- Email: [email protected]
Infections and Cardiovascular Disease in Patients with Chronic Kidney Disease
Infections and Cardiovascular Disease in Patients with Chronic Kidney Disease Robert N. Foley Although interest in the nexus of cardiovascular disease and chronic kidney disease (CKD) has mushroomed, especially in the in past 5 years, activity in the arena of CKD-related infection has been much more modest. This development is surprising when one considers the increasing evidence that links inflammation, kidney disease, and cardiovascular disease. Also, major infections, such as pneumonia and septicemia, are paradigmatic inflammatory states, and accumulating evidence indicates that they are a common antecedent of new cardiovascular events in dialysis patients. Major infections are associated with higher rates of cardiovascular events and death in dialysis patients, and similar associations have been observed in community settings. Although recent studies suggest that hospitalization for major infections is much more common in nondialysis CKD than in the general population, the prognostic implications remain unexplored. © 2006 by the National Kidney Foundation, Inc. Index Words: Infection; Cardiovascular; Chronic kidney disease; Dialysis
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any recent studies have suggested associations between chronic kidney disease (CKD) and higher mortality estimates. These studies have typically included patients with overt kidney disease attending nephrology clinics or survivors of major cardiac events. Perhaps the most persuasive evidence, however, has come from community-based studies that show graded associations between declining glomerular filtration rate (GFR) and rising cardiovascular event and death rates, even when adjustment is made for traditional risk markers. 1– 6 Much of the adverse prognosis of CKD is widely believed to reflect increased risks of cardiovascular disease, and vice versa. This hypothesis seems reasonable, given the highly vascular nature of the kidney, and given that several major risk factors are shared for dysfunction of either system. Interest in the nexus of cardiovascular disease and CKD has mushroomed, especially in the in past 5 years. Figure 1 summarizes the annual accrual of citations, derived from a PubMed search in March 2006, and shows marked growth in research activity that involves the overlap of cardiovascular disease and CKD. The search terms “chronic kidney disease” or “chronic renal failure” or “chronic renal impairment” and “cardiac” or “heart” or “vascular” or “cardiovascular,” limited to human reports for 1990 and 2005, yielded 282 and 1,058 citations, respectively, a 3.8-fold increase. Activity in the arena of CKD-related infection also grew during this time but much more modestly. When “infection” was substi-
tuted for “cardiac” or “heart” or “vascular” or “cardiovascular,” the annual citation rate grew from 126 and to 242, a 1.9-fold increase. Apparently, infection has become relatively less interesting to the nephrology research community, given that the ratio of the cardiovascular citations to infection citations grew from 2.2 in 1990 to 4.4 in 2005 (P ⬍ .0001). This failure to keep pace is surprising, especially when one considers that major infections are among the most common direct cause of acute kidney failure, 7 the many ties between microinflammation and cardiovascular disease, 8 and the observation that proinflammatory and inflammatory cytokine balance is abnormal in CKD. 9 –11 Major infections, such as pneumonia and septicemia, are paradigmatic inflammatory states. If the hypothesis that microinflammation leads to both cardiovascular disease and CKD is true, more extreme degrees of inflammation would likely lead to even more disease; thus, the failure to study major infections in populations at risk for CKD seems difficult to justify. The observation that septicemia is a common, apparently potent, antecedent association of new carFrom the Chronic Disease Research Group, University of Minnesota, Minneapolis, MN Address correspondence to Robert N. Foley, MB, Chronic Disease Research Group, 914 South 8th Street, Suite D-206, Minneapolis, MN 55404. E-mail: [email protected]. © 2006 by the National Kidney Foundation, Inc. 1548-5595/06/1303-0004$32.00/0 doi:10.1053/j.ackd.2006.04.006
Advances in Chronic Kidney Disease, Vol 13, No 3 (July), 2006: pp 205-208
205
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Robert N. Foley
CV
Ratio
Infection and CV
1200 1000 800 600 400 200
19 9 19 0 9 19 1 9 19 2 93 19 9 19 4 9 19 5 96 19 9 19 7 9 19 8 9 20 9 0 20 0 0 20 1 0 20 2 0 20 3 0 20 4 05
0
5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0
Ratio CV/Infection
Infection
Figure 1. Annual citation rates for cardiovascular disease (CV) and infection in patients with CKD, 1990 to 2005, restricted to studies involving human subjects.
diovascular events in dialysis patients 12,13 further underscores the need for basic epidemiologic information about major infections in CKD populations.
Potential Links Between Infection, Inflammation, CKD, and Cardiovascular Disease Few studies have examined the associations between major acute infections, CKD, and cardiovascular disease. Major acute infections are paradigmatic examples of massive, acute inflammation (“macroinflammation” might be a reasonable descriptive term). Downstream effects include dysfunction of endothelial, redox, coagulation, and cardiovascular systems, all of which occurs in the face of diminished cellular oxygen availability, cytokine storm, sympathetic overload, complement activation, and vasoconstriction of some vascular beds (including that of the kidney).7,14 These processes have been implicated in the pathogenesis of both acute cardiovascular and renal dysfunction, and longer-term effects are biologically plausible. Chronic infection, chronic inflammation, and cardiovascular disease also appear to exhibit potentially lethal synergy,15,16 and some of the pathophysiologic constructs can be summarized as follows: the fatty streak consists predominantly of macrophages and some T cells; lipid deposition leads to expression of leukocyte adhesion molecules on endothelial cells, followed by chemokine production and further leukocyte recruitment;
and anti-inflammatory cytokines, such as interleukin-10 and transforming growth factor, appear to be antiatherosclerotic.17 Observational studies in the general population suggest that chronic infections and coronary artery disease may be linked. For example, higher than expected Chlamydia titers have been found in patients with coronary artery disease.18 The causality of this observation, however, has been challenged by the findings of trials of azithromycin therapy, which had no effect on cardiovascular event rates.19 –22 Perhaps the most suggestive general-population evidence that links common infections to cardiovascular disease comes from the United Kingdom General Practice Research Database (GPRD) study of more than 5 million patients. Cardiovascular-event rates were similar before and after influenza, tetanus, and pneumococcal vaccination. Cardiovascular events, however, occurred considerably more often after systemic respiratory-tract infections, especially in the initial 3 days, when the risk ratios were 4.95 for myocardial infarction and 3.19 for stroke. Risk ratios gradually fell in the ensuing weeks. Similar, albeit less dramatic, findings were seen after urinarytract infections.23
Clinical Epidemiology of Major Infections in CKD Populations The clinical epidemiology of major infections in patients with (nondialysis) CKD has yet to be addressed systematically. A recent report examined event rates among prevalent Medicare recipients, followed from January 1, 2002 until December 31, 2003.24 Hospital billing codes were used to define rates of pneumonia and septicemia, and rates were adjusted for race, sex, and diabetes mellitus. Event rates climbed as follows within each age category: no CKD ⬍ nondialysis CKD ⬍ dialysis CKD. For example, among those aged 65 years or more, adjusted rates of pneumonia were 32.3, 86.2, and 171.5 per 1,000 patient-years, respectively. The corresponding rates for septicemia admissions were 13.1, 44.4, and 178.4, respectively. Thus, the nondialysis CKD group had pneumonia and septicemia rates that were 2.7 and 3.9 times greater than expected, respec-
Infections and Cardiovascular Disease in CKD
tively. However, billing claims that suggest the presence of CKD probably reflect the presence of relatively advanced disease stage.25 Whether major infections hasten the onset of CKD, end-stage renal disease, cardiovascular disease, and death remains to be determined, but the magnitude of the observed event rates suggests that future investigation is warranted. More information is available regarding the clinical epidemiology of septicemia in dialysis populations, a group in whom infection is the second most-commonly reported cause of death, and infection-attributed mortality is believed to be 100 to 300 times higher than in the general population.26 In a nationwide study in the United States, hospital admission claims were used to estimate septicemia rates in the first year of dialysis therapy.12 Rates in hemodialysis patients rose by 51% between 1991 and 1999, from 11.6 to 17.5 per 100 patientyears. Although older age and the presence of comorbid illnesses were associated with the development of septicemia, the dominant association was very clearly the initial modality of dialysis therapy; hemodialysis patients had event rates double those seen in peritonealdialysis patients. Several studies suggest that the use of venous catheters for vascular access is the major determinant of septicemia risk in hemodialysis patients.13,27,28 In the study cited above, septicemia was strikingly associated with the future occurrence of cardiovascular events. For example, in the first 6 months after septicemia, adjusted hazards ratios were approximately 4 times higher than expected for myocardial infarction, congestive heart failure, stroke, and peripheral vascular-disease events. Although cardiovascular risk declined with the passage of time, postsepticemia hazards ratios remained at least 50% higher through 5 years of follow-up.12 On a cautionary note, many of the associations we observed could partially reflect residual confounding, and cause-and-effect relations remain very much unproven. Similarly, whether the pathophysiologic paradigms that relate microinflammation to cardiovascular disease apply in macroinflammatory states remains speculative.
207
Conclusions Although nontrivial infections appear to be common in patients with CKD, they have received remarkably little focused research activity, whether mechanistic, observational, or therapeutic. Given the potential pathogenetic relations between inflammation, cardiovascular disease, and kidney disease, this knowledge gap is surprising and potentially important for identifying effective intervention strategies.
References 1. Fried LF, Shlipak MG, Crump C, et al: Renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals. J Am Coll Cardiol 41:1364-1372, 2003 2. Henry RM, Kostense PJ, Bos G, et al: Mild renal insufficiency is associated with increased cardiovascular mortality: The Hoorn Study. Kidney Int 62:14021407, 2002 3. Muntner P, He J, Hamm L, et al: Renal insufficiency and subsequent death resulting from cardiovascular disease in the United States. J Am Soc Nephrol 13: 745-753, 2002 4. Anavekar NS, McMurray JJ, Velazquez EJ, et al: Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 351:1285-1295, 2004 5. Go AS, Chertow GM, Fan D, et al: Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 351:1296-1305, 2004 6. Shlipak MG, Fried LF, Cushman M, et al: Cardiovascular mortality risk in chronic kidney disease: Comparison of traditional and novel risk factors. JAMA 293:1737-1745, 2005 7. Schrier RW, Wang W: Acute renal failure and sepsis. N Engl J Med 351:159-169, 2004 8. Ross R: Atherosclerosis—an inflammatory disease. N Engl J Med 340:115-126, 1999 9. Landray MJ, Wheeler DC, Lip GY, et al: Inflammation, endothelial dysfunction, and platelet activation in patients with chronic kidney disease: The Chronic Renal Impairment in Birmingham (CRIB) study. Am J Kidney Dis 43:244-253, 2004 10. Beddhu S, Kimmel PL, Ramkumar N, et al: Associations of metabolic syndrome with inflammation in CKD: Results from the Third National Health and Nutrition Examination Survey (NHANES III). Am J Kidney Dis 46:577-586, 2005 11. Foley RN, Wang C, Collins AJ: Cardiovascular risk factor profiles and kidney function stage in the US general population: The NHANES III study. Mayo Clin Proc 80:1270-1277, 2005 12. Foley RN, Guo H, Snyder JJ, et al: Septicemia in the United States dialysis population, 1991 to 1999. J Am Soc Nephrol 15:1038-1045, 2004
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Robert N. Foley
13. Ishani A, Collins AJ, Herzog CA, et al: Septicemia, access and cardiovascular disease in dialysis patients: The USRDS Wave 2 study. Kidney Int 68:311-318, 2005 14. Hotchkiss RS, Karl IE: The pathophysiology and treatment of sepsis. N Engl J Med 348:138-150, 2003 15. Ridker PM, Cushman M, Stampfer MJ, et al: Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 336:973-979, 1997 16. Ridker PM, Hennekens CH, Buring JE, et al: C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 342:836-843, 2000 17. Hansson GK: Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352:1685-1695, 2005 18. Saikku P, Leinonen M, Mattila K, et al: Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet 2:983-986, 1988 19. O’Connor CM, Dunne MW, Pfeffer MA, et al: Azithromycin for the secondary prevention of coronary heart disease events: The WIZARD study: A randomized controlled trial. JAMA 290:1459-1466, 2003 20. Cercek B, Shah PK, Noc M, et al: Effect of short-term treatment with azithromycin on recurrent ischaemic events in patients with acute coronary syndrome in the Azithromycin in Acute Coronary Syndrome
21.
22.
23.
24.
25.
26.
27.
28.
(AZACS) trial: A randomised controlled trial. Lancet 361:809-813, 2003 Grayston JT, Kronmal RA, Jackson LA, et al: Azithromycin for the secondary prevention of coronary events. N Engl J Med 352:1637-1645, 2005 Cannon CP, Braunwald E, McCabe CH, et al: Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med 352:1646-1654, 2005 Smeeth L, Thomas SL, Hall AJ, et al: Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med 351:2611-2618, 2004 U.S. Renal Data System: USRDS 2005 Annual Data Report. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2005 Winkelmayer WC, Schneeweiss S, Mogun H, et al: Identification of individuals with CKD from Medicare claims data: A validation study. Am J Kidney Dis 46:225-232, 2005 Sarnak MJ, Jaber BL: Mortality caused by sepsis in patients with end-stage renal disease compared with the general population. Kidney Int 58:1758-1764, 2000 Marr KA, Sexton DJ, Conlon PJ, et al: Catheter-related bacteremia and outcome of attempted catheter salvage in patients undergoing hemodialysis. Ann Intern Med 127:275-280, 1997 Hoen B, Paul-Dauphin A, Hestin D, et al: EPIBACDIAL: A multicenter prospective study of risk factors for bacteremia in chronic hemodialysis patients. J Am Soc Nephrol 9:869-876, 1998
M
any recent studies have suggested associations between chronic kidney disease (CKD) and higher mortality estimates. These studies have typically included patients with overt kidney disease attending nephrology clinics or survivors of major cardiac events. Perhaps the most persuasive evidence, however, has come from community-based studies that show graded associations between declining glomerular filtration rate (GFR) and rising cardiovascular event and death rates, even when adjustment is made for traditional risk markers. 1– 6 Much of the adverse prognosis of CKD is widely believed to reflect increased risks of cardiovascular disease, and vice versa. This hypothesis seems reasonable, given the highly vascular nature of the kidney, and given that several major risk factors are shared for dysfunction of either system. Interest in the nexus of cardiovascular disease and CKD has mushroomed, especially in the in past 5 years. Figure 1 summarizes the annual accrual of citations, derived from a PubMed search in March 2006, and shows marked growth in research activity that involves the overlap of cardiovascular disease and CKD. The search terms “chronic kidney disease” or “chronic renal failure” or “chronic renal impairment” and “cardiac” or “heart” or “vascular” or “cardiovascular,” limited to human reports for 1990 and 2005, yielded 282 and 1,058 citations, respectively, a 3.8-fold increase. Activity in the arena of CKD-related infection also grew during this time but much more modestly. When “infection” was substi-
tuted for “cardiac” or “heart” or “vascular” or “cardiovascular,” the annual citation rate grew from 126 and to 242, a 1.9-fold increase. Apparently, infection has become relatively less interesting to the nephrology research community, given that the ratio of the cardiovascular citations to infection citations grew from 2.2 in 1990 to 4.4 in 2005 (P ⬍ .0001). This failure to keep pace is surprising, especially when one considers that major infections are among the most common direct cause of acute kidney failure, 7 the many ties between microinflammation and cardiovascular disease, 8 and the observation that proinflammatory and inflammatory cytokine balance is abnormal in CKD. 9 –11 Major infections, such as pneumonia and septicemia, are paradigmatic inflammatory states. If the hypothesis that microinflammation leads to both cardiovascular disease and CKD is true, more extreme degrees of inflammation would likely lead to even more disease; thus, the failure to study major infections in populations at risk for CKD seems difficult to justify. The observation that septicemia is a common, apparently potent, antecedent association of new carFrom the Chronic Disease Research Group, University of Minnesota, Minneapolis, MN Address correspondence to Robert N. Foley, MB, Chronic Disease Research Group, 914 South 8th Street, Suite D-206, Minneapolis, MN 55404. E-mail: [email protected]. © 2006 by the National Kidney Foundation, Inc. 1548-5595/06/1303-0004$32.00/0 doi:10.1053/j.ackd.2006.04.006
Advances in Chronic Kidney Disease, Vol 13, No 3 (July), 2006: pp 205-208
205
206
Robert N. Foley
CV
Ratio
Infection and CV
1200 1000 800 600 400 200
19 9 19 0 9 19 1 9 19 2 93 19 9 19 4 9 19 5 96 19 9 19 7 9 19 8 9 20 9 0 20 0 0 20 1 0 20 2 0 20 3 0 20 4 05
0
5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0
Ratio CV/Infection
Infection
Figure 1. Annual citation rates for cardiovascular disease (CV) and infection in patients with CKD, 1990 to 2005, restricted to studies involving human subjects.
diovascular events in dialysis patients 12,13 further underscores the need for basic epidemiologic information about major infections in CKD populations.
Potential Links Between Infection, Inflammation, CKD, and Cardiovascular Disease Few studies have examined the associations between major acute infections, CKD, and cardiovascular disease. Major acute infections are paradigmatic examples of massive, acute inflammation (“macroinflammation” might be a reasonable descriptive term). Downstream effects include dysfunction of endothelial, redox, coagulation, and cardiovascular systems, all of which occurs in the face of diminished cellular oxygen availability, cytokine storm, sympathetic overload, complement activation, and vasoconstriction of some vascular beds (including that of the kidney).7,14 These processes have been implicated in the pathogenesis of both acute cardiovascular and renal dysfunction, and longer-term effects are biologically plausible. Chronic infection, chronic inflammation, and cardiovascular disease also appear to exhibit potentially lethal synergy,15,16 and some of the pathophysiologic constructs can be summarized as follows: the fatty streak consists predominantly of macrophages and some T cells; lipid deposition leads to expression of leukocyte adhesion molecules on endothelial cells, followed by chemokine production and further leukocyte recruitment;
and anti-inflammatory cytokines, such as interleukin-10 and transforming growth factor, appear to be antiatherosclerotic.17 Observational studies in the general population suggest that chronic infections and coronary artery disease may be linked. For example, higher than expected Chlamydia titers have been found in patients with coronary artery disease.18 The causality of this observation, however, has been challenged by the findings of trials of azithromycin therapy, which had no effect on cardiovascular event rates.19 –22 Perhaps the most suggestive general-population evidence that links common infections to cardiovascular disease comes from the United Kingdom General Practice Research Database (GPRD) study of more than 5 million patients. Cardiovascular-event rates were similar before and after influenza, tetanus, and pneumococcal vaccination. Cardiovascular events, however, occurred considerably more often after systemic respiratory-tract infections, especially in the initial 3 days, when the risk ratios were 4.95 for myocardial infarction and 3.19 for stroke. Risk ratios gradually fell in the ensuing weeks. Similar, albeit less dramatic, findings were seen after urinarytract infections.23
Clinical Epidemiology of Major Infections in CKD Populations The clinical epidemiology of major infections in patients with (nondialysis) CKD has yet to be addressed systematically. A recent report examined event rates among prevalent Medicare recipients, followed from January 1, 2002 until December 31, 2003.24 Hospital billing codes were used to define rates of pneumonia and septicemia, and rates were adjusted for race, sex, and diabetes mellitus. Event rates climbed as follows within each age category: no CKD ⬍ nondialysis CKD ⬍ dialysis CKD. For example, among those aged 65 years or more, adjusted rates of pneumonia were 32.3, 86.2, and 171.5 per 1,000 patient-years, respectively. The corresponding rates for septicemia admissions were 13.1, 44.4, and 178.4, respectively. Thus, the nondialysis CKD group had pneumonia and septicemia rates that were 2.7 and 3.9 times greater than expected, respec-
Infections and Cardiovascular Disease in CKD
tively. However, billing claims that suggest the presence of CKD probably reflect the presence of relatively advanced disease stage.25 Whether major infections hasten the onset of CKD, end-stage renal disease, cardiovascular disease, and death remains to be determined, but the magnitude of the observed event rates suggests that future investigation is warranted. More information is available regarding the clinical epidemiology of septicemia in dialysis populations, a group in whom infection is the second most-commonly reported cause of death, and infection-attributed mortality is believed to be 100 to 300 times higher than in the general population.26 In a nationwide study in the United States, hospital admission claims were used to estimate septicemia rates in the first year of dialysis therapy.12 Rates in hemodialysis patients rose by 51% between 1991 and 1999, from 11.6 to 17.5 per 100 patientyears. Although older age and the presence of comorbid illnesses were associated with the development of septicemia, the dominant association was very clearly the initial modality of dialysis therapy; hemodialysis patients had event rates double those seen in peritonealdialysis patients. Several studies suggest that the use of venous catheters for vascular access is the major determinant of septicemia risk in hemodialysis patients.13,27,28 In the study cited above, septicemia was strikingly associated with the future occurrence of cardiovascular events. For example, in the first 6 months after septicemia, adjusted hazards ratios were approximately 4 times higher than expected for myocardial infarction, congestive heart failure, stroke, and peripheral vascular-disease events. Although cardiovascular risk declined with the passage of time, postsepticemia hazards ratios remained at least 50% higher through 5 years of follow-up.12 On a cautionary note, many of the associations we observed could partially reflect residual confounding, and cause-and-effect relations remain very much unproven. Similarly, whether the pathophysiologic paradigms that relate microinflammation to cardiovascular disease apply in macroinflammatory states remains speculative.
207
Conclusions Although nontrivial infections appear to be common in patients with CKD, they have received remarkably little focused research activity, whether mechanistic, observational, or therapeutic. Given the potential pathogenetic relations between inflammation, cardiovascular disease, and kidney disease, this knowledge gap is surprising and potentially important for identifying effective intervention strategies.
References 1. Fried LF, Shlipak MG, Crump C, et al: Renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals. J Am Coll Cardiol 41:1364-1372, 2003 2. Henry RM, Kostense PJ, Bos G, et al: Mild renal insufficiency is associated with increased cardiovascular mortality: The Hoorn Study. Kidney Int 62:14021407, 2002 3. Muntner P, He J, Hamm L, et al: Renal insufficiency and subsequent death resulting from cardiovascular disease in the United States. J Am Soc Nephrol 13: 745-753, 2002 4. Anavekar NS, McMurray JJ, Velazquez EJ, et al: Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 351:1285-1295, 2004 5. Go AS, Chertow GM, Fan D, et al: Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 351:1296-1305, 2004 6. Shlipak MG, Fried LF, Cushman M, et al: Cardiovascular mortality risk in chronic kidney disease: Comparison of traditional and novel risk factors. JAMA 293:1737-1745, 2005 7. Schrier RW, Wang W: Acute renal failure and sepsis. N Engl J Med 351:159-169, 2004 8. Ross R: Atherosclerosis—an inflammatory disease. N Engl J Med 340:115-126, 1999 9. Landray MJ, Wheeler DC, Lip GY, et al: Inflammation, endothelial dysfunction, and platelet activation in patients with chronic kidney disease: The Chronic Renal Impairment in Birmingham (CRIB) study. Am J Kidney Dis 43:244-253, 2004 10. Beddhu S, Kimmel PL, Ramkumar N, et al: Associations of metabolic syndrome with inflammation in CKD: Results from the Third National Health and Nutrition Examination Survey (NHANES III). Am J Kidney Dis 46:577-586, 2005 11. Foley RN, Wang C, Collins AJ: Cardiovascular risk factor profiles and kidney function stage in the US general population: The NHANES III study. Mayo Clin Proc 80:1270-1277, 2005 12. Foley RN, Guo H, Snyder JJ, et al: Septicemia in the United States dialysis population, 1991 to 1999. J Am Soc Nephrol 15:1038-1045, 2004
208
Robert N. Foley
13. Ishani A, Collins AJ, Herzog CA, et al: Septicemia, access and cardiovascular disease in dialysis patients: The USRDS Wave 2 study. Kidney Int 68:311-318, 2005 14. Hotchkiss RS, Karl IE: The pathophysiology and treatment of sepsis. N Engl J Med 348:138-150, 2003 15. Ridker PM, Cushman M, Stampfer MJ, et al: Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 336:973-979, 1997 16. Ridker PM, Hennekens CH, Buring JE, et al: C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 342:836-843, 2000 17. Hansson GK: Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352:1685-1695, 2005 18. Saikku P, Leinonen M, Mattila K, et al: Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet 2:983-986, 1988 19. O’Connor CM, Dunne MW, Pfeffer MA, et al: Azithromycin for the secondary prevention of coronary heart disease events: The WIZARD study: A randomized controlled trial. JAMA 290:1459-1466, 2003 20. Cercek B, Shah PK, Noc M, et al: Effect of short-term treatment with azithromycin on recurrent ischaemic events in patients with acute coronary syndrome in the Azithromycin in Acute Coronary Syndrome
21.
22.
23.
24.
25.
26.
27.
28.
(AZACS) trial: A randomised controlled trial. Lancet 361:809-813, 2003 Grayston JT, Kronmal RA, Jackson LA, et al: Azithromycin for the secondary prevention of coronary events. N Engl J Med 352:1637-1645, 2005 Cannon CP, Braunwald E, McCabe CH, et al: Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med 352:1646-1654, 2005 Smeeth L, Thomas SL, Hall AJ, et al: Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med 351:2611-2618, 2004 U.S. Renal Data System: USRDS 2005 Annual Data Report. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2005 Winkelmayer WC, Schneeweiss S, Mogun H, et al: Identification of individuals with CKD from Medicare claims data: A validation study. Am J Kidney Dis 46:225-232, 2005 Sarnak MJ, Jaber BL: Mortality caused by sepsis in patients with end-stage renal disease compared with the general population. Kidney Int 58:1758-1764, 2000 Marr KA, Sexton DJ, Conlon PJ, et al: Catheter-related bacteremia and outcome of attempted catheter salvage in patients undergoing hemodialysis. Ann Intern Med 127:275-280, 1997 Hoen B, Paul-Dauphin A, Hestin D, et al: EPIBACDIAL: A multicenter prospective study of risk factors for bacteremia in chronic hemodialysis patients. J Am Soc Nephrol 9:869-876, 1998