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Soluble CD14 and Endotoxin Levels in Hemodialysis Patients: A Tale of 2 Molecules

2009; Elsevier BV; Volume: 54; Issue: 6 Linguagem: Inglês

10.1053/j.ajkd.2009.09.003

1523-6838

Victor F. Seabra, George Thomas, Bertrand L. Jaber,

Renal function and acid-base balance

Related Articles, pp. 1062 and 1072 Related Articles, pp. 1062 and 1072 Despite the use of traditional approaches to treat cardiovascular disease, including diet modification, smoking cessation, blood pressure and diabetes control, and use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, statins, and antiplatelet agents, cardiovascular disease remains the leading cause of death in dialysis patients.1Levey A.S. Beto J.A. Coronado B.E. et al.Controlling the epidemic of cardiovascular disease in chronic renal disease: what do we know? What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease.Am J Kidney Dis. 1998; 32: 853-906Abstract Full Text PDF PubMed Scopus (841) Google Scholar This suggests an important role by other coexisting nontraditional risk factors that are associated with kidney failure and dialysis per se, including putative uremic toxins, endothelial dysfunction, hyperparathyroidism, vascular calcification, and inflammation.1Levey A.S. Beto J.A. Coronado B.E. et al.Controlling the epidemic of cardiovascular disease in chronic renal disease: what do we know? What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease.Am J Kidney Dis. 1998; 32: 853-906Abstract Full Text PDF PubMed Scopus (841) Google Scholar Of these nontraditional risk factors, inflammatory markers are associated strongly with cardiovascular mortality risk.2de Mutsert R. Grootendorst D.C. Axelsson J. Boeschoten E.W. Krediet R.T. Dekker F.W. Excess mortality due to interaction between protein-energy wasting, inflammation and cardiovascular disease in chronic dialysis patients.Nephrol Dial Transplant. 2008; 23: 2957-2964Crossref PubMed Scopus (139) Google Scholar, 3Honda 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 (425) Google Scholar, 4Rao M. Jaber B.L. Balakrishnan V.S. Inflammatory biomarkers and cardiovascular risk: association or cause and effect?.Semin Dial. 2006; 19: 129-135Crossref PubMed Scopus (38) Google Scholar There are several sources of inflammation in the dialysis population, including systemic disorders (eg, vasculitis, systemic lupus erythematosus, and systemic infections), uremia, bioincompatibility of the dialysis apparatus, and exposure to soluble bacterial products, such as endotoxin. Plasma endotoxin levels are increased in dialysis patients5Nisbeth U. Hallgren R. Eriksson O. Danielson B.G. Endotoxemia in chronic renal failure.Nephron. 1987; 45: 93-97Crossref PubMed Scopus (38) Google Scholar, 6Szeto C.C. Kwan B.C. Chow K.M. et al.Endotoxemia is related to systemic inflammation and atherosclerosis in peritoneal dialysis patients.Clin J Am Soc Nephrol. 2008; 3: 431-436Crossref PubMed Scopus (170) Google Scholar, 7Sun P.P. Perianayagam M.C. Jaber B.L. Sevelamer hydrochloride use and circulating endotoxin in hemodialysis patients: a pilot cross-sectional study.J Ren Nutr. 2009; 19: 432-438Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar and correlate with inflammatory marker levels and atherosclerosis in both the general population8Wiedermann C.J. Kiechl S. Dunzendorfer S. et al.Association of endotoxemia with carotid atherosclerosis and cardiovascular disease: prospective results from the Bruneck Study.J Am Coll Cardiol. 1999; 34: 1975-1981Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar and dialysis patients.6Szeto C.C. Kwan B.C. Chow K.M. et al.Endotoxemia is related to systemic inflammation and atherosclerosis in peritoneal dialysis patients.Clin J Am Soc Nephrol. 2008; 3: 431-436Crossref PubMed Scopus (170) Google Scholar Likely factors contributing to increased blood endotoxin levels in dialysis patients include contaminated dialysate,9Panichi V. Tetta C. Rindi P. Palla R. Lonnemann G. Plasma C-reactive protein is linked to backfiltration associated interleukin-6 production.ASAIO J. 1998; 44: M415-M417Crossref PubMed Scopus (47) Google Scholar, 10Hosoya N. Sakai K. Backdiffusion rather than backfiltration enhances endotoxin transport through highly permeable dialysis membranes.ASAIO Trans. 1990; 36: M311-M313PubMed Google Scholar intestinal bacterial translocation associated with uremia-induced impaired mucosal barrier,11Magnusson M. Magnusson K.E. Sundqvist T. Denneberg T. Impaired intestinal barrier function measured by differently sized polyethylene glycols in patients with chronic renal failure.Gut. 1991; 32: 754-759Crossref PubMed Scopus (116) Google Scholar, 12de Almeida Duarte J.B. de Aguilar-Nascimento J.E. Nascimento M. Nochi Jr, R.J. Bacterial translocation in experimental uremia.Urol Res. 2004; 32: 266-270Crossref PubMed Scopus (65) Google Scholar recurrent bacterial infections, and reduced elimination caused by impaired liver macrophage function.5Nisbeth U. Hallgren R. Eriksson O. Danielson B.G. Endotoxemia in chronic renal failure.Nephron. 1987; 45: 93-97Crossref PubMed Scopus (38) Google Scholar Although several bacterial toxins can induce host inflammatory responses, lipopolysaccharide or endotoxin is considered the most powerful and best-studied molecule.13Heumann D. Roger T. Initial responses to endotoxins and Gram-negative bacteria.Clin Chim Acta. 2002; 323: 59-72Crossref PubMed Scopus (284) Google Scholar In blood, lipopolysaccharide-binding protein, a lipid transfer molecule, forms a complex with endotoxin, which is transferred to membrane-bound CD14 (mCD14) present on monocytes, soluble CD14 (sCD14) present in blood and body fluids, or high-density lipoprotein (HDL) present in blood. This process results in either cell activation through mCD14 or neutralization of endotoxin through HDL.13Heumann D. Roger T. Initial responses to endotoxins and Gram-negative bacteria.Clin Chim Acta. 2002; 323: 59-72Crossref PubMed Scopus (284) Google Scholar sCD14, which is produced primarily through cleavage of mCD14, might either facilitate delivery of lipopolysaccharide to cells that do not express mCD14 or inactivate endotoxin by shuttling the molecule to HDL or antagonize mCD14-positive cell activation by competing with mCD14 binding (Fig 1).13Heumann D. Roger T. Initial responses to endotoxins and Gram-negative bacteria.Clin Chim Acta. 2002; 323: 59-72Crossref PubMed Scopus (284) Google Scholar However, this suppressive effect requires sCD14 concentrations that are much higher (∼70 μg/mL) than those normally present in blood.14Haziot A. Rong G.W. Bazil V. Silver J. Goyert S.M. Recombinant soluble CD14 inhibits LPS-induced tumor necrosis factor-alpha production by cells in whole blood.J Immunol. 1994; 152: 5868-5876PubMed Google Scholar In the hemodialysis population, sCD14 levels are increased compared with healthy volunteers and increase further after a dialysis session, possibly because of exposure to trace amounts of endotoxin.15Nockher W.A. Scherberich J.E. Monocyte cell-surface CD14 expression and soluble CD14 antigen in hemodialysis: evidence for chronic exposure to LPS.Kidney Int. 1995; 48: 1469-1476Crossref PubMed Scopus (57) Google Scholar, 16Mitzner S. Stange J. Pichel K. et al.Increased soluble CD14 levels in patients on hemodialysis Influence of dialysate endotoxin or incompatibility to dialyzer membranes?.ASAIO J. 1995; 41: M707-M708Crossref PubMed Scopus (6) Google Scholar In this issue of the American Journal of Kidney Diseases, 2 prospective cohort studies explore the relationship of circulating endotoxin and sCD14 levels to adverse clinical outcomes in prevalent patients undergoing maintenance hemodialysis.17Raj D.S.C. Carrero J.J. Shah V.O. et al.Soluble CD14 levels, interleukin-6 and mortality among prevalent hemodialysis patients.Am J Kidney Dis. 2009; 54: 1072-1080Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 18Raj D.S.C. Shah V.O. Rambod M. Kovesdy C.P. Kalantar-Zadeh K. Association of soluble endotoxin receptor CD14 and mortality among patients undergoing hemodialysis.Am J Kidney Dis. 2009; 54: 1062-1071Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Selected characteristics of the 2 studies are listed in Table 1. The studies were conducted in Sweden and the United States, with 211 and 310 patients analyzed, respectively. Follow-up was close to 2.5 years in both studies. Mean time on dialysis therapy was 50 months in the US study and 29 months in the Swedish study. Dialyzer reuse practices were allowed in only the US cohort. The US cohort was 10 years younger (55 vs 65 years), and interestingly, despite a higher percentage of diabetic patients (57% vs 23%), experienced a lower annual mortality rate than the Swedish cohort (∼10% vs 14%). Nevertheless, both studies showed lower annual mortality rates compared with previously published reports for dialysis patients in the United States (24%) and Sweden (25%).19US Renal Data SystemUSRDS 2008 Annual Data Report.http://www.usrds.org/Google Scholar, 20Yoshino M. Kuhlmann M.K. Kotanko P. et al.International differences in dialysis mortality reflect background general population atherosclerotic cardiovascular mortality.J Am Soc Nephrol. 2006; 17: 3510-3519Crossref PubMed Scopus (115) Google ScholarTable 1Selected Study CharacteristicsSwedish Study17Raj D.S.C. Carrero J.J. Shah V.O. et al.Soluble CD14 levels, interleukin-6 and mortality among prevalent hemodialysis patients.Am J Kidney Dis. 2009; 54: 1072-1080Abstract Full Text Full Text PDF PubMed Scopus (72) Google ScholarAmerican Study18Raj D.S.C. Shah V.O. Rambod M. Kovesdy C.P. Kalantar-Zadeh K. Association of soluble endotoxin receptor CD14 and mortality among patients undergoing hemodialysis.Am J Kidney Dis. 2009; 54: 1062-1071Abstract Full Text Full Text PDF PubMed Scopus (50) Google ScholarStudy period2003-20072004-2006Study designProspective cohortProspective cohortNo. of participating dialysis centers58No. of participants enrolled247310No. of participants analyzed211310Mean time on dialysis (mo)2950Mean age (y)6555Men (%)5652Presence of diabetes mellitus (%)2357Dialyzer type (%)Polyamide (59), polysulfone (35), other (6)Not reportedDialyzer reuse practiceNot allowedAllowedMean single-pool Kt/VNot reported1.7Mean serum albumin (g/dL)3.54.0Median sCD14 (3rd tertile lower limit) (μg/mL)3.2 (>3.6)6.8 (>7.8)Median endotoxin (EU/mL)0.65Not measuredAll-cause mortality (%)3723sCD14 hazard ratio for mortality (3rd vs 1st tertile) Unadjusted (95% CI)1.94 (1.13-3.32)2.59 (1.39-4.83) Adjusted (95% CI)3.11 (1.49-6.46)1.94 (1.01-3.75)Note: Conversion factors for units: albumin in g/dL to g/L, ×10.Abbreviations: CI, confidence interval; sCD14, soluble CD14. Open table in a new tab Note: Conversion factors for units: albumin in g/dL to g/L, ×10. Abbreviations: CI, confidence interval; sCD14, soluble CD14. sCD14 levels were higher in women and current smokers.17Raj D.S.C. Carrero J.J. Shah V.O. et al.Soluble CD14 levels, interleukin-6 and mortality among prevalent hemodialysis patients.Am J Kidney Dis. 2009; 54: 1072-1080Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar Patients on treatment with statins, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β-blockers, or acetylsalicylic acid derivates had significantly lower sCD14 levels.17Raj D.S.C. Carrero J.J. Shah V.O. et al.Soluble CD14 levels, interleukin-6 and mortality among prevalent hemodialysis patients.Am J Kidney Dis. 2009; 54: 1072-1080Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar Both studies showed that sCD14 levels not only strongly correlated with levels of other inflammatory markers, such as interleukin 6 and C-reactive protein, but also independently predicted mortality. The highest sCD14 tertile was associated with an increased risk of all-cause death (hazard ratios, 1.94-2.59), which persisted after adjustment for several clinical and laboratory variables, as well as inflammatory markers (hazard ratios, 1.94-3.11). One shortcoming of the US study is that endotoxin was not measured. However, the Swedish study performed these measurements, showing that endotoxin levels strongly predict sCD14 levels.17Raj D.S.C. Carrero J.J. Shah V.O. et al.Soluble CD14 levels, interleukin-6 and mortality among prevalent hemodialysis patients.Am J Kidney Dis. 2009; 54: 1072-1080Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar However, there was no association between endotoxin level and mortality. Although sCD14 levels are increased in dialysis patients,15Nockher W.A. Scherberich J.E. Monocyte cell-surface CD14 expression and soluble CD14 antigen in hemodialysis: evidence for chronic exposure to LPS.Kidney Int. 1995; 48: 1469-1476Crossref PubMed Scopus (57) Google Scholar these are the first 2 studies that link this marker to mortality in this patient population. However, limitations of the 2 studies include the relatively small sample size, selection biases with the inclusion of younger patients in 1 report, single measurements of the markers that are subject to variation over time, and lack of analyses of cause-specific mortality, including cardiovascular and infectious mortality. Additional details for dialyzer reuse practices in the US cohort might have provided insight into the influence of reuse germicides, number of dialyzer reuses, and flux properties on sCD14 levels. The pathophysiologic role of endotoxemia and sCD14 in dialysis patients is speculative. Although sCD14 might be a footprint for the exposure of monocytes to endotoxin, other bacterial components interact with the CD14 ligand, including Gram-positive bacterial peptidoglycans and lipoteichoic acid.13Heumann D. Roger T. Initial responses to endotoxins and Gram-negative bacteria.Clin Chim Acta. 2002; 323: 59-72Crossref PubMed Scopus (284) Google Scholar Because systemic infections caused by Gram-positive cocci, such as Staphylococcus species, are more salient in dialysis patients, one is mindful of whether increased sCD14 levels might reflect recurrent Gram-positive bacterial infections. Analysis of the relationship of sCD14 levels with vascular access type and history of access-related infections might have shed some light on this hypothesis. The profile of the 2 study populations precludes generalization to incident dialysis patients who might have a different “inflammatory profile” because of shorter exposure to bacterial endotoxin from dialysis and vascular access-related infections. This also would be true for patients with chronic kidney disease who are not yet on dialysis therapy. In conclusion, the 2 reports provided in this issue of the American Journal of Kidney Diseases show in 2 separate cohorts that sCD14 levels correlate positively with levels of several inflammatory markers and independently predict mortality in patients on maintenance hemodialysis therapy. A pooled analysis of the 2 studies might provide greater insight. Although the authors highlight the role of sCD14 in dialysis patients and one might argue for including this marker for risk stratification in clinical trials aimed at reducing endotoxin exposure, the role of sCD14 in the host inflammatory cascade remains to be elucidated. Financial Disclosure: None Association of Soluble Endotoxin Receptor CD14 and Mortality Among Patients Undergoing HemodialysisAmerican Journal of Kidney DiseasesVol. 54Issue 6PreviewCD14 is a key molecule in innate immunity that mediates cell activation and signaling in response to endotoxin and other bacterial wall-derived components. CD14 protein exists in soluble (sCD14) and membrane-bound forms. The correlates of sCD14 in persons undergoing long-term hemodialysis (HD) therapy are not known. We hypothesized that increased sCD14 levels in HD patients are associated with proinflammatory cytokine activation and increased mortality. Full-Text PDF Soluble CD14 Levels, Interleukin 6, and Mortality Among Prevalent Hemodialysis PatientsAmerican Journal of Kidney DiseasesVol. 54Issue 6PreviewCD14 is a pattern-recognition receptor that has a central immunomodulatory role in proinflammatory signaling in response to a variety of ligands, including endotoxin. CD14 protein is present in 2 forms: soluble (sCD14) and membrane bound. Here, we studied the implications of increased sCD14 levels in hemodialysis patients. We hypothesized that sCD14 level increase may link to cytokine activation and protein-energy wasting, predisposing to increased mortality risk. Full-Text PDF