HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fried, L. F. Articles by Newman, A. B. Search for Related Content PubMed PubMed Citation Articles by Fried, L. F. Articles by Newman, A. B.

CLINICAL STUDY: CARDIAC ISSUES IN WOMEN AND THE ELDERLY

Renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals

Linda F. Fried, MD, MPH^*,*, Michael G. Shlipak, MD, MPH, Casey Crump, MD, PhD^||, Anthony J. Bleyer, MD^¶, John S. Gottdiener, MD, FACC^#, Richard A. Kronmal, PhD^||, Lewis H. Kuller, MD, DrPH, FACC^** and Anne B. Newman, MD, MPH^**

^* Renal Section, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA
Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
Medicine Service, Veterans Affairs Medical Center, San Francisco, California, USA
Departments of Medicine, Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA
^|| Department of Biostatistics, University of Washington, Seattle, Washington, USA
^¶ Section of Nephrology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
^# Division of Cardiology, St. Francis Hospital, Roslyn, New York, USA
^** Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA
Division of Geriatric Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

Manuscript received May 20, 2002; revised manuscript received December 4, 2002, accepted December 30, 2002.

^* Reprint requests and correspondence: Dr. Linda F. Fried, VA Pittsburgh Healthcare System, 111F-U, University Drive C, Pittsburgh, Pennsylvania 15240, USA.
lff9+{at}pitt.edu

	Abstract

Top Abstract Methods Results Discussion References

 
OBJECTIVES: This study was designed to evaluate the relationship between elevated creatinine levels and cardiovascular events.

BACKGROUND: End-stage renal disease is associated with high cardiovascular morbidity and mortality. The association of mild to moderate renal insufficiency with cardiovascular outcomes remains unclear.

METHODS: We analyzed data from the Cardiovascular Health Study, a prospective population-based study of subjects, aged >65 years, who had a serum creatinine measured at baseline (n = 5,808) and were followed for a median of 7.3 years. Proportional hazards models were used to examine the association of creatinine to all-cause mortality and incident cardiovascular mortality and morbidity. Renal insufficiency was defined as a creatinine level 1.5 mg/dl in men or 1.3 mg/dl in women.

RESULTS: An elevated creatinine level was present in 648 (11.2%) participants. Subjects with elevated creatinine had higher overall (76.7 vs. 29.5/1,000 years, p < 0.001) and cardiovascular (35.8 vs. 13.0/1,000 years, p < 0.001) mortality than those with normal creatinine levels. They were more likely to develop cardiovascular disease (54.0 vs. 31.8/1,000 years, p < 0.001), stroke (21.1 vs. 11.9/1,000 years, p < 0.001), congestive heart failure (38.7 vs. 17/1,000 years, p < 0.001), and symptomatic peripheral vascular disease (10.6 vs. 3.5/1,000 years, p < 0.001). After adjusting for cardiovascular risk factors and subclinical disease measures, elevated creatinine remained a significant predictor of all-cause and cardiovascular mortality, total cardiovascular disease (CVD), claudication, and congestive heart failure (CHF). A linear increase in risk was observed with increasing creatinine.

CONCLUSIONS: Elevated creatinine levels are common in older adults and are associated with increased risk of mortality, CVD, and CHF. The increased risk is apparent early in renal disease.

Abbreviations and Acronyms   AAI   ankle-arm index   CHF   congestive heart failure   CHS   Cardiovascular Health Study   CI   confidence interval   CRP   C-reactive protein   CVD   cardiovascular disease   HDL   high-density lipoprotein   HR   hazards ratio   IMT   intima-media thickness   LDL   low-density lipoprotein   MI   myocardial infarction

The prevalence of renal dysfunction rises with age, particularly after age 70 (11). The elderly also have the highest incidence of cardiac events (12) and thus would experience the greatest burden from both cardiovascular disease (CVD) and renal disease. The Cardiovascular Health Study (CHS) is a population-based, longitudinal study of CVD and stroke in men and women aged >65 years. Previous analyses of CHS have found elevated creatinine levels to be among the predictors of total mortality (13) and congestive heart failure (CHF) (14). This report investigates in depth the association of elevated creatinine with cardiovascular events and mortality.

	Methods

Top Abstract Methods Results Discussion References

 
Subjects.   The CHS participants were recruited from Medicare eligibility lists at four locations: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh, Pennsylvania (15). They were invited to participate if they were community dwelling adults over the age of 65, were expected to remain in the area for the next three years, and were able to give informed consent without a proxy. There was not an upper limit of creatinine that defined ineligibility for CHS. The initial cohort was recruited from 1989 to 1990, and a second cohort of 687 African Americans was recruited from 1992 to 1993, resulting in a total of 5,888 participants. Baseline serum creatinine measurements were missing for 80 participants (1.4%), so the final sample for this report is 5,808.

The details of the initial exam have been described elsewhere (15). The baseline examination included interviews and questionnaires regarding medical history, medication use, physical activity, and functional status. Laboratory tests were performed after an 8- to 12-h fast. Baseline cardiovascular status was determined by a review of old records and by electrocardiogram, echocardiography, carotid artery ultrasound, and ankle-arm index (15–17).

We defined an elevated creatinine level using a gender-defined cutoff (1.3 mg/dl for women and 1.5 mg/dl for men), based on prior studies (4,6). We also categorized serum creatinine levels as <1.10, 1.10 to 1.29, 1.30 to 1.49, 1.50 to 1.69, and 1.70 mg/dl to evaluate the presence of a trend with renal dysfunction and cardiovascular risk.

Variables.   Detailed methods for blood drawing, quality assurance, and assay performances have been described previously (17). Serum chemistries, including creatinine, were performed on the Kodak Ektachem 700 Analyzer (Eastman Kodak, Rochester, New York); The Olympus Demand System (Olympus, Lake Success, New York) was used for total and high-density lipoprotein (HDL) cholesterol and triglycerides; low-density lipoprotein (LDL) cholesterol was calculated by the Friedewald formula (18). Fibrinogen was measured in a BBL fibrometer (Becton Dickinson, Cockeysville, Maryland); factor VII was performed using Coag-A-Mate (Organon Teknika, Durham, North Carolina). C-reactive protein was measured using an enzyme-linked immunosorbent assay (19).

Diabetes was defined as the use of insulin or oral hypoglycemic agents, a fasting glucose level 140 mg/dl, or a 2-h glucose level after a 75-g glucose challenge of >200 mg/dl. Impaired glucose tolerance was defined as a fasting glucose level <140 mg/dl but 2-h glucose level between 140 and 199 mg/dl. Prevalent coronary heart disease was defined as the history of any of the following: reported or silent MI or angina, previous coronary bypass surgery or angioplasty, or use of nitrates. Subclinical CVD was defined for subjects without prevalent CVD at baseline as: ankle-arm index (AAI) 0.9, common carotid intima-media thickness (IMT) in upper quintile (>1.20 mm), maximum carotid stenosis 50%, major ECG abnormality (ventricular conduction defect, major Q-wave abnormalities, left ventricular hypertrophy, isolated ST-T wave abnormalities, atrial fibrillation, first degree AV block, or left ventricular ejection fraction borderline or abnormal (20).

Clinical outcomes were ascertained every six months. The primary endpoints collected were all-cause mortality, cardiovascular mortality and morbidity (myocardial infarction [MI], angina, CHF, peripheral vascular disease, stroke, and transient ischemic attack). Event ascertainment followed a defined protocol, and events were adjudicated by committee (21). Cardiovascular disease was defined as any of the following: reported or silent MI, reported angina, coronary artery bypass surgery or angioplasty, use of nitrates, stroke, or transient ischemic attack. The current report examines events through June 30, 1997. The median follow-up was 7.3 years (mean 6.5, range 0.0 to 8.1).

Statistical analysis.   Demographic characteristics, cardiovascular risk factors, and subclinical CVD prevalence at baseline were compared using t test, Kruskal Wallis test, or chi-square test where appropriate. Event rates were compared with Poisson. For nonfatal events, only time to the first event was included in the calculation of rates. For the survival curves, we fitted a Cox proportional hazards model and plotted predicted survival at the average predictor, adjusting for age within the model. Cox proportional hazards models were used to examine the relationship of creatinine with total mortality and each of the cardiovascular outcomes. The main focus was on incident CVD events. Therefore, for these analyses, those with a prior history of the event were excluded. In order to examine subjects with prevalent disease at baseline, we examined the first recurrent MI or cerebrovascular accident event in subjects who had prior MI or cerebrovascular accident. The whole CHS sample was used to evaluate mortality outcomes. Multivariate analysis was conducted to determine the independent association of creatinine categories with each outcome. A backwards stepwise model was used (subject to p < 0.2). The relationship of creatinine with outcomes was nonlinear. Creatinine was categorized and forced into the model.

As renal impairment and CVD rise with age, the initial model was age-adjusted. The second model adjusted for age and subclinical cardiovascular variables (AAI, common carotid IMT, maximum carotid stenosis, major electrocardiographic abnormalities [yes/no], and left ventricular ejection fraction) to determine the extent to which prevalent vascular disease confounded the association of creatinine levels with CVD. Ankle-arm index and common carotid IMT were entered as continuous variables. Maximum carotid stenosis was classified as none, 1% to 24%, 25% to 49%, 50% to 74%, 75% to 99%, and 100%. Left ventricular ejection fraction was classified as normal, borderline, or abnormal.

The third model included age, gender, race, physical activity, LDL cholesterol, HDL cholesterol, triglycerides, systolic and diastolic blood pressure, diabetes, smoking status, fibrinogen, factor VII, aspirin use, and CRP. Lipid values, systolic and diastolic blood pressure, fibrinogen, factor VII, and CRP values were entered as continuous variables. The fourth model adjusted for all the above demographic, comorbidity, biochemical, and vascular disease measures. Interactions of creatinine with gender, diabetes, and race were examined.

STATA Statistical Software, Release 7.0 (Stata Corporation, Inc., College Station, Texas) was used for the analyses. A p value <0.05 was considered statistically significant. Confidence intervals (CI) are expressed as 95% CI.

	Results

Top Abstract Methods Results Discussion References

 
The number of participants in CHS who had elevated creatinine was 648 (11.2%) at baseline, as defined by a serum creatinine 1.3 mg/dl for women and 1.5 mg/dl for men. The mean serum creatinine was 1.2 ± 0.4 mg/dl (range 0.6 to 10.0) in men and 0.9 ± 0.3 mg/dl (range 0.4 to 7.3) in women. The characteristics of those with and without an elevated creatinine are summarized in Table 1. Those with an elevated creatinine were older, more likely to smoke, and had higher levels of inflammatory and prothrombotic markers. Low-density lipoprotein cholesterol levels in both groups were similar, but participants with elevated creatinine had higher triglycerides and lower HDL levels. Those with elevated creatinine had a higher prevalence at baseline of clinical and subclinical CVD; 278 (42.9%) of people with an elevated creatinine had prevalent disease at baseline compared with 1,200 (23.2%) of people without (p < 0.0001). The prevalence of subclinical disease was 446 (68.8%) among individuals with elevated creatinine levels versus 2,260 (43.8%) of those without elevated creatinine (p < 0.001).

View larger version (14K): [in this window] [in a new window]   Figure 1 Age-adjusted survival of subjects in Cardiovascular Health Study (CHS), by serum creatinine (mg/dl).

	Discussion

Top Abstract Methods Results Discussion References

Hemmelgram et al. (22) found that elevated creatinine predicted poor long-term survival in patients undergoing coronary angiography. Mildly to moderately elevated creatinine levels are a risk factor for adverse outcomes after cardiac and noncardiac surgery (23,24). However, these findings may not be generalizable to other populations. In the Framingham study, Culleton et al. (6) found that all-cause mortality was higher than in men with normal creatinine levels. In contrast to our study, however, they did not find that it was a risk factor in women, once they adjusted for age and cardiac risk factors. A recent analysis of the NHANES 2 follow-up data found that those with renal insufficiency had a higher total and cardiovascular mortality rate, after controlling for traditional risk factors (3). They did not have data on nonfatal events or on subclinical disease measurements.

The reasons mild elevation of creatinine is associated with adverse outcomes are not clear. Some risk factors, such as an elevated calcium-phosphorus product, which could promote vascular calcification, do not appear to increase until the glomerular filtration rate is <30 ml/min (25). A possible explanation is that persons with renal insufficiency have greater atherosclerosis burden. However, despite adjustment for several measures of subclinical atherosclerosis, a greater cardiovascular risk remained associated with elevated creatinine levels. Though elevated creatinine was a predictor of CVD as a combined outcome, for many of the individual cardiovascular outcomes, it was no longer an independent predictor after adjustment for other risk factors. It could be that elevated creatinine is a marker of the presence of multiple metabolic abnormalities and that the unexplained risk associated with an elevated creatinine level is due to other factors that were not measured. In particular, we do not have data on proteinuria. In the HOPE trial (2), microalbuminuria was a significant risk factor for CVD events, which was independent of an elevated creatinine level or history of diabetes.

Many of the features associated with renal insufficiency are similar to those described in the metabolic syndrome: hypertension, high triglyceride levels, and low HDL cholesterol. This syndrome has also been associated with increased cardiovascular risk (26). Like the metabolic syndrome (27,28), elevated creatinine levels have been associated with small dense LDL and hyperfibrinogenemia (29,30). Elevated creatinine levels may not be merely a marker of atherosclerosis and increased prevalence of risk factors. Renal disease could also worsen the severity of risk factors, such as hypertension and hyperlipidemia (7). If this hypothesis is true, risk factors would be mediators of the increased risk and could explain why elevated creatinine was no longer a predictor for MI or stroke after adjustment. We do not have longitudinal data on the change in risk factors with the change in creatinine to test this hypothesis.

The kidney is the site of metabolism of many molecules. Chronic renal insufficiency is associated with higher levels of inflammatory markers and homocysteine (10,31–33), which have been associated with cardiovascular events (34–36). Cytokines have been implicated in the pathogenesis of heart failure (37,38). This may be one explanation for why elevated creatinine was a predictor of CHF in our study. Anemia is a common feature of renal disease, as the kidney is the site of erythropoietin synthesis. Levin et al. (39) found that a decline in hemoglobin and an increase in systolic blood pressure predicted an increase in left ventricular mass index in persons with chronic kidney disease, which may be a precursor to the development of heart failure. In our study, we controlled for CRP, systolic blood pressure, and hemoglobin. Elevated creatinine remained an independent predictor of CHF after controlling for these factors.

Study limitations.   Muscle mass tends to decline with age. Therefore, a creatinine level of 1.5 mg/dl in a 75-year-old does not represent the same degree of renal impairment as it does in a 55-year-old (40). A limitation of our study is the lack of more precise measurements of renal function. More precise methods, such as iothalamate clearances, are difficult and expensive to do in large epidemiologic studies, and 24-h creatinine clearances are unreliable (41). The Modification of Diet in Renal Disease formulas, which have been advocated as a more accurate measure of renal function, have not been validated in the elderly (42). Serum creatinine has the advantage of being widely available and a common part of routine chemistry panels. It would, therefore, be relatively easy to use as a screening test for identifying patients at increased risk.

Conclusions.   More than 10% of our cohort had elevated serum creatinine levels, defined as 1.5 mg/dl in men or 1.3 mg/dl in women. As there is an increased risk of CVD in individuals with an elevated creatine, this implies that an elevated creatinine, defined this way, may have a substantial attributable risk for CVD and mortality in the elderly population. As the population ages, the prevalence of renal insufficiency and CVD may also grow. That elevated creatinine is associated with a high prevalence of cardiac risk factors suggests that attention to risk factor reduction may impact the high risk of CVD. A recent Canadian study suggests that cardiac risk factors are inadequately addressed in patients with renal insufficiency (43). In that study, 35% of those with renal insufficiency and established CVD had a blood pressure >140/90 mm Hg; 45% were receiving aspirin, 50% were receiving beta-blockers and only 50% of those with hyperlipidemia were on statins. There is a lack of research on prevention of CVD in individuals with renal insufficiency. The National Cholesterol Education Program (NCEP) Adult Treatment Panel III recommended that diabetes be considered a coronary heart disease equivalent (44). In a similar fashion, the National Kidney Foundation Task Force on Cardiovascular Disease recommended that patients with chronic kidney disease be considered in the highest risk group for cardiovascular events (45). Although this recommendation was not adopted by NCEP, our study supports this recommendation.

In summary, our study found that mildly elevated creatinine levels are predictive of cardiovascular morbidity and mortality. Elevated creatinine was associated with a high prevalence of cardiac risk factors. Further studies aimed at risk reduction of traditional and novel risk factors in those with renal insufficiency are needed in order to have an impact in this high-risk population.

	Footnotes

 
The researchers received funding from the National Heart, Lung, and Blood Institute, contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129 and N01-HC-15103.

	References

Top Abstract Methods Results Discussion References

 

1. Sarnak MJ, Levey AS. Cardiovascular disease and chronic renal disease: a new paradigm. Am J Kidney Dis. 2000;35:S117–131[Medline]
2. for the HOPE InvestigatorsMann JFE, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med. 2001;134:629–636[Abstract/Free Full Text]
3. Muntner P, He J, Hamm L, Loria C, Whelton PK. Renal insufficiency and subsequent death resulting from cardiovascular disease in the United States. J Am Soc Nephrol. 2002;13:745–753[Abstract/Free Full Text]
4. Shlipak MG, Simon JA, Grady D, Lin F, Wenger NK, Furberg CD. Renal insufficiency and cardiovascular events in postmenopausal women with coronary heart disease. J Am Coll Cardiol. 2001;38:705–711[Abstract/Free Full Text]
5. Ruilope LM, Salvetti A, Jamerson K, et al. Renal function and intensive lowering of blood pressure in hypertensive participants of the Hypertension Optimal Treatment (HOT) study. J Am Soc Nephrol. 2001;12:218–225[Abstract/Free Full Text]
6. Culleton BF, Larson MG, Wilson PWF, Evans JC, Parfrey PS, Levy D. Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency. Kidney Int. 1999;56:2214–2219[CrossRef][Medline]
7. Parfrey PS, Foley RN. The clinical epidemiology of cardiac disease in chronic renal failure. J Am Soc Nephrol. 1999;10:1606–1615[Free Full Text]
8. Coresh J, Longenecker JC, Miller ER, Young HJ, Klag MJ. Epidemiology of cardiovascular risk factors in chronic renal disease. J Am Soc Nephrol. 1998;9:S24–30[CrossRef][Medline]
9. Kielstein JT, Frolich JC, Haller H, Fliser D. ADMA (asymmetric dimethylarginine): an atherosclerotic disease mediating agent in patients with renal disease? Nephrol Dial Transplant. 2001;16:1742–1745[Free Full Text]
10. Shlipak MG, Fried LF, Crump C, et al. Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency. Circulation. 2003;107:87–92[Abstract/Free Full Text]
11. Culleton BF, Larson MG, Evans JC, et al. Prevalence and correlates of elevated serum creatinine levels. Arch Intern Med. 1999;159:1785–1790[Abstract/Free Full Text]
12. for the Coordinating Committee of the National Cholesterol Education ProgramGrundy SM, Cleeman JI, Rifkind BM, Kuller LH. Cholesterol lowering in the elderly population. Arch Intern Med. 1999;159:1670–1678[Abstract/Free Full Text]
13. for the Cardiovascular Health Study Collaborative Research GroupFried LP, Kronmal RA, Newman AB, et al. Risk factors for five-year mortality in older adults: the Cardiovascular Health Study. JAMA. 1998;279:585–592[Abstract/Free Full Text]
14. Gottdiener JS, Arnold AM, Aurigemma GP, et al. Predictors of congestive heart failure in the elderly: the Cardiovascular Health Study. J Am Coll Cardiol. 2000;35:1628–1637[Abstract/Free Full Text]
15. for the Cardiovascular Health Study Research Group (CHS)Fried LP, Borhani NO, Enright P, et al. The Cardiovascular Health Study: design and rationale. Ann Epidemiol. 1991;1:263–276[Medline]
16. Psaty BM, Kuller LH, Bild D, et al. Methods of assessing prevalent cardiovascular disease in the Cardiovascular Health Study. Ann Epidemiol. 1995;5:270–277[CrossRef][Medline]
17. Cushman M, Cornell ES, Howard PR, Bovill EG, Tracy RP. Laboratory methods and quality assurance in the Cardiovascular Health Study. Clin Chem. 1995;41:264–270[Abstract/Free Full Text]
18. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma without the use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–501[Abstract]
19. Macy EM, Hayes TE, Tracy RP. Variability in the measurement of C-reactive protein in healthy subjects: implications for reference intervals and epidemiological applications. Clin Chem. 1997;43:52–58[Abstract/Free Full Text]
20. Kuller L, Borhani N, Furberg C, et al. Prevalence of subclinical atherosclerosis and cardiovascular disease and association with risk factors in the Cardiovascular Health Study. Am J Epidemiol. 1994;139:1164–1179[Abstract/Free Full Text]
21. Ives DG, Fitzpatrick AL, Bild DE, et al. Surveillance and ascertainment of cardiovascular events: the Cardiovascular Health Study. Ann Epidemiol. 1995;5:278–285[CrossRef][Medline]
22. Hemmelgram BR, Ghali WA, Quan H, et al. Poor long-term survival after coronary angiography in patients with renal insufficiency. Am J Kidney Dis. 2001;37:64–72[Medline]
23. Participants of VA Cooperative Study #5Anderson RJ, O’Brien M, MaWhinney S, et al. Renal failure predisposes patients to adverse outcome after coronary artery bypass surgery. Kidney Int. 1999;55:1057–1062[CrossRef][Medline]
24. Study of Perioperative Ischemia Research GroupBrowner WS, Li J, Mangano DT, for the. In-hospital and long-term mortality in male veterans following noncardiac surgery. JAMA. 1992;268:228–232[Abstract]
25. Delmez JA, Slatopolsky E. Hyperphosphatemia: its consequences and treatment in patients with chronic renal disease. Am J Kidney Dis. 1992;19:303–317[Medline]
26. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001;24:683–689[Abstract/Free Full Text]
27. Hulthe J, Bokemark L, Wikstrand J, Fagerberg B. The metabolic syndrome, LDL particle size, and atherosclerosis: the Atherosclerosis and Insulin Resistance (AIR) study. Arterioscler Thromb Vasc Biol. 2000;20:2140–2147[Abstract/Free Full Text]
28. Bruno G, Cavallo-Perin P, Bargero G, et al. Hyperfibrinogenemia and metabolic syndrome in type 2 diabetes: a population-based study. Diabetes Metab Res Rev. 2001;17:124–130[CrossRef][Medline]
29. Wanner C, Krane V, Metzger T, Quaschning T. Lipid changes and statins in chronic renal insufficiency and dialysis. J Nephrol. 2001;14(Suppl 4):S76–80[Medline]
30. Catena C, Zingaro L, Casaccio D, Sechi LA. Abnormalities of coagulation in hypertensive patients with reduced creatinine clearance. Am J Med. 2000;109:556–561[CrossRef][Medline]
31. Descamps-Latscha B, Herbelin A, Nguyen AT, et al. Balance between IL-1ß, TNF, and their specific inhibitors in chronic renal failure and maintenance dialysis. Relationships with activation markers of T cells, B cells, and monocytes. J Immunol. 1995;154:882–892[Abstract]
32. Herbelin A, Urena P, Nguyen AT, Zingraff J, Descamps-Latscha B. Elevated circulating levels in interleukin-6 in patients with chronic renal failure. Kidney Int. 1991;39:954–960[Medline]
33. Bostom AG, Culleton BF. Hyperhomocysteinemia in chronic renal disease. J Am Soc Nephrol. 1999;10:891–900[Free Full Text]
34. Tracy RP, Memaitre RN, Psaty BM, et al. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly: results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol. 1997;17:1121–1127[Abstract/Free Full Text]
35. Harris TB, Ferrucci L, Tracy RP, et al. Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med. 1999;106:506–512[CrossRef][Medline]
36. Stampfer MJ, Malinow R, Willett WC, et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in U.S. physicians. JAMA. 1992;268:877–881[Abstract]
37. McTiernan CF, Feldman AM. The role of tumor necrosis factor alpha in the pathophysiology of congestive heart failure. Curr Cardiol Rep. 2000;2:189–197[Medline]
38. Roig E, Orus J, Pare C, et al. Serum interleukin-6 in congestive heart failure secondary to idiopathic dilated cardiomyopathy. Am J Cardiol. 1998;82:688–690[CrossRef][Medline]
39. Levin A, Thompson R, Ethier J, et al. Left ventricular mass index increase in early renal disease: impact of decline in hemoglobin. Am J Kidney Dis. 1999;34:125–134[Medline]
40. Fliser D, Franek E, Joest M, Block S, Mutschler E, Ritz E. Renal function in the elderly: impact of hypertension and cardiac function. Kidney Int. 1997;51:1196–1204[Medline]
41. AASK Pilot Study InvestigatorsCoresh J, Toto RD, Kirk KA, et al. Creatinine clearance as a measure of GFR in screenees for the African-American Study of Kidney Disease and Hypertension pilot study. Am J Kidney Dis. 1998;32:32–42[Medline]
42. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med. 1999;130:461–470[Abstract/Free Full Text]
43. Tonelli M, Bohm C, Pandeya S, Gill J, Levin A, Kiberd BA. Cardiac risk factors and the use of cardioprotective medications in patients with chronic renal insufficiency. Am J Kidney Dis. 2001;37:484–489[Medline]
44. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. 2001;285:2486–2497[Free Full Text]
45. Levey AS, Beto JA, Coronado BE, et al. Controlling the epidemic of cardiovascular disease in chronic renal disease: what do we know? What do we need to learn? Where do we go from here? Am J Kidney Dis. 1998;32:853–906[Medline]

This article has been cited by other articles:

				Y. P. Liew, J. R. Bartholomew, S. Demirjian, J. Michaels, and M. J. Schreiber Jr. Combined Effect of Chronic Kidney Disease and Peripheral Arterial Disease on All-Cause Mortality in a High-Risk Population Clin. J. Am. Soc. Nephrol., July 1, 2008; 3(4): 1084 - 1089. [Abstract] [Full Text] [PDF]

				C. R. Harper and T. A. Jacobson Managing dyslipidemia in chronic kidney disease. J. Am. Coll. Cardiol., June 24, 2008; 51(25): 2375 - 2384. [Abstract] [Full Text] [PDF]

				D. D. Schocken, E. J. Benjamin, G. C. Fonarow, H. M. Krumholz, D. Levy, G. A. Mensah, J. Narula, E. S. Shor, J. B. Young, and Y. Hong Prevention of Heart Failure: A Scientific Statement From the American Heart Association Councils on Epidemiology and Prevention, Clinical Cardiology, Cardiovascular Nursing, and High Blood Pressure Research; Quality of Care and Outcomes Research Interdisciplinary Working Group; and Functional Genomics and Translational Biology Interdisciplinary Working Group Circulation, May 13, 2008; 117(19): 2544 - 2565. [Abstract] [Full Text] [PDF]

				M. Cirillo, M. P. Lanti, A. Menotti, M. Laurenzi, M. Mancini, A. Zanchetti, and N. G. De Santo Definition of Kidney Dysfunction as a Cardiovascular Risk Factor: Use of Urinary Albumin Excretion and Estimated Glomerular Filtration Rate Arch Intern Med, March 24, 2008; 168(6): 617 - 624. [Abstract] [Full Text] [PDF]

				W. Rosamond, K. Flegal, K. Furie, A. Go, K. Greenlund, N. Haase, S. M. Hailpern, M. Ho, V. Howard, B. Kissela, et al. Heart Disease and Stroke Statistics--2008 Update: A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee Circulation, January 29, 2008; 117(4): e25 - e146. [Full Text] [PDF]

				D. Pereg, A. Tirosh, T. Shochat, D. Hasdai, and for the Metabolic, Lifestyle and Nutrition Assessm Mild renal dysfunction associated with incident coronary artery disease in young males Eur. Heart J., January 2, 2008; 29(2): 198 - 203. [Abstract] [Full Text] [PDF]

				J. J. Brugts, E. Boersma, M. Chonchol, J. W. Deckers, M. Bertrand, W. J. Remme, R. Ferrari, K. Fox, M. L. Simoons, and on behalf of the EUROPA Investigators The Cardioprotective Effects of the Angiotensin-Converting Enzyme Inhibitor Perindopril in Patients With Stable Coronary Artery Disease Are Not Modified by Mild to Moderate Renal Insufficiency: Insights From the EUROPA Trial J. Am. Coll. Cardiol., November 27, 2007; 50(22): 2148 - 2155. [Abstract] [Full Text] [PDF]

				M. Yoshida, H. Tomiyama, J. Yamada, Y. Koji, K. Shiina, M. Nagata, and A. Yamashina Relationships among Renal Function Loss within the Normal to Mildly Impaired Range, Arterial Stiffness, Inflammation, and Oxidative Stress Clin. J. Am. Soc. Nephrol., November 1, 2007; 2(6): 1118 - 1124. [Abstract] [Full Text] [PDF]

				M. A. Corriere and K. J. Hansen Commentary on "The Role of Embolic Protection Devices in Renal Artery Stenting" Perspectives in Vascular Surgery and Endovascular Therapy, September 1, 2007; 19(3): 272 - 274. [PDF]

				R. N. Foley, C. Wang, A. Ishani, and A. J. Collins NHANES III: Influence of Race on GFR Thresholds and Detection of Metabolic Abnormalities J. Am. Soc. Nephrol., September 1, 2007; 18(9): 2575 - 2582. [Abstract] [Full Text] [PDF]

				S. G. Wannamethee, P. H. Whincup, L. Lennon, and N. Sattar Circulating Adiponectin Levels and Mortality in Elderly Men With and Without Cardiovascular Disease and Heart Failure Arch Intern Med, July 23, 2007; 167(14): 1510 - 1517. [Abstract] [Full Text] [PDF]

				M. C. Foster, S.-J. Hwang, M. G. Larson, N. I. Parikh, J. B. Meigs, R. S. Vasan, T. J. Wang, D. Levy, and C. S. Fox Cross-Classification of Microalbuminuria and Reduced Glomerular Filtration Rate: Associations Between Cardiovascular Disease Risk Factors and Clinical Outcomes Arch Intern Med, July 9, 2007; 167(13): 1386 - 1392. [Abstract] [Full Text] [PDF]

				V. Menon, M. G. Shlipak, X. Wang, J. Coresh, T. Greene, L. Stevens, J. W. Kusek, G. J. Beck, A. J. Collins, A. S. Levey, et al. Cystatin C as a Risk Factor for Outcomes in Chronic Kidney Disease Ann Intern Med, July 3, 2007; 147(1): 19 - 27. [Abstract] [Full Text] [PDF]

				E. Ingelsson, J. Sundstrom, L. Lind, U. Riserus, A. Larsson, S. Basu, and J. Arnlov Low-grade albuminuria and the incidence of heart failure in a community-based cohort of elderly men Eur. Heart J., July 2, 2007; 28(14): 1739 - 1745. [Abstract] [Full Text] [PDF]

				K. A.A. Fox, E. M. Antman, G. Montalescot, S. Agewall, B. SomaRaju, F. W.A. Verheugt, J. Lopez-Sendon, H. Hod, S. A. Murphy, and E. Braunwald The Impact of Renal Dysfunction on Outcomes in the ExTRACT-TIMI 25 Trial J. Am. Coll. Cardiol., June 12, 2007; 49(23): 2249 - 2255. [Abstract] [Full Text] [PDF]

				A. Kottgen, S. D. Russell, L. R. Loehr, C. M. Crainiceanu, W. D. Rosamond, P. P. Chang, L. E. Chambless, and J. Coresh Reduced Kidney Function as a Risk Factor for Incident Heart Failure: The Atherosclerosis Risk in Communities (ARIC) Study J. Am. Soc. Nephrol., April 1, 2007; 18(4): 1307 - 1315. [Abstract] [Full Text] [PDF]

				B. R. Hemmelgarn, B. J. Manns, J. Zhang, M. Tonelli, S. Klarenbach, M. Walsh, B. F. Culleton, and for the Alberta Kidney Disease Network Association between Multidisciplinary Care and Survival for Elderly Patients with Chronic Kidney Disease J. Am. Soc. Nephrol., March 1, 2007; 18(3): 993 - 999. [Abstract] [Full Text] [PDF]

				W. Van Biesen, D. De Bacquer, F. Verbeke, J. Delanghe, N. Lameire, and R. Vanholder The glomerular filtration rate in an apparently healthy population and its relation with cardiovascular mortality during 10 years Eur. Heart J., February 2, 2007; 28(4): 478 - 483. [Abstract] [Full Text] [PDF]

				K. Wattanakit, A. R. Folsom, E. Selvin, J. Coresh, A. T. Hirsch, and B. D. Weatherley Kidney Function and Risk of Peripheral Arterial Disease: Results from the Atherosclerosis Risk in Communities (ARIC) Study J. Am. Soc. Nephrol., February 1, 2007; 18(2): 629 - 636. [Abstract] [Full Text] [PDF]

				E. Ingelsson, K. Bjorklund-Bodegard, L. Lind, J. Arnlov, and J. Sundstrom Congestive Heart Failure and Diurnal Blood Pressure Pattern--Reply JAMA, December 20, 2006; 296(23): 2800 - 2800. [Full Text] [PDF]

				S. G. Wannamethee, A. G. Shaper, G. D.O. Lowe, L. Lennon, A. Rumley, and P. H. Whincup Renal function and cardiovascular mortality in elderly men: the role of inflammatory, procoagulant, and endothelial biomarkers Eur. Heart J., December 2, 2006; 27(24): 2975 - 2981. [Abstract] [Full Text] [PDF]

				N.C. Edwards, R.P. Steeds, C.J. Ferro, and J.N. Townend The treatment of coronary artery disease in patients with chronic kidney disease QJM, November 1, 2006; 99(11): 723 - 736. [Abstract] [Full Text] [PDF]

				K. Wattanakit, J. Coresh, P. Muntner, J. Marsh, and A. R. Folsom Cardiovascular Risk Among Adults With Chronic Kidney Disease, With or Without Prior Myocardial Infarction J. Am. Coll. Cardiol., September 19, 2006; 48(6): 1183 - 1189. [Abstract] [Full Text] [PDF]

				P. A. McCullough, M. E. Bertrand, J. A. Brinker, and F. Stacul A Meta-Analysis of the Renal Safety of Isosmolar Iodixanol Compared With Low-Osmolar Contrast Media J. Am. Coll. Cardiol., August 15, 2006; 48(4): 692 - 699. [Abstract] [Full Text] [PDF]

A. M. Walker, G. Schneider, J. Yeaw, B. Nordstrom, S. Robbins, and D. Pettitt Anemia as a Predictor of Cardiovascular Events in Patients with Elevated Serum Creatinine J. Am. Soc. Nephrol., August 1, 2006; 17(8): 2293 - 2298. [Abstract] [Full Text]