT.27:1248-1258. Dialysis 12. Summers S. The pathophysiology of vascular calcification: are tomography correlates poorly with coronary artery angiogra. J Clin Invest. 16. Ejerblad S. Circulation. Am J Kidney Dis.94: in uremic patients undergoing dialysis.118: 2008.4 Alain Guerin 8. 1748-1757. . Huffer WE. Figg N. Majesky MW. Eriksson I. Duan D. Mentaverri R. Mozar A. 145:415-428. Weil RD. Ibels LS. 34(suppl 1):S16-20. 2004. Figueiredo J-L.66. Fitzpatrick LA. Hofbauer LC. ing smooth muscle cell apoptosis.61:638-647. Shroff RC. Severson A. 2007. Nahrendorf M. Arterial lesions of Exploring the biology of vascular calcification in chronic kid. 1994. Schoppet M. Shanahan CM. Moe SM. Sharples EJ. Circulation. phy in dialysis patients. Brazier M. Medial artery Osteogenesis associates with inflammation in early-stage calcification in ESRD patients is associated with deposition atherosclerosis evaluated by molecular imaging in vivo.3:1542-1547. 2004. 13. ney disease: what’s circulating? Kidney Int. Craswell PW.116:2841-2850.