Long-Term Longitudinal Stability of Kidney Filtration Marker Measurements: Implications for Epidemiological Studies and Clinical Care.

BACKGROUND: Establishment and improvement of glomerular filtration rate estimating equations requires accurate and precise laboratory measurement procedures (MPs) for filtration markers. The Advanced Research and Diagnostic Laboratory (ARDL) at the University of Minnesota, which has served as the central laboratory for the Chronic Kidney Disease Epidemiology Collaboration since 2009, has implemented several quality assurance measures to monitor the accuracy and stability of filtration marker assays over time. METHODS: To assess longitudinal stability for filtration marker assays, a 40-sample calibration panel was created using pooled serum, divided into multiple frozen aliquots stored at -80 °C. ARDL monitored 4 markers-creatinine, cystatin C, beta-2-microglobulin (B2M) and beta-trace protein-measuring 15 calibration panel aliquots from 2009 to 2019. Initial target values were established using the mean of the first 3 measurements performed in 2009-10, and differences from target were monitored over time. New MPs for cystatin C and B2M were added in 2012, with target values established using the first measurement. RESULTS: The mean percentage difference from mean target values across time was <2% for all original MPs (-0.59% for creatinine; -0.94% for cystatin C; -0.82% for B2M; 1.24% for beta-trace protein). CONCLUSIONS: Close monitoring of filtration marker trends with a calibration panel at ARDL demonstrates remarkable long-term stability of the MPs. Routine use of a calibration panel for both research studies and clinical care is recommended for filtration markers where longitudinal monitoring is important to detect analytical biases, which can mask or confound true clinical trends in patients.

Estimating glomerular filtration rate from serum creatinine and cystatin C.

BACKGROUND: Estimates of glomerular filtration rate (GFR) that are based on serum creatinine are routinely used; however, they are imprecise, potentially leading to the overdiagnosis of chronic kidney disease. Cystatin C is an alternative filtration marker for estimating GFR. METHODS: Using cross-sectional analyses, we developed estimating equations based on cystatin C alone and in combination with creatinine in diverse populations totaling 5352 participants from 13 studies. These equations were then validated in 1119 participants from 5 different studies in which GFR had been measured. Cystatin and creatinine assays were traceable to primary reference materials. RESULTS: Mean measured GFRs were 68 and 70 ml per minute per 1.73 m(2) of body-surface area in the development and validation data sets, respectively. In the validation data set, the creatinine-cystatin C equation performed better than equations that used creatinine or cystatin C alone. Bias was similar among the three equations, with a median difference between measured and estimated GFR of 3.9 ml per minute per 1.73 m(2) with the combined equation, as compared with 3.7 and 3.4 ml per minute per 1.73 m(2) with the creatinine equation and the cystatin C equation (P=0.07 and P=0.05), respectively. Precision was improved with the combined equation (interquartile range of the difference, 13.4 vs. 15.4 and 16.4 ml per minute per 1.73 m(2), respectively [P=0.001 and P<0.001]), and the results were more accurate (percentage of estimates that were >30% of measured GFR, 8.5 vs. 12.8 and 14.1, respectively [P<0.001 for both comparisons]). In participants whose estimated GFR based on creatinine was 45 to 74 ml per minute per 1.73 m(2), the combined equation improved the classification of measured GFR as either less than 60 ml per minute per 1.73 m(2) or greater than or equal to 60 ml per minute per 1.73 m(2) (net reclassification index, 19.4% [P<0.001]) and correctly reclassified 16.9% of those with an estimated GFR of 45 to 59 ml per minute per 1.73 m(2) as having a GFR of 60 ml or higher per minute per 1.73 m(2). CONCLUSIONS: The combined creatinine-cystatin C equation performed better than equations based on either of these markers alone and may be useful as a confirmatory test for chronic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).

Extracorporeal ultrafiltration vs. conventional diuretic therapy in advanced decompensated heart failure.

Compared with conventional diuretic (CD) therapy, ultrafiltration (UF) is associated with greater weight loss and fewer re-hospitalizations in patients admitted with decompensated heart failure (HF). Concerns have been raised regarding its safety and efficacy in patients with more advanced heart failure. The authors conducted a single-center, prospective, randomized controlled trial in patients with advanced HF admitted to an intensive care unit for hemodynamically guided therapy, comparing UF (n=17) with CD (n=19) at admission. The primary end point was the time required for pulmonary capillary wedge pressure (PCWP) to be maintained at a value of ≤18 mm Hg for at least 4 consecutive hours. Secondary end points included levels of cytokines and neurohormones, as well as several clinical outcomes. In our study cohort, the time to achieve the primary end point was lower in the UF group but did not reach statistical significance (P = .08). UF resulted in greater weight reduction, higher total volume removed, and shorter hospital length of stay. There were no differences in kidney function, biomarkers, or adverse events. In patients with advanced HF under hemodynamically tailored therapy, UF can be safely performed to achieve higher average volume removed than CD therapy without leading to adverse outcomes.

Imprecision of urinary iothalamate clearance as a gold-standard measure of GFR decreases the diagnostic accuracy of kidney function estimating equations.

BACKGROUND: Evaluating the accuracy of estimated glomerular filtration rate (eGFR) derived from serum creatinine (SCr) and serum cystatin C (SCysC) equations requires gold-standard measures of GFR. However, the influence of imprecise measured GFRs (mGFRs) on estimates of equation error is unknown. STUDY DESIGN: Diagnostic test study. SETTING & PARTICIPANTS: 1,995 participants from the Modification of Diet in Renal Disease (MDRD) Study and African American Study of Kidney Disease and Hypertension (AASK) with at least 2 baseline mGFRs from iodine 125-iothalamate urinary clearances, 1 standardized SCr value, and 1 SCysC value. INDEX TESTS: eGFRs calculated using the 4-variable isotope-dilution mass spectrometry (IDMS)-traceable MDRD Study equation, the Chronic Kidney Disease (CKD) Epidemiology Collaboration (CKD-EPI) SCysC equation, the CKD-EPI SCr-SCysC equation, and mGFRs collected from another prerandomization visit. REFERENCE TESTS: A single reference mGFR, average of 2, and average of 3 mGFRs; additional analysis limited to consistent mGFRs (difference 30%. Reducing and quantifying errors in gold-standard measurements of GFR is critical to fully estimating the accuracy of GFR estimates.

Subclinical myocardial necrosis and cardiovascular risk in stable patients undergoing elective cardiac evaluation.

OBJECTIVE: The presence of subclinical myocardial necrosis as a prodrome to longer-term adverse cardiac event risk has been debated. The debate has focused predominantly within patients with acute coronary syndrome, and on issues of troponin assay variability and accuracy of detection, rather than on the clinical significance of the presence of subclinical myocardial necrosis (ie, "troponin leak") within stable cardiac patients. Herein, we examine the relationship between different degrees of subclinical myocardial necrosis and long-term adverse clinical outcomes within a stable cardiac patient population with essentially normal renal function. METHODS AND RESULTS: Sequential consenting patients (N=3828; median creatinine clearance, 100 mL/min/1.73m(2)) undergoing elective diagnostic coronary angiography with cardiac troponin I (cTnI) levels below the diagnostic cut-off for defining myocardial infarction (<0.03 ng/mL) were evaluated. The relationship of subclinical myocardial necrosis with incident major adverse cardiovascular events (defined as any death, myocardial infarction, or stroke) over 3-year follow-up was examined. "Probable" (cTnI 0.001-0.008 ng/mL) and "definite" (cTnI 0.009-0.029 ng/mL) subclinical myocardial necrosis were observed frequently within the cohort (34% and 18%, respectively). A linear relationship was observed between the magnitude of subclinical myocardial necrosis and risk of 3-year incident major adverse cardiovascular events, particularly in those with cTnI 0.009 ng/mL or higher (hazard ratio, 3.00; 95% confidence interval, 2.4-3.8), even after adjustment for traditional risk factors, C-reactive protein, and creatinine clearance. The presence of subclinical myocardial necrosis was associated with elevations in acute phase proteins (C-reactive protein, ceruloplasmin; P<0.01 each) and reduction in systemic antioxidant enzyme activities (arylesterase; P<0.01) but showed no significant associations with multiple specific measures of oxidant stress, and showed borderline associations with myeloperoxidase, a marker of leukocyte activation. CONCLUSIONS: In stable cardiology patients, prodromal subclinical myocardial necrosis is associated with substantially higher long-term risk for major adverse cardiovascular events. The underlying mechanisms contributing to this minimal troponin leak phenomenon warrants further investigation.

Method of glomerular filtration rate estimation affects prediction of mortality risk.

Decreased kidney function, determined using a serum creatinine-based estimation of GFR, is associated with a higher risk for mortality from cardiovascular disease. Equations incorporating cystatin C improve the estimation of GFR, but whether this improves the prediction of risk for mortality is unknown. We measured cystatin C on 6942 adult participants in the Third National Health and Nutrition Examination Survey Linked Mortality File, including all participants who had high serum creatinine (>1.2 mg/dl for men; >1.0 mg/dl for women) or were older than 60 yr and 25% random sample of participants who were younger than 60 yr. We estimated GFR using equations that included standardized serum creatinine, cystatin C, or both. Participant data were linked to the National Death Index. A total of 1573 (22.7%) deaths (713 deaths from cardiovascular disease) occurred during a median of 8 yr. Lower estimated GFR based on cystatin C was strongly associated with higher risk for overall and cardiovascular mortality across the range of normal to moderately decreased estimated GFR. Creatinine-based estimates of GFR resulted in weaker associations, with the association between estimated GFR and all-cause mortality reversed at higher levels of estimated GFR. An equation using both creatinine and cystatin C (in addition to age, race, and gender) resulted in weaker associations than equations using only cystatin C (with or without age, race, and gender). In conclusion, despite better performance in terms of estimating GFR, equations based on both cystatin C and creatinine do not predict mortality as well as equations based on cystatin C alone.

A new equation to estimate glomerular filtration rate.

BACKGROUND: Equations to estimate glomerular filtration rate (GFR) are routinely used to assess kidney function. Current equations have limited precision and systematically underestimate measured GFR at higher values. OBJECTIVE: To develop a new estimating equation for GFR: the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. DESIGN: Cross-sectional analysis with separate pooled data sets for equation development and validation and a representative sample of the U.S. population for prevalence estimates. SETTING: Research studies and clinical populations ("studies") with measured GFR and NHANES (National Health and Nutrition Examination Survey), 1999 to 2006. PARTICIPANTS: 8254 participants in 10 studies (equation development data set) and 3896 participants in 16 studies (validation data set). Prevalence estimates were based on 16,032 participants in NHANES. MEASUREMENTS: GFR, measured as the clearance of exogenous filtration markers (iothalamate in the development data set; iothalamate and other markers in the validation data set), and linear regression to estimate the logarithm of measured GFR from standardized creatinine levels, sex, race, and age. RESULTS: In the validation data set, the CKD-EPI equation performed better than the Modification of Diet in Renal Disease Study equation, especially at higher GFR (P < 0.001 for all subsequent comparisons), with less bias (median difference between measured and estimated GFR, 2.5 vs. 5.5 mL/min per 1.73 m(2)), improved precision (interquartile range [IQR] of the differences, 16.6 vs. 18.3 mL/min per 1.73 m(2)), and greater accuracy (percentage of estimated GFR within 30% of measured GFR, 84.1% vs. 80.6%). In NHANES, the median estimated GFR was 94.5 mL/min per 1.73 m(2) (IQR, 79.7 to 108.1) vs. 85.0 (IQR, 72.9 to 98.5) mL/min per 1.73 m(2), and the prevalence of chronic kidney disease was 11.5% (95% CI, 10.6% to 12.4%) versus 13.1% (CI, 12.1% to 14.0%). LIMITATION: The sample contained a limited number of elderly people and racial and ethnic minorities with measured GFR. CONCLUSION: The CKD-EPI creatinine equation is more accurate than the Modification of Diet in Renal Disease Study equation and could replace it for routine clinical use. PRIMARY FUNDING SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases.

Detection of soluble angiotensin-converting enzyme 2 in heart failure: insights into the endogenous counter-regulatory pathway of the renin-angiotensin-aldosterone system.

OBJECTIVES: We sought to determine whether circulating soluble angiotensin-converting enzyme 2 (sACE2) is increased in the plasma of patients with heart failure (HF). BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is an integral membrane protein that antagonizes the actions of angiotensin II and prevents the development of HF in animal models. However, because of the need for invasive cardiac tissue sampling, little is known about whether ACE2 is involved in the pathophysiology of HF in humans. METHODS: We developed a sensitive and specific assay to measure sACE2 activity in human plasma and screened a heterogeneous group of patients suspected of having clinical HF. RESULTS: Increasing sACE2 plasma activity strongly correlated with a clinical diagnosis of HF (p = 0.0002), worsening left ventricular ejection fraction (p < 0.0001), and increasing B-type natriuretic peptide levels (p < 0.0001). Similar to B-type natriuretic peptide, sACE2 activity reflected the severity of HF, with increasing levels associated with worsening New York Heart Association functional class (p < 0.0001). These associations were independent of other disease states and medication use. We found that sACE2 activity was increased in patients with both ischemic and nonischemic cardiomyopathies and also in patients with clinical HF but a preserved left ventricular ejection fraction. CONCLUSIONS: Soluble ACE2 activity is increased in patients with HF and correlates with disease severity, suggesting that a cardioprotective arm of the renin-angiotensin-aldosterone system is active in HF.

Impact of myocardial function on cystatin C measurements in chronic systolic heart failure.

BACKGROUND: The influence of myocardial function on plasma levels of cystatin C (CysC), a sensitive marker of renal function, in chronic systolic heart failure (HF) has not been well established. METHODS: We prospectively identified 139 subjects with stable, chronic HF (left ventricular ejection fraction < or = 35%) and measured plasma levels of CysC. We prospectively tracked patients' long-term adverse clinical outcomes (death, cardiac transplantation, and HF hospitalizations). RESULTS: Plasma levels of CysC were elevated in 41% of patients with preserved renal function and directly correlated with N-terminal prohormone brain natriuretic peptide (r = 0.57, P < .0001). There was a significant association between CysC and mitral E/septal E' ratio (r = 0.34, P < .001), right ventricular systolic dysfunction severity (r = 0.30, P < .001), and mitral regurgitation severity (r = 0.31, P < .001), but not left ventricular ejection fraction. At the cutoff of 1.23 mg/dL, CysC remains a significant independent risk factor for adverse clinical outcomes (hazard ratio 1.88, 95% confidence interval 1.15-3.09, P = .012) after adjusting for estimated glomerular filtration rate, left ventricular ejection fraction, and E/septal E'. CONCLUSION: CysC is associated with more advanced left ventricular diastolic dysfunction and right ventricular systolic dysfunction and remains an independent predictor of long-term prognosis in chronic systolic HF after adjusting for myocardial factors.

Cystatin C and creatinine in an HIV cohort: the nutrition for healthy living study.

BACKGROUND: Human immunodeficiency virus (HIV)-infected persons have an increased risk of chronic kidney disease (CKD). Serum creatinine level may underestimate the prevalence of CKD in subjects with decreased lean body mass or liver disease. Level of serum cystatin C, an alternative kidney function marker, is independent of lean body mass. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 250 HIV-infected subjects on highly active antiretroviral therapy in the Nutrition for Healthy Living (NFHL) cohort; 2,628 National Health and Nutrition Examination Survey (NHANES) 2001-2002 subjects. PREDICTORS & OUTCOMES: Comparison of serum creatinine levels in NFHL to those in NHANES subjects; comparison of CKD in NFHL subjects ascertained using serum creatinine versus cystatin C levels. MEASUREMENTS: Standardized serum creatinine, serum cystatin C, glomerular filtration rate (GFR) estimated from serum creatinine and cystatin C levels. RESULTS: Creatinine levels were lower in NFHL than NHANES subjects despite greater rates of hepatitis, diabetes, and drug use (mean difference, -0.18 mg/dL; P < 0.001 adjusted for age, sex, and race). Of NFHL subjects, only 2.4% had a creatinine-based estimated GFR less than 60 mL/min/1.73 m(2), but 15.2% had a cystatin-based estimated GFR less than 60 mL/min/1.73 m(2). LIMITATIONS: GFR was estimated rather than measured. Other factors in addition to GFR may affect creatinine and cystatin C levels. Measurements of proteinuria were not available. CONCLUSIONS: Serum creatinine levels may overestimate GFRs in HIV-infected subjects. Kidney disease prevalence may be greater than previously appreciated.

Usefulness of C-reactive protein and left ventricular diastolic performance for prognosis in patients with left ventricular systolic heart failure.

High-sensitivity C-reactive protein (hs-CRP) is a hepatocyte-derived inflammatory cytokine shown to be increased in the setting of acute heart failure (HF), particularly with increased intracardiac filling pressures. In the chronic HF setting, the relation between hs-CRP and echocardiographic indexes of left ventricular (LV) diastolic performance has not been examined. We measured plasma hs-CRP levels using a particle-enhanced immunonephelometry assay (Dade Behring, Inc., Deerfield, Illinois) in 136 subjects with chronic HF (LV ejection fraction [EF]

A prospective crossover study comparing secretin-stimulated endoscopic and Dreiling tube pancreatic function testing in patients evaluated for chronic pancreatitis.

BACKGROUND: Direct pancreatic function tests (PFT) are conventionally performed with use of double-lumen "Dreiling" collection tubes. We have developed an endoscopic collection method (ePFT) that eases the performance of these tests. OBJECTIVE: Our aim was to compare the bicarbonate results obtained from the secretin ePFT and Dreiling PFT methods in patients evaluated for chronic pancreatitis. DESIGN: A prospective crossover design was used to compare the PFT methods. SETTING: Tertiary care referral center. PATIENTS AND INTERVENTIONS: Twenty-four patients undergoing an evaluation for chronic pancreatitis underwent the secretin-stimulated ePFT and Dreiling PFT methods on separate days. MAIN OUTCOME MEASUREMENTS: Duodenal fluid bicarbonate concentrations and estimated bicarbonate outputs were compared. RESULTS: The mean difference in peak bicarbonate concentration (Dreiling PFT minus ePFT) was 7 mEq/L (SD 20) and not statistically significant (P = .11). A good correlation in peak bicarbonate concentrations (r = 0.74, 95% CI, 0.48-0.88) and estimated bicarbonate output (r = 0.78, 95% CI, 0.54-0.90) was observed between the two PFT methods. LIMITATION: The sensitivities and specificities of the secretin ePFT and Dreiling PFT could not be compared because of the lack of a histologic gold standard. CONCLUSION: The secretin ePFT yields results similar to those of the Dreiling PFT in patients evaluated for chronic pancreatitis.

Serum cystatin C in the United States: the Third National Health and Nutrition Examination Survey (NHANES III).

BACKGROUND: Serum cystatin C increasingly is used as a marker of glomerular filtration rate and cardiovascular risk. However, information for serum cystatin C levels in the general population, specifically across a wide age range and different ethnicities, is lacking. OBJECTIVES: To determine nationally representative serum cystatin C levels, estimate the prevalence of increased cystatin C levels in the general population, and identify factors associated with increased cystatin C levels. STUDY DESIGN: Cross-sectional survey. SETTING AND PARTICIPANTS: A nationally representative subsample of 7,596 participants aged 12 years or older in the Third National Health and Nutrition Examination Survey conducted in 1988-1994. PREDICTORS: Age, sex, race/ethnicity, risk factors for chronic kidney disease. OUTCOMES: Continuous serum cystatin C levels and serum cystatin C level greater than 1.12 mg/L. MEASUREMENTS: Cystatin C was measured in 2006 from stored sera by using an automated particle-enhanced nephelometric assay. RESULTS: Overall median serum cystatin C level was 0.85 mg/L. Median cystatin C levels increased steeply with age and were greater in males and non-Hispanic white persons, even in a healthy subgroup of 20- to 39-year-olds. Prevalences of increased serum cystatin C levels (>1.12 mg/L) were 1%, 41%, and greater than 50% in all persons aged younger than 20 years, 60 years or older, and 80 years or older. In persons aged 60 years and older, older age, non-Hispanic white ethnicity, hypertension, current smoking, lower levels of education and high-density lipoprotein cholesterol, and increased body mass index, C-reactive protein, and triglyceride values were associated significantly with increased serum cystatin C levels. LIMITATIONS: No measured glomerular filtration rate, single measurement of cystatin C, cross-sectional study design. CONCLUSIONS: Serum cystatin C level is related to sex and ethnicity, even in young healthy individuals. The prevalence of increased cystatin C levels increases dramatically with age, reaching greater than 50% after the age of 80 years in both sexes and all ethnic groups.

Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD.

BACKGROUND: Serum cystatin C was proposed as a potential replacement for serum creatinine in glomerular filtration rate (GFR) estimation. We report the development and evaluation of GFR-estimating equations using serum cystatin C alone and serum cystatin C, serum creatinine, or both with demographic variables. STUDY DESIGN: Test of diagnostic accuracy. SETTING & PARTICIPANTS: Participants screened for 3 chronic kidney disease (CKD) studies in the United States (n = 2,980) and a clinical population in Paris, France (n = 438). REFERENCE TEST: Measured GFR (mGFR). INDEX TEST: Estimated GFR using the 4 new equations based on serum cystatin C alone, serum cystatin C, serum creatinine, or both with age, sex, and race. New equations were developed by using linear regression with log GFR as the outcome in two thirds of data from US studies. Internal validation was performed in the remaining one third of data from US CKD studies; external validation was performed in the Paris study. MEASUREMENTS: GFR was measured by using urinary clearance of iodine-125-iothalamate in the US studies and chromium-51-EDTA in the Paris study. Serum cystatin C was measured by using Dade-Behring assay, standardized serum creatinine values were used. RESULTS: Mean mGFR, serum creatinine, and serum cystatin C values were 48 mL/min/1.73 m(2) (5th to 95th percentile, 15 to 95), 2.1 mg/dL, and 1.8 mg/L, respectively. For the new equations, coefficients for age, sex, and race were significant in the equation with serum cystatin C, but 2- to 4-fold smaller than in the equation with serum creatinine. Measures of performance in new equations were consistent across the development and internal and external validation data sets. Percentages of estimated GFR within 30% of mGFR for equations based on serum cystatin C alone, serum cystatin C, serum creatinine, or both levels with age, sex, and race were 81%, 83%, 85%, and 89%, respectively. The equation using serum cystatin C level alone yields estimates with small biases in age, sex, and race subgroups, which are improved in equations including these variables. LIMITATIONS: Study population composed mainly of patients with CKD. CONCLUSIONS: Serum cystatin C level alone provides GFR estimates that are nearly as accurate as serum creatinine level adjusted for age, sex, and race, thus providing an alternative GFR estimate that is not linked to muscle mass. An equation including serum cystatin C level in combination with serum creatinine level, age, sex, and race provides the most accurate estimates.

Calibration of serum creatinine in the National Health and Nutrition Examination Surveys (NHANES) 1988-1994, 1999-2004.

BACKGROUND: The calibration of serum creatinine values to standardized creatinine and the commutability of serum creatinine across surveys are essential to the correct use of National Health and Nutrition Examination Survey (NHANES) data for kidney function and for generating estimates of the burden of kidney disease in the United States. STUDY DESIGN: Calibration study of serum creatinine in NHANES III (1988-1994) and NHANES 1999-2000, 2001-2002, and 2003-2004 to directly compare creatinine measurements from the original surveys with standard creatinine measured using an assay traceable to known gold-standard methods. We also assessed predictors of differences between methods (potential interferences) in this general population. SETTING & PARTICIPANTS: The NHANES are ongoing cross-sectional surveys of the civilian noninstitutionalized population of the United States. We selected random samples of approximately 200 stored specimens from persons aged 60 years or older from each survey (NHANES III, 1999-2000, 2001-2002, and 2003-2004). MEASUREMENTS: Stored serum specimens from the 4 NHANES surveys were analyzed for serum creatinine by using a Roche enzymatic assay implemented at the Cleveland Clinic Research Laboratory (CCRL). The Roche assay is traceable to gold-standard reference methods. The original NHANES serum creatinine values were obtained using the Jaffé method (kinetic alkaline picrate) implemented in several different laboratories. RESULTS: Overall agreement between the original NHANES values (Jaffé method) and CCRL measurements (Roche enzymatic) was high, but substantial biases were observed in NHANES III and 1999-2000. No bias was observed in NHANES 2001-2002 and 2003-2004. Final calibration equations to correct serum creatinine values in the relevant surveys are provided. Assay differences were independent of sex, race/ethnicity, and bilirubin and triglyceride levels, but weakly related to age and glucose concentration. LIMITATIONS: We were not able to examine drift in measurements over time within each survey or directly evaluate freeze-thaw effects. CONCLUSIONS: The magnitude of differences in serum creatinine measurements in NHANES III and 1999-2000 from standard creatinine would result in large differences in estimates of kidney function (10% to 20%). Thus, correction of original creatinine values in NHANES III and 1999-2000 is essential, but no correction is needed for NHANES 2001-2002 or 2003-2004.

Prevalence of chronic kidney disease in the United States.

CONTEXT: The prevalence and incidence of kidney failure treated by dialysis and transplantation in the United States have increased from 1988 to 2004. Whether there have been changes in the prevalence of earlier stages of chronic kidney disease (CKD) during this period is uncertain. OBJECTIVE: To update the estimated prevalence of CKD in the United States. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analysis of the most recent National Health and Nutrition Examination Surveys (NHANES 1988-1994 and NHANES 1999-2004), a nationally representative sample of noninstitutionalized adults aged 20 years or older in 1988-1994 (n = 15,488) and 1999-2004 (n = 13,233). MAIN OUTCOME MEASURES: Chronic kidney disease prevalence was determined based on persistent albuminuria and decreased estimated glomerular filtration rate (GFR). Persistence of microalbuminuria (>30 mg/g) was estimated from repeat visit data in NHANES 1988-1994. The GFR was estimated using the abbreviated Modification of Diet in Renal Disease Study equation reexpressed to standard serum creatinine. RESULTS: The prevalence of both albuminuria and decreased GFR increased from 1988-1994 to 1999-2004. The prevalence of CKD stages 1 to 4 increased from 10.0% (95% confidence interval [CI], 9.2%-10.9%) in 1988-1994 to 13.1% (95% CI, 12.0%-14.1%) in 1999-2004 with a prevalence ratio of 1.3 (95% CI, 1.2-1.4). The prevalence estimates of CKD stages in 1988-1994 and 1999-2004, respectively, were 1.7% (95% CI, 1.3%-2.2%) and 1.8% (95% CI, 1.4%-2.3%) for stage 1; 2.7% (95% CI, 2.2%-3.2%) and 3.2% (95% CI, 2.6%-3.9%) for stage 2; 5.4% (95% CI, 4.9%-6.0%) and 7.7% (95% CI, 7.0%-8.4%) for stage 3; and 0.21% (95% CI, 0.15%-0.27%) and 0.35% (0.25%-0.45%) for stage 4. A higher prevalence of diagnosed diabetes and hypertension and higher body mass index explained the entire increase in prevalence of albuminuria but only part of the increase in the prevalence of decreased GFR. Estimation of GFR from serum creatinine has limited precision and a change in mean serum creatinine accounted for some of the increased prevalence of CKD. CONCLUSIONS: The prevalence of CKD in the United States in 1999-2004 is higher than it was in 1988-1994. This increase is partly explained by the increasing prevalence of diabetes and hypertension and raises concerns about future increased incidence of kidney failure and other complications of CKD.

Impact of creatinine calibration on performance of GFR estimating equations in a pooled individual patient database.

BACKGROUND: Variation in performance of glomerular filtration rate (GFR) estimating equations is related to variation in calibration of the creatinine assay across clinical laboratories. STUDY DESIGN: Cross-sectional analysis. SETTING & PARTICIPANTS: 6 research studies and 4 clinical populations including 5,504 participants who had GFR measured using urinary clearance of iothalamate. MEASUREMENTS: Standardized serum creatinine values obtained by means of calibration to the Cleveland Clinic Research Laboratory using frozen specimens, a calibration panel, and/or survey results from the College of American Pathologists. PREDICTOR: Noncalibrated serum creatinine assayed in research and clinical laboratories compared with standardized serum creatinine. OUTCOME: Difference between measured GFR versus GFR estimated from the Modification of Diet in Renal Disease (MDRD) Study and Cockcroft-Gault equations. RESULTS: For a noncalibrated serum creatinine value of 1 mg/dL (88.4 micromol/L), standardized serum creatinine value was 0.07 mg/dL (6.2 micromol/L) less than noncalibrated values. In the pooled data set, for the MDRD Study equation, calibration improved median percentage of difference between measured and estimated GFR from 9.0% (interquartile range [IQR], 28%) to 5.8% (IQR, 28%) and improved the percentage of estimates within 30% of measured GFR (P30) from 80% to 83%. The effect of calibration was greater at higher levels of GFR and varied across studies. For the Cockcroft-Gault equation, calibration worsened the median percentage of difference from -2.0% (IQR, 38%) to -11.4% (IQR, 39%), and the P30, from 74% to 69%. LIMITATIONS: College of American Pathologist samples were used for calibration of clinical populations; calibration factors do not account for drift over time in the serum creatinine assay; calibration cannot account for variation in assay performance among individuals. CONCLUSION: Calibration improves the performance of the MDRD Study equation. After calibration, larger errors remain for GFR estimates greater than 60 mL/min/1.73 m2 (>1 mL/s/1.73 m2).

Expressing the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate with standardized serum creatinine values.

PURPOSE: We sought to reexpress the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation for estimation of glomerular filtration rate (GFR) using serum creatinine (S(cr)) standardized to reference methods. METHODS: Serum specimens included creatinine reference materials prepared by the College of American Pathologists (CAP), traceable to primary reference material at the NIST, with assigned values traceable to isotope dilution mass spectrometry (IDMS), a calibration panel prepared by the Cleveland Clinic Research Laboratory (CCRL), and frozen samples from the MDRD Study. Split specimens were measured at the CCRL using the Roche enzymatic and Beckman CX3 kinetic alkaline picrate assays. RESULTS: Roche enzymatic assay results on CAP samples were comparable to IDMS-assigned values. Beckman CX3 assay results in 2004-2005 were significantly higher than but highly correlated with simultaneous Roche enzymatic assay results (r(2) = 0.9994 on 40 CCRL samples) and showed minimal but significant upward drift from Beckman CX3 assay results during the MDRD Study in 1989-1991 (r(2) = 0.9987 in 253 samples). Combining these factors, standardized S(cr) = 0.95 x original MDRD Study S(cr). The reexpressed 4-variable MDRD Study equation for S(cr) (mg/dL) is GFR = 175 x standardized S(cr)(-1.154) x age(-0.203) x 1.212 (if black) x 0.742 (if female), and for S(cr) (micromol/L) is GFR = 30849 x standardized S(cr)(-1.154) x age(-0.203) x 1.212 (if black) x 0.742 (if female) [GFR in mL x min(-1) x (1.73 m(2))(-1)]. CONCLUSION: When the calibration of S(cr) methods is traceable to the S(cr) reference system, GFR should be estimated using the MDRD Study equation that has been reexpressed for standardized S(cr).

Risk stratification for patients undergoing nonurgent percutaneous coronary intervention using N-terminal pro-B-type natriuretic peptide: a Clopidogrel for the Reduction of Events During Observation (CREDO) substudy.

BACKGROUND: The utility of N-terminal pro-BNP (NT-proBNP) measurement as a prognostic marker during nonurgent percutaneous coronary intervention (PCI) has been suggested in several studies. The comparative prognostic values between NT-proBNP levels and left ventricular ejection fraction (LVEF) in the nonurgent PCI setting are unclear. METHODS: CREDO was a double blind, placebo-controlled, randomized trial comparing 2 clopidogrel regimens before and after nonurgent PCI. Baseline NT-proBNP levels and LVEF were measured in 1468 subjects using the Roche Elecsys proBNP assay (Roche Diagnostics, Indianapolis, IN), and the 1-year combined end point of death/myocardial infarction (MI)/stroke was analyzed according to NT-proBNP quartiles in impaired and preserved LVEF. RESULTS: In this patient cohort (mean age 61.6 +/- 10 years, 22% with LVEF < 50%), the median NT-proBNP level was 131 pg/mL. Increasing quartiles of NT-proBNP were associated with a higher rate of death, MI, and the combined end point (but not stroke) at 1 year, including those with LVEF > or = 50% (P < .001 for trend). This prognostic power for death and MI remained robust even when adjusted for other clinical or biochemical markers including cardiac troponin, creatinine clearance, and high-sensitive C-reactive protein (hazard ratio 1.249, P = .006). Despite its robust prognostic value, baseline NT-proBNP levels did not identify patients with enhanced benefit from pre-procedural and prolonged clopidogrel therapy. CONCLUSIONS: In patients undergoing a nonurgent PCI, NT-proBNP levels may provide important prognostic value for death and MI, even in patients with preserved cardiac function, However, NT-proBNP levels were unable to identify patients with enhanced benefit from pre-procedural and prolonged clopidogrel therapy.

Plasma myeloperoxidase levels in patients with chronic heart failure.

Increased oxidative stress and endothelial dysfunction are commonly observed in patients with chronic heart failure (HF). The relation between myeloperoxidase (MPO), an inflammatory marker with mechanistic links to plaque vulnerability and abnormal ventricular remodeling, and degrees of severity in chronic HF has not been reported. Plasma MPO levels were measured in 105 normal controls (no history of HF or left ventricular dysfunction) and 102 patients with chronic systolic HF (left ventricular ejection fraction <50%), and the relations among plasma MPO levels, plasma B-type natriuretic peptide levels, and the left ventricular ejection fraction were examined. Plasma MPO levels in patients with chronic systolic HF were significantly elevated compared with those of healthy controls (1,158 +/- 2,965 vs 204 +/- 139 pM, p <0.0001). Plasma MPO levels increased in parallel with increasing New York Heart Association class (p <0.0001) and were correlated with plasma B-type natriuretic peptide levels (Spearman's r = 0.39, p <0.0001). Levels of MPO were strongly associated with the prevalence of HF (unadjusted odds ratio 30.3, 95% confidence interval 11.1 to 94.5) and remained significant when adjusted for age and B-type natriuretic peptide (odds ratio 27.7, 95% confidence interval 3.6 to 371.1). In conclusion, in a cohort of patients with chronic HF, plasma MPO levels were elevated compared with those of normal controls and were associated with worsening functional class.