Plasma interleukin-6 is independently associated with mortality in both hemodialysis and pre-dialysis patients with chronic kidney disease
2009; Elsevier BV; Volume: 77; Issue: 6 Linguagem: Inglês
10.1038/ki.2009.503
ISSN1523-1755
AutoresDaniela V. Barreto, Fellype Carvalho Barreto, Sophie Liabeuf, M. Temmar, Horst‐Dieter Lemke, Christophe Tribouilloy, Gabriel Choukroun, Raymond Vanholder, Ziad A. Massy,
Tópico(s)Chronic Kidney Disease and Diabetes
ResumoChronic inflammation associated with chronic kidney disease predicts all-cause and cardiovascular mortality in hemodialysis patients. Here we sought to evaluate the association between plasma levels of the inflammatory mediator interleukin-6 (IL-6) and mortality and aortic calcification/stiffness in 125 patients at different stages (2-5D) of chronic kidney disease. Using multivariate linear regression, we found that plasma IL-6 was independently associated with C-reactive protein, albumin and the stage of chronic kidney disease, but not the aortic calcification score or pulse wave velocity. During follow-up studies (median of 829 days), 38 patients died, 22 from cardiovascular events. Plasma IL-6 significantly predicted overall and cardiovascular mortality; this association persisted after multiple adjustments or restricting the analysis to pre-dialysis patients. Moreover, IL-6 was a significantly better predictor of mortality than C-reactive protein, albumin or tumor necrosis factor-α. Hence, plasma IL-6 independently predicted overall and cardiovascular mortality in patients at different stages of chronic kidney disease; however, whether lowering plasma IL-6 will affect the outcome of chronic kidney disease will require more direct evaluation. Chronic inflammation associated with chronic kidney disease predicts all-cause and cardiovascular mortality in hemodialysis patients. Here we sought to evaluate the association between plasma levels of the inflammatory mediator interleukin-6 (IL-6) and mortality and aortic calcification/stiffness in 125 patients at different stages (2-5D) of chronic kidney disease. Using multivariate linear regression, we found that plasma IL-6 was independently associated with C-reactive protein, albumin and the stage of chronic kidney disease, but not the aortic calcification score or pulse wave velocity. During follow-up studies (median of 829 days), 38 patients died, 22 from cardiovascular events. Plasma IL-6 significantly predicted overall and cardiovascular mortality; this association persisted after multiple adjustments or restricting the analysis to pre-dialysis patients. Moreover, IL-6 was a significantly better predictor of mortality than C-reactive protein, albumin or tumor necrosis factor-α. Hence, plasma IL-6 independently predicted overall and cardiovascular mortality in patients at different stages of chronic kidney disease; however, whether lowering plasma IL-6 will affect the outcome of chronic kidney disease will require more direct evaluation. Cardiovascular disease is extremely prevalent in chronic kidney disease (CKD) settings and accounts for the majority of deaths in this population.1.Parfrey P.S. Foley R.N. The clinical epidemiology of cardiac disease in chronic renal failure.J Am Soc Nephrol. 1999; 10: 1606-1615PubMed Google Scholar It has been repeatedly shown that advanced CKD is associated with a state of chronic inflammation, as evidenced by either elevated levels of various pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, etc.) or altered levels of acute-phase proteins (C-reactive protein (CRP), albumin, fetuin-A, etc.).2.Kato A. Odamaki M. Takita T. et al.Association between interleukin-6 and carotid atherosclerosis in hemodialysis patients.Kidney Int. 2002; 61: 1143-1152Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 3.Herbelin A. Urena P. Nguyen A.T. et al.Elevated circulating levels of interleukin-6 in patients with chronic renal failure.Kidney Int. 1991; 39: 954-960Abstract Full Text PDF PubMed Scopus (258) Google Scholar, 4.Cavaillon J.M. Poignet J.L. Fitting C. et al.Serum interleukin-6 in long-term hemodialyzed patients.Nephron. 1992; 60: 307-313Crossref PubMed Scopus (78) Google Scholar In addition to individual genetic predispositions,5.Liu Y. Berthier-Schaad Y. Fallin M.D. et al.IL-6 haplotypes, inflammation, and risk for cardiovascular disease in a multiethnic dialysis cohort.J Am Soc Nephrol. 2006; 17: 863-870Crossref PubMed Scopus (101) Google Scholar the uremic state probably increases the peripheral cell release of pro-inflammatory cytokines and slows removal of the latter—resulting in a net increase. Importantly, this chronic inflammation state has been shown to predict all-cause and cardiovascular mortality in hemodialysis patients,6.Kalantar-Zadeh K. Kopple J.D. Humphreys M.H. et al.Comparing outcome predictability of markers of malnutrition-inflammation complex syndrome in haemodialysis patients.Nephrol Dial Transplant. 2004; 19: 1507-1519Crossref PubMed Scopus (205) Google Scholar, 7.Qureshi A.R. Alvestrand A. Divino-Filho J.C. et al.Inflammation, malnutrition, and cardiac disease as predictors of mortality in hemodialysis patients.J Am Soc Nephrol. 2002; 13: S28-S36PubMed Google Scholar, 8.Yeun J.Y. Levine R.A. Mantadilok V. et al.C-Reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients.Am J Kidney Dis. 2000; 35: 469-476Abstract Full Text Full Text PDF PubMed Scopus (765) Google Scholar, 9.Panichi V. Rizza G.M. Paoletti S. et al.Chronic inflammation and mortality in haemodialysis: effect of different renal replacement therapies. Results from the RISCAVID study.Nephrol Dial Transplant. 2008; 23: 2337-2343Crossref PubMed Scopus (165) Google Scholar which suggests that high inflammatory responsiveness to environmental stimuli may determine the mortality risk in this population. However, few studies have evaluated the inflammatory profile of individuals at the earlier CKD stages10.Descamps-Latscha B. Herbelin A. Nguyen A.T. et al.Balance between IL-1 beta, TNF-alpha, and their specific inhibitors in chronic renal failure and maintenance dialysis. Relationships with activation markers of T cells, B cells, and monocytes.J Immunol. 1995; 154: 882-892PubMed Google Scholar, 11.Bolton C.H. Downs L.G. Victory J.G. et al.Endothelial dysfunction in chronic renal failure: roles of lipoprotein oxidation and pro-inflammatory cytokines.Nephrol Dial Transplant. 2001; 16: 1189-1197Crossref PubMed Scopus (241) Google Scholar, 12.Oberg B.P. McMenamin E. Lucas F.L. et al.Increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease.Kidney Int. 2004; 65: 1009-1016Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar and none of them examined the association of this profile with outcomes in these patients. Interleukin-6 (IL-6) is a 26 kDa protein produced by the liver. It is considered to be crucial in the acute-phase inflammatory response and promotes lymphocyte activation and proliferation, B-cell differentiation, leukocyte recruitment and regulation of the synthesis of acute phase proteins, fibrinogen, and albumin.13.Stenvinkel P. Ketteler M. Johnson R.J. et al.IL-10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia--the good, the bad, and the ugly.Kidney Int. 2005; 67: 1216-1233Abstract Full Text Full Text PDF PubMed Scopus (619) Google Scholar Plasma levels of IL-6 are known to be significantly higher in severely ill patients with acute renal failure who die than in those who survive to hospital discharge (independently of sepsis status).14.Rao M. Guo D. Perianayagam M.C. et al.Plasma interleukin-6 predicts cardiovascular mortality in hemodialysis patients.Am J Kidney Dis. 2005; 45: 324-333Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar In addition, in the elderly 15.Vasan R.S. Sullivan L.M. Roubenoff R. et al.Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham Heart Study.Circulation. 2003; 107: 1486-1491Crossref PubMed Scopus (580) Google Scholar,16.Cesari M. Penninx B.W. Newman A.B. et al.Inflammatory markers and onset of cardiovascular events: results from the Health ABC study.Circulation. 2003; 108: 2317-2322Crossref PubMed Scopus (762) Google Scholar and CKD patients on dialysis,17.Tripepi G. Mallamaci F. Zoccali C. Inflammation markers, adhesion molecules, and all-cause and cardiovascular mortality in patients with ESRD: searching for the best risk marker by multivariate modeling.J Am Soc Nephrol. 2005; 16: S83-S88Crossref PubMed Scopus (206) Google Scholar,18.Honda H. Qureshi A.R. Heimburger O. et al.Serum albumin, C-reactive protein, interleukin 6, and fetuin a as predictors of malnutrition, cardiovascular disease, and mortality in patients with ESRD.Am J Kidney Dis. 2006; 47: 139-148Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar plasma IL-6 levels have been shown to better predict death than IL-1β, TNF-α, CRP or albumin levels do. Hence, the aim of this study in a cohort of patients at different CKD stages (2 to 5D) was to verify the association between plasma IL-6 levels on one hand and mortality and two important cardiovascular surrogate markers (namely aortic calcification and stiffness) on the other. The distribution of IL-6 levels by CKD stage is depicted in Figure 1. The IL-6 levels tended to rise as CKD progressed with the increase becoming statistically significant at CKD stages 5 and 5D. Further examination confirmed an inverse linear relationship between IL-6 levels and the eGFR when the analysis was restricted to pre-dialysis CKD patients at stages 2–5, as shown in Figure 2.Figure 2Linear regression curve. Relationship between log-normalized plasma IL-6 levels and the estimated glomerular filtration rate, for pre-dialysis stage 2–5 CKD patients (n=82); r2=0.122; P=0.001.View Large Image Figure ViewerDownload (PPT) Tables 1 and 2 show the main characteristics of the study population, as a function of the median IL-6 plasma level. Patients with plasma IL-6 >2.97 pg/ml were significantly older, had lower diastolic blood pressure, were less likely to be treated with statins and angiotensin-converting enzyme (ACE)/angiotensin II type 1 receptor (ARA-2) inhibitors and were more likely to suffer from late-stage CKD (that is, 5 and 5D). These patients had higher CRP and triglyceride levels and significantly lower hemoglobin and albumin levels. They had higher pulse wave velocity (PWV) values and tended to have higher aortic calcification scores.Table 1Main demographic and clinical characteristics, as a function of the median plasma IL-6 levelsAll (n=125)IL-6 ≤2.97 pg/ml (n=63)IL-6 >2.97 pg/ml (n=62)P-valueAge (years)67±1265±1370±110.031Male gender n (%)77(62)37 (59)40 (64)0.506Body mass index (kg/m2)28±627±629±60.137SBP (mm Hg)154±26154±25153±280.833DBP (mm Hg)81±1283±1278±120.015Pulse pressure (mm Hg)73±2371±2375±230.305Diabetes n (%)52 (42)22 (35)30 (48)0.127Smoking habit n (%)an=121.48 (40)26 (41)22 (38)0.708Presence of CVD n (%)40 (32)18 (29)22 (35)0.407Framingham risk score8.0±3.67.8±3.68.3±3.50.397Current statin use n (%)75 (60)44 (70)31 (50)0.024Current ACE/ARA-2 inhibitor use n (%)74 (59)44 (70)30 (48)0.015CKD stage n (%)0.002 28 (6.4)7 (11.1)1 (1.6) 333 (26.4)23 (36.5)10 (16.1) 431 (24.8)16 (25.4)15 (24.2) 510 (8)3 (4.8)7 (11.3) 5D43 (34.4)14 (22.2)29 (46.8)Central venous access n (%)9 (7.2)7 (11.1)2 (3.2)0.164Abbreviations: ACE, angiotensin-converting enzyme; ARA-2, angiotensin II type 1 receptor; CKD, chronic kidney disease; CVD, cardiovascular disease; DBP, diastolic blood pressure; SBP, systolic blood pressure.Data are means±s.d. or number (frequency) for binary variables.a n=121. Open table in a new tab Table 2Main biochemical and vascular measurements as a function of the plasma IL-6 level (relative to the median).All (n=125)IL-6 ≤2.97 pg/ml (n=63)IL-6 >2.97 pg/ml (n=62)P-valueIL-6 (pg/ml)5.25±7.89 (2.97; 1.5–6.1)1.54±0.76 (1.6; 0.9–1.9)9.03±9.87 (6.1; 4.1–9.7)—Calcium (mmol/l)2.30±0.182.32±0.152.27±0.200.171Phosphate (mmol/l)1.29±0.451.23±0.361.34±0.520.198Intact-PTH (pg/ml)139±142 (81; 46–173)119±116 (71; 45–142)161±163 (119; 58–194)0.101Hemoglobin (g/l)12.0±1.712.4±1.411.5±1.80.003Albumin (g/l)37±639±635±5<0.0001C-reactive protein (mg/l)10.4±23.1 (3.5; 1.3–8.9)3.52±7.02 (1.5; 0.6–4.1)17.4±30.6 (7.4; 3.4–20.1)<0.0001TNF-α (pg/ml)3.99±1.92 (3.6; 2.2–5.1)3.80±1.79 (3.3; 2.2–5.1)4.2±2.04 (4.1; 2.5–5.1)0.193Total cholesterol (mmol/l)4.9±1.15.0±1.04.8±1.20.412HDL cholesterol (mmol/l)1.34±0.51.40±0.51.28±0.50.180Triglycerides (mmol/l)2.05±1.351.78±0.12.35±1.60.024Aortic calcification score (%)an=108.3.18±3.11 (2.2; 0.8–4.4)2.72±2.95 (1.5; 0.6–4.0)3.63±3.22 (2.6; 0.9–5.3)0.070PWV (m/s)15±414±316±40.007Abbreviations: HDL, high-density lipoprotein; PTH, parathyroid hormone; PWV, pulse wave velocity; TNF, tumor necrosis factor. Data are means±s.d. and (median; percentile 25–75) for variables with non-Gaussian distribution.a n=108. Open table in a new tab Abbreviations: ACE, angiotensin-converting enzyme; ARA-2, angiotensin II type 1 receptor; CKD, chronic kidney disease; CVD, cardiovascular disease; DBP, diastolic blood pressure; SBP, systolic blood pressure. Data are means±s.d. or number (frequency) for binary variables. Abbreviations: HDL, high-density lipoprotein; PTH, parathyroid hormone; PWV, pulse wave velocity; TNF, tumor necrosis factor. Data are means±s.d. and (median; percentile 25–75) for variables with non-Gaussian distribution. In univariate linear regression analyses, CRP (r2=0.435; P<0.0001), triglyceride (r2=0.042; β=0.156; P=0.024) and intact PTH levels (r2=0.035; P=0.039), and the CKD stage (r2=0.144; P<0.0001) were directly associated with higher plasma IL-6 levels. Conversely, albumin (r2=0.198; P<0.0001), hemoglobin (r2=0.084; P=0.001) and calcium levels (r2=0.034; P=0.041) and ongoing use of ACE/ARA-2 inhibitors (r2=0.064; P=0.005) and statins (r2=0.028; P=0.06) were inversely associated with plasma IL-6 levels. There was no significant linear correlation between plasma IL-6 levels and the aortic calcification score or the PWV. In a multivariate linear regression analysis, only CRP, albumin and the CKD stage were found to be independently associated with plasma IL-6 levels, as detailed in Table 3.Table 3Multivariate linear regression analysis—variables independently associated with plasma IL-6 levels (log-normalized)β (95% CI)P-valueCKD stage0.182 (0.085–0.279)<0.0001Albumin-0.038 (-0.060 to -0.016)0.001C-reactive protein (log-normalized)0.380 (0.288–0.473) 2.97 pg/ml). When restricting the analysis to stage 2–5 pre-dialysis CKD patients, plasma IL-6 levels remained a predictor of overall and cardiovascular mortality, in both crude analysis (log-rank P=0.009 and P=0.02, respectively) (Figure 4) and the Cox regression analysis (Table 5). An additional analysis confirmed plasma IL-6 as a better predictor of death than the three other acute inflammatory response markers assayed in the study (CRP, albumin and TNF-α), when either considering all patients (Table 6) or restricting the analysis to pre-dialysis CKD patients at stages 2–5 (data not shown).Table 4Univariate and multivariate Cox regression analysis of risk factors at baseline for all-cause mortalityModels of patient survival (event n=38)RR95% CIP-valueUnadjusted IL-6aIL-6 entered as categorical variable (IL-6 >2.97 pg/ml vs IL-6 ≤2.97 pg/ml; median).2.8371.406–5.7260.004 Log-normalized IL-6bIL-6 entered as continuous variable.1.748cSummarizing the risk of a 1-s.d. (1.025, that is, 2.787 pg/ml) increment in log-normalized IL-6.1.258–2.4310.001Model 1dModel 1: adjusted for age, hemoglobin, aortic calcification score, CKD stage. IL-6aIL-6 entered as categorical variable (IL-6 >2.97 pg/ml vs IL-6 ≤2.97 pg/ml; median).2.3521.035–5.3430.041 Log-normalized IL-6bIL-6 entered as continuous variable.1.670cSummarizing the risk of a 1-s.d. (1.025, that is, 2.787 pg/ml) increment in log-normalized IL-6.1.113–2.5040.013Abbreviations: CI, confidence interval; RR, risk ratio.a IL-6 entered as categorical variable (IL-6 >2.97 pg/ml vs IL-6 ≤2.97 pg/ml; median).b IL-6 entered as continuous variable.c Summarizing the risk of a 1-s.d. (1.025, that is, 2.787 pg/ml) increment in log-normalized IL-6.d Model 1: adjusted for age, hemoglobin, aortic calcification score, CKD stage. Open table in a new tab Figure 4Crude analysis of mortality in pre-dialysis patients. (a) Kaplan–Meyer estimates of overall mortality for patients at CKD stages 2–5 (n=82) as a function of median plasma IL-6 levels. (b) Kaplan–Meyer estimates of cardiovascular mortality for patients at CKD stages 2–5 (n=82) as a function of median plasma IL-6 levels.View Large Image Figure ViewerDownload (PPT)Table 5Univariate and multivariate Cox regression analysis of risk factors at baseline for all-cause mortality in pre-dialysis CKD patients stages 2–5 (n=82)Models of patient survival (event n=18)RR95% CIP-valueUnadjusted IL-6aIL-6 entered as categorical variable (IL-6 >2.42 pg/ml vs IL-6 ≤2.42 pg/ml; median).3.9451.298–11.9950.016 Log-normalized IL-6bIL-6 entered as a continuous variable.2.04cSummarizing the risk of a 1-s.d. (1.025, that is, 2.787 pg/ml) increment in log-normalized IL-6.1.187–3.5250.010Model 1dModel 1: adjusted for age and aortic calcification score. IL-6aIL-6 entered as categorical variable (IL-6 >2.42 pg/ml vs IL-6 ≤2.42 pg/ml; median).4.201.190–14.8290.026 Log-normalized IL-6bIL-6 entered as a continuous variable.2.118cSummarizing the risk of a 1-s.d. (1.025, that is, 2.787 pg/ml) increment in log-normalized IL-6.1.138–3.9420.018Abbreviations: CI, confidence interval; CKD, chronic kidney disease; RR, risk ratio.a IL-6 entered as categorical variable (IL-6 >2.42 pg/ml vs IL-6 ≤2.42 pg/ml; median).b IL-6 entered as a continuous variable.c Summarizing the risk of a 1-s.d. (1.025, that is, 2.787 pg/ml) increment in log-normalized IL-6.d Model 1: adjusted for age and aortic calcification score. Open table in a new tab Table 6Relative risk for albumin, CRP and IL-6 to mortality in a Cox proportional hazard (n=125)Hazard ratio (95% confidence interval)UnivariateP-valueMultivariateaAdjusted variables included age, CKD stage, and aortic calcification score in each biomarker model.P-valueAlbumin0.959 (0.912–1.009)0.1040.929 (0.874–0.986)0.016Log-normalized CRP1.245 (1.004–1.543)0.0461.194 (0.943–1.512)0.140Log-normalized TNF1.159 (0.546–2.459)0.7020.798 (0.355–1.791)0.584Log-normalized IL-61.725 (1.251–2.378)0.0011.700 (1.158–2.495)0.007Abbreviations: CKD, chronic kidney disease; CRP, C-reactive protein; TNF, tumor necrosis factor.a Adjusted variables included age, CKD stage, and aortic calcification score in each biomarker model. Open table in a new tab Abbreviations: CI, confidence interval; RR, risk ratio. Abbreviations: CI, confidence interval; CKD, chronic kidney disease; RR, risk ratio. Abbreviations: CKD, chronic kidney disease; CRP, C-reactive protein; TNF, tumor necrosis factor. In this study, we showed that plasma levels of IL-6 augment with CKD stage (particularly at CKD stages 5 and 5D). Importantly, plasma IL-6 levels predicted overall and cardiovascular mortality, even after adjusting for several covariates (that is, age, serum hemoglobin levels, aortic calcification score, and CKD stage) or restricting the analysis to the pre-dialysis CKD patients at stages 2–5. Lastly, plasma IL-6's power to predict mortality was greater than three other important biomarkers of inflammation assayed in the study cohort, namely CRP, TNF-α, and albumin. The pathological pathway underlying the chronic inflammation state associated with uremia is still poorly understood. Even though various dialysis-related factors (for example, poor dialyzer membrane biocompatibility, dialysate contamination, type of vascular access, etc.) may promote a persistent, low-grade inflammatory response, the present data showing augmented plasma IL-6 levels in earlier CKD stages suggest that the role of loss of kidney function or the kidney disease etiology are at least as important in modulating inflammation or inflammation mediators. It is possible that uremia activates inflammation and/or triggers a reduction in the renal clearance of pro-inflammatory cytokines. Moreover, advanced age and diabetic status (both of which are factors known to contribute to sustained inflammatory activity) were not associated with plasma IL-6 levels in the study population, which substantiates the effect of renal dysfunction. In a previous cross-sectional study including CKD stage 5 and 5D patients, individuals with stable angina and normal renal function and healthy controls, it was reported that serum creatinine was the sole independent determinant of plasma IL-6 levels.11.Bolton C.H. Downs L.G. Victory J.G. et al.Endothelial dysfunction in chronic renal failure: roles of lipoprotein oxidation and pro-inflammatory cytokines.Nephrol Dial Transplant. 2001; 16: 1189-1197Crossref PubMed Scopus (241) Google Scholar Conversely, and in contrast to our own findings, the only other study to have evaluated plasma IL-6 levels in patients at earlier CKD stages (3–5) found that this interleukin was significantly elevated in the CKD patients (compared with healthy controls), but that there was no association with the estimated glomerular filtration rate (GFR).12.Oberg B.P. McMenamin E. Lucas F.L. et al.Increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease.Kidney Int. 2004; 65: 1009-1016Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar This divergence most probably reflects the effects of the latter study's small sample size (n=60) and/or differences in the IL-6 assay and GFR estimation.12.Oberg B.P. McMenamin E. Lucas F.L. et al.Increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease.Kidney Int. 2004; 65: 1009-1016Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar The epidemiological association between plasma IL-6 levels and mortality has repeatedly been reported in different sub settings in both the general population19.Harris T.B. Ferrucci L. Tracy R.P. et al.Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly.Am J Med. 1999; 106: 506-512Abstract Full Text Full Text PDF PubMed Scopus (1205) Google Scholar,20.Ridker P.M. Rifai N. Stampfer M.J. et al.Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men.Circulation. 2000; 101: 1767-1772Crossref PubMed Scopus (1927) Google Scholar and hemodialysis patients.9.Panichi V. Rizza G.M. Paoletti S. et al.Chronic inflammation and mortality in haemodialysis: effect of different renal replacement therapies. Results from the RISCAVID study.Nephrol Dial Transplant. 2008; 23: 2337-2343Crossref PubMed Scopus (165) Google Scholar, 14.Rao M. Guo D. Perianayagam M.C. et al.Plasma interleukin-6 predicts cardiovascular mortality in hemodialysis patients.Am J Kidney Dis. 2005; 45: 324-333Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 18.Honda H. Qureshi A.R. Heimburger O. et al.Serum albumin, C-reactive protein, interleukin 6, and fetuin a as predictors of malnutrition, cardiovascular disease, and mortality in patients with ESRD.Am J Kidney Dis. 2006; 47: 139-148Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar, 21.Pecoits-Filho R. Barany P. Lindholm B. et al.Interleukin-6 is an independent predictor of mortality in patients starting dialysis treatment.Nephrol Dial Transplant. 2002; 17: 1684-1688Crossref PubMed Scopus (331) Google Scholar However, to the best of our knowledge, this is the first study to report such an association in a cohort including patients at earlier (pre-dialysis) CKD stages. In this respect, there is much evidence to suggest that pre-dialysis CKD patients are also at a greater risk of cardiovascular disease and the associated morbidity and mortality. Notably, most patients with CKD stages 3–5 will die of cardiovascular complications before developing end-stage renal disease.22.K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.Am J Kidney Dis. 2002; 39: S1-S266Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar Recent reports indicate that IL-6 might be involved in cardiovascular pathologies—perhaps even directly by affecting the atherosclerotic burden, as high plasma IL-6 levels have been related to the risk of coronary death and major coronary events in patients with unstable angina.23.Koukkunen H. Penttila K. Kemppainen A. et al.C-reactive protein, fibrinogen, interleukin-6 and tumour necrosis factor-alpha in the prognostic classification of unstable angina pectoris.Ann Med. 2001; 33: 37-47Crossref PubMed Scopus (163) Google Scholar,24.Wang J. Zhang S. Jin Y. et al.Elevated levels of platelet-monocyte aggregates and related circulating biomarkers in patients with acute coronary syndrome.Int J Cardiol. 2007; 115: 361-365Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar Furthermore, IL-6 mRNA has been detected in coronary plaque samples obtained from patients having undergone heart transplantation or atherectomy.25.Schieffer B. Schieffer E. Hilfiker-Kleiner D. et al.Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability.Circulation. 2000; 101: 1372-1378Crossref PubMed Scopus (578) Google Scholar Accordingly, in an experimental model of Apo-E-deficient mice, it has been shown that the injection of recombinant IL-6 accelerated atherosclerosis.26.Huber S.A. Sakkinen P. Conze D. et al.Interleukin-6 exacerbates early atherosclerosis in mice.Arterioscler Thromb Vasc Biol. 1999; 19: 2364-2367Crossref PubMed Scopus (423) Google Scholar This hypothesis is corroborated by the fact that higher plasma IL-6 levels predict the risk of future myocardial infarction among apparently healthy men20.Ridker P.M. Rifai N. Stampfer M.J. et al.Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men.Circulation. 2000; 101: 1767-1772Crossref PubMed Scopus (1927) Google Scholar and have been associated with severe congestive heart failure.25.Schieffer B. Schieffer E. Hilfiker-Kleiner D. et al.Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability.Circulation. 2000; 101: 1372-1378Crossref PubMed Scopus (578) Google Scholar,27.Torre-Amione G. Kapadia S. Benedict C. et al.Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD).J Am Coll Cardiol. 1996; 27: 1201-1206Abstract Full Text PDF PubMed Scopus (1018) Google Scholar In hemodialysis patients, a positive association has been reported between plasma IL-6 levels and carotid intima-media thickness but not the presence of carotid plaque.2.Kato A. Odamaki M. Takita T. et al.Association between interleukin-6 and carotid atherosclerosis in hemodialysis patients.Kidney Int. 2002; 61: 1143-1152Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar Furthermore, in a small peritoneal dialysis cohort, Stompor et al.28.Stompor T. Rajzer M. Sulowicz W. et al.An association between aortic pulse wave velocity, blood pressure and chronic inflammation in ESRD patients on peritoneal dialysis.Int J Artif Organs. 2003; 26: 188-195PubMed Google Scholar fou
Referência(s)