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

Abstract

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 (ρ=-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 (ρ=-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.

Keywords: CKD; endotoxin; inflammation; microbiome; soluble CD14.

Figure 1.

Plasma soluble CD14, endotoxin, and renal function. Distribution of plasma soluble CD14 (A) and endotoxin (B) levels as a function of eGFR. Between-group comparisons are Bonferroni-corrected.

Figure 2.

Kaplan–Meier showing death by tertiles of soluble CD14 concentration. Tertiles 1–3: 12, 17, and 24 deaths, respectively. Log-rank test, P=0.02.

Figure 3.

Kaplan–Meier curve of time to first cardiovascular event by tertiles of soluble CD14 concentration. Tertiles 1–3: 18, 29, and 31 cardiovascular events, respectively. Log-rank test, P=0.01.

Figure 4.

Kaplan–Meier renal survival curve by tertiles of soluble CD14 concentration. Tertiles 1–3: 23, 47, and 62 renal progressors, respectively. Log-rank test, P<0.001.