Chronic Kidney Disease in the Elderly — How to Assess Risk
http://www.100md.com
《新英格兰医药杂志》
Chronic kidney disease is an important problem in the elderly and is associated with a high risk of kidney failure, cardiovascular disease, and death.1,2 The disorder is indicated either by a glomerular filtration rate (GFR) of less than 60 ml per minute per 1.73 m2 of body-surface area or by the presence of kidney damage, assessed most commonly by the finding of albuminuria for three or more consecutive months.3 The severity of chronic kidney disease can be classified according to the level of the GFR, regardless of the cause, as follows: stage 1, kidney damage with a normal or increased GFR; stage 2, kidney damage with a mild decrease in GFR; stage 3, a moderate decrease in GFR; stage 4, a severe decrease in GFR; and stage 5, kidney failure (i.e., a GFR of less than 15 ml per minute per 1.73 m2 or conditions requiring dialysis).
Accumulating evidence strongly suggests that chronic kidney disease is an independent risk factor for cardiovascular disease, even at low levels of albuminuria (30 to 300 mg of albumin per day, the equivalent of microalbuminuria) or a moderate reduction in the estimated GFR (to 30 to 59 ml per minute per 1.73 m2, or the equivalent of stage 3 disease).4 Among persons 60 to 69 years of age, approximately 18 percent have albuminuria and 7 percent have an estimated GFR of less than 60 ml per minute per 1.73 m2. In persons 70 years of age or older, those percentages increase to 30 and 26, respectively.3
GFR cannot be measured directly and is usually estimated from the serum creatinine concentration or with creatinine-based estimating equations,5 each of which has several limitations. Cystatin C has been proposed as a serum measure that may be superior to creatinine as an index of GFR. In a study reported in this issue of the Journal, Shlipak and colleagues examined the association of measures of kidney function with mortality and cardiovascular disease during 10 years of follow-up among 4637 elderly patients in the Cardiovascular Health Study, a population-based prospective cohort study.6 Neither urinary albumin excretion nor GFR was measured, but levels of serum cystatin C and creatinine were determined. Serum cystatin C was a better predictor of mortality and cardiovascular disease than was either serum creatinine alone or the GFR estimated from serum creatinine.
Higher levels of cystatin C were associated with a graded increase in the risk of all outcomes that were examined. A significant increase in the risk of death was observed with values of cystatin C that were as low as 1.0 to 1.1 mg per liter (i.e., the middle quintile), corresponding in this study to a mean (±SD) serum creatinine level of 0.97±0.17 mg per deciliter and an estimated GFR of 72±12 ml per minute per 1.73 m2. In contrast, risks were significantly increased only for the highest levels of serum creatinine (i.e., 1.26 mg per deciliter for men and 0.96 mg per deciliter for women) and for the lowest levels of estimated GFR (i.e., <56 ml per minute per 1.73 m2). One explanation for these findings is that cystatin C is a better marker of filtration than is creatinine. Another explanation is that factors other than GFR that affect serum levels of creatinine and cystatin C differentially confound the relationships between these measures and outcome. We suspect that both explanations are correct.
It is well recognized that serum creatinine alone is unsatisfactory for estimating the level of GFR.7 Physiological processes other than GFR also determine the serum creatinine level (Table 1) — in particular, the generation of creatinine from muscle metabolism. Since muscle mass declines with age, serum creatinine levels may not rise appreciably in elderly persons, even with a reduction in GFR to less than 60 ml per minute per 1.73 m2. Equations for estimating the GFR improve on the accuracy of the levels of serum creatinine alone by incorporating demographic and clinical variables as surrogates for physiological determinants of serum creatinine.
Table 1. Comparison of Creatinine and Cystatin C as Filtration Markers.
In the equation used in the Modification of Diet in Renal Disease (MDRD) Study, the factors of age, sex, and race are surrogates for muscle mass.8 Many chronic illnesses, including cardiovascular disease, affect muscle mass, through malnutrition, inflammation, and deconditioning. Thus, people with chronic illness are more likely to have lower levels of serum creatinine than are healthy people, even for the same level of GFR and the same age, sex, and race. In such persons, estimating equations based on serum creatinine may overestimate GFR. In a cohort study, this relationship between chronic illness and serum creatinine would confound the relationship between creatinine-based estimates of GFR and mortality. This probably accounts for the observation in the study by Shlipak et al. of a "J-shaped curve" describing an increased risk of outcomes among participants with the highest levels of estimated GFR and lowest levels of serum creatinine. It would also account for the observation that within defined ranges of cystatin C, a higher serum creatinine level was associated with a lower death rate.
Cystatin C is a nonglycosylated 13,000-dalton basic protein that is filtered by the glomeruli and reabsorbed and catabolized by the tubular epithelial cells, with only small amounts excreted in the urine (Table 1).9 It has not been thoroughly evaluated as a filtration marker. The absence of urinary excretion makes it difficult to study variation in the urinary clearance and generation of cystatin. The generation of cystatin C appears to be less variable across populations and over time than does creatinine. Serum levels of cystatin C may also be affected by extrarenal elimination. Most but not all studies show that serum cystatin C is a better index of GFR than is serum creatinine alone.10 However, as compared with creatinine-based GFR estimates, there may not be an advantage to using cystatin C.10
The relationship between cystatin C and outcomes may also be confounded by factors that affect the serum level of cystatin and that are independent of GFR, including older age, male sex, smoking, higher weight, and higher levels of C-reactive protein.11 Unlike chronic illness, which weakens the relationship between serum creatinine and outcome, these variables strengthen the apparent relationship between serum cystatin C and outcome.
Another important issue to consider in using serum markers to assess GFR is the standardization of assays across clinical laboratories. Serum creatinine assays vary according to positive interference by serum proteins, which is relatively greater at lower levels of serum creatinine. It is well recognized that failure to calibrate the creatinine assay to the laboratory that developed the estimating equation can introduce a systematic error in estimated GFR, particularly at a high GFR.12 Shlipak and colleagues used the equation in the MDRD Study but did not calibrate their assay to the MDRD Study laboratory. Calibration probably would have raised the GFR estimates reported in their study,13 although it would have had little effect on the classification into quintiles. A standardization program for serum creatinine assays is currently being implemented by the National Kidney Disease Education Program,14 which should facilitate interpretation of GFR estimates. The cystatin C assay is more precise than are assays for serum creatinine, especially in the low range.15 However, cystatin C has not been standardized across clinical laboratories.
The study by Shlipak et al.6 suggests that the increased risk of cardiovascular disease among elderly patients with chronic kidney disease may be stronger and occur at higher levels of GFR than previously suspected. It also reinforces the need for an improved understanding of the relationship between cardiovascular disease and chronic kidney disease.5 Future research that focuses on developing more accurate estimating equations for GFR — on the basis of serum levels of creatinine, cystatin C, or both — would be important. Cohort studies that measure both urinary albumin excretion and estimated GFR and assess their combined association with the risk of various outcomes are needed. Predictive models for cardiovascular disease in patients with chronic kidney disease should be developed, analogous to the Framingham risk score in the general population, to guide clinical decision making and public policy.
What can be done right now to assess the risk among elderly patients? Clinicians should measure albuminuria and estimate GFR from serum creatinine to detect chronic kidney disease. Patients who are found to have chronic kidney disease should undergo appropriate evaluation and treatment according to the cause and stage of their disease. Moreover, patients with chronic kidney disease should be considered to be in the highest risk group for cardiovascular disease and should receive intensive risk-reduction therapy.
Supported in part by a grant (R01 DK53869-05, to Dr. Levey) from the National Institutes of Health.
We are indebted to Josef Coresh, M.D., and to Tom Greene, Ph.D., for contributing greatly to the ideas described here.
Source Information
From Tufts–New England Medical Center, Boston.
References
Renal Data System. 2004 Annual data report. Bethesda, Md.: National Institute of Diabetes and Digestive and Kidney Diseases, 2004. (Accessed March 18, 2005, at http://www.usrds.org/adr.htm.)
Go A, Chertow G, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296-1305.
National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39:Suppl 1:S1-S266.
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.
Stevens LA, Levey AS. Clinical implications for estimating equations for glomerular filtration rate. Ann Intern Med 2004;141:959-961.
Shlipak MG, Sarnak MJ, Katz R, et al. Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med 2005;352:2049-2060.
Perrone RD, Madias NE, Levey AS. Serum creatinine as an index of renal function: new insights into old concepts. Clin Chem 1992;38:1933-1953.
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.
Grubb AO. Cystatin C -- properties and use as diagnostic marker. Adv Clin Chem 2000;35:63-99.
Hoek FJ, Kemperman FA, Krediet RT. A comparison between cystatin C, plasma creatinine and the Cockcroft and Gault formula for the estimation of glomerular filtration rate. Nephrol Dial Transplant 2003;18:2024-2031.
Knight EL, Verhave JC, Spiegelman D, et al. Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int 2004;65:1416-1421.
Coresh J, Astor BC, McQuillan G, et al. Calibration and random variation of the serum creatinine assay as critical elements of using equations to estimate glomerular filtration rate. Am J Kidney Dis 2002;39:920-929.
Manjunath G, Tighiouart H, Ibrahim H, et al. Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J Am Coll Cardiol 2003;41:47-55.
National Kidney Disease Education Program. Information for health professionals. Bethesda, Md.: National Institute for Diabetes and Digestive and Kidney Diseases, 2004. (Accessed April 28, 2005, at http://www.nkdep.nih.gov/healthprofessionals/index.htm.)
Laterza OF, Price CP, Scott MG. Cystatin C: an improved estimator of glomerular filtration rate? Clin Chem 2002;48:699-707.(Lesley A. Stevens, M.D., )
Accumulating evidence strongly suggests that chronic kidney disease is an independent risk factor for cardiovascular disease, even at low levels of albuminuria (30 to 300 mg of albumin per day, the equivalent of microalbuminuria) or a moderate reduction in the estimated GFR (to 30 to 59 ml per minute per 1.73 m2, or the equivalent of stage 3 disease).4 Among persons 60 to 69 years of age, approximately 18 percent have albuminuria and 7 percent have an estimated GFR of less than 60 ml per minute per 1.73 m2. In persons 70 years of age or older, those percentages increase to 30 and 26, respectively.3
GFR cannot be measured directly and is usually estimated from the serum creatinine concentration or with creatinine-based estimating equations,5 each of which has several limitations. Cystatin C has been proposed as a serum measure that may be superior to creatinine as an index of GFR. In a study reported in this issue of the Journal, Shlipak and colleagues examined the association of measures of kidney function with mortality and cardiovascular disease during 10 years of follow-up among 4637 elderly patients in the Cardiovascular Health Study, a population-based prospective cohort study.6 Neither urinary albumin excretion nor GFR was measured, but levels of serum cystatin C and creatinine were determined. Serum cystatin C was a better predictor of mortality and cardiovascular disease than was either serum creatinine alone or the GFR estimated from serum creatinine.
Higher levels of cystatin C were associated with a graded increase in the risk of all outcomes that were examined. A significant increase in the risk of death was observed with values of cystatin C that were as low as 1.0 to 1.1 mg per liter (i.e., the middle quintile), corresponding in this study to a mean (±SD) serum creatinine level of 0.97±0.17 mg per deciliter and an estimated GFR of 72±12 ml per minute per 1.73 m2. In contrast, risks were significantly increased only for the highest levels of serum creatinine (i.e., 1.26 mg per deciliter for men and 0.96 mg per deciliter for women) and for the lowest levels of estimated GFR (i.e., <56 ml per minute per 1.73 m2). One explanation for these findings is that cystatin C is a better marker of filtration than is creatinine. Another explanation is that factors other than GFR that affect serum levels of creatinine and cystatin C differentially confound the relationships between these measures and outcome. We suspect that both explanations are correct.
It is well recognized that serum creatinine alone is unsatisfactory for estimating the level of GFR.7 Physiological processes other than GFR also determine the serum creatinine level (Table 1) — in particular, the generation of creatinine from muscle metabolism. Since muscle mass declines with age, serum creatinine levels may not rise appreciably in elderly persons, even with a reduction in GFR to less than 60 ml per minute per 1.73 m2. Equations for estimating the GFR improve on the accuracy of the levels of serum creatinine alone by incorporating demographic and clinical variables as surrogates for physiological determinants of serum creatinine.
Table 1. Comparison of Creatinine and Cystatin C as Filtration Markers.
In the equation used in the Modification of Diet in Renal Disease (MDRD) Study, the factors of age, sex, and race are surrogates for muscle mass.8 Many chronic illnesses, including cardiovascular disease, affect muscle mass, through malnutrition, inflammation, and deconditioning. Thus, people with chronic illness are more likely to have lower levels of serum creatinine than are healthy people, even for the same level of GFR and the same age, sex, and race. In such persons, estimating equations based on serum creatinine may overestimate GFR. In a cohort study, this relationship between chronic illness and serum creatinine would confound the relationship between creatinine-based estimates of GFR and mortality. This probably accounts for the observation in the study by Shlipak et al. of a "J-shaped curve" describing an increased risk of outcomes among participants with the highest levels of estimated GFR and lowest levels of serum creatinine. It would also account for the observation that within defined ranges of cystatin C, a higher serum creatinine level was associated with a lower death rate.
Cystatin C is a nonglycosylated 13,000-dalton basic protein that is filtered by the glomeruli and reabsorbed and catabolized by the tubular epithelial cells, with only small amounts excreted in the urine (Table 1).9 It has not been thoroughly evaluated as a filtration marker. The absence of urinary excretion makes it difficult to study variation in the urinary clearance and generation of cystatin. The generation of cystatin C appears to be less variable across populations and over time than does creatinine. Serum levels of cystatin C may also be affected by extrarenal elimination. Most but not all studies show that serum cystatin C is a better index of GFR than is serum creatinine alone.10 However, as compared with creatinine-based GFR estimates, there may not be an advantage to using cystatin C.10
The relationship between cystatin C and outcomes may also be confounded by factors that affect the serum level of cystatin and that are independent of GFR, including older age, male sex, smoking, higher weight, and higher levels of C-reactive protein.11 Unlike chronic illness, which weakens the relationship between serum creatinine and outcome, these variables strengthen the apparent relationship between serum cystatin C and outcome.
Another important issue to consider in using serum markers to assess GFR is the standardization of assays across clinical laboratories. Serum creatinine assays vary according to positive interference by serum proteins, which is relatively greater at lower levels of serum creatinine. It is well recognized that failure to calibrate the creatinine assay to the laboratory that developed the estimating equation can introduce a systematic error in estimated GFR, particularly at a high GFR.12 Shlipak and colleagues used the equation in the MDRD Study but did not calibrate their assay to the MDRD Study laboratory. Calibration probably would have raised the GFR estimates reported in their study,13 although it would have had little effect on the classification into quintiles. A standardization program for serum creatinine assays is currently being implemented by the National Kidney Disease Education Program,14 which should facilitate interpretation of GFR estimates. The cystatin C assay is more precise than are assays for serum creatinine, especially in the low range.15 However, cystatin C has not been standardized across clinical laboratories.
The study by Shlipak et al.6 suggests that the increased risk of cardiovascular disease among elderly patients with chronic kidney disease may be stronger and occur at higher levels of GFR than previously suspected. It also reinforces the need for an improved understanding of the relationship between cardiovascular disease and chronic kidney disease.5 Future research that focuses on developing more accurate estimating equations for GFR — on the basis of serum levels of creatinine, cystatin C, or both — would be important. Cohort studies that measure both urinary albumin excretion and estimated GFR and assess their combined association with the risk of various outcomes are needed. Predictive models for cardiovascular disease in patients with chronic kidney disease should be developed, analogous to the Framingham risk score in the general population, to guide clinical decision making and public policy.
What can be done right now to assess the risk among elderly patients? Clinicians should measure albuminuria and estimate GFR from serum creatinine to detect chronic kidney disease. Patients who are found to have chronic kidney disease should undergo appropriate evaluation and treatment according to the cause and stage of their disease. Moreover, patients with chronic kidney disease should be considered to be in the highest risk group for cardiovascular disease and should receive intensive risk-reduction therapy.
Supported in part by a grant (R01 DK53869-05, to Dr. Levey) from the National Institutes of Health.
We are indebted to Josef Coresh, M.D., and to Tom Greene, Ph.D., for contributing greatly to the ideas described here.
Source Information
From Tufts–New England Medical Center, Boston.
References
Renal Data System. 2004 Annual data report. Bethesda, Md.: National Institute of Diabetes and Digestive and Kidney Diseases, 2004. (Accessed March 18, 2005, at http://www.usrds.org/adr.htm.)
Go A, Chertow G, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296-1305.
National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39:Suppl 1:S1-S266.
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.
Stevens LA, Levey AS. Clinical implications for estimating equations for glomerular filtration rate. Ann Intern Med 2004;141:959-961.
Shlipak MG, Sarnak MJ, Katz R, et al. Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med 2005;352:2049-2060.
Perrone RD, Madias NE, Levey AS. Serum creatinine as an index of renal function: new insights into old concepts. Clin Chem 1992;38:1933-1953.
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.
Grubb AO. Cystatin C -- properties and use as diagnostic marker. Adv Clin Chem 2000;35:63-99.
Hoek FJ, Kemperman FA, Krediet RT. A comparison between cystatin C, plasma creatinine and the Cockcroft and Gault formula for the estimation of glomerular filtration rate. Nephrol Dial Transplant 2003;18:2024-2031.
Knight EL, Verhave JC, Spiegelman D, et al. Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int 2004;65:1416-1421.
Coresh J, Astor BC, McQuillan G, et al. Calibration and random variation of the serum creatinine assay as critical elements of using equations to estimate glomerular filtration rate. Am J Kidney Dis 2002;39:920-929.
Manjunath G, Tighiouart H, Ibrahim H, et al. Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J Am Coll Cardiol 2003;41:47-55.
National Kidney Disease Education Program. Information for health professionals. Bethesda, Md.: National Institute for Diabetes and Digestive and Kidney Diseases, 2004. (Accessed April 28, 2005, at http://www.nkdep.nih.gov/healthprofessionals/index.htm.)
Laterza OF, Price CP, Scott MG. Cystatin C: an improved estimator of glomerular filtration rate? Clin Chem 2002;48:699-707.(Lesley A. Stevens, M.D., )