Pathophysiology of vascular calcification in chronic kidney disease.
Patients with chronic kidney disease (CKD) on dialysis have 2- to 5-fold more coronary artery calcification than age-matched individuals with angiographically proven coronary artery disease. In addition to increased traditional risk factors, CKD patients also have a number of nontraditional cardiovascular risk factors that may play a prominent role in the pathogenesis of arterial calcification, including duration of dialysis and disorders of mineral metabolism. In histological specimens from the inferior epigastric artery of dialysis patients, we have found expression of the osteoblast differentiation factor core binding factor alpha-1 (Cbfa1) and several bone-associated proteins (osteopontin, bone sialoprotein, alkaline phosphatase, type I collagen) in both the intima and medial layers when calcification was present. In cultured vascular smooth muscle cells, the addition of pooled serum from dialysis patients (versus normal healthy controls) accelerated mineralization and increased expression of Cbfa1, osteopontin, and alkaline phosphatase to a similar magnitude as does beta-glycerophosphate alone. However, a lack of inhibitors of calcification may also be important. Dialysis patients with low levels of serum fetuin-A, a circulating inhibitor of mineralization, have increased coronary artery calcification and fetuin-A can inhibit mineralization of vascular smooth muscle cells in vitro. These data support that elevated levels of phosphorus and/or other potential uremic toxins may play an important role by transforming vascular smooth muscle cells into osteoblast-like cells, which can produce a matrix of bone collagen and noncollagenous proteins. This nidus can then mineralize if the balance of pro-mineralizing factors outweighs inhibitory factors.
Moe
Sharon M
SM
Indiana University School of Medicine, Wishard Memorial Hospital, 1001 W 10th St, OPW 526 Indianapolis, IN 46202, USA. smoe@iupui.edu
Chen
Neal X
NX
D000818:Animals; D001018:Aortic Diseases / Q000517:prevention & control; D001161:Arteriosclerosis / Q000453:epidemiology / Q000503:physiopathology* / Q000517:prevention & control; D001798:Blood Proteins / Q000494:pharmacology / Q000627:therapeutic use; D001842:Bone and Bones / Q000378:metabolism; D002114:Calcinosis / Q000503:physiopathology*; D002454:Cell Differentiation; D002908:Chronic Disease; D050657:Core Binding Factor alpha Subunits; D003327:Coronary Disease / Q000453:epidemiology / Q000503:physiopathology* / Q000517:prevention & control; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000502:physiology; D018450:Disease Progression; D004852:Epoxy Compounds / Q000627:therapeutic use; D006801:Humans; D058574:Integrin-Binding Sialoprotein; D007674:Kidney Diseases / Q000503:physiopathology* / Q000628:therapy; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D015676:Osteonectin / Q000378:metabolism; D053495:Osteopontin; D010710:Phosphates / Q000378:metabolism; D011073:Polyamines; D011095:Polyethylenes / Q000627:therapeutic use; D015995:Prevalence; D016032:Randomized Controlled Trials as Topic; D006435:Renal Dialysis; D012307:Risk Factors; D000069603:Sevelamer; D012795:Sialoglycoproteins / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000502:physiology; D014511:Uremia / Q000503:physiopathology / Q000628:therapy; D060749:alpha-2-HS-Glycoprotein
C556354:AHSG protein, human; C556357:Ahsg protein, mouse; D001798:Blood Proteins; D050657:Core Binding Factor alpha Subunits; D004268:DNA-Binding Proteins; D004852:Epoxy Compounds; C546871:IBSP protein, human; C546872:Ibsp protein, mouse; D058574:Integrin-Binding Sialoprotein; D015676:Osteonectin; D010710:Phosphates; D011073:Polyamines; D011095:Polyethylenes; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D014157:Transcription Factors; D060749:alpha-2-HS-Glycoprotein; C406688:core binding factor alpha; D053495:Osteopontin; D000069603:Sevelamer