Use of Measures of Inflammation and Kidney Function for Prediction of Atherosclerotic Vascular Disease Events and Death in Patients With CKD: Findings From the CRIC Study

Abstract

Rationale & objective: Traditional risk estimates for atherosclerotic vascular disease (ASVD) and death may not perform optimally in the setting of chronic kidney disease (CKD). We sought to determine whether the addition of measures of inflammation and kidney function to traditional estimation tools improves prediction of these events in a diverse cohort of patients with CKD.

Study design: Observational cohort study.

Setting & participants: 2,399 Chronic Renal Insufficiency Cohort (CRIC) Study participants without a history of cardiovascular disease at study entry.

Predictors: Baseline plasma levels of biomarkers of inflammation (interleukin 1β [IL-1β], IL-1 receptor antagonist, IL-6, tumor necrosis factor α [TNF-α], transforming growth factor β, high-sensitivity C-reactive protein, fibrinogen, and serum albumin), measures of kidney function (estimated glomerular filtration rate [eGFR] and albuminuria), and the Pooled Cohort Equation probability (PCEP) estimate.

Outcomes: Composite of ASVD events (incident myocardial infarction, peripheral arterial disease, and stroke) and death.

Analytical approach: Cox proportional hazard models adjusted for PCEP estimates, albuminuria, and eGFR.

Results: During a median follow-up of 7.3 years, 86, 61, 48, and 323 participants experienced myocardial infarction, peripheral arterial disease, stroke, or death, respectively. The 1-decile greater levels of IL-6 (adjusted HR [aHR], 1.12; 95% CI, 1.08-1.16; P<0.001), TNF-α (aHR, 1.09; 95% CI, 1.05-1.13; P<0.001), fibrinogen (aHR, 1.07; 95% CI, 1.03-1.11; P<0.001), and serum albumin (aHR, 0.96; 95% CI, 0.93-0.99; P<0.002) were independently associated with the composite ASVD-death outcome. A composite inflammation score (CIS) incorporating these 4 biomarkers was associated with a graded increase in risk for the composite outcome. The incidence of ASVD-death increased across the quintiles of risk derived from PCEP, kidney function, and CIS. The addition of eGFR, albuminuria, and CIS to PCEP improved (P=0.003) the area under the receiver operating characteristic curve for the composite outcome from 0.68 (95% CI, 0.66-0.71) to 0.73 (95% CI, 0.71-0.76).

Limitations: Data for cardiovascular death were not available.

Conclusions: Biomarkers of inflammation and measures of kidney function are independently associated with incident ASVD events and death in patients with CKD. Traditional cardiovascular risk estimates could be improved by adding markers of inflammation and measures of kidney function.

Keywords: C-reactive protein (CRP); Myocardial infarction (MI); Pooled Cohort Equation probability (PCEP); albuminuria; atherosclerosis; atherosclerotic vascular disease (ASVD); cardiovascular disease (CVD); chronic kidney function (CKD); cytokines; estimated glomerular filtration rate (eGFR); inflammatory biomarkers; kidney function; risk stratification; stroke.

Figure 1.

Patient flow into the study

Figure 2.

Kaplan Meier estimates of freedom from the ASVD-death composite outcome stratified by quintile of the composite inflammation score (CIS), which was computed by adding the deciles of IL-6, TNF-α, fibrinogen and reverse-coded serum albumin. Log-rank chi-square 162.28 (p<0.001). Adjusted hazard ratios (HR) for quintiles 2 through 5 are shown, versus quintile 1, based on a multivariable Cox proportional hazard model using CIS quintile coded as a class variable, adjusting for PCEP, eGFR, and UACR.