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• W2000086607 abstract "Circulating CD34-positive (CD34+) cells, a population that includes endothelial progenitor cells, are believed to contribute to vascular homeostasis. Here we determine the prognostic value of CD34+ cell measurements in 216 chronic hemodialysis patients. A total of 43 cardiovascular events and 13 deaths occurred over an average 23 months follow-up in this cohort. A cutoff number for circulating CD34+ cells was determined by receiver operating characteristic curve analysis to maximize the power of the CD34+ cell count in predicting future cardiovascular events. Based on this, 93 patients were categorized as having low and 123 patients as having high numbers of CD34+ cells, determined by flow cytometry at the time of enrollment. Both cumulative cardiovascular event-free survival and all-cause survival were significantly less in the group of patients with low numbers of CD34+ cells. By multivariate analyses, a low level of circulating CD34+ cells was an independent and significant predictor for both cardiovascular events and all-cause mortality. Our study shows that a reduced number of circulating CD34+ cells is significantly associated with vascular risks and all-cause mortality in patients on chronic hemodialysis. These cells may be a useful biomarker. Circulating CD34-positive (CD34+) cells, a population that includes endothelial progenitor cells, are believed to contribute to vascular homeostasis. Here we determine the prognostic value of CD34+ cell measurements in 216 chronic hemodialysis patients. A total of 43 cardiovascular events and 13 deaths occurred over an average 23 months follow-up in this cohort. A cutoff number for circulating CD34+ cells was determined by receiver operating characteristic curve analysis to maximize the power of the CD34+ cell count in predicting future cardiovascular events. Based on this, 93 patients were categorized as having low and 123 patients as having high numbers of CD34+ cells, determined by flow cytometry at the time of enrollment. Both cumulative cardiovascular event-free survival and all-cause survival were significantly less in the group of patients with low numbers of CD34+ cells. By multivariate analyses, a low level of circulating CD34+ cells was an independent and significant predictor for both cardiovascular events and all-cause mortality. Our study shows that a reduced number of circulating CD34+ cells is significantly associated with vascular risks and all-cause mortality in patients on chronic hemodialysis. These cells may be a useful biomarker. It is well known that cardiovascular disease (CVD) is the leading cause of death among chronic hemodialysis (HD) patients.1.Pastan S. Bailey J. Dialysis therapy.N Engl J Med. 1998; 338: 1428-1437Crossref PubMed Scopus (215) Google Scholar However, the traditional risk factors (including hypertension and increased low-density lipoprotein (LDL) cholesterol) and uremia-related risk factors (hemodynamic overload, abnormal calcium metabolism, and so on) do not fully explain the extent and severity of CVD observed among this population.2.Moeslinger T. Spieckermann P.G. Urea-induced inducible nitric oxide synthase inhibition and macrophage proliferation.Kidney Int Suppl. 2001; 78: S2-S8Crossref PubMed Google Scholar,3.Cheung A.K. Sarnak M.J. Yan G. et al.Atherosclerotic cardiovascular disease risks in chronic hemodialysis patients.Kidney Int. 2000; 58: 353-362Abstract Full Text Full Text PDF PubMed Scopus (630) Google Scholar,4.Yasuda K. Kasuga H. Aoyama T. et al.Comparison of percutaneous coronary intervention with medication in the treatment of coronary artery disease in hemodialysis patients.J Am Soc Nephrol. 2006; 17: 2322-2332Crossref PubMed Scopus (43) Google Scholar Growing evidence suggests that bone-marrow-derived circulating progenitor cells, including CD34-positive (CD34+) cells, contribute to vascular homeostasis in adults,5.Asahara T. Murohara T. Sullivan A. et al.Isolation of putative progenitor endothelial cells for angiogenesis.Science. 1997; 275: 964-967Crossref PubMed Scopus (7389) Google Scholar,6.Carmeliet P. Angiogenesis in health and disease.Nat Med. 2003; 9: 653-660Crossref PubMed Scopus (3286) Google Scholar not only as a pool of endothelial progenitor cells (EPCs) but also as the source of growth/angiogenesis factors.7.Majka M. Janowska-Wieczorek A. Ratajczak J. et al.Numerous growth factors, cytokines, and chemokines are secreted by human CD34(+) cells, myeloblasts, erythroblasts, and megakaryoblasts and regulate normal hematopoiesis in an autocrine/paracrine manner.Blood. 2001; 97: 3075-3085Crossref PubMed Scopus (408) Google Scholar The level of EPCs has been shown to predict future events and deaths from CVD among patients with coronary artery disease (CAD).8.Schmidt-Lucke C. Rossig L. Fichtlscherer S. et al.Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair.Circulation. 2005; 111: 2981-2987Crossref PubMed Scopus (966) Google Scholar,9.Werner N. Kosiol S. Schiegl T. et al.Circulating endothelial progenitor cells and cardiovascular outcomes.N Engl J Med. 2005; 353: 999-1007Crossref PubMed Scopus (1806) Google Scholar We have also shown that a lower number of circulating CD34+ cells is significantly associated with vascular risks.10.Okada S. Makino H. Nagumo A. et al.Circulating CD34-positive cell number is associated with brain natriuretic peptide level in type 2 diabetic patients.Diabetes Care. 2008; 31: 157-158Crossref PubMed Scopus (11) Google Scholar,11.Taguchi A. Matsuyama T. Moriwaki H. et al.Circulating CD34-positive cells provide an index of cerebrovascular function.Circulation. 2004; 109: 2972-2975Crossref PubMed Scopus (170) Google Scholar,12.Taguchi A. Matsuyama T. Nakagomi T. et al.Circulating CD34-positive cells provide a marker of vascular risk associated with cognitive impairment.J Cereb Blood Flow Metab. 2008; 28: 445-449Crossref PubMed Scopus (20) Google Scholar Several researchers have demonstrated that patients on dialysis had a lower EPC count than did control subjects.13.de Groot K. Bahlmann F.H. Sowa J. et al.Uremia causes endothelial progenitor cell deficiency.Kidney Int. 2004; 66: 641-646Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar,14.Choi J.H. Kim K.L. Huh W. et al.Decreased number and impaired angiogenic function of endothelial progenitor cells in patients with chronic renal failure.Arterioscler Thromb Vasc Biol. 2004; 24: 1246-1252Crossref PubMed Scopus (288) Google Scholar,15.Eizawa T. Murakami Y. Matsui K. et al.Circulating endothelial progenitor cells are reduced in hemodialysis patients.Curr Med Res Opin. 2003; 19: 627-633Crossref PubMed Scopus (79) Google Scholar,16.Steiner S. Schaller G. Puttinger H. et al.History of cardiovascular disease is associated with endothelial progenitor cells in peritoneal dialysis patients.Am J Kidney Dis. 2005; 46: 520-528Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar However, there is no definite consensus concerning the absolute number of EPCs in HD patients and its relationship with the prognosis. These observations prompted us to conduct the present study. We hypothesize that circulating CD34+ cells accelerate the repair of the dysfunctional endothelium, and that a reduced number of these cells results in poor outcomes in chronic HD patients. In this study, we measured the levels of circulating CD34+ cells and prospectively analyzed first CV (cardiovascular) events and deaths by any cause. Out of 216 chronic HD patients who participated in this study, none was lost to follow-up, and none received kidney transplants. The number of circulating CD34+ cells ranged from 0.07 to 2.17/μl (median, 0.41/μl), with a mean (±s.d.) of 0.49±0.32/μl. The age of the patients was 65±11 years (range, 35–94 years). A multivariate regression analysis revealed that factors positively associated with the CD34+ cell count were gender (male), elevated white blood cell count, and high serum albumin, whereas the negatively associated factors were advanced age and smoking (Table 1).Table 1Relationship between CD34+ cell count and baseline variables on multivariate regression analysisβP-valueMale0.1970.021Age-0.1570.039Duration of HD0.0010.99Diabetes0.0540.50Hypertension-0.0790.24Smoking-0.2940.0001Body mass index0.0430.57History of CVD-0.0350.61Hemoglobin-0.1240.54WBC0.300<0.0001Albumin0.1480.049HDL cholesterol-0.0360.61LDL cholesterol-0.0580.39Ca × Pi0.0920.19Intact PTH0.1970.34C-reactive protein-0.0020.97KT/Vurea0.0800.36Ca × Pi, calcium-phosphate product; CVD, cardiovascular disease; HD, hemodialysis; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PTH, parathyroid hormone; KT/Vurea; urea clearance × time normalized by total body water; WBC, white blood cell. P-values <0.05 are shown in bold. Open table in a new tab Ca × Pi, calcium-phosphate product; CVD, cardiovascular disease; HD, hemodialysis; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PTH, parathyroid hormone; KT/Vurea; urea clearance × time normalized by total body water; WBC, white blood cell. P-values <0.05 are shown in bold. To further clarify the importance of CD34+ cells, we then determined a cutoff value. A receiver operating characteristic (ROC) curve analysis showed 0.37/μl to be the value (area under the curve=0.707) to maximize the power of circulating CD34+ cell levels as a predictor of a CV event (Figure 1). The patients were categorized into two groups according to the cell count at the time of enrollment: the low CD34+ group representing 93 patients with circulating CD34+ cell counts less than 0.37/μl (a mean of 0.23±0.08/μl) and the high CD34+ group representing 123 patients with counts of 0.37/μl or greater (a mean of 0.69±0.30/μl). The baseline characteristics are shown in Table 2. Patients in the low CD34+ group were older (68±9 years) than those in the high CD34+ group (62±11 years) (P<0.0001). White blood cell counts were lower in the former group than in the latter. Body mass index and calcium-phosphate product (Ca × Pi) levels were also lower in the patients of the low CD34+ group. Gender, duration of HD, smoking, incidence of diabetes, history of CVD, and the use of erythropoietin, were comparable between the two groups. Medications commonly used to decrease CVD, including statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium antagonists, β-blockers were also comparable (Table 2).Table 2Baseline characteristics of the low/high CD34+ groupsAll patients (n=216)Low CD34+ group (CD34+<0.37/μl) (n=93)High CD34+ group (CD34+>0.37/μl) (n=123)P-valueMale (%)122 (56.4)50 (53.7)72 (58.5)0.48Age (years)65±1168±962±11<0.0001Duration of HD (years)8.1±7.18.7±7.77.8±6.70.39Diabetes (%)105 (48.6)44 (47.3)61 (49.5)0.73Hypertension (%)157 (72.7)67 (72.0)90 (74.3)0.7Smoking (%)64 (29.6)32 (34.7)32 (26.0)0.16Body mass index20.7±3.219.9±2.721.4±3.40.0008History of CVD (%)94 (43.5)46 (49.5)48 (39.0)0.12CD34+ cells (/μl)0.49±0.320.69±0.300.23±0.080.0001Hemoglobin (g/100 ml)10.6±1.110.3±1.110.5±1.30.11WBC (103/μl)5.9±1.95.4±1.66.4±1.9<0.0001Albumin (mg/100 ml)3.6±0.33.5±0.33.6±0.30.11HDL cholesterol (mg/100 ml)41±1342±1240±140.3LDL cholesterol (mg/100 ml)77±2775±2776±260.93Ca × Pi49.7±11.847.2±11.651.7±11.70.0062Intact PTH (ng/ml)122±114116±130126±1010.52C-reactive protein (mg/100 ml)0.42±0.860.45±0.780.36±0.830.41KT/Vurea1.46±0.231.49±0.241.44±0.220.1Erythropoietin (U/kg)93±6699±6986±640.5Statins (%)27 (12.5)10 (10.8)17 (13.8)0.49ARB (%)87 (40.3)36 (38.7)51 (41.5)0.68ACEI (%)38 (17.6)15 (16.1)23 (18.7)0.62Ca antagonist (%)133 (61.6)60 (64.5)73 (59.4)0.44β-Blocker (%)45 (20.8)24 (25.8)21 (17.1)0.12ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; Ca × Pi, calcium-phosphate product; CVD, cardiovascular disease; HD, hemodialysis; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PTH, parathyroid hormone; KT/Vurea; urea clearance × time normalized by total body water; WBC, white blood cell.P-values <0.05 are shown in bold. Open table in a new tab ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; Ca × Pi, calcium-phosphate product; CVD, cardiovascular disease; HD, hemodialysis; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PTH, parathyroid hormone; KT/Vurea; urea clearance × time normalized by total body water; WBC, white blood cell. P-values <0.05 are shown in bold. Table 3 shows the incidence of outcomes. In the low CD34+ group, a CV event occurred in 27 out of 93 patients (29%) and 5 patients died from CVD (5.4%). In the high CD34+ group, a CV event occurred in 16 (13%) and only 1 patient died of CVD. Concerning death by any cause, 10 patients (10.8%) died in the low CD34+ group, whereas three (2.4%) died in the high CD34+ group (Table 3). The cumulative CV event-free survival was significantly lower in the low CD34+ group (70.6%) than the high CD34+ group (86.8%) (P=0.0034; Figure 2). The cumulative all-cause survival was also lower in the low CD34+ group (89.2%) than in the high CD34+ group (97.5%) (P=0.012; Figure 3).Table 3First cardiovascular events and all-cause death during follow-up periodAll patients (n=216)Low CD34+ group (CD34+<0.37/μl) (n=93)High CD34+ group (CD34+>0.37/μl) (n=123)Total number of CV events (%)43 (19.9)27 (29.0)aP=0.0032 vs high CD34+ group.16 (13.0)Nonfatal Coronary artery disease271611 PCI251510 CABG211 Stroke532 PAD532Fatal Congestive heart failure330 Stroke101 Myocardial infarction110 Valve disease110Total number of death (%)13 (6.0)10 (10.8)bP=0.012 vs high CD34+ group.3 (2.4) Congestive heart failure532 Stroke321 Myocardial infarction110 Valve disease110 Infection220 Ischemic colitis110CV, cardiovascular; CABG; coronary artery bypass graft; PAD, peripheral artery disease; PCI, percutaneous coronary intervention.a P=0.0032 vs high CD34+ group.b P=0.012 vs high CD34+ group. Open table in a new tab Figure 3Cumulative all-cause survival in the low/high CD34+ groups. All-cause survival was analyzed for the low CD34+ group (CD34+ cells <0.37/μl, n=93) and the high CD34+ group (CD34+ cells >0.37/μl, n=123).View Large Image Figure ViewerDownload (PPT) CV, cardiovascular; CABG; coronary artery bypass graft; PAD, peripheral artery disease; PCI, percutaneous coronary intervention. Factors associated with CV events are shown in Table 4. In univariate analyses, the incidence of CV events was significantly associated with a level of circulating CD34+ cells lower than 0.37/μl (hazard ratio (HR), 2.90; 95% CI, 1.45–5.81; P=0.0026), advanced age (HR, 1.03; 95% CI, 1.01–1.06; P=0.021), a history of CVD (HR, 7.85; 95% CI, 2.43–12.50; P=0.0045), a low level of serum albumin (HR, 0.24; 95% CI, 0.08–0.67; P=0.0066), or a high level of LDL cholesterol (HR, 1.02; 95% CI, 1.01–1.03; P=0.0048). In a multivariate regression analysis, a level of circulating CD34+ cells lower than 0.37/μl (HR, 2.23; 95% CI, 1.09–4.58; P=0.028), a history of CVD (HR, 6.19; 95% CI, 1.63–9.90; P=0.014), a low level of serum albumin (HR, 0.33; 95% CI, 0.11–0.99; P=0.049), and a high level of LDL cholesterol (HR, 1.02; 95% CI, 1.01–1.03; P=0.011) were identified as independent predictors of CV events among chronic HD patients (Table 4).Table 4HR for cardiovascular events on Cox proportional hazard modelsUnivariateMultivariateHR (95% CI)P-valueHR (95% CI)P-valueCD34+ cells<0.37/μl2.90 (1.45–5.81)0.00262.23 (1.09–4.58)0.028Male0.87 (0.39–1.45)0.4Age (years)1.03 (1.01–1.06)0.0211.01 (0.97–1.04)0.77Duration of HD (years)1.01 (0.95–1.04)0.93Diabetes1.76 (0.90–3.43)0.099Hypertension1.05 (0.54–2.17)0.89Smoking1.38 (0.74–2.59)0.31Body mass index0.90 (0.80–1.01)0.075History of CVD7.85 (2.43–12.50)0.00456.19 (1.63–9.90)0.014Hemoglobin (g/100 ml)0.93 (0.72–1.21)0.57WBC (103/μl)1.02 (0.87–1.19)0.81Albumin (mg/100 ml)0.24 (0.08–0.67)0.00660.33 (0.11–0.99)0.049HDL cholesterol (mg/100 ml)0.99 (0.97–1.02)0.59LDL cholesterol (mg/100 ml)1.02 (1.01–1.03)0.00481.02 (1.01–1.03)0.011Ca × Pi1.01 (0.92–1.11)0.74Intact PTH (ng/ml)1.00 (0.99–1.01)0.37C-reactive protein (mg/100 ml)1.18 (0.89–1.56)0.26KT/Vurea0.81 (0.22–2.98)0.75Erythropoietin (U/kg)1.00 (0.99–1.01)0.34Statins1.20 (0.46–3.23)0.7ARB0.96 (0.38–8.40)0.93ACEI1.47 (0.63–3.45)0.37Ca antagonist0.91 (0.57–2.11)0.78β-Blocker1.08 (0.42–2.02)0.84ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; Ca × Pi, calcium-phosphate product; CVD, cardiovascular disease; HD, hemodialysis; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PTH, parathyroid hormone; KT/Vurea; urea clearance × time normalized by total body water; WBC, white blood cell. Multivariate model includes variable with P<0.05 by univariate analysis. P-values <0.05 are shown in bold. Open table in a new tab ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; Ca × Pi, calcium-phosphate product; CVD, cardiovascular disease; HD, hemodialysis; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PTH, parathyroid hormone; KT/Vurea; urea clearance × time normalized by total body water; WBC, white blood cell. Multivariate model includes variable with P<0.05 by univariate analysis. P-values <0.05 are shown in bold. Factors associated with all-cause deaths are shown in Table 5. In univariate analyses, all-cause death was significantly associated with a level of circulating CD34+ cells lower than 0.37/μl, advanced age, a low body mass index, or a low level of serum albumin. In a multivariate regression analysis, a level of circulating CD34+ cells lower than 0.37/μl (HR, 5.02; 95% CI, 1.08–23.25; P=0.040), advanced age (HR, 1.09; 95% CI, 1.02–1.15; P=0.0082), and a low level of serum albumin (HR, 0.16; 95% CI, 0.01–0.44; P=0.0018) were identified as independent predictors of all-cause death among chronic HD patients (Table 5).Table 5HR for all-cause mortality on Cox proportional hazard modelsUnivariateMultivariateHR (95% CI)P-valueHR (95% CI)P-valueCD34+ cells<0.37/μl6.17 (1.34–18.57)0.0195.02 (1.08–23.25)0.04Male0.92 (0.28–3.02)0.88Age (years)1.11 (1.04–1.18)0.00091.09 (1.02–1.15)0.0082Duration of HD (years)1.03 (0.94–1.10)0.63Diabetes1.86 (0.54–6.32)0.32Hypertension1.03 (0.27–3.86)0.96Smoking1.32 (0.43–4.04)0.62Body mass index0.73 (0.57–0.92)0.00870.79 (0.62–1.01)0.054History of CVD2.35 (0.72–7.69)0.15Hemoglobin (g/100 ml)0.86 (0.52–1.42)0.56WBC (103/μl)1.07 (0.83–1.37)0.62Albumin (mg/100 ml)0.19 (0.08–0.58)0.00060.16 (0.01–0.44)0.0018HDL cholesterol0.99 (0.97–1.04)0.69LDL cholesterol1.01 (0.99–1.03)0.33Ca × Pi1.02 (0.98–1.07)0.75Intact PTH (ng/ml)1.00 (0.99–1.02)0.48C-reactive protein1.04 (0.51–2.08)0.91KT/Vurea0.56 (0.07–4.78)0.6Erythropoietin1.01 (0.99–1.02)0.34Statins1.80 (0.38–8.40)0.45ARB0.32 (0.07–1.51)0.66ACEI0.60 (0.08–4.80)0.63Ca antagonist0.73 (0.46–4.08)0.56β-Blocker0.57 (0.17–1.87)0.36ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; Ca × Pi, calcium-phosphate product; CVD, cardiovascular disease; HD, hemodialysis; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PTH, parathyroid hormone; KT/Vurea; urea clearance × time normalized by total body water; WBC, white blood cell. Multivariate model includes variable with P<0.05 by univariate analysis. P-values <0.05 are shown in bold. Open table in a new tab ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; Ca × Pi, calcium-phosphate product; CVD, cardiovascular disease; HD, hemodialysis; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PTH, parathyroid hormone; KT/Vurea; urea clearance × time normalized by total body water; WBC, white blood cell. Multivariate model includes variable with P<0.05 by univariate analysis. P-values <0.05 are shown in bold. At 3 years after enrollment, 20 HD patients were randomly selected from among the participants, and the second and the third measurements of CD34+ cell count were conducted at an interval of 1 month. A good correlation was observed between these two additional measurements, which were then averaged for each of the 20 patients. When this value was compared to the first measurement conducted upon enrollment, a correlation was observed, suggesting that the CD34+ cell count is stable over a 3-year period (Figure 4). Recent studies have shown that a low number of EPCs is associated with a poor CV outcome among non-HD patients who had CAD.8.Schmidt-Lucke C. Rossig L. Fichtlscherer S. et al.Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair.Circulation. 2005; 111: 2981-2987Crossref PubMed Scopus (966) Google Scholar,9.Werner N. Kosiol S. Schiegl T. et al.Circulating endothelial progenitor cells and cardiovascular outcomes.N Engl J Med. 2005; 353: 999-1007Crossref PubMed Scopus (1806) Google Scholar The present study clearly demonstrated that a reduced number of CD34+ cells in the peripheral blood was significantly associated with future CV events as well as all-cause deaths in chronic HD patients. Of importance is the fact that the absolute number of CD34+ cells obtained from chronic HD patients was much lower (0.49±0.32/μl) than that obtained from patients with cerebrovascular disease (1.1±0.31/μl) or control subjects (1.6±0.2/μl).11.Taguchi A. Matsuyama T. Moriwaki H. et al.Circulating CD34-positive cells provide an index of cerebrovascular function.Circulation. 2004; 109: 2972-2975Crossref PubMed Scopus (170) Google Scholar We measured the levels of CD34+ cells but not the levels of EPCs, which are positive for both CD34 and kinase insert domain receptor. We have shown that circulating CD34+ cell levels are associated with ischemic stroke,11.Taguchi A. Matsuyama T. Moriwaki H. et al.Circulating CD34-positive cells provide an index of cerebrovascular function.Circulation. 2004; 109: 2972-2975Crossref PubMed Scopus (170) Google Scholar brain natriuretic peptide level in type 2 diabetes patients,10.Okada S. Makino H. Nagumo A. et al.Circulating CD34-positive cell number is associated with brain natriuretic peptide level in type 2 diabetic patients.Diabetes Care. 2008; 31: 157-158Crossref PubMed Scopus (11) Google Scholar and vascular risk associated with cognitive impairment.12.Taguchi A. Matsuyama T. Nakagomi T. et al.Circulating CD34-positive cells provide a marker of vascular risk associated with cognitive impairment.J Cereb Blood Flow Metab. 2008; 28: 445-449Crossref PubMed Scopus (20) Google Scholar We have also shown that administration of CD34+ cell ameliorates cerebral ischemia in mice.17.Taguchi A. Soma T. Tanaka H. et al.Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model.J Clin Invest. 2004; 114: 330-338Crossref PubMed Scopus (672) Google Scholar In humans, injection of CD34+ cells derived from peripheral blood improved the ischemia of the lower limbs.18.Tateishi-Yuyama E. Matsubara H. Murohara T. et al.Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial.Lancet. 2002; 360: 427-435Abstract Full Text Full Text PDF PubMed Scopus (1499) Google Scholar These results support the hypothesis that circulating CD34+ cells are involved in the pathogenesis of CVD. Indeed, a recent study by Fadini et al.19.Fadini G.P. de Kreutzenberg S.V. Coracina A. et al.Circulating CD34+ cells, metabolic syndrome, and cardiovascular risk.Eur Heart J. 2006; 27: 2247-2255Crossref PubMed Scopus (192) Google Scholar demonstrates that the levels of CD34+ cells predict cardiovascular outcome more strongly than the levels of EPCs. In addition, previous studies have shown that our method for quantifying circulating CD34+ cells is simple and reproducible.10.Okada S. Makino H. Nagumo A. et al.Circulating CD34-positive cell number is associated with brain natriuretic peptide level in type 2 diabetic patients.Diabetes Care. 2008; 31: 157-158Crossref PubMed Scopus (11) Google Scholar,11.Taguchi A. Matsuyama T. Moriwaki H. et al.Circulating CD34-positive cells provide an index of cerebrovascular function.Circulation. 2004; 109: 2972-2975Crossref PubMed Scopus (170) Google Scholar,12.Taguchi A. Matsuyama T. Nakagomi T. et al.Circulating CD34-positive cells provide a marker of vascular risk associated with cognitive impairment.J Cereb Blood Flow Metab. 2008; 28: 445-449Crossref PubMed Scopus (20) Google Scholar,20.Kikuchi-Taura A. Soma T. Matsuyama T. et al.A new protocol for quantifying CD34(+) cells in peripheral blood of patients with cardiovascular disease.Tex Heart Inst J. 2006; 33: 427-429PubMed Google Scholar,21.Sutherland D.R. Anderson L. Keeney M. et al.The ISHAGE guidelines for CD34+ cell determination by flow cytometry. International Society of Hematotherapy and Graft Engineering.J Hematother. 1996; 5: 213-226Crossref PubMed Scopus (1022) Google Scholar Moreover, the present study demonstrated that the CD34+ cell count is relatively stable over 3 years. Therefore, the measurement of CD34+ cells would be useful for screening a high-risk population such as chronic HD patients. In the present study, we set the death from any cause, not the death from CVD, as the primary end point. We presumed that the number of CV deaths would be too small to draw a definite conclusion. Moreover, we thought that all-cause death may be more suitable for this study because it would be difficult to identify all deaths by CVD in chronic HD patients. In fact, both patients whose recorded cause of death was infection had suffered strokes, and one had severe peripheral vascular disease. Although these two patients did not die from CVD directly, their atherosclerotic vascular diseases likely contributed to their outcomes. We tried to enroll all of the out patients undergoing HD in the clinic. Therefore, it is not likely that there was a selection bias. The major limitation of the present study would be the sample size. It is known that cardiovascular events and all-cause mortality in Japanese are significantly lower than those among Caucasians and African Americans.4.Yasuda K. Kasuga H. Aoyama T. et al.Comparison of percutaneous coronary intervention with medication in the treatment of coronary artery disease in hemodialysis patients.J Am Soc Nephrol. 2006; 17: 2322-2332Crossref PubMed Scopus (43) Google Scholar,22.Shoji T. Tsubakihara Y. Fujii M. et al.Hemodialysis-associated hypotension as an independent risk factor for two-year mortality in hemodialysis patients.Kidney Int. 2004; 66: 1212-1220Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar In the present study, only 13 (6%) out of 216 patients died during the follow-up period. To draw a more definite conclusion, a larger population would need to be studied. Moreover, a previous study has shown that HD patients who had an elevated number of circulating endothelial cells were at risk for a CV event probably because endothelial cells had become detached from the injured endothelium.23.Koc M. Richards H.B. Bihorac A. et al.Circulating endothelial cells are associated with future vascular events in hemodialysis patients.Kidney Int. 2005; 67: 1078-1083Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar A study to clarify the relationship between circulating endothelial cells and CD34+ cells would be worth pursuing. In summary, the present study demonstrates that a low level of circulating CD34+ cells predicts both future CV events and all-cause deaths in chronic HD patients. Pending further studies, we propose that a single measurement of CD34+ cells taken from the peripheral blood is useful in identifying chronic HD patients at high risk. All the outpatients who underwent maintenance HD therapy in Nagoya Kyoritsu Hospital were eligible for this study. Patients who experienced a vascular event within 30 days of measurements, and those with evidence of infection and/or malignant disease were excluded. A total of 216 chronic HD patients were enrolled in this study between March 2005 and May 2005. The study was performed according to the guidelines of the Declaration of Helsinki Principles, and all patients gave their informed written consent to participate in this study, which was approved by the local ethics committee. Clinical follow-up was conducted until April 2007. The data for all participants were obtained from medical records kept during the clinical follow-up period. Patients were adequately managed with regular HD treatment three times a week, and routine screening tests for CVD were performed as described previously.4.Yasuda K. Kasuga H. Aoyama T. et al.Comparison of percutaneous coronary intervention with medication in the treatment of coronary artery disease in hemodialysis patients.J Am Soc Nephrol. 2006; 17: 2322-2332Crossref PubMed Scopus (43) Google Scholar In brief, a standard electrocardiogram and chest X-ray were taken every month, and an echocardiogram and a treadmill exercise test were performed at least once a year. When a patient showed abnormal findings in these routine tests or symptoms of CAD during the follow-up period, coronary angiography was adequately and promptly performed. The classification of previous events was made on the basis of medical records and personal interviews. Causes of deaths were determined by examination of hospital records, autopsy reports, and medical files of the patients' general practitioners. CV events were defined as incidents requiring hospitalization due to CVD including CAD, stroke, and peripheral artery disease, or incidents requiring hospitalization for the purpose of percutaneous coronary intervention or coronary artery bypass graft. Deaths from CVD including CAD, congestive heart failure, stroke, arrhythmia, or valve disease were also defined as CV events. End points were the first CV event and all-cause death. Using a modification of the International Society of Hematotherapy and Graft Engineering guidelines,18.Tateishi-Yuyama E. Matsubara H. Murohara T. et al.Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial.Lancet. 2002; 360: 427-435Abstract Full Text Full Text PDF PubMed Scopus (1499) Google Scholar the precise number of circulating CD34+ cells was quantified as described (the cumulative intraassay coefficient of variation was about 7%).11.Taguchi A. Matsuyama T. Moriwaki H. et al.Circulating CD34-positive cells provide an index of cerebrovascular function.Circulation. 2004; 109: 2972-2975Crossref PubMed Scopus (170) Google Scholar,19.Fadini G.P. de Kreutzenberg S.V. Coracina A. et al.Circulating CD34+ cells, metabolic syndrome, and cardiovascular risk.Eur Heart J. 2006; 27: 2247-2255Crossref PubMed Scopus (192) Google Scholar Briefly, 0.2 ml of heparinized peripheral blood drawn from the arterial–venous shunt vessel before starting HD was incubated with antibodies to CD34 and CD45, and 7AAD (Stem count kit; Beckman Coulter, Fullerton, CA, USA) followed by lysis of red blood cells. After adding internal controls (Stem count kit; Beckman Coulter), samples were concentrated by centrifugation and analyzed by Coulter CYTOMICS FC500 and XL System II software (Beckman Coulter). Using this method, CD34+ cells were clearly observed as a discrete population of CD34+/CD45mild/7AAD− cells. To examine the stability of the CD34+ cell count, additional measurements were performed. In May 2008, 20 patients were randomly selected from among the participants. The first measurement had been performed upon enrollment. A second blood sample was taken in May 2008, and a third sample was taken 1 month later. The association between the second and the third measurements was analyzed. Then, these two values were averaged for each of the 20 patients, and compared to the first measurement. First, the relationship between the CD34+ count and other baseline clinical valuables was studied by a multivariable regression analysis. Next, a cutoff number of circulating CD34+ cells (0.37/μl) was determined by ROC analysis (area under the curve=0.707) to maximize the power of the CD34+ cell count in predicting future CV events. The patients were then categorized into two groups according to the cell count at the time of enrollment; a low CD34+ group (CD34+ cells <0.37/μl, n=93) or a high CD34+ group (CD34+ cells >0.37/μl, n=123). The cumulative survival rates in each group were estimated by the Kaplan–Meier method, and the differences in survival rates between groups were evaluated by log-rank (Mantle–Cox) method. Student's t-test was used for comparison of quantitative data between the groups. HRs and confidence intervals were calculated for each factor by a Cox univariate analysis, and prognostic factors to predict cardiac events or all-cause death were determined. All the prognostic valuables with P<0.25 were entered into a Cox multivariable analysis to determine independent predictors. All the analyses were performed using a software program, StatView 5.0 (SAS Institute, Cary, NC, USA). Data were expressed as the mean value±s.d. Differences were considered significant when P-value was <0.05. All the authors declared no competing interests. This work was partly supported by a Grant-in-Aid for Scientific Research from the Ministry of Health, Labour and Welfare (H19-Tyojyu-029), and a research grant for Research on Human Genome, Tissue Engineering Food Biotechnology from the Ministry of Health, Labor and Welfare (H17-regeneration-010). Dr Taguchi is the principal investigator and Dr Maruyama and Dr Soma are the collaborators of the former grant, and Dr Matsuo is the collaborator of the latter grant." @default.
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• W2000086607 title "Low circulating CD34+ cell count is associated with poor prognosis in chronic hemodialysis patients" @default.
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