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Josef Coresh - One of the best experts on this subject based on the ideXlab platform.
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change in albuminuria and GFR? as end points for clinical trials in early stages of ckd a scientific workshop sponsored by the national kidney foundation in collaboration with the us food and drug administration and european medicines agency
American Journal of Kidney Diseases, 2020Co-Authors: Andrew S. Levey, Lesley A. Inker, Tom Greene, Josef Coresh, Morgan E Grams, Ron T Gansevoort, Hiddo J L Heerspink, Hocine Tighiouart, Kunihiro MatsushitaAbstract:The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) are currently willing to consider a 30% to 40% glomerular filtration rate (GFR?) decline as a surrogate end point for kidney failure for clinical trials of kidney disease progression under appropriate conditions. However, these end points may not be practical for early stages of kidney disease. In March 2018, the National Kidney Foundation sponsored a scientific workshop in collaboration with the FDA and EMA to evaluate changes in albuminuria or GFR? as candidate surrogate end points. Three parallel efforts were presented: meta-analyses of observational studies (cohorts), meta-analyses of clinical trials, and simulations of trial design. In cohorts, after accounting for measurement error, relationships between change in urinary albumin-creatinine ratio (UACR) or estimated GFR? (eGFR?) slope and the clinical outcome of kidney disease progression were strong and consistent. In trials, the posterior median R2 of treatment effects on the candidate surrogates with the clinical outcome was 0.47 (95% Bayesian credible interval [BCI], 0.02-0.96) for early change in UACR and 0.72 (95% BCI, 0.05-0.99) when restricted to baseline UACR>30mg/g, and 0.97 (95% BCI, 0.78-1.00) for total eGFR? slope at 3 years and 0.96 (95% BCI, 0.63-1.00) for chronic eGFR? slope (ie, the slope excluding the first 3 months from baseline, when there might be acute changes in eGFR?). The magnitude of the relationships of changes in the candidate surrogates with risk for clinical outcome was consistent across cohorts and trials: a UACR reduction of 30% or eGFR? slope reduction by 0.5 to 1.0mL/min/1.73m2 per year were associated with an HR of ∼0.7 for the clinical outcome in cohorts and trials. In simulations, using GFR? slope as an end point substantially reduced the required sample size and duration of follow-up compared with the clinical end point when baseline eGFR? was high, treatment effects were uniform, and there was no acute effect of the treatment. We conclude that both early change in albuminuria and GFR? slope fulfill criteria for surrogacy for use as end points in clinical trials for chronic kidney disease progression under certain conditions, with stronger support for change in GFR? than albuminuria. Implementation requires understanding conditions under which each surrogate is likely to perform well and restricting its use to those settings.
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Novel Filtration Markers for GFR? Estimation.
EJIFCC, 2017Co-Authors: Amy B. Karger, Lesley A. Inker, Andrew S. Levey, Josef Coresh, John H EckfeldtAbstract:Creatinine-based glomerular filtration rate estimation (eGFR?cr) has been improved and refined since the 1970s through both the Modification of Diet in Renal Disease (MDRD) Study equation in 1999 and the CKD Epidemiology Collaboration (CKD-EPI) equation in 2009, with current clinical practice dependent primarily on eGFR? for accurate assessment of GFR?. However, researchers and clinicians have recognized limitations of relying on creatinine as the only filtration marker, which can lead to inaccurate GFR? estimates in certain populations due to the influence of non-GFR? determinants of serum or plasma creatinine. Therefore, recent literature has proposed incorporation of multiple serum or plasma filtration markers into GFR? estimation to improve precision and accuracy and decrease the impact of non-GFR? determinants for any individual biomarker. To this end, the CKD-EPI combined creatinine-cystatin C equation (eGFR?cr-cys) was developed in 2012 and demonstrated superior accuracy to equations relying on creatinine or cystatin C alone (eGFR?cr or eGFR?cys). Now, the focus has broadened to include additional novel filtration markers to further refine and improve GFR? estimation. Beta-2-microglobulin (B2M) and beta-trace-protein (BTP) are two filtration markers with established assays that have been proposed as candidates for improving both GFR? estimation and risk prediction. GFR? estimating equations based on B2M and BTP have been developed and validated, with the CKD-EPI combined BTP-B2M equation (eGFR?BTP-B2M) demonstrating similar performance to eGFR? and eGFR?. Additionally, several studies have demonstrated that both B2M and BTP are associated with outcomes in CKD patients, including cardiovascular events, ESRD and mortality. This review will primarily focus on these two biomarkers, and will highlight efforts to identify additional candidate biomarkers through metabolomics-based approaches.
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serum β trace protein and β2 microglobulin as predictors of esrd mortality and cardiovascular disease in adults with ckd in the chronic renal insufficiency cohort cric study
American Journal of Kidney Diseases, 2016Co-Authors: Meredith C Foster, Andrew S. Levey, Josef Coresh, John H Eckfeldt, Robert G Nelson, Ramachandran S Vasan, Paul L Kimmel, Jeffrey R Schelling, Michael S Simonson, James H SondheimerAbstract:Background Serum β-trace protein (BTP) and β 2 -microglobulin (B2M) are independently associated with end-stage renal disease (ESRD) and mortality in the general population and high-risk groups with diabetes or advanced chronic kidney disease (CKD). Less is known about their associations with outcomes and predictive ability in adults with moderate CKD. Study Design Prospective cohort study. Setting & Participants 3,613 adults from the CRIC (Chronic Renal Insufficiency Cohort) Study (45% women; mean age, 57.9 years; 41.0% non-Hispanic black; 51.9% with diabetes). Predictors BTP and B2M levels with a reciprocal transformation to reflect their associations with filtration, creatinine-based estimated glomerular filtration rate (eGFR? cr ), measured GFR?, and a 4-marker composite score combining BTP, B2M, creatinine, and cystatin C levels. Predictors were standardized as z scores for comparisons across filtration markers. Outcomes ESRD, all-cause mortality, and new-onset cardiovascular disease. Results During a 6-year median follow-up, 755 (21%) participants developed ESRD, 653 died, and 292 developed new-onset cardiovascular disease. BTP, B2M, and the 4-marker composite score were independent predictors of ESRD and all-cause mortality, and B2M and the 4-marker composite score of cardiovascular events, after multivariable adjustment. These associations were stronger than those observed for eGFR? cr ( P vs eGFR? cr ≤0.02). The 4-marker composite score led to improvements in C statistic and 2.5-year risk reclassification beyond eGFR? cr for all outcomes. Limitations Filtration markers measured at one time point; measured GFR? available in subset of cohort. Conclusions BTP and B2M levels may contribute additional risk information beyond eGFR? cr , and the use of multiple markers may improve risk prediction beyond this well-established marker of kidney function among persons with moderate CKD.
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GFR? decline and subsequent risk of established kidney outcomes a meta analysis of 37 randomized controlled trials
American Journal of Kidney Diseases, 2014Co-Authors: Hiddo J L Heerspink, Andrew S. Levey, Josef Coresh, Hocine Tighiouart, Kunihiro Matsushita, Yingying Sang, Shoshana H Ballew, Hasi Mondal, Lesley A. InkerAbstract:Background The currently established end points for clinical trials of progression of chronic kidney disease (CKD) are end-stage renal disease and doubling of serum creatinine level, which approximates a 57% decline in estimated glomerular filtration rate (eGFR?). There is increased interest in using alternative end points in clinical trials to shorten trial duration and reduce sample size. As part of an evaluation of using lesser declines in GFR? as alternative end points, we examined the associations of various levels of eGFR? decline with the subsequent development of established end points and assess the consistency of alternate levels of eGFR? decline across varying clinical manifestations of kidney disease and interventions. Study Design Observational analysis of randomized controlled trials. Setting & Participants 9,488 participants in 37 randomized controlled trials in CKD. Predictor Alternative end points, defined as 30% and 40% declines in eGFR? from baseline to month 12. Effect modification by baseline eGFR?, proteinuria, cause of disease, and interventions. Outcomes Established end point, defined as end-stage renal disease, eGFR? 2 , or doubling of serum creatinine level. Results From baseline to 12 months, 16.1% and 7.8% of participants had eGFR? declines of ≥30% or ≥40%, respectively. Over a median follow-up of 2.0 (IQR, 1.2-3.1) years after the 12-month baseline period, 2,661 established end points were observed. A strong linear association was observed between eGFR? decline and subsequent established end points. HRs for the established end point for 30% and 40% decreases in eGFR? compared to a 0% decline were 9.6 (95% CI, 7.3-12.6) and 20.3 (95% CI, 14.1-29.3), respectively. The associations were consistent regardless of baseline eGFR?, proteinuria, causes of disease, and interventions. Limitations Observational study subject to residual confounding. Conclusions The strong associations between lesser declines in eGFR? and the subsequent development of established end points were consistent across different clinical characteristics of kidney disease and interventions and support implementation of alternative end points in clinical trials of CKD progression.
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GFR? estimation from physiology to public health
American Journal of Kidney Diseases, 2014Co-Authors: Andrew S. Levey, Lesley A. Inker, Josef CoreshAbstract:Estimating glomerular filtration rate (GFR?) is essential for clinical practice, research, and public health. Appropriate interpretation of estimated GFR? (eGFR?) requires understanding the principles of physiology, laboratory medicine, epidemiology, and biostatistics used in the development and validation of GFR? estimating equations. Equations developed in diverse populations are less biased at higher GFR?s than equations developed in chronic kidney disease (CKD) populations and are more appropriate for general use. Equations that include multiple endogenous filtration markers are more precise than equations including a single filtration marker. The CKD-EPI (CKD Epidemiology Collaboration) equations are the most accurate GFR? estimating equations that have been evaluated in large diverse populations and are applicable for general clinical use. The 2009 CKD-EPI creatinine equation is more accurate in estimating GFR? and prognosis than the 2006 MDRD (Modification of Diet in Renal Disease) Study equation and provides lower estimates of prevalence of decreased eGFR?. It is useful as a "first test" for decreased eGFR? and should replace the MDRD Study equation for routine reporting of serum creatinine–based eGFR? by clinical laboratories. The 2012 CKD-EPI cystatin C equation is as accurate as the 2009 CKD-EPI creatinine equation in estimating GFR?, does not require specification of race, and may be more accurate in patients with decreased muscle mass. The 2012 CKD-EPI creatinine–cystatin C equation is more accurate than the 2009 CKD-EPI creatinine and 2012 CKD-EPI cystatin C equations and is useful as a confirmatory test for decreased eGFR? as determined by serum creatinine-based eGFR?. Further improvement in GFR? estimating equations will require development in more broadly representative populations, including diverse racial and ethnic groups, use of multiple filtration markers, and evaluation using statistical techniques to compare eGFR? to "true GFR?."
Andrew S. Levey - One of the best experts on this subject based on the ideXlab platform.
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change in albuminuria and GFR? as end points for clinical trials in early stages of ckd a scientific workshop sponsored by the national kidney foundation in collaboration with the us food and drug administration and european medicines agency
American Journal of Kidney Diseases, 2020Co-Authors: Andrew S. Levey, Lesley A. Inker, Tom Greene, Josef Coresh, Morgan E Grams, Ron T Gansevoort, Hiddo J L Heerspink, Hocine Tighiouart, Kunihiro MatsushitaAbstract:The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) are currently willing to consider a 30% to 40% glomerular filtration rate (GFR?) decline as a surrogate end point for kidney failure for clinical trials of kidney disease progression under appropriate conditions. However, these end points may not be practical for early stages of kidney disease. In March 2018, the National Kidney Foundation sponsored a scientific workshop in collaboration with the FDA and EMA to evaluate changes in albuminuria or GFR? as candidate surrogate end points. Three parallel efforts were presented: meta-analyses of observational studies (cohorts), meta-analyses of clinical trials, and simulations of trial design. In cohorts, after accounting for measurement error, relationships between change in urinary albumin-creatinine ratio (UACR) or estimated GFR? (eGFR?) slope and the clinical outcome of kidney disease progression were strong and consistent. In trials, the posterior median R2 of treatment effects on the candidate surrogates with the clinical outcome was 0.47 (95% Bayesian credible interval [BCI], 0.02-0.96) for early change in UACR and 0.72 (95% BCI, 0.05-0.99) when restricted to baseline UACR>30mg/g, and 0.97 (95% BCI, 0.78-1.00) for total eGFR? slope at 3 years and 0.96 (95% BCI, 0.63-1.00) for chronic eGFR? slope (ie, the slope excluding the first 3 months from baseline, when there might be acute changes in eGFR?). The magnitude of the relationships of changes in the candidate surrogates with risk for clinical outcome was consistent across cohorts and trials: a UACR reduction of 30% or eGFR? slope reduction by 0.5 to 1.0mL/min/1.73m2 per year were associated with an HR of ∼0.7 for the clinical outcome in cohorts and trials. In simulations, using GFR? slope as an end point substantially reduced the required sample size and duration of follow-up compared with the clinical end point when baseline eGFR? was high, treatment effects were uniform, and there was no acute effect of the treatment. We conclude that both early change in albuminuria and GFR? slope fulfill criteria for surrogacy for use as end points in clinical trials for chronic kidney disease progression under certain conditions, with stronger support for change in GFR? than albuminuria. Implementation requires understanding conditions under which each surrogate is likely to perform well and restricting its use to those settings.
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Knowing your GFR?—when is the number not (exactly) the number?
Kidney International, 2019Co-Authors: Lesley A. Inker, Andrew S. LeveyAbstract:All methods used to measure and estimate glomerular filtration rate (GFR?) are associated with systematic or random error, which leads to differences in measured GFR? (mGFR?) and estimated GFR? (eGFR?) from "true GFR?." In this issue of Kidney International, Rowe et al. evaluate time-to-time variability using repeated assessments of mGFR? and eGFR? within a short time frame. They show that biological variability is larger for mGFR? than eGFR?, and the magnitude of reference change values when interpreting changes in mGFR? and eGFR?.
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Novel Filtration Markers for GFR? Estimation.
EJIFCC, 2017Co-Authors: Amy B. Karger, Lesley A. Inker, Andrew S. Levey, Josef Coresh, John H EckfeldtAbstract:Creatinine-based glomerular filtration rate estimation (eGFR?cr) has been improved and refined since the 1970s through both the Modification of Diet in Renal Disease (MDRD) Study equation in 1999 and the CKD Epidemiology Collaboration (CKD-EPI) equation in 2009, with current clinical practice dependent primarily on eGFR? for accurate assessment of GFR?. However, researchers and clinicians have recognized limitations of relying on creatinine as the only filtration marker, which can lead to inaccurate GFR? estimates in certain populations due to the influence of non-GFR? determinants of serum or plasma creatinine. Therefore, recent literature has proposed incorporation of multiple serum or plasma filtration markers into GFR? estimation to improve precision and accuracy and decrease the impact of non-GFR? determinants for any individual biomarker. To this end, the CKD-EPI combined creatinine-cystatin C equation (eGFR?cr-cys) was developed in 2012 and demonstrated superior accuracy to equations relying on creatinine or cystatin C alone (eGFR?cr or eGFR?cys). Now, the focus has broadened to include additional novel filtration markers to further refine and improve GFR? estimation. Beta-2-microglobulin (B2M) and beta-trace-protein (BTP) are two filtration markers with established assays that have been proposed as candidates for improving both GFR? estimation and risk prediction. GFR? estimating equations based on B2M and BTP have been developed and validated, with the CKD-EPI combined BTP-B2M equation (eGFR?BTP-B2M) demonstrating similar performance to eGFR? and eGFR?. Additionally, several studies have demonstrated that both B2M and BTP are associated with outcomes in CKD patients, including cardiovascular events, ESRD and mortality. This review will primarily focus on these two biomarkers, and will highlight efforts to identify additional candidate biomarkers through metabolomics-based approaches.
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serum β trace protein and β2 microglobulin as predictors of esrd mortality and cardiovascular disease in adults with ckd in the chronic renal insufficiency cohort cric study
American Journal of Kidney Diseases, 2016Co-Authors: Meredith C Foster, Andrew S. Levey, Josef Coresh, John H Eckfeldt, Robert G Nelson, Ramachandran S Vasan, Paul L Kimmel, Jeffrey R Schelling, Michael S Simonson, James H SondheimerAbstract:Background Serum β-trace protein (BTP) and β 2 -microglobulin (B2M) are independently associated with end-stage renal disease (ESRD) and mortality in the general population and high-risk groups with diabetes or advanced chronic kidney disease (CKD). Less is known about their associations with outcomes and predictive ability in adults with moderate CKD. Study Design Prospective cohort study. Setting & Participants 3,613 adults from the CRIC (Chronic Renal Insufficiency Cohort) Study (45% women; mean age, 57.9 years; 41.0% non-Hispanic black; 51.9% with diabetes). Predictors BTP and B2M levels with a reciprocal transformation to reflect their associations with filtration, creatinine-based estimated glomerular filtration rate (eGFR? cr ), measured GFR?, and a 4-marker composite score combining BTP, B2M, creatinine, and cystatin C levels. Predictors were standardized as z scores for comparisons across filtration markers. Outcomes ESRD, all-cause mortality, and new-onset cardiovascular disease. Results During a 6-year median follow-up, 755 (21%) participants developed ESRD, 653 died, and 292 developed new-onset cardiovascular disease. BTP, B2M, and the 4-marker composite score were independent predictors of ESRD and all-cause mortality, and B2M and the 4-marker composite score of cardiovascular events, after multivariable adjustment. These associations were stronger than those observed for eGFR? cr ( P vs eGFR? cr ≤0.02). The 4-marker composite score led to improvements in C statistic and 2.5-year risk reclassification beyond eGFR? cr for all outcomes. Limitations Filtration markers measured at one time point; measured GFR? available in subset of cohort. Conclusions BTP and B2M levels may contribute additional risk information beyond eGFR? cr , and the use of multiple markers may improve risk prediction beyond this well-established marker of kidney function among persons with moderate CKD.
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comparing GFR? estimating equations using cystatin c and creatinine in elderly individuals
Journal of The American Society of Nephrology, 2015Co-Authors: Andrew S. Levey, Vilmundur Gudnason, Gudny Eiriksdottir, Margret B Andresdottir, Hrefna Gudmundsdottir, Olafur S Indridason, Runolfur Palsson, Gary F Mitchell, Lesley A. InkerAbstract:Current guidelines recommend reporting eGFR? using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations unless other equations are more accurate, and recommend the combination of creatinine and cystatin C (eGFR?cr-cys) as more accurate than either eGFR?cr or eGFR?cys alone. However, preferred equations and filtration markers in elderly individuals are debated. In 805 adults enrolled in the community-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, we measured GFR? (mGFR?) using plasma clearance of iohexol, standardized creatinine and cystatin C, and eGFR? using the CKD-EPI, Japanese, Berlin Initiative Study (BIS), and Caucasian and Asian pediatric and adult subjects (CAPA) equations. We evaluated equation performance using bias, precision, and two measures of accuracy. We first compared the Japanese, BIS, and CAPA equations with the CKD-EPI equations to determine the preferred equations, and then compared eGFR?cr and eGFR?cys with eGFR?cr-cys using the preferred equations. Mean (SD) age was 80.3 (4.0) years. Median (25th, 75th) mGFR? was 64 (52, 73) ml/min per 1.73 m 2 , and the prevalence of decreased GFR? was 39% (95% confidence interval, 35.8 to 42.5). Among 24 comparisons with the other equations, CKD-EPI equations performed better in 9, similar in 13, and worse in 2. Using the CKD-EPI equations, eGFR?cr-cys performed better than eGFR?cr in four metrics, better than eGFR?cys in two metrics, and similar to eGFR?cys in two metrics. In conclusion, neither the Japanese, BIS, nor CAPA equations were superior to the CKD-EPI equations in this cohort of community-dwelling elderly individuals. Using the CKD-EPI equations, eGFR?cr-cys performed better than eGFR?cr or eGFR?cys.
Lesley A. Inker - One of the best experts on this subject based on the ideXlab platform.
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change in albuminuria and GFR? as end points for clinical trials in early stages of ckd a scientific workshop sponsored by the national kidney foundation in collaboration with the us food and drug administration and european medicines agency
American Journal of Kidney Diseases, 2020Co-Authors: Andrew S. Levey, Lesley A. Inker, Tom Greene, Josef Coresh, Morgan E Grams, Ron T Gansevoort, Hiddo J L Heerspink, Hocine Tighiouart, Kunihiro MatsushitaAbstract:The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) are currently willing to consider a 30% to 40% glomerular filtration rate (GFR?) decline as a surrogate end point for kidney failure for clinical trials of kidney disease progression under appropriate conditions. However, these end points may not be practical for early stages of kidney disease. In March 2018, the National Kidney Foundation sponsored a scientific workshop in collaboration with the FDA and EMA to evaluate changes in albuminuria or GFR? as candidate surrogate end points. Three parallel efforts were presented: meta-analyses of observational studies (cohorts), meta-analyses of clinical trials, and simulations of trial design. In cohorts, after accounting for measurement error, relationships between change in urinary albumin-creatinine ratio (UACR) or estimated GFR? (eGFR?) slope and the clinical outcome of kidney disease progression were strong and consistent. In trials, the posterior median R2 of treatment effects on the candidate surrogates with the clinical outcome was 0.47 (95% Bayesian credible interval [BCI], 0.02-0.96) for early change in UACR and 0.72 (95% BCI, 0.05-0.99) when restricted to baseline UACR>30mg/g, and 0.97 (95% BCI, 0.78-1.00) for total eGFR? slope at 3 years and 0.96 (95% BCI, 0.63-1.00) for chronic eGFR? slope (ie, the slope excluding the first 3 months from baseline, when there might be acute changes in eGFR?). The magnitude of the relationships of changes in the candidate surrogates with risk for clinical outcome was consistent across cohorts and trials: a UACR reduction of 30% or eGFR? slope reduction by 0.5 to 1.0mL/min/1.73m2 per year were associated with an HR of ∼0.7 for the clinical outcome in cohorts and trials. In simulations, using GFR? slope as an end point substantially reduced the required sample size and duration of follow-up compared with the clinical end point when baseline eGFR? was high, treatment effects were uniform, and there was no acute effect of the treatment. We conclude that both early change in albuminuria and GFR? slope fulfill criteria for surrogacy for use as end points in clinical trials for chronic kidney disease progression under certain conditions, with stronger support for change in GFR? than albuminuria. Implementation requires understanding conditions under which each surrogate is likely to perform well and restricting its use to those settings.
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Knowing your GFR?—when is the number not (exactly) the number?
Kidney International, 2019Co-Authors: Lesley A. Inker, Andrew S. LeveyAbstract:All methods used to measure and estimate glomerular filtration rate (GFR?) are associated with systematic or random error, which leads to differences in measured GFR? (mGFR?) and estimated GFR? (eGFR?) from "true GFR?." In this issue of Kidney International, Rowe et al. evaluate time-to-time variability using repeated assessments of mGFR? and eGFR? within a short time frame. They show that biological variability is larger for mGFR? than eGFR?, and the magnitude of reference change values when interpreting changes in mGFR? and eGFR?.
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Novel Filtration Markers for GFR? Estimation.
EJIFCC, 2017Co-Authors: Amy B. Karger, Lesley A. Inker, Andrew S. Levey, Josef Coresh, John H EckfeldtAbstract:Creatinine-based glomerular filtration rate estimation (eGFR?cr) has been improved and refined since the 1970s through both the Modification of Diet in Renal Disease (MDRD) Study equation in 1999 and the CKD Epidemiology Collaboration (CKD-EPI) equation in 2009, with current clinical practice dependent primarily on eGFR? for accurate assessment of GFR?. However, researchers and clinicians have recognized limitations of relying on creatinine as the only filtration marker, which can lead to inaccurate GFR? estimates in certain populations due to the influence of non-GFR? determinants of serum or plasma creatinine. Therefore, recent literature has proposed incorporation of multiple serum or plasma filtration markers into GFR? estimation to improve precision and accuracy and decrease the impact of non-GFR? determinants for any individual biomarker. To this end, the CKD-EPI combined creatinine-cystatin C equation (eGFR?cr-cys) was developed in 2012 and demonstrated superior accuracy to equations relying on creatinine or cystatin C alone (eGFR?cr or eGFR?cys). Now, the focus has broadened to include additional novel filtration markers to further refine and improve GFR? estimation. Beta-2-microglobulin (B2M) and beta-trace-protein (BTP) are two filtration markers with established assays that have been proposed as candidates for improving both GFR? estimation and risk prediction. GFR? estimating equations based on B2M and BTP have been developed and validated, with the CKD-EPI combined BTP-B2M equation (eGFR?BTP-B2M) demonstrating similar performance to eGFR? and eGFR?. Additionally, several studies have demonstrated that both B2M and BTP are associated with outcomes in CKD patients, including cardiovascular events, ESRD and mortality. This review will primarily focus on these two biomarkers, and will highlight efforts to identify additional candidate biomarkers through metabolomics-based approaches.
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comparing GFR? estimating equations using cystatin c and creatinine in elderly individuals
Journal of The American Society of Nephrology, 2015Co-Authors: Andrew S. Levey, Vilmundur Gudnason, Gudny Eiriksdottir, Margret B Andresdottir, Hrefna Gudmundsdottir, Olafur S Indridason, Runolfur Palsson, Gary F Mitchell, Lesley A. InkerAbstract:Current guidelines recommend reporting eGFR? using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations unless other equations are more accurate, and recommend the combination of creatinine and cystatin C (eGFR?cr-cys) as more accurate than either eGFR?cr or eGFR?cys alone. However, preferred equations and filtration markers in elderly individuals are debated. In 805 adults enrolled in the community-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, we measured GFR? (mGFR?) using plasma clearance of iohexol, standardized creatinine and cystatin C, and eGFR? using the CKD-EPI, Japanese, Berlin Initiative Study (BIS), and Caucasian and Asian pediatric and adult subjects (CAPA) equations. We evaluated equation performance using bias, precision, and two measures of accuracy. We first compared the Japanese, BIS, and CAPA equations with the CKD-EPI equations to determine the preferred equations, and then compared eGFR?cr and eGFR?cys with eGFR?cr-cys using the preferred equations. Mean (SD) age was 80.3 (4.0) years. Median (25th, 75th) mGFR? was 64 (52, 73) ml/min per 1.73 m 2 , and the prevalence of decreased GFR? was 39% (95% confidence interval, 35.8 to 42.5). Among 24 comparisons with the other equations, CKD-EPI equations performed better in 9, similar in 13, and worse in 2. Using the CKD-EPI equations, eGFR?cr-cys performed better than eGFR?cr in four metrics, better than eGFR?cys in two metrics, and similar to eGFR?cys in two metrics. In conclusion, neither the Japanese, BIS, nor CAPA equations were superior to the CKD-EPI equations in this cohort of community-dwelling elderly individuals. Using the CKD-EPI equations, eGFR?cr-cys performed better than eGFR?cr or eGFR?cys.
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GFR? decline and subsequent risk of established kidney outcomes a meta analysis of 37 randomized controlled trials
American Journal of Kidney Diseases, 2014Co-Authors: Hiddo J L Heerspink, Andrew S. Levey, Josef Coresh, Hocine Tighiouart, Kunihiro Matsushita, Yingying Sang, Shoshana H Ballew, Hasi Mondal, Lesley A. InkerAbstract:Background The currently established end points for clinical trials of progression of chronic kidney disease (CKD) are end-stage renal disease and doubling of serum creatinine level, which approximates a 57% decline in estimated glomerular filtration rate (eGFR?). There is increased interest in using alternative end points in clinical trials to shorten trial duration and reduce sample size. As part of an evaluation of using lesser declines in GFR? as alternative end points, we examined the associations of various levels of eGFR? decline with the subsequent development of established end points and assess the consistency of alternate levels of eGFR? decline across varying clinical manifestations of kidney disease and interventions. Study Design Observational analysis of randomized controlled trials. Setting & Participants 9,488 participants in 37 randomized controlled trials in CKD. Predictor Alternative end points, defined as 30% and 40% declines in eGFR? from baseline to month 12. Effect modification by baseline eGFR?, proteinuria, cause of disease, and interventions. Outcomes Established end point, defined as end-stage renal disease, eGFR? 2 , or doubling of serum creatinine level. Results From baseline to 12 months, 16.1% and 7.8% of participants had eGFR? declines of ≥30% or ≥40%, respectively. Over a median follow-up of 2.0 (IQR, 1.2-3.1) years after the 12-month baseline period, 2,661 established end points were observed. A strong linear association was observed between eGFR? decline and subsequent established end points. HRs for the established end point for 30% and 40% decreases in eGFR? compared to a 0% decline were 9.6 (95% CI, 7.3-12.6) and 20.3 (95% CI, 14.1-29.3), respectively. The associations were consistent regardless of baseline eGFR?, proteinuria, causes of disease, and interventions. Limitations Observational study subject to residual confounding. Conclusions The strong associations between lesser declines in eGFR? and the subsequent development of established end points were consistent across different clinical characteristics of kidney disease and interventions and support implementation of alternative end points in clinical trials of CKD progression.
Akira Hishida - One of the best experts on this subject based on the ideXlab platform.
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revised equations for estimated GFR? from serum creatinine in japan
American Journal of Kidney Diseases, 2009Co-Authors: Seiichi Matsuo, Masaru Horio, Hitoshi Yokoyama, Yoshinari Yasuda, Kosaku Nitta, Enyu Imai, Kimio Tomita, Kunihiro Yamagata, Yasuhiko Tomino, Akira HishidaAbstract:BACKGROUND: Estimation of glomerular filtration rate (GFR?) is limited by differences in creatinine generation among ethnicities. Our previously reported GFR?-estimating equations for Japanese had limitations because all participants had a GFR? less than 90 mL/min/1.73 m2 and serum creatinine was assayed in different laboratories. STUDY DESIGN: Diagnostic test study using a prospective cross-sectional design. New equations were developed in 413 participants and validated in 350 participants. All samples were assayed in a central laboratory. SETTING & PARTICIPANTS: Hospitalized Japanese patients in 80 medical centers. Patients had not participated in the previous study. REFERENCE TEST: Measured GFR? (mGFR?) computed from inulin clearance. INDEX TEST: Estimated GFR? (eGFR?) by using the modified isotope dilution mass spectrometry (IDMS)-traceable 4-variable Modification of Diet in Renal Disease (MDRD) Study equation using the previous Japanese Society of Nephrology Chronic Kidney Disease Initiative (JSN-CKDI) coefficient of 0.741 (equation 1), the previous JSN-CKDI equation (equation 2), and new equations derived in the development data set: modified MDRD Study using a new Japanese coefficient (equation 3), and a 3-variable Japanese equation (equation 4). MEASUREMENTS: Performance of equations was assessed by means of bias (eGFR? - mGFR?), accuracy (percentage of estimates within 15% or 30% of mGFR?), root mean squared error, and correlation coefficient. RESULTS: In the development data set, the new Japanese coefficient was 0.808 (95% confidence interval, 0.728 to 0.829) for the IDMS-MDRD Study equation (equation 3), and the 3-variable Japanese equation (equation 4) was eGFR? (mL/min/1.73 m2) = 194 x Serum creatinine(-1.094) x Age(-0.287) x 0.739 (if female). In the validation data set, bias was -1.3 +/- 19.4 versus -5.9 +/- 19.0 mL/min/1.73 m2 (P = 0.002), and accuracy within 30% of mGFR? was 73% versus 72% (P = 0.6) for equation 3 versus equation 1 and -2.1 +/- 19.0 versus -7.9 +/- 18.7 mL/min/1.73 m(2) (P < 0.001) and 75% versus 73% (P = 0.06) for equation 4 versus equation 2 (P = 0.06), respectively. LIMITATION: Most study participants had chronic kidney disease, and some may have had changing GFR?s. CONCLUSION: The new Japanese coefficient for the modified IDMS-MDRD Study equation and the new Japanese equation are more accurate for the Japanese population than the previously reported equations.
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Revised Equations for Estimated GFR? From Serum Creatinine in Japan
American Journal of Kidney Diseases, 2009Co-Authors: Seiichi Matsuo, Masaru Horio, Hitoshi Yokoyama, Yoshinari Yasuda, Kosaku Nitta, Enyu Imai, Kimio Tomita, Kunihiro Yamagata, Yasuhiko Tomino, Akira HishidaAbstract:Background: Estimation of glomerular filtration rate (GFR?) is limited by differences in creatinine generation among ethnicities. Our previously reported GFR?-estimating equations for Japanese had limitations because all participants had a GFR? less than 90 mL/min/1.73 m2and serum creatinine was assayed in different laboratories. Study Design: Diagnostic test study using a prospective cross-sectional design. New equations were developed in 413 participants and validated in 350 participants. All samples were assayed in a central laboratory. Setting & Participants: Hospitalized Japanese patients in 80 medical centers. Patients had not participated in the previous study. Reference Test: Measured GFR? (mGFR?) computed from inulin clearance. Index Test: Estimated GFR? (eGFR?) by using the modified isotope dilution mass spectrometry (IDMS)-traceable 4-variable Modification of Diet in Renal Disease (MDRD) Study equation using the previous Japanese Society of Nephrology Chronic Kidney Disease Initiative (JSN-CKDI) coefficient of 0.741 (equation 1), the previous JSN-CKDI equation (equation 2), and new equations derived in the development data set: modified MDRD Study using a new Japanese coefficient (equation 3), and a 3-variable Japanese equation (equation 4). Measurements: Performance of equations was assessed by means of bias (eGFR?-mGFR?), accuracy (percentage of estimates within 15% or 30% of mGFR?), root mean squared error, and correlation coefficient. Results: In the development data set, the new Japanese coefficient was 0.808 (95% confidence interval, 0.728 to 0.829) for the IDMS-MDRD Study equation (equation 3), and the 3-variable Japanese equation (equation 4) was eGFR? (mL/min/1.73 m2) = 194 × Serum creatinine-1.094× Age-0.287× 0.739 (if female). In the validation data set, bias was -1.3 ± 19.4 versus -5.9 ± 19.0 mL/min/1.73 m2(P = 0.002), and accuracy within 30% of mGFR? was 73% versus 72% (P = 0.6) for equation 3 versus equation 1 and-2.1±19.0 versus-7.9±18.7 mL/min/1.73m2(P
Harold I Feldman - One of the best experts on this subject based on the ideXlab platform.
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measured GFR? does not outperform estimated GFR? in predicting ckd related complications
Journal of The American Society of Nephrology, 2011Co-Authors: Kathleen J Propert, Lee L Hamm, Jiang He, Edgar R Miller, Michael G Shlipak, Valerie Teal, Raymond R Townsend, Matthew R Weir, Jillian Wilson, Harold I FeldmanAbstract:Although many assume that measurement of glomerular filtration rate (GFR?) using a marker such as iothalamate (iGFR?) is superior to equation-estimated GFR? (eGFR?), each of these methods has distinct disadvantages. Because physicians often use renal function to guide the screening for various CKD-associated complications, one method to compare the clinical utility of iGFR? and eGFR? is to determine the strength of their association with CKD-associated comorbidities. Using a subset of 1214 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study, we determined the cross-sectional associations between known complications of CKD and iGFR?, eGFR? estimated from serum creatinine (eGFR?_Cr), and eGFR? estimated from cystatin C (eGFR?_cysC). We found that none of the measures of renal function strongly associated with CKD complications and that the relative strengths of associations varied according to the outcome of interest. For example, iGFR? demonstrated better discrimination than eGFR?_Cr and eGFR?_cysC for outcomes of anemia and hemoglobin concentration; however, both eGFR?_Cr and eGFR?_cysC demonstrated better discrimination than iGFR? for outcomes of hyperphosphatemia and phosphorus level. iGFR? and eGFR? had similar strengths of association with hyperkalemia/potassium level and with metabolic acidosis/bicarbonate level. In conclusion, iothalamate measurement of GFR? is not consistently superior to equation-based estimations of GFR? in explaining CKD-related comorbidities. These results raise questions regarding the conventional view that iGFR? is the “gold standard” measure of kidney function.
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relationship of estimated GFR? and coronary artery calcification in the cric chronic renal insufficiency cohort study
American Journal of Kidney Diseases, 2011Co-Authors: Matthew J Budoff, Valerie Teal, Jim Lash, Daniel J Rader, Muredach P Reilly, Emile R Mohler, Wei Yang, Leigh Rosen, Melanie Glenn, Harold I FeldmanAbstract:Background Coronary artery calcification (CAC) is associated with increased mortality risk in the general population. Although individuals with chronic kidney disease (CKD) are at markedly increased mortality risk, the incidence, prevalence, and prognosis of CAC in CKD are not well understood. Study Design Cross-sectional observational study. Setting & Participants Analysis of 1,908 participants who underwent coronary calcium scanning as part of the multiethnic CRIC (Chronic Renal Insufficiency Cohort) Study. Predictor Estimated glomerular filtration rate (eGFR?) computed using the Modification of Diet in Renal Disease (MDRD) Study equation, stratified by race, sex, and diabetic status. eGFR? was treated as a continuous and a categorical variable compared with the reference value of >60 mL/min/1.73 m 2 . Measurements CAC detected using computed tomography (CT) using either an Imatron C-300 electron beam computed tomography (CT) scanner or multidetector CT scanner. CAC was computed using Agatston score as a categorical variable. Analyses were performed using ordinal logistic regression. Results We found a strong and graded relationship between lower eGFR? and increasing CAC. In unadjusted models, ORs increased from 1.68 (95% CI, 1.23-2.31) for eGFR? of 50-59 mL/min/1.73 m 2 to 2.82 (95% CI, 2.06-3.85) for eGFR? 2 . Multivariable adjustment only partially attenuated the results (OR, 1.53; 95% CI, 1.07-2.20) for eGFR? 2 . Limitations Use of eGFR? rather than measured GFR?. Conclusions We showed a graded relationship between severity of CKD and CAC independent of traditional risk factors. These findings support recent guidelines that state that if vascular calcification is present, it should be considered as a complementary component to be included in the decision making required for individualizing CKD treatment.