Serum free sulfhydryl status associates with new-onset chronic kidney disease in the general population

Abstract

Background Serum sulfhydryl groups (R-SH, free thiols) reliably reflect the systemic redox status in health and disease. As oxidation of R-SH occurs rapidly by reactive oxygen species (ROS), oxidative stress is accompanied by reduced levels of free thiols. Oxidative stress has been implicated in the pathophysiology of chronic kidney disease (CKD), in which redox imbalance may precede the onset of CKD. Therefore, we aimed to investigate associations between serum free thiols and the risk of incident CKD as defined by renal function decline and albuminuria in a population-based cohort study. Methods Subjects without CKD ( n = 4,745) who participated in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, a prospective, population-based cohort study in the Netherlands, were included. Baseline protein-adjusted serum free thiols were studied for their associations with the development of CKD, defined as a composite outcome of an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m 2 , urinary 24-h albumin excretion (UAE) > 30 mg/24-h, or both. Results Median level of protein-adjusted serum free thiols at baseline was 5.14 μmol/g of protein (interquartile range [IQR]: 4.50–5.75 μmol/g) and median eGFR was 96 mL/min/1.73 m 2 [IQR: 85–106]. Protein-adjusted serum free thiols were significantly associated with incident CKD (hazard ratio [HR] per doubling 0.42 [95% confidence interval [CI]: 0.36–0.52, P < 0.001), even after adjustment for traditional risk factors (HR 0.67 [95% CI: 0.47–0.94], P =0.022). In secondary analyses, the highest tertile of protein-adjusted serum free thiols was inversely associated with incident UAE >30 mg/24-h after full adjustment for confounding factors (HR per doubling 0.70 [95% CI: 0.51–0.96], P =0.028). Conclusion Higher levels of serum R-SH, reflecting less oxidative stress, are associated with a decreased risk of developing CKD in subjects from the general population. This association is primarily driven by incident CKD as defined by UAE.

Systemic oxidative stress associates with new-onset hypertension in the general population

“…Protein-adjusted serum free thiol levels could be interpreted as a reflection of the balance between oxidants and antioxidant availability (or "overall redox poise") [12]. Previous studies also demonstrated a predictive value of protein-adjusted serum free thiols in relation to cardiovascular and renal disease outcomes [14,[16][17][18][19][20].…”

“…Quantification of systemic free thiol concentrations is considered as a useful, minimally invasive, and reproducible means to establish the degree of systemic oxidative stress in both health and disease, making it an attractive clinical monitoring tool for oxidative stress-mediated human diseases [14][15][16]. For instance, free thiols have been associated with the development of new-onset cardiovascular disease and chronic kidney disease [17][18][19][20]. Furthermore, free thiols strongly correlate with a number of relevant cardiovascular risk factors, such as smoking, obesity, and alcohol consumption [12,19].…”

Oxidized Albumin: Evaluation of Oxidative Stress as a Marker for the Progression of Kidney Disease

“…Content and CKD Onset in the General Population Bourgonje et al recently followed the association between serum free thiol group (-SH group) content and CKD development over a 10 year period using 4745 subjects from the general population without CKD (median estimated glomerular filtration rate (eGFR): 96 mL/min/1.73 m 2 ) that were enrolled in The Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study in the Netherlands. 23) The results indicated that residents with a low serum free thiol group content at the time of entry had a higher risk of developing CKD (eGFR less than 60 mL/min/1.73 m 2 or daily urinary albumin excretion of 30 mg or more). Considering that about 80% of the free thiol group content in serum is derived from Cys34 of albumin, this result suggests that the decrease in reduced albumin (unmodified albumin), that is, the increase in the levels of oxidized albumin, could be associated with the onset of CKD.…”

Blood Thiol Redox State in Chronic Kidney Disease

“…Recently, in subjects without CKD ( n = 4745) who participated in the Prevention of End-stage REnal and Vascular Disease (PREVEND) study, elevated serum free thiol concentrations—adjusted to the total serum protein—were shown to be associated with a lower risk of the new-onset of CKD in this population, constituting a possible marker for the identification of the individuals who are most at risk of developing the disease. Therefore, the assessment of the serum free sulfhydryl status would be useful for preventive purposes, in order to mitigate the future burden of CKD in the general population [ 61 ].…”