Serum peroxiredoxin-4, a biomarker of oxidative stress, associates with new-onset chronic kidney disease: A population-based cohort study

Abstract

Background: Chronic Kidney Disease (CKD), is often detected late due to its asymptomatic nature in the early stage of the disease. Overproduction of reactive oxygen species contributes to various pathological processes through oxidative stress (OS), impacting on cellular structures and functions with previous studies suggesting a link between OS and CKD progression. This study investigated the association between serum peroxiredoxin-4 (Prx4), a biomarker of oxidative stress, and the development of CKD in the general population.

Methods: This study featured data from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort, involving 5341 participants without CKD at baseline who underwent extensive prospective health evaluations. Serum Prx4 levels were quantified using an immunoluminometric assay. The primary outcome was new-onset CKD as defined by the composite of urinary albumin excretion (UAE) > 30 mg/24-h, an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m², or both.

Results: Baseline median Prx4 level was 0.65 [interquartile range (IQR): 0.42-1.04] U/L, median eGFR was 98 [IQR: 87-108] mL/min/1.73 m², and median UAE was 8.1 [IQR: 6.0-12.1] mg/L. During a median follow-up of 10.4 [IQR: 6.3-11.4] years, 867 (16.2 %) patients developed new-onset CKD. Higher Prx4 levels were significantly associated with an increased risk of CKD (hazard ratio (HR) per doubling: 1.29 [95 % confidence interval (CI): 1.21-1.37], p < 0.001), also after adjustment for risk factors including sex, smoking status, systolic blood pressure, high-sensitive C-reactive protein, chronic heart failure, diabetes mellitus and dyslipidemia (HR per doubling: 1.16 [1.06-1.24], p < 0.001). Sensitivity analyses confirmed the robustness of these findings.

Conclusions: This study supports the hypothesis that systemic oxidative stress, reflected by higher serum Prx4 levels, is significantly associated with the risk of developing CKD in the general population. These findings suggest that Prx4 could be a valuable biomarker for early risk stratification and prevention strategies in CKD management.

Keywords: CKD biomarker; Chronic kidney disease; Oxidative stress; Peroxiredoxin-4; Prx4.

Graphical abstract

Fig. 1

CONSORT Flowchart of participant selection within the PREVEND cohort study.

Fig. 2

A Directed Acyclic Graph (DAG) illustrates the hypothesized causal relationships that underlie the connection between systemic oxidative stress (indicated by serum Prx4 levels) and the likelihood of developing chronic kidney disease (CKD) in the general population. Following the DAG, a distinct set of confounding factors were accounted for through conditioning to ensure the derivation of an unconfounded effect estimate.

Fig. 3

Kaplan-Meier survival curves for tertiles of Prx4, representing CKD-free survival based on the composite outcome of incident CKD (eGFR, UAE or both (A), as well as the individual determinants of eGFR (<60 mL/min/1.73 m²) (B) and UAE (>30 mg/24-h) (C). Highest rates of incident CKD were observed in the highest tertile (T3) of Prx4 (log-rank tests, all p < 0.001).

Fig. 4

Stratified analyses for the association between serum Prx4 levels and the risk of incident CKD across various subgroups. Hazard ratios (HRs) are shown with corresponding 95 % confidence intervals (95%CIs).