Chronic Kidney Disease Predicts Cardiovascular Disease
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《新英格兰医药杂志》
The prevalence of end-stage renal disease continues to rise in the United States. Even more disturbingly, the current number of patients with early chronic kidney disease — the pool from which future end-stage renal disease patients will emerge — exceeds the present number with end-stage renal disease by a factor of 30 to 60.1,2 However, early chronic kidney disease will not progress to end-stage renal disease in all patients. Indeed, many will probably die of other conditions first. Over the past few years, investigators have shown that many people in this vast pool of patients with chronic kidney disease have cardiovascular disease and die prematurely from this condition instead of surviving long enough to face dialysis or transplantation.3,4 Two articles in this issue of the Journal tighten the epidemiologic link between chronic kidney disease and cardiovascular disease. Beginning with quite different populations — a large, community-based sample from a health maintenance organization5 and survivors of myocardial infarction from the Valsartan in Acute Myocardial Infarction Trial (VALIANT)6 — both studies report a graded, inverse relation between initial renal function and the subsequent risks of death and complications from cardiovascular disease.
The connections between chronic kidney disease and cardiovascular disease are probably numerous.3 Insofar as chronic vascular disease occurs through general mechanisms that act in all circulatory beds, renal vascular dysfunction may signify a vascular system that is in some way unusually sensitive to classic risk factors. That is, renal dysfunction may simply serve as a convenient, quantifiable surrogate for systemic vascular disease. Much as an ophthalmoscopic examination can be used to gauge the degree of hypertensive disease even outside of the eye, the quantitation of renal function seems to provide an index of overall vascular health. Furthermore, people with chronic kidney disease tend to have an excess of traditional risk factors for cardiovascular disease, such as hypertension, diabetes, and hyperlipidemia.3 However, their predisposition to cardiovascular disease persists even after statistical adjustment for this overabundance of standard risk factors.
Renal disease also engenders an environment that promotes cardiovascular injury in ways that are more or less specific to chronic kidney disease. Calcium and phosphorous dysregulation with vascular calcification, anemia, and hyperhomocysteinemia are among the often-cited cardiovascular liabilities of chronic kidney disease.7,8,9 As yet, however, studies have not quantitated the degree to which these or other nontraditional risk factors account for the accelerated cardiovascular disease of renal insufficiency. Finally, Anavekar et al., as part of VALIANT,6 report that prophylactic therapies such as aspirin or beta-blockers are curiously underused in patients with lower levels of kidney function, a phenomenon they term "therapeutic nihilism." Perhaps the constellation of findings in the patient with chronic kidney disease connotes a degree of debility that wrongly discourages physicians from applying useful preventive strategies. None of these proposed connections between cardiovascular disease and chronic kidney disease — functional marker, the aggregation of traditional risk factors, the influence of nontraditional uremic risk factors, or nihilism — would be mutually exclusive.
Both of the current reports reinforce the importance of early detection of chronic kidney disease, not only to slow the progression to end-stage renal disease but also in this case to identify risk factors for cardiovascular disease. These studies highlight the effectiveness of a simple, practical, but extremely important approach to assessing kidney function. They use the physiological process that has come to be identified with renal function, the glomerular filtration rate (GFR). In particular, the studies use a prediction equation that incorporates the serum creatinine level, age, sex, and race in estimating GFR. The Modification of Diet in Renal Disease (MDRD) equation, named after the study in which it was developed, is currently the best-validated means of transforming a serum creatinine measurement into a GFR in adults.10
Investigators first measured GFR about 70 years ago, using the infusion of the exogenous marker inulin. More recently, other exogenous markers have been developed. However, formal measurement of GFR by these means is time-consuming, expensive, and generally unsuitable for clinical practice. Creatinine is a more useful, if not entirely perfect, endogenous marker of GFR. Measurement of its urinary clearance, although still used to approximate the GFR, is cumbersome and fraught with errors, largely owing to inaccurate urine collection. The inference of GFR from the serum creatinine level alone is complicated by the differing rates of creatinine production between persons, mainly because of variations in muscle mass. Thus, women and the elderly often have deceptively low serum creatinine levels, despite having major depressions in GFR. Moreover, the inverse relation between the serum creatinine level and the GFR further clouds straightforward interpretation. For example, in a 30-year-old man with an initial serum creatinine level of 1.0 mg per deciliter (88.4 mmol per liter), an increase in his creatinine level to 2.0 mg per deciliter (176.8 mmol per liter) will signify a decrease in his GFR by 50 percent, but only when his creatinine level exceeds 10.0 mg per deciliter (884.0 mmol per liter) will his GFR approach 0 percent. Physicians often misinterpret the numerically small initial changes as clinically insignificant. The MDRD equation accounts for these factors.10
Unfortunately, the MDRD equation is too complex to solve with just paper and pencil. However, a calculator at the National Kidney Disease Education Program Web site can be used and is suitable for downloading to a handheld calculator.11 Better yet, clinical laboratories can automatically perform the calculation with simple adjustments of their information systems. In this way, the clinician can receive an estimate of a patient's GFR along with his or her creatinine level. Many laboratories have already begun to provide this service.
In the two current study populations, the risk of cardiovascular disease began to rise once the GFR dropped below 60 ml per minute per 1.73 m2 of body-surface area.5,6 This value corresponds to a serum creatinine level between 1.0 and 1.7 mg per deciliter (88.4 and 150.3 μmol per liter) for people over 40 years old, depending on exact age, sex, and race. Although these values are largely within the normal range for many laboratories, a person with a GFR of 60 ml per minute per 1.73 m2 has a level of kidney function that is half that of the average 30-year-old. Furthermore, in addition to a risk of cardiovascular disease, other effects of renal insufficiency, such as declining hemoglobin and rising homocysteine levels, begin to appear at this stage.8,9 Thus, a GFR of 60 ml per minute per 1.73 m2 does not necessarily represent early renal disease but may seem to if one relies solely on the serum creatinine level.
In many cases of chronic kidney disease, albuminuria appears before the GFR falls. On this basis, guidelines call for yearly measurement of urinary album levels in patients with diabetes, and a recent cost-effectiveness analysis supported the use of regular dipstick testing for urinary protein in patients with hypertension and people over 60 years old.12,13 Albuminuria, like GFR, predicts cardiovascular disease.3 However, not all people with a reduced GFR have albuminuria, and many more serum creatinine measurements are ordered than quantitative urinary albumin measurements.14 In fact, a creatinine measurement is often part of standard clinical metabolic panels, and if estimates of GFR were to be included in these reports, the rate of discovery of unsuspected chronic kidney disease would be improved.
Although the GFR has essentially become synonymous with renal function, the kidney performs many other functions. Not only does it regulate fluid volume and electrolyte and acid balance but it also makes hormones and secretes and metabolizes organic toxins and xenobiotics. If one of these other functions were measurably deranged earlier in the course of renal disease and, better still, could clearly be identified as causative of cardiovascular disease or other uremic signs and symptoms, then the need for creatinine-based GFR measurements might eventually be superseded. For the present, an estimate of the GFR that is based on the serum creatinine level provides the best measure of renal function and is a powerful predictor of cardiovascular disease.
Source Information
From the National Kidney Disease Education Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md.
References
Renal Data System. USRDS 2003 annual data report: atlas of end-stage renal disease in the United States. Bethesda, Md.: National Institute of Diabetes and Digestive and Kidney Diseases, 2003.
Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 2003;41:1-12.
Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 2003;108:2154-2169.
McClellan WM, Langston RD, Presley R. Medicare patients with cardiovascular disease have a high prevalence of chronic kidney disease and a high rate of progression to end-stage renal disease. J Am Soc Nephrol 2004;15:1912-1919.
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu C. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296-1306.
Anavekar NS, McMurray JJV, Velazquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 2004;351:1285-1295.
Goodman WG, London G, Amann K, et al. Vascular calcification in chronic kidney disease. Am J Kidney Dis 2004;43:572-579.
Francis ME, Eggers PW, Hostetter TH, Briggs JP. Association between serum homocysteine and markers of impaired kidney function in adults in the United States. Kidney Int 2004;66:303-312.
Astor BC, Muntner P, Levin A, Eustace JA, Coresh J. Association of kidney function with anemia: the Third National Health and Nutrition Examination Survey (1988-1994). Arch Intern Med 2002;162:1401-1408.
Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003;139:137-147.
National Kidney Disease Education Program. Information for health professionals. (Accessed August 16, 2004, at http://www.nkdep.nih.gov/healthprofessionals/index.htm.)
Boulware LE, Jaar BG, Tarver-Carr ME, Brancati FL, Powe NR. Screening for proteinuria in US adults: a cost-effectiveness analysis. JAMA 2003;290:3101-3114.
Eknoyan G, Hostetter T, Bakris GL, et al. Proteinuria and other markers of chronic kidney disease: a position statement of the National Kidney Foundation (NKF) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Am J Kidney Dis 2003;42:617-622.
Kramer HJ, Nguyen QD, Curhan G, Hsu CY. Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus. JAMA 2003;289:3273-3277.(Thomas H. Hostetter, M.D.)
The connections between chronic kidney disease and cardiovascular disease are probably numerous.3 Insofar as chronic vascular disease occurs through general mechanisms that act in all circulatory beds, renal vascular dysfunction may signify a vascular system that is in some way unusually sensitive to classic risk factors. That is, renal dysfunction may simply serve as a convenient, quantifiable surrogate for systemic vascular disease. Much as an ophthalmoscopic examination can be used to gauge the degree of hypertensive disease even outside of the eye, the quantitation of renal function seems to provide an index of overall vascular health. Furthermore, people with chronic kidney disease tend to have an excess of traditional risk factors for cardiovascular disease, such as hypertension, diabetes, and hyperlipidemia.3 However, their predisposition to cardiovascular disease persists even after statistical adjustment for this overabundance of standard risk factors.
Renal disease also engenders an environment that promotes cardiovascular injury in ways that are more or less specific to chronic kidney disease. Calcium and phosphorous dysregulation with vascular calcification, anemia, and hyperhomocysteinemia are among the often-cited cardiovascular liabilities of chronic kidney disease.7,8,9 As yet, however, studies have not quantitated the degree to which these or other nontraditional risk factors account for the accelerated cardiovascular disease of renal insufficiency. Finally, Anavekar et al., as part of VALIANT,6 report that prophylactic therapies such as aspirin or beta-blockers are curiously underused in patients with lower levels of kidney function, a phenomenon they term "therapeutic nihilism." Perhaps the constellation of findings in the patient with chronic kidney disease connotes a degree of debility that wrongly discourages physicians from applying useful preventive strategies. None of these proposed connections between cardiovascular disease and chronic kidney disease — functional marker, the aggregation of traditional risk factors, the influence of nontraditional uremic risk factors, or nihilism — would be mutually exclusive.
Both of the current reports reinforce the importance of early detection of chronic kidney disease, not only to slow the progression to end-stage renal disease but also in this case to identify risk factors for cardiovascular disease. These studies highlight the effectiveness of a simple, practical, but extremely important approach to assessing kidney function. They use the physiological process that has come to be identified with renal function, the glomerular filtration rate (GFR). In particular, the studies use a prediction equation that incorporates the serum creatinine level, age, sex, and race in estimating GFR. The Modification of Diet in Renal Disease (MDRD) equation, named after the study in which it was developed, is currently the best-validated means of transforming a serum creatinine measurement into a GFR in adults.10
Investigators first measured GFR about 70 years ago, using the infusion of the exogenous marker inulin. More recently, other exogenous markers have been developed. However, formal measurement of GFR by these means is time-consuming, expensive, and generally unsuitable for clinical practice. Creatinine is a more useful, if not entirely perfect, endogenous marker of GFR. Measurement of its urinary clearance, although still used to approximate the GFR, is cumbersome and fraught with errors, largely owing to inaccurate urine collection. The inference of GFR from the serum creatinine level alone is complicated by the differing rates of creatinine production between persons, mainly because of variations in muscle mass. Thus, women and the elderly often have deceptively low serum creatinine levels, despite having major depressions in GFR. Moreover, the inverse relation between the serum creatinine level and the GFR further clouds straightforward interpretation. For example, in a 30-year-old man with an initial serum creatinine level of 1.0 mg per deciliter (88.4 mmol per liter), an increase in his creatinine level to 2.0 mg per deciliter (176.8 mmol per liter) will signify a decrease in his GFR by 50 percent, but only when his creatinine level exceeds 10.0 mg per deciliter (884.0 mmol per liter) will his GFR approach 0 percent. Physicians often misinterpret the numerically small initial changes as clinically insignificant. The MDRD equation accounts for these factors.10
Unfortunately, the MDRD equation is too complex to solve with just paper and pencil. However, a calculator at the National Kidney Disease Education Program Web site can be used and is suitable for downloading to a handheld calculator.11 Better yet, clinical laboratories can automatically perform the calculation with simple adjustments of their information systems. In this way, the clinician can receive an estimate of a patient's GFR along with his or her creatinine level. Many laboratories have already begun to provide this service.
In the two current study populations, the risk of cardiovascular disease began to rise once the GFR dropped below 60 ml per minute per 1.73 m2 of body-surface area.5,6 This value corresponds to a serum creatinine level between 1.0 and 1.7 mg per deciliter (88.4 and 150.3 μmol per liter) for people over 40 years old, depending on exact age, sex, and race. Although these values are largely within the normal range for many laboratories, a person with a GFR of 60 ml per minute per 1.73 m2 has a level of kidney function that is half that of the average 30-year-old. Furthermore, in addition to a risk of cardiovascular disease, other effects of renal insufficiency, such as declining hemoglobin and rising homocysteine levels, begin to appear at this stage.8,9 Thus, a GFR of 60 ml per minute per 1.73 m2 does not necessarily represent early renal disease but may seem to if one relies solely on the serum creatinine level.
In many cases of chronic kidney disease, albuminuria appears before the GFR falls. On this basis, guidelines call for yearly measurement of urinary album levels in patients with diabetes, and a recent cost-effectiveness analysis supported the use of regular dipstick testing for urinary protein in patients with hypertension and people over 60 years old.12,13 Albuminuria, like GFR, predicts cardiovascular disease.3 However, not all people with a reduced GFR have albuminuria, and many more serum creatinine measurements are ordered than quantitative urinary albumin measurements.14 In fact, a creatinine measurement is often part of standard clinical metabolic panels, and if estimates of GFR were to be included in these reports, the rate of discovery of unsuspected chronic kidney disease would be improved.
Although the GFR has essentially become synonymous with renal function, the kidney performs many other functions. Not only does it regulate fluid volume and electrolyte and acid balance but it also makes hormones and secretes and metabolizes organic toxins and xenobiotics. If one of these other functions were measurably deranged earlier in the course of renal disease and, better still, could clearly be identified as causative of cardiovascular disease or other uremic signs and symptoms, then the need for creatinine-based GFR measurements might eventually be superseded. For the present, an estimate of the GFR that is based on the serum creatinine level provides the best measure of renal function and is a powerful predictor of cardiovascular disease.
Source Information
From the National Kidney Disease Education Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md.
References
Renal Data System. USRDS 2003 annual data report: atlas of end-stage renal disease in the United States. Bethesda, Md.: National Institute of Diabetes and Digestive and Kidney Diseases, 2003.
Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 2003;41:1-12.
Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 2003;108:2154-2169.
McClellan WM, Langston RD, Presley R. Medicare patients with cardiovascular disease have a high prevalence of chronic kidney disease and a high rate of progression to end-stage renal disease. J Am Soc Nephrol 2004;15:1912-1919.
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu C. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296-1306.
Anavekar NS, McMurray JJV, Velazquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 2004;351:1285-1295.
Goodman WG, London G, Amann K, et al. Vascular calcification in chronic kidney disease. Am J Kidney Dis 2004;43:572-579.
Francis ME, Eggers PW, Hostetter TH, Briggs JP. Association between serum homocysteine and markers of impaired kidney function in adults in the United States. Kidney Int 2004;66:303-312.
Astor BC, Muntner P, Levin A, Eustace JA, Coresh J. Association of kidney function with anemia: the Third National Health and Nutrition Examination Survey (1988-1994). Arch Intern Med 2002;162:1401-1408.
Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003;139:137-147.
National Kidney Disease Education Program. Information for health professionals. (Accessed August 16, 2004, at http://www.nkdep.nih.gov/healthprofessionals/index.htm.)
Boulware LE, Jaar BG, Tarver-Carr ME, Brancati FL, Powe NR. Screening for proteinuria in US adults: a cost-effectiveness analysis. JAMA 2003;290:3101-3114.
Eknoyan G, Hostetter T, Bakris GL, et al. Proteinuria and other markers of chronic kidney disease: a position statement of the National Kidney Foundation (NKF) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Am J Kidney Dis 2003;42:617-622.
Kramer HJ, Nguyen QD, Curhan G, Hsu CY. Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus. JAMA 2003;289:3273-3277.(Thomas H. Hostetter, M.D.)