Serum free sulfhydryl status is associated with patient and graft survival in renal transplant recipients

Abstract

Oxidative stress contributes significantly to graft failure, morbidity and mortality in renal transplant recipients (RTR). In cells, free sulfhydryl groups (reduced thiols, R-SH) are the transducers of redoxregulated events; their oxidation status is modulated by interaction with reactive oxygen and nitrogen oxide species and thought to be in equilibrium with the circulating pool. We hypothesized that high levels of serum free thiols are a reflection of a favorable redox status and therefore positively associated with cardiovascular risk parameters, patient and graft survival in RTR.To test this, reactive free thiol groups (R-SH; corrected for total protein) were quantified in serum of 695 RTR (57% male, 53±13 yr, functioning graft ≥1 yr) using Ellman's Reagent, and R-SH determinants were evaluated with multivariable linear regression models. Associations between R-SH and mortality or graft failure were assessed using multivariable Cox regression analyses.In multivariable models, male gender, estimated glomerular filtration rate and serum thiosulfate Serum R-SH are associated with a beneficial cardiovascular risk profile and better patient and graft survival in RTR, suggesting potential usefulness as low-cost, high-throughput screening tool for whole-body redox status in translational studies. Whether R-SH modification improves long-term outcome of RTR warrants further exploration.

Systemic Oxidative Stress Is Increased in Postmenopausal Women and Independently Associates with Homocysteine Levels

“…Mean serum free thiol concentrations were 780 ± 80.9 µM for reproductive women and 762.9 ± 85.3 µM for menopausal women (p < 0.001 after correction for age, Figure S1). Concentration ranges of serum free thiols were in accordance with previous studies that used the same detection method [20][21][22][23][24]. Median age of reproductive women was 30 years (interquartile range (IQR) 22-42 years), whereas menopausal women had a median age of 54 years (IQR: 50-59 years).…”

The Reactive Species Interactome: Evolutionary Emergence, Biological Significance, and Opportunities for Redox Metabolomics and Personalized Medicine

“…Another highly significant association was found between total free thiol status in serum and clinical outcome in unrelated clinical conditions (61, 105). Given the overall complexity of the extracellular antioxidant network and its link to intracellular redox status, the latter was utterly unexpected.…”

“…In renal transplant recipients, protein-adjusted serum-free thiols were found to predict graft failure and patient survival (61, 105). In a small cohort of stable chronic heart failure patients, there was a positive association between protein-adjusted serum-free thiols and a favorable disease outcome (61, 105).…”

“…In a small cohort of stable chronic heart failure patients, there was a positive association between protein-adjusted serum-free thiols and a favorable disease outcome (61, 105). Interestingly, a study evaluating the concentration of serum protein thiols in a wide range of species concluded that free thiol levels are positively associated with life span, suggesting that control of redox status has retained its importance from evolution to modern-day (patho)physiology (146).…”

International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors

“…In vivo, its therapeutic efficacy in rodent models of LPS-induced lung injury (Sakaguchi et al, 2014), galactosamine/LPS-induced acute liver failure (Shirozu et al, 2014), angiotensin-induced hypertension and hypertensive heart disease (Snijder et al, 2014;Snijder et al, 2015), global cerebral ischemia (Marutani et al, 2015), vascular calcification (Subhash et al, 2015), and hyperoxaluric renal dysfunction (Bijarnia et al, 2015) can be seen at doses ranging from 10 to 2000 (mg/kg)/day. In clinical observational studies, plasma thiosulfate levels show positive correlations, with improved clinical outcomes in renal transplantation Frenay et al, 2016). On the mechanistic side, one must keep in mind that thiosulfate is likely to have multiple pharmacological actions in addition to being a generator of H 2 S. On the practical side, however, given the fact that sodium thiosulfate (STS) is a safe clinically used drug that is approved for the therapy of sodium nitroprusside/cyanide intoxication (Baskin et al, 1992;Hall and Guest, 1992); the clinical and experimental therapeutic opportunities around STS are substantial and there may be various opportunities to repurpose STS for the experimental therapy of a variety of diseases that may benefit from H 2 S supplementation.…”