Original Investigation
Dialysis
Association of Soluble Endotoxin Receptor CD14 and Mortality Among Patients Undergoing Hemodialysis

https://doi.org/10.1053/j.ajkd.2009.06.028Get rights and content

Background

CD14 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.

Study Design

Cohort study.

Setting & Participants

310 long-term HD patients who participated in the Nutritional and Inflammatory Evaluation in Dialysis (NIED) Study, a cohort derived from a pool of more than 3,000 HD outpatients during 5 years in 8 DaVita maintenance dialysis facilities in the South Bay Los Angeles, CA, area.

Predictors

sCD14 levels in serum.

Outcomes

33-month mortality.

Results

Mean sCD14 level was 7.24 ± 2.45 μg/mL. Tumor necrosis factor α level was the strongest correlate of sCD14 level (r = +0.24; P < 0.001), followed by interleukin 6 level (r = +0.18; P = 0.002), serum ferritin level (r = +0.21; P < 0.001), total iron-binding capacity (r = −0.19; P < 0.001), body mass index (r = −0.15; P = 0.008), vintage (r = +0.14; P = 0.01), low-density lipoprotein cholesterol level (r = +0.13; P = 0.03), and body fat (r = −0.11; P = 0.06). During the 33-month follow-up, 71 (23%) patients died. Multivariable Cox proportional analysis adjusted for case-mix and other nutritional and inflammatory confounders, including serum tumor necrosis factor α, C-reactive protein, and interleukin 6 levels, showed that compared with the lowest sCD14 tertile, sCD14 levels in the third tertile (>7.8 μg/mL) were associated with greater death risk (hazard ratio, 1.94; 95% confidence interval, 1.01 to 3.75; P = 0.04).

Limitations

Survivor bias in combined incident/prevalent studies.

Conclusions

Increased sCD14 level is related positively to markers of inflammation and negatively to nutritional status and is an independent predictor of mortality in long-term HD patients. Additional studies are needed to examine the usefulness of sCD14 level in risk stratification and the clinical decision-making process in HD patients.

Section snippets

Patient Population

We studied long-term HD patients who participated in the Nutritional and Inflammatory Evaluation in Dialysis (NIED) Study.12 The original patient cohort was derived from a pool of more than 3,000 HD outpatients during 5 years in 8 DaVita maintenance dialysis facilities in the South Bay Los Angeles, CA, area (see the NIED Study website at www.NIEDStudy.org for more details, as well as previous publications13, 14, 15). Inclusion criteria were outpatients who had been undergoing HD treatment for

Results

The 310 participants in the study were 55.1 ± 14.7 years old and included 48% women, 52% Hispanics, 30% African Americans, and 57% patients with diabetes. Mean dialysis vintage was 50 ± 35 months (median, 45 months; quartile [Q] 1 to Q3, range, 25 to 68). Mean sCD14 level was 7.24 ± 2.45 μg/ml. Table 1 lists relevant demographic, clinical, and laboratory measures across tertiles of sCD14. Age, dialysis vintage, and levels of serum alkaline phosphatase, ferritin, homocysteine, and the 3

Discussion

In this cohort of 310 long-term HD outpatients in Southern California, we found that greater circulating sCD14 level is associated with greater 33-month death risk. The increasing trend of mortality associated with greater sCD14 levels was robust to controlling for case-mix and other nutritional and inflammatory measures, including serum IL-6 and TNF-α levels. Maintenance HD patients in the third tertile of sCD14 levels had an almost-2 fold increased death risk (HR, 1.94) after adjustment for

Acknowledgements

The authors thank Ms Stephanie Griffith and Dr Victor Goh at Harbor-UCLA GCRC Core Laboratories for the management of blood samples and measurement of inflammatory markers; the hard-working collaborating dietitians in 10 DaVita dialysis facilities in Los Angeles South Bay area; and DaVita teammates in these facilities.

Some data were presented during the Spring Clinical Meeting of the National Kidney Foundation in March 25-29, 2009 in Nashville, TN.

Support: This study was supported by National

References (41)

  • S. Beddhu et al.

    A simple comorbidity scale predicts clinical outcomes and costs in dialysis patients

    Am J Med

    (2000)
  • E.E. Nelson et al.

    Anthropometric norms for the dialysis population

    Am J Kidney Dis

    (1990)
  • A.J. Williams et al.

    Body composition, treatment time, and outcome in hemodialysis patients

    J Ren Nutr

    (1999)
  • R.M. Raymond

    Skeletal muscle metabolism and insulin resistance during endotoxin shock in the dog

    Am J Emerg Med

    (1984)
  • S.D. Anker et al.

    Elevated soluble CD14 receptors and altered cytokines in chronic heart failure

    Am J Cardiol

    (1997)
  • G.H. Heine et al.

    CD14(++)CD16+ monocytes but not total monocyte numbers predict cardiovascular events in dialysis patients

    Kidney Int

    (2008)
  • K. Kalantar-Zadeh et al.

    Reverse epidemiology of cardiovascular risk factors in maintenance dialysis patients

    Kidney Int

    (2003)
  • K. Kalantar-Zadeh et al.

    Association of morbid obesity and weight change over time with cardiovascular survival in hemodialysis population

    Am J Kidney Dis

    (2005)
  • C.C. Szeto et al.

    Endotoxemia is related to systemic inflammation and atherosclerosis in peritoneal dialysis patients

    Clin J Am Soc Nephrol

    (2008)
  • S. Yamagami et al.

    Detection of endotoxin antibody in long-term dialysis patients

    Int J Artif Organs

    (1990)
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    Originally published online as doi:10.1053/j.ajkd.2009.06.028 on August 21, 2009.

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