Non-traditional risk factors predict coronary calcification in chronic kidney disease in a population-based cohort
2007; Elsevier BV; Volume: 73; Issue: 5 Linguagem: Inglês
10.1038/sj.ki.5002716
ISSN1523-1755
AutoresUsman Baber, James A. de Lemos, Amit Khera, Darren K. McGuire, Torbjørn Omland, Robert D. Toto, S. Susan Hedayati,
Tópico(s)Vitamin D Research Studies
ResumoThe increased burden of cardiovascular disease in chronic kidney disease cannot be explained by traditional risk factors alone. Here, we evaluated the impact of non-traditional factors on the association of chronic kidney disease with coronary artery calcification using logistic regression among 2672 Dallas Heart Study patients of whom 220 had chronic kidney disease. The prevalence of coronary calcification significantly increased across all chronic kidney disease stages and this remained independently associated with coronary calcification after adjusting for traditional factors. The calcium × phosphorus product, homocysteine, and osteoprotegerin each diminished the magnitude of association between kidney disease and coronary calcification. After adjustment for these, the association between kidney disease and coronary calcification was no longer significant with the effects most prominent in the stages 3–5 subgroup. Our study has identified three non-traditional independent predictors of coronary calcification that diminished the association between chronic kidney disease and coronary calcification. These factors may represent novel mechanistic links warranting further investigation. The increased burden of cardiovascular disease in chronic kidney disease cannot be explained by traditional risk factors alone. Here, we evaluated the impact of non-traditional factors on the association of chronic kidney disease with coronary artery calcification using logistic regression among 2672 Dallas Heart Study patients of whom 220 had chronic kidney disease. The prevalence of coronary calcification significantly increased across all chronic kidney disease stages and this remained independently associated with coronary calcification after adjusting for traditional factors. The calcium × phosphorus product, homocysteine, and osteoprotegerin each diminished the magnitude of association between kidney disease and coronary calcification. After adjustment for these, the association between kidney disease and coronary calcification was no longer significant with the effects most prominent in the stages 3–5 subgroup. Our study has identified three non-traditional independent predictors of coronary calcification that diminished the association between chronic kidney disease and coronary calcification. These factors may represent novel mechanistic links warranting further investigation. Excess cardiovascular morbidity and mortality are well-known complications of end-stage renal disease.1United States Renal Data System (USRDS)United States Renal Data System (USRDS) 2000 Annual Data Report: atlas of end-stage renal disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD2000Google Scholar,2Foley R.N. Clinical epidemiology of cardiac disease in dialysis patients: left ventricular hypertrophy, ischemic heart disease, and cardiac failure.Semin Dial. 2003; 16: 111-117Crossref PubMed Scopus (153) Google Scholar Recent studies have firmly established that pre-dialysis chronic kidney disease (CKD) is also independently associated with incident cardiovascular disease (CVD) and adverse cardiovascular outcomes.3Anavekar N.S. McMurray J.V. Velazquez E.J. et al.Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction.N Engl J Med. 2004; 351: 1285-1295Crossref PubMed Scopus (1581) Google Scholar, 4Go A.S. Chertow G.M. Fan D. et al.Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (8249) Google Scholar, 5Manjunath G. 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Ibrahim H. et al.Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community.J Am Coll Cardiol. 2003; 41: 47-55Abstract Full Text Full Text PDF PubMed Scopus (663) Google Scholar A portion of this elevated risk may be due to the increased burden of concomitant CVD risk factors prevalent in patients with CKD, such as hypertension, diabetes mellitus, and dyslipidemia, factors that are less well controlled among CKD vs non-CKD populations.8Parikh N.I. Hwang S. Larson M.G. et al.Cardiovascular disease risk factors in chronic kidney disease.Arch Intern Med. 2006; 166: 1884-1891Crossref PubMed Scopus (165) Google Scholar However, CKD remains a strong and independent predictor of CVD risk even after adjustment for these traditional factors,3Anavekar N.S. McMurray J.V. Velazquez E.J. et al.Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction.N Engl J Med. 2004; 351: 1285-1295Crossref PubMed Scopus (1581) Google Scholar, 4Go A.S. Chertow G.M. Fan D. et al.Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (8249) Google Scholar, 5Manjunath G. Tighiouart H. Ibrahim H. et al.Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community.J Am Coll Cardiol. 2003; 41: 47-55Abstract Full Text Full Text PDF PubMed Scopus (663) Google Scholar, 6Manjunath G. Tighiouart H. Coresh J. et al.Level of kidney function as a risk factor for cardiovascular outcomes in the elderly.Kidney Int. 2003; 63: 1121-1129Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar, 7Muntner P. He J. Hamm L. et al.Renal insufficiency and subsequent death resulting from cardiovascular disease in the United States.J Am Soc Nephrol. 2002; 13: 745-753PubMed Google Scholar suggesting that the association between the two disease states may be mediated by non-traditional CVD risk factors. Evaluation of non-traditional factors may identify additional independent predictors of coronary atherosclerosis that may further attenuate the association between CKD and CVD and represent novel mechanistic links in the development of atherosclerotic disease among patients with CKD. We analyzed data from a large, multiethnic, probability-based community cohort to assess the degree to which traditional and non-traditional risk factors modify the association between CKD and CVD, using coronary artery calcification (CAC) as a surrogate marker of coronary atherosclerosis.9Arad Y. Spadaro L.A. Goodman K. et al.Prediction of coronary events with electron beam computed tomography.J Am Coll Cardiol. 2000; 36: 1253-1260Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar, 10Kondos G.T. Hoff J.A. Sevrukov A. et al.Electron-beam tomography coronary artery calcium and cardiac events. A 37-month follow-up of 5635 initially asymptomatic low-to-intermediate risk adults.Circulation. 2003; 107: 2571-2576Crossref PubMed Scopus (631) Google Scholar, 11Rumberger J.A. Simons B. Fitzpatrick L.A. et al.Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area. A histopathologic correlative study.Circulation. 1995; 92: 2157-2162Crossref PubMed Scopus (1191) Google Scholar The cohort had a mean age of 45.2±9.3 years. Among the 2672 participants, 45.0% were male and 48.8% were African American. Prevalences of hypertension, diabetes, and hypercholesterolemia were 32.0, 11.3, and 13.4%, respectively. Two hundred and fifty-two (9.4%) had CAC scores ≥100 and 2420 (90.6%) had scores <100. CKD prevalence was 19.4% among those with CAC≥100 and 7.1% with CAC<100 (P<0.0001). There were 220 patients with CKD, of whom 170 (77.3%) had CKD stages 1–2 and 50 (22.7%) had CKD stages 3–5. The prevalence of CAC≥100 increased significantly across CKD stages, from 8.3% in non-CKD patients to 16.5% in patients with CKD stages 1–2 and 42.0% among those with CKD stages 3–5 (trend P-value <0.0001). CKD patients were older, and a greater proportion was African American and had a history of diabetes mellitus or hypertension as compared to those without CKD (Table 1). Across stages of renal dysfunction, significant increases were observed for levels of calcium, phosphorus, calcium × phosphorous product (CPP), homocysteine (HCY), C-reactive protein (CRP), and osteoprotegerin (OPG) (Table 1).Table 1Clinical and biochemical parameters by CKD stagesaContinuous variables with normal distribution are reported as mean±s.d. Continuous variables with non-normal distribution are reported as median (interquartile range). Categorical variables are reported as percentages.Independent variablesNo CKD (n=2452)CKD stages 1–2 (n=170)CKD stages 3–5 (n=50)P-valueTraditional risk factors Age (years)44.9±9.347.3±9.152.5±7.7<0.0001 Male sex (%)44.454.744.00.03 African-American race (%)47.367.762.0<0.0001 Family history of myocardial infarction (%)32.237.146.00.06 History of smoking (%)28.232.938.00.14 Diabetes mellitus (%)9.334.730.0<0.0001 Hypertension (%)29.755.964.0<0.0001 Hypercholesterolemia (%)13.214.820.00.32Non-traditional risk factors Homocysteine (μmol l−1)8.8±3.810.1±13.315.5±7.6<0.0001 Calcium (mg per 100 ml)9.3±0.49.3±0.49.4±0.60.0009 Phosphorus (mg per 100 ml)3.2±0.63.2±0.63.7±1.0<0.0001 Calcium × phosphorus product (mg2 per 100 ml2)29.6±5.430.1±6.135.2±10.4<0.0001 C-reactive protein (mg l−1)2.7 (1.1, 6.3)3.6 (1.6, 7.8)3.7 (1.8, 9.7)0.003 Lipoprotein (a) (nmol l−1)47.2 (17.7, 106.8)54.9 (24.1, 105.0)62.1 (25.4, 132.1)0.16 Small LDL subclass (mg per 100 ml cholesterol)5.6 (0.0, 27.2)9.8 (0.0, 39.0)0.0 (0.0, 17.2)0.02 Osteoprotegerin (pg ml−1)1193.5 (870.5, 1582.1)1247.2 (943.6, 1892.0)1420.2 (1015.9, 2272.0)0.0004CKD, chronic kidney disease; LDL, low-density lipoprotein.a Continuous variables with normal distribution are reported as mean±s.d. Continuous variables with non-normal distribution are reported as median (interquartile range). Categorical variables are reported as percentages. Open table in a new tab CKD, chronic kidney disease; LDL, low-density lipoprotein. All traditional and non-traditional factors tested in univariable models, with the exception of lipoprotein (a) (Lp (a)) and small low-density lipoprotein (LDL) subclass, were significantly and positively associated with CAC≥100 (Table 2). Prevalent CKD was also significantly associated with CAC≥100 (odds ratio (OR) 3.18, 95% confidence interval (95% CI) 2.24–4.50).Table 2Univariable logistic models for the associations between variables and CAC≥100VariableOR (95% CI)P-valueTraditional Age (per year increase)1.14 (1.12–1.16)<0.0001 Male sex2.38 (1.82–3.12)<0.0001 African-American race1.64 (1.26–2.14)<0.0001 Family history of myocardial infarction2.12 (1.63–2.75)<0.0001 History of smoking2.02 (1.55–2.64)<0.0001 Diabetes mellitus3.30 (2.42–4.51)<0.0001 Hypertension4.48 (3.41–5.88)<0.0001 Hypercholesterolemia3.24 (2.41–4.37)<0.0001Non-traditional Chronic kidney disease3.18 (2.24–4.50)<0.0001 Homocysteine (μmol l−1)aPer unit increase.1.06 (1.03–1.08)<0.0001 Calcium (mg per 100 ml)aPer unit increase.2.31 (1.62–3.30)<0.0001 Phosphorus (mg per 100 ml)aPer unit increase.1.33 (1.08–1.65)0.0092 Calcium × phosphorus product (mg2 per 100 ml2)aPer unit increase.1.05 (1.03–1.07)<0.0001 Log C-reactive proteinaPer unit increase.1.19 (1.06–1.33)0.002 Lp (a) tertile 2 vs 1bTertile 1 represents lowest tertile and tertile 3 represents highest tertile.1.55 (1.03–2.33)0.09 Lp (a) tertile 3 vs 1bTertile 1 represents lowest tertile and tertile 3 represents highest tertile.1.89 (0.55–6.54)0.09 Small LDL tertile 2 vs 1bTertile 1 represents lowest tertile and tertile 3 represents highest tertile.1.21 (0.79–1.85)0.37 Small LDL tertile 3 vs 1bTertile 1 represents lowest tertile and tertile 3 represents highest tertile.1.98 (0.67–5.85)0.37 Log osteoprotegerinaPer unit increase.1.97 (1.56–2.49) 100 was attenuated but remained statistically significant (OR 2.38, 95% CI 1.15–4.95). Sensitivity analysis using a CAC cut-off of ≥30 instead of ≥100 for logistic models revealed similar results and did not change the main findings of this study. The overall accuracy of the logistic models using CAC≥30 was also similar to the models using CAC≥100 (c-statistic of 0.86 and 0.87, respectively). Sensitivity analysis performed excluding seven patients who responded 'yes' to the question 'do you have or have you ever had chronic kidney failure requiring dialysis' decreased the magnitude of association between any CKD and CAC and attenuated the association of CKD stages 3–5 with CAC once all non-traditional factors were entered into the final model (OR 1.88, 95% CI 0.85–4.14). The principal new finding in this study is that the non-traditional risk factors CPP, OPG and HCY diminished the association between CKD and clinically relevant CAC. This finding suggests that pathways represented by these markers (such as vascular calcification, endothelial injury, and accelerated thrombosis) may contribute to the excess burden of coronary artery disease observed in patients with CKD. Furthermore, the attenuation of the association between CKD and CAC observed with these non-traditional factors appeared to be stronger at advanced stages of CKD vs earlier stages, whereas traditional risk factors appear to exert their effect at both CKD stages. This important new finding in a relatively young, multiethnic cohort extends previous findings from studies performed in older populations.12Dellegrottaglie S. Saran R. Gillespie B. et al.Prevalence and predictors of cardiovascular calcium in chronic kidney disease (from the prospective longitudinal RRI-CKD study).Am J Cardiol. 2006; 98: 571-576Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 13Mehrotra R. Budoff M. Christenson P. et al.Determinants of coronary artery calcification in diabetics with and without nephropathy.Kidney Int. 2004; 66: 2022-2031Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 14Merjanian 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, 15Qunibi W.Y. Abouzahr F. Mizani M.R. et al.Cardiovascular calcification in Hispanic Americans (HA) with chronic kidney disease (CKD) due to type 2 diabetes.Kidney Int. 2005; 68: 271-277Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 16Tomiyama C. Higa A. Dalboni M.A. et al.The impact of traditional and non-traditional risk factors on coronary calcification in pre-dialysis patients.Nephrol Dial Transplant. 2006; 21: 2464-2471Crossref PubMed Scopus (103) Google Scholar An alternative explanation is that our cohort is relatively young, and thus contributions from traditional risk factors may be of a lesser degree than in older CKD populations. The enhanced effect of non-traditional risk factors at more advanced (vs milder) stages of CKD is biologically plausible, as the metabolic and hemodynamic alterations associated with CKD progress as GFR declines and may provide the proper milieu for the development of accelerated atherosclerosis. Elevations in serum parathyroid hormone, for example, do not occur until GFR decreases below 70 ml per min per 1.73m2,17National Kidney Foundation K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Kidney disease outcome quality initiative.Am J Kidney Dis. 2002; 39: S1-S246Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar and mean serum phosphorus levels do not increase rapidly until GFR declines to below 40 ml per min per 1.73 m2.18Kestenbaum B. Sampson J.N. Rudser K.D. et al.Serum phosphate levels and mortality risk among people with chronic kidney disease.J Am Soc Nephrol. 2005; 16: 520-528Crossref PubMed Scopus (869) Google Scholar In contrast to most previous studies that involved CKD patients on chronic dialysis, our study evaluating the relationship between calcium, phosphorus, CPP, and CAC involved patients with earlier stages of CKD. Only 7 of 2672 had been or were currently on hemodialysis, and the exclusion of those patients did not alter the results considerably except that, as expected, it decreased the magnitude of the association between CKD and CAC. Although elevated CPP has been reported to be an independent predictor of mortality in dialysis patients,19Block G.A. Klassen P.S. Lazarus J.M. et al.Mineral metabolism, mortality, and morbidity in maintenance hemodialysis.J Am Soc Nephrol. 2004; 15: 2208-2218Crossref PubMed Scopus (2080) Google Scholar studies evaluating the relationship between various indices of calcium/phosphorus homeostasis and CAC in pre-dialysis CKD patients have generated inconsistent results.12Dellegrottaglie S. Saran R. Gillespie B. et al.Prevalence and predictors of cardiovascular calcium in chronic kidney disease (from the prospective longitudinal RRI-CKD study).Am J Cardiol. 2006; 98: 571-576Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 13Mehrotra R. Budoff M. Christenson P. et al.Determinants of coronary artery calcification in diabetics with and without nephropathy.Kidney Int. 2004; 66: 2022-2031Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 14Merjanian 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, 15Qunibi W.Y. Abouzahr F. Mizani M.R. et al.Cardiovascular calcification in Hispanic Americans (HA) with chronic kidney disease (CKD) due to type 2 diabetes.Kidney Int. 2005; 68: 271-277Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 16Tomiyama C. Higa A. Dalboni M.A. et al.The impact of traditional and non-traditional risk factors on coronary calcification in pre-dialysis patients.Nephrol Dial Transplant. 2006; 21: 2464-2471Crossref PubMed Scopus (103) Google Scholar, 20Russo D. Corrao S. Miranda I. et al.Progression of coronary artery calcification in predialysis patients.Am J Nephrol. 2007; 27: 152-158Crossref PubMed Scopus (79) Google Scholar, 21Russo D. Palmiero G. De Blasio A. et al.Coronary artery calcification in patients with CRF not undergoing dialysis.Am J Kidney Dis. 2004; 44: 1024-1030Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar In fact, the National Kidney Foundation guidelines regarding management of calcium/phosphorus homeostasis, such as desired parathyroid hormone levels, are opinion based rather than evidence based for pre-dialysis stages 3 and 4 CKD.17National Kidney Foundation K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Kidney disease outcome quality initiative.Am J Kidney Dis. 2002; 39: S1-S246Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar Two earlier studies reported a positive association between serum phosphorus levels and CAC or CAC progression in such patients.16Tomiyama C. Higa A. Dalboni M.A. et al.The impact of traditional and non-traditional risk factors on coronary calcification in pre-dialysis patients.Nephrol Dial Transplant. 2006; 21: 2464-2471Crossref PubMed Scopus (103) Google Scholar,20Russo D. Corrao S. Miranda I. et al.Progression of coronary artery calcification in predialysis patients.Am J Nephrol. 2007; 27: 152-158Crossref PubMed Scopus (79) Google Scholar A graded independent relationship between higher levels of serum phosphorus and risk of death and cardiovascular events was reported in patients with previous myocardial infarct, most of whom had phosphorus levels within the normal range.22Tonelli M. Sacks F. Pfeffer M. et al.Relation between serum phosphate level and cardiovascular event rate in people with coronary disease.Circulation. 2005; 112: 2627-2633Crossref PubMed Scopus (645) Google Scholar Our results extend these observations as we found that calcium, phosphorus, and CPP were all positively associated with CAC, and each diminished the association between CKD and CAC in multivariable models, with CPP causing the greatest attenuation. The c-statistics of the multivariable models for CAC were the same when either calcium or phosphorus was included in separate models (both 0.87), indicating that both variables are similarly contributing to the model fit. More importantly, this effect was observed in a population with mean CPP levels of 35.2 mg2 per 100 ml2, well below the level of 55 mg2 per 100 ml2 previously associated with increased cardiovascular risk in chronic dialysis patients.19Block G.A. Klassen P.S. Lazarus J.M. et al.Mineral metabolism, mortality, and morbidity in maintenance hemodialysis.J Am Soc Nephrol. 2004; 15: 2208-2218Crossref PubMed Scopus (2080) Google Scholar This suggests that even the modest perturbations in calcium/phosphorus metabolism observed in patients with earlier stages of CKD may contribute to coronary calcification. Large prospective interventional trials are needed to investigate whether more aggressive control of CPP in the pre-dialysis phase of CKD may decrease future risk of CVD. We found that HCY had a modest impact on the association between CKD stages 3–5 and CAC. Although levels of HCY are elevated among pre-dialysis CKD vs non-CKD patients,23Bostom A.G. Shemin D. Lapane K.L. et al.Hyperhomocysteinemia, hyperfibrinogenemia, and lipoprotein (a) excess in maintenance dialysis patients: a matched case–control study.Atherosclerosis. 1996; 125: 91-101Abstract Full Text PDF PubMed Scopus (97) Google Scholar,24Muntner P. Hamm L.L. Kusek J.W. et al.The prevalence of nontraditional risk factors for coronary heart disease in patients with chronic kidney disease.Ann Intern Med. 2004; 140: 9-17Crossref PubMed Scopus (339) Google Scholar less is known regarding the CVD risk associated with hyperhomocysteinemia in such subjects. Five previous studies examining the relationship between CKD and CAC did not include HCY as a covariate.12Dellegrottaglie S. Saran R. Gillespie B. et al.Prevalence and predictors of cardiovascular calcium in chronic kidney disease (from the prospective longitudinal RRI-CKD study).Am J Cardiol. 2006; 98: 571-576Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 13Mehrotra R. Budoff M. Christenson P. et al.Determinants of coronary artery calcification in diabetics with and without nephropathy.Kidney Int. 2004; 66: 2022-2031Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 14Merjanian 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, 15Qunibi W.Y. Abouzahr F. Mizani M.R. et al.Cardiovascular calcification in Hispanic Americans (HA) with chronic kidney disease (CKD) due to type 2 diabetes.Kidney Int. 2005; 68: 271-277Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 16Tomiyama C. Higa A. Dalboni M.A. et al.The impact of traditional and non-traditional risk factors on coronary calcification in pre-dialysis patients.Nephrol Dial Transplant. 2006; 21: 2464-2471Crossref PubMed Scopus (103) Google Scholar Two other studies, however, demonstrated an association between HCY and cardiovascular events in either pre-dialysis CKD or kidney transplant recipients.25Jungers P. Chauveau P. Blandin O. et al.Hyperhomocysteinemia is associated with atherosclerotic occlusive arterial accidents in predialysis chronic renal failure patients.Miner Electrolyte Metab. 1997; 23: 170-173PubMed Google Scholar,26Massy Z.A. Chadefaux-Vekemans B. Chevalier A. et al.Hyperhomocysteinaemia: a significant risk factor for cardiovascular disease in renal transplant recipients.Nephrol Dial Transplant. 1994; 9: 1103-1108Crossref PubMed Scopus (157) Google Scholar Our results are consistent with these latter observations and suggest that the increased CVD risk conferred by HCY in dialysis patients27Buccianti G. Baragetti I. Bamonti F. et al.Plasma homocysteine levels and cardiovascular mortality in patients with end-stage renal disease.J Nephrol. 2004; 17: 405-410PubMed Google Scholar,28Moustapha A. Naso A. Nahlawi M. et al.Prospective study of hyperhomocysteinemia as an adverse cardiovascular risk factor in end-stage renal disease.Circulation. 1998; 97: 138-141Crossref PubMed Scopus (401) Google Scholar may begin in the pre-dialysis disease phase and may be due to its contribution to coronary atherosclerosis burden.29Chao C.L. Tsai H.H. Lee C.M. The graded effect of hyperhomocysteinemia on the severity and extent of coronary atherosclerosis.Atherosclerosis. 1999; 147: 379-386Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar,30Rasouli M.L. Nasir K. Blumenthal R.S. et al.Plasma homocysteine predicts progression of atherosclerosis.Atherosclerosis. 2005; 181: 159-165Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar It should be noted, unfortunately, that the excess risk attributable to HCY in patients with advanced CKD may not be modifiable with folic acid and vitamin B therapy.31Jamison R.L. Hartigan P. Kaufman J.S. et al.Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial.JAMA. 2007; 298: 1163-1170Crossref PubMed Scopus (372) Google Scholar OPG diminished the association between CKD stages 3–5 and CAC scores ≥100, suggesting that OPG may contribute to the increased risk of CVD observed in these patients. OPG functions as a regulator of bone resorption by inhibiting osteoclastogenesis.32Simonet W.S. Lacey D.L. Dunstan C.R. et al.Osteoprotegerin: a novel secreted protein involved in the regulation of bone density.Cell. 1997; 89: 309-319Abstract Full Text Full Text PDF PubMed Scopus (4093) Google Scholar The mechanisms responsible for the observed association between OPG and arterial calcification remain poorly understood and appear paradoxical. For example, OPG-deficient mice develop widespread arterial calcifications,33Bucay N. Sarosi I. Dunstan C.R. et al.Osteoprotegerin-deficient mice develop early-onset osteoporosis and arterial calcification.Genes Dev. 1998; 12: 1260-1268Crossref PubMed Scopus (2025) Google Scholar whereas serum OPG levels are higher in subjects with greater amounts of coronary calcification.34Abedin M. Omland T. Ueland T. et al.Relation of osteoprotegerin to coronary calcium and aortic plaque (from the Dallas Heart Study).Am J Cardiol. 2007; 99: 513-518Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 35Mazzaferro S. Pasquali M. Pugliese F. et al.Serum levels of calcification inhibition proteins and coronary artery calcium score: comparison between transplantation and dialysis.Am J Nephrol. 2007; 27: 75-83Crossref PubMed Scopus (40) Google Scholar, 36Nitta K. Akiba T. Uchida K. et al.The progression of vascular calcification and serum osteoprotegerin levels in patients on long-term hemodialysis.Am J Kidney Dis. 2003; 42: 303-309Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 37Jono S. Ikari Y. Shioi A. et al.Serum osteoprotegerin levels are associated with the presence and severity of coronary artery disease.Circulation. 2002; 106: 1192-1194Crossref PubMed Scopus (444) Google Scholar In fact, a U-shaped association between OPG and all-cause mortality has been described in hemodialysis patients in the presence of inflammation.38Morena M. Terrier N. Jaussent I. et al.Plasma osteoprotegerin is associated with mortality in hemodialysis patients.J Am Soc Nephrol. 2006; 17: 262-270Crossref PubMed Scopus (137) Google Scholar One potential hypothesis is that OPG expression increases in the setting of pre-existing calcification and acts in a compensatory manner to minimize further calcification. Another explanation is that OPG directly contributes to vascular calcification by promoting a low bone turnover state.39Coen G. Ballanti P. Balducci A. et al.Serum osteoprotegerin and renal osteodystrophy.Nephrol Dial Transplant. 2002; 17: 233-238Crossref PubMed Scopus (110) Google Scholar In this context, the ability of bone to take up a mineral load is diminished,40Kurz P. Monier-Faugere M.C. Bognar B. et al.Evidence for abnormal calcium homeostasis in patients with adynamic bone disease.Kidney Int. 1994; 46: 855-861Abstract Full Text PDF PubMed Scopus (282) Google Scholar which might favor extra-skeletal calcification. Studies involving CKD patients, however, have been limited either to those with stage 5 CKD before and after dialysis initiation or to renal transplant recipients. Our findings extend these observations by suggesting that OPG may promote coronary calcification in earlier CKD stages and could possibly serve as a biomarker to assess CVD risk among pre-dialysis CKD patients. Despite the established association between various non-traditional risk factors (such as anemia, measures of inflammation, and calcium/phosphorus homeostasis) and poor cardiovascular outcomes in dialysis patients, there are few data regarding such factors in patients with pre-dialysis CKD. Our results suggest that novel pathways represented by HCY, CPP, and OPG may promote CVD in patients with moderate to severe pre-dialysis CKD. If validated using other measures of atherosclerosis and in cohort studies with adequate numbers of clinical events, these findings could have important clinical and therapeutic implications. These novel factors may assist in risk assessment of patients with CKD, to determine which are at highest risk for adverse CV events and require the most aggressive preventive therapies. Alternatively, if these factors are causally related to CVD in patients with CKD, they may serve as therapeutic targets. For example, the CPP target for treatment may need to be lowered in stages 3–5 pre-dialysis CKD.18Kestenbaum B. Sampson J.N. Rudser K.D. et al.Serum phosphate levels and mortality risk among people with chronic kidney disease.J Am Soc Nephrol. 2005; 16: 520-528Crossref PubMed Scopus (869) Google Scholar Therapies targeting receptor activator of nuclear factor-κB (RANK) and RANK ligand may merit investigation as targets for CVD prevention in patients with CKD.38Morena M. Terrier N. Jaussent I. et al.Plasma osteoprotegerin is associated with mortality in hemodialysis patients.J Am Soc Nephrol. 2006; 17: 262-270Crossref PubMed Scopus (137) Google Scholar Larger, prospective studies are needed to determine whether these non-traditional factors play a critical role in development of CVD, and interventional trials are required to investigate whether modification of these factors may decrease cardiovascular morbidity and mortality. Our study is not without limitation and due to its cross-sectional nature cannot imply a causal relationship between non-traditional risk factors and CAC. Biochemical parameters, including urine microalbumin, were measured once and might not reflect actual levels over time. In addition, we were unable to adjust for certain confounders, such as intact parathyroid hormone, anemia, and fibrinogen, that are associated with either CAC or CVD risk among CKD patients. Although we controlled for diabetes in all of the multivariable models, diabetics comprised only 30% of the subgroup with CKD, and therefore these findings should be confirmed in populations with a greater proportion of diabetic nephropathy. We evaluated a limited number of non-traditional cardiovascular risk markers that were available in the Dallas Heart Study database and did not evaluate several others, such as asymmetric dimethyl arginine (ADMA)41Mallamaci F. Tripepi G. Cutrupi S. et al.Prognostic value of combined use of biomarkers of inflammation, endothelial dysfunction, and myocardiopathy in patients with ESRD.Kidney Int. 2005; 67: 2330-2337Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar and fetuin A,42Cozzolino M. Brancaccio D. Gallieni M. Slatopolsky E. Pathogenesis of vascular calcification in chronic kidney disease.Kidney Int. 2005; 68: 429-436Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar that have shown promise in patients with CKD. Even though using a CAC score ≥100 as our main outcome measure makes our findings more clinically relevant, coronary calcification is only a surrogate marker of cardiovascular outcomes among patients with preserved renal function.9Arad Y. Spadaro L.A. Goodman K. et al.Prediction of coronary events with electron beam computed tomography.J Am Coll Cardiol. 2000; 36: 1253-1260Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar, 10Kondos G.T. Hoff J.A. Sevrukov A. et al.Electron-beam tomography coronary artery calcium and cardiac events. A 37-month follow-up of 5635 initially asymptomatic low-to-intermediate risk adults.Circulation. 2003; 107: 2571-2576Crossref PubMed Scopus (631) Google Scholar, 11Rumberger J.A. Simons B. Fitzpatrick L.A. et al.Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area. A histopathologic correlative study.Circulation. 1995; 92: 2157-2162Crossref PubMed Scopus (1191) Google Scholar Less is known regarding the relationship between CAC and outcomes in CKD, although CAC scores were associated with clinically evident coronary artery disease among pre-dialysis CKD patients.12Dellegrottaglie S. Saran R. Gillespie B. et al.Prevalence and predictors of cardiovascular calcium in chronic kidney disease (from the prospective longitudinal RRI-CKD study).Am J Cardiol. 2006; 98: 571-576Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar We found that non-traditional cardiovascular risk factors diminished the association between clinically relevant CAC and CKD. This effect was strongest and most consistent in those with more advanced CKD. Non-traditional factors such as increased CPP, HCY, and OPG are more prevalent in CKD vs non-CKD populations and might partially explain the excessive cardiovascular morbidity and mortality in CKD patients. Future prospective studies are necessary to investigate the potential mechanistic relationships between non-traditional risk factors and CKD and to determine whether modifying such risk factors will improve outcomes.
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