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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.)

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.)

Background: The commonly accepted threshold of glomerular filtration rate (GFR) to define chronic kidney disease (CKD) is less than 60 mL/min/1.73 m 2 . This threshold is based partly on associations between estimated GFR (eGFR) and the frequency of adverse outcomes. The association is weaker in older adults, which has created disagreement about the appropriateness of the threshold for these persons. In addition, the studies measuring these associations included relatively few outcomes and estimated GFR on the basis of creatinine level (eGFR cr ), which may be less accurate in older adults., Objective: To evaluate associations in older adults between eGFR cr versus eGFR based on creatinine and cystatin C levels (eGFR cr-cys ) and 8 outcomes., Design: Population-based cohort study., Setting: Stockholm, Sweden, 2010 to 2019., Participants: 82 154 participants aged 65 years or older with outpatient creatinine and cystatin C testing., Measurements: Hazard ratios for all-cause mortality, cardiovascular mortality, and kidney failure with replacement therapy (KFRT); incidence rate ratios for recurrent hospitalizations, infection, myocardial infarction or stroke, heart failure, and acute kidney injury., Results: The associations between eGFR cr-cys and outcomes were monotonic, but most associations for eGFR cr were U-shaped. In addition, eGFR cr-cys was more strongly associated with outcomes than eGFR cr . For example, the adjusted hazard ratios for 60 versus 80 mL/min/1.73 m 2 for all-cause mortality were 1.2 (95% CI, 1.1 to 1.3) for eGFR cr-cys and 1.0 (CI, 0.9 to 1.0) for eGFR cr , and for KFRT they were 2.6 (CI, 1.2 to 5.8) and 1.4 (CI, 0.7 to 2.8), respectively. Similar findings were observed in subgroups, including those with a urinary albumin-creatinine ratio below 30 mg/g., Limitation: No GFR measurements., Conclusion: Compared with low eGFR cr in older patients, low eGFR cr-cys was more strongly associated with adverse outcomes and the associations were more uniform., Primary Funding Source: Swedish Research Council, National Institutes of Health, and Dutch Kidney Foundation., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-1138.

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.

Context.—: Use of cystatin C for glomerular filtration rate estimation (eGFR) has garnered heightened interest as a means to avoid race-based medicine, since eGFRcys equations do not require specification of race. Before considering more widespread use of cystatin C, it is important to confirm that assays provide accurate measurements of cystatin C concentration, to ensure accurate GFR estimates., Objective.—: To determine if the accuracy of cystatin C measurements in laboratories participating in the College of American Pathologists (CAP) Cystatin C (CYS) survey has improved since 2014., Design.—: Two fresh frozen serum pools, the first from healthy donors without chronic kidney disease (CKD), and the second from patients with CKD, along with a synthetically prepared elevated cystatin C pool, were sent to laboratories participating in the 2019 CYS-A survey. Target values were established by using 2 immunoassays and a bracketed 2-point calibration with diluted ERM-DA471/IFCC reference material., Results.—: For the healthy donor fresh frozen pool (ERM-DA471/IFCC-traceable target of 0.725 mg/L), the all-method mean (standard deviation, coefficient of variation) was 0.731 mg/L (0.071, 9.7%). For the CKD pool (ERM-DA471/IFCC-traceable target of 2.136 mg/L), the all-method mean was 2.155 mg/L (0.182, 8.4%). For the synthetically spiked pool (ERM-DA471/IFCC-traceable target of 1.843 mg/L), the all-method mean was 1.886 mg/L (0.152, 8.1%). This represents marked improvement in accuracy and between-method agreement compared to the 2014 CAP survey., Conclusions.—: Manufacturers have markedly improved accuracy and between-method agreement of cystatin C measurement procedures since 2014, which allows for greater confidence in estimated GFR relying on cystatin C.

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 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.)

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.

Glomerular filtration rate (GFR) estimating equations are widely used, but their accuracy is limited by the need for race-ethnicity factors and imprecision of the estimated GFR. In this issue, Bukabau et al. evaluated the accuracy of GFR estimating equations and race-ethnicity factors in 2 centers in sub-Saharan Africa. The authors determined that the African American factor is not applicable and that newer equations are not more accurate than the Chronic Kidney Disease Epidemiology Collaboration equations recommended by current guidelines., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

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.)

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: Studies in chronic kidney disease populations suggest that the non-glomerular filtration rate (GFR) determinants of serum levels of the low-molecular-weight protein filtration markers cystatin C, β 2 -microglobulin (B2M), and beta-trace protein (BTP) are less affected by age, sex, and ethnicity than those of creatinine., Study Design: Cross-sectional study., Setting & Participants: Predominantly elderly participants selected from the Age, Gene/Environment Susceptibility Kidney Study (AGES-Kidney; N=683; mean [SD] age, 79 [4] years; GFR, 62 [17]mL/min/1.73 m 2 ) and from the Multi-Ethnic Study of Atherosclerosis Kidney Study (MESA-Kidney; N=273; mean [SD] age, 70.5 [9] years; GFR, 73 [19]mL/min/1.73 m 2 )., Predictors: Demographic and clinical factors hypothesized to be associated with conditions affecting non-GFR determinants of the filtration markers., Outcomes: Measured GFRs and estimated GFRs (eGFRs) based on creatinine, cystatin C, B2M, and BTP levels (eGFR cr, eGFR cys , eGFR B2M , and eGFR BTP , respectively). Residual associations of factors with eGFR after accounting for measured GFR as the parameter of interest., Results: eGFR cys , eGFR B2M , and eGFR BTP had significantly less strong residual associations with age and sex than eGFR cr in both AGES-Kidney and MESA-Kidney and were not associated with ethnicity (black vs white) in MESA-Kidney. After adjusting for age, sex, and ethnicity, residual associations with most clinical factors were smaller than observed with age and sex. eGFR cys and eGFR B2M , but not eGFR BTP , had significant residual associations with C-reactive protein levels in both studies., Limitations: Small sample size may limit power to detect associations. Participants may be healthier than the general population., Conclusions: Similar to previous studies in chronic kidney disease, in community-dwelling elders, cystatin C, B2M, and BTP levels are less affected than creatinine level by age and sex and are not affected by ethnicity. Both cystatin C and B2M levels may be affected by inflammation. These findings are important for the development and use of GFR estimating equations based on low-molecular-weight serum proteins throughout the range in GFRs., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

All living kidney donor candidates undergo evaluation of GFR. Guidelines recommend measured GFR (mGFR), using either an endogenous filtration marker or creatinine clearance, rather than estimated GFR (eGFR), but measurement methods are difficult, time consuming and costly. We investigated whether GFR estimated from serum creatinine (eGFRcr) with or without sequential cystatin C is sufficiently accurate to identify donor candidates with high probability that mGFR is above or below thresholds for clinical decision making. We combined the pretest probability for mGFR thresholds <60, <70, ≥80, and ≥90 mL/min per 1.73 m(2) based on demographic characteristics (from the National Health and Nutrition Examination Survey) with test performance of eGFR (categorical likelihood ratios from the Chronic Kidney Disease Epidemiology Collaboration) to compute posttest probabilities. Using data from the Scientific Registry of Transplant Recipients, 53% of recent living donors had predonation eGFRcr high enough to ensure ≥95% probability that predonation mGFR was ≥90 mL/min per 1.73 m(2) , suggesting that mGFR may not be necessary in a large proportion of donor candidates. We developed a Web-based application to compute the probability, based on eGFR, that mGFR for a donor candidate is above or below a range of thresholds useful in living donor evaluation and selection., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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 (eGFRcr-cys) as more accurate than either eGFRcr or eGFRcys 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 eGFRcr and eGFRcys with eGFRcr-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, eGFRcr-cys performed better than eGFRcr in four metrics, better than eGFRcys in two metrics, and similar to eGFRcys 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, eGFRcr-cys performed better than eGFRcr or eGFRcys., (Copyright © 2015 by the American Society of Nephrology.)

Context: Cystatin C is becoming an increasingly popular biomarker for estimating glomerular filtration rate, and accurate measurements of cystatin C concentrations are necessary for accurate estimates of glomerular filtration rate., Objective: To assess the accuracy of cystatin C concentration measurements in laboratories participating in the College of American Pathologists CYS Survey., Design: Two fresh frozen serum pools, the first from apparently healthy donors and the second from patients with chronic kidney disease, were prepared and distributed to laboratories participating in the CYS Survey along with the 2 usual processed human plasma samples. Target values were established for each pool by using 2 immunoassays and ERM DA471/IFCC international reference material., Results: For the normal fresh frozen pool (ERM-DA471/IFCC-traceable target of 0.960 mg/L), the all-method mean (SD, % coefficient of variation [CV]) reported by all of the 123 reporting laboratories was 0.894 mg/L (0.128 mg/L, 14.3%). For the chronic kidney disease pool (ERM-DA471/IFCC-traceable target of 2.37 mg/L), the all-method mean (SD, %CV) was 2.258 mg/L (0.288 mg/L, 12.8%). There were substantial method-specific biases (mean milligram per liter reported for the normal pool was 0.780 for Siemens, 0.870 for Gentian, 0.967 for Roche, 1.061 for Diazyme, and 0.970 for other/not specified reagents; and mean milligram per liter reported for the chronic kidney disease pool was 2.052 for Siemens, 2.312 for Gentian, 2.247 for Roche, 2.909 for Diazyme, and 2.413 for other/not specified reagents)., Conclusions: Manufacturers need to improve the accuracy of cystatin C measurement procedures if cystatin C is to achieve its full potential as a biomarker for estimating glomerular filtration rate.

Background and Objectives: Kidney disease progression, assessed by change in eGFR on the basis of creatinine, is an independent risk factor for cardiovascular disease and death. This study aimed to evaluate whether changes in multiple filtration markers, individually and combined, were associated with cardiovascular disease and death., Design, Setting, Participants, & Measurements: Creatinine, cystatin C, and β2-microglobulin were measured among 9716 Atherosclerosis Risk in Communities Study participants in 1990-1992 and 1996-1998. Percentage change in three filtration markers (eGFR on the basis of creatinine, eGFR on the basis of cystatin C, and 1/β2-microglobulin) individually and the average of percentage change across all three filtration markers were calculated. Cardiovascular events and deaths were ascertained from 1996 to 2011. Cox regression models were adjusted for established risk factors for cardiovascular disease and mortality and first measurement of eGFR on the basis of creatinine., Results: During a median follow-up of 14 years, there were 1922 cardiovascular events and 2285 deaths from any cause. Decline of >30% in each filtration marker was significantly associated with higher risk of mortality compared with stable kidney function (-9.9% to +9.9% change in the filtration marker) with hazard ratios (95% confidence intervals) of 1.91 (1.67 to 2.18) for eGFR on the basis of creatinine, 2.29 (1.99 to 2.63) for eGFR on the basis of cystatin C, and 2.48 (2.15 to 2.86) for 1/β2-microglobulin, with similar associations for cardiovascular disease. An average decline of >30% across the three markers was strongly associated with higher risk of all-cause mortality (hazard ratio, 2.82; 95% confidence interval, 2.42 to 3.29)., Conclusions: Kidney disease progression was assessed using >30% decline in eGFR on the basis of creatinine, eGFR on the basis of cystatin C, and 1/β2-microglobulin and average decline of >30% across the three filtration markers is strongly associated with risk of cardiovascular disease and death., (Copyright © 2015 by the American Society of Nephrology.)

Importance: Because early-stage kidney disease is asymptomatic and is associated with both morbidity and mortality, laboratory measurements are required for its detection., Objective: To summarize evidence supporting the use of laboratory tests for glomerular filtration rate (GFR) and albuminuria to detect and stage acute kidney injury, acute kidney diseases and disorders, and chronic kidney disease in adults., Evidence Review: We reviewed recent guidelines from various professional groups identified via the National Guideline Clearing House and author knowledge, and systematically searched MEDLINE for other sources of evidence for selected topics., Findings: The KDIGO (Kidney Disease Improving Global Outcomes) guidelines define and stage acute and chronic kidney diseases by GFR and albuminuria. For initial assessment of GFR, measuring serum creatinine and reporting estimated GFR based on serum creatinine (eGFRcr) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation is recommended. If confirmation of GFR is required because of conditions that affect serum creatinine independent of GFR (eg, extremes of muscle mass or diet), or interference with the assay, cystatin C should be measured and estimated GFR should be calculated and reported using cystatin C (eGFRcys) and serum creatinine (eGFRcr-cys) or GFR should be measured directly using a clearance procedure. Initial assessment of albuminuria includes measuring urine albumin and creatinine in an untimed spot urine collection and reporting albumin-to-creatinine ratio. If confirmation of albuminuria is required because of diurnal variation or conditions affecting creatinine excretion, such as extremes of muscle mass or diet, the albumin excretion rate should be measured from a timed urine collection., Conclusions and Relevance: Detection and staging of acute and chronic kidney diseases can be relatively simple. Because of the morbidity and mortality associated with kidney disease, early diagnosis is important and should be pursued in at-risk populations.

Background: Glomerular filtration rate (GFR) estimating equations using the combination of creatinine and cystatin C (eGFRcr-cys) are more accurate than equations using either alone (eGFRcr or eGFRcys). New guidelines suggest measuring cystatin C as a confirmatory test when eGFRcr may be inaccurate, but do not specify demographic or clinical conditions in which eGFRcys or eGFRcr-cys are more accurate than eGFRcr nor which estimate to use in such circumstances., Methods: We compared the performance of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations in 1119 subjects in the CKD-EPI cystatin C external validation dataset. Subgroups were defined by eGFRcr, age, sex, diabetes status and body mass index (BMI). The reference test was GFR measured using urinary or plasma clearance of exogenous filtration markers. Cystatin C and creatinine assays were traceable to primary reference materials. Accuracy was defined as the absolute difference in eGFR compared with mGFR., Results: The mean mGFR was 70 ± 41 (SD) mL/min/1.73 m(2). eGFRcys was more accurate than eGFRcr at lower BMI and less accurate at higher BMI, especially at higher levels of eGFRcr. There were small differences in accuracy in people according to the diabetes status. eGFRcr-cys was as accurate or more accurate than eGFRcr or eGFRcys in these and all other subgroups., Conclusions: eGFRcr-cys, but not eGFRcys, is more accurate than eGFRcr in most subgroups we studied, suggesting preferential use of eGFRcr-cys when serum cystatin C is measured as a confirmatory test to obtain more accurate eGFR. Further studies are necessary to evaluate diagnostic strategies for using eGFRcys and eGFRcr-cys., (© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

OBJECTIVE Serum cystatin C is an alternative to serum creatinine for estimating glomerular filtration rate (GFR), since cystatin C is less influenced by age and muscle mass. Among persons with diabetes, we compared the performance of GFR estimated using cystatin C (eGFRcys) with that using creatinine (eGFRcr) for the identification of reduced kidney function and its association with diabetes complications. RESEARCH DESIGN AND METHODS We analyzed data from adult participants from the 1999-2002 National Health and Nutrition Examination Survey with available cystatin C (N = 4,457). Kidney function was dichotomized as preserved (eGFR ≥60 mL/min/1.73 m(2)) or reduced (eGFR <60 mL/min/1.73 m(2)) using the 2012 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) cystatin C and the 2009 CKD-EPI creatinine equations. RESULTS Among 778 persons with diabetes, the prevalence of reduced kidney function was 16.5% using eGFRcr and 22.0% using eGFRcys. More persons with diabetes were reclassified from preserved kidney function by eGFRcr to reduced kidney function by eGFRcys than persons without diabetes (odds ratio 3.1 [95% CI 1.9-4.9], P < 0.001). The associations between lower eGFR and higher prevalence of albuminuria, retinopathy, peripheral arterial disease, and coronary artery disease were robust regardless of filtration marker. Similarly, the risk of all-cause mortality increased with lower eGFRcr and eGFRcys. Only lower eGFRcys was significantly associated with cardiovascular mortality. CONCLUSIONS More persons with diabetes had reduced kidney function by eGFRcys than by eGFRcr, and lower eGFRcys was strongly associated with diabetes complications. Whether eGFRcys is superior to eGFRcr in approximating true kidney function in a diabetic population requires additional study.

Background: Adding the measurement of cystatin C to that of serum creatinine to determine the estimated glomerular filtration rate (eGFR) improves accuracy, but the effect on detection, staging, and risk classification of chronic kidney disease across diverse populations has not been determined., Methods: We performed a meta-analysis of 11 general-population studies (with 90,750 participants) and 5 studies of cohorts with chronic kidney disease (2960 participants) for whom standardized measurements of serum creatinine and cystatin C were available. We compared the association of the eGFR, as calculated by the measurement of creatinine or cystatin C alone or in combination with creatinine, with the rates of death (13,202 deaths in 15 cohorts), death from cardiovascular causes (3471 in 12 cohorts), and end-stage renal disease (1654 cases in 7 cohorts) and assessed improvement in reclassification with the use of cystatin C., Results: In the general-population cohorts, the prevalence of an eGFR of less than 60 ml per minute per 1.73 m(2) of body-surface area was higher with the cystatin C-based eGFR than with the creatinine-based eGFR (13.7% vs. 9.7%). Across all eGFR categories, the reclassification of the eGFR to a higher value with the measurement of cystatin C, as compared with creatinine, was associated with a reduced risk of all three study outcomes, and reclassification to a lower eGFR was associated with an increased risk. The net reclassification improvement with the measurement of cystatin C, as compared with creatinine, was 0.23 (95% confidence interval [CI], 0.18 to 0.28) for death and 0.10 (95% CI, 0.00 to 0.21) for end-stage renal disease. Results were generally similar for the five cohorts with chronic kidney disease and when both creatinine and cystatin C were used to calculate the eGFR., Conclusions: The use of cystatin C alone or in combination with creatinine strengthens the association between the eGFR and the risks of death and end-stage renal disease across diverse populations. (Funded by the National Kidney Foundation and others.).

Background: The US prevalence of reduced estimated glomerular filtration rate (eGFR) based on serum creatinine level increased during the decade ending in 2002. National Health and Nutrition Examination Survey (NHANES) cystatin C measurements recently were calibrated to the international standard, allowing for an independent test of the trend in prevalence of reduced eGFR using cystatin C level., Study Design: Cross-sectional surveys performed during 2 periods., Setting & Participants: Nationally representative subsamples of adult participants from NHANES III (1988-1994) and the NHANES 1999-2002 surveys., Predictor: Survey period., Outcomes: Prevalence of reduced GFR, defined as eGFR <60 mL/min/1.73 m² based on levels of serum creatinine, cystatin C, or both (eGFRcr, eGFRcys, and eGFRcr-cys), using estimating equations developed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)., Measurements: Serum cystatin C level, measured from stored samples in 2006, calibrated to the international standard in 2012., Results: Between 1988-1994 and 1999-2002, the prevalence of reduced eGFRcr, eGFRcys, and eGFRcr-cys increased from 4.7% (95% CI, 4.1%-5.3%) to 6.5% (95% CI, 5.9%-7.1%) (P < 0.001), from 5.5% (95% CI, 4.6%-6.5%) to 8.7% (95% CI, 7.5%-10.0%) (P < 0.001), and from 4.4% (95% CI, 3.7%-5.2%) to 7.1% (95% CI, 6.2%-8.0%) (P < 0.001), respectively. The higher prevalence of reduced GFR in the later period was observed in all subgroups of age, race, sex, and GFR categories. After adjusting for changes in the US population by age, sex, race, diabetes, hypertension, and body mass index, prevalence ratios of reduced GFR in the later versus earlier survey were 1.24 (95% CI, 1.09-1.45), 1.34 (95% CI, 1.15-1.67), and 1.33 (95% CI, 1.17-1.65) using eGFRcr, eGFRcys, and eGFRcr-cys, respectively., Limitations: Likely underascertainment of persons with GFR <15 mL/min/1.73 m²; GFR was estimated and not measured; comparability of laboratory assays based on a calibration subsample., Conclusions: The prevalence of reduced eGFRcys in the US civilian noninstitutionalized population increased between 1988-1994 and 1999-2002, confirming the increase observed in the prevalence of reduced eGFRcr., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: New filtration markers, including β-trace protein (BTP) and β₂-microglobulin (B2M), may, similar to cystatin C, enable a stronger prediction of mortality compared to serum creatinine-based estimated glomerular filtration rate (eGFRcr). We sought to evaluate these mortality associations in a representative sample of US adults., Study Design: Prospective cohort study., Setting & Participants: 6,445 adults 20 years or older from the Third National Health and Nutrition Examination Survey (1988-1994) with mortality linkage through December 31, 2006., Predictors: Serum cystatin C, BTP, and B2M levels and eGFRcr categorized into quintiles, with the highest quintile (lowest for eGFRcr) split into tertiles (subquintiles Q5a-Q5c)., Outcomes: All-cause, cardiovascular disease, and coronary heart disease mortality., Measurements: Demographic- and multivariable-adjusted Cox proportional hazard models., Results: During follow-up, 2,392 deaths (cardiovascular, 1,079; coronary heart disease, 605) occurred. Levels of all 4 filtration markers were associated with mortality risk after adjusting for demographics (P trend<0.02). Adjusted for mortality risk factors, compared to the middle quintile, the highest subquintiles for cystatin C (Q5c: HR, 1.94; 95% CI, 1.43-2.62), BTP (Q5c: HR, 2.14; 95% CI, 1.56-2.94), and B2M (Q5c: HR, 2.58; 95% CI, 1.96-3.41) were associated with increased all-cause mortality risk, whereas the association was weaker for eGFRcr (Q5c: HR, 1.31; 95% CI, 0.84-2.04). Associations persisted for the novel markers and not for eGFRcr at eGFRcr ≥60 mL/min/1.73 m². Trends were similar for cardiovascular disease and coronary heart disease mortality., Limitations: Single measurements of markers from long-term stored samples., Conclusions: The strong association of cystatin C level with mortality compared with serum creatinine estimates is shared by BTP and B2M. This supports the utility of alternative filtration markers beyond creatinine when improved risk prediction related to decreased GFR is needed., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Our objective was to quantify short-term total within-person variability in standard and nontraditional kidney measures using national data., Study Design: Repeated examination study of serum and urine kidney measures., Setting & Participants: Participants 18 years or older in the Third National Health and Nutrition Examination Survey (NHANES III) who had repeated blood and urine samples collected during visits occurring approximately 18 days apart., Measurements: Standardized serum creatinine, standardized cystatin C, β-trace protein (BTP), β(2)-microglobulin (B2M), and urine albumin and creatinine. We calculated the within-person coefficient of variation (CV(w)), which includes both biological and analytical variability. We also evaluated the impact of variability on estimates of the prevalence of reduced estimated glomerular filtration rate and albuminuria., Results: Serum cystatin C level demonstrated the lowest short-term within-person variability (CV(w) = 6.8%). Serum creatinine and B2M levels (CV(w) = 7.6% and 8.4%, respectively) also had low variability. BTP level had the most variability of the serum markers (CV(w) = 11.6%). As expected, urine albumin and urine creatinine measurements showed high variability (CV(w) >30% for both); however, albumin-creatinine ratio performed much better than either measure alone, with CV(w) of 11.3%. The effect of short-term variability on the prevalence of reduced estimated glomerular filtration rate was moderate, with an ~20% lower prevalence when defined based on single measurements compared to repeated application of the same test approximately 18 days apart. Repeated testing for albuminuria had a larger effect, showing a 33% lower prevalence of albuminuria when repeated testing was applied., Limitations: Only 2 measurements available. General population with low prevalence of kidney disease., Conclusions: Our results suggest that creatinine, cystatin C, and B2M levels have similarly low short-term variability. BTP level was more variable compared with the other serum filtration markers. Urine albumin and creatinine levels were highly variable and may benefit from repeated assessments to reduce the misclassification of albuminuria., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: β-trace protein (βTP), β2-microglobulin (β2M), and cystatin C (CysC) have advantages over creatinine for estimating GFR and prognosis. This study compares the distribution of all four markers in the general population and their associations with possible determinants of GFR., Design, Setting, Participants, & Measurements: βTP and β2M were measured in 7596 participants (aged ≥12 years) of the Third National Health and Nutrition Examination Survey (1988-1994). βTP and β2M concentrations and the proportion of persons with elevated (≥99th percentile for young healthy participants) βTP (≥0.81 mg/L), β2M (≥2.80 mg/L), standardized CysC (≥1.03 mg/L), and creatinine (≥1.2 mg/dl for men and ≥1.0 mg/dl for women) were compared across demographic and clinical factors., Results: Elevated βTP, β2M, and CysC showed stronger associations with age than elevated serum creatinine, the prevalence of elevated levels reaching 47%, 44%, 58%, and 26%, respectively, by age 80 years. βTP, CysC, and creatinine were higher in men but β2M was not associated with sex. Mexican Americans had lower βTP, β2M, CysC, and creatinine compared with non-Hispanic whites. Hypertension and higher C-reactive protein were associated with elevations in all markers, whereas non-Hispanic black race, body mass index, diabetes, smoking status, triglycerides, HDL cholesterol, and education were not associated in a consistent manner across the different markers., Conclusions: βTP, β2M, CysC, and creatinine differ in their associations with demographic and clinical factors, suggesting variation in their non-GFR determinants. Future studies should examine these markers with measured GFR to determine their diagnostic and prognostic utility.

Objective: Patients with diabetes have a high risk of end-stage renal disease (ESRD). We examined whether prediction of this outcome, according to chronic kidney disease (CKD) staging by creatinine-based estimates of the glomerular filtration rate (eGFRcreat), is improved by further staging with serum cystatin C-based estimates (eGFRcyst)., Research Design and Methods: Patients with diabetes in CKD stages 1-3 were selected from three cohorts: two from Joslin Diabetes Center, one with type 1 diabetes (N = 364) and one with type 2 diabetes (N = 402), and the third from the Finnish Diabetic Nephropathy (FinnDiane) Study of type 1 (N = 399). Baseline serum concentrations of creatinine and cystatin C were measured in all patients. Follow-up averaged 8-10 years and onsets of ESRD (n = 246) and death unrelated to ESRD (n = 159) were ascertained., Results: Although CKD staging by eGFRcyst was concordant with that by eGFRcreat for 62% of Joslin patients and 73% of FinnDiane patients, those given a higher stage by eGFRcyst than eGFRcreat had a significantly higher risk of ESRD than those with concordant staging in all three cohorts (hazard ratio 2.3 [95% CI 1.8-3.1]). Similarly, patients at a lower stage by eGFRcyst than by eGFRcreat had a lower risk than those with concordant staging (0.30 [0.13-0.68]). Deaths unrelated to ESRD followed the same pattern, but differences were not as large., Conclusions: In patients with diabetes, CKD staging based on eGFRcyst significantly improves ESRD risk stratification based on eGFRcreat. This conclusion can be generalized to patients with type 1 and type 2 diabetes and to diabetic patients in the U.S. and Finland.

Objective: To evaluate the performance of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine, cystatin C, and creatinine-cystatin C estimating equations in HIV-positive patients., Methods: We evaluated the performance of the Modification of Diet in Renal Disease (MDRD) Study and CKD-EPI creatinine 2009, CKD-EPI cystatin C 2012, and CKD-EPI creatinine-cystatin C 2012 glomerular filtration rate (GFR) estimating equations compared with GFR measured using plasma clearance of iohexol in 200 HIV-positive patients on stable antiretroviral therapy. Creatinine and cystatin C assays were standardized to certified reference materials., Results: Of the 200 participants, median (IQR) CD4 count was 536 (421) and 61% had an undetectable HIV viral load. Mean (SD) measured GFR (mGFR) was 87 (26) mL/min per 1.73 m. All CKD-EPI equations performed better than the MDRD Study equation. All 3 CKD-EPI equations had similar bias and precision. The cystatin C equation was not more accurate than the creatinine equation. The creatinine-cystatin C equation was significantly more accurate than the cystatin C equation, and there was a trend toward greater accuracy than the creatinine equation. Accuracy was equal or better in most subgroups with the combined equation compared to either alone., Conclusions: The CKD-EPI cystatin C equation does not seem to be more accurate than the CKD-EPI creatinine equation in patients who are HIV-positive, supporting the use of the CKD-EPI creatinine equation for routine clinical care for use in North American populations with HIV. The use of both filtration markers together as a confirmatory test for decreased estimated GFR based on creatinine in individuals who are HIV-positive requires further study.

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

Background: Cystatin C level predicts mortality more strongly than serum creatinine level. It is unknown whether this advantage extends to other outcomes, such as kidney failure, or whether other novel renal filtration markers share this advantage in predicting outcomes., Study Design: Observational cohort study., Setting & Participants: 9,988 participants in the Atherosclerosis Risk in Communities (ARIC) Study, a population-based study in 4 US communities, followed for approximately 10 years., Predictors: Serum creatinine-based estimated glomerular filtration rate calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (eGFR(CKD-EPI)) and cystatin C, β-trace protein (BTP), and β(2)-microglobulin (B2M) levels., Outcomes: Mortality, coronary heart disease, heart failure, and kidney failure., Results: Higher cystatin C and B2M concentrations were associated more strongly with mortality (n = 1,425) than BTP level and all were associated more strongly than eGFR(CKD-EPI) (adjusted HR for the upper 6.7 percentile compared with the lowest quintile: 1.6 [95% CI, 1.3-1.9] for eGFR(CKD-EPI), 2.9 [95% CI, 2.3-3.6] for cystatin C level, 1.9 [95% CI, 1.5-2.4] for BTP level, and 3.0 [95% CI, 2.4-3.8] for B2M level). Similar patterns were observed for coronary heart disease (n = 1,279), heart failure (n = 803), and kidney failure (n = 130). The addition of cystatin C, BTP, and B2M levels to models including eGFR(CKD-EPI) and all covariates, including urinary albumin-creatinine ratio, significantly improved risk prediction for all outcomes (P < 0.001)., Limitations: No direct measurement of GFR., Conclusions: B2M and, to a lesser extent, BTP levels share cystatin C's advantage over eGFR(CKD-EPI) in predicting outcomes, including kidney failure. These additional markers may be helpful in improving estimation of risk associated with decreased kidney function beyond current estimates based on eGFR(CKD-EPI)., (Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Serum levels of creatinine, cystatin C, or β trace protein allow estimation of GFR, but whether these markers contribute additional prognostic information beyond that reflected in GFR is unknown. Here, we analyzed data from the Modification of Diet in Renal Disease study, which provided baseline levels of these markers for 816 participants with a median follow-up of 16.6 years. We examined associations between the reciprocals of these filtration markers and (125)I iothalamate GFR, expressed per SD, with kidney failure and mortality. In univariate analysis, lower GFR and higher levels of each filtration marker associated with a higher risk for all outcomes. After adjustment for GFR in a Cox proportional hazards model, higher creatinine associated with a higher risk for kidney failure but a lower risk for all-cause mortality. Higher cystatin C and β trace protein associated with a higher risk for both kidney failure and all-cause mortality. In models including either cystatin C or β trace protein, the association of GFR with all-cause mortality was no longer significant after the addition of the filtration marker, suggesting the possibility of multicollinearity. In summary, after adjustment for GFR, levels of creatinine, cystatin C, and β trace protein, each remained directly associated with kidney failure but differed with respect to their associations with mortality. These differences may be a result of non-GFR-related associations of filtration markers, residual confounding by GFR, or collinearity between the filtration markers and GFR. β trace protein and cystatin C seem to provide more consistent prognostic information than creatinine.

Purpose of Review: There is much interest in cystatin C to replace or supplement serum creatinine to estimate the glomerular filtration rate (GFR). Here we review the performance of cystatin C and combined creatinine-cystatin C estimating equations compared to creatinine-based estimating equations in chronic and acute kidney disease., Recent Findings: Drift in the cystatin C assay has had a large effect on the results reported using cystatin C, but these issues are not routinely considered in evaluation of GFR-estimating equations. The recently released primary reference material for cystatin C will allow less difference among assays in the future. There does not appear to be a consistent message among published studies as to whether cystatin C-based equations are better than creatinine-based equations in the general population or those with chronic kidney disease (CKD), as well as those with reduced muscle mass or chronic illness, or acute kidney injury. Cystatin C could be used in combination with creatinine as a confirmatory test for estimated GFR from creatinine., Summary: Cystatin C may have a role to estimate GFR in selected circumstances, and the next set of studies should be directed at developing implementation strategies for its use.