Inflammation, hemostasis, and the risk of kidney function decline in the Atherosclerosis Risk in Communities (ARIC) Study

Abstract

Background: Inflammation and hemostasis may increase the risk of kidney function decline; however, data from prospective studies are sparse.

Study design: The Atherosclerosis Risk in Communities (ARIC) Study, a prospective observational cohort.

Setting & participants: We used data from 14,854 middle-aged adults from 4 different US communities.

Predictor: Markers of inflammation and hemostasis were examined.

Outcomes & measurements: The risk of kidney function decrease associated with these markers was studied. Glomerular filtration rate (GFR) was calculated from serum creatinine levels using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation. Chronic kidney disease (CKD) was defined as: (1) a decrease in estimated GFR to less than 60 mL/min/1.73 m2 from greater than 60 mL/min/1.73 m2 at baseline, or (2) a hospitalization discharge or death coded for CKD. Serum creatinine was measured at baseline and the 3- and 9-year follow-up visits. Hazard ratios (HRs) of CKD associated with increased levels of inflammatory and hemostatic variables were estimated by using multivariate Cox proportional hazards regression.

Results: 1,787 cases of CKD developed between 1987 and 2004. After adjusting for demographics, smoking, blood pressure, diabetes, lipid levels, prior myocardial infarction, antihypertensive use, alcohol use, year of marker measurement, and baseline renal function using estimated GFR, the risk of incident CKD increased with increasing quartiles of white blood cell count (HR quartile 4 versus quartile 1, 1.30; 95% confidence interval [CI], 1.12 to 1.50; P trend = 0.001), fibrinogen (HR, 1.25; 95% CI, 1.09 to 1.44; P < 0.001), von Willebrand factor (HR, 1.46; 95% CI, 1.26 to 1.68; P < 0.001), and factor VIIIc (HR, 1.39; 95% CI, 1.20 to 1.60; P < 0.001). A strong inverse association was found between serum albumin level and risk of CKD (HR, 0.63; 95% CI, 0.55 to 0.72; P < 0.001). No independent association was found with factor VIIc level.

Limitations: Although we lacked a direct measure of kidney function, associations were robust to case definitions.

Conclusions: Markers of inflammation and hemostasis are associated with greater risk of kidney function decrease. Findings suggest that inflammation and hemostasis are antecedent pathways for CKD.

Figure 1. CKD-free Time for Inflammatory and Hemostatic Markers by Quartiles, ARIC 1987–2004

Serum albumin level is reported in g/dL, total WBC count in 10^3/uL, and fibrinogen in mg/dL. Log-rank p-values < 0.001 for all

Figure 2. Adjusted Incidence Rates of CKD by each Hemostatic and Inflammatory factor, ARIC, 1987–2004

Incidence rates (and 95% confidence intervals (shaded area) of CKD by concentration of hemostatic and inflammatory markers. The curve represents minimally adjusted incidence rates based on a Poisson regression model including a fifth-order polynomial for albumin(A), WBC(B), fibrinogen(C), von Willebrand Factor(D), Factor VIIc(E), or, Factor VIIIc(F), adjusted to the incidence rate for a 60 year old white man with a baseline eGFR of 90 mL/min/1.73 m². The histogram represents the frequency distribution of A-E in the (5th-95th percentile of the) study sample. Serum albumin level is reported in g/dL, total WBC count in 10^3/uL, and fibrinogen in mg/dL.