Serum Myeloperoxidase and Mortality in Maintenance Hemodialysis Patients
2006; Elsevier BV; Volume: 48; Issue: 1 Linguagem: Inglês
10.1053/j.ajkd.2006.03.047
ISSN1523-6838
AutoresKamyar Kalantar‐Zadeh, Marie-Luise Brennan, Stanley L. Hazen,
Tópico(s)Muscle and Compartmental Disorders
ResumoBackground: During inflammation, myeloperoxidase (MPO) is released, for which its measurement in systemic circulation may be used as an index of leukocyte activation and oxidant stress. MPO levels correlate with angiographic evidence of coronary atherosclerosis and cardiovascular events in subjects with chest pain within the general population. We hypothesized that serum MPO levels are associated with adverse clinical outcomes in maintenance hemodialysis (MHD) patients. Methods: MPO levels were determined in serum samples from 356 MHD patients at the start of a 3-year cohort. Results: Patients (46% women, 28% blacks, 54% with diabetes) were 54.6 ± 14.6 (SD) years old and had undergone MHD for a median period of 26 months. Measured serum MPO level was 2,005 ± 1,877 pmol/L (median, 1,444 pmol/L; interquartile range, 861 to 2,490 pmol/L). MHD patients with greater total body fat had greater MPO levels. MPO level had statistically significant (P < 0.01) and positive correlations with values for serum C-reactive protein (CRP; r = +0.15), interleukin 6 (IL-6; r = +0.23), tumor necrosis factor α (TNF-α; r = +0.21), and white blood cell count (r = +0.21). A death hazard ratio for each 1,000-pmol/L increase in serum MPO level was 1.14 (95% confidence interval [CI], 1.03 to 1.26; P = 0.01) after controlling for age, race (black), diabetes mellitus, dialysis vintage, Charlson comorbidity score, history of previous cardiovascular disease, blood hemoglobin level, and serum concentrations of albumin, CRP, IL-6, and TNF-α. After dividing MPO values into 3 equal groups (tertiles), the death hazard ratio of the highest tertile (versus the middle tertile) was 1.82 (95% CI, 1.07 to 3.10; P = 0.03). Conclusion: Serum MPO levels correlate with levels of markers of inflammation and prospective mortality risk in MHD patients. Background: During inflammation, myeloperoxidase (MPO) is released, for which its measurement in systemic circulation may be used as an index of leukocyte activation and oxidant stress. MPO levels correlate with angiographic evidence of coronary atherosclerosis and cardiovascular events in subjects with chest pain within the general population. We hypothesized that serum MPO levels are associated with adverse clinical outcomes in maintenance hemodialysis (MHD) patients. Methods: MPO levels were determined in serum samples from 356 MHD patients at the start of a 3-year cohort. Results: Patients (46% women, 28% blacks, 54% with diabetes) were 54.6 ± 14.6 (SD) years old and had undergone MHD for a median period of 26 months. Measured serum MPO level was 2,005 ± 1,877 pmol/L (median, 1,444 pmol/L; interquartile range, 861 to 2,490 pmol/L). MHD patients with greater total body fat had greater MPO levels. MPO level had statistically significant (P < 0.01) and positive correlations with values for serum C-reactive protein (CRP; r = +0.15), interleukin 6 (IL-6; r = +0.23), tumor necrosis factor α (TNF-α; r = +0.21), and white blood cell count (r = +0.21). A death hazard ratio for each 1,000-pmol/L increase in serum MPO level was 1.14 (95% confidence interval [CI], 1.03 to 1.26; P = 0.01) after controlling for age, race (black), diabetes mellitus, dialysis vintage, Charlson comorbidity score, history of previous cardiovascular disease, blood hemoglobin level, and serum concentrations of albumin, CRP, IL-6, and TNF-α. After dividing MPO values into 3 equal groups (tertiles), the death hazard ratio of the highest tertile (versus the middle tertile) was 1.82 (95% CI, 1.07 to 3.10; P = 0.03). Conclusion: Serum MPO levels correlate with levels of markers of inflammation and prospective mortality risk in MHD patients. MYELOPEROXIDASE (MPO), an abundant enzyme secreted by neutrophils, monocytes, and certain tissue macrophages during phagocyte activation, is a major component of the bactericidal armamentarium of leukocytes.1Daugherty A. Dunn J.L. Rateri D.L. Heinecke J.W. Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions.J Clin Invest. 1994; 94: 437-444Crossref PubMed Scopus (1103) Google Scholar In acute inflammatory conditions, MPO is released in the extracellular medium and participates in innate immune defense mechanisms through formation of microbicidal reactive oxidant species. However, MPO-generated oxidants also can damage normal tissues, contributing to inflammatory injury and potentially participating in the pathogenesis of cardiovascular disease.1Daugherty A. Dunn J.L. Rateri D.L. Heinecke J.W. Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions.J Clin Invest. 1994; 94: 437-444Crossref PubMed Scopus (1103) Google Scholar, 2Pecoits-Filho R. Stenvinkel P. Marchlewska A. et al.A functional variant of the myeloperoxidase gene is associated with cardiovascular disease in end-stage renal disease patients.Kidney Int Suppl. 2003; 84: S172-S176Crossref PubMed Scopus (124) Google Scholar, 3Upritchard J.E. Sutherland W.H. Oxidation of heparin-treated low density lipoprotein by peroxidases.Atherosclerosis. 1999; 146: 211-219Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 4Nikpoor B. Turecki G. Fournier C. Theroux P. Rouleau G.A. A functional myeloperoxidase polymorphic variant is associated with coronary artery disease in French-Canadians.Am Heart J. 2001; 142: 336-339Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar, 5Zhang R. Brennan M.L. Fu X. et al.Association between myeloperoxidase levels and risk of coronary artery disease.JAMA. 2001; 286: 2136-2142Crossref PubMed Scopus (753) Google Scholar, 6Brennan M.L. Hazen S.L. Emerging role of myeloperoxidase and oxidant stress markers in cardiovascular risk assessment.Curr Opin Lipidol. 2003; 14: 353-359Crossref PubMed Scopus (144) Google Scholar Because of the many links between elevated MPO levels and atherosclerosis, recent interest has focused on a potential role for MPO and its oxidants as clinical predictors of cardiovascular risk in the general population.1Daugherty A. Dunn J.L. Rateri D.L. Heinecke J.W. Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions.J Clin Invest. 1994; 94: 437-444Crossref PubMed Scopus (1103) Google Scholar, 2Pecoits-Filho R. Stenvinkel P. Marchlewska A. et al.A functional variant of the myeloperoxidase gene is associated with cardiovascular disease in end-stage renal disease patients.Kidney Int Suppl. 2003; 84: S172-S176Crossref PubMed Scopus (124) Google Scholar, 3Upritchard J.E. Sutherland W.H. Oxidation of heparin-treated low density lipoprotein by peroxidases.Atherosclerosis. 1999; 146: 211-219Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 4Nikpoor B. Turecki G. Fournier C. Theroux P. Rouleau G.A. A functional myeloperoxidase polymorphic variant is associated with coronary artery disease in French-Canadians.Am Heart J. 2001; 142: 336-339Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar, 5Zhang R. Brennan M.L. Fu X. et al.Association between myeloperoxidase levels and risk of coronary artery disease.JAMA. 2001; 286: 2136-2142Crossref PubMed Scopus (753) Google Scholar, 7Hazen S.L. Myeloperoxidase and plaque vulnerability.Arterioscler Thromb Vasc Biol. 2004; 24: 1143-1146Crossref PubMed Scopus (80) Google Scholar Recent studies showed that MPO levels identify those among high-risk patients who are at increased risk for near-term cardiac events, highlighting the potential usefulness of MPO measurement for risk stratification in high-risk individuals.8Brennan M.L. Penn M.S. Van Lente F. et al.Prognostic value of myeloperoxidase in patients with chest pain.N Engl J Med. 2003; 349: 1595-1604Crossref PubMed Scopus (909) Google Scholar, 9Vita J.A. Brennan M.L. Gokce N. et al.Serum myeloperoxidase levels independently predict endothelial dysfunction in humans.Circulation. 2004; 110: 1134-1139Crossref PubMed Scopus (311) Google Scholar, 10Baldus S. Heeschen C. Meinertz T. et al.Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes.Circulation. 2003; 108: 1440-1445Crossref PubMed Scopus (836) Google Scholar However, very few studies examined the role of MPO in patients with chronic kidney disease (CKD) and their outcomes. Hemodialysis treatment, even with the use of biocompatible membranes and ultrapure dialysate, may contribute to an increase in leukocyte activation and enhanced oxidative stress.11Cohen M.S. Elliott D.M. Chaplinski T. Pike M.M. Niedel J.E. A defect in the oxidative metabolism of human polymorphonuclear leukocytes that remain in circulation early in hemodialysis.Blood. 1982; 60: 1283-1289PubMed Google Scholar, 12Locatelli F. Canaud B. Eckardt K.U. Stenvinkel P. Wanner C. Zoccali C. Oxidative stress in end-stage renal disease An emerging threat to patient outcome.Nephrol Dial Transplant. 2003; 18: 1272-1280Crossref PubMed Scopus (606) Google Scholar, 13Epperlein M.M. Nourooz-Zadeh J. Jayasena S.D. Hothersall J.S. Noronha-Dutra A. Neild G.H. Nature and biological significance of free radicals generated during bicarbonate hemodialysis.J Am Soc Nephrol. 1998; 9: 457-463PubMed Google Scholar Recent genetic studies reported that the presence of a functional variant of the MPO gene is associated with rate of cardiovascular disease in French-Canadian men,4Nikpoor B. Turecki G. Fournier C. Theroux P. Rouleau G.A. A functional myeloperoxidase polymorphic variant is associated with coronary artery disease in French-Canadians.Am Heart J. 2001; 142: 336-339Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar as well as a group of patients with CKD.2Pecoits-Filho R. Stenvinkel P. Marchlewska A. et al.A functional variant of the myeloperoxidase gene is associated with cardiovascular disease in end-stage renal disease patients.Kidney Int Suppl. 2003; 84: S172-S176Crossref PubMed Scopus (124) Google Scholar However, to our knowledge, serum MPO has not been measured systematically in large cohorts of dialysis patients. Moreover, whether serum MPO levels are linked to malnutrition-inflammation-cachexia syndrome (MICS), a strong predictor of clinical outcome and survival in patients with CKD, has not been examined. Here, we measured serum MPO levels in a large cohort of maintenance hemodialysis (MHD) patients, examined its relationship with clinical and laboratory surrogates of nutrition and inflammation, and evaluated whether serum MPO levels predict mortality risk in these patients. Subjects participating in the Nutritional and Inflammatory Evaluation in Dialysis (NIED) Study originated from a pool of approximately 1,300 MHD outpatients in 8 DaVita Inc dialysis facilities in the South Bay–Los Angeles area (see NIED Study Web site: www.NIEDStudy.org for more details, as well as previous publications14Colman S. Bross R. Benner D. et al.The Nutritional and Inflammatory Evaluation in Dialysis Patients (NIED) Study Overview of the NIED Study and the role of dietitians.J Ren Nutr. 2005; 15: 231-243Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). Inclusion criteria were outpatients who had been undergoing MHD for at least 8 weeks, were 18 years or older, and signed a local institutional review board–approved consent form. Patients with an anticipated life expectancy less than 6 months (eg, because of metastatic malignancy or advanced human immunodeficiency virus disease) were excluded. In the initial phase of the NIED Study (October 2001 to March 2002), 385 patients from 8 dialysis units signed the written consent form. Subsequently, blood samples were obtained from 367 of these individuals because 18 patients were not present in the dialysis units at the time of blood drawing. After the planned laboratory measurements were performed (discussed later), residual sera of all except 11 patients remained and were frozen for future investigations. The medical chart of each MHD patient was reviewed thoroughly by a nephrologist (K.K.-Z.), and data pertaining to underlying kidney disease, cardiovascular history, and other comorbid conditions were extracted. A modified version of the Charlson Comorbidity Index, ie, without the age and kidney disease components, was used to assess the severity of comorbidity.15Fried L. Bernardini J. Piraino B. Charlson Comorbidity Index as a predictor of outcomes in incident peritoneal dialysis patients.Am J Kidney Dis. 2001; 37: 337-342Abstract Full Text PDF PubMed Scopus (192) Google Scholar, 16Beddhu S. Bruns F.J. Saul M. Seddon P. Zeidel M.L. A simple comorbidity scale predicts clinical outcomes and costs in dialysis patients.Am J Med. 2000; 108: 609-613Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar Control samples were selected randomly from volunteers at the time of blood donation and included 289 subjects (age ≥ 21 years) without obvious history of coronary artery disease. Healthy volunteers were 54 ± 12 years old and included 80% men. The Institutional Review Board at the Cleveland Clinic Foundation (Cleveland, OH) approved the study protocol for the controls. To measure percentage of body fat and estimate lean body mass, near-infrared interactance17Kalantar-Zadeh K. Block G. Kelly M.P. Schroepfer C. Rodriguez R.A. Humphreys M.H. Near infra-red interactance for longitudinal assessment of nutrition in dialysis patients.J Ren Nutr. 2001; 11: 23-31Abstract Full Text PDF PubMed Scopus (32) Google Scholar, 18Kalantar-Zadeh K. Dunne E. Nixon K. et al.Near infra-red interactance for nutritional assessment of dialysis patients.Nephrol Dial Transplant. 1999; 14: 169-175Crossref PubMed Scopus (59) Google Scholar technology was used at the same time as the foregoing anthropometric measurements. A commercial near-infrared interactance sensor with a coefficient of variation of 0.5% for total body fat measurement (portable Futrex 6100; Gaithersburg, MD; www.futrex.com) was used. Near-infrared measurements were performed by placing a Futrex sensor on the nonaccess upper arm for several seconds, after entering the required data (date of birth, sex, weight, and height) for each patient. Near-infrared measurements of body fat were shown to correlate significantly with other nutritional measures in MHD patients.17Kalantar-Zadeh K. Block G. Kelly M.P. Schroepfer C. Rodriguez R.A. Humphreys M.H. Near infra-red interactance for longitudinal assessment of nutrition in dialysis patients.J Ren Nutr. 2001; 11: 23-31Abstract Full Text PDF PubMed Scopus (32) Google Scholar, 18Kalantar-Zadeh K. Dunne E. Nixon K. et al.Near infra-red interactance for nutritional assessment of dialysis patients.Nephrol Dial Transplant. 1999; 14: 169-175Crossref PubMed Scopus (59) Google Scholar Predialysis blood samples and postdialysis serum urea nitrogen levels were obtained on a midweek day and coincided chronologically with quarterly blood tests at DaVita facilities. Single-pool Kt/V was used to represent weekly dialysis dose. All routine laboratory measurements were performed by DaVita Laboratories (Deland, FL) by using automated methods. Serum C-reactive protein (CRP) and 2 proinflammatory cytokines, interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), were measured as indices of degree of inflammation. High-sensitivity CRP was measured by using a turbidometric immunoassay in which a serum sample is mixed with latex beads coated with antihuman CRP antibodies, forming an insoluble aggregate (WPCI, Osaka, Japan; unit, milligrams per liter; normal range, <3.0 mg/L).19Ridker P.M. Rifai N. Rose L. Buring J.E. Cook N.R. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events.N Engl J Med. 2002; 347: 1557-1565Crossref PubMed Scopus (3006) Google Scholar, 20Erbagci A.B. Tarakcioglu M. Aksoy M. et al.Diagnostic value of CRP and Lp(a) in coronary heart disease.Acta Cardiol. 2002; 57: 197-204Crossref PubMed Scopus (42) Google Scholar High sensitivity IL-6 and TNF-α immunoassay kits based on a solid-phase sandwich enzyme-linked immunosorbent assay using recombinant human IL-6 and TNF-α were used to measure serum proinflammatory cytokines (R&D Systems, Minneapolis, MN; units: picograms per milliliter; normal range: IL-6, <9.9 pg/mL; TNF-α, <4.7 pg/mL).21Pecoits-Filho R. Barany P. Lindholm B. Heimburger O. Stenvinkel P. Interleukin-6 is an independent predictor of mortality in patients starting dialysis treatment.Nephrol Dial Transplant. 2002; 17: 1684-1688Crossref PubMed Scopus (343) Google Scholar, 22Stenvinkel P. Heimburger O. Jogestrand T. Elevated interleukin-6 predicts progressive carotid artery atherosclerosis in dialysis patients Association with Chlamydia pneumoniae seropositivity.Am J Kidney Dis. 2002; 39: 274-282Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar, 23Beutler B. Cerami A. The biology of cachectin/TNF—A primary mediator of host response.Ann Rev Immunol. 1989; 7: 625-655Crossref PubMed Scopus (1481) Google Scholar CRP and cytokines were measured in the General Clinical Research Center Laboratories of Harbor-UCLA Medical Center. Serum prealbumin was analyzed by using an antigen-antibody complex assay, and total homocysteine concentrations were determined by means of high-performance liquid chromatography at Harbor-UCLA Clinical Laboratories. Frozen sera were transported to Cleveland Clinic General Clinical Research Center Laboratories for MPO measurements. A clinically validated and approved sandwich-based enzyme-linked immunosorbent assay (CardioMPO; PrognostiX, Cleveland, OH) was used to measure serum MPO. MPO assay performance showed an assay limit of quantification of 13 pmol/L, intraplate and interplate coefficients of variance of 5.5% and 6.2%, and near quantitative recovery of MPO when spiked in serum (96.7% ± 2.6%), respectively. Laboratory technicians were blinded to patient identifiers and clinical parameters. Conventional analysis of variance, Kruskal-Wallis test, and chi-square were used, as appropriate, to detect significant differences among tertiles of MPO. Multivariate regression analyses and analysis of covariance were performed to obtain adjusted P controlled for case-mix and comorbidity covariates. Pearson and Spearman correlation coefficients (r) were used for analyses of associations, as appropriate. To calculate relative risks for death, we obtained hazard ratios (HRs) by using Cox proportional hazard models after controlling for the mentioned covariates. Plots of log (−log [survival rate]) against log (survival time) were performed to establish the validity of the proportionality assumption. Kaplan-Meier analyses were used to assess differences in surviving proportions among tertiles of MPO. Case-mix covariates included sex (female), age, race (black versus other), and dialysis vintage (number of months on MHD treatment); comorbidity covariates included diabetes mellitus (yes/no), history of cardiovascular disease (yes/no), and Charlson Comorbidity Index; and laboratory covariates in fully adjusted multivariate models included blood hemoglobin and serum MPO, CRP, IL-6, TNF-α, and albumin concentrations. Fiducial limits are given as mean ± SD or median and interquartile range. Risk ratios include 95% confidence intervals (CIs). P less than 0.05 or a 95% CI that did not span 1.0 is considered statistically significant. P between 0.05 and 0.20 also is listed with 2 decimals for the sake of potential type II errors. Descriptive and multivariate statistics were carried out using the statistical software Stata, version 9.0 (Stata Corp, College Station, TX). The 356 MHD patients under study included 46% women, 28% blacks, and 54% patients with diabetes. They were 54.6 ± 14.6 years old and had undergone MHD for a median vintage of 26 months (interquartile range, 13 to 51 months). Figure 1 shows the distribution of measured serum MPO among 356 MHD patients. For MHD patients at the start of the cohort, serum MPO averaged 2,005 ± 1,877 pmol/L (median, 1,444 pmol/L; interquartile range, 861 to 2,490 pmol/L; minimum, 27 pmol/L; maximum, 13,268 pmol/L). Control subjects had an average MPO level of 2,032 ± 724 pmol/L (median, 1,755 pmol/L). To examine the relationship between different levels of serum MPO and relevant clinical and laboratory measures, serum MPO was divided into 3 equal tertiles (Table 1). The highest MPO tertile included more women, but this difference was not statistically significant. Diabetes proportion and age distribution were similar across the 3 groups. Near-infrared measured total body fat and body mass index (BMI) were incrementally greater across increasing MPO tertiles. Of inflammatory markers, serum CRP and TNF-α were high in the highest MPO tertile, and serum IL-6 was almost equally high in the 2 higher MPO tertiles. Serum parathyroid hormone and lactate dehydrogenase levels, peripheral white blood cell (WBC) count, and administered dose of erythropoietin showed an increasing trend across increasing MPO tertiles.Table 1Baseline Demographic, Clinical, and Laboratory Measures for 3 Tertiles of Serum MPO Levels in 356 MHD PatientsVariableLowest Tertile: 27-994 pmol/L (n = 118)Middle Tertile: 997-2,116 pmol/L (n = 119)Highest Tertile: 2,118-13,268 pmol/L (n = 119)Analysis of Variance PMultivariate Adjusted PSex (% female)4242520.3NARace (% black)2329300.4NADiabetes mellitus (%)5354560.9NAAll-cause death (%)2829340.5NACardiovascular death (%)4745470.9NAAge (y)55 ± 1556 ± 1453 ± 140.21NADialysis vintage (mo)37.5 ± 37.632.8 ± 28.939.1 ± 34.10.3NACharlson Comorbidity Index1.9 ± 1.42.0 ± 1.52.1 ± 1.70.8NANear-infrared total body fat (%)24.5 ± 10.926.6 ± 10.328.4 ± 110.030.01BMI (kg/m2)25.2 ± 5.926.6 ± 6.127.6 ± 60.020.02Kt/V (single pool)1.58 ± 0.281.56 ± 0.281.59 ± 0.290.60.8Serum MPO (pmol/L)667 ± 2231,483 ± 3213,863 ± 2,213<0.001NACRP (mg/L)5.9 ± 5.75.7 ± 5.38.0 ± 11.10.040.03IL-6 (ng/L)10.6 ± 12.830.4 ± 8328.5 ± 52.60.010.04TNF-α (ng/L)6.9 ± 3.67.4 ± 3.910.1 ± 9<0.001<0.001Albumin (g/dL)3.85 ± 0.43.81 ± 0.33.87 ± 0.30.30.4Prealbumin (mg/dL)28.7 ± 8.827.5 ± 10.327.8 ± 9.60.60.6Total cholesterol (mg/dL)142.1 ± 47.9143.6 ± 46.5148.6 ± 45.40.50.24Total homocysteine (μmol/L)24.8 ± 10.824.6 ± 12.523.9 ± 12.50.80.5Creatinine (mg/dL)10.4 ± 3.210.8 ± 3.510.9 ± 3.30.50.23Calcium (mg/dL)9.3 ± 0.79.3 ± 0.69.3 ± 0.70.70.4Phosphorus (mg/dL)5.7 ± 1.55.8 ± 1.56.0 ± 1.50.30.18Intact parathyroid hormone (pg/mL)287 ± 256344 ± 359396 ± 4590.090.07Lactate dehydrogenase (U/L)159 ± 35166 ± 38170 ± 480.140.09Blood hemoglobin (g/dL)11.9 ± 111.9 ± 111.9 ± 0.90.90.7WBCs (× 1,000)6.8 ± 1.77.2 ± 3.27.9 ± 2.40.002<0.001Administered erythropoietin (U/wk)⁎Multivariate adjusted regression controls for age, sex, race (black), vintage, diabetes, Charlson Comorbidity Index, and history of cardiovascular disease.12,860 ± 7,96915,492 ± 13,35315,967 ± 14,2760.140.19NOTE. P < 0.20 are in bold type for convenient comparison. To convert serum creatinine in mg/dL to μmol/L, multiply by 88.4; albumin and hemoglobin in g/dL to g/L, multiply by 10; calcium in mg/dL to mmol/L, multiply by 0.2495; cholesterol in mg/dL to mmol/L, multiply by 0.02586; phosphorus in mg/dL to mmol/L, multiply by 0.3229.Abbreviation: NA, not applicable. Multivariate adjusted regression controls for age, sex, race (black), vintage, diabetes, Charlson Comorbidity Index, and history of cardiovascular disease. Open table in a new tab NOTE. P < 0.20 are in bold type for convenient comparison. To convert serum creatinine in mg/dL to μmol/L, multiply by 88.4; albumin and hemoglobin in g/dL to g/L, multiply by 10; calcium in mg/dL to mmol/L, multiply by 0.2495; cholesterol in mg/dL to mmol/L, multiply by 0.02586; phosphorus in mg/dL to mmol/L, multiply by 0.3229. Abbreviation: NA, not applicable. To assess the relationship of these markers with MPO levels within the MHD cohort, Spearman correlation coefficients were evaluated (Table 2). Associations between levels of serum MPO and the 3 inflammatory markers were moderate and statistically significant. Peripheral WBC count, near-infrared measured body fat percentage, and BMI also had significant and positive associations with serum MPO levels. Scatter diagrams showing associations between serum MPO and values for serum CRP, IL-6, TNF-α, and WBCs are shown in Fig 2.Table 2Comparison of Spearman Correlation Coefficients (r) of Serum MPO With 3 Measures of Inflammation: Serum CRP, IL-6, and TNF-αVariablesMPOCRPIL-6TNF-αSerum CRP (mg/L)0.15⁎P < 0.01.IL-6 (ng/L)0.23⁎P < 0.01.0.39⁎P < 0.01.TNF-α (ng/L)0.21⁎P < 0.01.0.090.30⁎P < 0.01.Sex (female)0.08−0.030.030.03Race (black)0.060.13†P between 0.05 and 0.01.0.050.01Diabetes mellitus0.030.060.08−0.09Age (y)−0.030.15⁎P < 0.01.0.11†P between 0.05 and 0.01.0.13†P between 0.05 and 0.01.Dialysis vintage (mo)0.060.040.12†P between 0.05 and 0.01.0.18⁎P < 0.01.Charlson Comorbidity Index0.040.14⁎P < 0.01.0.14⁎P < 0.01.0.01Near-infrared total body fat (%)0.16⁎P < 0.01.0.14†P between 0.05 and 0.01.0.15⁎P < 0.01.0.02BMI (kg/m2)0.17⁎P < 0.01.0.26⁎P < 0.01.0.13†P between 0.05 and 0.01.0.02Kt/V (single pool)0.05−0.100.020.14†P between 0.05 and 0.01.Albumin (g/dL)0.02−0.22⁎P < 0.01.−0.35⁎P < 0.01.0.01Prealbumin (mg/dL)0.05−0.20⁎P < 0.01.−0.43⁎P < 0.01.0.10Total cholesterol (mg/dL)0.06−0.04−0.10†P between 0.05 and 0.01.0.00Total homocysteine (μmol/L)−0.07−0.10−0.060.07Creatinine (mg/dL)0.05−012†P between 0.05 and 0.01.−0.20⁎P < 0.01.0.07Calcium (mg/dL)0.02−0.070.090.09Phosphorus (mg/dL)0.11†P between 0.05 and 0.01.0.070.090.01Intact parathyroid hormone (pg/mL)0.12†P between 0.05 and 0.01.0.050.050.05Lactate dehydrogenase (U/L)0.080.040.17⁎P < 0.01.0.10Blood hemoglobin (g/dL)0.00−0.10−0.080.02WBCs (× 1,000)0.21⁎P < 0.01.0.11†P between 0.05 and 0.01.0.18⁎P < 0.01.0.02Administered erythropoietin (U/wk)0.050.26⁎P < 0.01.0.30⁎P < 0.01.0.07NOTE. Correlation coefficients of 0.15 or greater are in bold type for convenient comparison. P < 0.01.† P between 0.05 and 0.01. Open table in a new tab NOTE. Correlation coefficients of 0.15 or greater are in bold type for convenient comparison. To examine the mortality predictability of MPO and compare it with levels of the 3 measured inflammatory markers, Cox proportional hazard regressions were modeled (Table 3). The a priori selected increment in each variable was approximately half of 1 SD or interquartile range. For each 1,000-pmol/L increase in serum MPO level, there was 8% to 15% increase in risk for death during the observed 3-year interval according to the level of multivariate adjustment. In the fully adjusted model in which case-mix and comorbid variables, along with all 5 laboratory markers of inflammation and blood hemoglobin, were added, only serum MPO, CRP, and albumin levels remained predictive of mortality risk, with similar associations noted (Table 3). The ability of serum MPO level to predict mortality risk did not change with controlling for these inflammatory markers, indicating its statistical independence in this regard. Figure 3 shows Kaplan-Meier survival analysis for the 3 tertiles of MPO. Adjusted death HR for the highest compared with the lowest tertile was not statistically significant. However, when the highest MPO tertile was compared with the middle MPO tertile, death HR was 1.70 (95% CI, 1.03 to 2.78; P = 0.04). HR of the lowest compared with the middle MPO tertile was 1.16 (95% CI, 0.70 to 1.90; P = 0.6).Table 3Relative Risk for Death During the 3-Year Follow-Up Period in 256 MHD Patients Based on Cox Proportional Hazard RegressionSerum MeasuresUnadjustedCase-Mix AdjustedCase-Mix & Comorbidity AdjustedCase-Mix, Comorbidity, & Laboratory Values AdjustedMPO (each 1,000 pmol/L↑)1.08 (1.00-1.16) P = 0.051.15 (1.06-1.26) P = 0.0011.15 (1.05-1.26) P = 0.0021.14 (1.03-1.26) P = 0.01CRP (each 5 mg/L↑)1.13 (1.05-1.22) P = 0.0011.21 (1.11-1.32) P < 0.0011.24 (1.13-1.37) P < 0.0011.16 (1.04-1.30) P = 0.01IL-6 (each 10 ng/L↑)1.01 (0.99-1.03) P = 0.201.01 (0.99-1.04) P = 0.211.01 (0.98-1.03) P = 0.41.00 (0.97-1.03) P = 0.8TNF-α (each 5 ng/L↑)0.98 (0.83-1.16) P = 0.71.06 (0.90-1.23) P = 0.51.06 (0.91-1.24) P = 0.50.94 (0.78-1.13) P = 0.5Albumin (each 0.1 g/dL↓)1.20 (1.14-1.25) P < 0.0011.18 (1.11-1.24) P < 0.0011.16 (1.09-1.23) P < 0.0011.15 (1.08-1.23) P < 0.001NOTE. Case-mix adjustment included age, sex, race (black), and dialysis vintage; comorbidity adjustment included diabetes mellitus, history of cardiovascular disease, and Charlson Comorbidity Index; and laboratory value adjustment included serum MPO, CRP, IL-6, TNF-α, albumin, and hemoglobin values. Open table in a new tab NOTE. Case-mix adjustment included age, sex, race (black), and dialysis vintage; comorbidity adjustment included diabetes mellitus, history of cardiovascular disease, and Charlson Comorbidity Index; and laboratory value adjustment included serum MPO, CRP, IL-6, TNF-α, albumin, and hemoglobin values. The present studies show that serum MPO levels in MHD patients independently predict 3-year mortality risks despite statistical adjustments for multiple alternative inflammation markers and other clinical correlates of mortality risk in the population. Interestingly, we observed that MPO levels correlated with levels of CRP and the proinflammatory cytokines IL-6 and TNF-α, but only CRP and MPO levels predicted mortality after multiple logistic regression analyses. Serum MPO level also was associated with higher body fat percentage and higher WBC count. These findings may have important clinical implications for the management of inflammation and oxidative stress in MHD patients. Human MPO is a 140-kd hemoprotein composed of 4 subunits and is stored in azurophilic granules of neutrophils, monocytes, and certain tissue macrophages.2Pecoits-Filho R. Stenvinkel P. Marchlewska A. et al.A functional variant of the myeloperoxidase gene is associate
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