When man turns to stone: Extraosseous calcification in uremic patients
2004; Elsevier BV; Volume: 65; Issue: 6 Linguagem: Inglês
10.1111/j.1523-1755.2004.00664.x
ISSN1523-1755
Autores Tópico(s)Heterotopic Ossification and Related Conditions
ResumoA 53-year-old man lost a kidney 35 years ago after an accident. Hypertension was detected 18 years ago, but he declined treatment. Last year he presented to the Aachen University Hospital with end-stage renal disease (ESRD), presumably due to hypertensive renal damage. Ambulatory peritoneal dialysis (PD) was started. In view of recurrent compliance problems, including skipping of PD exchanges, a transfer to hemodialysis (HD) was planned, which he refused. Finally, he was admitted again with uremic gastritis, pericardial effusion, polyneuropathy, and a urinary tract infection. The PD dose was increased, appropriate therapy for his medical problems was initiated, and his condition improved. Despite these measures, his serum phosphate rose from usual levels of 2.5 to 3.0 mmol/L to a maximum of 4.8 mmol/L. The serum calcium remained normal. He admitted dietary phosphate excesses and having skipped his phosphate binders (sevelamer plus calcium acetate), claiming that the pills were too big to swallow. Within 3 days he developed an abscess-like yet painless lesion on his thumb Figure 1a, which was identified as a calcification on radiograph Figure 1b. A bone scintigraphy Figure 2, chest Figure 3a, and cranial CT Figure 3b, as well as an ophthalmologic examination Figure 4 confirmed widespread extraosseous calcifications, involving but not limited to the lungs, pericardium, large arteries, abdominal wall, and conjunctiva. Serum fetuin-A was 0.33 g/L (normal range 0.5 to 1.0 g/L), and his IC50 calcium-phosphate precipitation inhibitory activity in serum was 10.2 μL (normal IC50 6.4 ± 2.6 μL).Figure 2Bone scintigraphic image of Patient 1 following the injection of 570 MBq 99mTc-HDP. Note extensive calcification of the lungs (arrows), right thumb (arrow), upper sternum, thyroid region, and base of the skull.View Large Image Figure ViewerDownload (PPT)Figure 3AChest CT image of Patient 1. Note the large pericardial calcifications (arrows) as well as calcification of the descending aorta (arrowhead).View Large Image Figure ViewerDownload (PPT)Figure 3BCranial CT image of Patient 1 demonstrating massive vascular calcification of the medial and anterior cerebral arteries.View Large Image Figure ViewerDownload (PPT)Figure 4Conjunctival calcifications in Patient 1.View Large Image Figure ViewerDownload (PPT) A 64-year-old woman weighing 48 kg has undergone chronic HD in a private dialysis center for the past 17 years. She had ESRD due to tubulointerstitial nephropathy. She underwent surgery for tertiary hyperparathyroidism 7 years ago, and had reimplantation of one gland. Secondary hyperparathyroidism recurred; the iPTH serum levels ranged between 133 and 632 ng/L (mean 308 ng/L) over the past 6 years. Over the last 5 years, no episodes of hypercalcemia (that is, serum calcium >2.55 mmol/L) had been documented, and her serum phosphate had been well controlled with low doses of an aluminum-containing phosphate binder (mean serum phosphate over the previous 5 years was 1.36 ± 0.39 mmol/L; range, 0.7 to 2.57 mmol/L; N = 63). Last year, she was admitted to the Aachen University Hospital because of unstable angina. Angiography revealed diffuse coronary artery disease without options for interventional measures. Radiographic and CT evaluations documented extensive mitral valve ring calcifications, pericardial calcifications, and widespread vascular disease, including coronary calcification. C-reactive protein was chronically elevated, with a mean of 31 mg/L (range 28 to 38 mg/L). Serum fetuin-A was 0.38 g/L, and her IC50 calcium-phosphate precipitation inhibitory activity in serum was 13.6 μL. Dr. Jürgen Floege(Professor of Medicine, Director, Renal Division, University Hospital, Aachen, Germany): These two patients provide important insights into the pathogenesis of uremic extraosseous calcification. Whereas Patient 1 is apparently a case of noncompliance and "metastatic" calcification, why does Patient 2 have such extensive calcification? She is not particularly old, not diabetic, ate little, and consequently had a low phosphate intake, was compliant with her medication, had not received calcium-containing phosphate binders over recent years, and had never had a markedly elevated calcium-phosphate product. Before embarking on this discussion, three points need to be clear: (1) I will attempt to avoid mixing data obtained in patients with ESRD with data from patients with normal renal function, as the pathogenetic principles overlap only in part. Also, insights into cardiovascular disease gained in one group can be completely different in the other, a phenomenon termed "reverse epidemiology" [1.Kalantar-Zadeh K. Block G. Humphreys M.H. Kopple J.D. Reverse epidemiology of cardiovascular risk factors in maintenance dialysis patients.Kidney Int. 2003; 63: 793-808Abstract Full Text Full Text PDF PubMed Scopus (941) Google Scholar]. (2) For didactic purposes, I will discuss vascular, valvular, organ, and soft tissue calcifications together, realizing that they may have different origins. However, in most cases, currently available information is too limited to distinguish different pathogenetic pathways. (3) Again, for didactic purposes and largely because of a lack of available data, I will use the global term "calcification" for extraosseous mineralization, realizing that important histologic and chemical subsets of calcification exist. Calcification in patients with ESRD can produce a range of pathologies, including calcific uremic arteriolopathy (formerly termed "calciphylaxis"; not covered in this review) [2.Wilmer W.A. Magro C.M. Calciphylaxis: Emerging concepts in prevention, diagnosis, and treatment.Semin Dial. 2002; 15: 172-186Crossref PubMed Scopus (261) Google Scholar], extraosseous soft tissue Figure 5 and solid organ calcification, corneal and conjunctival calcification, peritoneal calcification, and vascular and valvular calcification [3.Milliner D.S. Zinsmeister A.R. Lieberman E. Landing B. Soft tissue calcification in pediatric patients with end-stage renal disease.Kidney Int. 1990; 38: 931-936Abstract Full Text PDF PubMed Scopus (264) Google Scholar, 4.London G.M. Pannier B. Marchais S.J. Guerin A.P. Calcification of the aortic valve in the dialyzed patient.J Am Soc Nephrol. 2000; 11: 778-783PubMed Google Scholar, 5.Kuzela D.C. Huffer W.E. Conger J.D. Winter S.D. Hammond W.S. Soft tissue calcification in chronic dialysis patients.Am J Pathol. 1977; 86: 403-424PubMed Google Scholar, 6.Ibels L.S. Alfrey A.C. Huffer W.E. et al.Arterial calcification and pathology in uremic patients undergoing dialysis.Am J Med. 1979; 66: 790-796Abstract Full Text PDF PubMed Scopus (281) Google Scholar, 7.Maher E.R. Young G. Smyth-Walsh B. et al.Aortic and mitral valve calcification in patients with end-stage renal disease.Lancet. 1987; 2: 875-877Abstract PubMed Scopus (234) Google Scholar]. Nephrologists have been plagued by these complications from the early days of dialysis [3.Milliner D.S. Zinsmeister A.R. Lieberman E. Landing B. Soft tissue calcification in pediatric patients with end-stage renal disease.Kidney Int. 1990; 38: 931-936Abstract Full Text PDF PubMed Scopus (264) Google Scholar, 4.London G.M. Pannier B. Marchais S.J. Guerin A.P. Calcification of the aortic valve in the dialyzed patient.J Am Soc Nephrol. 2000; 11: 778-783PubMed Google Scholar, 5.Kuzela D.C. Huffer W.E. Conger J.D. Winter S.D. Hammond W.S. Soft tissue calcification in chronic dialysis patients.Am J Pathol. 1977; 86: 403-424PubMed Google Scholar, 7.Maher E.R. Young G. Smyth-Walsh B. et al.Aortic and mitral valve calcification in patients with end-stage renal disease.Lancet. 1987; 2: 875-877Abstract PubMed Scopus (234) Google Scholar, 8.Contiguglia S.R. Alfrey A.C. Miller N.L. et al.Nature of soft tissue calcification in uremia.Kidney Int. 1973; 4: 229-235Abstract Full Text PDF PubMed Scopus (120) Google Scholar]. For example, data obtained in 120 uremic children between 1960 and 1983 revealed soft tissue calcification in 60%, most frequently involving blood vessels, lung, kidney, myocardium, central nervous system, and gastric mucosa [3.Milliner D.S. Zinsmeister A.R. Lieberman E. Landing B. Soft tissue calcification in pediatric patients with end-stage renal disease.Kidney Int. 1990; 38: 931-936Abstract Full Text PDF PubMed Scopus (264) Google Scholar]. Autopsy findings in the 1970s confirmed soft tissue, including vascular, calcification in 50% to 80% of HD patients [5.Kuzela D.C. Huffer W.E. Conger J.D. Winter S.D. Hammond W.S. Soft tissue calcification in chronic dialysis patients.Am J Pathol. 1977; 86: 403-424PubMed Google Scholar, 6.Ibels L.S. Alfrey A.C. Huffer W.E. et al.Arterial calcification and pathology in uremic patients undergoing dialysis.Am J Med. 1979; 66: 790-796Abstract Full Text PDF PubMed Scopus (281) Google Scholar]. Thus, extraosseous calcification is neither a new nor a dramatically increasing problem in uremic patients. The latter impression may exist because new, non-invasive techniques have increased our ability to detect calcifications.Figure 5B,CIntraoperative aspect, showing large nodules of whitish material (B). Histologic examination disclosed 2 calcified areas (C) of different morphology separated by a fibrous septum (F). Whereas the left calcified area shows larger crystals and more cellular reaction, including osteoclast-like cells (insert), the right calcified zone evokes relatively little cellular response (PAS stain, magnification ×50; with insert ×200; specimen kindly provided by R. Knüchel-Clarke, Dept. of Pathology, University Hospital Aachen) (C).View Large Image Figure ViewerDownload (PPT) Vascular calcification involves large- and medium-sized arteries, whereas veins virtually never calcify unless placed into the arterial system. In rare cases, vascular prostheses also calcify. Intimal calcification only occurs within inflammatory atherosclerotic plaques, whereas in mediasclerosis (Mönckeberg sclerosis) muscular arteries undergo noninflammatory medial calcification. In mediasclerosis, elastic laminae chiefly in the inner two-thirds of the media calcify around fractured disorganized elastin fibers [9.Reid J.D. Andersen M.E. Medial calcification (whitlockite) in the aorta.Atherosclerosis. 1993; 101: 213-224Abstract Full Text PDF PubMed Scopus (56) Google Scholar, 10.Proudfoot D. Shanahan C.M. Biology of calcification in vascular cells: Intima versus media.Herz. 2001; 26: 245-251Crossref PubMed Scopus (154) Google Scholar], and formation of bone-like trabecular structures results. Glycoxidative modification of elastin in uremia might contribute to this process [11.Sakata N. Noma A. Yamamoto Y. et al.Modification of elastin by pentosidine is associated with the calcification of aortic media in patients with end-stage renal disease.Nephrol Dial Transplant. 2003; 18: 1601-1609Crossref PubMed Scopus (34) Google Scholar]. Mediasclerosis commonly occurs with normal aging, but it is markedly aggravated in uremia [6.Ibels L.S. Alfrey A.C. Huffer W.E. et al.Arterial calcification and pathology in uremic patients undergoing dialysis.Am J Med. 1979; 66: 790-796Abstract Full Text PDF PubMed Scopus (281) Google Scholar, 12.Merjanian R. Budoff M. Adler S. et al.Coronary artery, aortic wall, and valvular calcification in nondialyzed individuals with type 2 diabetes and renal disease.Kidney Int. 2003; 64: 263-271Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar] and diabetes mellitus [12.Merjanian R. Budoff M. Adler S. et al.Coronary artery, aortic wall, and valvular calcification in nondialyzed individuals with type 2 diabetes and renal disease.Kidney Int. 2003; 64: 263-271Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar], conditions associated with accelerated aging of various tissues [10.Proudfoot D. Shanahan C.M. Biology of calcification in vascular cells: Intima versus media.Herz. 2001; 26: 245-251Crossref PubMed Scopus (154) Google Scholar]. The arterial tree has considerable variability in the susceptibility and the type of calcification. In older HD patients, calcification in the aortic wall and radial artery consistently involves both the intima and media, whereas in younger dialysis patients, isolated mediasclerosis predominates [11.Sakata N. Noma A. Yamamoto Y. et al.Modification of elastin by pentosidine is associated with the calcification of aortic media in patients with end-stage renal disease.Nephrol Dial Transplant. 2003; 18: 1601-1609Crossref PubMed Scopus (34) Google Scholar, 13.Moe S.M. O'Neill K.D. Duan D. et al.Medial artery calcification in ESRD patients is associated with deposition of bone matrix proteins.Kidney Int. 2002; 61: 638-647Abstract Full Text Full Text PDF PubMed Scopus (388) Google Scholar]. However, at least in the iliac artery, intimal lesions with microcalcifications have been described even in uremic children [14.Nayir A. Bilge I. Kilicaslan I. et al.Arterial changes in paediatric haemodialysis patients undergoing renal transplantation.Nephrol Dial Transplant. 2001; 16: 2041-2047Crossref PubMed Scopus (43) Google Scholar]. Vascular calcification is not a random process in chronic HD patients. For example, calcification of the internal thoracic or hepatic arteries is unusual [15.Ura M. Sakata R. Nakayama Y. et al.The impact of chronic renal failure on atherosclerosis of the internal thoracic arteries.Ann Thorac Surg. 2001; 71: 148-151Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 16.Okuda K. Kobayashi S. Hayashi H. et al.Case-control study of calcification of the hepatic artery in chronic hemodialysis patients: Comparison with the abdominal aorta and splenic artery.J Gastroenterol Hepatol. 2002; 17: 91-95Crossref PubMed Scopus (16) Google Scholar]. Valvular calcifications often start at the site of valve insertion, in particular the mitral annulus, and then extend in the direction of the cusps. Commissural fusion and stenosis, particularly of the aortic valve, develop in advanced stages [4.London G.M. Pannier B. Marchais S.J. Guerin A.P. Calcification of the aortic valve in the dialyzed patient.J Am Soc Nephrol. 2000; 11: 778-783PubMed Google Scholar, 7.Maher E.R. Young G. Smyth-Walsh B. et al.Aortic and mitral valve calcification in patients with end-stage renal disease.Lancet. 1987; 2: 875-877Abstract PubMed Scopus (234) Google Scholar]. Compared with nonrenal disease populations, patients with ESRD are much more likely to have basal mitral leaflet calcification and papillary muscle calcification; also, calcification of intervalvular fibrosa and of the tricuspid annulus is noted only in ESRD patients [17.Bittrick J. D'Cruz I.A. Wall B.M. et al.Differences and similarities between patients with and without end-stage renal disease, with regard to location of intracardiac calcification.Echocardiography. 2002; 19: 1-6Crossref PubMed Scopus (7) Google Scholar]. In cases of uremic tumor-like calcinosis, the most common sites are the elbows, hips, hands, and wrists [18.Cofan F. Garcia S. Combalia A. et al.Uremic tumoral calcinosis in patients receiving longterm hemodialysis therapy.J Rheumatol. 1999; 26: 379-385PubMed Google Scholar]. The calcium deposits are typically multiple, para-articular, labile, and have a fluid-viscous consistency [19.Steinbach L.S. Johnston J.O. Tepper E.F. et al.Tumoral calcinosis: Radiologic-pathologic correlation.Skeletal Radiol. 1995; 24: 573-578Crossref PubMed Scopus (82) Google Scholar]. "Active" lesions, that is, calcification centers surrounded by mononuclear or multinuclear macrophages, osteoclast-like giant cells, fibroblasts, and chronic inflammatory elements, can be distinguished from "inactive" lesions, in which calcified material is surrounded by fibrous tissue Figure 5. Extraosseous calcifications in uremic patients can vary in chemical composition, even within the same site. Soft tissue and vascular calcifications in uremic patients can contain amorphous calcium phosphate or hydroxyapatite (Ca5(PO4)3OH), that is, the same form of calcium crystals as in bone [8.Contiguglia S.R. Alfrey A.C. Miller N.L. et al.Nature of soft tissue calcification in uremia.Kidney Int. 1973; 4: 229-235Abstract Full Text PDF PubMed Scopus (120) Google Scholar, 20.Schwarz U. Buzello M. Ritz E. et al.Morphology of coronary atherosclerotic lesions in patients with end-stage renal failure.Nephrol Dial Transplant. 2000; 15: 218-223Crossref PubMed Scopus (509) Google Scholar, 21.LeGeros R.Z. Formation and transformation of calcium phosphates: Relevance to vascular calcification.Z Kardiol. 2001; 90: 116-124PubMed Google Scholar]. Another form of calcium (magnesium) phosphate, whitlockite (CaMg3)(PO4)2, has been reported in the elastic laminae in the media of non-uremic human aorta [9.Reid J.D. Andersen M.E. Medial calcification (whitlockite) in the aorta.Atherosclerosis. 1993; 101: 213-224Abstract Full Text PDF PubMed Scopus (56) Google Scholar] as well as in uremic visceral organs [8.Contiguglia S.R. Alfrey A.C. Miller N.L. et al.Nature of soft tissue calcification in uremia.Kidney Int. 1973; 4: 229-235Abstract Full Text PDF PubMed Scopus (120) Google Scholar]. Finally, brushites (CaHPO4·2H2O) were found solely in stenotic arteriovenous fistulas of patients undergoing HD [22.Olsson L.F. Odselius R. Ribbe E. Hegbrant J. Evidence of calcium phosphate depositions in stenotic arteriovenous fistulas.Am J Kidney Dis. 2001; 38: 377-383Abstract Full Text PDF PubMed Scopus (24) Google Scholar]. Calcium oxalate crystals, unless associated with primary oxalosis, are not detected in the uremic vasculature [20.Schwarz U. Buzello M. Ritz E. et al.Morphology of coronary atherosclerotic lesions in patients with end-stage renal failure.Nephrol Dial Transplant. 2000; 15: 218-223Crossref PubMed Scopus (509) Google Scholar]. The calcification pattern in large arteries as seen on conventional radiographs, patchy, irregular versus linear, "tramline"-like deposits, allows a crude distinction between atherosclerotic intimal and medial vascular calcification [23.London G.M. Guerin A.P. Marchais S.J. et al.Arterial media calcification in end-stage renal disease: Impact on all-cause and cardiovascular mortality.Nephrol Dial Transplant. 2003; 18: 1731-1740Crossref PubMed Scopus (1433) Google Scholar]. But ultrasound, intravascular ultrasound, and optical coherence tomography can provide better differentiation of vascular calcification types. Other techniques employed for detecting vascular or other calcifications include echocardiography, digital subtraction angiography, magnetic resonance tomography, and bone scintigraphy [7.Maher E.R. Young G. Smyth-Walsh B. et al.Aortic and mitral valve calcification in patients with end-stage renal disease.Lancet. 1987; 2: 875-877Abstract PubMed Scopus (234) Google Scholar, 24.Gruppen M.P. Groothoff J.W. Prins M. et al.Cardiac disease in young adult patients with end-stage renal disease since childhood: A Dutch cohort study.Kidney Int. 2003; 63: 1058-1065Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar] Figure 2. The two most widely used methods for detecting vascular, and particularly coronary, calcifications are electron-beam computed tomography (EBCT) and multi-row helical computerized tomography (CT) [25.Braun J. Oldendorf M. Moshage W. et al.Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients.Am J Kidney Dis. 1996; 27: 394-401Abstract Full Text PDF PubMed Scopus (703) Google Scholar, 26.Ketteler M. Bongartz P. Westenfeld R. et al.Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: A cross-sectional study.Lancet. 2003; 361: 827-833Abstract Full Text Full Text PDF PubMed Scopus (760) Google Scholar, 27.Goodman W.G. Goldin J. Kuizon B.D. et al.Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.N Engl J Med. 2000; 342: 1478-1483Crossref PubMed Scopus (2331) Google Scholar]. Multi-row helical CT offers better signal-to-noise ratio and higher spatial resolution, whereas EBCT offers better temporal resolution and fewer cardiac motion artefacts [28.Halliburton S.S. Stillman A.E. White R.D. Noninvasive quantification of coronary artery calcification: methods and prognostic value.Cleve Clin J Med. 2002; 69: S6-11Crossref PubMed Google Scholar]. Semi-quantitative assessments can be performed using the Agatston score (the product of plaque area and a density factor), total calcium volume, or a calcium mass score [28.Halliburton S.S. Stillman A.E. White R.D. Noninvasive quantification of coronary artery calcification: methods and prognostic value.Cleve Clin J Med. 2002; 69: S6-11Crossref PubMed Google Scholar]. Neither CT method, however, can distinguish between calcifications of the vascular intima and media. In contrast to atherosclerotic intimasclerosis, mediasclerosis is generally nonocclusive. Mediasclerosis reduces the dampening ability of blood vessels and thus induces pseudohypertension and increased pulse wave velocity [29.London G.M. Cardiovascular disease in chronic renal failure: Pathophysiologic aspects.Semin Dial. 2003; 16: 85-94Crossref PubMed Scopus (241) Google Scholar]. Through these mechanisms waves return more quickly from the periphery, further augmenting the systolic wave and lowering diastolic pressure. The resultant higher pulse pressure, like aortic stiffness and pulse wave velocity, is associated with a higher mortality rate in ESRD patients [29.London G.M. Cardiovascular disease in chronic renal failure: Pathophysiologic aspects.Semin Dial. 2003; 16: 85-94Crossref PubMed Scopus (241) Google Scholar, 30.Safar M.E. Blacher J. Pannier B. et al.Central pulse pressure and mortality in end-stage renal disease.Hypertension. 2002; 39: 735-738Crossref PubMed Scopus (665) Google Scholar, 31.Guerin A.P. Blacher J. Pannier B. et al.Impact of aortic stiffness attenuation on survival of patients in end-stage renal failure.Circulation. 2001; 103: 987-992Crossref PubMed Scopus (857) Google Scholar]. By increasing left-ventricular afterload, a high aortic pulse wave velocity is also associated with left-ventricular hypertrophy [29.London G.M. Cardiovascular disease in chronic renal failure: Pathophysiologic aspects.Semin Dial. 2003; 16: 85-94Crossref PubMed Scopus (241) Google Scholar]. Similarly, valvular and cardiac calcifications are associated with the development of left-ventricular hypertrophy, heart failure, coronary ischemia, arrhythmias, valvular stenosis, increased risk of infective endocarditis, and, in rare cases, thromboses with emboli [4.London G.M. Pannier B. Marchais S.J. Guerin A.P. Calcification of the aortic valve in the dialyzed patient.J Am Soc Nephrol. 2000; 11: 778-783PubMed Google Scholar, 5.Kuzela D.C. Huffer W.E. Conger J.D. Winter S.D. Hammond W.S. Soft tissue calcification in chronic dialysis patients.Am J Pathol. 1977; 86: 403-424PubMed Google Scholar, 7.Maher E.R. Young G. Smyth-Walsh B. et al.Aortic and mitral valve calcification in patients with end-stage renal disease.Lancet. 1987; 2: 875-877Abstract PubMed Scopus (234) Google Scholar, 24.Gruppen M.P. Groothoff J.W. Prins M. et al.Cardiac disease in young adult patients with end-stage renal disease since childhood: A Dutch cohort study.Kidney Int. 2003; 63: 1058-1065Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 32.Doulton T. Sabharwal N. Cairns H.S. et al.Infective endocarditis in dialysis patients: New challenges and old.Kidney Int. 2003; 64: 720-727Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar]. The degree of vascular or valvular calcification in HD patients correlates with the severity of cardiovascular disease as determined clinically, and predicts cardiovascular and all-cause mortality [23.London G.M. Guerin A.P. Marchais S.J. et al.Arterial media calcification in end-stage renal disease: Impact on all-cause and cardiovascular mortality.Nephrol Dial Transplant. 2003; 18: 1731-1740Crossref PubMed Scopus (1433) Google Scholar, 29.London G.M. Cardiovascular disease in chronic renal failure: Pathophysiologic aspects.Semin Dial. 2003; 16: 85-94Crossref PubMed Scopus (241) Google Scholar, 33.Raggi P. Boulay A. Chasan-Taber S. et al.Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease?.J Am Coll Cardiol. 2002; 39: 695-701Abstract Full Text Full Text PDF PubMed Scopus (951) Google Scholar, 34.Wang A.Y. Wang M. Woo J. et al.Cardiac valve calcification as an important predictor for all-cause mortality and cardiovascular mortality in long-term peritoneal dialysis patients: A prospective study.J Am Soc Nephrol. 2003; 14: 159-168Crossref PubMed Scopus (347) Google Scholar]. Whether the presence of coronary calcifications in uremic patients has a similar high predictive value for future cardiac events, as in the general population, where it predicts total atherosclerotic plaque burden [35.Taylor A.J. Feuerstein I. Wong H. et al.Do conventional risk factors predict subclinical coronary artery disease? Results from the Prospective Army Coronary Calcium Project.Am Heart J. 2001; 141: 463-468Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar], is unknown. Soft tissue "metastatic" calcifications in dialysis patients are typically multiple, painless, large, and can become symptomatic with nerve compression and impairment of joint mobility [18.Cofan F. Garcia S. Combalia A. et al.Uremic tumoral calcinosis in patients receiving longterm hemodialysis therapy.J Rheumatol. 1999; 26: 379-385PubMed Google Scholar] Figure 5. Rare consequences of calcifications include vasculopathic proximal myopathy, penile necrosis, rupture of calcified tendons, respiratory failure, breast pain due to calcification of mammary vessels, headache due to dural calcification, and symptoms related to spinal compression. Age and time on dialysis are central determinants of extraosseous and, in particular, vascular and valvular calcifications Table 1, but even pediatric dialysis patients are not spared [3.Milliner D.S. Zinsmeister A.R. Lieberman E. Landing B. Soft tissue calcification in pediatric patients with end-stage renal disease.Kidney Int. 1990; 38: 931-936Abstract Full Text PDF PubMed Scopus (264) Google Scholar, 5.Kuzela D.C. Huffer W.E. Conger J.D. Winter S.D. Hammond W.S. Soft tissue calcification in chronic dialysis patients.Am J Pathol. 1977; 86: 403-424PubMed Google Scholar, 14.Nayir A. Bilge I. Kilicaslan I. et al.Arterial changes in paediatric haemodialysis patients undergoing renal transplantation.Nephrol Dial Transplant. 2001; 16: 2041-2047Crossref PubMed Scopus (43) Google Scholar, 24.Gruppen M.P. Groothoff J.W. Prins M. et al.Cardiac disease in young adult patients with end-stage renal disease since childhood: A Dutch cohort study.Kidney Int. 2003; 63: 1058-1065Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 25.Braun J. Oldendorf M. Moshage W. et al.Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients.Am J Kidney Dis. 1996; 27: 394-401Abstract Full Text PDF PubMed Scopus (703) Google Scholar, 27.Goodman W.G. Goldin J. Kuizon B.D. et al.Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.N Engl J Med. 2000; 342: 1478-1483Crossref PubMed Scopus (2331) Google Scholar, 34.Wang A.Y. Wang M. Woo J. et al.Cardiac valve calcification as an important predictor for all-cause mortality and cardiovascular mortality in long-term peritoneal dialysis patients: A prospective study.J Am Soc Nephrol. 2003; 14: 159-168Crossref PubMed Scopus (347) Google Scholar, 36.Oh J. Wunsch R. Turzer M. et al.Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal failure.Circulation. 2002; 106: 100-105Crossref PubMed Scopus (611) Google Scholar, 37.Goldsmith D.J. Covic A. Sambrook P.A. Ackrill P. Vascular calcification in long-term haemodialysis patients in a single unit: A retrospective analysis.Nephron. 1997; 77: 37-43Crossref PubMed Scopus (199) Google Scholar]. The development of calcifications can progress very rapidly, and calcification scores both in vessels and valves can increase by 20% to 30% within only one year [25.Braun J. Oldendorf M. Moshage W. et al.Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients.Am J Kidney Dis. 1996; 27: 394-401Abstract Full Text PDF PubMed Scopus (703) Google Scholar, 38.Chertow G.M. Burke S.K. Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients.Kidney Int. 2002; 62: 245-252Abstract Full Text Full Text PDF PubMed Scopus (1269) Google Scholar].Table 1Factors promoting or inhibiting extraosseous calcification in vitro and in vivoEffect on calcificationReferencesPromoting factors Age of patient↑(epidemiologic studies)25.Braun J. Oldendorf M. Moshage W. et al.Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients.Am J Kidney Dis. 1996; 27: 394-401Abstract Full Text PDF PubMed Scopus (703) Google Scholar, 27.Goodman W.G. Goldin J. Kuizon B.D. et al.Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.N Engl J Med. 2000; 342: 1478-1483Crossref PubMed Scopus (2331) Google Scholar, 33.Raggi P. Boulay A. Chasan-Taber S. et al.Cardiac calcification in adult hemodialysis patients. A link betw
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