From the Departments of Internal Medicine (A.M., A.N., M.N., A.G.),
Biostatistics and Epidemiology (K.A.), Cell Biology (D.W.J.), Cardiology
(K.R.), and Nephrology and Hypertension (V.W.D.), The Cleveland Clinic
Foundation, Cleveland, Ohio. Dr Gupta is currently at the Department of
Cardiology, Sinai Samaritan Medical Center, Milwaukee, Wis.
Correspondence to Killian Robinson, MD, Desk F15, Department of Cardiology, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail robinsk{at}ccsmtp.ccf.org
Methods and Results—In all, 167 patients (93 men, 74 women; mean
age, 56.3±14.7 years) were followed for a mean duration of 17.4±6.4
months. Cardiovascular events and causes of mortality
were related to total homocysteine values and other
cardiovascular risk factors. Cox regression
analysis was used to identify the independent predictors for
cardiovascular events and mortality. Fifty-five
patients (33%) developed cardiovascular events and 31
(19%) died, 12 (8%) of cardiovascular causes. Total
plasma homocysteine values ranged between 7.9 and 315.0 µmol/L.
Levels were higher in patients who had cardiovascular
events or died of cardiovascular causes (43.0±48.6
versus 26.9±14.9 µmol/L, P=.02). The relative
risk (RR) for cardiovascular events, including death,
increased 1% per µmol/L increase in total homocysteine
concentration (RR, 1.01; CI, 1.00 to 1.01; P=.01).
Conclusions—These prospective observations confirm that
hyperhomocysteinemia is an independent risk factor for
cardiovascular morbidity and mortality in end-stage
renal disease, with an increased RR of 1% per µmol/L increase
in total homocysteine concentration. Interventional studies are needed
to evaluate the possible effects of modifying this risk factor in these
patients.
Total Plasma Homocysteine
Risk Factors for Vascular Disease
Diagnostic Criteria for Vascular Events
Thromboembolic Episodes
Atherosclerosis
Peripheral Vascular Disease
Cerebrovascular Disease
Cardiovascular Death
Statistical Analysis
Relationship of Homocysteine to Cardiovascular Outcomes
In this study, patients who developed cardiovascular
complications had higher baseline homocysteine concentrations, on
average, than those who did not develop cardiovascular
events. Independent predictors for cardiovascular
complications or death included increased homocysteine concentration,
diabetes mellitus, and increasing age. The relative risk for the
occurrence of cardiovascular events or death increased
1% for each µmol/L increase in homocysteine concentration.
The mechanisms by which homocysteine enhances thrombosis and
atherosclerosis remain uncertain. The major focus of
current studies, however, is on endothelium as the site
of initiation of vascular damage. Postulated mechanisms include direct
endothelial cytotoxicity12 13 or
encouragement of smooth muscle cell growth and inhibition of
endothelial cell proliferation.14
Oxidant stress may play a role in endothelial cell
damage.13 In monkeys, diet-induced
hyperhomocysteinemia is associated with altered
endothelium-dependent vascular
function,15 and in humans, homocysteine may
inhibit endothelium-dependent dilation, suggesting
interference with nitric oxide.16
Limitations of the present study include the relatively short
duration of follow-up (18 months) and the small patient numbers, which
did not permit analysis of subsets such as women or the
elderly. Assessment of the relative contribution of homocysteine levels
to the risk of thrombotic compared with atherosclerotic events was also
difficult. Nevertheless, the data demonstrate the expected rates of
overall cardiovascular events according to prevailing
homocysteine levels in ESRD and will be useful in developing
interventional studies.
In summary, prospective observations confirm that patients with
increased homocysteine concentrations are more likely to develop fatal
or nonfatal thrombotic or atherosclerotic complications. Because
homocysteine concentrations can be reduced by the administration of
folic acid either alone or combined with vitamin
B6 or
B12,17 18 19 interventional
studies are now justified to evaluate such treatment.
Received September 17, 1997;
revision received October 30, 1997;
accepted November 1, 1997.
2.
Chauveau P, Chadefaux B, Coude M, Aupetit J,
Hannedouche T, Kamoun P, Jungers P. Hyperhomocysteinaemia, a risk
factor for atherosclerosis in chronic uremic patients.
Kidney Int. 1993;43(suppl 41):S72–S77.
3.
Bachmann J, Tepel M, Raidt H, Riezler R, Graefe U,
Langer K, Zidek W. Hyperhomocysteinemia and the risk for vascular
disease in hemodialysis patients. J Am Soc Nephrol. 1995;6:121–125.[Abstract]
4.
Robinson K, Gupta A, Dennis V, Arheart K, Chaudhary D,
Green R, Vigo P, Mayer EL, Selhub J, Kutner M, Jacobsen DW.
Hyperhomocysteinemia confers an independent increased risk of
atherosclerosis in end-stage renal disease and is
closely linked to plasma folate and pyridoxine concentrations.
Circulation. 1996;94:2743–2748.
5.
Jacobsen DW, Gatautis VJ, Green R, Robinson K, Savon
SR, Secic M, Ji J, Otto JM, Taylor LM. Rapid HPLC determination of
total homocysteine and other thiols in serum and plasma: sex
differences and correlation with cobalamin and folate levels in healthy
subjects. Clin Chem. 1994;40:873–881.
6.
Ueland PM, Refsum H, Brattström L. Plasma
homocysteine and cardiovascular disease. In: Francis RB
Jr, ed. Atherosclerotic Cardiovascular Disease,
Hemostasis, and Endothelial Function. New York,
NY: Marcel Dekker Inc; 1992:183–236.
7.
Mayer EM, Jacobsen DW, Robinson K. Homocysteine and
coronary atherosclerosis. J Am Coll
Cardiol. 1996;27:517–527.[Abstract]
8.
Graham IM, Daly LE, Refsum HM, Robinson K,
Brattström LE, Ueland PM, Palma-Reis RJ, Boers GHJ, Sheahan RG,
Israelsson B, Uiterwaal CS, Meleady R. Plasma homocysteine as a risk
factor for vascular disease: the European Concerted Action Project.
JAMA. 1997;277:1775–1781.
9.
Arnesen E, Refsum H, Bonaa KH, Ueland PM, Forde OH,
Nordrehaug JE. Serum total homocysteine and coronary heart
disease. Int J Epidemiol. 1995;24:704–709.
10.
Robinson K, Mayer EL, Miller DP, Green R, van Lente F,
Gupta A, Kottke-Marchant K, Savon SR, Selhub J, Nissen SE, Kutner M,
Topol E, Jacobsen DW. Hyperhomocysteinemia and low pyridoxal phosphate:
common and independent reversible risk factors for coronary
artery disease. Circulation. 1995;92:2825–2830.
11.
Shemin D, Bostom AG, Verhoef P, Nadeau M, Jacques PF,
Selhub J, Dworkin L, Rosenberg IH. Total plasma homocysteine (tHCY)
levels and mortality in dialysis patients. J Am Soc
Nephrol. 1996;7:1464. Abstract.
12.
Starkebaum G, Harlan JM. Endothelial
cell injury due to copper-catalyzed hydrogen peroxide generation from
homocysteine. J Clin Invest. 1986;77:1370–1376.
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Loscalzo J. The oxidant stress of
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Schlegel R, Lee ME. Promotion of vascular smooth muscle cell growth by
homocysteine: a link to atherosclerosis. Proc
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© 1998 American Heart Association, Inc.
Brief Rapid Communications
Prospective Study of Hyperhomocysteinemia as an Adverse Cardiovascular Risk Factor in End-Stage Renal Disease
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Retrospective and
case-control studies show that hyperhomocysteinemia is an independent
risk factor for atherosclerosis in patients with
end-stage renal disease. We studied prospectively the association
between total homocysteine and cardiovascular outcomes.
Key Words: homocysteine • risk factors • kidney • artherosclerosis • thrombosis
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
The 1-year mortality
rate for patients on dialysis in the United States between 1991 and
1993 was 23%, with cardiovascular and cerebrovascular
diseases accounting for 
47% of these deaths.1
Case-control studies show that high total plasma homocysteine (tHcy)
concentrations (>14.5 µmol/L) increase the risk for vascular
events in these patients independent of other known risk factors such
as diabetes, hypertension,
hypercholesterolemia, and
smoking.2 3 4 This study examines prospectively
the association between tHcy and cardiovascular events
in patients with end-stage renal disease (ESRD).
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Subjects
We studied 176 patients with ESRD on dialysis for at least 90
days. One hundred thirty were on hemodialysis and 46 on peritoneal
dialysis. We previously reported the association between homocysteine
values and vascular events in these patients by use of a case-control
design.4
Baseline predialysis tHcy values were determined between March
and April 1995 by the method of Jacobsen et
al.5
Total fasting cholesterol concentrations were
measured on the same samples as used for measurement of homocysteine.
Hypercholesterolemia, hypertension, diabetes
mellitus, and smoking status were defined in our previous
report.4
All vascular events that occurred after homocysteine
concentrations were originally measured in this patient population were
documented. Clinical criteria were used for the diagnosis of these
events, which were confirmed by standard tests.
Device-related or venous thrombosis was diagnosed by contrast
angiography and/or duplex ultrasound. Unexplained ischemic
stroke was diagnosed by clinical presentation, CT, and
MRI.
Coronary Artery Disease Events
New coronary artery disease events that developed after
the measurement of the baseline homocysteine concentration were
diagnosed in the presence of (1) documented myocardial infarction or
unstable angina, (2) a stenosis of 
70% of at least one major
epicardial coronary vessel at coronary angiography, (3)
an abnormal cardiac functional test defined as a detectable wall motion
abnormality on dobutamine
echocardiography or the presence of reversible
perfusion defects on persantine or sestamibi thallium tests, or (4) a
requirement for coronary revascularization
by percutaneous angioplasty or bypass surgery.
Peripheral vascular disease was diagnosed by the
development of intermittent claudication, accompanied by diminished
pulses on clinical examination and combined with measurements of
peripheral vascular resistance and/or angiography.
New-onset cerebrovascular disease was always suspected in
patients with recent onset of new neurological symptoms, eg, aphasia,
focal deficits, or unilateral paresis and was confirmed by CT or
MRI.
Cardiovascular death was confirmed from death
certificates as well as hospital and other medical records and
observers' accounts. Sudden death was included as a
cardiovascular event.
Descriptive statistics are reported as frequency and percent for
categorical data and as mean and SD or median and interquartile range
for continuous data. Percentages were compared by Pearson's
2 test or Fisher's exact test, depending on
the frequencies. Student's t test was used to compare
continuous variables. Cox regression was used to evaluate the
significance of risk factors for cardiovascular events
and for a composite end point of cardiovascular events
and cardiovascular mortality. To ascertain the effect
of arteriovenous fistula thrombosis on the risk attributable to tHcy,
we built two separate models. Age, sex, and homocysteine were always
included. A stepwise procedure was used to choose other significant
risk factors for the model from a set of variables that included
smoking, diabetes, hypertension, total cholesterol, LDL
cholesterol, and creatinine. Risk ratios and
95% confidence limits are reported. Statistical test results having a
probability of 
.05 are considered statistically significant.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
There were 176 patients with ESRD at baseline. Nine (5%) were
lost to follow-up. The remaining 167 patients were followed for a mean
duration of 17.4±6.4 months. Their mean age was 56.3±14.7 years, and
93 (56%) were men. Hypertension and diabetes were present in 142
patients (85%) and 55 patients (33%), respectively. Fifty-nine
patients (35%) had a history of current smoking or of ever having
smoked. Mean cholesterol and creatinine
concentrations were 189.3±71.2 and 12.2±4.4 mg/dL,
respectively. Mean tHcy concentration was 32.7±32.2 µmol/L, and
median concentration was 25.4 µmol/L (interquartiles, 19.7 and
33.5 µmol/L). Ninety percent of patients were
hyperhomocysteinemic, with values >14.5
µmol/L.4 The demographic data for patients in
each quartile of tHcy are shown in Table 1
.
View this table:
[in a new window]
Table 1. Demographic and Clinical Characteristics of Study
Patients in Each Quartile of Total Homocysteine Concentration
Of the 167 patients, 55 (33%) had one or more
cardiovascular complications within the follow-up
period. Overall, 31 patients (19%) died, 12 (8%) of
cardiovascular causes (see Table 2). tHcy concentrations were higher, on
average, in patients with cardiovascular complications
than in those without (43.4±50.6 versus 27.4±14.9 µmol/L,
P=.03). Similarly, mean tHcy concentration was higher in the
group of patients who had adverse cardiovascular events
(complication or death) than in those who did not (43.0±48.6 versus
26.9±14.9 µmol/L, P=.02). Patients in the upper
quartile of homocysteine values (>33.6 µmol/L) were more likely
to develop a cardiovascular complication than patients
in the lower three quartiles (18 of 40, 45%, versus 37 of 127, 29%;
P=.06). Similarly, cardiovascular deaths
were more common in patients in the upper quartile of tHcy values than
in those in the lower three quartiles (7 of 40, 18%, versus 5 of 116,
4%; P=.01). Cox regression analysis showed that
tHcy (RR, 1.01; CI, 1.00 to 1.01; P=.01) and diabetes
mellitus (RR, 2.38; CI, 1.43 to 3.96; P<.01) were
independent predictors for cardiovascular complications
or death. This corresponds to an increase in relative risk for
cardiovascular events or death of 1% per µmol/L
increase in tHcy concentration. When arteriovenous fistula thrombosis
events were excluded from the cardiovascular events,
analysis showed that tHcy (RR, 1.01; CI, 1.00 to 1.01;
P=.03) and diabetes (RR, 2.27; CI, 1.23 to 4.20;
P=.01) remained independent predictors for
cardiovascular complications or death. The
Figure depicts the probability for
event-free survival for patients with mean homocysteine concentrations
of 10, 33, and 100 µmol/L.
View this table:
[in a new window]
Table 2. Cardiovascular Complications and
Causes of Cardiovascular Death in Study Patients
View larger version (16K):
[in a new window]
Figure 1. Probability for event-free survival during the follow-up
period for patients with mean homocysteine (Hcy) values of 10, 33, and
100 µmol/L.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
This study extends our previous case-control
analysis4 and confirms prospectively that
there is a relationship between homocysteine concentrations and
vascular complications in patients with ESRD. There was a high
incidence of cardiovascular complications, including
death, in this population, which is characterized by high prevalences
of hypertension, hypercholesterolemia,
diabetes, and smoking. In both retrospective and prospective studies,
hyperhomocysteinemia is a common and independent risk factor for
cardiovascular disease,6 7 8 9 10 11 and
case-control studies indicate a similar association in
ESRD.2 3 4
Acknowledgments
This study was supported in part by the Baxter Extramural Grant
Program and by grant HL-52234 (Dr Jacobsen) from the Heart, Lung, and
Blood Institute of the National Institutes of Health. We acknowledge
the secretarial assistance of Marie Scott and the cooperation of other
physicians in the Department of Nephrology and Hypertension
for permission to study patients under their care. The authors also
acknowledge the expert technical assistance provided by Diane Pexa,
Susan R. Savon, and Ruth V. Earley.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
1.
US Renal Data System, USRDS. Annual Data Report;
National Institutes of Health, National Institute of Diabetes and
Digestive and Kidney Diseases, Bethesda, Md, April 1996, 1996.
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J. Oh, R. Wunsch, M. Turzer, M. Bahner, P. Raggi, U. Querfeld, O. Mehls, and F. Schaefer Advanced Coronary and Carotid Arteriopathy in Young Adults With Childhood-Onset Chronic Renal Failure Circulation, July 2, 2002; 106(1): 100 - 105. [Abstract] [Full Text] [PDF]
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S. Billion, B. Tribout, E. Cadet, C. Queinnec, J. Rochette, P. Wheatley, and P. Bataille Hyperhomocysteinaemia, folate and vitamin B12 in unsupplemented haemodialysis patients: effect of oral therapy with folic acid and vitamin B12 Nephrol. Dial. Transplant., March 1, 2002; 17(3): 455 - 461. [Abstract] [Full Text] [PDF]
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I. B. Salusky and W. G. Goodman Cardiovascular calcification in end-stage renal disease Nephrol. Dial. Transplant., February 1, 2002; 17(2): 336 - 339. [Abstract] [Full Text] [PDF]
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F. Kronenberg, E. Kuen, E. Ritz, P. Konig, G. Kraatz, K. Lhotta, J. F. E. Mann, G. A. Muller, U. Neyer, W. Riegel, et al. Apolipoprotein A-IV Serum Concentrations Are Elevated in Patients with Mild and Moderate Renal Failure J. Am. Soc. Nephrol., February 1, 2002; 13(2): 461 - 469. [Abstract] [Full Text] [PDF]
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B. Bayes, M. C. Pastor, J. Bonal, J. Junca, and R. Romero Homocysteine and lipid peroxidation in haemodialysis: role of folinic acid and vitamin E Nephrol. Dial. Transplant., November 1, 2001; 16(11): 2172 - 2175. [Abstract] [Full Text] [PDF]
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A. N. FRIEDMAN, A. G. BOSTOM, J. SELHUB, A. S. LEVEY, and I. H. ROSENBERG The Kidney and Homocysteine Metabolism J. Am. Soc. Nephrol., October 1, 2001; 12(10): 2181 - 2189. [Abstract] [Full Text] [PDF]
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J. A. Tice, E. Ross, P. G. Coxson, I. Rosenberg, M. C. Weinstein, M. G. M. Hunink, P. A. Goldman, L. Williams, and L. Goldman Cost-effectiveness of Vitamin Therapy to Lower Plasma Homocysteine Levels for the Prevention of Coronary Heart Disease: Effect of Grain Fortification and Beyond JAMA, August 22, 2001; 286(8): 936 - 943. [Abstract] [Full Text] [PDF]
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S. E. Vollset, H. Refsum, A. Tverdal, O. Nygard, J. E. Nordrehaug, G. S Tell, and P. M. Ueland Plasma total homocysteine and cardiovascular and noncardiovascular mortality: the Hordaland Homocysteine Study Am. J. Clinical Nutrition, July 1, 2001; 74(1): 130 - 136. [Abstract] [Full Text] [PDF]
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F. Gradaus, K. Ivens, A. J. Peters, P. Heering, F.-C. Schoebel, B. Grabensee, and B.-E. Strauer Angiographic progression of coronary artery disease in patients with end-stage renal disease Nephrol. Dial. Transplant., June 1, 2001; 16(6): 1198 - 1202. [Abstract] [Full Text] [PDF]
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 C Le Feuvre, G Dambrin, G Helft, F Beygui, M Touam, J P Grünfeld, A Vacheron, and J P Metzger Clinical outcome following coronary angioplasty in dialysis patients: a case-control study in the era of coronary stenting Heart, May 1, 2001; 85(5): 556 - 560. [Abstract] [Full Text]
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M. E. Suliman, J. C. D. Filho, P. Barany, B. Anderstam, B. Lindholm, and J. Bergstrom Effects of methionine loading on plasma and erythrocyte sulphur amino acids and sulph-hydryls before and after co-factor supplementation in haemodialysis patients Nephrol. Dial. Transplant., January 1, 2001; 16(1): 102 - 110. [Abstract] [Full Text] [PDF]
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J. H. M. Smits, J. van der Linden, P. J. Blankestijn, and T. J. Rabelink Coagulation and haemodialysis access thrombosis Nephrol. Dial. Transplant., November 1, 2000; 15(11): 1755 - 1760. [Full Text] [PDF]
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J. Dierkes, U. Domrose, S. Westphal, A. Ambrosch, H.-P. Bosselmann, K. H. Neumann, and C. Luley Cardiac Troponin T Predicts Mortality in Patients With End-Stage Renal Disease Circulation, October 17, 2000; 102(16): 1964 - 1969. [Abstract] [Full Text] [PDF]
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P. J. Stubbs, M. K. Al-Obaidi, R. M. Conroy, MusB, P. O. Collinson, MRCPath, I. M. Graham, FRCPI, and M. I. M. Noble Effect of Plasma Homocysteine Concentration on Early and Late Events in Patients With Acute Coronary Syndromes Circulation, August 8, 2000; 102(6): 605 - 610. [Abstract] [Full Text] [PDF]
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A. A. House, G. A. Wells, J. G. Donnelly, S. P. Nadler, and P. C. Hebert Randomized trial of high-flux vs low-flux haemodialysis: effects on homocysteine and lipids Nephrol. Dial. Transplant., July 1, 2000; 15(7): 1029 - 1034. [Abstract] [Full Text] [PDF]
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G. SUNDER-PLASSMANN, M. FÖDINGER, H. BUCHMAYER, M. PAPAGIANNOPOULOS, J. WOJCIK, J. KLETZMAYR, B. ENZENBERGER, O. JANATA, W. C. WINKELMAYER, G. PAUL, et al. Effect of High Dose Folic Acid Therapy on Hyperhomocysteinemia in Hemodialysis Patients: Results of the Vienna Multicenter Study J. Am. Soc. Nephrol., June 1, 2000; 11(6): 1106 - 1116. [Abstract] [Full Text]
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H. KIMURA, F. GEJYO, S. SUZUKI, and R. MIYAZAKI The C677T Methylenetetrahydrofolate Reductase Gene Mutation in Hemodialysis Patients J. Am. Soc. Nephrol., May 1, 2000; 11(5): 885 - 893. [Abstract] [Full Text]
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E. K. Hoogeveen, P. J. Kostense, C. Jakobs, J. M. Dekker, G. Nijpels, R. J. Heine, L. M. Bouter, and C. D. A. Stehouwer Hyperhomocysteinemia Increases Risk of Death, Especially in Type 2 Diabetes : 5-Year Follow-Up of the Hoorn Study Circulation, April 4, 2000; 101(13): 1506 - 1511. [Abstract] [Full Text] [PDF]
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C. Zoccali Cardiovascular risk in uraemic patients--is it fully explained by classical risk factors? Nephrol. Dial. Transplant., April 1, 2000; 15(4): 454 - 457. [Full Text] [PDF]
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C.-L. Chao, T.-L. Kuo, and Y.-T. Lee Effects of Methionine-Induced Hyperhomocysteinemia on Endothelium-Dependent Vasodilation and Oxidative Status in Healthy Adults Circulation, February 8, 2000; 101(5): 485 - 490. [Abstract] [Full Text] [PDF]
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C LE FEUVRE Angioplasty and stenting in patients with renal disease Heart, January 1, 2000; 83(1): 7 - 8. [Full Text] [PDF]
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A. G. BOSTOM Homocysteine: "Expensive Creatinine" or Important,Modifiable Risk Factor for Arteriosclerotic Outcomes in Renal TransplantRecipients? J. Am. Soc. Nephrol., January 1, 2000; 11(1): 149 - 151. [Full Text]
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L. El-Khairy, P. M Ueland, O. Nygard, H. Refsum, and S. E Vollset Lifestyle and cardiovascular disease risk factors as determinants of total cysteine in plasma: the Hordaland Homocysteine Study Am. J. Clinical Nutrition, December 1, 1999; 70(6): 1016 - 1024. [Abstract] [Full Text] [PDF]
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A. G. Bostom and J. Selhub Homocysteine and Arteriosclerosis : Subclinical and Clinical Disease Associations Circulation, May 11, 1999; 99(18): 2361 - 2363. [Full Text] [PDF]
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D. SHEMIN, K. L. LAPANE, L. BAUSSERMAN, E. KANAAN, S. KAHN, L. DWORKIN, and A. G. BOSTOM Plasma Total Homocysteine and Hemodialysis Access Thrombosis: AProspective Study J. Am. Soc. Nephrol., May 1, 1999; 10(5): 1095 - 1099. [Abstract] [Full Text]
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A. G. BOSTOM and B. F. CULLETON Hyperhomocysteinemia in Chronic Renal Disease J. Am. Soc. Nephrol., April 1, 1999; 10(4): 891 - 900. [Full Text]
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M.F. Bellamy, I.F.W. McDowell, M.W. Ramsey, M. Brownlee, C. Bones, R.G. Newcombe, and M.J. Lewis Hyperhomocysteinemia After an Oral Methionine Load Acutely Impairs Endothelial Function in Healthy Adults Circulation, November 3, 1998; 98(18): 1848 - 1852. [Abstract] [Full Text] [PDF]
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L. H. Kuller and R. W. Evans Homocysteine, Vitamins, and Cardiovascular Disease Circulation, July 21, 1998; 98(3): 196 - 199. [Full Text] [PDF]
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K. Bennett-Richards, M. Kattenhorn, A. Donald, G. Oakley, Z. Varghese, L. Rees, and J.E. Deanfield Does Oral Folic Acid Lower Total Homocysteine Levels and Improve Endothelial Function in Children With Chronic Renal Failure? Circulation, April 16, 2002; 105(15): 1810 - 1815. [Abstract] [Full Text] [PDF]
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