Documente Academic
Documente Profesional
Documente Cultură
Review Article
Calciphylaxis
Sagar U. Nigwekar, M.D., M.M.Sc., Ravi Thadhani, M.D., M.P.H.,
and Vincent M. Brandenburg, M.D.
C
From the Division of Nephrology, Depart- alciphylaxis is a rare, life-threatening syndrome of vascular
ment of Medicine, Massachusetts Gen- calcification characterized by occlusion of microvessels in the subcutaneous
eral Hospital, Boston (S.U.N., R.T.); the
Departments of Biomedical Sciences and adipose tissue and dermis that results in intensely painful, ischemic skin
Medicine, Cedars-Sinai Medical Center, lesions. Once calciphylaxis has been diagnosed, the prognosis is generally poor
Los Angeles (R.T.); and the Department (survival, <1 year).1-3 The disorder, which is underrecognized,4 typically affects
of Cardiology, RWTH (Rheinisch–West-
fälische Technische Hochschule) Aachen patients with end-stage renal disease (ESRD),2,5 a population with a high prevalence
University Hospital, Aachen (V.M.B.), and of extraskeletal calcifications. A clear majority of such calcifications do not repre-
the Department of Cardiology, Rhein-Maas sent calciphylaxis, which cannot be placed on a simple continuum of vascular
Klinikum, Würselen (V.M.B.) — both in
Germany. Address reprint requests to Dr. calcification. However, an improved understanding of vascular calcification has
Brandenburg at the Department of Cardi- helped to elucidate the pathogenesis of calciphylaxis and promising approaches to
ology, University Hospital RWTH Aachen, treatment.
Pauwelsstraße 30, D-52057 Aachen, Ger-
many, or at vincent.brandenburg@post Calciphylaxis also occurs in patients with earlier stages of chronic kidney dis-
.r wth-aachen.de. ease,2,5 acute kidney injury,6 or prior receipt of a kidney transplant,7 and in rare
N Engl J Med 2018;378:1704-14. cases, it occurs in patients with normal kidney function.2,5,8,9 We therefore prefer
DOI: 10.1056/NEJMra1505292 the name calciphylaxis to calcific uremic arteriolopathy, which is another name
Copyright © 2018 Massachusetts Medical Society. for this entity.10 This review presents the current understanding of calciphylaxis
and provides a framework for its interdisciplinary management.
A B C D
E G H
J K L
Cl inic a l Cl a ssific at ion 10,000 in Germany,5 and less than 1 per 10,000
in Japan.22 A report from the United States sug-
Calciphylaxis can be classified as uremic (in pa- gests an increasing incidence,23 which may be due
tients with ESRD) or nonuremic (in patients with to an actual increase, heightened awareness of
normal renal function or earlier stages of chronic the disorder, or both. The interval from the ini-
kidney disease). The lesions in affected patients tiation of dialysis to the appearance of calciphy-
can be classified as central (involving central laxis ranges from 30 months in the United
areas within subcutaneous adipose tissue such States1 and Germany5 to 105 months in Japan.24
as the abdomen or thighs) or peripheral (restrict- Patients treated with peritoneal dialysis have
ed to peripheral sites that have limited adipose a higher incidence of calciphylaxis than those
tissue, such as the digits). In addition, lesions treated with hemodialysis25,26; however, the under-
can be nonulcerated (in the earlier stages of the lying mechanisms are unclear. The incidence in
disease) or ulcerated (in later stages). kidney-transplant recipients and in patients with
The lesions are similar whether or not patients earlier stages of chronic kidney disease is un-
have kidney disease; however, 70 to 80% of le- known.
sions in patients with ESRD have a central dis- Several reports suggest that the mean age at
tribution,1,14 as compared with approximately 50% the time of diagnosis is 50 to 70 years 2,5,14,25;
of lesions in patients who do not have ESRD.8,14 very few patients are children.27 Approximately
Patients without ESRD have a better prognosis 60 to 70% of patients with calciphylaxis are
(1-year mortality, 25 to 45%8,9) than those who women.3,5,14 In a U.S. study involving 1030 pa-
have ESRD (1-year mortality, 45 to 80%1-3), prob- tients with calciphylaxis who were dependent on
ably because of the differences in coexisting hemodialysis, 49% were white and 28% were
conditions and the location of lesions. Patients black,1 a racial distribution approximating that
with central lesions are more likely to have a of patients undergoing hemodialysis in the United
high body-mass index than patients without States.
central lesions,1 are more likely to be women,1
and have a higher risk of death.18 The presence R isk Fac t or s
of ulcerated (late) lesions reduces the 6-month
survival rate to 20%. 3
Table 1 lists risk factors for calciphylaxis,1,8,17,25,28-31
which include obesity, diabetes mellitus, female
sex, and dependence on dialysis for more than
His t opathol o gic a l Fe at ur e s
2 years. Obesity and diabetes mellitus are also
Characteristic histologic features of calciphylaxis risk factors for calciphylaxis in patients with-
(Fig. 1K and 1L) include calcification, fibrointi- out ESRD.8,9
mal hyperplasia, and thrombosis in microvessels Elevations in phosphate and calcium levels
in the subcutaneous adipose tissue and dermis, increase the risk of subsequent calciphylaxis in
often accompanied by necrosis of epidermal and patients undergoing dialysis.1 Patients with calci-
adipose tissue, dermal–epidermal separation, phylaxis have high parathyroid hormone (PTH)
panniculitis, proliferation of dermal endothelial levels at the start of treatment with dialysis,1 and
cells, and extravascular calcifications.19,20 The mean primary hyperparathyroidism8 and administration
diameter of the involved microvessels is 100 μm of recombinant PTH31 are risk factors for calci-
(range, 40 to 600).15 Calcified lesions consist of phylaxis in patients who do not have ESRD. At
calcium and phosphate in a molar ratio of 1.7, clinical presentation, however, approximately 45%
which matches that of hydroxyapatite.21 of dialysis-dependent patients with calciphylaxis
have PTH levels below the recommended target
range.5 These observations suggest overuse of
Epidemiol o gy
calcium and vitamin D supplements, leading to
Calciphylaxis, although rare, has been reported PTH suppression and adynamic bone (low bone
worldwide, with an estimated annualized inci- turnover), which may exacerbate extraskeletal
dence of 35 cases per 10,000 patients undergo- calcium depositions.32 Fibroblast growth factor 23
ing hemodialysis in the United States,1 4 per (FGF-23), a phosphaturic hormone, is increased
Normal histology
Epidermis
Dermis
↑RUNX2
Elastin fibers
Ca
PO4 PPi
Internal
elastic lamina Endothelial
cell damage
Matrix
vesicles
LUMEN
Thrombosis ↑VEGF-A
↑BMP-2
↑BMP-4
c-MGP
Ca2+ Vitamin K
Calcium deficiency or
hydroxyapatite PO4
antagonism
Fetuin-A
PPi
Inflammation
boxylated MGP probably promotes increased cu- (RUNX2).21,46 Another calcification inhibitor is
taneous expression of BMP-221 and BMP-445 and fetuin-A, which is involved in the formation of
further osteogenic transcription, as evidenced calciprotein particles that transport mineral
by increased runt-related transcription factor 2 nanocrystals.42 Fetuin-A is down-regulated in
trol group and the retrospective nature of the menopausal women, vitamin K2 supplementa-
study preclude definitive conclusions regarding tion (menaquinone-7 administered at a dose of
the effectiveness of sodium thiosulfate. 180 μg daily for 3 years) reduced aortic stiffness
Although successful use of sodium thiosulfate (measured as carotid–femoral pulse wave veloc-
for the treatment of calciphylaxis was first re- ity with the use of mechanotransducers) and
ported more than a decade ago, only now are common carotid-artery stiffness (measured ac-
two ongoing trials investigating its safety and cording to the stiffness index β with the use of
efficacy (Current Controlled Trials number, echotracking and oscillometry).74 Moreover, vita-
ISRCTN73380053; and ClinicalTrials.gov number, min K1 supplementation (phytonadione adminis-
NCT03150420). Nevertheless, sodium thiosulfate tered at a dose of 2 mg daily for 12 months)
is frequently used to treat calciphylaxis. A typical slowed the progress of aortic-valve calcification
dose is 25 g in 100 ml of solution given intrave- (measured by means of computed tomography)
nously three times a week during the last 30 to by 57%, as compared with placebo, in patients
60 minutes of hemodialysis. The optimal dura- with mild-to-moderate aortic stenosis.75 The ef-
tion of the treatment course is unclear. Pharma- ficacy of vitamin K supplementation for calci-
cokinetic simulations may be used to estimate phylaxis, however, is unclear, with no support for
the dose for hemodialysis at various levels of the superiority of a specific form of vitamin K
intensity.68 The dosing for patients undergoing (K1 or K2). A proof-of-concept study of vitamin K1
peritoneal dialysis, patients who are not being supplementation (10 mg administered orally three
treated with dialysis, and children is less stan- times weekly after hemodialysis) is currently
dardized. Adverse effects include volume over- under way (NCT02278692).
load, hypocalcemia, QT-interval prolongation, hy-
potension, and metabolic acidosis. These adverse Sum m a r y a nd F u t ur e Dir ec t ions
effects can be avoided with intralesional admin-
istration, which may be an alternative approach Calciphylaxis is a complex disorder of microvas-
for patients with early and limited disease.69 cular calcification that is typically manifested as
Bisphosphonates are pyrophosphate analogues painful cutaneous lesions and results in poor
that have been used successfully to treat patients outcomes. Currently, there are no approved thera-
with genetic ENPP1 deficiency.70 In a prospective pies for calciphylaxis; however, ongoing trials
series of 11 patients, bisphosphonates halted the are examining end points that include pain in-
progression of lesions in all the patients starting tensity and lesion characteristics. Although some
at 2 to 4 weeks after treatment initiation.71 Fur- risk factors for calciphylaxis are now better under-
ther investigation of bone-vascular cross-talk is stood, animal models that recapitulate this rare
needed to understand the role of bisphospho- human condition would be helpful to gain a
nates and other agents that modify bone (e.g., better understanding of pathogenesis and to test
receptor activator of nuclear factor-κB ligand novel therapeutic agents.
inhibitor and antisclerostin antibody). Dr. Nigwekar reports receiving grant support from Sanofi
Decisions regarding anticoagulation therapy Aventis, Hope Pharmaceuticals, and Allena Pharmaceuticals, and
consulting fees from Epizon; Dr. Thadhani, receiving consulting
should be individualized after an assessment of fees from Fresenius Medical Care; and Dr. Brandenburg, receiv-
the risk of bleeding versus the risk of thrombo- ing grant support paid to the European Calciphylaxis Network
sis. If ongoing anticoagulation therapy is favored, (EuCalNet) from Amgen, grant support from Sanifit, Bayer, and
Pharmacosmos, and lecture fees from Pfizer. No other potential
the selection of an agent should be based on the conflict of interest relevant to this article was reported.
patient’s kidney function and the indication for Disclosure forms provided by the authors are available with
anticoagulation.72 the full text of this article at NEJM.org.
We thank Donald B. Bloch, M.D., Paul R. Conlin, M.D., Kath-
In a study involving patients 60 to 80 years of ryn Lucchesi, Ph.D., and James B. Meigs, M.D., for critical review
age, vitamin K1 supplementation (phylloquinone of an earlier version of the manuscript; and Daniela Kroshinsky,
at a dose of 500 μg per day) slowed the progres- M.D., M.P.H., Rosalynn Nazarian, M.D., and Jeremy Goverman,
M.D. (all members of the Massachusetts General Hospital’s Multi-
sion of preexisting coronary-artery calcification disciplinary Calciphylaxis Program) for providing clinical im-
by 6% at 3 years of follow-up.73 In healthy post- ages and sharing their viewpoints.
References
1. Nigwekar SU, Zhao S, Wenger J, et al. of palliative care and patient-reported out- et al. Ecto-5′-nucleotidase CD73 (NT5E),
A nationally representative study of calcific come measures to address reduced qual- vitamin D receptor and FGF23 gene poly-
uremic arteriolopathy risk factors. J Am ity of life in patients with calciphylaxis: morphisms may play a role in the develop-
Soc Nephrol 2016;27:3421-9. a systematic review. Br J Dermatol 2017; ment of calcific uremic arteriolopathy in
2. McCarthy JT, El-Azhary RA, Patzelt 177:1510-8. dialysis patients — data from the German
MT, et al. Survival, risk factors, and effect 17. Nigwekar SU. Calciphylaxis. Curr Opin Calciphylaxis Registry. PLoS One 2017;
of treatment in 101 patients with calci- Nephrol Hypertens 2017;26:276-81. 12(2):e0172407.
phylaxis. Mayo Clin Proc 2016;91:1384-94. 18. Zitt E, König M, Vychytil A, et al. Use 31. Spanakis EK, Sellmeyer DE. Nonuremic
3. Fine A, Zacharias J. Calciphylaxis is of sodium thiosulphate in a multi-inter- calciphylaxis precipitated by teriparatide
usually non-ulcerating: risk factors, out- ventional setting for the treatment of cal- [rhPTH(1-34)] therapy in the setting of
come and therapy. Kidney Int 2002;61: ciphylaxis in dialysis patients. Nephrol chronic warfarin and glucocorticoid treat-
2210-7. Dial Transplant 2013;28:1232-40. ment. Osteoporos Int 2014;25:1411-4.
4. Brandenburg VM, Evenepoel P, Floege 19. Mochel MC, Arakaki RY, Wang G, 32. Mawad HW, Sawaya BP, Sarin R, Mal-
J, et al. Lack of evidence does not justify Kroshinsky D, Hoang MP. Cutaneous cal- luche HH. Calcific uremic arteriolopathy
neglect: how can we address unmet medi- ciphylaxis: a retrospective histopatholog- in association with low turnover uremic
cal needs in calciphylaxis? Nephrol Dial ic evaluation. Am J Dermatopathol 2013; bone disease. Clin Nephrol 1999;52:160-6.
Transplant 2016;31:1211-9. 35:582-6. 33. Scialla JJ, Lau WL, Reilly MP, et al. Fi-
5. Brandenburg VM, Kramann R, Rothe 20. Chen TY, Lehman JS, Gibson LE, broblast growth factor 23 is not associat-
H, et al. Calcific uraemic arteriolopathy Lohse CM, El-Azhary RA. Histopathology ed with and does not induce arterial calci-
(calciphylaxis): data from a large nation- of calciphylaxis: cohort study with clini- fication. Kidney Int 2013;83:1159-68.
wide registry. Nephrol Dial Transplant cal correlations. Am J Dermatopathol 2017; 34. Yamada S, Giachelli CM. Vascular cal-
2017;32:126-32. 39:795-802. cification in CKD-MBD: roles for phos-
6. Honda Y, Endo Y, Tanizaki H, et al. 21. Kramann R, Brandenburg VM, Schur phate, FGF23, and Klotho. Bone 2017;100:
Calciphylaxis associated with acute renal gers LJ, et al. Novel insights into osteo- 87-93.
failure in multicentric Castleman’s dis- genesis and matrix remodelling associat- 35. Nigwekar SU, Bhan I, Turchin A, et al.
ease. Eur J Dermatol 2015;25:497-9. ed with calcific uraemic arteriolopathy. Statin use and calcific uremic arteriolopa-
7. Vanparys J, Sprangers B, Sagaert X, Nephrol Dial Transplant 2013;28:856-68. thy: a matched case-control study. Am J
Kuypers DR. Chronic wounds in a kidney 22. Hayashi M. Calciphylaxis: diagnosis Nephrol 2013;37:325-32.
transplant recipient with moderate renal and clinical features. Clin Exp Nephrol 36. Santos PW, He J, Tuffaha A, Wetmore
impairment. Acta Clin Belg 2013;68:128-31. 2013;17:498-503. JB. Clinical characteristics and risk fac-
8. Nigwekar SU, Wolf M, Sterns RH, Hix 23. Nigwekar SU, Solid CA, Ankers E, et al. tors associated with mortality in calcific
JK. Calciphylaxis from nonuremic causes: Quantifying a rare disease in adminis- uremic arteriolopathy. Int Urol Nephrol
a systematic review. Clin J Am Soc trative data: the example of calciphylaxis. 2017;49:2247-56.
Nephrol 2008;3:1139-43. J Gen Intern Med 2014;29:Suppl 3:S724- 37. Nigwekar SU, Bloch DB, Nazarian
9. Kalajian AH, Malhotra PS, Callen JP, S731. RM, et al. Vitamin K-dependent carboxyl-
Parker LP. Calciphylaxis with normal re- 24. Hayashi M, Takamatsu I, Kanno Y, ation of matrix Gla protein influences the
nal and parathyroid function: not as rare Yoshida T, Abe T, Sato Y. A case-control risk of calciphylaxis. J Am Soc Nephrol
as previously believed. Arch Dermatol study of calciphylaxis in Japanese end- 2017;28:1717-22.
2009;145:451-8. stage renal disease patients. Nephrol Dial 38. Selye H, Gentile G, Prioreschi P. Cuta-
10. Coates T, Kirkland GS, Dymock RB, Transplant 2012;27:1580-4. neous molt induced by calciphylaxis in
et al. Cutaneous necrosis from calcific 25. Zhang Y, Corapi KM, Luongo M, the rat. Science 1961;134:1876-7.
uremic arteriolopathy. Am J Kidney Dis Thadhani R, Nigwekar SU. Calciphylaxis 39. Dobry AS, Ko LN, St John J, Sloan JM,
1998;32:384-91. in peritoneal dialysis patients: a single Nigwekar S, Kroshinsky D. Association
11. Polizzotto MN, Bryan T, Ashby MA, center cohort study. Int J Nephrol Reno- between hypercoagulable conditions and
Martin P. Symptomatic management of vasc Dis 2016;9:235-41. calciphylaxis in patients with renal dis-
calciphylaxis: a case series and review 26. Sprague SM. Painful skin ulcers in ease: a case-control study. JAMA Derma-
of the literature. J Pain Symptom Manage a hemodialysis patient. Clin J Am Soc tol 2018;154:182-7.
2006;32:186-90. Nephrol 2014;9:166-73. 40. Moe SM, Chen NX. Calciphylaxis and
12. Ghosh T, Winchester DS, Davis MDP, 27. Araya CE, Fennell RS, Neiberger RE, vascular calcification: a continuum of ex-
El-Azhary R, Comfere NI. Early clinical Dharnidharka VR. Sodium thiosulfate tra-skeletal osteogenesis. Pediatr Nephrol
presentations and progression of calci- treatment for calcific uremic arteriolopa- 2003;18:969-75.
phylaxis. Int J Dermatol 2017;56:856-61. thy in children and young adults. Clin J 41. Shroff R, Long DA, Shanahan C.
13. Daudén E, Oñate MJ. Calciphylaxis. Am Soc Nephrol 2006;1:1161-6. Mechanistic insights into vascular calcifi-
Dermatol Clin 2008;26:557-68. 28. James LR, Lajoie G, Prajapati D, Gan cation in CKD. J Am Soc Nephrol 2013;24:
14. Weenig RH, Sewell LD, Davis MD, BS, Bargman JM. Calciphylaxis precipi- 179-89.
McCarthy JT, Pittelkow MR. Calciphylax- tated by ultraviolet light in a patient with 42. Schafer C, Heiss A, Schwarz A, et al.
is: natural history, risk factor analysis, end-stage renal disease secondary to sys- The serum protein alpha 2-Heremans-
and outcome. J Am Acad Dermatol 2007; temic lupus erythematosus. Am J Kidney Schmid glycoprotein/fetuin-A is a system-
56:569-79. Dis 1999;34:932-6. ically acting inhibitor of ectopic calcifica-
15. Case Records of the Massachusetts 29. Amuluru L, High W, Hiatt KM, et al. tion. J Clin Invest 2003;112:357-66.
General Hospital (Case 7-2007). N Engl J Metal deposition in calcific uremic arte- 43. Luo G, Ducy P, McKee MD, et al.
Med 2007;356:1049-57. riolopathy. J Am Acad Dermatol 2009;61: Spontaneous calcification of arteries and
16. Riemer CA, El-Azhary RA, Wu KL, 73-9. cartilage in mice lacking matrix GLA pro-
Strand JJ, Lehman JS. Underreported use 30. Rothe H, Brandenburg V, Haun M, tein. Nature 1997;386:78-81.
44. Schurgers LJ, Uitto J, Reutelingsperger 55. Araki N, Misawa S, Shibuya K, et al. lution of calciphylaxis after urgent kidney
CP. Vitamin K-dependent carboxylation of POEMS syndrome and calciphylaxis: an transplantation in 3 patients with end-
matrix Gla-protein: a crucial switch to unrecognized cause of abnormal small stage kidney failure. Transplant Direct
control ectopic mineralization. Trends vessel calcification. Orphanet J Rare Dis 2016;2(11):e113.
Mol Med 2013;19:217-26. 2016;11:35. 67. Nigwekar SU, Brunelli SM, Meade D,
45. Griethe W, Schmitt R, Jurgensen JS, 56. Mutch DM, Rouault C, Keophiphath Wang W, Hymes J, Lacson E Jr. Sodium
Bachmann S, Eckardt KU, Schindler R. M, Lacasa D, Clément K. Using gene ex- thiosulfate therapy for calcific uremic ar-
Bone morphogenic protein-4 expression in pression to predict the secretome of dif- teriolopathy. Clin J Am Soc Nephrol 2013;
vascular lesions of calciphylaxis. J Nephrol ferentiating human preadipocytes. Int J 8:1162-70.
2003;16:728-32. Obes (Lond) 2009;33:354-63. 68. Singh RP, Derendorf H, Ross EA. Sim-
46. Nigwekar SU, Jiramongkolchai P, 57. Cassius C, Moguelet P, Monfort JB, ulation-based sodium thiosulfate dosing
Wunderer F, et al. Increased bone mor- et al. Calciphylaxis in haemodialysed pa- strategies for the treatment of calciphy-
phogenetic protein signaling in the cuta- tients: diagnostic value of calcifications laxis. Clin J Am Soc Nephrol 2011;6:1155-
neous vasculature of patients with calci- in cutaneous biopsy. Br J Dermatol 2018; 9.
phylaxis. Am J Nephrol 2017;46:429-38. 178:292-3. 69. Strazzula L, Nigwekar SU, Steele D,
47. Smith ER, Cai MM, McMahon LP, 58. Paul S, Rabito CA, Vedak P, Nigwekar et al. Intralesional sodium thiosulfate for
et al. Serum fetuin-A concentration and SU, Kroshinsky D. The role of bone scin- the treatment of calciphylaxis. JAMA Der-
fetuin-A-containing calciprotein particles tigraphy in the diagnosis of calciphylaxis. matol 2013;149:946-9.
in patients with chronic inflammatory dis- JAMA Dermatol 2017;153:101-3. 70. Ramjan KA, Roscioli T, Rutsch F, Sil-
ease and renal failure. Nephrology (Carl- 59. Shmidt E, Murthy NS, Knudsen JM, lence D, Munns CF. Generalized arterial
ton) 2013;18:215-21. et al. Net-like pattern of calcification on calcification of infancy: treatment with
48. Sowers KM, Hayden MR. Calcific ure- plain soft-tissue radiographs in patients bisphosphonates. Nat Clin Pract Endocri-
mic arteriolopathy: pathophysiology, re- with calciphylaxis. J Am Acad Dermatol nol Metab 2009;5:167-72.
active oxygen species and therapeutic 2012;67:1296-301. 71. Torregrosa JV, Sánchez-Escuredo A,
approaches. Oxid Med Cell Longev 2010; 60. Wilmer WA, Voroshilova O, Singh I, Barros X, Blasco M, Campistol JM. Clini-
3:109-21. Middendorf DF, Cosio FG. Transcutane- cal management of calcific uremic arteri-
49. St Hilaire C, Ziegler SG, Markello TC, ous oxygen tension in patients with cal- olopathy before and after therapeutic in-
et al. NT5E mutations and arterial calcifi- ciphylaxis. Am J Kidney Dis 2001;37:797- clusion of bisphosphonates. Clin Nephrol
cations. N Engl J Med 2011;364:432-42. 806. 2015;83:231-4.
50. Albright RA, Stabach P, Cao W, et al. 61. An J, Devaney B, Ooi KY, Ford S, Fraw- 72. King BJ, El-Azhary RA, McEvoy MT, et
ENPP1-Fc prevents mortality and vascular ley G, Menahem S. Hyperbaric oxygen in al. Direct oral anticoagulant medications
calcifications in rodent model of general- the treatment of calciphylaxis: a case se- in calciphylaxis. Int J Dermatol 2017;56:
ized arterial calcification of infancy. Nat ries and literature review. Nephrology 1065-70.
Commun 2015;6:10006. (Carlton) 2015;20:444-50. 73. Shea MK, O’Donnell CJ, Hoffmann U,
51. Lomashvili KA, Narisawa S, Millán 62. Fouque D, Kalantar-Zadeh K, Kopple J, et al. Vitamin K supplementation and pro-
JL, O’Neill WC. Vascular calcification is et al. A proposed nomenclature and diag- gression of coronary artery calcium in
dependent on plasma levels of pyrophos- nostic criteria for protein-energy wasting older men and women. Am J Clin Nutr
phate. Kidney Int 2014;85:1351-6. in acute and chronic kidney disease. Kid- 2009;89:1799-807.
52. Pillai ICL, Li S, Romay M, et al. Car- ney Int 2008;73:391-8. 74. Knapen MH, Braam LA, Drummen
diac fibroblasts adopt osteogenic fates and 63. The EVOLVE Trial Investigators. Effect NE, Bekers O, Hoeks AP, Vermeer C. Mena-
can be targeted to attenuate pathological of cinacalcet on cardiovascular disease in quinone-7 supplementation improves arte-
heart calcification. Cell Stem Cell 2017; patients undergoing dialysis. N Engl J Med rial stiffness in healthy postmenopausal
20(2):218-232.e5. 2012;367:2482-94. women: a double-blind randomised clinical
53. Chen NX, O’Neill K, Akl NK, Moe SM. 64. Nigwekar SU, Sprague SM. We do too trial. Thromb Haemost 2015; 113:1135-
Adipocyte induced arterial calcification is many parathyroidectomies for calciphy- 44.
prevented with sodium thiosulfate. Bio- laxis. Semin Dial 2016;29:312-4. 75. Brandenburg VM, Reinartz S, Kaesler
chem Biophys Res Commun 2014; 449: 65. Baldwin C, Farah M, Leung M, et al. N, et al. Slower progress of aortic valve
151-6. Multi-intervention management of calci- calcification with vitamin K supplemen-
54. Mikhaylova L, Malmquist J, Nurmins- phylaxis: a report of 7 cases. Am J Kidney tation: results from a prospective inter-
kaya M. Regulation of in vitro vascular Dis 2011;58:988-91. ventional proof-of-concept study. Circula-
calcification by BMP4, VEGF and Wnt3a. 66. Nordheim E, Dahle DO, Syse IM, Ås- tion 2017;135:2081-3.
Calcif Tissue Int 2007;81:372-81. berg A, Reisæter AV, Hartmann A. Reso- Copyright © 2018 Massachusetts Medical Society.