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Significance Statement: eGFR from creatinine, cystatin C, or both has been primarily used in search of biomarkers for GFR decline. Whether the relationships between biomarkers and eGFR decline are similar to associations with measured GFR (mGFR) decline has not been investigated. This study revealed that some biomarkers showed statistically significant different associations with eGFR decline compared with mGFR decline, particularly for eGFR from cystatin C. The findings indicate that non-GFR-related factors, such as age, sex, and body mass index, influence the relationship between biomarkers and eGFR decline. Therefore, the results of biomarker studies using eGFR, particularly eGFRcys, should be interpreted with caution and perhaps validated with mGFR., Background: Several serum protein biomarkers have been proposed as risk factors for GFR decline using eGFR from creatinine or cystatin C. We investigated whether eGFR can be used as a surrogate end point for measured GFR (mGFR) when searching for biomarkers associated with GFR decline., Methods: In the Renal Iohexol Clearance Survey, GFR was measured with plasma iohexol clearance in 1627 individuals without diabetes, kidney, or cardiovascular disease at baseline. After 11 years of follow-up, 1409 participants had one or more follow-up GFR measurements. Using logistic regression and interval-censored Cox regression, we analyzed the association between baseline levels of 12 serum protein biomarkers with the risk of accelerated GFR decline and incident CKD for both mGFR and eGFR., Results: Several biomarkers exhibited different associations with eGFR decline compared with their association with mGFR decline. More biomarkers showed different associations with eGFRcys decline than with eGFRcre decline. Most of the different associations of eGFR decline versus mGFR decline remained statistically significant after adjustment for age, sex, and body mass index, but several were attenuated and not significant after adjusting for the corresponding baseline mGFR or eGFR., Conclusions: In studies of some serum protein biomarkers, eGFR decline may not be an appropriate surrogate outcome for mGFR decline. Although the differences from mGFR decline are attenuated by adjustment for confounding factors in most cases, some persist. Therefore, proposed biomarkers from studies using eGFR should preferably be validated with mGFR., (Copyright © 2023 by the American Society of Nephrology.)

Background: The accuracy of estimation of kidney function with the use of routine metabolic tests, such as measurement of the serum creatinine level, has been controversial. The European Kidney Function Consortium (EKFC) developed a creatinine-based equation (EKFC eGFRcr) to estimate the glomerular filtration rate (GFR) with a rescaled serum creatinine level (i.e., the serum creatinine level is divided by the median serum creatinine level among healthy persons to control for variation related to differences in age, sex, or race). Whether a cystatin C-based EKFC equation would increase the accuracy of estimated GFR is unknown., Methods: We used data from patients in Sweden to estimate the rescaling factor for the cystatin C level in adults. We then replaced rescaled serum creatinine in the EKFC eGFRcr equation with rescaled cystatin C, and we validated the resulting EKFC eGFRcys equation in cohorts of White patients and Black patients in Europe, the United States, and Africa, according to measured GFR, levels of serum creatinine and cystatin C, age, and sex., Results: On the basis of data from 227,643 patients in Sweden, the rescaling factor for cystatin C was estimated at 0.83 for men and women younger than 50 years of age and 0.83 + 0.005 × (age - 50) for those 50 years of age or older. The EKFC eGFRcys equation was unbiased, had accuracy that was similar to that of the EKFC eGFRcr equation in both White patients and Black patients (11,231 patients from Europe, 1093 from the United States, and 508 from Africa), and was more accurate than the Chronic Kidney Disease Epidemiology Collaboration eGFRcys equation recommended by Kidney Disease: Improving Global Outcomes. The arithmetic mean of EKFC eGFRcr and EKFC eGFRcys further improved the accuracy of estimated GFR over estimates from either biomarker equation alone., Conclusions: The EKFC eGFRcys equation had the same mathematical form as the EKFC eGFRcr equation, but it had a scaling factor for cystatin C that did not differ according to race or sex. In cohorts from Europe, the United States, and Africa, this equation improved the accuracy of GFR assessment over that of commonly used equations. (Funded by the Swedish Research Council.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Serum creatinine (Scr) is the major contributing variable in glomerular filtration rate (GFR) estimating equations. Serum cystatin C (ScysC) based GFR estimating (eGFR)-equations have also been developed. The present study investigates the relation between 'rescaled' levels of these renal biomarkers (with reference interval of [0.67-1.33]) and measured GFR (mGFR)., Methods: We evaluated the diagnostic ability to detect impaired kidney function of the rescaled renal biomarkers in 8584 subjects from 12 cohorts with measured GFR, standardized Scr and ScysC. We calculated sensitivity and specificity of the rescaled biomarkers to identify kidney disease, with reference to a fixed (60mL/min/1.73m 2 ) as well as an age-dependent threshold for mGFR., Results: The upper reference limit of 1.33 for rescaled renal biomarkers is closely related to the age-dependent threshold for defining kidney status by mGFR with sensitivity and specificity for the rescaled biomarkers close to 90% for all ages. If the fixed threshold of 60mL/min/1.73m 2 for mGFR is used, then lower specificity in children and sensitivity in older adults are observed., Conclusions: Impaired kidney function can be diagnosed by rescaled renal biomarkers instead of eGFR-equations using the fixed threshold of 1.33 for all ages, consistent with an age-dependent threshold of mGFR., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: We recently published and validated the new serum creatinine (Scr)-based full-age-spectrum equation (FAS crea ) for estimating the glomerular filtration rate (GFR) for healthy and kidney-diseased subjects of all ages. The equation was based on the concept of normalized Scr and shows equivalent to superior prediction performance to the currently recommended equations for children, adolescents, adults and older adults., Methods: Based on an evaluation of the serum cystatin C (ScysC) distribution, we defined normalization constants for ScysC ( Q cysC  =   0.82 mg/L for ages <70 years and Q cysC  =   0.95 mg/L for ages ≥70 years). By replacing Scr/ Q crea in the FAS crea equation with ScysC/ Q cysC , or with the average of both normalized biomarkers, we obtained new ScysC-based (FAS cysC ) and combined Scr-/ScysC-based FAS equations (FAS combi ). To validate the new FAS cysC and FAS combi we collected data on measured GFR, Scr, ScysC, age, gender, height and weight from 11 different cohorts including n  = 6132 unique white subjects (368 children, aged ≤18 years, 4295 adults and 1469 older adults, aged ≥70 years)., Results: In children and adolescents, the new FAS cysC equation showed significantly better performance [percentage of patients within 30% of mGFR (P30) = 86.1%] than the Caucasian Asian Paediatric Adult Cohort equation (P30 = 76.6%; P < 0.0001), or the ScysC-based Schwartz equation (P30 = 68.8%; P < 0.0001) and the FAS combi equation outperformed all equations with P30 = 92.1% (P < 0.0001). In adults, the FAS cysC equation (P30 = 82.6%) performed equally as well as the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI cysC ) (P30 = 80.4%) and the FAS combi equation (P30 = 89.9%) was also equal to the combined CKD-EPI equation (P30 = 88.2%). In older adults, FAS cysC was superior (P30 = 88.2%) to CKD-EPI cysC (P30 = 84.4%; P < 0.0001) and the FAS combi equation (P30 = 91.2%) showed significantly higher performance than the combined CKD-EPI equation (P30 = 85.6%) (P < 0.0001)., Conclusion: The FAS equation is not only applicable to all ages, but also for all recommended renal biomarkers and their combinations., (© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Glomerular filtration rate<60 mL/min/1.73 m2 is associated with increased cardiovascular risk. Cystatin C is believed to be a better tool than creatinine for detection of mild renal dysfunction (>60 mL/min/1.73 m2) and possibly a more sensitive marker for cardiovascular risk and all-cause mortality. We examined the association of cystatin C with cardiovascular morbidity and all-cause mortality in a prospective population-based study., Methods: Cystatin C was measured in 2852 men and 3153 women in the Tromsø Study 1994/95. Gender-specific associations during 12 years of follow-up for all-cause mortality and 9.5 years for myocardial infarction (MI) and ischaemic stroke were assessed (Cox proportional hazard ratios, HRs)., Results: During follow-up, 591 MIs, 293 ischaemic strokes and 1262 deaths occurred. In women, HR for all-cause mortality was increased in the upper cystatin C quartile (≥0.93 mg/L) compared with the lowest quartile (≤0.73 mg/L); 1.38, 95% confidence interval 1.04-1.84. A significant interaction with gender was observed. One SD (0.17 mg/L) increase in cystatin C was associated with 9% higher risk of death in women, also when persons with a cancer history were excluded. Crude HRs for MI and ischaemic stroke were increased in both genders, but the associations did not persist after multivariable adjustments. No independent associations with end points were observed in non-gender-specific analyses., Conclusions: Cystatin C was not independently associated with fatal and non-fatal MI or ischaemic stroke in the general population. However, cystatin C was a risk factor for all-cause mortality in women.

Background: The equations used to estimate glomerular filtration rate (GFR) based on serum creatinine level are limited by their dependence on muscle mass. Although cystatin C level predicts clinical outcomes better than creatinine level in the general population, its role in estimating GFR in the reference range is unclear. Cystatin C level is not influenced by muscle mass, but by several other non-GFR determinants. We investigated whether regression models using cystatin C level alone or in combination with creatinine level in principle would improve GFR estimation in the general population compared with models using creatinine level alone., Study Design: Study of diagnostic accuracy., Setting & Participants: A representative sample (n = 1,621; aged 50-62 years) of the general population in Tromsø, Norway, without coronary heart disease, stroke, diabetes mellitus, or kidney disease. Individuals had participated in the Renal Iohexol Clearance Survey (RENIS-T6), part of the sixth Tromsø Study., Index Test: Performance of multiple linear and fractional polynomial regression models with plasma creatinine and/or cystatin C levels as independent variables and measured GFR as a dependent variable., Reference Test: Plasma iohexol clearance., Other Measurements: Creatinine measured with an enzymatic method. Cystatin C measured with a particle-enhanced turbidimetric immunoassay., Results: In internal validation of models with cystatin C, creatinine, or both levels, percentages of GFR estimates within 10% of measured GFR were 61% (95% CI, 58%-63%), 62% (95% CI, 59%-64%), and 68% (95% CI, 65%-70%), respectively. Models with either cystatin C or creatinine level had very similar precision and ability to detect GFR <90 mL/min/1.73 m(2), whereas models based on both markers performed better., Limitations: Only middle-aged individuals of European ancestry were investigated. Lack of standardization between cystatin C assays. No external validation of regression models., Conclusions: Models based on cystatin C alone are not superior to those based on creatinine, but models based on both markers can improve GFR estimation in the reference range., (Copyright © 2011 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Estimation of the GFR (eGFR) using creatinine- or cystatin C-based equations is imperfect, especially when the true GFR is normal or near-normal. Modest reductions in eGFR from the normal range variably predict cardiovascular morbidity. If eGFR associates not only with measured GFR (mGFR) but also with cardiovascular risk factors, the effects of these non-GFR-related factors might bias the association between eGFR and outcome. To investigate these potential non-GFR-related associations between eGFR and cardiovascular risk factors, we measured GFR by iohexol clearance in a sample from the general population (age 50 to 62 years) without known cardiovascular disease, diabetes, or kidney disease. Even after adjustment for mGFR, eGFR associated with traditional cardiovascular risk factors in multiple regression analyses. More risk factors influenced cystatin C-based eGFR than creatinine-based eGFR, adjusted for mGFR, and some of the risk factors exhibited nonlinear effects in generalized additive models (P<0.05). These results suggest that eGFR, calculated using standard creatinine- or cystatin C-based equations, partially depends on factors other than the true GFR. Thus, estimates of cardiovascular risk associated with small changes in eGFR must be interpreted with caution., (Copyright © 2011 by the American Society of Nephrology)

Accurate measurement of glomerular filtration rate (GFR) is complicated and costly; therefore, GFR is commonly estimated by assessing creatinine or cystatin C concentrations. Because estimates based on cystatin C predict cardiovascular disease better than creatinine, these estimates have been hypothesized to be superior to those based on creatinine, when the GFR is near the normal range. To test this, we measured GFR by iohexol clearance in a representative sample of middle-aged (50-62 years) individuals in the general population, excluding those with coronary heart or kidney disease, stroke or diabetes mellitus. Bias, precision (median and interquartile range of estimated minus measured GFR (mGFR)), and accuracy (percentage of estimates within 30% of mGFR) of published cystatin C and creatinine-based GFR equations were compared in a total of 1621 patients. The cystatin C-based equation with the highest accuracy (94%) had a bias of 3.5 and precision of 18 ml/min per 1.73 m², whereas the most accurate (95%) creatinine-based equation had a bias of 2.9 and precision of 15 ml/min per 1.73 m² The best equation, based on both cystatin C and creatinine, had a bias of 7.6 ml/min per 1.73 m², precision of 15 ml/min per 1.73 m², and accuracy of 92%. Thus, estimates of GFR based on cystatin C were not superior to those based on creatinine in the general population. Hence, the better prediction of cardiovascular disease by cystatin C than creatinine measurements, found by others, may be due to factors other than GFR.