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Assessing glomerular filtration rate (GFR) is critical for diagnosis, staging, and management of kidney disease. However, accuracy of estimated GFR (eGFR) is limited by large errors (>30% error present in >10-50% of patients), adversely impacting patient care. Errors often result from variation across populations of non-GFR determinants affecting the filtration markers used to estimate GFR. We hypothesized that combining multiple filtration markers with non-overlapping non-GFR determinants into a panel GFR could improve eGFR accuracy, extending current recognition that adding cystatin C to serum creatinine improves accuracy. Non-GFR determinants of markers can affect the accuracy of eGFR in two ways: first, increased variability in the non-GFR determinants of some filtration markers among application populations compared to the development population may result in outlying values for those markers. Second, systematic differences in the non-GFR determinants of some markers between application and development populations can lead to biased estimates in the application populations. Here, we propose and evaluate methods for estimating GFR based on multiple markers in applications with potentially higher rates of outlying predictors than in development data. We apply transfer learning to address systematic differences between application and development populations. We evaluated a panel of 8 markers (5 metabolites and 3 low molecular weight proteins) in 3,554 participants from 9 studies. Results show that contamination in two strongly predictive markers can increase imprecision by more than two-fold, but outlier identification with robust estimation can restore precision nearly fully to uncontaminated data. Furthermore, transfer learning can yield similar results with even modest training set sample size. Combining both approaches addresses both sources of error in GFR estimates. Once the laboratory challenge of developing a validated targeted assay for additional metabolites is overcome, these methods can inform the use of a panel eGFR across diverse clinical settings, ensuring accuracy despite differing non-GFR determinants., Competing Interests: Dr. Inker reports research grants to institution from the National Institute of Health/National Institute of Diabetes and Digestive and Kidney Diseases (grant 1R01DK116790), National Kidney Foundation, Chinnocks, Omeros and Reata Pharmaceuticals; consulting fees from Diamtrix; and participation on the medical advisory council for Alport Foundation and the scientific advisory board for National Kidney Foundation. Dr. Levey reports research grants to institution from the National Institute of Diabetes and Digestive and Kidney Diseases and National Kidney Foundation; royalties from UpToDate; honoraria from academic medical centers for visiting Professorships or Lectures; payment from AstraZeneca for participation on data safety/advisory board for clinical trials of Dapagliflozin. Dr. Greene reports research grants from the National Kidney Foundation, Collaborative Study Group, National Institutes of Health, and Patient-Centered Outcomes Research Institute. Dr. Haaland reports NIH R01 grant ad consulting fees from the National Kidney Foundation. Dr. Coresh reports grants from the National Institutes of Health and being scientific advisor to healthy.io. Dr. Kalil reports receiving research grant from Eurofins. Dr. Shlipak reports grants to his institution from Bayer Pharmaceuticals and National Institutes of Health – National Institute of Aging, National Institute of Diabetes and Digestive and Kidney Diseases, and National Heart Lung and Blood Institute; consulting fees from Cricket Health; honorarium from Boehringer Ingelheim, Astra Zeneca, and Bayer pharmaceuticals; payment for expert testimony from Hagens Berman International law firm; and serving as Chairman board of directors of Northern California Institute for Research and Education. Consulting fees and payments from commercial companies provided support in the form of salaries for authors but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. These commercial affiliations do not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Fino et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Pharmacologic interventions to slow chronic kidney disease progression, such as ACE-inhibitors, angiotensin receptor blockers, or sodium glucose co-transporter 2 inhibitors, often produce acute treatment effects on glomerular filtration rate (GFR) that differ from their long-term chronic treatment effects. Observational studies assessing the implications of acute effects cannot distinguish acute effects from GFR changes unrelated to the treatment. Here, we performed meta-regression analysis of multiple trials to isolate acute effects to determine their long-term implications. In 64 randomized controlled trials (RCTs), enrolling 154,045 participants, we estimated acute effects as the mean between-group difference in GFR slope from baseline to three months, effects on chronic GFR slope (starting at three months after randomization), and effects on three composite kidney endpoints defined by kidney failure (GFR 15 ml/min/1.73m 2 or less, chronic dialysis, or kidney transplantation) or sustained GFR declines of 30%, 40% or 57% decline, respectively. We used Bayesian meta-regression to relate acute effects with treatment effects on chronic slope and the composite kidney endpoints. Overall, acute effects were not associated with treatment effects on chronic slope. Acute effects were associated with the treatment effects on composite kidney outcomes such that larger negative acute effects were associated with lesser beneficial effects on the composite kidney endpoints. Associations were stronger when the kidney composite endpoints were defined by smaller thresholds of GFR decline (30% or 40%). Results were similar in a subgroup of interventions with supposedly hemodynamic effects that acutely reduce GFR. For studies with GFR 60 mL/min/1.73m 2 or under, negative acute effects were associated with larger beneficial effects on chronic GFR slope. Thus, our data from a large and diverse set of RCTs suggests that acute effects of interventions may influence the treatment effect on clinical kidney outcomes., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Black individuals are historically underrepresented in oncology clinical trials. One potential reason for this is the prevalence of kidney disease in Black individuals, utilization of estimated creatinine clearance as a surrogate for glomerular filtration rate (GFR) in oncology, and GFR-based trial eligibility criteria. We characterized the representation of racial minorities in anticancer agent pivotal trials and examined if GFR-based trial eligibility criteria impact the proportion of Black individuals in trial populations., Methods: We constructed a data repository for anticancer drugs FDA-approved from 2015 to 2019 and associated pivotal trials, from which we extracted trial population racial compositions and GFR-based trial eligibility criteria. We calculated the participation-to-incidence ratio (PIR) and participation-to-mortality ratio (PMR) for a variety of cancer sites, where PIR or PMR >1.2 and <0.8 indicate overrepresentation and underrepresentation, respectively. We evaluated the relationship between GFR eligibility cutoffs and the proportion of Black enrollees with Spearman rank correlation coefficient., Results: We assessed 24,698 patients in 74 trials. Black individuals were underrepresented in all trials (PIR ≤0.48, PMR ≤0.50). For trials with GFR-based eligibility criteria (n = 49), a lower GFR cutoff was modestly associated with a higher proportion of Black enrollees (r = -0.29, p = 0.039). This relationship was strengthened for trials that only used estimated creatinine clearance to estimate GFR (r = -0.43, p = 0.004)., Conclusions: GFR-related eligibility, and specifically the use of estimated creatinine clearance, may contribute to Black individuals being disproportionately excluded from cancer clinical trials. This highlights the need for implementation of contemporary GFR equations and other interventions to boost racial minority trial enrollment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: β 2 -Microglobulin (B2M) and β-trace protein (BTP) are novel endogenous filtration markers that may improve the accuracy of estimated glomerular filtration rate (eGFR) beyond creatinine and cystatin C (eGFR cr-cys ), but they have not been assessed in patients with cancer., Study Design: Cross-sectional analysis., Setting & Participants: Prospective cohort of 1,200 patients with active solid tumors recruited between April 2015 and September 2017., Exposure: CKD-EPI equations without race combining B2M and/or BTP with creatinine with or without cystatin C (2-, 3-, or 4-marker panel eGFR)., Outcome: Performance of equations compared with eGFR cr-cys and non-GFR determinants of serum B2M and BTP (S B2M , and S BTP , respectively). Measured GFR (mGFR) was determined using the plasma clearance of chromium-51 labeled ethylenediamine tetraacetic acid ( 51 Cr-EDTA)., Analytical Approach: Bias was defined as the median of the differences between mGFR and eGFR, and 1-P 30 was defined as the percentage of estimates that differed by more than 30% from the mGFR (1-P 30 ). Linear regression was used to assess association of clinical and laboratory variables with S B2M , and S BTP after adjustment for mGFR., Results: Mean age and mGFR were 58.8±13.2 SD years and 78.4±21.7 SD mL/min/1.73m 2 , respectively. Performance of the 3-marker and 4-marker panel equations was better than eGFR cr-cys (lesser bias and 1-P 30 ). Performance of 2-marker panel equations was as good as eGFR cr-cys (lesser bias and similar 1-P 30 ). S B2M and S BTP were not strongly influenced by cancer site., Limitations: Participants may have had better clinical performance status than the general population of patients with solid tumors., Conclusions: B2M and BTP can improve the accuracy of eGFR and may be useful as confirmatory tests in patients with solid tumors, either by inclusion in a multimarker panel equation with creatinine and cystatin C, or by substituting for cystatin C in combination with creatinine., Plain-Language Summary: The most accurate method to assess estimate kidney function is estimated glomerular filtration rate (eGFR) using creatinine and cystatin C (eGFR cr-cys ). We studied whether using β2-microglobulin (B2M) and/or β-trace protein (BTP) with creatinine with or without cystatin C (2-, 3-, or 4-marker panel eGFR) might be useful in patients with active solid tumors. The performance of the 3-marker and 4-marker panel equations was better than eGFR cr-cys . Performance of 2-marker panel equations was as good as eGFR cr-cys . We conclude that B2M and BTP can improve the accuracy of eGFR and may be useful as a confirmatory test in patients with solid tumors either by inclusion in multimarker panel equation with creatinine and cystatin C or by substituting for cystatin C in combination with creatinine., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Accurate assessment of GFR is crucial to guiding drug eligibility, dosing of systemic therapy, and minimizing the risks of both undertreatment and toxicity in patients with cancer. Up to 32% of patients with cancer have baseline CKD, and both malignancy and treatment may cause kidney injury and subsequent CKD. To date, there has been lack of guidance to standardize approaches to GFR estimation in the cancer population. In this two-part statement from the American Society of Onco-Nephrology, we present key messages for estimation of GFR in patients with cancer, including the choice of GFR estimating equation, use of race and body surface area adjustment, and anticancer drug dose-adjustment in the setting of CKD. These key messages are based on a systematic review of studies assessing GFR estimating equations using serum creatinine and cystatin C in patients with cancer, against a measured GFR comparator. The preponderance of current data involving validated GFR estimating equations involves the CKD Epidemiology Collaboration (CKD-EPI) equations, with 2508 patients in whom CKD-EPI using serum creatinine and cystatin C was assessed (eight studies) and 15,349 in whom CKD-EPI with serum creatinine was assessed (22 studies). The former may have improved performance metrics and be less susceptible to shortfalls of eGFR using serum creatinine alone. Since included studies were moderate quality or lower, the American Society of Onco-Nephrology Position Committee rated the certainty of evidence as low. Additional studies are needed to assess the accuracy of other validated eGFR equations in patients with cancer. Given the importance of accurate and timely eGFR assessment, we advocate for the use of validated GFR estimating equations incorporating both serum creatinine and cystatin C in patients with cancer. Measurement of GFR via exogenous filtration markers should be considered in patients with cancer for whom eGFR results in borderline eligibility for therapies or clinical trials., (Copyright © 2024 by the American Society of Nephrology.)

Significance Statement: New eGFR equations from Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and European Kidney Function Consortium (EKFC) using creatinine (eGFRcr), cystatin C (eGFRcys), and both (eGFRcr-cys) have sufficient accuracy for use in clinical practice, leading to uncertainty in selecting equations for implementation. The authors evaluated performance of equations in an independent population of 4050 adults and evaluated other considerations important for implementation. They found that CKD-EPI and EKFC equations are approaching convergence, with better performance of eGFRcr-cys equations in the overall group and fewer differences among race, sex, and age subgroups than eGFRcr equations. Larger differences among eGFRcr equations reflect regional population differences in creatinine, forcing a trade-off between accuracy and uniformity in global implementation of eGFRcr equations. More widespread use of cystatin C could avoid this trade-off., Background: New CKD-EPI and EKFC eGFR equations using eGFRcr, eGFRcys, and both (eGFRcr-cys) have sufficient accuracy for use in clinical practice. A better understanding of the equations, including their performance in race, sex and age subgroups, is important for selection of eGFR equations for global implementation., Methods: We evaluated performance (bias and P 30 ) of equations and methods used for equation development in an independent study population comprising 4050 adults pooled from 12 studies. The mean (SD) measured GFR was 76.4 (29.6) ml/min per 1.73 m 2 and age 57.0 (17.4) years, with 1557 (38%) women and 579 (14%) Black participants., Results: Coefficients for creatinine, cystatin C, age, and sex in the CKD-EPI and EKFC equations are similar. Performance of the eGFRcr-cys equations in the overall population (bias <±5 ml/min per 1.73 m 2 and P 30 >90%) was better than the eGFRcr or eGFRcys equations, with fewer differences among race, sex, and age subgroups. Differences in performance across subgroups reflected differences in diversity of source populations and use of variables for race and sex for equation development. Larger differences among eGFRcr equations reflected regional population differences in non-GFR determinants of creatinine., Conclusion: CKD-EPI and EKFC equations are approaching convergence. It is not possible to maximize both accuracy and uniformity in selecting one of the currently available eGFRcr equations for implementation across regions. Decisions should consider methods for equation development in addition to performance. Wider use of cystatin C with creatinine could maximize both accuracy and uniformity of GFR estimation using currently available equations., (Copyright © 2023 by the American Society of Nephrology.)

Importance: Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US., Objective: To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes., Design, Setting, and Participants: Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021., Exposures: The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR)., Main Outcomes and Measures: The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses., Results: Within the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with higher risk for each of the 10 adverse outcomes, including those in the mildest categories of chronic kidney disease. For example, among people with a UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m2 based on creatinine alone was associated with significantly higher hospitalization rates compared with an eGFR of 90 to 104 mL/min/1.73 m2 (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.3]; 161 vs 79 events per 1000 person-years; excess absolute risk, 22 events per 1000 person-years [95% CI, 19-25 events per 1000 person-years])., Conclusions and Relevance: In this retrospective analysis of 114 cohorts, lower eGFR based on creatinine alone, lower eGFR based on creatinine and cystatin C, and more severe UACR were each associated with increased rates of 10 adverse outcomes, including adverse kidney outcomes, cardiovascular diseases, and hospitalizations.

Importance: At a given estimated glomerular filtration rate (eGFR), individuals who are Black have higher rates of mortality and kidney failure with replacement therapy (KFRT) compared with those who are non-Black. Whether the recently adopted eGFR equations without race preserve racial differences in risk of mortality and KFRT at a given eGFR is unknown., Objective: To assess whether eGFR equations with and without race and cystatin C document racial differences in risk of KFRT and mortality in populations including Black and non-Black participants., Design, Setting, and Participants: Retrospective individual-level data analysis of 62 011 participants from 5 general population and 3 chronic kidney disease (CKD) US-based cohorts with serum creatinine, cystatin C, and follow-up for KFRT and mortality from 1988 to 2018., Exposures: Chronic Kidney Disease Epidemiology Collaboration equation with serum creatinine (eGFRcr with and without race), cystatin C (eGFRcys without race), or both markers (eGFRcr-cys without race)., Main Outcomes and Measures: The prevalence of decreased eGFR at baseline and hazard ratios of KFRT and mortality in Black vs non-Black participants were calculated, adjusted for age and sex. Analyses were performed within each cohort and with random-effect meta-analyses of the models., Results: Among 62 011 participants (20 773 Black and 41 238 non-Black; mean age, 63 years; 53% women), the prevalence ratio (95% CI; percent prevalences) of eGFR less than 60 mL/min/1.73 m2 comparing Black with non-Black participants was 0.98 (95% CI, 0.93-1.03; 11% vs 12%) for eGFRcr with race, 0.95 (95% CI, 0.91-0.98; 17% vs 18%) for eGFRcys, and 1.2 (95% CI, 1.2-1.3; 13% vs 11%) for eGFRcr-cys but was 1.8 (95% CI, 1.7-1.8; 15% vs 9%) for eGFRcr without race. During a mean follow-up of 13 years, 8% and 4% of Black and non-Black participants experienced KFRT and 34% and 39% died, respectively. Decreased eGFR was associated with significantly greater risk of both outcomes for all equations. At an eGFR of 60 mL/min/1.73 m2, the hazard ratios for KFRT comparing Black with non-Black participants were 2.8 (95% CI, 1.6-4.9) for eGFRcr with race, 3.0 (95% CI, 1.5-5.8) for eGFRcys, and 2.8 (95% CI, 1.4-5.4) for eGFRcr-cys vs 1.3 (95% CI, 0.8-2.1) for eGFRcr without race. The 5-year absolute risk differences for KFRT comparing Black with non-Black participants were 1.4% (95% CI, 0.2%-2.6%) for eGFRcr with race, 1.1% (95% CI, 0.2%-1.9%) for eGFRcys, and 1.3% (95% CI, 0%-2.6%) for eGFRcr-cys vs 0.37% (95% CI, -0.32% to 1.05%) for eGFRcr without race. Similar patterns were observed for mortality., Conclusions and Relevance: In this retrospective analysis of 8 US cohorts including Black and non-Black individuals, the eGFR equation without race that included creatinine and cystatin C, but not the eGFR equation without race that included creatinine without cystatin C, demonstrated racial differences in the risk of KFRT and mortality throughout the range of eGFR. The eGFRcr-cys equation may be preferable to the eGFRcr equation without race for assessing racial differences in the risk of KFRT and mortality associated with low eGFR.

Background: Acute changes in GFR can occur after initiation of interventions targeting progression of CKD. These acute changes complicate the interpretation of long-term treatment effects., Methods: To assess the magnitude and consistency of acute effects in randomized clinical trials and explore factors that might affect them, we performed a meta-analysis of 53 randomized clinical trials for CKD progression, enrolling 56,413 participants with at least one estimated GFR measurement by 6 months after randomization. We defined acute treatment effects as the mean difference in GFR slope from baseline to 3 months between randomized groups. We performed univariable and multivariable metaregression to assess the effect of intervention type, disease state, baseline GFR, and albuminuria on the magnitude of acute effects., Results: The mean acute effect across all studies was -0.21 ml/min per 1.73 m 2 (95% confidence interval, -0.63 to 0.22) over 3 months, with substantial heterogeneity across interventions (95% coverage interval across studies, -2.50 to +2.08 ml/min per 1.73 m 2 ). We observed negative average acute effects in renin angiotensin system blockade, BP lowering, and sodium-glucose cotransporter 2 inhibitor trials, and positive acute effects in trials of immunosuppressive agents. Larger negative acute effects were observed in trials with a higher mean baseline GFR., Conclusion: The magnitude and consistency of acute GFR effects vary across different interventions, and are larger at higher baseline GFR. Understanding the nature and magnitude of acute effects can help inform the optimal design of randomized clinical trials evaluating disease progression in CKD., (Copyright © 2022 by the American Society of Nephrology.)

Background: Current equations for estimated glomerular filtration rate (eGFR) that use serum creatinine or cystatin C incorporate age, sex, and race to estimate measured GFR. However, race in eGFR equations is a social and not a biologic construct., Methods: We developed new eGFR equations without race using data from two development data sets: 10 studies (8254 participants, 31.5% Black) for serum creatinine and 13 studies (5352 participants, 39.7% Black) for both serum creatinine and cystatin C. In a validation data set of 12 studies (4050 participants, 14.3% Black), we compared the accuracy of new eGFR equations to measured GFR. We projected the prevalence of chronic kidney disease (CKD) and GFR stages in a sample of U.S. adults, using current and new equations., Results: In the validation data set, the current creatinine equation that uses age, sex, and race overestimated measured GFR in Blacks (median, 3.7 ml per minute per 1.73 m 2 of body-surface area; 95% confidence interval [CI], 1.8 to 5.4) and to a lesser degree in non-Blacks (median, 0.5 ml per minute per 1.73 m 2 ; 95% CI, 0.0 to 0.9). When the adjustment for Black race was omitted from the current eGFR equation, measured GFR in Blacks was underestimated (median, 7.1 ml per minute per 1.73 m 2 ; 95% CI, 5.9 to 8.8). A new equation using age and sex and omitting race underestimated measured GFR in Blacks (median, 3.6 ml per minute per 1.73 m 2 ; 95% CI, 1.8 to 5.5) and overestimated measured GFR in non-Blacks (median, 3.9 ml per minute per 1.73 m 2 ; 95% CI, 3.4 to 4.4). For all equations, 85% or more of the eGFRs for Blacks and non-Blacks were within 30% of measured GFR. New creatinine-cystatin C equations without race were more accurate than new creatinine equations, with smaller differences between race groups. As compared with the current creatinine equation, the new creatinine equations, but not the new creatinine-cystatin C equations, increased population estimates of CKD prevalence among Blacks and yielded similar or lower prevalence among non-Blacks., Conclusions: New eGFR equations that incorporate creatinine and cystatin C but omit race are more accurate and led to smaller differences between Black participants and non-Black participants than new equations without race with either creatinine or cystatin C alone. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.)., (Copyright © 2021 Massachusetts Medical Society.)

Rationale & Objective: An early change in proteinuria is considered a reasonably likely surrogate end point in immunoglobulin A nephropathy (IgAN) and can be used as a basis for accelerated approval of therapies, with verification in a postmarketing confirmatory trial. Glomerular filtration rate (GFR) slope is a recently validated surrogate end point for chronic kidney disease progression and may be considered as the end point used for verification. We undertook a meta-analysis of clinical trials in IgAN to compare treatment effects on change in proteinuria versus change in estimated GFR (eGFR) slope., Study Design: Individual patient-level meta-analysis., Setting & Study Populations: Individual data of 1,037 patients from 12 randomized trials., Selection Criteria for Studies: Randomized trials of IgAN with proteinuria measurements at baseline and 6 (range, 2.5-14) months and at least a further 1 year of follow-up for the clinical outcome., Analytical Approach: For each trial, we estimated the treatment effects on proteinuria and on the eGFR slope, computed as the total slope starting at baseline or the chronic slope starting 3 months after randomization. We used a Bayesian mixed-effects analysis to relate the treatment effects on proteinuria to effects on GFR slope across these studies and developed a prediction model for the treatment effect on the GFR slope based on the effect on proteinuria., Results: Across all studies, treatment effects on proteinuria accurately predicted treatment effects on the total slope at 3 years (median R 2  = 0.88; 95% Bayesian credible interval [BCI], 0.06-1) and on the chronic slope (R 2  = 0.98; 95% BCI, 0.29-1). For future trials, an observed treatment effect of approximately 30% reduction in proteinuria would confer probabilities of at least 90% for nonzero treatment benefits on the total and chronic slopes of eGFR. We obtained similar results for proteinuria at 9 and 12 months and total slope at 2 years., Limitations: Study population restricted to 12 trials of small sample size, leading to wide BCIs. There was heterogeneity among trials with respect to study design and interventions., Conclusions: These results provide new evidence supporting that early reduction in proteinuria can be used as a surrogate end point for studies of chronic kidney disease progression in IgAN., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

For almost 2 decades, equations that use serum creatinine, age, sex, and race to estimate glomerular filtration rate (GFR) have included "race" as Black or non-Black. Given considerable evidence of disparities in health and health care delivery in African American communities, some regard keeping a race term in GFR equations as a practice that differentially influences access to care and kidney transplantation. Others assert that race captures important non-GFR determinants of serum creatinine and its removal from the calculation may perpetuate other disparities. The National Kidney Foundation (NKF) and American Society of Nephrology (ASN) established a task force in 2020 to reassess the inclusion of race in the estimation of GFR in the United States and its implications for diagnosis and subsequent management of patients with, or at risk for, kidney diseases. This interim report details the process, initial assessment of evidence, and values defined regarding the use of race to estimate GFR. We organized activities in phases: (1) clarify the problem and examine evidence, (2) evaluate different approaches to address use of race in GFR estimation, and (3) make recommendations. In phase 1, we constructed statements about the evidence and defined values regarding equity and disparities; race and racism; GFR measurement, estimation, and equation performance; laboratory standardization; and patient perspectives. We also identified several approaches to estimate GFR and a set of attributes to evaluate these approaches. Building on evidence and values, the attributes of alternative approaches to estimate GFR will be evaluated in the next phases and recommendations will be made., (Copyright © 2021 National KidneyFoundation, Inc and the American Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Rationale and Objective: Glomerular filtration rate (GFR) estimation based on creatinine and cystatin C (eGFR cr-cys ) is more accurate than estimated GFR (eGFR) based on creatinine or cystatin C alone (eGFR cr or eGFR cys , respectively), but the inclusion of creatinine in eGFR cr-cys requires specification of a person's race. β 2 -Microglobulin (B2M) and β-trace protein (BTP) are alternative filtration markers that appear to be less influenced by race than creatinine is., Study Design: Study of diagnostic test accuracy., Setting and Participants: Development in a pooled population of 7 studies with 5,017 participants with and without chronic kidney disease. External validation in a pooled population of 7 other studies with 2,245 participants., Tests Compared: Panel eGFR using B2M and BTP in addition to cystatin C (3-marker panel) or creatinine and cystatin C (4-marker panel) with and without age and sex or race., Outcomes: GFR measured as the urinary clearance of iothalamate, plasma clearance of iohexol, or plasma clearance of [ 51 Cr]EDTA., Results: Mean measured GFRs were 58.1 and 83.2 mL/min/1.73 m 2 , and the proportions of Black participants were 38.6% and 24.0%, in the development and validation populations, respectively. In development, addition of age and sex improved the performance of all equations compared with equations without age and sex, but addition of race did not further improve the performance. In validation, the 4-marker panels were more accurate than the 3-marker panels (P < 0.001). The 3-marker panel without race was more accurate than eGFR cys (percentage of estimates greater than 30% different from measured GFR [1 - P 30 ] of 15.6% vs 17.4%; P = 0.01), and the 4-marker panel without race was as accurate as eGFR cr-cys (1 - P 30 of 8.6% vs 9.4%; P = 0.2). Results were generally consistent across subgroups., Limitations: No representation of participants with severe comorbid illness and from geographic areas outside of North America and Europe., Conclusions: The 4-marker panel eGFR is as accurate as eGFR cr-cys without requiring specification of race. A more accurate race-free eGFR could be an important advance., (Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

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., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose of Review: There is a paucity of therapies for chronic kidney disease (CKD), in part because of the slow nature of the disease which poses challenges in selection of endpoints in randomized controlled trials (RCT). There is increasing evidence for the use of glomerular filtration rate (GFR)-based endpoints either as percentage decline using time-to-event analyses, or as difference in slope between treatment arms. We reviewed the rationale for using surrogate endpoints and optimal methods for their evaluation prior to their use and evidence for GFR-based endpoints and particularly GFR slope as validated surrogate endpoints and considerations for their use in RCTs., Recent Findings: In an individual patient meta-analysis of 47 studies (60 620 participants), treatment effects on the clinical endpoint were accurately predicted from treatment effects on 3-year total slope [median R = 0.97 (95% Bayesian confidence interval (BCI), 0.78-1.00] and on the chronic slope [R = 0.96 (95% BCI, 0.63-1.00)]. In a simulation study, GFR slope substantially reduced the required sample size and duration of follow-up compared to the clinical endpoint given high baseline GFR and absence of acute treatment effect. In the presence of acute effect, results were more complicated., Summary: GFR decline is accepted, and GFR slope is being considered, by regulatory authorities as a validated surrogate endpoint for CKD RCTs.

Assessment of GFR is central to clinical practice, research, and public health. Current Kidney Disease Improving Global Outcomes guidelines recommend measurement of serum creatinine to estimate GFR as the initial step in GFR evaluation. Serum creatinine is influenced by creatinine metabolism as well as GFR; hence, all equations to estimate GFR from serum creatinine include surrogates for muscle mass, such as age, sex, race, height, or weight. The guideline-recommended equation in adults (the 2009 Chronic Kidney Disease Epidemiology Collaboration creatinine equation) includes a term for race (specified as black versus nonblack), which improves the accuracy of GFR estimation by accounting for differences in non-GFR determinants of serum creatinine by race in the study populations used to develop the equation. In that study, blacks had a 16% higher average measured GFR compared with nonblacks with the same age, sex, and serum creatinine. The reasons for this difference are only partly understood, and the use of race in GFR estimation has limitations. Some have proposed eliminating the race coefficient, but this would induce a systematic underestimation of measured GFR in blacks, with potential unintended consequences at the individual and population levels. We propose a more cautious approach that maintains and improves accuracy of GFR estimates and avoids disadvantaging any racial group. We suggest full disclosure of use of race in GFR estimation, accommodation of those who decline to identify their race, and shared decision making between health care providers and patients. We also suggest mindful use of cystatin C as a confirmatory test as well as clearance measurements. It would be preferable to avoid specification of race in GFR estimation if there was a superior, evidence-based substitute. The goal of future research should be to develop more accurate methods for GFR estimation that do not require use of race or other demographic characteristics., (Copyright © 2020 by the American Society of Nephrology.)

Background: Population mean GFR is lower in older age, but it is unknown whether healthy aging is associated with preserved rather than lower GFR in some individuals., Methods: We investigated the cross-sectional association between measured GFR, age, and health in persons aged 50-97 years in the general population through a meta-analysis of iohexol clearance measurements in three large European population-based cohorts. We defined a healthy person as having no major chronic disease or risk factors for CKD and all others as unhealthy. We used a generalized additive model to study GFR distribution by age according to health status., Results: There were 935 (22%) GFR measurements in persons who were healthy and 3274 (78%) in persons who were unhealthy. The mean GFR was lower in older age by -0.72 ml/min per 1.73 m 2 per year (95% confidence interval [95% CI], -0.96 to -0.48) for men who were healthy versus -1.03 ml/min per 1.73 m 2 per year (95% CI, -1.25 to -0.80) for men who were unhealthy, and by -0.92 ml/min per 1.73 m 2 per year (95% CI, -1.14 to -0.70) for women who were healthy versus -1.22 ml/min per 1.73 m 2 per year (95% CI, -1.43 to -1.02) for women who were unhealthy. For healthy and unhealthy people of both sexes, both the 97.5th and 2.5th GFR percentiles exhibited a negative linear association with age., Conclusions: Healthy aging is associated with a higher mean GFR compared with unhealthy aging. However, both the mean and 97.5 percentiles of the GFR distribution are lower in older persons who are healthy than in middle-aged persons who are healthy. This suggests that healthy aging is not associated with preserved GFR in old age., (Copyright © 2020 by the American Society of Nephrology.)

Importance: It is uncertain whether and when angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) treatment should be discontinued in individuals with low estimated glomerular filtration rate (eGFR)., Objective: To investigate the association of ACE-I or ARB therapy discontinuation after eGFR decreases to below 30 mL/min/1.73 m2 with the risk of mortality, major adverse cardiovascular events (MACE), and end-stage kidney disease (ESKD)., Design, Setting, and Participants: This retrospective, propensity score-matched cohort study included 3909 patients from an integrated health care system that served rural areas of central and northeastern Pennsylvania. Patients who initiated ACE-I or ARB therapy from January 1, 2004, to December 31, 2018, and had an eGFR decrease to below 30 mL/min/1.73 m2 during therapy were enrolled, with follow-up until January 25, 2019., Exposures: Individuals were classified based on whether they discontinued ACE-I or ARB therapy within 6 months after an eGFR decrease to below 30 mL/min/1.73 m2., Main Outcomes and Measures: The association between ACE-I or ARB therapy discontinuation and mortality during the subsequent 5 years was assessed using multivariable Cox proportional hazards regression models, adjusting for patient characteristics at the time of the eGFR decrease in a propensity score-matched sample. Secondary outcomes included MACE and ESKD., Results: Of the 3909 individuals receiving ACE-I or ARB treatment who experienced an eGFR decrease to below 30 mL/min/1.73 m2 (2406 [61.6%] female; mean [SD] age, 73.7 [12.6] years), 1235 discontinued ACE-I or ARB therapy within 6 months after the eGFR decrease and 2674 did not discontinue therapy. A total of 434 patients (35.1%) who discontinued ACE-I or ARB therapy and 786 (29.4%) who did not discontinue therapy died during a median follow-up of 2.9 years (interquartile range, 1.3-5.0 years). In the propensity score-matched sample of 2410 individuals, ACE-I or ARB therapy discontinuation was associated with a higher risk of mortality (hazard ratio [HR], 1.39; 95% CI, 1.20-1.60]) and MACE (HR, 1.37; 95% CI, 1.20-1.56), but no statistically significant difference in the risk of ESKD was found (HR, 1.19; 95% CI, 0.86-1.65)., Conclusions and Relevance: The findings suggest that continuing ACE-I or ARB therapy in patients with declining kidney function may be associated with cardiovascular benefit without excessive harm of ESKD.

Evaluation of glomerular filtration rate (GFR) is central to the assessment of kidney function in medical practice, research and public health. Measured GFR (mGFR) remains the reference standard, but the past 20 years have seen major advances in estimated GFR (eGFR). Both eGFR and mGFR are associated with error compared with true GFR. eGFR is now recommended by clinical practice guidelines, regulatory agencies and public health agencies for the initial evaluation of GFR, with measured GFR (mGFR) typically considered an important confirmatory test, depending on how accurate the assessment of GFR needs to be for application to the clinical, research or public health setting. Our approach is to use initial and confirmatory tests as needed to develop a final assessment of true GFR. We suggest that GFR evaluation might be improved by more complete implementation of current recommendations and by further research to improve the accuracy of mGFR and eGFR.

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 R 2 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/1.73m 2 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., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Most opioids undergo kidney excretion. The goal of this study was to evaluate opioid-associated risks of death and hospitalization across the range of eGFR., Design, Setting, Participants, & Measurements: The study population included adult primary care patients in Geisinger Health (Danville, PA) between 2008 and 2017. People receiving their first opioid prescription were propensity matched to people receiving NSAIDS (and, in sensitivity analysis, gabapentinoids) and the risk of death and hospitalization were compared, classifying opioid medication exposure as time-varying daily oral morphine milligram equivalents (MMEs) across time-varying eGFR., Results: The propensity-matched cohort included 46,246 patients prescribed either opioids or NSAIDs between 2008 and 2017 (mean [SD] age, 54 [16] years; 56% female; 3% of black race). Prescriptions for 1-59 and ≥60 MMEs were associated with higher risk of death (HR, 1.70; 95% CI, 1.41 to 2.05 for 1-59 MMEs; HR, 2.25; 95% CI, 1.82 to 2.79 for ≥60 MMEs) and hospitalization (HR, 1.38; 95% CI, 1.30 to 1.46 for 1-59 MMEs; HR, 1.68; 95% CI, 1.56 to 1.81 for ≥60 MMEs) compared with NSAID prescriptions, when evaluated at eGFR 80 ml/min per 1.73 m 2 . The relative risk of death associated with ≥60 MMEs was higher at lower GFR ( e.g. , eGFR, 40 ml/min per 1.73 m 2 ; HR, 3.94; 95% CI, 2.70 to 5.75; P for interaction, 0.01). When gabapentinoids were used as the comparison medication, only ≥60 MMEs were significantly associated with higher risk of death (HR, 2.72; 95% CI, 1.71 to 4.34), although both 1-59 and ≥60 MMEs were associated with risk of hospitalization (HR, 1.22; 95% CI, 1.04 to 1.43 for 1-59 MMEs; HR, 1.54; 95% CI, 1.28 to 1.86 for ≥60 MMEs)., Conclusions: The receipt of prescription opioids was associated with a higher risk of death and hospitalization compared with other pain medications, particularly with higher doses and at lower eGFR., (Copyright © 2019 by the American Society of Nephrology.)

Background: Randomized trials of CKD treatments traditionally use clinical events late in CKD progression as end points. This requires costly studies with large sample sizes and long follow-up. Surrogate end points like GFR slope may speed up the evaluation of new therapies by enabling smaller studies with shorter follow-up., Methods: We used statistical simulations to identify trial situations where GFR slope provides increased statistical power compared with the clinical end point of doubling of serum creatinine or kidney failure. We simulated GFR trajectories based on data from 47 randomized treatment comparisons. We evaluated the sample size required for adequate statistical power based on GFR slopes calculated from baseline and from 3 months follow-up., Results: In most scenarios where the treatment has no acute effect, analyses of GFR slope provided similar or improved statistical power compared with the clinical end point, often allowing investigators to shorten follow-up by at least half while simultaneously reducing sample size. When patients' GFRs are higher, the power advantages of GFR slope increase. However, acute treatment effects within several months of randomization can increase the risk of false conclusions about therapies based on GFR slope. Care is needed in study design and analysis to avoid such false conclusions., Conclusions: Use of GFR slope can substantially increase statistical power compared with the clinical end point, particularly when baseline GFR is high and there is no acute effect. The optimum GFR-based end point depends on multiple factors including the rate of GFR decline, type of treatment effect and study design., (Copyright © 2019 by the American Society of Nephrology.)

Background: Decline in eGFR is a biologically plausible surrogate end point for the progression of CKD in clinical trials. However, it must first be tested to ensure strong associations with clinical outcomes in diverse populations, including patients with higher eGFR., Methods: To investigate the association between 1-, 2-, and 3-year changes in eGFR (slope) with clinical outcomes over the long term, we conducted a random effects meta-analysis of 3,758,551 participants with baseline eGFR≥60 ml/min per 1.73 m 2 and 122,664 participants with eGFR<60 ml/min per 1.73 m 2 from 14 cohorts followed for an average of 4.2 years., Results: Slower eGFR decline by 0.75 ml/min per 1.73 m 2 per year over 2 years was associated with lower risk of ESKD in participants with baseline eGFR≥60 ml/min per 1.73 m 2 (adjusted hazard ratio, 0.70; 95% CI, 0.68 to 0.72) and eGFR<60 ml/min per 1.73 m 2 (0.71; 95% CI, 0.68 to 0.74). The relationship was stronger with 3-year slope. For a rapidly progressing population with predicted 5-year risk of ESKD of 8.3%, an intervention that reduced eGFR decline by 0.75 ml/min per 1.73 m 2 per year over 2 years would reduce the ESKD risk by 1.6%. For a hypothetical low-risk population with a predicted 5-year ESKD risk of 0.58%, the same intervention would reduce the risk by only 0.13%., Conclusions: Slower decline in eGFR was associated with lower risk of subsequent ESKD, even in participants with eGFR≥60 ml/min per 1.73 m 2 , but those with the highest risk would be expected to benefit the most., (Copyright © 2019 by the American Society of Nephrology.)

Background: Surrogate end points are needed to assess whether treatments are effective in the early stages of CKD. GFR decline leads to kidney failure, but regulators have not approved using differences in the change in GFR from the beginning to the end of a randomized, controlled trial as an end point in CKD because it is not clear whether small changes in the GFR slope will translate to clinical benefits., Methods: To assess the use of GFR slope as a surrogate end point for CKD progression, we performed a meta-analysis of 47 RCTs that tested 12 interventions in 60,620 subjects. We estimated treatment effects on GFR slope (mean difference in GFR slope between the randomized groups), for the total slope starting at baseline, chronic slope starting at 3 months after randomization, and on the clinical end point (doubling of serum creatinine, GFR<15 ml/min per 1.73 m 2 , or ESKD) for each study. We used Bayesian mixed-effects analyses to describe the association of treatment effects on GFR slope with the clinical end point and to test how well the GFR slope predicts a treatment's effect on the clinical end point., Results: Across all studies, the treatment effect on 3-year total GFR slope (median R 2 =0.97; 95% Bayesian credible interval [BCI], 0.78 to 1.00) and on the chronic slope ( R 2 0.96; 95% BCI, 0.63 to 1.00) accurately predicted treatment effects on the clinical end point. With a sufficient sample size, a treatment effect of 0.75 ml/min per 1.73 m 2 /yr or greater on total slope over 3 years or chronic slope predicts a clinical benefit on CKD progress with at least 96% probability., Conclusions: With large enough sample sizes, GFR slope may be a viable surrogate for clinical end points in CKD RCTs., (Copyright © 2019 by the American Society of Nephrology.)

Background: Estimation of glomerular filtration rate (GFR) using estimated glomerular filtration rate creatinine (eGFRcr) is central to clinical practice but has limitations. We tested the hypothesis that serum metabolomic profiling can identify novel markers that in combination can provide more accurate GFR estimates., Methods: We performed a cross-sectional study of 200 African American Study of Kidney Disease and Hypertension (AASK) and 265 Multi-Ethnic Study of Atherosclerosis (MESA) participants with measured GFR (mGFR). Untargeted gas chromatography/dual mass spectrometry- and liquid chromatography/dual mass spectrometry-based quantification was followed by the development of targeted assays for 15 metabolites. On the log scale, GFR was estimated from single- and multiple-metabolite panels and compared with eGFR using the Chronic Kidney Disease Epidemiology equations with creatinine and/or cystatin C using established metrics, including the proportion of errors >30% of mGFR (1-P30), before and after bias correction., Results: Of untargeted metabolites in the AASK and MESA, 283 of 780 (36%) and 387 of 1447 (27%), respectively, were significantly correlated (P ≤ 0.001) with mGFR. A targeted metabolite panel eGFR developed in the AASK and validated in the MESA was more accurate (1-P30 3.7 and 1.9%, respectively) than eGFRcr [11.2 and 18.5%, respectively (P < 0.001 for both)] and estimating GFR using cystatin C (eGFRcys) [10.6% (P = 0.02) and 9.1% (P < 0.05), respectively] but was not consistently better than eGFR using both creatinine and cystatin C [3.7% (P > 0.05) and 9.1% (P < 0.05), respectively]. A panel excluding creatinine and demographics still performed well [1-P30 6.4% (P = 0.11) and 3.4% (P < 0.001) in the AASK and MESA] versus eGFRcr., Conclusions: Multimetabolite panels can enable accurate GFR estimation. Metabolomic equations, preferably excluding creatinine and demographic characteristics, should be tested for robustness and generalizability as a potential confirmatory test when eGFRcr is unreliable., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background and Objectives: Data are scarce on blood metabolite associations with proteinuria, a strong risk factor for adverse kidney outcomes. We sought to investigate associations of proteinuria with serum metabolites identified using untargeted profiling in populations with CKD., Design, Setting, Participants, & Measurements: Using stored serum samples from the African American Study of Kidney Disease and Hypertension (AASK; n =962) and the Modification of Diet in Renal Disease (MDRD) study ( n =620), two rigorously conducted clinical trials with per-protocol measures of 24-hour proteinuria and GFR, we evaluated cross-sectional associations between urine protein-to-creatinine ratio and 637 known, nondrug metabolites, adjusting for key clinical covariables. Metabolites significantly associated with proteinuria were tested for associations with CKD progression., Results: In the AASK and the MDRD study, respectively, the median urine protein-to-creatinine ratio was 80 (interquartile range [IQR], 28-359) and 188 (IQR, 54-894) mg/g, mean age was 56 and 52 years, 39% and 38% were women, 100% and 7% were black, and median measured GFR was 48 (IQR, 35-57) and 28 (IQR, 18-39) ml/min per 1.73 m 2 . Linear regression identified 66 serum metabolites associated with proteinuria in one or both studies after Bonferroni correction ( P <7.8×10 -5 ), 58 of which were statistically significant in a meta-analysis ( P <7.8×10 -4 ). The metabolites with the lowest P values ( P <10 -27 ) were 4-hydroxychlorthalonil and 1,5-anhydroglucitol; all six quantified metabolites in the phosphatidylethanolamine pathway were also significant. Of the 58 metabolites associated with proteinuria, four were associated with ESKD in both the AASK and the MDRD study., Conclusions: We identified 58 serum metabolites with cross-sectional associations with proteinuria, some of which were also associated with CKD progression., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019&#95;02&#95;07&#95;CJASNPodcast&#95;19&#95;03&#95;.mp3., (Copyright © 2019 by the American Society of Nephrology.)

Background: Clinical practice guidelines recommend estimation of glomerular filtration rate (eGFR) using validated equations based on serum creatinine (eGFRcr), cystatin C (eGFRcys), or both (eGFRcr-cys). However, when compared with the measured GFR (mGFR), only eGFRcr-cys meets recommended performance standards. Our goal was to develop a more accurate eGFR method using a panel of metabolites without creatinine, cystatin C, or demographic variables., Methods: An ultra-performance liquid chromatography-tandem mass spectrometry assay for acetylthreonine, phenylacetylglutamine, pseudouridine, and tryptophan was developed, and a 20-day, multiinstrument analytical validation was conducted. The assay was tested in 2424 participants with mGFR data from 4 independent research studies. A new GFR equation (eGFRmet) was developed in a random subset (n = 1615) and evaluated in the remaining participants (n = 809). Performance was assessed as the frequency of large errors [estimates that differed from mGFR by at least 30% (1 - P 30 ); goal <10%]., Results: The assay had a mean imprecision (≤10% intraassay, ≤6.9% interassay), linearity over the quantitative range ( r 2 > 0.98), and analyte recovery (98.5%-113%). There was no carryover, no interferences observed, and analyte stability was established. In addition, 1 - P 30 in the validation set for eGFRmet (10.0%) was more accurate than eGFRcr (13.1%) and eGFRcys (12.0%) but not eGFRcr-cys (8.7%). Combining metabolites, creatinine, cystatin C, and demographics led to the most accurate equation (7.0%). Neither equation had substantial variation among population subgroups., Conclusions: The new eGFRmet equation could serve as a confirmatory test for GFR estimation., (© 2018 American Association for Clinical Chemistry.)

Rationale & Objective: Chronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework., Study Design: Cross-sectional individual participant-level analyses in a global consortium., Setting & Study Populations: 17 CKD and 38 general population and high-risk cohorts., Selection Criteria for Studies: Cohorts in the CKD Prognosis Consortium with data for eGFR and albuminuria, as well as a measurement of hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, or calcium, or hypertension., Data Extraction: Data were obtained and analyzed between July 2015 and January 2018., Analytical Approach: We modeled the association of eGFR and albuminuria with hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, and calcium values using linear regression and with hypertension and categorical definitions of each abnormality using logistic regression. Results were pooled using random-effects meta-analyses., Results: The CKD cohorts (n=254,666 participants) were 27% women and 10% black, with a mean age of 69 (SD, 12) years. The general population/high-risk cohorts (n=1,758,334) were 50% women and 2% black, with a mean age of 50 (16) years. There was a strong graded association between lower eGFR and all laboratory result abnormalities (ORs ranging from 3.27 [95% CI, 2.68-3.97] to 8.91 [95% CI, 7.22-10.99] comparing eGFRs of 15 to 29 with eGFRs of 45 to 59mL/min/1.73m 2 ), whereas albuminuria had equivocal or weak associations with abnormalities (ORs ranging from 0.77 [95% CI, 0.60-0.99] to 1.92 [95% CI, 1.65-2.24] comparing urinary albumin-creatinine ratio > 300 vs < 30mg/g)., Limitations: Variations in study era, health care delivery system, typical diet, and laboratory assays., Conclusions: Lower eGFR was strongly associated with higher odds of multiple laboratory result abnormalities. Knowledge of risk associations might help guide management in the heterogeneous group of patients with CKD., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the frequency of, risk factors for, and outcomes after elevated levels of vancomycin., Patients and Methods: We identified hospitalizations among 21,285 individuals in which intravenous vancomycin was given between August 29, 2007, and October 10, 2014. We investigated frequency and risk factors for elevated vancomycin levels (trough levels >30 mg/L) as well as associations with subsequent acute kidney injury (AKI), length of stay, and in-hospital mortality., Results: Among the 21,285 patients, the mean age was 62.9 years, and 10,478 (49.2%) were female. Trough levels of vancomycin were checked in 7422 patients, and 755 elevated levels were detected. Compared with patients with trough levels checked but no elevated levels found, those with elevated levels had longer duration of vancomycin therapy (median, 6.0 days vs 3.4 days; P<.001) and slightly higher doses (mean, 1.72 g vs 1.58 g; P<.001). Patients with higher body mass index or lower estimated glomerular filtration rate had more elevated levels. In propensity-matched analyses, patients had higher risk of incident AKI after elevated levels compared with patients without elevated levels (hazard ratio, 1.55; 95% CI, 1.09-2.20; P=.02), as well as longer subsequent length of stay (relative risk, 1.14; 95% CI, 1.02-1.28; P=.03) but similar in-hospital mortality., Conclusion: In this study, elevated vancomycin levels were common, particularly in patients with higher body mass index and lower estimated glomerular filtration rate, and were associated with greater subsequent AKI and length of stay., (Copyright © 2018 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Chronic kidney disease is an increasing health burden. Estimating equations using serum concentrations of creatinine and cystatin C facilitate the assessment of kidney function as reflected in estimated glomerular filtration rate (eGFR). Reduced eGFR is associated with increased risk for numerous adverse outcomes and is an important aspect in many clinical situations. However, current equations are suboptimal in some clinical settings. The review focuses on approaches to improve the estimation of GFR and aims to familiarize the reader with the underlying methodological hypotheses how new markers could contribute to improve the overall performance of estimating equations., Recent Findings: Low molecular weight proteins such as β-trace-protein and β-2-microglobulin, as well as newly discovered metabolites, show promise as new filtration markers, as they might be beneficial in populations in which creatinine or cystatin C are inaccurate. We propose that the combination of multiple novel markers, alone or in combination with creatinine, cystatin C or demographics, can potentially improve GFR estimation. For special populations such as dialysis patients, separate equations have been developed to estimate residual kidney function., Summary: Current GFR estimating equations are an essential part of routine clinical practice but have limitations. The use of multiple markers combined in a single equation appears to be the most promising approach. Future research is required to validate proposed equations in diverse populations.

Rationale & Objective: Determining whether a change in estimated glomerular filtration rate (eGFR) or albuminuria is clinically significant requires knowledge of short-term within-person variability of the measurements, which few studies have addressed in the setting of chronic kidney disease., Study Design: Cross-sectional study with multiple collections over less than 4 weeks., Setting & Participants: Clinically stable outpatients with chronic kidney disease (N=50; mean age, 56.8 years; median eGFR, 40mL/min/1.73m 2 ; median urinary albumin-creatinine ratio (UACR), 173mg/g)., Exposure: Repeat measurements from serially collected samples across 3 study visits., Outcomes: Measurements of urine albumin concentration (UAC), UACR, and plasma creatinine, cystatin C, β 2 -microglobulin (B2M), and beta trace protein (BTP)., Analytical Approach: We calculated within-person coefficients of variation (CV w ) values and corresponding reference change positive and negative (RCV pos and RCV neg ) values using log-transformed measurements., Results: Median CV w (RCV pos ; RCV neg ) values of filtration markers were 5.4% (+16%; -14%) for serum creatinine, 4.1% (+12%; -11%) for cystatin C, 7.4% (+23%; -18%) for BTP, and 5.6% (+17%; -14%) for B2M. Results for albuminuria were 33.2% (+145%; -59%) for first-morning UAC, 50.6% (+276%; -73%) for random spot UAC, 32.5% (+141%; -58%) for first-morning UACR, and 29.7% (124%; -55%) for random spot UACR. CV w values for filtration markers were comparable across the range of baseline eGFRs. CV w values for UAC and UACR were comparable across the range of baseline albuminuria values., Limitations: Small sample size limits the ability to detect differences in variability across markers. Participants were recruited and followed up in a clinical and not research setting, so some preanalytical factors could not be controlled., Conclusions: eGFR markers appear to have relatively low short-term within-person variability, whereas variability in albuminuria appears to be high, making it difficult to distinguish random variability from meaningful biologic changes., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: All randomized trials of direct oral anticoagulants in atrial fibrillation excluded patients with severe kidney disease. The safety and effectiveness of direct oral anticoagulants across the range of eGFR in real-world settings is unknown. Our objective is to quantify the risk of bleeding and benefit of ischemic stroke prevention for direct oral anticoagulants compared with warfarin in patients with atrial fibrillation with and without CKD., Design, Setting, Participants, & Measurements: We created a propensity score-matched cohort of 3206 patients with atrial fibrillation and direct oral anticoagulant use and 3206 patients with atrial fibrillation using warfarin from October of 2010 to February of 2017 in an electronic health record (Geisinger Health System). The risks of bleeding and ischemic stroke were compared between direct oral anticoagulant and warfarin users using Cox proportional hazards regression, stratified by eGFR (≥60 and <60 ml/min per 1.73 m 2 )., Results: The mean (SD) age of the 6412 participants was 72 (12) years, 47% were women, and average eGFR was 69 (21) ml/min per 1.73 m 2 . There were 1181 bleeding events and 466 ischemic strokes over 7391 person-years of follow-up. Compared with warfarin use, the hazard ratios (HRs) (95% confidence interval [95% CI]) of bleeding associated with direct oral anticoagulant use were 1.01 (0.88 to 1.17) and 1.23 (1.02 to 1.48) for those with eGFR≥60 and eGFR<60 ml/min per 1.73 m 2 , respectively ( P -interaction=0.10). There was no difference between direct oral anticoagulant and warfarin users in the risk of ischemic stroke: HRs (95% CI) of 0.94 (0.74 to 1.18) and 1.02 (0.76 to 1.37) for those with eGFR≥60 and eGFR<60 ml/min per 1.73 m 2 , respectively ( P -interaction=0.70). Similar findings were observed with individual drugs., Conclusions: In a large health care system, patients with eGFR<60 ml/min per 1.73 m 2 who took direct oral anticoagulants for atrial fibrillation had slightly higher risk of bleeding compared with those on warfarin, but similar benefits from prevention of ischemic stroke., (Copyright © 2018 by the American Society of Nephrology.)

Background: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations are recommended for glomerular filtration rate (GFR) estimation in the general population. They have not been evaluated in community-based populations, including Blacks at higher levels of GFR, but are commonly applied in such populations., Methods: In an ancillary study of Multi-Ethnic Study of Atherosclerosis conducted at one site, we evaluated the performance of the CKD-EPI equations for creatinine (eGFRcr), cystatin C (eGFRcys) or the combination (eGFRcr-cys) compared with GFR measured as plasma clearance of iohexol., Results: Among 294 participants, the mean age was 71 (SD 9) years, 47% were Black, 48% were women and the mean measured GFR (mGFR) was 72.6 (SD 18.8) mL/min/1.73 m2. The CKD-EPI equations overestimated mGFR with a larger median bias for eGFRcr and eGFRcr-cys than eGFRcys [-8.3 (95% confidence interval -9.7, -6.5), -7.8 (-9.2, -6.2) and -3.7 (-5.0, -1.8) mL/min/1.73 m2, respectively], with smaller bias for those with lower compared with higher eGFR and by race compared with sex., Conclusion: The small differential bias of the CKD-EPI equation between races suggests that they can be used in Blacks as well as Whites in older community-based adults. The large differential bias in women versus men in all equations is in contrast to other studies and is unexplained. Further studies are required in multiracial and multiethnic community-based cohorts, taking into account differences in GFR measurement methods., (© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Increases in measured inulin clearance, measured creatinine clearance, and estimated glomerular filtration rate (eGFR) have been observed with bardoxolone methyl in 7 studies enrolling approximately 2,600 patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). The largest of these studies was Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), a multinational, randomized, double-blind, placebo-controlled phase 3 trial which enrolled patients with T2D and CKD stage 4. The BEACON trial was terminated after preliminary analyses showed that patients randomized to bardoxolone methyl experienced significantly higher rates of heart failure events. We performed post-hoc analyses to characterize changes in kidney function induced by bardoxolone methyl., Methods: Patients in -BEACON (n = 2,185) were randomized 1: 1 to receive once-daily bardoxolone methyl (20 mg) or placebo. We compared the effects of bardoxolone methyl and placebo on a post-hoc composite renal endpoint consisting of ≥30% decline from baseline in eGFR, eGFR <15 mL/min/1.73 m2, and end-stage renal disease (ESRD) events (provision of dialysis or kidney transplantation)., Results: Consistent with prior studies, patients randomized to bardoxolone methyl experienced mean increases in eGFR that were sustained through study week 48. Moreover, increases in eGFR from baseline were sustained 4 weeks after cessation of treatment. Patients randomized to bardoxolone methyl were significantly less likely to experience the composite renal endpoint (hazards ratio 0.48 [95% CI 0.36-0.64]; p < 0.0001)., Conclusions: Bardoxolone methyl preserves kidney function and may delay the onset of ESRD in patients with T2D and stage 4 CKD., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

The recent Kidney Disease Improving Global Outcomes 2012 CKD guidelines recommend estimating GFR from serum creatinine (eGFR cr ) as a first-line test to assess kidney function and using cystatin C or measured glomerular filtration rate (GFR) as confirmatory tests. eGFR cr may be inaccurate in people with variation in muscle mass or diet, and eGFR cys is not more accurate than eGFR cr. eGFR crcys is more accurate than either, but it is not independent of eGFR cr . Measured GFR is not practical and is susceptible to error due to variation in clearance methods and in the behavior of exogenous filtration markers. Over the past few years, we have hypothesized, and begun to test the hypothesis, that a panel of filtration markers (panel eGFR) from a single blood draw would require fewer demographic or clinical variables and could estimate GFR as accurately as measured GFR. In this article, we describe the conceptual background and rationale for this hypothesis and summarize our work thus far including evaluation of novel low-molecular-weight proteins and metabolites and then outline how we envision that such a panel could be used in clinical practice, research, and public health., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Living donor kidney transplantation is the preferred treatment option for ESRD. However, recent data suggest a small increase in the long-term risk of kidney failure in living kidney donors when compared to healthy nondonors. These data have led to a need for reconsideration of how donor candidates are evaluated and selected for donation. A Kidney Disease: Improving Global Outcomes (KDIGO) work group completed a comprehensive clinical practice guideline for evaluation of living kidney donor candidates in 2017, based on systematic evidence review, de novo evidence generation, and expert opinion. Central to the evaluation framework is assessment of glomerular filtration rate (GFR), which is used to screen for kidney disease and aid the prediction of long-term kidney failure risk after donation. Accurate estimation of the level of GFR and risk of kidney failure, and communication of estimated risks, can support evidence-based donor selection and shared decision-making. In this review, we discuss approaches to optimal GFR estimation in the donor evaluation process, long-term risk projection, and risk communication to donor candidates, integrating recommendations from the new KDIGO guideline, other recent literature, and experience from our own research and practice. We conclude by highlighting topics for further research in this important area of transplant medicine., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)