Plasma Levels of Soluble CD14 Independently Predict Mortality in HIV Infection

Sandler, Netanya G.; Wand, Handan; Roque, Annelys; Law, Matthew; Nason, Martha; Nixon, Daniel E.; Pedersen, Court; Ruxrungtham, Kiat; Lewin, Sharon R.; Emery, Sean; Neaton, James D.; Brenchley, Jason M.; Deeks, Steven G.; Sereti, Irini; Douek, Daniel C.

doi:10.1093/infdis/jiq118

Cited by 945 publications

(978 citation statements)

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“…Although plasma levels of sCD14 have been linked to exposure to endotoxin (13,21), we did not observe a correlation between endotoxin and sCD14 levels. Furthermore, plasma sCD14, but not endotoxin levels, was predictive of adverse outcomes in our cohort, a finding also noted in previous studies (14,25). This does not, however, preclude a pathophysiologic role of endotoxemia in CKD as previously explained.…”

Section: Discussionsupporting

confidence: 88%

“…In this study, we did not observe a significant association between plasma sCD14 and endotoxin levels. Other investigators have also reported lack of association between endotoxin and sCD14 (25). Interestingly, we noted higher levels of endotoxin in patients with eGFR.60 ml/min per 1.73 m 2 .…”

Section: Discussionsupporting

confidence: 46%

“…Investigators have reported that higher levels of plasma sCD14 are associated with increased mortality in patients with HIV infection (25) and those with gram-negative sepsis (35). We also explored the relationship between sCD14 and CV events, again demonstrating the prognostic role of sCD14 with respect to CVD in CKD.…”

Section: Discussionmentioning

confidence: 95%

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Associations of Soluble CD14 and Endotoxin with Mortality, Cardiovascular Disease, and Progression of Kidney Disease among Patients with CKD

Poesen

Ramezani

Claes

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives CD14 plays a key role in the innate immunity as pattern-recognition receptor of endotoxin. Higher levels of soluble CD14 (sCD14) are associated with overall mortality in hemodialysis patients. The influence of kidney function on plasma sCD14 levels and its relationship with adverse outcomes in patients with CKD not yet on dialysis is unknown. This study examines the associations between plasma levels of sCD14 and endotoxin with adverse outcomes in patients with CKD.Design, setting, participants, & measurements We measured plasma levels of sCD14 and endotoxin in 495 Leuven Mild-to-Moderate CKD Study participants. Mild-to-moderate CKD was defined as presence of kidney damage or eGFR,60 ml/min per 1.73 m 2 for $3 months, with exclusion of patients on RRT. Study participants were enrolled between November 2005 and September 2006.Results Plasma sCD14 was negatively associated with eGFR (r=-0.34, P,0.001). During a median follow-up of 54 (interquartile range, 23-58) months, 53 patients died. Plasma sCD14 was predictive of mortality, even after adjustment for renal function, Framingham risk factors, markers of mineral bone metabolism, and nutritional and inflammatory parameters (hazard ratio [HR] per SD higher of 1.90; 95% confidence interval [95% CI],1.32 to 2.74; P,0.001). After adjustment for the same risk factors, plasma sCD14 was also a predictor of cardiovascular disease (HR, 1.30; 95% CI, 1.00 to 1.69; P=0.05). Although plasma sCD14 was associated with progression of CKD, defined as reaching ESRD or doubling of serum creatinine in models adjusted for CKD-specific risk factors (HR, 1.24; 95% CI, 1.01 to 1.52; P=0.04), significance was lost when adjusted for proteinuria (HR, 1.19; 95% CI, 0.96 to 1.48; P=0.11). There was neither correlation between plasma endotoxin and sCD14 (r=-0.06, P=0.20) nor was endotoxin independently associated with adverse outcome during follow-up.Conclusions Plasma sCD14 is elevated in patients with decreased kidney function and associated with mortality and cardiovascular disease in patients with CKD not yet on dialysis.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 46%

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Associations of Soluble CD14 and Endotoxin with Mortality, Cardiovascular Disease, and Progression of Kidney Disease among Patients with CKD

Poesen

Ramezani

Claes

et al. 2015

Clinical Journal of the American Society of Nephrology

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“…Recently, plasma levels of intestinal fatty acid binding protein (I-FABP), a marker of enterocyte damage (36), have also been used to correlate intestinal impairment and microbial translocation (37,38). Table 1 summarizes the characteristics of the principal microbial translocation markers measured in plasma/serum of HIV-infected patients.…”

Section: Measurement Of Microbial Translocationmentioning

confidence: 99%

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

2013

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SUMMARYIn pathogenic simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) infections, the translocation of microbial products from the gastrointestinal (GI) tract to portal and systemic circulation has been proposed as a major driver of the chronic immune activation that is associated with disease progression. Consistently, microbial translocation is not present in nonpathogenic SIV infections of natural host species.In vivostudies demonstrated that HIV/SIV-associated microbial translocation results from a series of immunopathological events occurring at the GI mucosa: (i) early and severe mucosal CD4+depletion, (ii) mucosal immune hyperactivation/persistent inflammation; (iii) damage to the integrity of the intestinal epithelium with enterocyte apoptosis and tight junction disruption; and (iv) subverted the gut microbiome, with a predominance of opportunistic bacteria. Directin situevidence of microbial translocation has been provided for SIV-infected rhesus macaques showing translocated microbial products in the intestinal lamina propria and distant sites. While the mechanisms by which microbial translocation causes immune activation remain controversial, a key pathogenic event appears to be innate immunity activation via Toll-like receptors and other pathogen recognition receptors. Accumulating clinical observations suggest that microbial translocation might affect HIV disease progression, response to therapy, and non-AIDS comorbidities. Given its detrimental effect on overall immunity, several interventions to prevent/block microbial translocation are currently under investigation as novel therapeutic agents for HIV/AIDS.

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“…Bacterial translocation from the GI tract to the peripheral circulation has been extensively studied in HIV infection, but is also common in liver disease and other conditions (24)(25)(26)(27). Translocation occurs early in HIV infection due to depletion of gut CD41 lymphocytes and is not completely eradicated by ART, particularly in patients with a suboptimal CD4 cell count or HIV viral level responses (25,28).…”

Section: Bacteria and The Gi Tractmentioning

confidence: 99%

Heart–Lung Interaction via Infection

Morris

2014

Annals ATS

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Lung and cardiovascular disease are increasingly recognized to occur in the same patient populations. Infections, either through stimulation of inflammation or through direct infection, can lead to end-organ damage and have been postulated as a potential link between lung and cardiovascular diseases. Mechanisms by which infections may link lung and cardiac diseases include effects of systemic infections, microbial translocation of pathogens from the gastrointestinal tract or other sites, damaging effects of metabolic products, or influences of smoking on the microbiome.Other mechanisms, such as alterations in the local microbiome, environmental exposures, or immune regulation by microbial communities, may be important. These relationships are likely quite complex, with multiple routes between infection and disease possible. A better understanding of the links of infection to lung and heart disease can improve our understanding of the pathogenesis of these disorders and uncover novel therapeutic approaches.Keywords: microbial translocation; metabolomics; pulmonary function; cardiovascular; HIV Correspondence and requests for reprints should be addressed to Alison Morris, M.D., M.S.,

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Plasma Levels of Soluble CD14 Independently Predict Mortality in HIV Infection

Abstract: sCD14, a marker of monocyte response to LPS, is an independent predictor of mortality in HIV infection. Therapeutic attenuation of innate immune activation may improve survival in patients with HIV infection.

Cited by 945 publications

References 49 publications

Associations of Soluble CD14 and Endotoxin with Mortality, Cardiovascular Disease, and Progression of Kidney Disease among Patients with CKD

Associations of Soluble CD14 and Endotoxin with Mortality, Cardiovascular Disease, and Progression of Kidney Disease among Patients with CKD

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

Heart–Lung Interaction via Infection

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