Association of Soluble TNFR-1 Concentrations with Long-Term Decline in Kidney Function: The Multi-Ethnic Study of Atherosclerosis

Abstract

Background: TNF receptor-1 (TNFR-1), which plays a causative role in endothelial cell dysfunction and inflammation, is expressed on the cell surface in glomerular and peritubular capillary endothelium of the kidneys. Higher soluble TNF receptor-1 (sTNFR-1) concentrations are associated with kidney disease progression among persons with established diabetic kidney disease. However, no studies have assessed sTNFR-1's role in long-term kidney function changes in a multiethnic population without cardiovascular disease at baseline.

Methods: We tested associations between baseline sTNFR-1 concentrations and 10-year decline in eGFR (incident ≥40% decline and annual proportional decline) among 2548 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective cohort study. Serum creatinine concentrations were determined at enrollment and study years 3, 5, and 10.

Results: Mean age of participants was 61 years old, 53% were women, and mean baseline eGFR was 79 ml/min per 1.73 m². Serum sTNFR-1 was inversely associated with baseline eGFR. Over median follow-up of 9.3 years, 110 participants developed ≥40% decline in eGFR; each SD higher concentration of sTNFR1 was associated with higher risk of 40% eGFR decline (adjusted hazard ratio, 1.43; 95% confidence interval [95% CI], 1.16 to 1.77; P<0.001). The highest sTNFR-1 tertile was associated with adjusted annualized decline in eGFR of 1.94% (95% CI, 1.79 to 2.09). Associations persisted across subgroups defined by demographics, hypertension, diabetes, and baseline CKD status.

Conclusions: Elevated serum sTNFR-1 concentrations are associated with faster declines in eGFR over the course of a decade in a multiethnic population, independent of previously known risk factors for kidney disease progression.

Keywords: Chronic inflammation; chronic renal disease; endothelium; soluble tumor necrosis factor receptor-1.

Graphical abstract

Figure 1.

The adjusted association of serum soluble TNF receptor-1 (sTNFR-1) concentrations with ≥40% eGFR decline was linear. The smooth spline estimates the hazard ratio of ≥40% eGFR decline among Multi-Ethnic Study of Atherosclerosis participants according to baseline serum sTNFR-1 concentrations. Analyses are adjusted for age, age squared, and sex. Dotted lines represent 95% confidence intervals (95% CIs). Below the spline is the histogram of the distribution of sTNFR-1 to indicate the range of the data. TNFR-1, TNF receptor-1.

Figure 2.

Forest plot demonstrates consistent associations of serum soluble TNFR receptor-1 (sTNFR-1) concentrations with ≥40% eGFR decline (estimates are per SD of sTNFR-1). Hazard ratio (HR) estimates are adjusted for age, age squared, sex, race/ethnicity, site, education, body mass index, diabetes, and hypertension. 95% CI, 95% confidence interval; IFG, impaired fasting glucose.