Inflammation Biomarkers and Kidney Function Predict Atherosclerosis

Atherosclerosis, a chronic immunoinflammatory fibroproliferative disease, is characterized by lipid inflammation. Circulating levels of acute-phase proteins and proinflammatory cytokines are elevated in patients with chronic kidney disease (CKD). Results of previous population-based cohort studies of individuals in early stages of CKD and small studies of patients on dialysis therapy have suggested an association between inflammation and cardiovascular outcomes. Those results have not, to date, been validated in larger and more ethnically diverse CKD cohorts with a range of glomerular filtration rates (GFRs) and long-term follow-up for clinical outcomes.

The American College of Cardiology and American Heart Association recently introduced the new Pooled Cohort Equations to estimate the 10-year atherosclerotic vascular disease (ASVD) risk. However, the equations may not be applicable to patients with CKD. Richard L. Amdur, PhD, and colleagues conducted an observational cohort study in participants from the CRIC (Chronic Renal Insufficiency Cohort) study designed to examine the association of incident ASVD events and death with a panel of circulating inflammatory biomarkers and kidney function measures. The researchers also sought to assess whether adding measures of kidney function and biomarkers of inflammation would improve on traditional risk variables for stratifying the risk for ASVD outcomes and death among patients with CKD. Study results were reported in the American Journal of Kidney Diseases [2019;73(3):344-353].

High-sensitivity enzyme-linked immunosorbent assays (Quantikine HS, R&D Systems) were used to measure plasma interleukin 1 b (IL-1b ), IL-6, and tumor necrosis factor a (TNF-a) levels. Standard enzyme-linked immunosorbent assays (Quantikine, R&D Systems) were used to quantify IL-1 receptor-antagonist (IL-1RA) and transforming growth factor b (TGFb) levels. Serum albumin was measured using the bromcresol green method. Other measured biomarkers were high-sensitivity C-reactive protein (hs-CRP) and fibrinogen.

The primary outcome of interest was a composite of incident ASVD (myocardial infarction [MI], peripheral artery disease [PAD], or stroke) and death. Secondary outcomes included individual components of the primary outcome, as well as a cardiovascular disease composite (MI/stroke/PAD).

The CRIC study included 3939 participants. Of those, 1316 were excluded from the current analysis due to a history of cardiovascular disease, 104 were excluded due to missing data on inflammatory markers, 94 were excluded due to missing data on kidney function, and 26 were excluded for missing key data needed to calculate Pooled Cohort Equation probability (PCEP); the final cohort of patients available for multivariable analysis totaled 2399.

Follow-up continued for a median of 7.3 years. During the follow-up period, 86 participants experienced MI, 61 experienced PAD, and 48 participants experienced stroke; 323 participants died during follow-up. A total of 471 participants reached the primary outcome (composite of incident ASVD (MI, PAD, or stroke) and death.

At baseline, the mean age of the study participants was 56 years, 48% were women, 38% were black, and 41% had diabetes mellitus. Mean baseline estimated GFR (eGFR) was 44.1 mL/min/1.73 m² and median PCEP was 9.6%; 58% of the sample had a baseline raw PCEP ≥7,5%, and 46% were being treated with statins. Because IL-1b level was highly skewed, quintiles 1 and 2 were combined.

All eight inflammatory biomarkers measured had significant univariable associations in survival analysis. However, following adjustment for PCEP, eGFR, and albuminuria, the associations remained significant only for IL-6, TNF-a, hs-CRP, fibrinogen, and serum albumin values. When tested by marker quartile, all of those five markers had significant linear associations with the outcome (P<.001). The hs-CRP level became nonsignificant when the five markers were combined as predictors in a single Cox proportional hazards model for the composite outcome without other covariates.

There were independent associations between 1-decile greater levels of IL-6 (adjusted hazard ratio [aHR], 1.12; 95% confidence interval [CI], 1.08-1.16; P<.001), TNF-a (aHR, 1.09; 95% CI, 1.05-1.13; P<.001), fibrinogen (aHR, 1.07; 95% CI, 1.03-1.11; P<.001), and serum albumin (aHR, 0.96; 95% CI, 0.93-0.99; P<.001) and the composite ASVD-death outcome.

There was an association between a composite inflammation score (CIS) that incorporated those four biomarkers and a graded increase risk for the composite outcome. Across quintiles of risk derived from PCEP, kidney function, and CIS there were increases in ASVD-death. Adding eGFR, albuminuria, and CIS to PCEP improved (P=.003) the area under the received 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).

Lack of data for cardiovascular death was cited by the researches as a limitation to the study.

“To summarize, select inflammatory biomarkers are independently associated with a composite of incident MI, PAD, stroke, and death in patients with CKD. A composite inflammation score based on deciles of IL-6, TNF-a, fibrinogen, and reverse-coded serum albumin showed a positive and graded association with incident ASVD events and death. A risk score that incorporated PCEP, kidney function, and CIS was associated with the ASVD-death outcome. We found that inclusion of eGFR, albuminuria, and CIS improved the model discrimination beyond that achieved by PCEP. These observations should be confirmed in an independent cohort of patients with CKD,” the researchers said.

Takeaway Points

1. Among patients with chronic kidney disease, traditional risk estimates for atherosclerotic vascular disease and death may not be optimal; researchers conducted an observational cohort study to determine the advantage of adding measures of inflammation and kidney function.
2. There were independent associations between 1-decile greater levels of interleukin 6, tumor necrosis factor a, fibrinogen, and serum albumin and the composite ASVD-death outcome.
3. There was also an association between a composite inflammation score that incorporated those four biomarkers and a graded increased risk for the composite outcome.