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Estimating Glomerular Filtration Rate From Serum Creatinine in the General Population–Reply–I
LETTERS TO THE EDITOR
mg/dL to qualify for the diagnosis of CKD. The other recommended equation is based on characteristics of a combined population of CKD and non-CKD subjects. While not accounting for the effects of race on the interpretation of serum creatinine values, this equation accomplishes the set goal of identifying a GFR estimation equation that reduces the overdiagnosis of CKD without inducing an unreasonable level of underdiagnosis of the disease. Rule et al do not suggest use of the aforementioned equation in the calculation of GFR. Instead, they advocate embracement of sex-based threshold serum creatinine values. In doing so, they stray from inclusion of age as a component in GFR estimation. They propose that sex-based serum creatinine levels are appropriate heuristic measures for recognition of CKD by using the example that a 60-year-old woman with a serum creatinine level of 1.2 mg/dL would be found to have a normal GFR using their prediction equations. However, they fail to acknowledge that any woman older than 75 years who has a serum creatinine level of 1.2 mg/dL would qualify for the diagnosis of CKD by their combined-population equation. Thus, using sex-based serum creatinine values for identification of CKD would result in large-scale underdiagnosis of CKD within the geriatric community, a population at highest risk of CKD.2,3 Although the current MDRD equation may have limitations, it is essential that we appreciate and address any such limitations in any other identification system for CKD before we accept it as our gold standard. Jeffrey T. Cohen, MD Long Island Jewish Medical Center New Hyde Park, NY 1. Rule AD, Rodeheffer RJ, Larson TS, et al. Limitations of estimating glomerular filtration rate from serum creatinine in the general population [published correction appears in Mayo Clin Proc. 2006;81:1639]. Mayo Clin Proc. 2006;81:1427-1434. 2. Johnson CA, Levey AS, Coresh J, Levin A, Lau J, Eknoyan G. Clinical practice guidelines for chronic kidney disease in adults, part I: definition, disease stages, evaluation, treatment, and risk factors. Am Fam Physician. 2004;70:869-876. 3. Coresh J, Byrd-Holt D, Astor BC, et al. Chronic kidney disease awareness, prevalence, trends among U.S. adults, 1999-2000. J Am Soc Nephrol. 2005 Jan; 16:180-188. Epub 2004 Nov 24.
In reply: We appreciate Dr Cohen’s thoughtful commentary on our article. We will address his concern that using a sexspecific upper limit of normal for serum creatinine (SCr) to define CKD would result in large-scale underdiagnosis of the disease within the geriatric community. Our example of a 60-year-old white woman with a highnormal SCr level (1.2 mg/dL for the assay we used) showed an estimated GFR of 55 mL/min per 1.73 m2 using a CKD equation but an estimated GFR of 83 mL/min per 1.73 m2 using a healthy equation.1 Inadequate information is available to determine which equation is appropriate because both healthy and CKD populations can have normal SCr levels. Clinical context can help the clinician decide whether an SCr level near the threshold between normal and abnormal represents CKD by changing the pretest probability of CKD. How386
Mayo Clin Proc.
•
ever, clinical context can be limited or not available. When SCr is stable and clearly elevated (eg, 2.2 mg/dL), clinical context is unnecessary for identifying CKD because the SCr level is well outside the normal reference range, and the only disease process that leads to an elevated SCr level is a reduced GFR. Also noteworthy is that elderly adults with stable moderate reductions in estimated GFR (30-59 mL/min per 1.73 m2) have a substantially lower risk of mortality than younger persons with moderate reductions in estimated GFR.2 Elderly adults with moderate reductions in estimated GFR and highnormal SCr levels may have preserved muscle mass that is protective against mortality compared with elderly adults with low-normal SCr levels and decreased muscle mass. When GFR is measured directly (eg, iothalamate clearance), using a single threshold of 60 mL/min per 1.73 m2 to define the lower limit of normal is questionable. If any decline in GFR is defined as disease, then the lower limit of normal based on young adults is approximately 90 mL/min per 1.73 m2.3,4 Ninety-four percent of healthy elderly (>70 years) adults have a GFR below this threshold.5 If instead one defines any GFR lower than expected for an individual’s age as disease, then the lower limit of normal for a 75-year-old patient is 60 mL/min per 1.73 m2, which is too low for younger adults and too high for older adults.3-5 There is precedence for using agespecific disease thresholds in medicine (eg, pulmonary function tests). Because the age-related decline in GFR is offset by a concurrent age-related decline in muscle mass, SCr levels do not change with normal aging.4,5 When GFR is reduced more than expected with aging, a sex-specific elevated SCr level occurs.1 Using a calibrated assay,6 we recently found the upper limit of normal (97.5 percentile) for SCr to be 1.1 mg/dL instead of 1.2 mg/dL in white women and 1.3 mg/dL instead of 1.4 mg/dL in white men. We acknowledge that our data were unable to define the upper limit of normal for SCr in elderly (>70 years) and nonwhite ethnic groups. Andrew D. Rule, MD Stephen T. Turner, MD Mayo Clinic College of Medicine Rochester, Minn 1. Rule AD, Rodeheffer RJ, Larson TS, et al. Limitations of estimating glomerular filtration rate from serum creatinine in the general population [published correction appears in Mayo Clin Proc. 2006;81:1639]. Mayo Clin Proc. 2006;81:1427-1434. 2. O’Hare AM, Bertenthal D, Covinsky KE, et al. Mortality risk stratification in chronic kidney disease: one size for all ages? J Am Soc Nephrol. 2006 Mar; 17:846-853. Epub 2006 Feb 1. 3. Wesson LG. Physiology of the Human Kidney. New York, NY: Grune & Stratton; 1969. 4. Rule AD, Gussak HM, Pond GR, et al. Measured and estimated GFR in healthy potential kidney donors [published corrections appear in Am J Kidney Dis. 2004;44:1126 and 2005;46:170]. Am J Kidney Dis. 2004;43:112-119. 5. Fehrman-Ekholm I, Skeppholm L. Renal function in the elderly (>70 years old) measured by means of iohexol clearance, serum creatinine, serum urea and estimated clearance. Scand J Urol Nephrol. 2004;38:73-77. 6. Levey AS, Coresh J, Greene T, et al, Chronic Kidney Disease Epidemiology Collaboration. Using standardized serum creatinine values in the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145:247-254.
March 2007;82(3):383-386
•
www.mayoclinicproceedings.com
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
mg/dL to qualify for the diagnosis of CKD. The other recommended equation is based on characteristics of a combined population of CKD and non-CKD subjects. While not accounting for the effects of race on the interpretation of serum creatinine values, this equation accomplishes the set goal of identifying a GFR estimation equation that reduces the overdiagnosis of CKD without inducing an unreasonable level of underdiagnosis of the disease. Rule et al do not suggest use of the aforementioned equation in the calculation of GFR. Instead, they advocate embracement of sex-based threshold serum creatinine values. In doing so, they stray from inclusion of age as a component in GFR estimation. They propose that sex-based serum creatinine levels are appropriate heuristic measures for recognition of CKD by using the example that a 60-year-old woman with a serum creatinine level of 1.2 mg/dL would be found to have a normal GFR using their prediction equations. However, they fail to acknowledge that any woman older than 75 years who has a serum creatinine level of 1.2 mg/dL would qualify for the diagnosis of CKD by their combined-population equation. Thus, using sex-based serum creatinine values for identification of CKD would result in large-scale underdiagnosis of CKD within the geriatric community, a population at highest risk of CKD.2,3 Although the current MDRD equation may have limitations, it is essential that we appreciate and address any such limitations in any other identification system for CKD before we accept it as our gold standard. Jeffrey T. Cohen, MD Long Island Jewish Medical Center New Hyde Park, NY 1. Rule AD, Rodeheffer RJ, Larson TS, et al. Limitations of estimating glomerular filtration rate from serum creatinine in the general population [published correction appears in Mayo Clin Proc. 2006;81:1639]. Mayo Clin Proc. 2006;81:1427-1434. 2. Johnson CA, Levey AS, Coresh J, Levin A, Lau J, Eknoyan G. Clinical practice guidelines for chronic kidney disease in adults, part I: definition, disease stages, evaluation, treatment, and risk factors. Am Fam Physician. 2004;70:869-876. 3. Coresh J, Byrd-Holt D, Astor BC, et al. Chronic kidney disease awareness, prevalence, trends among U.S. adults, 1999-2000. J Am Soc Nephrol. 2005 Jan; 16:180-188. Epub 2004 Nov 24.
In reply: We appreciate Dr Cohen’s thoughtful commentary on our article. We will address his concern that using a sexspecific upper limit of normal for serum creatinine (SCr) to define CKD would result in large-scale underdiagnosis of the disease within the geriatric community. Our example of a 60-year-old white woman with a highnormal SCr level (1.2 mg/dL for the assay we used) showed an estimated GFR of 55 mL/min per 1.73 m2 using a CKD equation but an estimated GFR of 83 mL/min per 1.73 m2 using a healthy equation.1 Inadequate information is available to determine which equation is appropriate because both healthy and CKD populations can have normal SCr levels. Clinical context can help the clinician decide whether an SCr level near the threshold between normal and abnormal represents CKD by changing the pretest probability of CKD. How386
Mayo Clin Proc.
•
ever, clinical context can be limited or not available. When SCr is stable and clearly elevated (eg, 2.2 mg/dL), clinical context is unnecessary for identifying CKD because the SCr level is well outside the normal reference range, and the only disease process that leads to an elevated SCr level is a reduced GFR. Also noteworthy is that elderly adults with stable moderate reductions in estimated GFR (30-59 mL/min per 1.73 m2) have a substantially lower risk of mortality than younger persons with moderate reductions in estimated GFR.2 Elderly adults with moderate reductions in estimated GFR and highnormal SCr levels may have preserved muscle mass that is protective against mortality compared with elderly adults with low-normal SCr levels and decreased muscle mass. When GFR is measured directly (eg, iothalamate clearance), using a single threshold of 60 mL/min per 1.73 m2 to define the lower limit of normal is questionable. If any decline in GFR is defined as disease, then the lower limit of normal based on young adults is approximately 90 mL/min per 1.73 m2.3,4 Ninety-four percent of healthy elderly (>70 years) adults have a GFR below this threshold.5 If instead one defines any GFR lower than expected for an individual’s age as disease, then the lower limit of normal for a 75-year-old patient is 60 mL/min per 1.73 m2, which is too low for younger adults and too high for older adults.3-5 There is precedence for using agespecific disease thresholds in medicine (eg, pulmonary function tests). Because the age-related decline in GFR is offset by a concurrent age-related decline in muscle mass, SCr levels do not change with normal aging.4,5 When GFR is reduced more than expected with aging, a sex-specific elevated SCr level occurs.1 Using a calibrated assay,6 we recently found the upper limit of normal (97.5 percentile) for SCr to be 1.1 mg/dL instead of 1.2 mg/dL in white women and 1.3 mg/dL instead of 1.4 mg/dL in white men. We acknowledge that our data were unable to define the upper limit of normal for SCr in elderly (>70 years) and nonwhite ethnic groups. Andrew D. Rule, MD Stephen T. Turner, MD Mayo Clinic College of Medicine Rochester, Minn 1. Rule AD, Rodeheffer RJ, Larson TS, et al. Limitations of estimating glomerular filtration rate from serum creatinine in the general population [published correction appears in Mayo Clin Proc. 2006;81:1639]. Mayo Clin Proc. 2006;81:1427-1434. 2. O’Hare AM, Bertenthal D, Covinsky KE, et al. Mortality risk stratification in chronic kidney disease: one size for all ages? J Am Soc Nephrol. 2006 Mar; 17:846-853. Epub 2006 Feb 1. 3. Wesson LG. Physiology of the Human Kidney. New York, NY: Grune & Stratton; 1969. 4. Rule AD, Gussak HM, Pond GR, et al. Measured and estimated GFR in healthy potential kidney donors [published corrections appear in Am J Kidney Dis. 2004;44:1126 and 2005;46:170]. Am J Kidney Dis. 2004;43:112-119. 5. Fehrman-Ekholm I, Skeppholm L. Renal function in the elderly (>70 years old) measured by means of iohexol clearance, serum creatinine, serum urea and estimated clearance. Scand J Urol Nephrol. 2004;38:73-77. 6. Levey AS, Coresh J, Greene T, et al, Chronic Kidney Disease Epidemiology Collaboration. Using standardized serum creatinine values in the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145:247-254.
March 2007;82(3):383-386
•
www.mayoclinicproceedings.com
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.