SOD3 and IL-18 Predict the First Kidney Disease-Related Hospitalization or Death during the One-Year Follow-Up Period in Patients with End-Stage Renal Disease

Abstract

End-stage renal disease (ESRD) patients experience oxidative stress due to excess exogenous or endogenous oxidants and insufficient antioxidants. Hence, oxidative stress and inflammation cause endothelial damage, contributing to vascular dysfunction and atherosclerosis. Therefore, ESRD patients suffer more cardiovascular and hospitalization events than healthy people. This study aims to test the correlations between ROS, SOD3, IL-2, IL-6, and IL-18 and the first kidney disease-related hospitalization or death events in ESRD patients undergoing regular hemodialysis. A total of 212 participants was enrolled, including 45 normal healthy adults and 167 ESRD patients on regular dialysis. Blood samples from all participants were collected for ROS, SOD3, IL-2, IL-6, and IL-18 measurement at the beginning of the study, and every kidney disease-related admission or death was recorded for the next year. Multivariate analysis was conducted by fitting a linear regression model, logistic regression model, and Cox proportional hazards model to estimate the adjusted effects of risk factors, prognostic factors, or predictors on continuous, binary, and survival outcome data. The results showed that plasma SOD3 and serum IL-18 were two strong predictors of the first kidney disease-related hospitalization or death. In the Cox proportional hazards models (run in R), higher IL-18 concentration (>69.054 pg/mL) was associated with a hazard ratio of 3.376 for the first kidney disease-related hospitalization or death (95% CI: 1.2644 to 9.012), while log(SOD3) < 4.723 and dialysis clearance (Kt/V; 1.11 < value < 1.869) had a hazard ratio = 0.2730 (95% CI: 0.1133 to 0.6576) for reducing future kidney disease-related hospitalization or death. Other markers, including body mass index (BMI), transferrin saturation, total iron binding capacity, and sodium and alkaline phosphate, were also found to be significant in our study. These results reveal the new predictors SOD3 and IL-18 for the medical care of end-stage renal disease patients.

Keywords: end-stage renal disease (ESRD); first kidney disease-related hospitalization or mortality; inflammatory cytokines; interleukin-18 (IL-18); plasma superoxide dismutase 3 (SOD3); reactive oxygen species.

Figure 1

The enrollment flow chart of this study. A total of 211 participants, including 167 ESRD patients receiving regular hemodialysis at Jen-Ai Hospital or Xinren Clinic Hospital, and 45 healthy adults was enrolled. The Ethics Committee of the Clinical Center of Jen-Ai Hospital approved the study, and all the patients signed written informed consent.

Figure 2

Kaplan−Meier estimate of survival curve of time to the first kidney disease-related hospitalization or death. The 75th percentile of survival time was approximately 9.5 months.

Figure 3

Kaplan−Meier estimate of the survival curve for time to the first kidney disease-related hospitalization or death stratified by (A) all-cause hospitalization frequency, (B) all-cause hospitalization days, and (C) kidney disease-related hospitalization frequency. (A–C): Hospitalizations were all within one year before the start of the study.

Figure 3

Kaplan−Meier estimate of the survival curve for time to the first kidney disease-related hospitalization or death stratified by (A) all-cause hospitalization frequency, (B) all-cause hospitalization days, and (C) kidney disease-related hospitalization frequency. (A–C): Hospitalizations were all within one year before the start of the study.

Figure 4

Generalized additive model (GAM) plots of the first kidney disease-related hospitalization or death versus (A) hospitalization frequency within 1 year before the start of the study (0.3345 ± 0.0741, p < 0.0001), especially those with a level over 0.609; (B) BMI (kg/m²) (1.1039 ± 0.3986, p = 0.0056), high risk if BMI < 22.556; (C) cholesterol (mg/dL); and (D) age (years) (1.2961 ± 0.3834, p = 0.0007), high risk if age over 45.027 years and under 56.9 years.

Figure 5

Generalized additive model (GAM) plots of time to first kidney disease-related hospitalization or death versus (A) sodium (Na; mmol/L), (B) potassium (K; mmol/L), (C) phosphate (P; mg/dL), and (D) alkaline phosphate (U/L).

Figure 6

Generalized additive model (GAM) plots of time to first kidney disease-related hospitalization or death versus (A) serum iron (µg/dL); (B) total iron binding capacity (TIBC; µg/dL), TIBC level below 256.505 µg/dL having a poor outcome; and (C) transferrin saturation (TFS; %), TFS < 24.959% or >51.27% bringing high risk.

Figure 7

Generalized additive model (GAM) plots of the first kidney disease-related hospitalization or death versus (A) Kt/V, where Kt/V below 1.088 or over 1.992 brought a high risk; (B) log(SOD3), where log(SOD3) > 4.723 brought a high risk of events. Plasma SOD3 and Kt/V urea are closely related in the clinic. Given a log(SOD3) < 4.723 and Kt/V > 1.11 or <1.869, the patient has a lower risk of kidney disease-related hospitalization or death; and (C) IL-18 (pg/mL) (1.2166 ± 0.5010, p = 0.0152), where IL-18 over 69.054 conferred a high risk of events.