American Journal of Kidney Diseases
Volume 54, Issue 6 , Pages 990-992, December 2009

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

  • Victor F. Seabra, MD

      Affiliations

    • St Elizabeth's Medical Center, Boston, Massachusetts
    • ,
  • George Thomas, MD, MPH

      Affiliations

    • The Cleveland Clinic, Cleveland, Ohio
    • ,
  • Bertrand L. Jaber, MD, MS

      Affiliations

    • St Elizabeth's Medical Center, Boston, Massachusetts
    • Corresponding Author InformationAddress correspondence to Bertrand L. Jaber, MD, MS, Department of Medicine, St Elizabeth's Medical Center, 736 Cambridge St, Boston, MA 02135

Article Outline

 

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.1 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.1 Of these nontraditional risk factors, inflammatory markers are associated strongly with cardiovascular mortality risk.2, 3, 4

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 patients5, 6, 7 and correlate with inflammatory marker levels and atherosclerosis in both the general population8 and dialysis patients.6 Likely factors contributing to increased blood endotoxin levels in dialysis patients include contaminated dialysate,9, 10 intestinal bacterial translocation associated with uremia-induced impaired mucosal barrier,11, 12 recurrent bacterial infections, and reduced elimination caused by impaired liver macrophage function.5

Although several bacterial toxins can induce host inflammatory responses, lipopolysaccharide or endotoxin is considered the most powerful and best-studied molecule.13 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.13 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).13 However, this suppressive effect requires sCD14 concentrations that are much higher (∼70 μg/mL) than those normally present in blood.14 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.15, 16

  • View full-size image.
  • Figure 1. 

    Simplified scheme summarizing interactions of lipopolysaccharide (LPS) with membrane-bound (mCD14) and soluble CD14 (sCD14). Abbreviations: HDL, high-density lipoprotein; LBP, LPS-binding protein.

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.17, 18 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%).19, 20

Table 1. Selected Study Characteristics
Swedish Study17American Study18
Study period2003-20072004-2006
Study designProspective cohortProspective cohort
No. of participating dialysis centers58
No. of participants enrolled247310
No. of participants analyzed211310
Mean time on dialysis (mo)2950
Mean age (y)6555
Men (%)5652
Presence of diabetes mellitus (%)2357
Dialyzer type (%)Polyamide (59), polysulfone (35), other (6)Not reported
Dialyzer reuse practiceNot allowedAllowed
Mean single-pool Kt/VNot reported1.7
Mean serum albumin (g/dL)3.54.0
Median sCD14 (3rd tertile lower limit) (μg/mL)3.2(>3.6)6.8(>7.8)
Median endotoxin (EU/mL)0.65Not measured
All-cause mortality (%)3723
sCD14 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.

sCD14 levels were higher in women and current smokers.17 Patients on treatment with statins, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β-blockers, or acetylsalicylic acid derivates had significantly lower sCD14 levels.17 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.17 However, there was no association between endotoxin level and mortality.

Although sCD14 levels are increased in dialysis patients,15 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.13 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.

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Acknowledgements 

Financial Disclosure: None

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References 

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PII: S0272-6386(09)01185-8

doi:10.1053/j.ajkd.2009.09.003

Refers to article:

  • Association of Soluble Endotoxin Receptor CD14 and Mortality Among Patients Undergoing Hemodialysis , 21 August 2009

    Dominic S.C. Raj, Vallabh O. Shah, Mehdi Rambod, Csaba P. Kovesdy, Kamyar Kalantar-Zadeh
    American Journal of Kidney Diseases December 2009 (Vol. 54, Issue 6, Pages 1062-1071)

  • Soluble CD14 Levels, Interleukin 6, and Mortality Among Prevalent Hemodialysis Patients , 07 September 2009

    Dominic S.C. Raj, Juan J. Carrero, Vallabh O. Shah, Abdul R. Qureshi, Peter Bárány, Olof Heimbürger, Bengt Lindholm, Jennet Ferguson, Pope L. Moseley, Peter Stenvinkel
    American Journal of Kidney Diseases December 2009 (Vol. 54, Issue 6, Pages 1072-1080)

American Journal of Kidney Diseases
Volume 54, Issue 6 , Pages 990-992, December 2009

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