Inflammation and Progression of CKD: The CRIC Study

Abstract

Background and objectives: CKD is a global public health problem with significant mortality and morbidity.

Design, setting, participants, & measurements: We examined the multivariable association of plasma levels of IL-1, IL-1 receptor antagonist, IL-6, TNF-α, TGF-β, high-sensitivity C-reactive protein, fibrinogen, and serum albumin with progression of CKD in 3430 Chronic Renal Insufficiency Cohort study participants.

Results: Over a median follow-up time of 6.3 years, 899 participants reached the composite end point of ≥50% decline in eGFR from baseline or onset of ESRD. Elevated plasma levels of fibrinogen, IL-6, and TNF-α and lower serum albumin were associated with a greater decline in eGFR over time. After adjusting for demographics, BP, laboratory variables, medication use, and baseline eGFR, hazard ratios for the composite outcome were greater for the patients in the highest quartile of fibrinogen (hazard ratio, 2.05; 95% confidence interval, 1.64 to 2.55; P<0.001), IL-6 (hazard ratio, 1.44; 95% confidence interval, 1.17 to 1.77; P<0.01), and TNF-α (hazard ratio, 1.94; 95% confidence interval, 1.52 to 2.47; P<0.001) compared with those in the respective lowest quartiles. The hazard ratio was 3.48 (95% confidence interval, 2.88 to 4.21; P<0.001) for patients in the lowest serum albumin quartile relative to those in the highest quartile. When also adjusted for albuminuria, the associations of fibrinogen (hazard ratio, 1.49; 95% confidence interval, 1.20 to 1.86; P<0.001), serum albumin (hazard ratio, 1.52; 95% confidence interval, 1.24 to 1.87; P<0.001), and TNF-α (hazard ratio, 1.42; 95% confidence interval, 1.11 to 1.81; P<0.001) with outcome were attenuated but remained significant.

Conclusions: Elevated plasma levels of fibrinogen and TNF-α and decreased serum albumin are associated with rapid loss of kidney function in patients with CKD.

Keywords: C-Reactive Protein; Follow-Up Studies; Humans; Inflammation; Interleukin-6; Renal Insufficiency, Chronic; Tumor Necrosis Factor-alpha; albuminuria; chronic kidney disease; cytokines; end-stage renal disease; glomerular filtration rate.

Figure 1.

Kaplan–Meier survival estimates for the composite outcome stratified by baseline biomarker quartile (log rank chi–squared P value). (A) High–sensitivity C–reactive protein (CRP) and composite outcome (P=0.42). (B) Fibrinogen and composite outcome (P<0.001). (C) IL-1β and composite outcome (P<0.001). (D) IL-1 receptor antagonist (IL-1RA) and composite outcome (P=0.001). (E) IL-6 and composite outcome (P<0.001). (F) TNF-α and composite outcome (P<0.001). (G) TGF-β and composite outcome (P=0.06). (H) Serum albumin and composite outcome (P<0.001). Q, quartile.

Figure 1.

Kaplan–Meier survival estimates for the composite outcome stratified by baseline biomarker quartile (log rank chi–squared P value). (A) High–sensitivity C–reactive protein (CRP) and composite outcome (P=0.42). (B) Fibrinogen and composite outcome (P<0.001). (C) IL-1β and composite outcome (P<0.001). (D) IL-1 receptor antagonist (IL-1RA) and composite outcome (P=0.001). (E) IL-6 and composite outcome (P<0.001). (F) TNF-α and composite outcome (P<0.001). (G) TGF-β and composite outcome (P=0.06). (H) Serum albumin and composite outcome (P<0.001). Q, quartile.

Figure 2.

Moderators of Cox hazard ratio (HR) for the composite outcome for baseline cytokine levels. Cytokines are coded as continuous variables. Natural log is used for IL-6 and TNF-α. Covariates include baseline eGFR, age, sex, race, body mass index, urine albumin-to-creatinine ratio, hypertension, diabetes mellitus (DM), alcohol use, smoking, total cholesterol, and angiotensin–converting enzyme inhibitor/angiotensin receptor blocker. (A) Adjusted HR stratified by age ≥60 versus <60 years old. (B) Adjusted HR stratified by baseline eGFR ≥30 versus <30 ml/min per 1.73 m². (C) Adjusted HR stratified by black race. (D) Adjusted HR stratified by DM.

Figure 3.

Unadjusted association between inflammation score and incidence of the composite outcome. Error bars show the 95% confidence intervals. The inflammation score is the sum of baseline quartiles of IL-6, TNF-α, fibrinogen, and serum albumin (reverse scored). The association of these cytokines with the composite outcome is additive (chi square =422.34; P<0.001; Spearman r=0.34), and there is a significant linear trend (Cochran–Armitage trend test P<0.001).