title: 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 redox-regulated 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±13yr, functioning graft ≥1yr) 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 positively associated with R-SH while BMI, HbA1c, corrected calcium and NT-pro-BNP inversely associated with R-SH (model R2=0.26). During follow-up (3.1 [2.7-3.9] yrs), 79 (11%) patients died and 45 (7%) patients developed graft failure. R-SH correlated inversely with all-cause mortality (HR 0.58 [95% CI 0.45-0.75] per SD increase) and graft failure (HR 0.42 [0.30-0.59]; both P<0.001), independent of parameters with which R-SH significantly associated in the multivariable regression analyses, except for NT-pro-BNP. 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.
authors.affiliation: Pathology and Medical Biology, University Medical Center Groningen and University of Groningen, The Netherlands.
authors.forename: Anne-Roos S
authors.initials: AS
authors.lastname: Frenay
authors.affiliation: Nephrology, University Medical Center Groningen and University of Groningen, The Netherlands.
authors.forename: Martin H
authors.initials: MH
authors.lastname: de Borst
authors.affiliation: Department of Clinical Research, University of Bern, Inselspital, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Bachtler
authors.affiliation: Department of Clinical Research, University of Bern, Inselspital, Switzerland.
authors.forename: Nadine
authors.initials: N
authors.lastname: Tschopp
authors.affiliation: Nephrology, University Medical Center Groningen and University of Groningen, The Netherlands.
authors.forename: Charlotte A
authors.initials: CA
authors.lastname: Keyzer
authors.affiliation: Nephrology, University Medical Center Groningen and University of Groningen, The Netherlands.
authors.forename: Else
authors.initials: E
authors.lastname: van den Berg
authors.affiliation: Nephrology, University Medical Center Groningen and University of Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands.
authors.forename: Stephan J L
authors.initials: SJL
authors.lastname: Bakker
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Feelisch
authors.affiliation: Department of Clinical Research, University of Bern, Inselspital, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Pasch
authors.affiliation: Pathology and Medical Biology, University Medical Center Groningen and University of Groningen, The Netherlands. Electronic address: h.van.goor@umcg.nl.
authors.forename: Harry
authors.initials: H
authors.lastname: van Goor
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D015992:Body Mass Index; D002118:Calcium / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood / Q000175:diagnosis* / Q000473:pathology; D005260:Female; D005919:Glomerular Filtration Rate / Q000502:physiology; D006442:Glycated Hemoglobin / Q000378:metabolism; D006084:Graft Rejection / Q000097:blood / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology; D006085:Graft Survival; D006801:Humans; D016030:Kidney Transplantation / Q000009:adverse effects / Q000401:mortality; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020097:Natriuretic Peptide, Brain / Q000097:blood; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000097:blood; D016016:Proportional Hazards Models; D012737:Sex Factors; D013438:Sulfhydryl Compounds / Q000097:blood*; D013885:Thiosulfates / Q000097:blood*
chemical_list: D015415:Biomarkers; D002118:Calcium; D006442:Glycated Hemoglobin; D020097:Natriuretic Peptide, Brain; D010446:Peptide Fragments; D013438:Sulfhydryl Compounds; D013885:Thiosulfates; C517652:hemoglobin A1c protein, human; C109794:pro-brain natriuretic peptide (1-76)
keywords: Cardiovascular disease; Free thiols; Graft failure; Kidney transplantation; Mortality; Oxidative stress