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Vascular calcification: Hardening of the evidence

2006; Elsevier BV; Volume: 70; Issue: 9 Linguagem: Inglês

10.1038/sj.ki.5001892

1523-1755

Sharon M. Moe,

Heterotopic Ossification and Related Conditions

In the past several years, basic-science studies have shown that vascular calcification is an active, cell-mediated process. It is increased in the uremic milieu and with hyperphosphatemia and therefore should be preventable. Additional advances in imaging techniques have facilitated the diagnosis of arterial calcification, a critical initial step in the translation of this knowledge to patient care. In the past several years, basic-science studies have shown that vascular calcification is an active, cell-mediated process. It is increased in the uremic milieu and with hyperphosphatemia and therefore should be preventable. Additional advances in imaging techniques have facilitated the diagnosis of arterial calcification, a critical initial step in the translation of this knowledge to patient care. In the past ten years we have observed a major increase in the number of publications that examine vascular calcification in chronic kidney disease (CKD) patients, especially those receiving dialysis. Using the limited search terms ‘vascular calcification’ and ‘kidney/renal’ in PubMed, there were 11 articles in 1995 and 115 in 2005. Yet this issue is not new; studies in the 1970s clearly demonstrated that calcification in the intimal and medial layers of arteries was increased in patients with advanced kidney disease.1.Ibels L.S. Alfrey A.C. Haut L. et al.Preservation of function in experimental renal disease by dietary restriction of phosphate.N Engl J Med. 1978; 298: 122-126Crossref PubMed Scopus (224) Google Scholar Why has there been such an increase in interest in this field recently? There are several likely reasons. First, advances in basic-science research have demonstrated that vascular calcification is not just the passive process we once thought. Vascular smooth muscle cells retain pluripotential capability and can transform into osteoblast-like cells. These cells, at least in culture, can produce bone matrix proteins and will mineralize in the presence of calcium and phosphorus at levels common in CKD patients. Furthermore, uremic serum, oxidized proteins, low fetuin-A, interleukin-1, and interleukin-6 can all accelerate this process2.Moe S.M. Chen N.X. Pathophysiology of vascular calcification in chronic kidney disease.Circ Res. 2004; 95: 560-567Crossref PubMed Scopus (414) Google Scholar (Table 1). Observational studies have also shown these same factors to be associated with increased mortality in dialysis patients and, in some studies, with increased vascular or valvular calcification.3.Stenvinkel P. Wang K. Qureshi A.R. et al.Low fetuin-A levels are associated with cardiovascular death: impact of variations in the gene encoding fetuin.Kidney Int. 2005; 67: 2383-2392Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar,4.Wang A.Y. Woo J. Lam C.W. et al.Associations of serum fetuin-A with malnutrition, inflammation, atherosclerosis and valvular calcification syndrome and outcome in peritoneal dialysis patients.Nephrol Dial Transplant. 2005; 20: 1676-1685Crossref PubMed Scopus (268) Google Scholar Second, a major advance in technology has led to our ability to quantify the degree of calcification in a noninvasive manner with computed tomography (CT) scanners, either electron beam CT or multislice CT. This has allowed us to conduct observational and interventional studies that have greatly enhanced our understanding of the pathophysiology of the calcification process and the extremely high incidence of coronary artery, aorta, and valvular calcification. Nearly all series in dialysis patients from all over the world demonstrate that 70% of patients have significant calcification of the coronary arteries and aorta, and nearly 50% have valvular calcification.5.Hujairi N.M. Afzali B. Goldsmith D.J. Cardiac calcification in renal patients: what we do and don't know.Am J Kidney Dis. 2004; 43: 234-243Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Even 50% of patients new to dialysis have evidence of significant coronary artery calcification.6 Third, our once complacent acceptance of serum phosphorus levels of 7 mg/dl has been replaced by new knowledge that disorders of mineral metabolism and bone contribute to morbidity and mortality beyond fractures and bone pain. This recognition of the systemic nature of this problem led Kidney Disease: Improving Global Outcomes to coin the new term ‘CKD–mineral bone disorder’ (CKD–MBD) to describe the trilogy of abnormal biochemistries, bone, and extraskeletal calcification, while reserving the term ‘renal osteodystrophy’ to describe pathology limited to bone.7.Moe S. Drueke T. Cunningham J. et al.Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO).Kidney Int. 2006; 69: 1945-1953Abstract Full Text Full Text PDF PubMed Scopus (1456) Google Scholar Lastly, clinicians now have many new therapeutic options to treat CKD–MBD, one of which, sevelamer, has been shown to ameliorate coronary artery and aorta calcification in two randomized prospective trials.6.Block G.A. Spiegel D.M. Ehrlich J. et al.Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis.Kidney Int. 2005; 68: 1815-1824Abstract Full Text Full Text PDF PubMed Scopus (718) Google Scholar,8.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 (1327) Google ScholarTable 1Risk factors for vascular calcification, identified in human, animal, or in vitro studiesClinicalAgeDuration of dialysisKidney function/UremiaDiabetesKnown coronary artery diseaseAbnormal boneBiochemicalHyperphosphatemiaHypercalcemiaAbnormal parathyroid hormoneLow fetuin-AElevated cytokinesOxidative stressLow pyrophosphateDecreased MGPDecreased BMP-7MedicationsCalcium-containing phosphate bindersHigh-dose vitamin DCoumadin (decreases active MGP)MGP, matrix Gla protein; BMP, bone morphogenetic protein. Open table in a new tab MGP, matrix Gla protein; BMP, bone morphogenetic protein. How has this new knowledge changed the care of our patients? Recent clinical practice guidelines have attempted to guide the approach and the treatment of our patients using evidence ratings. The Kidney Disease Outcomes Quality Initiative bone and mineral guidelines, published in 2003, recommended more aggressive lowering of serum phosphorus calcium × and × phosphorus product. These guidelines also opined that there were some data, albeit not strong, to recommend that the amount of oral calcium in the form of phosphate binders be restricted to 1500 mg per day, and that calcium binders not be used in dialysis patients with low parathyroid hormone or evidence of vascular calcification in order to reduce the burden of calcification.9.National Kidney Foundation K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease.Am J Kidney Dis. 2003; 42: S1-S201Crossref PubMed Scopus (666) Google Scholar These recommendations were based on opinion, with a literature review cutoff of 2001. These guidelines also did not detail how to diagnose vascular calcification, or how to quantify the severity. The Kidney Disease Outcomes Quality Initiative cardiovascular guidelines, by a separate work group, recommended that screening for vascular calcification should be done, and that, if found by plain radiographs, calcification at another site should be sought (level C=weak evidence or opinion). These guidelines, published in 2005, further recommended that if vascular calcification is present at two or more sites, then consideration should be given to prescription of a non-calcium-containing phosphate binder (level B = moderately strong evidence). Both of these sets of guidelines lack definitive information on the sensitivity, specificity, and predictive value of these various noninvasive measures of arterial calcification. A consensus conference of international experts in the field of mineral and bone metabolism and vascular calcification, held in 2003, concluded that a calcification index should be developed.10.Goodman W.G. London G. Amann K. et al.Vascular calcification in chronic kidney disease.Am J Kidney Dis. 2004; 43: 572-579Abstract Full Text Full Text PDF PubMed Scopus (369) Google Scholar It was believed that such an index would facilitate the ability of a clinician to diagnose vascular and valvular calcification in order to predict which patients would have adverse cardiovascular outcomes. The conference attendees thought that this would be an important first step to identify the subset of subjects most likely to benefit from aggressive and, unfortunately, expensive interventions. Bellasi and colleagues11.Bellasi A. Ferramosca E. Muntner P. et al.Correlation of simple imaging tests and coronary artery calcium measured by computed tomography in hemodialysis patients.Kidney Int. 2006; 70: 1623-1628Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar (this issue) describe work that is the first step in developing such a calcification index. They performed electron beam CT to quantify coronary artery calcification in 140 dialysis patients in the United States and compared these results with those of tests that are less expensive, more commonly available, and with lower radiation exposure, including pulse pressure, echocardiography, and plain lateral abdominal film. They found a likelihood ratio (95% confidence interval) of a coronary artery calcification score of ≥100 by electron beam CT of 1.79 (1.09, 2.96) for calcification of the aorta or mitral valve, and 7.50 (2.89, 19.5) for a lateral lumbar X-ray score of ≥7. In contrast, there was no significant predictive value of pulse-pressure assessment. Although these results are encouraging, it should be emphasized that no area under the curve was above 0.8. These data represent an important first step to aid the clinician in risk stratification of vascular calcification in order to guide therapy. The next study to follow logically would be to evaluate combinations of factors, probably age, duration of dialysis, biochemistries, and one of these tests, to see whether the positive and negative predictive values improve. Most important, patients must be followed prospectively to determine whether this calcification index will predict mortality, and whether interventions that reduce the index lead to improvements in mortality. It is this last measure that remains the most frustrating to the nephrology community. Our dialysis patient population has dismal survival statistics, worse than those for many cancers, and we have failed to make a significant impact on mortality despite many new advances. Importantly, we lack large, prospective randomized clinical trials to guide clinical decision making, a luxury that so many other fields in medicine enjoy. Why is this so? One explanation is that many studies are simply underpowered. A second explanation is that the population of dialysis patients is relatively small compared with that for other diseases, which reduces the funding available to conduct such studies. Yet another explanation is that our patients on dialysis have so many problems that we cannot begin to treat all in a single study. The latter point is important, as it is likely that a combination of interventions will be required to reduce mortality. Despite this lack of evidence, we all routinely still provide these interventions to our patients, including enhancement of dialysis dose, correction of anemia, lowering of blood pressure, reduction of low-density lipoprotein with statins, improvement of glycemic control, and reduction of parathyroid hormone, because it makes biologic sense to do so. So what should we do with the hardening of the evidence on vascular calcification? The study by Bellasi and colleagues11.Bellasi A. Ferramosca E. Muntner P. et al.Correlation of simple imaging tests and coronary artery calcium measured by computed tomography in hemodialysis patients.Kidney Int. 2006; 70: 1623-1628Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar suggests that we can use simple screening tools to give us a roughly 70% chance of predicting significant coronary artery calcification in our dialysis patients. We can then choose to use those data in a number of ways, none of which will be strongly evidenced based. First, we can use the presence or absence of calcification to guide our choice of phosphate binders. Second, we can use the presence or absence of calcification to educate our patients on the need to be compliant with phosphate binders, antihypertensives, and intradialytic weight gains (to name a few). Third, we can use the presence of calcification to help prioritize which of the many expensive medications to use in our patients. The latter may be particularly important for governments and managed care providers around the world to make informed decisions. For example, some such entities require hypercalcemia to be present in order to justify the use of non-calcium-containing phosphate binders. Given the disconnect between hypercalcemia and vascular calcification, using more physiologically relevant criteria may make sense. Most importantly, we now have a sound rationale for using these noninvasive measures of calcification to define better criteria for study-population inclusion in studies that aim to reduce vascular calcification. Perhaps better-defined populations will lead to better studies, and, ultimately, the Holy Grail of nephrology — a reduction in mortality in dialysis patients. SM Moe is supported by the Veterans Administration and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. SM Moe is a consultant for Genzyme, Amgen, Abbott, Shire, and Cytochroma.