Nephrology

DENVER – A high intake of insoluble dietary fiber is associated with reduced inflammation and all-cause mortality in patients with chronic kidney disease, results from a large observational analysis showed.

The finding underscores the importance of a fiber-rich diet in this patient population, which often presents with a low intake of dietary fiber, Dr. Neelakanta A. Dadi said in an interview during a poster session at the annual meeting of the American Society of Nephrology.

“I think this study tells us that patients with chronic kidney disease need to consume more dietary fiber such as vegetables, fruits, and oatmeal,” said Dr. Dadi of the University of Utah, Salt Lake City.

He and his associates used the National Health and Nutrition Examination Survey III to evaluate the association between elevated C-reactive protein (defined as greater than 3 mg/L) and all-cause mortality in 1,105 patients with chronic kidney disease. The researchers estimated intake of insoluble dietary fiber from 24-hour recalls and obtained mortality data through the National Center for Health Statistics by linkage with National Death Index records through 2006.

Low total dietary fiber intake was defined as less than 13.5 g/day while high dietary fiber intake was defined as 13.5 g/day or greater.

The mean age of patients was 69 years and 36% were male.

In a multivariate logistic regression analysis adjusted for age, sex, race, smoking, alcohol, systolic blood pressure, diastolic blood pressure, cancer, physical activity, calorie intake, protein intake, myocardial infarction, heart failure, and stroke, each 10-g/day increase in dietary fiber was associated with a significantly decreased odds of elevated serum C-reactive protein and all-cause mortality (OR, 0.56 and 0.80). A similar association was seen after further adjustment for waist circumference, diabetes, triglycerides, and HDL cholesterol level (OR, 0.56 and 0.76).

Dr. Dadi said that the observational design of NHANES III is a limitation. “It remains unclear what the major cause of mortality is in this population,” he said. “It could be cancer or cardiovascular events.”

The study was funded by a National Kidney Foundation Fellowship Grant and by grants from the Public Health Service and the National Center for Research Resources.

DENVER – A high intake of insoluble dietary fiber is associated with reduced inflammation and all-cause mortality in patients with chronic kidney disease, results from a large observational analysis showed.

The finding underscores the importance of a fiber-rich diet in this patient population, which often presents with a low intake of dietary fiber, Dr. Neelakanta A. Dadi said in an interview during a poster session at the annual meeting of the American Society of Nephrology.

“I think this study tells us that patients with chronic kidney disease need to consume more dietary fiber such as vegetables, fruits, and oatmeal,” said Dr. Dadi of the University of Utah, Salt Lake City.

He and his associates used the National Health and Nutrition Examination Survey III to evaluate the association between elevated C-reactive protein (defined as greater than 3 mg/L) and all-cause mortality in 1,105 patients with chronic kidney disease. The researchers estimated intake of insoluble dietary fiber from 24-hour recalls and obtained mortality data through the National Center for Health Statistics by linkage with National Death Index records through 2006.

Low total dietary fiber intake was defined as less than 13.5 g/day while high dietary fiber intake was defined as 13.5 g/day or greater.

The mean age of patients was 69 years and 36% were male.

In a multivariate logistic regression analysis adjusted for age, sex, race, smoking, alcohol, systolic blood pressure, diastolic blood pressure, cancer, physical activity, calorie intake, protein intake, myocardial infarction, heart failure, and stroke, each 10-g/day increase in dietary fiber was associated with a significantly decreased odds of elevated serum C-reactive protein and all-cause mortality (OR, 0.56 and 0.80). A similar association was seen after further adjustment for waist circumference, diabetes, triglycerides, and HDL cholesterol level (OR, 0.56 and 0.76).

Dr. Dadi said that the observational design of NHANES III is a limitation. “It remains unclear what the major cause of mortality is in this population,” he said. “It could be cancer or cardiovascular events.”

The study was funded by a National Kidney Foundation Fellowship Grant and by grants from the Public Health Service and the National Center for Research Resources.

DENVER – A high intake of insoluble dietary fiber is associated with reduced inflammation and all-cause mortality in patients with chronic kidney disease, results from a large observational analysis showed.

The finding underscores the importance of a fiber-rich diet in this patient population, which often presents with a low intake of dietary fiber, Dr. Neelakanta A. Dadi said in an interview during a poster session at the annual meeting of the American Society of Nephrology.

“I think this study tells us that patients with chronic kidney disease need to consume more dietary fiber such as vegetables, fruits, and oatmeal,” said Dr. Dadi of the University of Utah, Salt Lake City.

He and his associates used the National Health and Nutrition Examination Survey III to evaluate the association between elevated C-reactive protein (defined as greater than 3 mg/L) and all-cause mortality in 1,105 patients with chronic kidney disease. The researchers estimated intake of insoluble dietary fiber from 24-hour recalls and obtained mortality data through the National Center for Health Statistics by linkage with National Death Index records through 2006.

Low total dietary fiber intake was defined as less than 13.5 g/day while high dietary fiber intake was defined as 13.5 g/day or greater.

The mean age of patients was 69 years and 36% were male.

In a multivariate logistic regression analysis adjusted for age, sex, race, smoking, alcohol, systolic blood pressure, diastolic blood pressure, cancer, physical activity, calorie intake, protein intake, myocardial infarction, heart failure, and stroke, each 10-g/day increase in dietary fiber was associated with a significantly decreased odds of elevated serum C-reactive protein and all-cause mortality (OR, 0.56 and 0.80). A similar association was seen after further adjustment for waist circumference, diabetes, triglycerides, and HDL cholesterol level (OR, 0.56 and 0.76).

Dr. Dadi said that the observational design of NHANES III is a limitation. “It remains unclear what the major cause of mortality is in this population,” he said. “It could be cancer or cardiovascular events.”

The study was funded by a National Kidney Foundation Fellowship Grant and by grants from the Public Health Service and the National Center for Research Resources.

DENVER – A high intake of insoluble dietary fiber is associated with reduced inflammation and all-cause mortality in patients with chronic kidney disease, results from a large observational analysis showed.

The finding underscores the importance of a fiber-rich diet in this patient population, which often presents with a low intake of dietary fiber, Dr. Neelakanta A. Dadi said in an interview during a poster session at the annual meeting of the American Society of Nephrology.

“I think this study tells us that patients with chronic kidney disease need to consume more dietary fiber such as vegetables, fruits, and oatmeal,” said Dr. Dadi of the University of Utah, Salt Lake City.

He and his associates used the National Health and Nutrition Examination Survey III to evaluate the association between elevated C-reactive protein (defined as greater than 3 mg/L) and all-cause mortality in 1,105 patients with chronic kidney disease. The researchers estimated intake of insoluble dietary fiber from 24-hour recalls and obtained mortality data through the National Center for Health Statistics by linkage with National Death Index records through 2006.

Low total dietary fiber intake was defined as less than 13.5 g/day while high dietary fiber intake was defined as 13.5 g/day or greater.

The mean age of patients was 69 years and 36% were male.

In a multivariate logistic regression analysis adjusted for age, sex, race, smoking, alcohol, systolic blood pressure, diastolic blood pressure, cancer, physical activity, calorie intake, protein intake, myocardial infarction, heart failure, and stroke, each 10-g/day increase in dietary fiber was associated with a significantly decreased odds of elevated serum C-reactive protein and all-cause mortality (OR, 0.56 and 0.80). A similar association was seen after further adjustment for waist circumference, diabetes, triglycerides, and HDL cholesterol level (OR, 0.56 and 0.76).

Dr. Dadi said that the observational design of NHANES III is a limitation. “It remains unclear what the major cause of mortality is in this population,” he said. “It could be cancer or cardiovascular events.”

The study was funded by a National Kidney Foundation Fellowship Grant and by grants from the Public Health Service and the National Center for Research Resources.

DENVER – A high intake of insoluble dietary fiber is associated with reduced inflammation and all-cause mortality in patients with chronic kidney disease, results from a large observational analysis showed.

The finding underscores the importance of a fiber-rich diet in this patient population, which often presents with a low intake of dietary fiber, Dr. Neelakanta A. Dadi said in an interview during a poster session at the annual meeting of the American Society of Nephrology.

“I think this study tells us that patients with chronic kidney disease need to consume more dietary fiber such as vegetables, fruits, and oatmeal,” said Dr. Dadi of the University of Utah, Salt Lake City.

He and his associates used the National Health and Nutrition Examination Survey III to evaluate the association between elevated C-reactive protein (defined as greater than 3 mg/L) and all-cause mortality in 1,105 patients with chronic kidney disease. The researchers estimated intake of insoluble dietary fiber from 24-hour recalls and obtained mortality data through the National Center for Health Statistics by linkage with National Death Index records through 2006.

Low total dietary fiber intake was defined as less than 13.5 g/day while high dietary fiber intake was defined as 13.5 g/day or greater.

The mean age of patients was 69 years and 36% were male.

In a multivariate logistic regression analysis adjusted for age, sex, race, smoking, alcohol, systolic blood pressure, diastolic blood pressure, cancer, physical activity, calorie intake, protein intake, myocardial infarction, heart failure, and stroke, each 10-g/day increase in dietary fiber was associated with a significantly decreased odds of elevated serum C-reactive protein and all-cause mortality (OR, 0.56 and 0.80). A similar association was seen after further adjustment for waist circumference, diabetes, triglycerides, and HDL cholesterol level (OR, 0.56 and 0.76).

Dr. Dadi said that the observational design of NHANES III is a limitation. “It remains unclear what the major cause of mortality is in this population,” he said. “It could be cancer or cardiovascular events.”

The study was funded by a National Kidney Foundation Fellowship Grant and by grants from the Public Health Service and the National Center for Research Resources.

DENVER – A high intake of insoluble dietary fiber is associated with reduced inflammation and all-cause mortality in patients with chronic kidney disease, results from a large observational analysis showed.

The finding underscores the importance of a fiber-rich diet in this patient population, which often presents with a low intake of dietary fiber, Dr. Neelakanta A. Dadi said in an interview during a poster session at the annual meeting of the American Society of Nephrology.

“I think this study tells us that patients with chronic kidney disease need to consume more dietary fiber such as vegetables, fruits, and oatmeal,” said Dr. Dadi of the University of Utah, Salt Lake City.

He and his associates used the National Health and Nutrition Examination Survey III to evaluate the association between elevated C-reactive protein (defined as greater than 3 mg/L) and all-cause mortality in 1,105 patients with chronic kidney disease. The researchers estimated intake of insoluble dietary fiber from 24-hour recalls and obtained mortality data through the National Center for Health Statistics by linkage with National Death Index records through 2006.

Low total dietary fiber intake was defined as less than 13.5 g/day while high dietary fiber intake was defined as 13.5 g/day or greater.

The mean age of patients was 69 years and 36% were male.

In a multivariate logistic regression analysis adjusted for age, sex, race, smoking, alcohol, systolic blood pressure, diastolic blood pressure, cancer, physical activity, calorie intake, protein intake, myocardial infarction, heart failure, and stroke, each 10-g/day increase in dietary fiber was associated with a significantly decreased odds of elevated serum C-reactive protein and all-cause mortality (OR, 0.56 and 0.80). A similar association was seen after further adjustment for waist circumference, diabetes, triglycerides, and HDL cholesterol level (OR, 0.56 and 0.76).

Dr. Dadi said that the observational design of NHANES III is a limitation. “It remains unclear what the major cause of mortality is in this population,” he said. “It could be cancer or cardiovascular events.”

The study was funded by a National Kidney Foundation Fellowship Grant and by grants from the Public Health Service and the National Center for Research Resources.

In patients with chronic kidney disease, high serum levels of phosphorus appear to be associated with increases in all-cause mortality, results of a large meta-analysis suggest.

There were no strong or consistent associations between increased levels of calcium and parathyroid hormone and all-cause mortality in this population of patients.

Such findings, coupled with the absence of randomized controlled trials, suggest that the evidentiary basis for "recommended targets of serum phosphorus, parathyroid hormone, and calcium in chronic kidney disease is poor," Dr. Suetonia C. Palmer of the department of medicine at the University of Otago, Christchurch, New Zealand, and colleagues reported in the March 16 issue of JAMA.

The researchers assessed the strength of the evidence linking each of the biomarkers with the risk of death, cardiovascular mortality, and nonfatal cardiovascular events in individuals with chronic kidney disease by searching MEDLINE and EMBASE databases for relevant cohort studies published from the late 1940s to December 2010. They also combed through reference lists from primary studies, review articles, and clinical guidelines (JAMA 2011;305:1119-27).

Of the 8,380 citations identified, 47 studies with a total of 327,644 patients were included in the final analysis. The population sizes of the studies ranged from 99 to 78,420 participants. Random effects meta-regression was used to summarize data across studies.

The investigators found that the risk of death increased 18% for every 1-mg/dL increase in serum phosphorus, for a relative risk (RR) of 1.18. No significant associations were seen between all-cause mortality and every 100-pg/mL increase in serum level of parathyroid hormone (RR 1.01), or for every 1-mg/dL increase in serum calcium level (RR 1.08).

The researchers were not able to estimate the association between each of the biomarkers and the risk of cardiovascular death in particular, because relevant data were available from only one adequately adjusted cohort study.

"The current data do not support the hypothesis that individuals with chronic kidney disease should have treatment to achieve targeted levels of serum parathyroid hormone or calcium to reduce mortality or cardiovascular morbidity, except at extreme levels in which hypocalcemia and hypercalcemia result in immediate, clinically apparent adverse events such as tetany and seizures," the researchers wrote.

"Furthermore, treating high phosphorus levels is linked to a substantial pill burden that is associated with lower quality of life in individuals with chronic kidney disease. While we do not conclude that normalizing serum levels of calcium or phosphorus or avoiding upper or lower extremes of serum level of parathyroid hormone is futile, high-quality evidence is required before specific treatment should be advocated strongly."

The authors acknowledged certain limitations of their work, including the fact that the studies used in the meta-analysis "are vulnerable to the unpredictable confounding effects of measured and unmeasured variables," and that the study did not evaluate the association between mortality and serum levels of alkaline phosphatase or vitamin D, "which are both emerging as predictors of outcomes in populations with and without chronic kidney disease in cohort studies."

Dr. Palmer disclosed that she was the recipient of a Don and Lorraine Jacquot Fellowship from the Royal Australasian College of Physicians and received travel support from the Amgen Dompe fellowship to the Consorzio Mario Negri Sud. A coauthor of the study, Petra Macaskill, Ph.D., reported receiving grant support from the Australian National Health and Medical Research Council.

In patients with chronic kidney disease, high serum levels of phosphorus appear to be associated with increases in all-cause mortality, results of a large meta-analysis suggest.

There were no strong or consistent associations between increased levels of calcium and parathyroid hormone and all-cause mortality in this population of patients.

Such findings, coupled with the absence of randomized controlled trials, suggest that the evidentiary basis for "recommended targets of serum phosphorus, parathyroid hormone, and calcium in chronic kidney disease is poor," Dr. Suetonia C. Palmer of the department of medicine at the University of Otago, Christchurch, New Zealand, and colleagues reported in the March 16 issue of JAMA.

The researchers assessed the strength of the evidence linking each of the biomarkers with the risk of death, cardiovascular mortality, and nonfatal cardiovascular events in individuals with chronic kidney disease by searching MEDLINE and EMBASE databases for relevant cohort studies published from the late 1940s to December 2010. They also combed through reference lists from primary studies, review articles, and clinical guidelines (JAMA 2011;305:1119-27).

Of the 8,380 citations identified, 47 studies with a total of 327,644 patients were included in the final analysis. The population sizes of the studies ranged from 99 to 78,420 participants. Random effects meta-regression was used to summarize data across studies.

The investigators found that the risk of death increased 18% for every 1-mg/dL increase in serum phosphorus, for a relative risk (RR) of 1.18. No significant associations were seen between all-cause mortality and every 100-pg/mL increase in serum level of parathyroid hormone (RR 1.01), or for every 1-mg/dL increase in serum calcium level (RR 1.08).

The researchers were not able to estimate the association between each of the biomarkers and the risk of cardiovascular death in particular, because relevant data were available from only one adequately adjusted cohort study.

"The current data do not support the hypothesis that individuals with chronic kidney disease should have treatment to achieve targeted levels of serum parathyroid hormone or calcium to reduce mortality or cardiovascular morbidity, except at extreme levels in which hypocalcemia and hypercalcemia result in immediate, clinically apparent adverse events such as tetany and seizures," the researchers wrote.

"Furthermore, treating high phosphorus levels is linked to a substantial pill burden that is associated with lower quality of life in individuals with chronic kidney disease. While we do not conclude that normalizing serum levels of calcium or phosphorus or avoiding upper or lower extremes of serum level of parathyroid hormone is futile, high-quality evidence is required before specific treatment should be advocated strongly."

The authors acknowledged certain limitations of their work, including the fact that the studies used in the meta-analysis "are vulnerable to the unpredictable confounding effects of measured and unmeasured variables," and that the study did not evaluate the association between mortality and serum levels of alkaline phosphatase or vitamin D, "which are both emerging as predictors of outcomes in populations with and without chronic kidney disease in cohort studies."

Dr. Palmer disclosed that she was the recipient of a Don and Lorraine Jacquot Fellowship from the Royal Australasian College of Physicians and received travel support from the Amgen Dompe fellowship to the Consorzio Mario Negri Sud. A coauthor of the study, Petra Macaskill, Ph.D., reported receiving grant support from the Australian National Health and Medical Research Council.

In patients with chronic kidney disease, high serum levels of phosphorus appear to be associated with increases in all-cause mortality, results of a large meta-analysis suggest.

There were no strong or consistent associations between increased levels of calcium and parathyroid hormone and all-cause mortality in this population of patients.

Such findings, coupled with the absence of randomized controlled trials, suggest that the evidentiary basis for "recommended targets of serum phosphorus, parathyroid hormone, and calcium in chronic kidney disease is poor," Dr. Suetonia C. Palmer of the department of medicine at the University of Otago, Christchurch, New Zealand, and colleagues reported in the March 16 issue of JAMA.

The researchers assessed the strength of the evidence linking each of the biomarkers with the risk of death, cardiovascular mortality, and nonfatal cardiovascular events in individuals with chronic kidney disease by searching MEDLINE and EMBASE databases for relevant cohort studies published from the late 1940s to December 2010. They also combed through reference lists from primary studies, review articles, and clinical guidelines (JAMA 2011;305:1119-27).

Of the 8,380 citations identified, 47 studies with a total of 327,644 patients were included in the final analysis. The population sizes of the studies ranged from 99 to 78,420 participants. Random effects meta-regression was used to summarize data across studies.

The investigators found that the risk of death increased 18% for every 1-mg/dL increase in serum phosphorus, for a relative risk (RR) of 1.18. No significant associations were seen between all-cause mortality and every 100-pg/mL increase in serum level of parathyroid hormone (RR 1.01), or for every 1-mg/dL increase in serum calcium level (RR 1.08).

The researchers were not able to estimate the association between each of the biomarkers and the risk of cardiovascular death in particular, because relevant data were available from only one adequately adjusted cohort study.

"The current data do not support the hypothesis that individuals with chronic kidney disease should have treatment to achieve targeted levels of serum parathyroid hormone or calcium to reduce mortality or cardiovascular morbidity, except at extreme levels in which hypocalcemia and hypercalcemia result in immediate, clinically apparent adverse events such as tetany and seizures," the researchers wrote.

"Furthermore, treating high phosphorus levels is linked to a substantial pill burden that is associated with lower quality of life in individuals with chronic kidney disease. While we do not conclude that normalizing serum levels of calcium or phosphorus or avoiding upper or lower extremes of serum level of parathyroid hormone is futile, high-quality evidence is required before specific treatment should be advocated strongly."

The authors acknowledged certain limitations of their work, including the fact that the studies used in the meta-analysis "are vulnerable to the unpredictable confounding effects of measured and unmeasured variables," and that the study did not evaluate the association between mortality and serum levels of alkaline phosphatase or vitamin D, "which are both emerging as predictors of outcomes in populations with and without chronic kidney disease in cohort studies."

Dr. Palmer disclosed that she was the recipient of a Don and Lorraine Jacquot Fellowship from the Royal Australasian College of Physicians and received travel support from the Amgen Dompe fellowship to the Consorzio Mario Negri Sud. A coauthor of the study, Petra Macaskill, Ph.D., reported receiving grant support from the Australian National Health and Medical Research Council.

In patients with chronic kidney disease, high serum levels of phosphorus appear to be associated with increases in all-cause mortality, results of a large meta-analysis suggest.

There were no strong or consistent associations between increased levels of calcium and parathyroid hormone and all-cause mortality in this population of patients.

Such findings, coupled with the absence of randomized controlled trials, suggest that the evidentiary basis for "recommended targets of serum phosphorus, parathyroid hormone, and calcium in chronic kidney disease is poor," Dr. Suetonia C. Palmer of the department of medicine at the University of Otago, Christchurch, New Zealand, and colleagues reported in the March 16 issue of JAMA.

The researchers assessed the strength of the evidence linking each of the biomarkers with the risk of death, cardiovascular mortality, and nonfatal cardiovascular events in individuals with chronic kidney disease by searching MEDLINE and EMBASE databases for relevant cohort studies published from the late 1940s to December 2010. They also combed through reference lists from primary studies, review articles, and clinical guidelines (JAMA 2011;305:1119-27).

Of the 8,380 citations identified, 47 studies with a total of 327,644 patients were included in the final analysis. The population sizes of the studies ranged from 99 to 78,420 participants. Random effects meta-regression was used to summarize data across studies.

The investigators found that the risk of death increased 18% for every 1-mg/dL increase in serum phosphorus, for a relative risk (RR) of 1.18. No significant associations were seen between all-cause mortality and every 100-pg/mL increase in serum level of parathyroid hormone (RR 1.01), or for every 1-mg/dL increase in serum calcium level (RR 1.08).

The researchers were not able to estimate the association between each of the biomarkers and the risk of cardiovascular death in particular, because relevant data were available from only one adequately adjusted cohort study.

"The current data do not support the hypothesis that individuals with chronic kidney disease should have treatment to achieve targeted levels of serum parathyroid hormone or calcium to reduce mortality or cardiovascular morbidity, except at extreme levels in which hypocalcemia and hypercalcemia result in immediate, clinically apparent adverse events such as tetany and seizures," the researchers wrote.

"Furthermore, treating high phosphorus levels is linked to a substantial pill burden that is associated with lower quality of life in individuals with chronic kidney disease. While we do not conclude that normalizing serum levels of calcium or phosphorus or avoiding upper or lower extremes of serum level of parathyroid hormone is futile, high-quality evidence is required before specific treatment should be advocated strongly."

The authors acknowledged certain limitations of their work, including the fact that the studies used in the meta-analysis "are vulnerable to the unpredictable confounding effects of measured and unmeasured variables," and that the study did not evaluate the association between mortality and serum levels of alkaline phosphatase or vitamin D, "which are both emerging as predictors of outcomes in populations with and without chronic kidney disease in cohort studies."

Dr. Palmer disclosed that she was the recipient of a Don and Lorraine Jacquot Fellowship from the Royal Australasian College of Physicians and received travel support from the Amgen Dompe fellowship to the Consorzio Mario Negri Sud. A coauthor of the study, Petra Macaskill, Ph.D., reported receiving grant support from the Australian National Health and Medical Research Council.

In patients with chronic kidney disease, high serum levels of phosphorus appear to be associated with increases in all-cause mortality, results of a large meta-analysis suggest.

There were no strong or consistent associations between increased levels of calcium and parathyroid hormone and all-cause mortality in this population of patients.

Such findings, coupled with the absence of randomized controlled trials, suggest that the evidentiary basis for "recommended targets of serum phosphorus, parathyroid hormone, and calcium in chronic kidney disease is poor," Dr. Suetonia C. Palmer of the department of medicine at the University of Otago, Christchurch, New Zealand, and colleagues reported in the March 16 issue of JAMA.

The researchers assessed the strength of the evidence linking each of the biomarkers with the risk of death, cardiovascular mortality, and nonfatal cardiovascular events in individuals with chronic kidney disease by searching MEDLINE and EMBASE databases for relevant cohort studies published from the late 1940s to December 2010. They also combed through reference lists from primary studies, review articles, and clinical guidelines (JAMA 2011;305:1119-27).

Of the 8,380 citations identified, 47 studies with a total of 327,644 patients were included in the final analysis. The population sizes of the studies ranged from 99 to 78,420 participants. Random effects meta-regression was used to summarize data across studies.

The investigators found that the risk of death increased 18% for every 1-mg/dL increase in serum phosphorus, for a relative risk (RR) of 1.18. No significant associations were seen between all-cause mortality and every 100-pg/mL increase in serum level of parathyroid hormone (RR 1.01), or for every 1-mg/dL increase in serum calcium level (RR 1.08).

The researchers were not able to estimate the association between each of the biomarkers and the risk of cardiovascular death in particular, because relevant data were available from only one adequately adjusted cohort study.

"The current data do not support the hypothesis that individuals with chronic kidney disease should have treatment to achieve targeted levels of serum parathyroid hormone or calcium to reduce mortality or cardiovascular morbidity, except at extreme levels in which hypocalcemia and hypercalcemia result in immediate, clinically apparent adverse events such as tetany and seizures," the researchers wrote.

"Furthermore, treating high phosphorus levels is linked to a substantial pill burden that is associated with lower quality of life in individuals with chronic kidney disease. While we do not conclude that normalizing serum levels of calcium or phosphorus or avoiding upper or lower extremes of serum level of parathyroid hormone is futile, high-quality evidence is required before specific treatment should be advocated strongly."

The authors acknowledged certain limitations of their work, including the fact that the studies used in the meta-analysis "are vulnerable to the unpredictable confounding effects of measured and unmeasured variables," and that the study did not evaluate the association between mortality and serum levels of alkaline phosphatase or vitamin D, "which are both emerging as predictors of outcomes in populations with and without chronic kidney disease in cohort studies."

Dr. Palmer disclosed that she was the recipient of a Don and Lorraine Jacquot Fellowship from the Royal Australasian College of Physicians and received travel support from the Amgen Dompe fellowship to the Consorzio Mario Negri Sud. A coauthor of the study, Petra Macaskill, Ph.D., reported receiving grant support from the Australian National Health and Medical Research Council.

In patients with chronic kidney disease, high serum levels of phosphorus appear to be associated with increases in all-cause mortality, results of a large meta-analysis suggest.

There were no strong or consistent associations between increased levels of calcium and parathyroid hormone and all-cause mortality in this population of patients.

Such findings, coupled with the absence of randomized controlled trials, suggest that the evidentiary basis for "recommended targets of serum phosphorus, parathyroid hormone, and calcium in chronic kidney disease is poor," Dr. Suetonia C. Palmer of the department of medicine at the University of Otago, Christchurch, New Zealand, and colleagues reported in the March 16 issue of JAMA.

The researchers assessed the strength of the evidence linking each of the biomarkers with the risk of death, cardiovascular mortality, and nonfatal cardiovascular events in individuals with chronic kidney disease by searching MEDLINE and EMBASE databases for relevant cohort studies published from the late 1940s to December 2010. They also combed through reference lists from primary studies, review articles, and clinical guidelines (JAMA 2011;305:1119-27).

Of the 8,380 citations identified, 47 studies with a total of 327,644 patients were included in the final analysis. The population sizes of the studies ranged from 99 to 78,420 participants. Random effects meta-regression was used to summarize data across studies.

The investigators found that the risk of death increased 18% for every 1-mg/dL increase in serum phosphorus, for a relative risk (RR) of 1.18. No significant associations were seen between all-cause mortality and every 100-pg/mL increase in serum level of parathyroid hormone (RR 1.01), or for every 1-mg/dL increase in serum calcium level (RR 1.08).

The researchers were not able to estimate the association between each of the biomarkers and the risk of cardiovascular death in particular, because relevant data were available from only one adequately adjusted cohort study.

"The current data do not support the hypothesis that individuals with chronic kidney disease should have treatment to achieve targeted levels of serum parathyroid hormone or calcium to reduce mortality or cardiovascular morbidity, except at extreme levels in which hypocalcemia and hypercalcemia result in immediate, clinically apparent adverse events such as tetany and seizures," the researchers wrote.

"Furthermore, treating high phosphorus levels is linked to a substantial pill burden that is associated with lower quality of life in individuals with chronic kidney disease. While we do not conclude that normalizing serum levels of calcium or phosphorus or avoiding upper or lower extremes of serum level of parathyroid hormone is futile, high-quality evidence is required before specific treatment should be advocated strongly."

The authors acknowledged certain limitations of their work, including the fact that the studies used in the meta-analysis "are vulnerable to the unpredictable confounding effects of measured and unmeasured variables," and that the study did not evaluate the association between mortality and serum levels of alkaline phosphatase or vitamin D, "which are both emerging as predictors of outcomes in populations with and without chronic kidney disease in cohort studies."

Dr. Palmer disclosed that she was the recipient of a Don and Lorraine Jacquot Fellowship from the Royal Australasian College of Physicians and received travel support from the Amgen Dompe fellowship to the Consorzio Mario Negri Sud. A coauthor of the study, Petra Macaskill, Ph.D., reported receiving grant support from the Australian National Health and Medical Research Council.

ORLANDO – Costly and unnecessary imaging studies are being performed in men with low-risk and medium-risk prostate cancer, whereas a worrisome number of men with high-risk disease do not receive adequate imaging prior to treatment.

An analysis of 30,183 patients found that 36% of men who were diagnosed with low-risk and 49% of those with intermediate-risk prostate cancer underwent at least one imaging study for staging.

The National Comprehensive Cancer Network (NCCN) and the American Urological Association (AUA) recommend using CT, MRI, and bone scan studies following the diagnosis of prostate cancer only in the setting of high-risk pathological features.

Only 61% of men who were diagnosed with this type of cancer, however, received the recommended imaging prior to treatment, Dr. Sandip M. Prasad, a urologic oncology fellow at the University of Chicago Medical Center, reported.

"Given that the risk of having non–organ confined disease is higher in men with higher Gleason scores, [prostate specific antigen level], or clinical stage, it is critical that these men have appropriate staging to rule out metastatic disease before undergoing local therapy," he said in an interview.

During the study period, men with low- and intermediate-risk prostate cancer did not require any additional imaging per NCCN guidelines; however, the most recently revised (January 2011) NCCN practice guideline allows for some men with intermediate-risk prostate cancer to undergo bone scan.

Dr. Prasad hypothesized that defensive medicine – or a lack of awareness of the AUA and NCCN guidelines – may have played a role in the overuse of the tests. Imaging may also provide reassurance for lower-risk patients that they do not have evidence of metastatic disease, although the likelihood that they would is very low.

The unnecessary tests do expose patients to harmful radiation, and may have cost American taxpayers $35 million, based on a low rate of Medicare reimbursement, he said. The cost may actually be greater because private insurers often reimburse at a higher rate for younger men.

"The gap seen in men with high-risk disease is harder to explain, although one could hypothesize that patient desire to rapidly be treated may drive early treatment without complete staging," Dr. Prasad said. "Men may also choose to have no additional imaging or treatment following diagnosis."

The analysis was based on SEER (Surveillance, Epidemiology, and End Results)–Medicare linked data on 30,183 men who were diagnosed with prostate cancer in 2004-2005. In all, 9,640 men had low-risk prostate cancer, 12,966 men had medium-risk prostate cancer, and 7,577 men had high-risk prostate cancer. Their median ages were 71 years, 73 years and 75 years, respectively.

A multivariate analysis revealed that imaging was less common in men who were educated (odds ratio, 0.084) and was more common in men who were older than 75 years (OR, 1.25), black (OR, 1.11), had a median income of more than $60,000 (OR, 1.19) and lived in rural areas (OR, 1.22), Dr. Prasad and his associates reported in a poster at the Genitourinary Cancers Symposium.

Among low-risk men, imaging was significantly more common in those treated with radiation/brachytherapy (46%; OR, 1.82) or cryotherapy (37%; OR, 1.44), but significantly less common with watchful waiting (14%; OR, 0.27).

Among high-risk patients, imaging was significantly more common in those treated with proton beam therapy (80%; OR, 2.14), radiation/brachytherapy (79%; OR, 2.21), and cryotherapy (74%; OR, 1.64), but significantly less common when men received androgen therapy (44%; OR, 0.62) or watchful waiting (21%; OR, 0.16), the researchers reported at the meeting, which was cosponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Prasad and his coauthors report no conflicts of interest.

ORLANDO – Costly and unnecessary imaging studies are being performed in men with low-risk and medium-risk prostate cancer, whereas a worrisome number of men with high-risk disease do not receive adequate imaging prior to treatment.

An analysis of 30,183 patients found that 36% of men who were diagnosed with low-risk and 49% of those with intermediate-risk prostate cancer underwent at least one imaging study for staging.

The National Comprehensive Cancer Network (NCCN) and the American Urological Association (AUA) recommend using CT, MRI, and bone scan studies following the diagnosis of prostate cancer only in the setting of high-risk pathological features.

Only 61% of men who were diagnosed with this type of cancer, however, received the recommended imaging prior to treatment, Dr. Sandip M. Prasad, a urologic oncology fellow at the University of Chicago Medical Center, reported.

"Given that the risk of having non–organ confined disease is higher in men with higher Gleason scores, [prostate specific antigen level], or clinical stage, it is critical that these men have appropriate staging to rule out metastatic disease before undergoing local therapy," he said in an interview.

During the study period, men with low- and intermediate-risk prostate cancer did not require any additional imaging per NCCN guidelines; however, the most recently revised (January 2011) NCCN practice guideline allows for some men with intermediate-risk prostate cancer to undergo bone scan.

Dr. Prasad hypothesized that defensive medicine – or a lack of awareness of the AUA and NCCN guidelines – may have played a role in the overuse of the tests. Imaging may also provide reassurance for lower-risk patients that they do not have evidence of metastatic disease, although the likelihood that they would is very low.

The unnecessary tests do expose patients to harmful radiation, and may have cost American taxpayers $35 million, based on a low rate of Medicare reimbursement, he said. The cost may actually be greater because private insurers often reimburse at a higher rate for younger men.

"The gap seen in men with high-risk disease is harder to explain, although one could hypothesize that patient desire to rapidly be treated may drive early treatment without complete staging," Dr. Prasad said. "Men may also choose to have no additional imaging or treatment following diagnosis."

The analysis was based on SEER (Surveillance, Epidemiology, and End Results)–Medicare linked data on 30,183 men who were diagnosed with prostate cancer in 2004-2005. In all, 9,640 men had low-risk prostate cancer, 12,966 men had medium-risk prostate cancer, and 7,577 men had high-risk prostate cancer. Their median ages were 71 years, 73 years and 75 years, respectively.

A multivariate analysis revealed that imaging was less common in men who were educated (odds ratio, 0.084) and was more common in men who were older than 75 years (OR, 1.25), black (OR, 1.11), had a median income of more than $60,000 (OR, 1.19) and lived in rural areas (OR, 1.22), Dr. Prasad and his associates reported in a poster at the Genitourinary Cancers Symposium.

Among low-risk men, imaging was significantly more common in those treated with radiation/brachytherapy (46%; OR, 1.82) or cryotherapy (37%; OR, 1.44), but significantly less common with watchful waiting (14%; OR, 0.27).

Among high-risk patients, imaging was significantly more common in those treated with proton beam therapy (80%; OR, 2.14), radiation/brachytherapy (79%; OR, 2.21), and cryotherapy (74%; OR, 1.64), but significantly less common when men received androgen therapy (44%; OR, 0.62) or watchful waiting (21%; OR, 0.16), the researchers reported at the meeting, which was cosponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Prasad and his coauthors report no conflicts of interest.

ORLANDO – Costly and unnecessary imaging studies are being performed in men with low-risk and medium-risk prostate cancer, whereas a worrisome number of men with high-risk disease do not receive adequate imaging prior to treatment.

An analysis of 30,183 patients found that 36% of men who were diagnosed with low-risk and 49% of those with intermediate-risk prostate cancer underwent at least one imaging study for staging.

The National Comprehensive Cancer Network (NCCN) and the American Urological Association (AUA) recommend using CT, MRI, and bone scan studies following the diagnosis of prostate cancer only in the setting of high-risk pathological features.

Only 61% of men who were diagnosed with this type of cancer, however, received the recommended imaging prior to treatment, Dr. Sandip M. Prasad, a urologic oncology fellow at the University of Chicago Medical Center, reported.

"Given that the risk of having non–organ confined disease is higher in men with higher Gleason scores, [prostate specific antigen level], or clinical stage, it is critical that these men have appropriate staging to rule out metastatic disease before undergoing local therapy," he said in an interview.

During the study period, men with low- and intermediate-risk prostate cancer did not require any additional imaging per NCCN guidelines; however, the most recently revised (January 2011) NCCN practice guideline allows for some men with intermediate-risk prostate cancer to undergo bone scan.

Dr. Prasad hypothesized that defensive medicine – or a lack of awareness of the AUA and NCCN guidelines – may have played a role in the overuse of the tests. Imaging may also provide reassurance for lower-risk patients that they do not have evidence of metastatic disease, although the likelihood that they would is very low.

The unnecessary tests do expose patients to harmful radiation, and may have cost American taxpayers $35 million, based on a low rate of Medicare reimbursement, he said. The cost may actually be greater because private insurers often reimburse at a higher rate for younger men.

"The gap seen in men with high-risk disease is harder to explain, although one could hypothesize that patient desire to rapidly be treated may drive early treatment without complete staging," Dr. Prasad said. "Men may also choose to have no additional imaging or treatment following diagnosis."

The analysis was based on SEER (Surveillance, Epidemiology, and End Results)–Medicare linked data on 30,183 men who were diagnosed with prostate cancer in 2004-2005. In all, 9,640 men had low-risk prostate cancer, 12,966 men had medium-risk prostate cancer, and 7,577 men had high-risk prostate cancer. Their median ages were 71 years, 73 years and 75 years, respectively.

A multivariate analysis revealed that imaging was less common in men who were educated (odds ratio, 0.084) and was more common in men who were older than 75 years (OR, 1.25), black (OR, 1.11), had a median income of more than $60,000 (OR, 1.19) and lived in rural areas (OR, 1.22), Dr. Prasad and his associates reported in a poster at the Genitourinary Cancers Symposium.

Among low-risk men, imaging was significantly more common in those treated with radiation/brachytherapy (46%; OR, 1.82) or cryotherapy (37%; OR, 1.44), but significantly less common with watchful waiting (14%; OR, 0.27).

Among high-risk patients, imaging was significantly more common in those treated with proton beam therapy (80%; OR, 2.14), radiation/brachytherapy (79%; OR, 2.21), and cryotherapy (74%; OR, 1.64), but significantly less common when men received androgen therapy (44%; OR, 0.62) or watchful waiting (21%; OR, 0.16), the researchers reported at the meeting, which was cosponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Prasad and his coauthors report no conflicts of interest.

CANCUN, MEXICO - Scleroderma patients on angiotensin-converting enzyme inhibitors at the onset of scleroderma renal crisis do not appear to have worse outcomes than do those not taking the antihypertensive agents prior to the acute renal function deterioration, according to preliminary data from the largest prospective cohort study of incident scleroderma renal crisis to date.

The finding further fuels the ongoing debate over the role of angiotensin-converting enzyme (ACE) inhibitors as prophylaxis for scleroderma renal crisis (SRC), lead investigator Dr. Marie Hudson reported at the annual meeting of the Canadian Rheumatology.

Although the use of ACE inhibitors since the 1980s has dramatically improved the outcome of SRC patients – prior to their widespread use for this indication, SRC mortality was more than 80% – there is still room for substantial improvement, explained Dr. Hudson, noting that the 1- and 5-year survival rates hover around 75% and 65%, respectively, and approximately 19% die within 3 months of diagnosis. It is possible that earlier intervention with ACE inhibitors might improve SRC outcomes. Most likely to benefit are individuals considered at risk for the complication, including those with diffuse and rapidly progressing skin involvement, history of glucocorticoid use, and positive analysis of anti-RNA polymerase III antibodies. But not everyone agrees, she said. "[Opponents] have suggested that prophylactic ACE inhibition could delay the diagnosis [of SRC] because of normalized blood pressure and as a result lead to worse outcomes."

Because a trial of ACE inhibitors in non-SRC patients could carry some risk for participants, Dr. Hudson, a rheumatologist at the Jewish General Hospital and a faculty member at McGill University, Montreal, and her colleagues in the International Scleroderma Renal Crisis study instead sought to evaluate the outcomes of scleroderma patients who presented with incident SRC while taking ACE inhibitors immediately prior to the onset of the condition. To date, they have identified 94 cases of incident SRC nationwide using an ongoing, Internet-based survey in which the investigators e-mail nearly 600 participating physicians worldwide every other week to ask about new cases of SRC, she said. For each new case identified, the investigators collect data on patient demographics, disease characteristics, and exposure to ACE inhibitors. The investigators send recruiting physicians a follow-up case report form 1 year after a patient is identified, she explained, noting that the primary outcome measure is death or dialysis dependence at 1 year after SRC onset.

Of the 94 cases identified so far, 90% had hypertensive SRC and 10% had normotensive SRC; 47% had a history of glucocorticoid use immediately prior to SRC onset, at a mean dose of 17 mg prednisone/day; 15% had anti-RNA polymerase III antibodies; and 23% were on ACE inhibitors prior to the onset of disease, said Dr. Hudson. "Proportionally, more of the normotensive SRC patients were on ACE inhibitors than hypotensive SRC patients."

An analysis of the 1-year follow up data that have been collected to date showed that more than 50% of the patients have died or remain on dialysis at 1 year, Dr. Hudson reported. "So far, there is no evidence that those exposed to ACE inhibitors prior to SRC had worse outcomes," she said, stressing that the findings are preliminary as the collection of 1-year follow-up data is ongoing.

As new data are collected and the findings are validated through additional studies, "we hope to offer new insight into the role of ACE inhibitors in patients with scleroderma," said Dr. Hudson. The use of the Internet-survey technology, in particular, has streamlined the research process because it has facilitated international collaboration and allowed the collection of a substantial amount of information on a rare condition in a short period of time, she said.

Dr. Hudson disclosed a financial relationship with Pfizer, which manufactures several ACE inhibitors.

CANCUN, MEXICO - Scleroderma patients on angiotensin-converting enzyme inhibitors at the onset of scleroderma renal crisis do not appear to have worse outcomes than do those not taking the antihypertensive agents prior to the acute renal function deterioration, according to preliminary data from the largest prospective cohort study of incident scleroderma renal crisis to date.

The finding further fuels the ongoing debate over the role of angiotensin-converting enzyme (ACE) inhibitors as prophylaxis for scleroderma renal crisis (SRC), lead investigator Dr. Marie Hudson reported at the annual meeting of the Canadian Rheumatology.

Although the use of ACE inhibitors since the 1980s has dramatically improved the outcome of SRC patients – prior to their widespread use for this indication, SRC mortality was more than 80% – there is still room for substantial improvement, explained Dr. Hudson, noting that the 1- and 5-year survival rates hover around 75% and 65%, respectively, and approximately 19% die within 3 months of diagnosis. It is possible that earlier intervention with ACE inhibitors might improve SRC outcomes. Most likely to benefit are individuals considered at risk for the complication, including those with diffuse and rapidly progressing skin involvement, history of glucocorticoid use, and positive analysis of anti-RNA polymerase III antibodies. But not everyone agrees, she said. "[Opponents] have suggested that prophylactic ACE inhibition could delay the diagnosis [of SRC] because of normalized blood pressure and as a result lead to worse outcomes."

Because a trial of ACE inhibitors in non-SRC patients could carry some risk for participants, Dr. Hudson, a rheumatologist at the Jewish General Hospital and a faculty member at McGill University, Montreal, and her colleagues in the International Scleroderma Renal Crisis study instead sought to evaluate the outcomes of scleroderma patients who presented with incident SRC while taking ACE inhibitors immediately prior to the onset of the condition. To date, they have identified 94 cases of incident SRC nationwide using an ongoing, Internet-based survey in which the investigators e-mail nearly 600 participating physicians worldwide every other week to ask about new cases of SRC, she said. For each new case identified, the investigators collect data on patient demographics, disease characteristics, and exposure to ACE inhibitors. The investigators send recruiting physicians a follow-up case report form 1 year after a patient is identified, she explained, noting that the primary outcome measure is death or dialysis dependence at 1 year after SRC onset.

Of the 94 cases identified so far, 90% had hypertensive SRC and 10% had normotensive SRC; 47% had a history of glucocorticoid use immediately prior to SRC onset, at a mean dose of 17 mg prednisone/day; 15% had anti-RNA polymerase III antibodies; and 23% were on ACE inhibitors prior to the onset of disease, said Dr. Hudson. "Proportionally, more of the normotensive SRC patients were on ACE inhibitors than hypotensive SRC patients."

An analysis of the 1-year follow up data that have been collected to date showed that more than 50% of the patients have died or remain on dialysis at 1 year, Dr. Hudson reported. "So far, there is no evidence that those exposed to ACE inhibitors prior to SRC had worse outcomes," she said, stressing that the findings are preliminary as the collection of 1-year follow-up data is ongoing.

As new data are collected and the findings are validated through additional studies, "we hope to offer new insight into the role of ACE inhibitors in patients with scleroderma," said Dr. Hudson. The use of the Internet-survey technology, in particular, has streamlined the research process because it has facilitated international collaboration and allowed the collection of a substantial amount of information on a rare condition in a short period of time, she said.

Dr. Hudson disclosed a financial relationship with Pfizer, which manufactures several ACE inhibitors.

CANCUN, MEXICO - Scleroderma patients on angiotensin-converting enzyme inhibitors at the onset of scleroderma renal crisis do not appear to have worse outcomes than do those not taking the antihypertensive agents prior to the acute renal function deterioration, according to preliminary data from the largest prospective cohort study of incident scleroderma renal crisis to date.

The finding further fuels the ongoing debate over the role of angiotensin-converting enzyme (ACE) inhibitors as prophylaxis for scleroderma renal crisis (SRC), lead investigator Dr. Marie Hudson reported at the annual meeting of the Canadian Rheumatology.

Although the use of ACE inhibitors since the 1980s has dramatically improved the outcome of SRC patients – prior to their widespread use for this indication, SRC mortality was more than 80% – there is still room for substantial improvement, explained Dr. Hudson, noting that the 1- and 5-year survival rates hover around 75% and 65%, respectively, and approximately 19% die within 3 months of diagnosis. It is possible that earlier intervention with ACE inhibitors might improve SRC outcomes. Most likely to benefit are individuals considered at risk for the complication, including those with diffuse and rapidly progressing skin involvement, history of glucocorticoid use, and positive analysis of anti-RNA polymerase III antibodies. But not everyone agrees, she said. "[Opponents] have suggested that prophylactic ACE inhibition could delay the diagnosis [of SRC] because of normalized blood pressure and as a result lead to worse outcomes."

Because a trial of ACE inhibitors in non-SRC patients could carry some risk for participants, Dr. Hudson, a rheumatologist at the Jewish General Hospital and a faculty member at McGill University, Montreal, and her colleagues in the International Scleroderma Renal Crisis study instead sought to evaluate the outcomes of scleroderma patients who presented with incident SRC while taking ACE inhibitors immediately prior to the onset of the condition. To date, they have identified 94 cases of incident SRC nationwide using an ongoing, Internet-based survey in which the investigators e-mail nearly 600 participating physicians worldwide every other week to ask about new cases of SRC, she said. For each new case identified, the investigators collect data on patient demographics, disease characteristics, and exposure to ACE inhibitors. The investigators send recruiting physicians a follow-up case report form 1 year after a patient is identified, she explained, noting that the primary outcome measure is death or dialysis dependence at 1 year after SRC onset.

Of the 94 cases identified so far, 90% had hypertensive SRC and 10% had normotensive SRC; 47% had a history of glucocorticoid use immediately prior to SRC onset, at a mean dose of 17 mg prednisone/day; 15% had anti-RNA polymerase III antibodies; and 23% were on ACE inhibitors prior to the onset of disease, said Dr. Hudson. "Proportionally, more of the normotensive SRC patients were on ACE inhibitors than hypotensive SRC patients."

An analysis of the 1-year follow up data that have been collected to date showed that more than 50% of the patients have died or remain on dialysis at 1 year, Dr. Hudson reported. "So far, there is no evidence that those exposed to ACE inhibitors prior to SRC had worse outcomes," she said, stressing that the findings are preliminary as the collection of 1-year follow-up data is ongoing.

As new data are collected and the findings are validated through additional studies, "we hope to offer new insight into the role of ACE inhibitors in patients with scleroderma," said Dr. Hudson. The use of the Internet-survey technology, in particular, has streamlined the research process because it has facilitated international collaboration and allowed the collection of a substantial amount of information on a rare condition in a short period of time, she said.

Dr. Hudson disclosed a financial relationship with Pfizer, which manufactures several ACE inhibitors.

DENVER – Moderate alcohol consumption among renal transplant recipients is inversely associated with posttransplant diabetes and all-cause mortality, results from a large single-center study showed.

The finding contradicts the notion that renal transplant recipients should refrain from alcohol use because of possible interaction with their immunosuppressive drugs, lead investigator Dorien M. Zelle said in an interview during a poster session at the annual meeting of the American Society of Nephrology.

"After renal transplantation, patients have a lot of restrictions," said Ms. Zelle, a PhD candidate at University Medical Center Groningen, The Netherlands. "Doctors advise them not to smoke, and they have to take a lot of medications. We should not advise them against moderate alcohol consumption, because we have shown that nondrinkers are doing worse than moderate drinkers after transplantation."

She went on to note that the Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Care of Kidney Transplant Recipients does mention specific alcohol restrictions for kidney transplant patients.

Ms. Zelle and her associates studied 600 renal transplant recipients who visited the medical center’s outpatient clinic between 2001 and 2003 and were at least 1 year post transplant. They filled out self-report questionnaires about their alcohol use and the researchers recorded mortality and graft failure until May 2009. Study participants were classified into one of four groups: abstainers, sporadic drinkers, moderate drinkers (range of 1 unit per week to 3 units per day), and heavy drinkers (4 or more units per day).

At baseline, the mean age of the 600 patients was 51 years and 12% had posttransplant diabetes. Nearly half (288, or 48%) were abstainers, 94 (16%) were sporadic drinkers, 210 (35%) were moderate drinkers, and 8 (1%) were heavy drinkers.

Ms. Zelle reported that during a median follow-up of 7 years, moderate drinkers had a 67% lower risk for diabetes compared with respondents in the other groups (OR = 0.33). In addition, 33 (15.7%) of the moderate drinkers died, compared with 75 (26%) of the abstainers, 23 (24.5%) of the sporadic drinkers, and 2 (25%) of the heavy drinkers.

Univariate Cox regression analysis revealed that moderate drinkers were 44% less likely to die after transplantation compared with respondents in the other groups (HR = 0.56). Adjustment for potential confounders including diabetes and smoking did not change this association.

Ms. Zelle acknowledged certain limitations of the study, including its single center design and the fact that alcohol consumption was measured at a single point in time. "It could be that some patients started drinking more or quit drinking during the course of the study," she said.

Ms. Zelle said that she had no relevant financial disclosures to make.

DENVER – Moderate alcohol consumption among renal transplant recipients is inversely associated with posttransplant diabetes and all-cause mortality, results from a large single-center study showed.

The finding contradicts the notion that renal transplant recipients should refrain from alcohol use because of possible interaction with their immunosuppressive drugs, lead investigator Dorien M. Zelle said in an interview during a poster session at the annual meeting of the American Society of Nephrology.

"After renal transplantation, patients have a lot of restrictions," said Ms. Zelle, a PhD candidate at University Medical Center Groningen, The Netherlands. "Doctors advise them not to smoke, and they have to take a lot of medications. We should not advise them against moderate alcohol consumption, because we have shown that nondrinkers are doing worse than moderate drinkers after transplantation."

She went on to note that the Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Care of Kidney Transplant Recipients does mention specific alcohol restrictions for kidney transplant patients.

Ms. Zelle and her associates studied 600 renal transplant recipients who visited the medical center’s outpatient clinic between 2001 and 2003 and were at least 1 year post transplant. They filled out self-report questionnaires about their alcohol use and the researchers recorded mortality and graft failure until May 2009. Study participants were classified into one of four groups: abstainers, sporadic drinkers, moderate drinkers (range of 1 unit per week to 3 units per day), and heavy drinkers (4 or more units per day).

At baseline, the mean age of the 600 patients was 51 years and 12% had posttransplant diabetes. Nearly half (288, or 48%) were abstainers, 94 (16%) were sporadic drinkers, 210 (35%) were moderate drinkers, and 8 (1%) were heavy drinkers.

Ms. Zelle reported that during a median follow-up of 7 years, moderate drinkers had a 67% lower risk for diabetes compared with respondents in the other groups (OR = 0.33). In addition, 33 (15.7%) of the moderate drinkers died, compared with 75 (26%) of the abstainers, 23 (24.5%) of the sporadic drinkers, and 2 (25%) of the heavy drinkers.

Univariate Cox regression analysis revealed that moderate drinkers were 44% less likely to die after transplantation compared with respondents in the other groups (HR = 0.56). Adjustment for potential confounders including diabetes and smoking did not change this association.

Ms. Zelle acknowledged certain limitations of the study, including its single center design and the fact that alcohol consumption was measured at a single point in time. "It could be that some patients started drinking more or quit drinking during the course of the study," she said.

Ms. Zelle said that she had no relevant financial disclosures to make.

DENVER – Moderate alcohol consumption among renal transplant recipients is inversely associated with posttransplant diabetes and all-cause mortality, results from a large single-center study showed.

The finding contradicts the notion that renal transplant recipients should refrain from alcohol use because of possible interaction with their immunosuppressive drugs, lead investigator Dorien M. Zelle said in an interview during a poster session at the annual meeting of the American Society of Nephrology.

"After renal transplantation, patients have a lot of restrictions," said Ms. Zelle, a PhD candidate at University Medical Center Groningen, The Netherlands. "Doctors advise them not to smoke, and they have to take a lot of medications. We should not advise them against moderate alcohol consumption, because we have shown that nondrinkers are doing worse than moderate drinkers after transplantation."

She went on to note that the Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Care of Kidney Transplant Recipients does mention specific alcohol restrictions for kidney transplant patients.

Ms. Zelle and her associates studied 600 renal transplant recipients who visited the medical center’s outpatient clinic between 2001 and 2003 and were at least 1 year post transplant. They filled out self-report questionnaires about their alcohol use and the researchers recorded mortality and graft failure until May 2009. Study participants were classified into one of four groups: abstainers, sporadic drinkers, moderate drinkers (range of 1 unit per week to 3 units per day), and heavy drinkers (4 or more units per day).

At baseline, the mean age of the 600 patients was 51 years and 12% had posttransplant diabetes. Nearly half (288, or 48%) were abstainers, 94 (16%) were sporadic drinkers, 210 (35%) were moderate drinkers, and 8 (1%) were heavy drinkers.

Ms. Zelle reported that during a median follow-up of 7 years, moderate drinkers had a 67% lower risk for diabetes compared with respondents in the other groups (OR = 0.33). In addition, 33 (15.7%) of the moderate drinkers died, compared with 75 (26%) of the abstainers, 23 (24.5%) of the sporadic drinkers, and 2 (25%) of the heavy drinkers.

Univariate Cox regression analysis revealed that moderate drinkers were 44% less likely to die after transplantation compared with respondents in the other groups (HR = 0.56). Adjustment for potential confounders including diabetes and smoking did not change this association.

Ms. Zelle acknowledged certain limitations of the study, including its single center design and the fact that alcohol consumption was measured at a single point in time. "It could be that some patients started drinking more or quit drinking during the course of the study," she said.

Ms. Zelle said that she had no relevant financial disclosures to make.

DENVER – Moderate alcohol consumption among renal transplant recipients is inversely associated with posttransplant diabetes and all-cause mortality, results from a large single-center study showed.

The finding contradicts the notion that renal transplant recipients should refrain from alcohol use because of possible interaction with their immunosuppressive drugs, lead investigator Dorien M. Zelle said in an interview during a poster session at the annual meeting of the American Society of Nephrology.

"After renal transplantation, patients have a lot of restrictions," said Ms. Zelle, a PhD candidate at University Medical Center Groningen, The Netherlands. "Doctors advise them not to smoke, and they have to take a lot of medications. We should not advise them against moderate alcohol consumption, because we have shown that nondrinkers are doing worse than moderate drinkers after transplantation."

She went on to note that the Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Care of Kidney Transplant Recipients does mention specific alcohol restrictions for kidney transplant patients.

Ms. Zelle and her associates studied 600 renal transplant recipients who visited the medical center’s outpatient clinic between 2001 and 2003 and were at least 1 year post transplant. They filled out self-report questionnaires about their alcohol use and the researchers recorded mortality and graft failure until May 2009. Study participants were classified into one of four groups: abstainers, sporadic drinkers, moderate drinkers (range of 1 unit per week to 3 units per day), and heavy drinkers (4 or more units per day).

At baseline, the mean age of the 600 patients was 51 years and 12% had posttransplant diabetes. Nearly half (288, or 48%) were abstainers, 94 (16%) were sporadic drinkers, 210 (35%) were moderate drinkers, and 8 (1%) were heavy drinkers.

Ms. Zelle reported that during a median follow-up of 7 years, moderate drinkers had a 67% lower risk for diabetes compared with respondents in the other groups (OR = 0.33). In addition, 33 (15.7%) of the moderate drinkers died, compared with 75 (26%) of the abstainers, 23 (24.5%) of the sporadic drinkers, and 2 (25%) of the heavy drinkers.

Univariate Cox regression analysis revealed that moderate drinkers were 44% less likely to die after transplantation compared with respondents in the other groups (HR = 0.56). Adjustment for potential confounders including diabetes and smoking did not change this association.

Ms. Zelle acknowledged certain limitations of the study, including its single center design and the fact that alcohol consumption was measured at a single point in time. "It could be that some patients started drinking more or quit drinking during the course of the study," she said.

Ms. Zelle said that she had no relevant financial disclosures to make.

DENVER – Moderate alcohol consumption among renal transplant recipients is inversely associated with posttransplant diabetes and all-cause mortality, results from a large single-center study showed.

The finding contradicts the notion that renal transplant recipients should refrain from alcohol use because of possible interaction with their immunosuppressive drugs, lead investigator Dorien M. Zelle said in an interview during a poster session at the annual meeting of the American Society of Nephrology.

"After renal transplantation, patients have a lot of restrictions," said Ms. Zelle, a PhD candidate at University Medical Center Groningen, The Netherlands. "Doctors advise them not to smoke, and they have to take a lot of medications. We should not advise them against moderate alcohol consumption, because we have shown that nondrinkers are doing worse than moderate drinkers after transplantation."

She went on to note that the Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Care of Kidney Transplant Recipients does mention specific alcohol restrictions for kidney transplant patients.

Ms. Zelle and her associates studied 600 renal transplant recipients who visited the medical center’s outpatient clinic between 2001 and 2003 and were at least 1 year post transplant. They filled out self-report questionnaires about their alcohol use and the researchers recorded mortality and graft failure until May 2009. Study participants were classified into one of four groups: abstainers, sporadic drinkers, moderate drinkers (range of 1 unit per week to 3 units per day), and heavy drinkers (4 or more units per day).

At baseline, the mean age of the 600 patients was 51 years and 12% had posttransplant diabetes. Nearly half (288, or 48%) were abstainers, 94 (16%) were sporadic drinkers, 210 (35%) were moderate drinkers, and 8 (1%) were heavy drinkers.

Ms. Zelle reported that during a median follow-up of 7 years, moderate drinkers had a 67% lower risk for diabetes compared with respondents in the other groups (OR = 0.33). In addition, 33 (15.7%) of the moderate drinkers died, compared with 75 (26%) of the abstainers, 23 (24.5%) of the sporadic drinkers, and 2 (25%) of the heavy drinkers.

Univariate Cox regression analysis revealed that moderate drinkers were 44% less likely to die after transplantation compared with respondents in the other groups (HR = 0.56). Adjustment for potential confounders including diabetes and smoking did not change this association.

Ms. Zelle acknowledged certain limitations of the study, including its single center design and the fact that alcohol consumption was measured at a single point in time. "It could be that some patients started drinking more or quit drinking during the course of the study," she said.

Ms. Zelle said that she had no relevant financial disclosures to make.

DENVER – Moderate alcohol consumption among renal transplant recipients is inversely associated with posttransplant diabetes and all-cause mortality, results from a large single-center study showed.

The finding contradicts the notion that renal transplant recipients should refrain from alcohol use because of possible interaction with their immunosuppressive drugs, lead investigator Dorien M. Zelle said in an interview during a poster session at the annual meeting of the American Society of Nephrology.

"After renal transplantation, patients have a lot of restrictions," said Ms. Zelle, a PhD candidate at University Medical Center Groningen, The Netherlands. "Doctors advise them not to smoke, and they have to take a lot of medications. We should not advise them against moderate alcohol consumption, because we have shown that nondrinkers are doing worse than moderate drinkers after transplantation."

She went on to note that the Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Care of Kidney Transplant Recipients does mention specific alcohol restrictions for kidney transplant patients.

Ms. Zelle and her associates studied 600 renal transplant recipients who visited the medical center’s outpatient clinic between 2001 and 2003 and were at least 1 year post transplant. They filled out self-report questionnaires about their alcohol use and the researchers recorded mortality and graft failure until May 2009. Study participants were classified into one of four groups: abstainers, sporadic drinkers, moderate drinkers (range of 1 unit per week to 3 units per day), and heavy drinkers (4 or more units per day).

At baseline, the mean age of the 600 patients was 51 years and 12% had posttransplant diabetes. Nearly half (288, or 48%) were abstainers, 94 (16%) were sporadic drinkers, 210 (35%) were moderate drinkers, and 8 (1%) were heavy drinkers.

Ms. Zelle reported that during a median follow-up of 7 years, moderate drinkers had a 67% lower risk for diabetes compared with respondents in the other groups (OR = 0.33). In addition, 33 (15.7%) of the moderate drinkers died, compared with 75 (26%) of the abstainers, 23 (24.5%) of the sporadic drinkers, and 2 (25%) of the heavy drinkers.

Univariate Cox regression analysis revealed that moderate drinkers were 44% less likely to die after transplantation compared with respondents in the other groups (HR = 0.56). Adjustment for potential confounders including diabetes and smoking did not change this association.

Ms. Zelle acknowledged certain limitations of the study, including its single center design and the fact that alcohol consumption was measured at a single point in time. "It could be that some patients started drinking more or quit drinking during the course of the study," she said.

Ms. Zelle said that she had no relevant financial disclosures to make.

At the American Society of Nephrology Renal Week 2010, one of the authors (A.D.R.) presented the following question at an In-Depth Nephrology Course on Geriatric Nephrology:

See related article

A 65-year-old woman donated a kidney to her son. Before donation, her serum creatinine level was 1.0 mg/dL, her estimated glomerular filtration rate (GFR) was 56 mL/min/1.73 m², and her measured GFR was 82 mL/min/1.73 m², which was below the 2.5th percentile for 20-year-old potential kidney donors. The patient had no albuminuria or hypertension and was otherwise healthy. The kidney was biopsied during the transplant surgery. The biopsy revealed 2 of 20 glomeruli as globally sclerosed, a focus of tubular atrophy, and mild arteriosclerosis (findings present in less than 2.5% of 20-year-old donors).

Choose one. Prior to donation, this woman had:

• Chronic kidney disease (CKD), and she should not have donated her kidney
• CKD, but kidney donation was reasonable
• Age-related (senescent) changes in her kidneys, and should not have donated her kidney
• Age-related (senescent) changes in her kidneys, but kidney donation was reasonable

Using an electronic response system, 36 (82%) of 44 physicians in the audience chose the last option, even though this patient meets the current definition of CKD (an estimated GFR less than 60 mL/min/1.73 m²) and has chronic parenchymal damage documented by a kidney biopsy.

PROBLEMS WITH THE GFR AND CKD CLASSIFICATION

This question highlights several key problems with the GFR and CKD classification.

First, in low-risk populations such as potential kidney donors, serum-creatinine-based equations such as the Modification of Diet in Renal Disease (MDRD) equation and the Chronic Kidney Disease Epidemiology Study (CKD-EPI) equation substantially underestimate the GFR.¹

Second, many healthy older adults with normal serum creatinine levels have an estimated GFR and a measured GFR below the normal range for young adults.²

Third, many healthy older adults have evidence of chronic parenchymal damage on renal biopsy, unlike healthy young adults.³

Finally, many health care providers did not previously recognize that people with a normal serum creatinine level could have a reduced GFR, and widespread use of the estimated GFR has addressed this problem. However, many physicians remain skeptical about efforts this past decade to classify age-related changes in kidney function as a “disease” in the absence of a clear benefit to older patients.⁴

TWO POINTS ABOUT THE ESTIMATED GFR

In this issue of the Cleveland Clinic Journal of Medicine, Simon and colleagues⁵ provide a balanced assessment of the benefits and pitfalls of using the estimated GFR in clinical practice. Two points they make deserve further discussion:

Bigger people make more creatinine. GFR can be reported in units of milliliters per minute, or in units normalized to body surface area (mL/min/1.73 m²). Contemporary equations for identifying and classifying CKD use the latter, because the GFR is considered inappropriately low when metabolic waste is not being adequately cleared. It is intuitive that smaller people require less absolute GFR than larger people, who generate more metabolic waste. Indexing GFR to 1.73 m² assumes that body surface area is a good surrogate for metabolic waste generation. However, whether body surface area is the best surrogate for the rate of metabolic waste generation has long been a subject of debate.⁶

The relationship between GFR and serum creatinine is not linear. Due to the inverse relationship between serum creatinine and GFR, a small change in serum creatinine from 0.9 to 1.2 mg/dL will represent a relatively large change in GFR (eg, 85 to 65 mL/min/1.73 m²), whereas a large change in serum creatinine from 5 to 9 mg/dL will represent a smaller change in GFR (eg, 10 to 5 mL/min/1.73 m²). The latter may be of great concern since it represents a fall in GFR to levels at which dialysis is likely needed. With the former, subtle changes in serum creatinine represent large changes in GFR, but there is also much more day-to-day variability in GFR in the normal or near-normal range than in the advanced range of kidney disease. This is one of the reasons the MDRD and CKD-EPI equations were developed, using logarithmic models that emphasize percentage instead of absolute differences in GFR.

BEYOND CREATININE?

As Simon and colleagues point out,⁵ although serum creatinine is a flawed surrogate for GFR, there are many problems with determining GFR by other means.

Direct GFR measurement relies on the use of an exogenous marker such as inulin or iothalamate that is infused or injected, followed by timed urine and plasma measurements to calculate GFR by the urinary clearance method (UV/P, where U is the concentration of the marker in the urine, V is the urine volume, and P is the concentration of the marker in the plasma). Alternatively, timed plasma measurements of the marker alone can be used to determine GFR by the plasma clearance method. The problem is that direct GFR measurement is costly, invasive, imprecise, time-consuming, and impractical in most clinical settings.

Exogenous markers for determining GFR are chosen because they are metabolically inert, are cleared by glomerular filtration without tubular secretion or reabsorption, and have no extrarenal clearance via the liver or intestines. Endogenous markers such as serum creatinine do not fulfill all of these ideal criteria.

Simon and colleagues highlight the problem of using the estimated GFR to screen for CKD in populations of ostensibly healthy persons.⁵ The MDRD and CKD-EPI equations contain demographic variables to approximate the creatinine generation rate. The primary source of creatinine generation is muscle, and the coefficients in these equations reflect the higher muscle mass of younger individuals, males, and African Americans. However, any creatinine-based equation is fundamentally flawed because overall health also affects muscle mass: healthy people have greater muscle mass than people with chronic illness, including those with CKD. Therefore, at the same serum creatinine level, a healthy person has a higher GFR than a patient with CKD.^1,7 This problem leads to circular reasoning, since you need to know whether the patient has CKD or is healthy in order to accurately estimate GFR, but estimated GFR is being used to determine whether the patient is healthy or has CKD.

Therefore, other endogenous markers that are also eliminated via glomerular filtration, such as cystatin C, have been used to construct equations that estimate GFR. Unfortunately, factors other than GFR, such as inflammation, can also influence blood cystatin C levels. This in turn impairs the accuracy of equations that use cystatin C to estimate GFR in the general population.⁸ No known endogenous marker of GFR can be used in all patients without any confounding factors.

To rectify this problem, recent studies have investigated the use of a confirmatory test to determine which patients with a creatinine-based estimated GFR less than 60 mL/min/1.73 m² actually have kidney disease or have a false-positive result due to higher-than-average creatinine generation. Both albuminuria and elevated serum cystatin C are examples of useful confirmatory tests that substantially decrease the misdiagnosis of CKD in healthy adults with an estimated GFR less than 60 mL/min/1.73 m².^9,10

Imagine if we identified and staged systemic lupus erythematosus on the basis of antinuclear antibody levels alone: this would parallel the current approach that largely uses serum creatinine alone to classify CKD. Confirmatory tests and considering patient-specific risk factors could avoid potential harm to healthy individuals and yet retain gains that have been made to improve the interpretation of serum creatinine levels in CKD patients.

At the American Society of Nephrology Renal Week 2010, one of the authors (A.D.R.) presented the following question at an In-Depth Nephrology Course on Geriatric Nephrology:

See related article

A 65-year-old woman donated a kidney to her son. Before donation, her serum creatinine level was 1.0 mg/dL, her estimated glomerular filtration rate (GFR) was 56 mL/min/1.73 m², and her measured GFR was 82 mL/min/1.73 m², which was below the 2.5th percentile for 20-year-old potential kidney donors. The patient had no albuminuria or hypertension and was otherwise healthy. The kidney was biopsied during the transplant surgery. The biopsy revealed 2 of 20 glomeruli as globally sclerosed, a focus of tubular atrophy, and mild arteriosclerosis (findings present in less than 2.5% of 20-year-old donors).

Choose one. Prior to donation, this woman had:

• Chronic kidney disease (CKD), and she should not have donated her kidney
• CKD, but kidney donation was reasonable
• Age-related (senescent) changes in her kidneys, and should not have donated her kidney
• Age-related (senescent) changes in her kidneys, but kidney donation was reasonable

Using an electronic response system, 36 (82%) of 44 physicians in the audience chose the last option, even though this patient meets the current definition of CKD (an estimated GFR less than 60 mL/min/1.73 m²) and has chronic parenchymal damage documented by a kidney biopsy.

PROBLEMS WITH THE GFR AND CKD CLASSIFICATION

This question highlights several key problems with the GFR and CKD classification.

First, in low-risk populations such as potential kidney donors, serum-creatinine-based equations such as the Modification of Diet in Renal Disease (MDRD) equation and the Chronic Kidney Disease Epidemiology Study (CKD-EPI) equation substantially underestimate the GFR.¹

Second, many healthy older adults with normal serum creatinine levels have an estimated GFR and a measured GFR below the normal range for young adults.²

Third, many healthy older adults have evidence of chronic parenchymal damage on renal biopsy, unlike healthy young adults.³

Finally, many health care providers did not previously recognize that people with a normal serum creatinine level could have a reduced GFR, and widespread use of the estimated GFR has addressed this problem. However, many physicians remain skeptical about efforts this past decade to classify age-related changes in kidney function as a “disease” in the absence of a clear benefit to older patients.⁴

TWO POINTS ABOUT THE ESTIMATED GFR

In this issue of the Cleveland Clinic Journal of Medicine, Simon and colleagues⁵ provide a balanced assessment of the benefits and pitfalls of using the estimated GFR in clinical practice. Two points they make deserve further discussion:

Bigger people make more creatinine. GFR can be reported in units of milliliters per minute, or in units normalized to body surface area (mL/min/1.73 m²). Contemporary equations for identifying and classifying CKD use the latter, because the GFR is considered inappropriately low when metabolic waste is not being adequately cleared. It is intuitive that smaller people require less absolute GFR than larger people, who generate more metabolic waste. Indexing GFR to 1.73 m² assumes that body surface area is a good surrogate for metabolic waste generation. However, whether body surface area is the best surrogate for the rate of metabolic waste generation has long been a subject of debate.⁶

The relationship between GFR and serum creatinine is not linear. Due to the inverse relationship between serum creatinine and GFR, a small change in serum creatinine from 0.9 to 1.2 mg/dL will represent a relatively large change in GFR (eg, 85 to 65 mL/min/1.73 m²), whereas a large change in serum creatinine from 5 to 9 mg/dL will represent a smaller change in GFR (eg, 10 to 5 mL/min/1.73 m²). The latter may be of great concern since it represents a fall in GFR to levels at which dialysis is likely needed. With the former, subtle changes in serum creatinine represent large changes in GFR, but there is also much more day-to-day variability in GFR in the normal or near-normal range than in the advanced range of kidney disease. This is one of the reasons the MDRD and CKD-EPI equations were developed, using logarithmic models that emphasize percentage instead of absolute differences in GFR.

BEYOND CREATININE?

As Simon and colleagues point out,⁵ although serum creatinine is a flawed surrogate for GFR, there are many problems with determining GFR by other means.

Direct GFR measurement relies on the use of an exogenous marker such as inulin or iothalamate that is infused or injected, followed by timed urine and plasma measurements to calculate GFR by the urinary clearance method (UV/P, where U is the concentration of the marker in the urine, V is the urine volume, and P is the concentration of the marker in the plasma). Alternatively, timed plasma measurements of the marker alone can be used to determine GFR by the plasma clearance method. The problem is that direct GFR measurement is costly, invasive, imprecise, time-consuming, and impractical in most clinical settings.

Exogenous markers for determining GFR are chosen because they are metabolically inert, are cleared by glomerular filtration without tubular secretion or reabsorption, and have no extrarenal clearance via the liver or intestines. Endogenous markers such as serum creatinine do not fulfill all of these ideal criteria.

Simon and colleagues highlight the problem of using the estimated GFR to screen for CKD in populations of ostensibly healthy persons.⁵ The MDRD and CKD-EPI equations contain demographic variables to approximate the creatinine generation rate. The primary source of creatinine generation is muscle, and the coefficients in these equations reflect the higher muscle mass of younger individuals, males, and African Americans. However, any creatinine-based equation is fundamentally flawed because overall health also affects muscle mass: healthy people have greater muscle mass than people with chronic illness, including those with CKD. Therefore, at the same serum creatinine level, a healthy person has a higher GFR than a patient with CKD.^1,7 This problem leads to circular reasoning, since you need to know whether the patient has CKD or is healthy in order to accurately estimate GFR, but estimated GFR is being used to determine whether the patient is healthy or has CKD.

Therefore, other endogenous markers that are also eliminated via glomerular filtration, such as cystatin C, have been used to construct equations that estimate GFR. Unfortunately, factors other than GFR, such as inflammation, can also influence blood cystatin C levels. This in turn impairs the accuracy of equations that use cystatin C to estimate GFR in the general population.⁸ No known endogenous marker of GFR can be used in all patients without any confounding factors.

To rectify this problem, recent studies have investigated the use of a confirmatory test to determine which patients with a creatinine-based estimated GFR less than 60 mL/min/1.73 m² actually have kidney disease or have a false-positive result due to higher-than-average creatinine generation. Both albuminuria and elevated serum cystatin C are examples of useful confirmatory tests that substantially decrease the misdiagnosis of CKD in healthy adults with an estimated GFR less than 60 mL/min/1.73 m².^9,10

Imagine if we identified and staged systemic lupus erythematosus on the basis of antinuclear antibody levels alone: this would parallel the current approach that largely uses serum creatinine alone to classify CKD. Confirmatory tests and considering patient-specific risk factors could avoid potential harm to healthy individuals and yet retain gains that have been made to improve the interpretation of serum creatinine levels in CKD patients.

At the American Society of Nephrology Renal Week 2010, one of the authors (A.D.R.) presented the following question at an In-Depth Nephrology Course on Geriatric Nephrology:

See related article

A 65-year-old woman donated a kidney to her son. Before donation, her serum creatinine level was 1.0 mg/dL, her estimated glomerular filtration rate (GFR) was 56 mL/min/1.73 m², and her measured GFR was 82 mL/min/1.73 m², which was below the 2.5th percentile for 20-year-old potential kidney donors. The patient had no albuminuria or hypertension and was otherwise healthy. The kidney was biopsied during the transplant surgery. The biopsy revealed 2 of 20 glomeruli as globally sclerosed, a focus of tubular atrophy, and mild arteriosclerosis (findings present in less than 2.5% of 20-year-old donors).

Choose one. Prior to donation, this woman had:

• Chronic kidney disease (CKD), and she should not have donated her kidney
• CKD, but kidney donation was reasonable
• Age-related (senescent) changes in her kidneys, and should not have donated her kidney
• Age-related (senescent) changes in her kidneys, but kidney donation was reasonable

Using an electronic response system, 36 (82%) of 44 physicians in the audience chose the last option, even though this patient meets the current definition of CKD (an estimated GFR less than 60 mL/min/1.73 m²) and has chronic parenchymal damage documented by a kidney biopsy.

PROBLEMS WITH THE GFR AND CKD CLASSIFICATION

This question highlights several key problems with the GFR and CKD classification.

First, in low-risk populations such as potential kidney donors, serum-creatinine-based equations such as the Modification of Diet in Renal Disease (MDRD) equation and the Chronic Kidney Disease Epidemiology Study (CKD-EPI) equation substantially underestimate the GFR.¹

Second, many healthy older adults with normal serum creatinine levels have an estimated GFR and a measured GFR below the normal range for young adults.²

Third, many healthy older adults have evidence of chronic parenchymal damage on renal biopsy, unlike healthy young adults.³

Finally, many health care providers did not previously recognize that people with a normal serum creatinine level could have a reduced GFR, and widespread use of the estimated GFR has addressed this problem. However, many physicians remain skeptical about efforts this past decade to classify age-related changes in kidney function as a “disease” in the absence of a clear benefit to older patients.⁴

TWO POINTS ABOUT THE ESTIMATED GFR

In this issue of the Cleveland Clinic Journal of Medicine, Simon and colleagues⁵ provide a balanced assessment of the benefits and pitfalls of using the estimated GFR in clinical practice. Two points they make deserve further discussion:

Bigger people make more creatinine. GFR can be reported in units of milliliters per minute, or in units normalized to body surface area (mL/min/1.73 m²). Contemporary equations for identifying and classifying CKD use the latter, because the GFR is considered inappropriately low when metabolic waste is not being adequately cleared. It is intuitive that smaller people require less absolute GFR than larger people, who generate more metabolic waste. Indexing GFR to 1.73 m² assumes that body surface area is a good surrogate for metabolic waste generation. However, whether body surface area is the best surrogate for the rate of metabolic waste generation has long been a subject of debate.⁶

The relationship between GFR and serum creatinine is not linear. Due to the inverse relationship between serum creatinine and GFR, a small change in serum creatinine from 0.9 to 1.2 mg/dL will represent a relatively large change in GFR (eg, 85 to 65 mL/min/1.73 m²), whereas a large change in serum creatinine from 5 to 9 mg/dL will represent a smaller change in GFR (eg, 10 to 5 mL/min/1.73 m²). The latter may be of great concern since it represents a fall in GFR to levels at which dialysis is likely needed. With the former, subtle changes in serum creatinine represent large changes in GFR, but there is also much more day-to-day variability in GFR in the normal or near-normal range than in the advanced range of kidney disease. This is one of the reasons the MDRD and CKD-EPI equations were developed, using logarithmic models that emphasize percentage instead of absolute differences in GFR.

BEYOND CREATININE?

As Simon and colleagues point out,⁵ although serum creatinine is a flawed surrogate for GFR, there are many problems with determining GFR by other means.

Direct GFR measurement relies on the use of an exogenous marker such as inulin or iothalamate that is infused or injected, followed by timed urine and plasma measurements to calculate GFR by the urinary clearance method (UV/P, where U is the concentration of the marker in the urine, V is the urine volume, and P is the concentration of the marker in the plasma). Alternatively, timed plasma measurements of the marker alone can be used to determine GFR by the plasma clearance method. The problem is that direct GFR measurement is costly, invasive, imprecise, time-consuming, and impractical in most clinical settings.

Exogenous markers for determining GFR are chosen because they are metabolically inert, are cleared by glomerular filtration without tubular secretion or reabsorption, and have no extrarenal clearance via the liver or intestines. Endogenous markers such as serum creatinine do not fulfill all of these ideal criteria.

Simon and colleagues highlight the problem of using the estimated GFR to screen for CKD in populations of ostensibly healthy persons.⁵ The MDRD and CKD-EPI equations contain demographic variables to approximate the creatinine generation rate. The primary source of creatinine generation is muscle, and the coefficients in these equations reflect the higher muscle mass of younger individuals, males, and African Americans. However, any creatinine-based equation is fundamentally flawed because overall health also affects muscle mass: healthy people have greater muscle mass than people with chronic illness, including those with CKD. Therefore, at the same serum creatinine level, a healthy person has a higher GFR than a patient with CKD.^1,7 This problem leads to circular reasoning, since you need to know whether the patient has CKD or is healthy in order to accurately estimate GFR, but estimated GFR is being used to determine whether the patient is healthy or has CKD.

Therefore, other endogenous markers that are also eliminated via glomerular filtration, such as cystatin C, have been used to construct equations that estimate GFR. Unfortunately, factors other than GFR, such as inflammation, can also influence blood cystatin C levels. This in turn impairs the accuracy of equations that use cystatin C to estimate GFR in the general population.⁸ No known endogenous marker of GFR can be used in all patients without any confounding factors.

To rectify this problem, recent studies have investigated the use of a confirmatory test to determine which patients with a creatinine-based estimated GFR less than 60 mL/min/1.73 m² actually have kidney disease or have a false-positive result due to higher-than-average creatinine generation. Both albuminuria and elevated serum cystatin C are examples of useful confirmatory tests that substantially decrease the misdiagnosis of CKD in healthy adults with an estimated GFR less than 60 mL/min/1.73 m².^9,10

Imagine if we identified and staged systemic lupus erythematosus on the basis of antinuclear antibody levels alone: this would parallel the current approach that largely uses serum creatinine alone to classify CKD. Confirmatory tests and considering patient-specific risk factors could avoid potential harm to healthy individuals and yet retain gains that have been made to improve the interpretation of serum creatinine levels in CKD patients.

Chronic kidney disease is most often discovered and diagnosed by primary care providers. The equations for estimating the glomerular filtration rate (GFR) facilitate earlier detection of this disease. However, the estimated GFR must be interpreted in the context of the individual patient. The diagnostic criteria and staging of chronic kidney disease must be understood so that it can be recognized and managed at the earliest possible stage. In this way, primary care physicians and nephrologists can better coordinate the care of these patients.

THE STAGES OF RENAL DISEASE AND THE GFR

Before 2002, an organized approach to the clinical management of patients with renal dysfunction was hampered by a lack of a standardized way to define this condition. This changed when the National Kidney Foundation, through the Kidney Disease Outcomes Quality Initiative (K/DOQI),¹ defined the stages of chronic kidney disease based on the GFR as estimated by the Modification of Diet in Renal Disease (MDRD) equation.^2,3

See related editorial

This system has increased the recognition of chronic kidney disease by the health care community and the general public. But the entire system hinges on the utility, accuracy, and reliability of the equations used to estimate the GFR.

In this article, we review the concepts of renal clearance and how to interpret the GFR in healthy patients and in those with chronic kidney disease. The following cases illustrate the interpretation of GFR in the context of patient care.

CASE 1: A 60-YEAR-OLD WOMAN WITH A ‘NORMAL’ CREATININE LEVEL

A 60-year-old white woman with no significant medical history has routine laboratory tests done as part of her annual physical examination. She weighs 135 pounds (61.2 kg) and is 64 inches (163 cm) tall. Her serum creatinine level is 1.1 mg/dL; her estimated GFR is 53 mL/min/1.73 m². A urine dipstick test for protein and blood is normal.

CASE 2: PROTEINURIA WITH A PRESERVED GFR

A 20-year-old African American man with no medical history is undergoing routine blood testing. His serum creatinine level is 1.1 mg/dL; his estimated GFR is reported as “> 60 mL/min/1.73 m²” (calculated at 109 mL/min/1.73 m²). He is 72 inches (183 cm) tall and weighs 180 pounds (83.0 kg); he lifts weights four times a week. Urine dipstick testing reveals 3+ proteinuria.

SERUM CREATININE: AN IMPERFECT MARKER OF KIDNEY FUNCTION

Of the various functions of the kidney, the ability of the glomeruli to filter the blood, as assessed by the GFR, is considered the best index of overall kidney function.^4,5 The GFR can be thought of as the clearance of a substance from the plasma by the kidney in a period of time. This is useful because no method is available to routinely and directly measure filtration across the glomerular basement membrane.

Substances that are cleared by the kidney are used to estimate the GFR. The ideal substance for this estimate is one that is cleared only by filtration and not through metabolism or excretion by other means.

The urinary clearance of the exogenous substance inulin is considered the gold standard method, but radioisotopes such as iothalamate and other markers have replaced inulin in clinical laboratories. Because these methods are expensive, time-consuming, and not widely available, alternative methods that use endogenous markers such as creatinine have been developed for clinical practice.

The serum creatinine concentration possesses many of the qualities of an ideal marker for estimating kidney function. Creatinine is produced by the body at a relatively constant rate under normal conditions and is easy and inexpensive to measure. However, it has several limitations:

• 

  Data presented in Rolin HA III, et al. Evaluation of glomerular filtration rate and renal plasma flow. In: Jacobson HR, et al, eds. The Principles and Practice of Nephrology. St. Louis: Mosby-Year Book 1995:8-13.

  Its clearance does not solely reflect glomerular filtration because the renal tubules also excrete it into the urine.⁶ As a result, creatinine clearance (see below) will tend to overestimate the GFR (Figure 1).
• The serum creatinine concentration is directly dependent on muscle mass, which varies with sex (women tend to have less muscle mass as a percent of body weight than men), age (muscle mass decreases with age), and race (African Americans have a higher serum creatinine level for the same GFR than other Americans).⁶ Thus, there is no “normal” value for serum creatinine that applies to all patients.
• 
  Other factors can alter the creatinine level without changing the GFR, such as changes in dietary protein intake, exercise, and drugs such as cimetidine⁷ and fibrates⁸ (Table 1).

Another important point is that the relationship between the serum creatinine concentration and the GFR is parabolic.⁹ At high kidney function, large changes in the GFR are reflected by very small changes in serum creatinine—the GFR must fall quite a bit before the serum creatinine level rises very much (points A to B in Figure 1). At lower kidney function, small changes in GFR are reflected by large changes in serum creatinine (points C to D in Figure 1). This phenomenon can cause physicians to view small changes in creatinine as unimportant in patients with creatinine levels in the normal or near-normal range. Conversely, small changes may be due to random error inherent in the methods of measuring creatinine rather than to changes in kidney function.

Because the serum creatinine concentration by itself may be misleading when estimating GFR, the National Kidney Foundation and the National Kidney Disease Education Program recommend that it not be used on its own to estimate kidney function.

ESTIMATING THE GFR

Measuring 24-hour creatinine clearance

Measuring 24-hour creatinine clearance involves measuring the concentrations of creatinine in the serum and the urine and the volume of urine excreted in 24 hours.

The 24-hour creatinine clearance was long considered the best alternative to the serum creatinine concentration for assessing kidney function, as it adjusts for changes in the creatinine concentration by taking into account creatinine’s excretion in the urine. However, 24-hour urine collection is burdensome for the patient, and the results are not always reliable because of variations in collection technique. Also, using the creatinine clearance does not resolve problems with using the serum creatinine concentration, such as tubular secretion and overestimation of GFR.

In an effort to more easily estimate GFR from blood tests alone, efforts to develop mathematical equations that more closely estimate GFR began over 40 years ago. These equations take into account factors such as age, sex, and ethnicity. The best known of these are the Cockcroft and Gault¹⁰ and the MDRD equations.⁵

The Cockcroft-Gault equation

The Cockcroft-Gault equation is fairly simple, using serum creatinine, ideal body weight, and an adjustment factor for sex. Its main drawbacks are that it was developed to model creatinine clearance, itself an imperfect estimation of GFR, and it depends heavily on the accuracy of the value for “lean” body weight used in the equation.

The MDRD equation

The MDRD equation has now largely replaced the Cockcroft-Gault equation. Developed using iothalamate GFR measurements, it therefore estimates GFR rather than the less-accurate creatinine clearance. Also, it is normalized to a standard body surface area (1.73 m²), obviating the need to determine ideal body weight.

Since the estimated GFR can often be calculated using data available in most electronic medical record systems, it can be reported directly with any laboratory report that includes a serum creatinine value.

The main drawback of the MDRD equation is that it tends to underestimate GFR at higher ranges of kidney function, ie, higher than 60 mL/min/1.73 m²).^3,11

The CKD-EPI equation

The Chronic Kidney Disease Epidemiology Collaboration study (CKD-EPI) equation,¹² published in 2009, is expected to eventually replace the currently used MDRD equation, as it performs better at higher ranges of GFR.

Although the CKD-EPI equation still lacks precision and accuracy, it underestimates GFR to a lesser degree than the MDRD equation in patients with preserved renal function. Also, it was developed with the objective of reporting a specific value even when the estimated GFR is greater than 60 mL/min/1.73 m². (In contrast, when laboratories use the MDRD equation, the recommendation is to report any value above this level as “greater than 60 mL/min/1.73 m²”).

A limitation of all equations that use the serum creatinine concentration to assess kidney function is the assumption that creatinine production is both stable over time and similar among patients. As a result, these equations should not be used in situations in which renal function is changing rapidly, such as in acute kidney injury. Also, they should be used with caution in patients at the extremes of body mass, since they underestimate GFR in very muscular patients (eg, as in case 2) and overestimate GFR in very small patients (eg, as in case 1).

Calculators for estimating the GFR using these equations are available on many Web sites (see www.kidney.org/professionals/kdoqi/gfr_calculator.cfm).

SCREEN EVERYONE AT RISK

In general, anyone at higher risk of chronic kidney disease should be screened for it. This group includes US minorities and patients with hypertension, cardiovascular disease, and diabetes mellitus, among others.¹³ Screening includes an assessment of estimated GFR and urinalysis for proteinuria or hematuria.

CHRONIC KIDNEY DISEASE DEFINED: DAMAGE AND DURATION

The kidney damage can be either parenchymal renal damage independent of GFR (for example, cystic disease, glomerular hematuria, or proteinuria) or depressed GFR independent of evidence of parenchymal renal disease (an estimated GFR of less than 60 mL/min/1.73 m²).

The duration component requires that the abnormality be present for at least 3 months (ie, chronic).

This definition has not been without controversy.

An unintended consequence of not reporting estimated GFR values above 60 mL/min/1.73 m² in absolute numbers is that providers may ignore changes in serum creatinine at estimated GFRs in this range, as they assume that the kidney function is “normal.” This may change in the future if the CKD-EPI equation is used, which produces less bias at slightly higher GFRs.

Providers may also tend to focus solely on the estimated GFR criterion and ignore other evidence of chronic kidney disease, such as abnormalities in urinalysis or imaging studies. For example, proteinuria has been shown to be more important than absolute GFR values in predicting progression of renal dysfunction and cardiovascular risk.¹⁴ Proteinuria, especially in the setting of an estimated GFR above 60 mL/min/1.73 m², can be missed if not screened for and underappreciated once found.

Moreover, in elderly patients, the current GFR equations underperform at borderline GFR values and can yield depressed values even at impressively “normal” serum creatinine levels. As a result, there is concern that chronic kidney disease is being overdiagnosed under the current system. This is especially worrisome in elderly white women without risk factors for chronic kidney disease (eg, as in case 1).

In addition, the question arises whether the arbitrary cutoff for chronic kidney disease— 60 mL/min/1.73 m²—applies to all populations.^15,16 The utility of classifying someone as having chronic kidney disease who has an estimated GFR of 55 mL/min/1.73 m² and no risk factors for chronic kidney disease (Table 2) should be questioned if the risk of progressing to end-stage renal disease or suffering a cardiovascular event is only minimally higher than in patients with a higher estimated GFR.^6,17 If the true purpose of developing the chronic kidney disease classification system is to improve patient care and outcomes, then it is of no benefit to overclassify such patients. Indeed, the stress induced by the diagnosis and the negative implications on insurance coverage and health care costs may outweigh any benefits.¹⁸

Nevertheless, these concerns do not invalidate the entire chronic kidney disease definition system, but have stimulated current efforts to improve it based on outcomes research.¹⁹

CASES REVISITED

Case 1: Problems with estimating GFR in a small woman

Case 1 has several points to note.

The patient’s small body size reflects low-level creatinine production. It is not atypical to find serum creatinine levels of 0.5 mg/dL in such patients. Thus, her serum creatinine level of 1.1 mg/dL may be abnormal. The fact that the MDRD equation “normalizes” the result to 1.73 m² of body surface area in patients with very low muscle mass will lead to an overestimation of GFR. However, she has no risk factors for chronic kidney disease.

Additionally, in up to two-thirds of patients kidney function declines with age.²⁰ Whether or not this is “normal aging” of the kidney, it is not clear that this decline in GFR reflects an underlying pathologic process.

Finally, since the patient is an older white woman, the estimated GFR tends to underestimate the true GFR. So while her body size may predispose to an overestimation of GFR, her age, race, and sex predispose to an underestimation of GFR. Many nephrologists would simply order urinalysis and ultrasonography to rule out other evidence of renal dysfunction, then recommend routine monitoring of kidney function in this case.

Case 2: Proteinuria is not normal

In case 2, because the patient is African American, young, and male, his creatinine level yields a higher estimated GFR than in case 1, despite having the same value. However, his estimated GFR still underestimates his true GFR because of his greater creatinine production due to his muscular physique.

This patient subsequently underwent iothalamate GFR testing, which yielded a GFR of 115 mL/min/1.73 m². However, he has dipstick-positive proteinuria, which, if confirmed on further testing, would meet the criteria for chronic kidney disease and put him at a higher risk of cardiovascular events and progression to lower kidney function than the patient in case 1. He also needs to be screened for undiagnosed hypertension and underlying glomerular disease.

REFERRAL TO (AND COLLABORATION WITH) A NEPHROLOGIST

Effective co-management with a nephrologist is essential for the overall health of the patient with chronic kidney disease, as well as slowing the progression to end-stage renal disease. Exactly when and to what extent the care of a patient with chronic kidney disease should be transferred to a nephrologist depends largely on the individual nephrologist and the comfort level of the primary care provider. When the referral does occur, effective communication between providers and a mutual understanding of the goals of care (eg, the blood pressure target) are essential to optimize patient care.

Chronic kidney disease is most often discovered and diagnosed by primary care providers. The equations for estimating the glomerular filtration rate (GFR) facilitate earlier detection of this disease. However, the estimated GFR must be interpreted in the context of the individual patient. The diagnostic criteria and staging of chronic kidney disease must be understood so that it can be recognized and managed at the earliest possible stage. In this way, primary care physicians and nephrologists can better coordinate the care of these patients.

THE STAGES OF RENAL DISEASE AND THE GFR

Before 2002, an organized approach to the clinical management of patients with renal dysfunction was hampered by a lack of a standardized way to define this condition. This changed when the National Kidney Foundation, through the Kidney Disease Outcomes Quality Initiative (K/DOQI),¹ defined the stages of chronic kidney disease based on the GFR as estimated by the Modification of Diet in Renal Disease (MDRD) equation.^2,3

See related editorial

This system has increased the recognition of chronic kidney disease by the health care community and the general public. But the entire system hinges on the utility, accuracy, and reliability of the equations used to estimate the GFR.

In this article, we review the concepts of renal clearance and how to interpret the GFR in healthy patients and in those with chronic kidney disease. The following cases illustrate the interpretation of GFR in the context of patient care.

CASE 1: A 60-YEAR-OLD WOMAN WITH A ‘NORMAL’ CREATININE LEVEL

A 60-year-old white woman with no significant medical history has routine laboratory tests done as part of her annual physical examination. She weighs 135 pounds (61.2 kg) and is 64 inches (163 cm) tall. Her serum creatinine level is 1.1 mg/dL; her estimated GFR is 53 mL/min/1.73 m². A urine dipstick test for protein and blood is normal.

CASE 2: PROTEINURIA WITH A PRESERVED GFR

A 20-year-old African American man with no medical history is undergoing routine blood testing. His serum creatinine level is 1.1 mg/dL; his estimated GFR is reported as “> 60 mL/min/1.73 m²” (calculated at 109 mL/min/1.73 m²). He is 72 inches (183 cm) tall and weighs 180 pounds (83.0 kg); he lifts weights four times a week. Urine dipstick testing reveals 3+ proteinuria.

SERUM CREATININE: AN IMPERFECT MARKER OF KIDNEY FUNCTION

Of the various functions of the kidney, the ability of the glomeruli to filter the blood, as assessed by the GFR, is considered the best index of overall kidney function.^4,5 The GFR can be thought of as the clearance of a substance from the plasma by the kidney in a period of time. This is useful because no method is available to routinely and directly measure filtration across the glomerular basement membrane.

Substances that are cleared by the kidney are used to estimate the GFR. The ideal substance for this estimate is one that is cleared only by filtration and not through metabolism or excretion by other means.

The urinary clearance of the exogenous substance inulin is considered the gold standard method, but radioisotopes such as iothalamate and other markers have replaced inulin in clinical laboratories. Because these methods are expensive, time-consuming, and not widely available, alternative methods that use endogenous markers such as creatinine have been developed for clinical practice.

The serum creatinine concentration possesses many of the qualities of an ideal marker for estimating kidney function. Creatinine is produced by the body at a relatively constant rate under normal conditions and is easy and inexpensive to measure. However, it has several limitations:

• 

  Data presented in Rolin HA III, et al. Evaluation of glomerular filtration rate and renal plasma flow. In: Jacobson HR, et al, eds. The Principles and Practice of Nephrology. St. Louis: Mosby-Year Book 1995:8-13.

  Its clearance does not solely reflect glomerular filtration because the renal tubules also excrete it into the urine.⁶ As a result, creatinine clearance (see below) will tend to overestimate the GFR (Figure 1).
• The serum creatinine concentration is directly dependent on muscle mass, which varies with sex (women tend to have less muscle mass as a percent of body weight than men), age (muscle mass decreases with age), and race (African Americans have a higher serum creatinine level for the same GFR than other Americans).⁶ Thus, there is no “normal” value for serum creatinine that applies to all patients.
• 
  Other factors can alter the creatinine level without changing the GFR, such as changes in dietary protein intake, exercise, and drugs such as cimetidine⁷ and fibrates⁸ (Table 1).

Another important point is that the relationship between the serum creatinine concentration and the GFR is parabolic.⁹ At high kidney function, large changes in the GFR are reflected by very small changes in serum creatinine—the GFR must fall quite a bit before the serum creatinine level rises very much (points A to B in Figure 1). At lower kidney function, small changes in GFR are reflected by large changes in serum creatinine (points C to D in Figure 1). This phenomenon can cause physicians to view small changes in creatinine as unimportant in patients with creatinine levels in the normal or near-normal range. Conversely, small changes may be due to random error inherent in the methods of measuring creatinine rather than to changes in kidney function.

Because the serum creatinine concentration by itself may be misleading when estimating GFR, the National Kidney Foundation and the National Kidney Disease Education Program recommend that it not be used on its own to estimate kidney function.

ESTIMATING THE GFR

Measuring 24-hour creatinine clearance

Measuring 24-hour creatinine clearance involves measuring the concentrations of creatinine in the serum and the urine and the volume of urine excreted in 24 hours.

The 24-hour creatinine clearance was long considered the best alternative to the serum creatinine concentration for assessing kidney function, as it adjusts for changes in the creatinine concentration by taking into account creatinine’s excretion in the urine. However, 24-hour urine collection is burdensome for the patient, and the results are not always reliable because of variations in collection technique. Also, using the creatinine clearance does not resolve problems with using the serum creatinine concentration, such as tubular secretion and overestimation of GFR.

In an effort to more easily estimate GFR from blood tests alone, efforts to develop mathematical equations that more closely estimate GFR began over 40 years ago. These equations take into account factors such as age, sex, and ethnicity. The best known of these are the Cockcroft and Gault¹⁰ and the MDRD equations.⁵

The Cockcroft-Gault equation

The Cockcroft-Gault equation is fairly simple, using serum creatinine, ideal body weight, and an adjustment factor for sex. Its main drawbacks are that it was developed to model creatinine clearance, itself an imperfect estimation of GFR, and it depends heavily on the accuracy of the value for “lean” body weight used in the equation.

The MDRD equation

The MDRD equation has now largely replaced the Cockcroft-Gault equation. Developed using iothalamate GFR measurements, it therefore estimates GFR rather than the less-accurate creatinine clearance. Also, it is normalized to a standard body surface area (1.73 m²), obviating the need to determine ideal body weight.

Since the estimated GFR can often be calculated using data available in most electronic medical record systems, it can be reported directly with any laboratory report that includes a serum creatinine value.

The main drawback of the MDRD equation is that it tends to underestimate GFR at higher ranges of kidney function, ie, higher than 60 mL/min/1.73 m²).^3,11

The CKD-EPI equation

The Chronic Kidney Disease Epidemiology Collaboration study (CKD-EPI) equation,¹² published in 2009, is expected to eventually replace the currently used MDRD equation, as it performs better at higher ranges of GFR.

Although the CKD-EPI equation still lacks precision and accuracy, it underestimates GFR to a lesser degree than the MDRD equation in patients with preserved renal function. Also, it was developed with the objective of reporting a specific value even when the estimated GFR is greater than 60 mL/min/1.73 m². (In contrast, when laboratories use the MDRD equation, the recommendation is to report any value above this level as “greater than 60 mL/min/1.73 m²”).

A limitation of all equations that use the serum creatinine concentration to assess kidney function is the assumption that creatinine production is both stable over time and similar among patients. As a result, these equations should not be used in situations in which renal function is changing rapidly, such as in acute kidney injury. Also, they should be used with caution in patients at the extremes of body mass, since they underestimate GFR in very muscular patients (eg, as in case 2) and overestimate GFR in very small patients (eg, as in case 1).

Calculators for estimating the GFR using these equations are available on many Web sites (see www.kidney.org/professionals/kdoqi/gfr_calculator.cfm).

SCREEN EVERYONE AT RISK

In general, anyone at higher risk of chronic kidney disease should be screened for it. This group includes US minorities and patients with hypertension, cardiovascular disease, and diabetes mellitus, among others.¹³ Screening includes an assessment of estimated GFR and urinalysis for proteinuria or hematuria.

CHRONIC KIDNEY DISEASE DEFINED: DAMAGE AND DURATION

The kidney damage can be either parenchymal renal damage independent of GFR (for example, cystic disease, glomerular hematuria, or proteinuria) or depressed GFR independent of evidence of parenchymal renal disease (an estimated GFR of less than 60 mL/min/1.73 m²).

The duration component requires that the abnormality be present for at least 3 months (ie, chronic).

This definition has not been without controversy.

An unintended consequence of not reporting estimated GFR values above 60 mL/min/1.73 m² in absolute numbers is that providers may ignore changes in serum creatinine at estimated GFRs in this range, as they assume that the kidney function is “normal.” This may change in the future if the CKD-EPI equation is used, which produces less bias at slightly higher GFRs.

Providers may also tend to focus solely on the estimated GFR criterion and ignore other evidence of chronic kidney disease, such as abnormalities in urinalysis or imaging studies. For example, proteinuria has been shown to be more important than absolute GFR values in predicting progression of renal dysfunction and cardiovascular risk.¹⁴ Proteinuria, especially in the setting of an estimated GFR above 60 mL/min/1.73 m², can be missed if not screened for and underappreciated once found.

Moreover, in elderly patients, the current GFR equations underperform at borderline GFR values and can yield depressed values even at impressively “normal” serum creatinine levels. As a result, there is concern that chronic kidney disease is being overdiagnosed under the current system. This is especially worrisome in elderly white women without risk factors for chronic kidney disease (eg, as in case 1).

In addition, the question arises whether the arbitrary cutoff for chronic kidney disease— 60 mL/min/1.73 m²—applies to all populations.^15,16 The utility of classifying someone as having chronic kidney disease who has an estimated GFR of 55 mL/min/1.73 m² and no risk factors for chronic kidney disease (Table 2) should be questioned if the risk of progressing to end-stage renal disease or suffering a cardiovascular event is only minimally higher than in patients with a higher estimated GFR.^6,17 If the true purpose of developing the chronic kidney disease classification system is to improve patient care and outcomes, then it is of no benefit to overclassify such patients. Indeed, the stress induced by the diagnosis and the negative implications on insurance coverage and health care costs may outweigh any benefits.¹⁸

Nevertheless, these concerns do not invalidate the entire chronic kidney disease definition system, but have stimulated current efforts to improve it based on outcomes research.¹⁹

CASES REVISITED

Case 1: Problems with estimating GFR in a small woman

Case 1 has several points to note.

The patient’s small body size reflects low-level creatinine production. It is not atypical to find serum creatinine levels of 0.5 mg/dL in such patients. Thus, her serum creatinine level of 1.1 mg/dL may be abnormal. The fact that the MDRD equation “normalizes” the result to 1.73 m² of body surface area in patients with very low muscle mass will lead to an overestimation of GFR. However, she has no risk factors for chronic kidney disease.

Additionally, in up to two-thirds of patients kidney function declines with age.²⁰ Whether or not this is “normal aging” of the kidney, it is not clear that this decline in GFR reflects an underlying pathologic process.

Finally, since the patient is an older white woman, the estimated GFR tends to underestimate the true GFR. So while her body size may predispose to an overestimation of GFR, her age, race, and sex predispose to an underestimation of GFR. Many nephrologists would simply order urinalysis and ultrasonography to rule out other evidence of renal dysfunction, then recommend routine monitoring of kidney function in this case.

Case 2: Proteinuria is not normal

In case 2, because the patient is African American, young, and male, his creatinine level yields a higher estimated GFR than in case 1, despite having the same value. However, his estimated GFR still underestimates his true GFR because of his greater creatinine production due to his muscular physique.

This patient subsequently underwent iothalamate GFR testing, which yielded a GFR of 115 mL/min/1.73 m². However, he has dipstick-positive proteinuria, which, if confirmed on further testing, would meet the criteria for chronic kidney disease and put him at a higher risk of cardiovascular events and progression to lower kidney function than the patient in case 1. He also needs to be screened for undiagnosed hypertension and underlying glomerular disease.

REFERRAL TO (AND COLLABORATION WITH) A NEPHROLOGIST

Effective co-management with a nephrologist is essential for the overall health of the patient with chronic kidney disease, as well as slowing the progression to end-stage renal disease. Exactly when and to what extent the care of a patient with chronic kidney disease should be transferred to a nephrologist depends largely on the individual nephrologist and the comfort level of the primary care provider. When the referral does occur, effective communication between providers and a mutual understanding of the goals of care (eg, the blood pressure target) are essential to optimize patient care.

Chronic kidney disease is most often discovered and diagnosed by primary care providers. The equations for estimating the glomerular filtration rate (GFR) facilitate earlier detection of this disease. However, the estimated GFR must be interpreted in the context of the individual patient. The diagnostic criteria and staging of chronic kidney disease must be understood so that it can be recognized and managed at the earliest possible stage. In this way, primary care physicians and nephrologists can better coordinate the care of these patients.

THE STAGES OF RENAL DISEASE AND THE GFR

Before 2002, an organized approach to the clinical management of patients with renal dysfunction was hampered by a lack of a standardized way to define this condition. This changed when the National Kidney Foundation, through the Kidney Disease Outcomes Quality Initiative (K/DOQI),¹ defined the stages of chronic kidney disease based on the GFR as estimated by the Modification of Diet in Renal Disease (MDRD) equation.^2,3

See related editorial

This system has increased the recognition of chronic kidney disease by the health care community and the general public. But the entire system hinges on the utility, accuracy, and reliability of the equations used to estimate the GFR.

In this article, we review the concepts of renal clearance and how to interpret the GFR in healthy patients and in those with chronic kidney disease. The following cases illustrate the interpretation of GFR in the context of patient care.

CASE 1: A 60-YEAR-OLD WOMAN WITH A ‘NORMAL’ CREATININE LEVEL

A 60-year-old white woman with no significant medical history has routine laboratory tests done as part of her annual physical examination. She weighs 135 pounds (61.2 kg) and is 64 inches (163 cm) tall. Her serum creatinine level is 1.1 mg/dL; her estimated GFR is 53 mL/min/1.73 m². A urine dipstick test for protein and blood is normal.

CASE 2: PROTEINURIA WITH A PRESERVED GFR

A 20-year-old African American man with no medical history is undergoing routine blood testing. His serum creatinine level is 1.1 mg/dL; his estimated GFR is reported as “> 60 mL/min/1.73 m²” (calculated at 109 mL/min/1.73 m²). He is 72 inches (183 cm) tall and weighs 180 pounds (83.0 kg); he lifts weights four times a week. Urine dipstick testing reveals 3+ proteinuria.

SERUM CREATININE: AN IMPERFECT MARKER OF KIDNEY FUNCTION

Of the various functions of the kidney, the ability of the glomeruli to filter the blood, as assessed by the GFR, is considered the best index of overall kidney function.^4,5 The GFR can be thought of as the clearance of a substance from the plasma by the kidney in a period of time. This is useful because no method is available to routinely and directly measure filtration across the glomerular basement membrane.

Substances that are cleared by the kidney are used to estimate the GFR. The ideal substance for this estimate is one that is cleared only by filtration and not through metabolism or excretion by other means.

The urinary clearance of the exogenous substance inulin is considered the gold standard method, but radioisotopes such as iothalamate and other markers have replaced inulin in clinical laboratories. Because these methods are expensive, time-consuming, and not widely available, alternative methods that use endogenous markers such as creatinine have been developed for clinical practice.

The serum creatinine concentration possesses many of the qualities of an ideal marker for estimating kidney function. Creatinine is produced by the body at a relatively constant rate under normal conditions and is easy and inexpensive to measure. However, it has several limitations:

• 

  Data presented in Rolin HA III, et al. Evaluation of glomerular filtration rate and renal plasma flow. In: Jacobson HR, et al, eds. The Principles and Practice of Nephrology. St. Louis: Mosby-Year Book 1995:8-13.

  Its clearance does not solely reflect glomerular filtration because the renal tubules also excrete it into the urine.⁶ As a result, creatinine clearance (see below) will tend to overestimate the GFR (Figure 1).
• The serum creatinine concentration is directly dependent on muscle mass, which varies with sex (women tend to have less muscle mass as a percent of body weight than men), age (muscle mass decreases with age), and race (African Americans have a higher serum creatinine level for the same GFR than other Americans).⁶ Thus, there is no “normal” value for serum creatinine that applies to all patients.
• 
  Other factors can alter the creatinine level without changing the GFR, such as changes in dietary protein intake, exercise, and drugs such as cimetidine⁷ and fibrates⁸ (Table 1).

Another important point is that the relationship between the serum creatinine concentration and the GFR is parabolic.⁹ At high kidney function, large changes in the GFR are reflected by very small changes in serum creatinine—the GFR must fall quite a bit before the serum creatinine level rises very much (points A to B in Figure 1). At lower kidney function, small changes in GFR are reflected by large changes in serum creatinine (points C to D in Figure 1). This phenomenon can cause physicians to view small changes in creatinine as unimportant in patients with creatinine levels in the normal or near-normal range. Conversely, small changes may be due to random error inherent in the methods of measuring creatinine rather than to changes in kidney function.

Because the serum creatinine concentration by itself may be misleading when estimating GFR, the National Kidney Foundation and the National Kidney Disease Education Program recommend that it not be used on its own to estimate kidney function.

ESTIMATING THE GFR

Measuring 24-hour creatinine clearance

Measuring 24-hour creatinine clearance involves measuring the concentrations of creatinine in the serum and the urine and the volume of urine excreted in 24 hours.

The 24-hour creatinine clearance was long considered the best alternative to the serum creatinine concentration for assessing kidney function, as it adjusts for changes in the creatinine concentration by taking into account creatinine’s excretion in the urine. However, 24-hour urine collection is burdensome for the patient, and the results are not always reliable because of variations in collection technique. Also, using the creatinine clearance does not resolve problems with using the serum creatinine concentration, such as tubular secretion and overestimation of GFR.

In an effort to more easily estimate GFR from blood tests alone, efforts to develop mathematical equations that more closely estimate GFR began over 40 years ago. These equations take into account factors such as age, sex, and ethnicity. The best known of these are the Cockcroft and Gault¹⁰ and the MDRD equations.⁵

The Cockcroft-Gault equation

The Cockcroft-Gault equation is fairly simple, using serum creatinine, ideal body weight, and an adjustment factor for sex. Its main drawbacks are that it was developed to model creatinine clearance, itself an imperfect estimation of GFR, and it depends heavily on the accuracy of the value for “lean” body weight used in the equation.

The MDRD equation

The MDRD equation has now largely replaced the Cockcroft-Gault equation. Developed using iothalamate GFR measurements, it therefore estimates GFR rather than the less-accurate creatinine clearance. Also, it is normalized to a standard body surface area (1.73 m²), obviating the need to determine ideal body weight.

Since the estimated GFR can often be calculated using data available in most electronic medical record systems, it can be reported directly with any laboratory report that includes a serum creatinine value.

The main drawback of the MDRD equation is that it tends to underestimate GFR at higher ranges of kidney function, ie, higher than 60 mL/min/1.73 m²).^3,11

The CKD-EPI equation

The Chronic Kidney Disease Epidemiology Collaboration study (CKD-EPI) equation,¹² published in 2009, is expected to eventually replace the currently used MDRD equation, as it performs better at higher ranges of GFR.

Although the CKD-EPI equation still lacks precision and accuracy, it underestimates GFR to a lesser degree than the MDRD equation in patients with preserved renal function. Also, it was developed with the objective of reporting a specific value even when the estimated GFR is greater than 60 mL/min/1.73 m². (In contrast, when laboratories use the MDRD equation, the recommendation is to report any value above this level as “greater than 60 mL/min/1.73 m²”).

A limitation of all equations that use the serum creatinine concentration to assess kidney function is the assumption that creatinine production is both stable over time and similar among patients. As a result, these equations should not be used in situations in which renal function is changing rapidly, such as in acute kidney injury. Also, they should be used with caution in patients at the extremes of body mass, since they underestimate GFR in very muscular patients (eg, as in case 2) and overestimate GFR in very small patients (eg, as in case 1).

Calculators for estimating the GFR using these equations are available on many Web sites (see www.kidney.org/professionals/kdoqi/gfr_calculator.cfm).

SCREEN EVERYONE AT RISK

In general, anyone at higher risk of chronic kidney disease should be screened for it. This group includes US minorities and patients with hypertension, cardiovascular disease, and diabetes mellitus, among others.¹³ Screening includes an assessment of estimated GFR and urinalysis for proteinuria or hematuria.

CHRONIC KIDNEY DISEASE DEFINED: DAMAGE AND DURATION

The kidney damage can be either parenchymal renal damage independent of GFR (for example, cystic disease, glomerular hematuria, or proteinuria) or depressed GFR independent of evidence of parenchymal renal disease (an estimated GFR of less than 60 mL/min/1.73 m²).

The duration component requires that the abnormality be present for at least 3 months (ie, chronic).

This definition has not been without controversy.

An unintended consequence of not reporting estimated GFR values above 60 mL/min/1.73 m² in absolute numbers is that providers may ignore changes in serum creatinine at estimated GFRs in this range, as they assume that the kidney function is “normal.” This may change in the future if the CKD-EPI equation is used, which produces less bias at slightly higher GFRs.

Providers may also tend to focus solely on the estimated GFR criterion and ignore other evidence of chronic kidney disease, such as abnormalities in urinalysis or imaging studies. For example, proteinuria has been shown to be more important than absolute GFR values in predicting progression of renal dysfunction and cardiovascular risk.¹⁴ Proteinuria, especially in the setting of an estimated GFR above 60 mL/min/1.73 m², can be missed if not screened for and underappreciated once found.

Moreover, in elderly patients, the current GFR equations underperform at borderline GFR values and can yield depressed values even at impressively “normal” serum creatinine levels. As a result, there is concern that chronic kidney disease is being overdiagnosed under the current system. This is especially worrisome in elderly white women without risk factors for chronic kidney disease (eg, as in case 1).

In addition, the question arises whether the arbitrary cutoff for chronic kidney disease— 60 mL/min/1.73 m²—applies to all populations.^15,16 The utility of classifying someone as having chronic kidney disease who has an estimated GFR of 55 mL/min/1.73 m² and no risk factors for chronic kidney disease (Table 2) should be questioned if the risk of progressing to end-stage renal disease or suffering a cardiovascular event is only minimally higher than in patients with a higher estimated GFR.^6,17 If the true purpose of developing the chronic kidney disease classification system is to improve patient care and outcomes, then it is of no benefit to overclassify such patients. Indeed, the stress induced by the diagnosis and the negative implications on insurance coverage and health care costs may outweigh any benefits.¹⁸

Nevertheless, these concerns do not invalidate the entire chronic kidney disease definition system, but have stimulated current efforts to improve it based on outcomes research.¹⁹

CASES REVISITED

Case 1: Problems with estimating GFR in a small woman

Case 1 has several points to note.

The patient’s small body size reflects low-level creatinine production. It is not atypical to find serum creatinine levels of 0.5 mg/dL in such patients. Thus, her serum creatinine level of 1.1 mg/dL may be abnormal. The fact that the MDRD equation “normalizes” the result to 1.73 m² of body surface area in patients with very low muscle mass will lead to an overestimation of GFR. However, she has no risk factors for chronic kidney disease.

Additionally, in up to two-thirds of patients kidney function declines with age.²⁰ Whether or not this is “normal aging” of the kidney, it is not clear that this decline in GFR reflects an underlying pathologic process.

Finally, since the patient is an older white woman, the estimated GFR tends to underestimate the true GFR. So while her body size may predispose to an overestimation of GFR, her age, race, and sex predispose to an underestimation of GFR. Many nephrologists would simply order urinalysis and ultrasonography to rule out other evidence of renal dysfunction, then recommend routine monitoring of kidney function in this case.

Case 2: Proteinuria is not normal

In case 2, because the patient is African American, young, and male, his creatinine level yields a higher estimated GFR than in case 1, despite having the same value. However, his estimated GFR still underestimates his true GFR because of his greater creatinine production due to his muscular physique.

This patient subsequently underwent iothalamate GFR testing, which yielded a GFR of 115 mL/min/1.73 m². However, he has dipstick-positive proteinuria, which, if confirmed on further testing, would meet the criteria for chronic kidney disease and put him at a higher risk of cardiovascular events and progression to lower kidney function than the patient in case 1. He also needs to be screened for undiagnosed hypertension and underlying glomerular disease.

REFERRAL TO (AND COLLABORATION WITH) A NEPHROLOGIST

Effective co-management with a nephrologist is essential for the overall health of the patient with chronic kidney disease, as well as slowing the progression to end-stage renal disease. Exactly when and to what extent the care of a patient with chronic kidney disease should be transferred to a nephrologist depends largely on the individual nephrologist and the comfort level of the primary care provider. When the referral does occur, effective communication between providers and a mutual understanding of the goals of care (eg, the blood pressure target) are essential to optimize patient care.