Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • JASN Podcasts
    • Article Collections
    • Archives
    • ASN Meeting Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Editorial Fellowship
    • Editorial Fellowship Team
    • Editorial Fellowship Application Process
  • More
    • About JASN
    • Advertising
    • Alerts
    • Feedback
    • Impact Factor
    • Reprints
    • Subscriptions
  • ASN Kidney News
  • Other
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology

User menu

  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
American Society of Nephrology
  • Other
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • JASN Podcasts
    • Article Collections
    • Archives
    • ASN Meeting Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Editorial Fellowship
    • Editorial Fellowship Team
    • Editorial Fellowship Application Process
  • More
    • About JASN
    • Advertising
    • Alerts
    • Feedback
    • Impact Factor
    • Reprints
    • Subscriptions
  • ASN Kidney News
  • Follow JASN on Twitter
  • Visit ASN on Facebook
  • Follow JASN on RSS
  • Community Forum
Dialysis
You have accessRestricted Access

Increased Plasma S-Nitrosothiol Concentrations Predict Cardiovascular Outcomes among Patients with End-Stage Renal Disease: A Prospective Study

Ziad A. Massy, Christine Fumeron, Didier Borderie, Philippe Tuppin, Thao Nguyen-Khoa, Marie-Odile Benoit, Christian Jacquot, Claude Buisson, Tilman B. Drüeke, Ohvanesse G. Ekindjian, Bernard Lacour and Marie-Christine Iliou
JASN February 2004, 15 (2) 470-476; DOI: https://doi.org/10.1097/01.ASN.0000106716.22153.BB
Ziad A. Massy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christine Fumeron
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Didier Borderie
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Philippe Tuppin
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Thao Nguyen-Khoa
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marie-Odile Benoit
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christian Jacquot
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Claude Buisson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tilman B. Drüeke
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ohvanesse G. Ekindjian
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bernard Lacour
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marie-Christine Iliou
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data Supps
  • Info & Metrics
  • View PDF
Loading

Abstract

ABSTRACT. The plasma concentrations of S-nitrosothiols, which are circulating nitric oxide metabolites with potential biologic activity, are increased among patients undergoing chronic hemodialysis (HD). However, the ability of S-nitrosothiols to release nitric oxide at physiologically relevant sites may be reduced among HD patients, because of impaired availability and/or activity of factors involved in S-nitrosothiol breakdown. The resultant lack of S-nitrosothiol bioavailability could contribute to the high cardiovascular risk for such patients. A possible relationship between plasma S-nitrosothiol levels and cardiac outcomes, as well as all-cause mortality rates, was investigated in a cohort of 250 chronic HD patients and who were undergoing regular dialysis three times per week were monitored for 1 yr. During that follow-up period, major cardiac events and all-cause deaths were prospectively recorded. At baseline, high plasma S-nitrosothiol levels (>2 μM, corresponding to the top quartile of all measured values) were independently associated with pulse pressure in an adjusted multivariate analysis (odds ratio, 1.03; 95% confidence interval, 1.01 to 1.05; P = 0.007). During the follow-up period, 36 patients died (16 as a result of cardiac causes) and 33 patients experienced major adverse cardiac events. In an adjusted Cox proportional-hazards model, high plasma S-nitrosothiol concentrations (i.e., the top quartile versus the three other quartiles) were an independent predictor of cardiac events (hazard ratio, 3.30; 95% confidence interval, 1.61 to 6.76; P = 0.001) but not of all-cause death. Therefore, among chronic HD patients, markedly elevated plasma S-nitrosothiol levels are associated with pulse pressure and predict cardiovascular outcomes. These findings support the hypothesis that impaired S-nitrosothiol bioavailability in uremia is an important factor for the excessive cardiovascular risk among HD patients.

Premature atherosclerosis is one of the primary causes of morbidity and death among patients with ESRD (1,2⇓). Among several classic and nonclassic mechanisms conferring increased cardiovascular risk, impairment of nitric oxide (NO) bioavailability has emerged as a potentially important mechanism. Impaired NO-mediated, endothelium-dependent vasodilation, an early marker of atherosclerosis, has been observed among patients with predialysis chronic renal failure (3) and patients with ESRD (4,5⇓). The impaired endothelium-dependent vasodilation could be linked to an absolute deficit of NO production. Indeed, increased levels of asymmetric dimethylarginine (ADMA), an active endogenous inhibitor of NO synthase, have been observed to be associated with the severity of atherosclerosis, independently of other vascular risk factors (6), and with concentric left ventricular hypertrophy and left ventricular dysfunction among patients with ESRD (7). Moreover, associations between ADMA levels and overall mortality or cardiovascular outcome rates were recently demonstrated among patients with ESRD (8).

However, the evidence for deficient NO synthesis among such patients remains inconclusive. Schmidt and Baylis (9) demonstrated that 24-h urinary nitrite/nitrate excretion was low among patients with chronic kidney disease, compared with healthy control subjects with similar dietary NO intake, suggesting that net endogenous NO production was decreased. However, elevated extrarenal NO production has been observed among patients with ESRD (10). Furthermore, it was recently reported that the plasma of patients undergoing chronic hemodialysis (HD) contained significantly higher S-nitrosothiol levels than did the plasma of healthy control subjects (11). S-Nitrosothiols, which are the result of reactions of NO with molecules containing functional sulfhydryl groups, are considered a NO pool with a potential for vasodilatory effects (12). This points to the presence of circulating NO metabolites with potential biologic activity and argues against an absolute quantitative NO deficiency among patients with ESRD. It should be noted, however, that elevated plasma S-nitrosothiol concentrations among HD patients could also be attributable to peroxynitrite detoxification via a reaction with thiols, to decrease nitrosative stress (11). It was recently demonstrated that nitrosothiol formation in vivo depends not only on the availability of NO and O2 but also on the degree of oxidative stress via changes in the steady-state concentration of thiyl radicals (13). There are also other explanations for elevated plasma S-nitrosothiol concentrations among HD patients, such as thiol retention of NO attributable to the accumulation of thiol molecules (14). The half-lives and renal or extrarenal clearances of plasma S-nitrosothiols in the general population and among patients with ESRD are still unknown. The issue seems even more complicated because of the heterogeneity of circulating S-nitrosothiol molecules.

The pathophysiologic consequences of high plasma S-nitrosothiol concentrations are unknown. It is possible that the ability of S-nitrosothiols to release NO at physiologically relevant sites is reduced among patients with ESRD because of impaired availability and/or activity of factors involved in S-nitrosothiol breakdown, such as ascorbate and several enzymes, including plasma glutathione peroxidase (GSH-Px) (15,16⇓). Marked ascorbate deficiencies and low levels of plasma GSH-Px activity have been observed among patients with ESRD (17). Ascorbate deficiency was recently suggested as a potential cause of elevated plasma S-nitrosothiol concentrations in preeclampsia (18). Therefore, an enhanced vasodilatory action of high S-nitrosothiol levels is improbable. On the contrary, a lack of S-nitrosothiol bioavailability might be involved in the pathogenesis of the impaired NO-mediated, endothelium-dependent vasodilation observed among patients with ESRD, favoring hypertension, left ventricular hypertrophy, and cardiovascular events. With these pathophysiologic considerations in mind, the aim of our study was to examine a possible association between plasma S-nitrosothiol levels and cardiac outcomes, as well as overall survival rates, in a cohort of chronic HD patients.

Materials and Methods

Study Protocol

We included in the study cohort all patients at least 18 yr of age who attended one of three large Parisian HD centers. All of the patients included had been undergoing intermittent HD treatment for >3 mo, with three sessions per week. They gave informed consent, according to local internal review board rules, and did not meet any of the following exclusion criteria: predialysis hemoglobin concentration of <8 g/dl, surgical treatment or severe infectious episode in the 8 d preceding the start of the study, acute coronary syndrome, acute cerebrovascular event, arterial revascularization in the 3 wk preceding the start of the study, or refusal to participate.

Patients

Medical data were recorded for each patient with routine computerized screening. We analyzed the history of ischemic heart disease, cardiovascular risk factors, and dialysis modalities. A diagnosis of ischemic heart disease was made with stringent criteria, such as a history of myocardial infarction, coronary artery revascularization, and/or significant stenosis on coronary artery angiograms. Patients were considered to be diabetic if they demonstrated fasting blood glucose levels of >126 mg/dl or were being treated with insulin. BP during the week of blood sample collection was determined by averaging three semiautomatic measurements before each HD session. Pulse pressure was calculated as the difference between systolic and diastolic BP. Patients were considered to have hypercholesterolemia if they exhibited serum total cholesterol concentrations of >200 mg/dl or were receiving lipid-lowering drugs. Information concerning current tobacco use was obtained with a questionnaire. Clinical and laboratory data were obtained for 302 patients. Exclusion criteria included recent initiation of dialysis, severe anemia, refusal or inability to participate, or blood samples unsuitable for S-nitrosothiol measurements. Clinical characteristics were not significantly different for the patients who participated in the study versus those who did not. Two hundred fifty patients were judged eligible for the study and included.

Echocardiography was performed according to the recommendations of the American Society of Echocardiography, on a dialysis-free day, in the 3 mo before or after inclusion. Left ventricular hypertrophy was defined as a left ventricular mass index of at least 134 g/m2 for men and 110 g/m2 for women (19).

The duration of the HD sessions and the type of membranes used for dialysis were not modified during the study; such choices were left to the discretion of the referring physician. Kt/V was calculated according to the second formula described by Daugirdas (20).

Biochemical Determinations

Blood samples were collected before the first dialysis session of the week. Blood samples (from an arteriovenous fistula) were collected in vacuum tubes. Blood hemoglobin levels were determined with a Coulter MAXM analyzer (Beckman Coulter, Villepinte, France). For the S-nitrosothiol assay, samples were centrifuged at 3500 rpm for 15 min immediately after collection, and serum and plasma were frozen in aliquots at −80°C. Plasma S-nitrosothiol concentrations were determined with a fluorometric method described previously (11), with a minor modification (21). Although the addition of ammonium sulfamate at neutral pH neutralized nitrite for the vast majority of HD patients, limited amounts of residual nitrite remained in the plasma of some patients. In those instances, we corrected the plasma S-nitrosothiol concentration by subtracting the residual nitrite level. The mean and the upper limit of normal plasma S-nitrosothiol concentrations were 0.45 and 1.57 μM, respectively. The assay demonstrated a within-assay variation coefficient of 7.7% and a between-assay variation coefficient of 7.9% for a mean S-nitrosothiol concentration of 2 μM. The detection limit of the assay was 0.1 μM.

Follow-Up Observations

At the 1-yr follow-up assessments, patient outcomes were evaluated (by chart review) by the nephrologists in charge of patient treatment, who were unaware of the S-nitrosothiol values. The primary endpoints were the first occurrence of a fatal or nonfatal major cardiac event and death from all causes. Major adverse cardiac events included cardiac death, nonfatal myocardial infarction, and unstable angina requiring coronary revascularization (angioplasty or bypass surgery). For patients who died, information concerning the circumstances and date of death was obtained and medical reports were procured. Heart failure attributable to fluid overload, which could usually be corrected with hemofiltration for patients without a history of heart failure, was not considered a cardiac event. Patients who received kidney transplants were monitored for 1 yr; they were not censored.

Statistical Methods

Baseline differences between groups with elevated versus normal S-nitrosothiol levels were assessed with the χ2 test and t test for univariate analyses. Multiple logistic regression models were used with the backward selection procedure to identify independent factors significantly associated with elevated plasma S-nitrosothiol values. The Kaplan-Meier product-limit method was used to examine survival rates. The equality of survivor function across groups was tested with the log rank test. The Cox proportional-hazards regression model was used with a stepwise procedure to identify the factors that were significant and predictive of cardiac and global mortality rates at 1 yr. The SAS computer package (SAS Institute, Cary, NC) was used for all statistical analyses. P < 0.05 was considered to be significant. Data are expressed as mean ± SD.

Results

Population Cohort

The main characteristics of the 250 patients included in the study are presented in Table 1. Some of the patients were treated with aspirin (26.8%), β-receptor blockers (31.2%), calcium antagonists (33.6%), angiotensin-converting enzyme inhibitors (24%), and/or lipid-lowering agents (27%). Seventy-six percent of the patients received subcutaneous erythropoietin therapy (106 ± 75 IU/kg per wk).

View this table:
  • View inline
  • View popup

Table 1. Main characteristics of the patient populationa

Biochemical Findings

The mean plasma S-nitrosothiol concentration was 1.77 ± 0.32 μM and the median was 1.78 μM. Theses values were three time higher than the normal mean plasma S-nitrosothiol concentration (11). According to the normal distribution of S-nitrosothiol levels, we divided the population into quartiles (<1.57, 1.57 to 1.78, 1.78 to 2.0, and >2.0 μM). The top quartile (n = 60) was considered “high titer,” compared with the three other quartiles (“low titer”). Parameters observed to be associated with elevated plasma S-nitrosothiol levels are presented in Table 2. Of note, no significant difference in Kt/V values was observed between the two groups (Table 2).

View this table:
  • View inline
  • View popup

Table 2. Factors associated with elevated plasma S-nitrosothiol levelsa

High S-nitrosothiol titers were significantly associated with elevated systolic BP and elevated pulse pressure, compared with low titers (Table 2). Because pulse pressure is highly correlated with systolic BP, we included only pulse pressure in the multivariate analysis. Pulse pressure remained independently predictive of elevated plasma S-nitrosothiol levels after adjustment for age, time on dialysis, history of ischemic cardiac disease, left ventricular mass, and hemoglobin levels.

One-Year Follow-Up Findings

All of the patients included in the study were monitored for 1 yr or until death. During the 1-yr follow-up period, 36 patients (14.4%) in the study population died, with 16 (6.46%) dying as a result of cardiac causes. Thirty-three patients (13.2%) experienced one or more major adverse cardiac events. Patients with elevated S-nitrosothiol levels demonstrated a significantly higher cardiac mortality rate, compared with patients with low levels (13.3% versus 4.2%, P = 0.012), and experienced more major adverse cardiac events (23.3% versus 10.0%, P = 0.009) (Figure 1). No difference in all-cause mortality rates according to S-nitrosothiol levels was observed (21.7% versus 12.1%, P = 0.068) (Figure 1).

Figure1
  • Download figure
  • Open in new tab
  • Download powerpoint

Figure 1. Kaplan-Meier survival curves for global death and major adverse cardiac events. Findings were compared for hemodialysis (HD) patients with plasma S-nitrosothiol (S-NO) concentrations in the top quartile and HD patients with S-nitrosothiol concentrations in the three other quartiles.

The results of the Cox proportional-hazards analysis are presented in Table 3. All-cause mortality rates depended on age and hemoglobin levels but not on S-nitrosothiol levels. Age (relative risk, 1.07), prior ischemic heart disease (relative risk, 3.93), and plasma S-nitrosothiol levels of >2.0 μM (i.e., the top quartile versus the three other quartiles) (relative risk, 3.30) were significant independent predictors of major adverse cardiac events.

View this table:
  • View inline
  • View popup

Table 3. Unadjusted and adjusted relative risks for global death, cardiac death, and major adverse cardiac events at 1 yr of follow-up monitoringa

In view of the limited number of events (33 patients experienced one or more major adverse cardiac events), we repeated the Cox proportional-hazards analysis and included only covariates with a significance of ≤0.01 in univariate analyses. The relative risk value for plasma S-nitrosothiol levels adjusted for age and prior ischemic heart disease remained unchanged at 3.30 (95% confidence interval, 1.61 to 6.76).

Discussion

Our findings demonstrate that high plasma S-nitrosothiol concentrations are associated with high pulse pressure and are predictive of negative cardiac outcomes among chronic HD patients. These findings support the hypothesis that impairment of S-nitrosothiol bioavailability is involved in the impairment of NO-mediated, endothelium-dependent vasodilation among patients with ESRD, consequently favoring hypertension and cardiovascular events.

This work confirms in a large cohort our previous observation of elevated plasma S-nitrosothiol concentrations among chronic HD patients (11). Recent work by Wlodek et al. (22) demonstrated that plasma S-nitrosothiol levels were higher among patients with chronic renal failure who were not yet undergoing dialysis, compared with healthy control subjects, and levels were slightly but not significantly higher among patients undergoing HD. In that report, however, the authors subsequently expressed S-nitrosothiol amounts per milligram of plasma protein and actually noted lower S-nitrosothiol levels for their HD patients, compared with healthy control subjects. The rationale for this expression is difficult to follow, because S-nitrosothiol molecules are not only peptide-linked, and the elevation of plasma S-nitrosothiol concentrations among patients with ESRD may be attributable to nonpeptidic, low-molecular weight molecules. Furthermore, Wlodek et al. (22) observed plasma S-nitrosothiol concentrations different from those observed in our study, but they used l-cysteine to obtain a standard calibration curve, whereas we used reduced glutathione to obtain the calibration curve. A direct comparison of the results obtained with the two methods is therefore difficult. Determinations of S-nitrosothiol levels have yielded highly variable results in various laboratories (23). We think that, in the absence of a standard method, any direct comparison of S-nitrosothiol concentrations measured in biologic fluids should be limited to results obtained with same methodologic procedure.

Recent epidemiologic studies demonstrated that pulse pressure is associated with the relative risk of cardiovascular events and all-cause death among chronic HD patients (24,25⇓). Arterial stiffness and early pulse wave reflection are the principal determinants of elevated systolic and pulse pressures among patients with ESRD and are associated with left ventricular hypertrophy (26). Recent animal and human data demonstrated a close relationship between reduced NO bioavailability and large-artery distensibility, leading to increased arterial stiffness (27–30⇓⇓⇓). The relationship between S-nitrosothiol levels and pulse pressure observed in this study does not indicate a causal association, because it remains possible, at least theoretically, that the observed increase in pulse pressure is responsible for an increase in NO release (31). In any case, the association between S-nitrosothiol levels and pulse pressure among patients undergoing HD may help link the impairment of NO-mediated, endothelium-dependent vasodilation to the generation of hypertension and consequently the increased frequency of cardiovascular events among patients with ESRD. We are currently undertaking a study to directly test the relationship between plasma S-nitrosothiol concentrations and endothelium-dependent functions, as well as arterial stiffness.

In addition to vascular remodeling, reduced S-nitrosothiol bioavailability may be involved in the genesis of cardiovascular events through other mechanisms, such as increased platelet activation, adhesion, and aggregation (15). Deficiencies of bioactive NO have been observed to be associated with arterial thrombosis in animal models, among individuals with endothelial dysfunction, and among patients with low extracellular GSH-Px activity (15). It was recently demonstrated that low-molecular weight plasma thiols (e.g., S-nitrosoglutathione) play important roles in the formation and activation of S-nitrosoalbumin reservoirs, potentiating NO-mediated inhibition of platelet aggregation (32). The overall decrease in glutathione concentrations among chronic HD patients (17), in association with a relative platelet selectivity of S-nitrosoglutathione (33), may greatly contribute to the compromised hemostasis of chronic renal failure.

The link between elevated plasma S-nitrosothiol concentrations and the development of cardiovascular complications has not been extensively evaluated. Previously, workers postulated that elevated plasma S-nitrosothiol concentrations among women with preeclampsia reflect insufficient nitrosothiol decomposition and NO release at sites that are critical for normal regulation of vascular tone, because of ascorbate deficiency (18). In the latter study, a correlation between S-nitrosothiol concentrations and systolic BP was observed, although it was at the limit of significance (r = 0.43, P = 0.06). Therefore, to the best of our knowledge, this work is the first systematic demonstration of an association between plasma S-nitrosothiol levels and cardiovascular disease in the clinical setting.

Patients with ESRD have high plasma ADMA concentrations, and the latter were observed to be associated with cardiovascular outcomes (8). They were also correlated with increased BP in different populations (34,35⇓). ADMA, an active endogenous inhibitor of NO synthase (36), could influence circulating S-nitrosothiol levels. Because we did not evaluate plasma ADMA levels, we cannot exclude the possibility of an additional increase in plasma S-nitrosothiol concentrations among HD patients when the ADMA-associated inhibition of NO production is lacking. However, that would not modify the impairment of S-nitrosothiol bioavailability among HD patients. If elevated plasma S-nitrosothiol concentrations reflect the intensity of nitrosative stress among HD patients, then they could be the trigger for high ADMA levels. Indeed, intracellular concentrations of ADMA are highly dependent on the activity of the enzyme dimethyldiaminohydrolase, which transforms ADMA into citrulline, and the activity of this enzyme is blocked by oxidative stress (37). This complex relationship is also currently under investigation in our laboratory.

We recognize that many pathways exist for the formation of S-nitrosothiols, which may play a significant role in the cardiovascular system (38). The elevation of circulating S-nitrosothiol levels could reflect a protective mechanism against nitrosative stress (15). In line with this view, we observed normal plasma nitrotyrosine levels among HD patients (11). In that case, S-nitrosothiols (and ADMA) may represent useful markers of cardiovascular disease in ESRD. However, S-nitrosothiols are considered to be potent vasodilators, the action of which is commonly associated with the ability to release NO at physiologically relevant sites (12,39⇓). We previously reported marked simultaneous decreases in ascorbate levels and plasma GSH-Px activity, together with increased plasma S-nitrosothiol concentrations, among patients with ESRD (17). Those findings suggest that, at least under those conditions, an enhanced vasodilatory action of S-nitrosothiols is improbable. It is possible that supplementation with molecules favoring S-nitrosothiol breakdown (e.g., ascorbate) could enhance the release of NO from S-nitrosothiols and thus correct the bioactive NO deficiency among patients with ESRD. In line with this hypothesis, Cross et al. (40) recently demonstrated that the acute administration of vitamin C reduced oxidative stress among patients with chronic renal failure and improved NO-mediated resistance vessel dilation. The effects of ascorbate supplementation on plasma S-nitrosothiol concentrations among HD patients remain to be tested in prospective studies.

In conclusion, elevated plasma S-nitrosothiol concentrations among HD patients are associated with high pulse pressure and prospectively predict cardiac outcomes. These findings support our theory of impaired S-nitrosothiol bioavailability, which might be an important risk factor for the excessive cardiovascular death rates among such patients. Intervention trials are needed to investigate the hypothesis that supplementation with molecules that enhance S-nitrosothiol breakdown could lead to increased NO release and favorably affect cardiovascular outcomes among patients with ESRD.

Acknowledgments

We have no conflict of interest to report. Dr. Massy had full access to all of the data in the study and had final responsibility for the decision to submit the manuscript for publication.

  • © 2004 American Society of Nephrology

References

  1. ↵
    Jungers P, Nguyen-Khoa T, Joly D, Choukroun G, Witko-Sarsat V, Massy ZA: Atherosclerotic complications in chronic renal failure: Epidemiology and predictive factors. Adv Nephrol 30: 177–199, 2000
  2. ↵
    London GM, Drüeke TB: Atherosclerosis and arteriosclerosis in chronic renal failure. Kidney Int 51: 1678–1695, 1997
    OpenUrlCrossRefPubMed
  3. ↵
    Thambyrajah J, Landray MJ, McGlynn FJ, Jones HJ, Wheeler DC, Townend JN: Abnormalities of endothelial function in patients with predialysis renal failure. Heart 83: 205–209, 2000
    OpenUrlAbstract/FREE Full Text
  4. ↵
    Joannides R, Bakkali EH, Le Roy F, Rivault O, Godin M, Moore N, Fillastre JP, Thuillez C: Altered flow-dependent vasodilatation of conduit arteries in maintenance haemodialysis. Nephrol Dial Transplant 12: 2623–2628, 1997
    OpenUrlCrossRefPubMed
  5. ↵
    van Guldener C, Lambert J, Janssen MJ, Donker AJ, Stehouwer CD: Endothelium-dependent vasodilatation and distensibility of large arteries in chronic haemodialysis patients. Nephrol Dial Transplant 12 [Suppl 2]: 14–18, 1997
  6. ↵
    Kielstein JT, Boger RH, Bode-Boger SM, Schaffer J, Barbey M, Koch KM, Frolich JC: Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: Relationship to treatment method and atherosclerotic disease. J Am Soc Nephrol 10: 594–600, 1999
    OpenUrlAbstract/FREE Full Text
  7. ↵
    Zoccali C, Mallamaci F, Maas R, Benedetto FA, Tripepi G, Malatino LS, Cataliotti A, Bellanuova I, Boger R: Left ventricular hypertrophy, cardiac remodeling and asymmetric dimethylarginine (ADMA) in hemodialysis patients. Kidney Int 62: 339–345, 2002
    OpenUrlCrossRefPubMed
  8. ↵
    Zoccali C, Bode-Boger S, Mallamaci F, Benedetto F, Tripepi G, Malatino L, Cataliotti A, Bellanuova I, Fermo I, Frolich J, Boger R: Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: A prospective study. Lancet 358: 2113–2117, 2001
    OpenUrlCrossRefPubMed
  9. ↵
    Schmidt RJ, Baylis C: Total nitric oxide production is low in patients with chronic renal disease. Kidney Int 58: 1261–1266, 2000
    OpenUrlCrossRefPubMed
  10. ↵
    Lau T, Owen W, Yu YM, Noviski N, Lyons J, Zurakowski D, Tsay R, Ajami A, Young VR, Castillo L: Arginine, citrulline, and nitric oxide metabolism in end-stage renal disease patients. J Clin Invest 105: 1217–1225, 2000
    OpenUrlCrossRefPubMed
  11. ↵
    Massy ZA, Borderie D, Nguyen-Khoa T, Drüeke TB, Ekindjian OG, Lacour B: Increased plasma S-nitrosothiol levels in chronic haemodialysis patients. Nephrol Dial Transplant 18: 153–157, 2003
    OpenUrlCrossRefPubMed
  12. ↵
    Rassaf T, Kleinbongard P, Preik M, Dejam A, Gharini P, Lauer T, Erckenbrecht J, Duschin A, Schulz R, Heusch G, Feelisch M, Kelm M: Plasma nitrosothiols contribute to the systemic vasodilator effects of intravenously applied NO: Experimental and clinical study on the fate of NO in human blood. Circ Res 91: 470–477, 2002
    OpenUrlAbstract/FREE Full Text
  13. ↵
    Jourd’heuil D, Jourd’heuil FL, Feelisch M: Oxidation and nitrosation of thiols at low micromolar exposure to nitric oxide: Evidence for a free radical mechanism. J Biol Chem 278: 15720–15726, 2003
    OpenUrlAbstract/FREE Full Text
  14. ↵
    Suliman ME, Anderstam B, Lindholm B, Bergstrom J: Total, free, and protein-bound sulphur amino acids in uraemic patients. Nephrol Dial Transplant 12: 2332–2338, 1997
    OpenUrlCrossRefPubMed
  15. ↵
    Loscalzo J: Nitric oxide insufficiency, platelet activation, and arterial thrombosis. Circ Res 88: 756–762, 2001
    OpenUrlAbstract/FREE Full Text
  16. ↵
    De Man JG, De Winter BY, Moreels TG, Herman AG, Pelckmans PA: S-Nitrosothiols and the nitrergic neurotransmitter in the rat gastric fundus: Effect of antioxidants and metal chelation. Br J Pharmacol 123: 1039–1046, 1998
    OpenUrlCrossRefPubMed
  17. ↵
    Nguyen-Khoa T, Massy ZA, De Bandt JP, Kebede M, Salama L, Lambrey G, Witko-Sarsat V, Drüeke TB, Lacour B, Thevenin M: Oxidative stress and haemodialysis: Role of inflammation and duration of dialysis treatment. Nephrol Dial Transplant 16: 335–340, 2001
    OpenUrlCrossRefPubMed
  18. ↵
    Tyurin VA, Liu SX, Tyurina YY, Sussman NB, Hubel CA, Roberts JM, Taylor RN, Kagan VE: Elevated levels of S-nitrosoalbumin in preeclampsia plasma. Circ Res 88: 1210–1215, 2001
    OpenUrlAbstract/FREE Full Text
  19. ↵
    Devereux RB, Lutas EM, Casale PN, Kligfield P, Eisenberg RR, Hammond IW, Miller DH, Reis G, Alderman MH, Laragh JH: Standardization of M-mode echocardiographic left ventricular anatomic measurements. J Am Coll Cardiol 4: 1222–1230, 1984
    OpenUrlCrossRefPubMed
  20. ↵
    Daugirdas JT: Second generation logarithmic estimates of single-pool variable volume Kt/V: An analysis of error. J Am Soc Nephrol 4: 1205–1213, 1993
    OpenUrlAbstract
  21. ↵
    Borderie D, Massy ZA, Nguyen-Khoa T, Drüeke TB, Ekindjian OG, Lacour B: Are plasma S-nitrosothiol levels elevated in chronic renal failure? Nephrol Dial Transplant 18: 2199–2201, 2003
    OpenUrlCrossRefPubMed
  22. ↵
    Wlodek PJ, Kucharczyk J, Sokolowska MM, Milkowski A, Markiewicz A, Smolenski OB, Wlodek LB: Alteration in plasma levels of nonprotein sulfhydryl compounds and S-nitrosothiols in chronic renal failure patients. Clin Chim Acta 327: 87–94, 2003
    OpenUrlCrossRefPubMed
  23. ↵
    Giustarini D, Milzani A, Colombo R, Dalle-Donne I, Rossi R: Nitric oxide and S-nitrosothiols in human blood. Clin Chim Acta 330: 85–98, 2003
    OpenUrlCrossRefPubMed
  24. ↵
    Tozawa M, Iseki K, Iseki C, Takishita S: Pulse pressure and risk of total mortality and cardiovascular events in patients on chronic hemodialysis. Kidney Int 61: 717–726, 2002
    OpenUrlCrossRefPubMed
  25. ↵
    Klassen PS, Lowrie EG, Reddan DN, DeLong ER, Coladonato JA, Szczech LA, Lazarus JM, Owen WF Jr: Association between pulse pressure and mortality in patients undergoing maintenance hemodialysis. JAMA 287: 1548–1555, 2002
    OpenUrlCrossRefPubMed
  26. ↵
    London GM, Marchais SJ, Guerin AP, Metivier F, Adda H: Arterial structure and function in end-stage renal disease. Nephrol Dial Transplant 17: 1713–1724, 2002
    OpenUrlCrossRefPubMed
  27. ↵
    Fitch RM, Vergona R, Sullivan ME, Wang YX: Nitric oxide synthase inhibition increases aortic stiffness measured by pulse wave velocity in rats. Cardiovasc Res 51: 351–358, 2001
    OpenUrlCrossRefPubMed
  28. ↵
    Wilkinson IB, Qasem A, McEniery CM, Webb DJ, Avolio AP, Cockcroft JR: Nitric oxide regulates local arterial distensibility in vivo. Circulation 105: 213–217, 2002
    OpenUrlAbstract/FREE Full Text
  29. ↵
    Kinlay S, Creager MA, Fukumoto M, Hikita H, Fang JC, Selwyn AP, Ganz P: Endothelium-derived nitric oxide regulates arterial elasticity in human arteries in vivo. Hypertension 38: 1049–1053, 2001
    OpenUrlAbstract/FREE Full Text
  30. ↵
    McVeigh GE, Allen PB, Morgan DR, Hanratty CG, Silke B: Nitric oxide modulation of blood vessel tone identified by arterial waveform analysis. Clin Sci 100: 387–393, 2001
    OpenUrlCrossRefPubMed
  31. ↵
    Recchia FA, Senzaki H, Saeki A, Byrne BJ, Kass DA: Pulse pressure-related changes in coronary flow in vivo are modulated by nitric oxide and adenosine. Circ Res 79: 849–856, 1996
    OpenUrlAbstract/FREE Full Text
  32. ↵
    Crane MS, Ollosson R, Moore KP, Rossi AG, Megson IL: Novel role for low molecular weight plasma thiols in nitric oxide-mediated control of platelet function. J Biol Chem 277: 46858–46863, 2002
    OpenUrlAbstract/FREE Full Text
  33. ↵
    de Belder AJ, MacAllister R, Radomski MW, Moncada S, Vallance PJ: Effects of S-nitroso-glutathione in the human forearm circulation: Evidence for selective inhibition of platelet activation. Cardiovasc Res 28: 691–694, 1994
    OpenUrlCrossRefPubMed
  34. ↵
    Miyazaki H, Matsuoka H, Cooke JP, Usui M, Ueda S, Okuda S, Imaizumi T: Endogenous nitric oxide synthase inhibitor: A novel marker of atherosclerosis. Circulation 99: 1141–1146, 1999
    OpenUrlAbstract/FREE Full Text
  35. ↵
    Kielstein JT, Bode-Boger SM, Frolich JC, Ritz E, Haller H, Fliser D: Asymmetric dimethylarginine, blood pressure, and renal perfusion in elderly subjects. Circulation 107: 1891–1895, 2003
    OpenUrlAbstract/FREE Full Text
  36. ↵
    Vallance P: Importance of asymmetrical dimethylarginine in cardiovascular risk. Lancet 358: 2096–2097, 2001
    OpenUrlCrossRefPubMed
  37. ↵
    Locatelli F, Canaud B, Eckardt KU, Stenvinkel P, Wanner C, Zoccali C: Oxidative stress in end-stage renal disease: An emerging threat to patient outcome. Nephrol Dial Transplant 18: 1272–1280, 2003
    OpenUrlCrossRefPubMed
  38. ↵
    Muller B, Kleschyov AL, Alencar JL, Vanin A, Stoclet JC: Nitric oxide transport and storage in the cardiovascular system. Ann NY Acad Sci 962: 131–139, 2002
    OpenUrlCrossRefPubMed
  39. ↵
    Hogg N: Biological chemistry and clinical potential of S-nitrosothiols. Free Radical Biol Med 28: 1478–1486, 2000
    OpenUrlCrossRefPubMed
  40. ↵
    Cross JM, Donald AE, Nuttall SL, Deanfield JE, Woolfson RG, Macallister RJ: Vitamin C improves resistance but not conduit artery endothelial function in patients with chronic renal failure. Kidney Int 63: 1433–1442, 2003
    OpenUrlCrossRefPubMed
PreviousNext
Back to top

In this issue

Journal of the American Society of Nephrology: 15 (2)
Journal of the American Society of Nephrology
Vol. 15, Issue 2
1 Feb 2004
  • Table of Contents
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article
Thank you for your help in sharing the high-quality science in JASN.
Enter multiple addresses on separate lines or separate them with commas.
Increased Plasma S-Nitrosothiol Concentrations Predict Cardiovascular Outcomes among Patients with End-Stage Renal Disease: A Prospective Study
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Increased Plasma S-Nitrosothiol Concentrations Predict Cardiovascular Outcomes among Patients with End-Stage Renal Disease: A Prospective Study
Ziad A. Massy, Christine Fumeron, Didier Borderie, Philippe Tuppin, Thao Nguyen-Khoa, Marie-Odile Benoit, Christian Jacquot, Claude Buisson, Tilman B. Drüeke, Ohvanesse G. Ekindjian, Bernard Lacour, Marie-Christine Iliou
JASN Feb 2004, 15 (2) 470-476; DOI: 10.1097/01.ASN.0000106716.22153.BB

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Increased Plasma S-Nitrosothiol Concentrations Predict Cardiovascular Outcomes among Patients with End-Stage Renal Disease: A Prospective Study
Ziad A. Massy, Christine Fumeron, Didier Borderie, Philippe Tuppin, Thao Nguyen-Khoa, Marie-Odile Benoit, Christian Jacquot, Claude Buisson, Tilman B. Drüeke, Ohvanesse G. Ekindjian, Bernard Lacour, Marie-Christine Iliou
JASN Feb 2004, 15 (2) 470-476; DOI: 10.1097/01.ASN.0000106716.22153.BB
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • References
  • Figures & Data Supps
  • Info & Metrics
  • View PDF

More in this TOC Section

  • Relative Contribution of Residual Renal Function and Different Measures of Adequacy to Survival in Hemodialysis Patients: An analysis of the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD)-2
  • Features of Chronic Hemodialysis Practice after the Marmara Earthquake
  • The Relationship Between Systemic and Whole-Body Hematocrit Is Not Constant during Ultrafiltration on Hemodialysis
Show more Dialysis

Cited By...

  • S-Nitrosylation in Cardiovascular Signaling
  • Low Total Vitamin C Plasma Level Is a Risk Factor for Cardiovascular Morbidity and Mortality in Hemodialysis Patients
  • Impaired vasodilation by red blood cells in sickle cell disease
  • Role of Circulating S-Nitrosothiols in Control of Blood Pressure
  • S-Nitrosoalbumin and Other S-Nitrosothiols in the Blood: Is Their Quantity of No Relevance?
  • S-Nitrosothiols in the Blood: Roles, Amounts, and Methods of Analysis
  • Google Scholar

Similar Articles

Related Articles

  • This Month’s Highlights
  • PubMed
  • Google Scholar

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Annual Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Author Resources
  • Editorial Fellowship Program
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • JASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About JASN
  • JASN Email Alerts
  • JASN Key Impact Information
  • JASN Podcasts
  • JASN RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Feedback
  • Follow on Twitter
  • Password/Email Address Changes
  • Subscribe to ASN Journals

© 2021 American Society of Nephrology

Print ISSN - 1046-6673 Online ISSN - 1533-3450

Powered by HighWire