Cystatin C-based Equations Research Articles

Comparison of the prevalence and associated factors of chronic kidney disease diagnosed by serum creatinine or cystatin C among young people living with HIV in Uganda

IntroductionYoung people living with HIV (YPLHIV) are at increased risk of developing chronic kidney disease (CKD) which is associated with high mortality and morbidity. Early diagnosis is important to halt progression. We aimed to estimate the prevalence and factors associated with CKD among YPLHIV in Kampala, Uganda, and to compare serum creatinine and cystatin C for early diagnosis of CKD in this population.MethodsA cross-sectional study with YPLHIV aged 10 to 24 years was conducted in seven HIV clinics. Participants provided a urine and blood sample to measure urinary albumin, proteinuria, serum creatinine and cystatin C levels at baseline and after three months. The estimated glomerular filtration rate (eGFR) was calculated using CKDEPI 2021, Cockroft-Gault and bedside Schwartz equations using creatinine or cystatin C. The albumin creatinine ratio (ACR) and proteinuria were measured. CKD was defined as either eGFR < 60 ml/min/1.73m2 or < 90 ml/min/1.73m2 or ACR above 30 mg/g on two separate occasions. Univariable and multivariable logistic regression were used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for factors associated with CKD.ResultsA total of 500 participants were enrolled. Most were female (56%; n = 280) and aged 10 to 17 years (66.9%; n = 335). CKD prevalence ranged from 0 to 23% depending on the criteria, equation and biomarker used. Cystatin C-based equations estimated higher prevalence of CKD compared to creatinine-based ones. Prevalence of ACR above 30 mg/g was 10.1% and of proteinuria 29%. Factors independently associated with CKD were age (aOR = 1.42; 95% CI:1.30–1.51) and male sex (aOR = 3.02; 95% CI:1.68–5.43).ConclusionCKD prevalence among YPLHIV varied substantially depending on definitions used and the current definition would likely lead to missed cases of CKD among YPLHIV. Estimating equations should be validated against measured GFR in YPLHIV and the optimal definition of CKD in this vulnerable population should be revised to optimise detection and opportunities for reducing disease progression.Clinical trial numberNot applicable.

Comparation of two cystatin C-based eGFR equations in assessing risk of all-cause mortality and incident cardiovascular disease

BackgroundChronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 and European Kidney Function Consortium (EKFC) 2023 both recently updated the equations to estimate the glomerular filtration rate (eGFR) using cystatin C; however, little is known about the benefits of using the equations for the risk stratification of health outcomes. We conducted this longitudinal study to compare the cystatin C CKD-EPI and EKFC equations to track the risks of cardiovascular disease and all-cause mortality among Chinese adults.MethodsWe used data from China Health and Retirement Longitudinal Study (CHARLS) between 2011 and 2018. Adjusted logistic regression models and restricted cubic spline functions were used to evaluate the relationships of cystatin C-based eGFR values with incidence of cardiovascular disease and mortality.ResultsA total of 6 496 participants were finally included in this study. The mean age of the participants was 59.6 (± 9.5) years, including 2996 (46.1%) males. There were 473 deaths and 1996 cases of cardiovascular disease observed during a maximum follow-up of 7.0 years. Using cystatin C-based CKD-EPI equation, people of eGFR < 60 mL/min/1.73 m2 had an increased risk of mortality (risk ratio [RR], 1.527; 95% CI, 1.068–2.178) and incident cardiovascular disease (RR, 1.363; 95% CI, 1.006–1.844), compared to those of eGFR ≥ 90 mL/min/1.73 m2. On the contrary, we did not observe significant associations of eGFR levels by EKFC equation with mortality nor cardiovascular disease.ConclusionsThe findings indicated that cystatin C-based eGFR using CKD-EPI equation is more closely associated with all-cause mortality and cardiovascular disease compared to EKFC equation among Chinese adults. The cystatin C-based eGFR by CKD-EPI equation should be monitored in health practice, which needs further validation in other populations.

Prediction of cardiovascular events and all-cause mortality using race and race-free estimated glomerular filtration rate in African Americans: the Jackson Heart Study.

New Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations without a race adjustment were developed to estimate the glomerular filtration rate (eGFR). We aimed to compare the performance of five CKD-EPI eGFR equations, with or without race, in predicting cardiovascular disease (CVD) events and all-cause mortality in Black Americans from the Jackson Heart Study. JHS is an ongoing population-based prospective cohort study of African Americans in the Jackson, Mississippi, metropolitan area. Five CKD-EPI equations were used to estimate GFR at baseline using serum creatinine (Cr) or cystatin C (cys), including 2009 eGFRcr(ASR [age, sex, race]), 2021 eGFRcr(AS [age and sex]), 2012 eGFRcr-cys(ASR), 2021 eGFRcr-cys(AS), 2012 eGFRcys(AS). Endpoints were incident CVD events and all-cause mortality. Cox proportional hazards regression was used to assess the associations between different eGFRs and outcomes adjusting for atherosclerotic risk factors. Harrell's C-statistics and Net Reclassification Index (NRI) were used to assess the predictive utility. Among 5,129 participants (average age 54.8 ± 12.8 yrs), 1898 were male (37.0%). eGFRcr(AS) provided lower estimates and resulting in a greater proportion of participants categorized as CKD than eGFRcr(ASR), eGFRcr-cys(ASR), eGFRcr-cys(AS) and eGFRcys(AS). A median follow-up of 13.7 and 14.3 years revealed 411 (9.3%) CVD incidents and 1,207 (23.5%) deaths. Lower eGFRs were associated with CVD incidents and all-cause mortality. eGFRcr-cys(ASR), eGFRcr-cys(AS) and eGFRcys(AS) were strongly associated with incident CVD events and all-cause mortality than eGFRcr(ASR) and eGFRcr(AS). A significant discrimination improvement was found in C-statistics for predicting incident CVD events and all-cause mortality after adding each eGFR measure to the basic model including atherosclerotic risk factors. Across a 7.5% 10-year risk threshold, eGFRcys(AS) improved net classification of all-cause mortality (NRI: 2.19, 95%CI: 0.08, 4.65%). eGFR based on creatinine omit race has the lowest mean and detects more CKD patients in Black population. The eGFRs incorporating cystatin C strengthens the association between the eGFR and the risks of incident CVD and all-cause mortality. Cystatin C-based eGFR equations might be more appropriate for predicting CVD and mortality among Black population.

Performance of the New CKD-EPI Creatinine-and Cystatin C-based Glomerular Filtration Rate Estimation Equation in Living Kidney Donor Candidate.

Accurate preoperative evaluation of renal function in living kidney donor candidates (LKDCs) is crucial to prevent kidney failure after nephrectomy. We examined the performance of various estimated glomerular filtration rate (eGFR) equations, including the new chronic kidney disease epidemiology collaboration (CKD-EPI) equation in LKDCs. We analyzed 752 LKDCs who were assessed for measured GFR by inulin clearance as part of routine pretransplant examination from 2006 to 2020. CKD-EPI2012 from cystatin C (CKD-EPI12cys), CKD-EPI2021 from creatinine (CKD-EPI21cr), CKD-EPI21cr-cys, Japanese modified (JPN) eGFRcr, and JPN eGFRcys were compared in determining the suitability for LKDCs. CKD-EPI12cys had the lowest absolute and relative biases, with higher P30 and P10, followed by JPN eGFRcys, CKD-EPI21cr, and CKD-EPI21cr-cys. The root mean square error was least for CKD-EPI12cys, then JPN eGFRcys, CKD-EPI21cr-cys, CKD-EPI21cr, and JPN eGFRcr. CKD-EPI21cr, CKD-EPI12cys, and CKD-EPI21cr-cys estimated GFR higher, whereas JPN eGFRcr estimated GFR lower. At the threshold of 90 mL/min/1.73 m2, CKD-EPI21cr had the highest percentage of misclassification at 37.37%, whereas JPN eGFRcr had the lowest percentage of misclassification at 6.91%. Using the age-adapted approach, JPN eGFRcr had the lowest percentage of misclassification into overestimation at 7.31%. All eGFR had >5.0%, and CKD-EPI21cr had the highest percentage of misclassification at 21.94%. Conversely, CKD-EPI21cr-cys had the lowest percentage of misclassification into underestimation at 3.19%, both at the threshold of 90 mL/min/1.73 m2 and the age-adapted approach. JPN eGFRcr had the highest percentage at 33.38% and 40.69%, respectively. In evaluating the renal function of Japanese LKDCs, the new CKD-EPI equation had a lower rate of underestimation but a relatively high rate of overestimation. New GFR estimation formulas are needed to be tailored to each ethnic group to enhance the accuracy and reliability of donor selection processes.

Comparison of the prevalence and associated factors of chronic kidney disease diagnosed by serum creatinine or cystatin C among young people living with HIV in Uganda.

Young people living with HIV (YPLHIV) are at increased risk of developing chronic kidney disease (CKD) which is associated with high mortality and morbidity. Early diagnosis is important to halt progression. We aimed to estimate the prevalence and factors associated with CKD among YPLHIV in Kampala, Uganda, and to compare serum creatinine and cystatin C for early diagnosis of CKD in this population. A cross-sectional study with YPLHIV aged 10 to 24 years was conducted in seven HIV clinics. Participants provided a urine and blood sample to measure urinary albumin, proteinuria, serum creatinine and cystatin C levels at baseline and after three months. The estimated glomerular filtration rate (eGFR) was calculated using CKDEPI 2021, Cockroft-Gault and bedside Schwartz equations using creatinine or cystatin C. The albumin creatinine ratio (ACR) and proteinuria were measured. CKD was defined as either eGFR <60ml/min/1.73m2 or <90ml/min/1.73m2 or ACR above 30mg/g on two separate occasions. Univariable and multivariable logistic regression were used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for factors associated with CKD. A total of 500 participants were enrolled. Most were female (56%; n=280) and aged 10 to 17 years (66.9%; n=335). CKD prevalence ranged from 0-23% depending on the criteria, equation and biomarker used. Cystatin C-based equations estimated higher prevalence of CKD compared to creatinine-based ones. Prevalence of ACR above 30mg/g was 10.1% and of proteinuria 29%. Factors independently associated with CKD were age (aOR=1.42; 95% CI:1.30-1.51) and male sex (aOR=3.02; 95% CI:1.68-5.43). CKD prevalence among YPLHIV varied substantially depending on definitions used and the current definition would likely lead to missed cases of CKD among YPLHIV. Estimating equations should be validated against measured GFR in YPLHIV and the optimal definition of CKD in this vulnerable population should be revised to optimise detection and opportunities for reducing disease progression.

Diabetic status and the performances of creatinine- and cystatin C-based eGFR equations.

The estimation of glomerular filtration rate (GFR) is one main tool to detect renal disease. The most used biomarker remains serum creatinine and the European Kidney Function Consortium (EKFCcrea) equation is the most validated in Europe. More recently, cystatin C, has been proposed. We studied the performances of the EKFC equations in a large cohort of subjects according to their diabetic status. Four cohorts from the EKFC dataset were retrospectively considered in which the diabetic status was available. GFR was measured by plasma clearances (mGFR) (iohexol or 51Cr-EDTA). The performance of the equations was assessed by calculating bias, precision (IQR) and P30 (percentage of eGFR-values within±30% of mGFR). In the whole population (n=6158), median [IQR] age was 61 [47;72] years, with 45.8% women. Mean mGFR was 60 [39;82] mL/min/1.73m². Compared to non-diabetic individuals (n=5124), diabetic patients (n=1034) were older, more frequently male, heavier, and had lower mGFR. The performance of the EKFCcys equation was similar to EKFCcrea, but the EKFCcrea+cys had better P30 than the single-biomarker equations. P30 values were substantially lower in diabetic patients than in non-diabetic but, according to a matched analysis, this is mainly explained by the difference in GFR levels between the two populations, not by diabetic status. We showed that equation combining creatinine and cystatin C present a better performance. If accuracy of equations seems better in non-diabetic than in diabetic individuals, it is more due to differences in GFR levels than to the diabetic status.

Accuracy of glomerular filtration rate estimation using creatinine and cystatin C for identifying and monitoring moderate chronic kidney disease: the eGFR-C study.

Estimation of glomerular filtration rate using equations based on creatinine is widely used to manage chronic kidney disease. In the UK, the Chronic Kidney Disease Epidemiology Collaboration creatinine equation is recommended. Other published equations using cystatin C, an alternative marker of kidney function, have not gained widespread clinical acceptance. Given higher cost of cystatin C, its clinical utility should be validated before widespread introduction into the NHS. Primary objectives were to: (1) compare accuracy of glomerular filtration rate equations at baseline and longitudinally in people with stage 3 chronic kidney disease, and test whether accuracy is affected by ethnicity, diabetes, albuminuria and other characteristics; (2) establish the reference change value for significant glomerular filtration rate changes; (3) model disease progression; and (4) explore comparative cost-effectiveness of kidney disease monitoring strategies. A longitudinal, prospective study was designed to: (1) assess accuracy of glomerular filtration rate equations at baseline (n = 1167) and their ability to detect change over 3 years (n = 875); (2) model disease progression predictors in 278 individuals who received additional measurements; (3) quantify glomerular filtration rate variability components (n = 20); and (4) develop a measurement model analysis to compare different monitoring strategy costs (n = 875). Primary, secondary and tertiary care. Adults (≥ 18 years) with stage 3 chronic kidney disease. Estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease equations. Measured glomerular filtration rate was the reference against which estimating equations were compared with accuracy being expressed as P30 (percentage of values within 30% of reference) and progression (variously defined) studied as sensitivity/specificity. A regression model of disease progression was developed and differences for risk factors estimated. Biological variation components were measured and the reference change value calculated. Comparative costs of monitoring with different estimating equations modelled over 10 years were calculated. Accuracy (P30) of all equations was ≥ 89.5%: the combined creatinine-cystatin equation (94.9%) was superior (p < 0.001) to other equations. Within each equation, no differences in P30 were seen across categories of age, gender, diabetes, albuminuria, body mass index, kidney function level and ethnicity. All equations showed poor (< 63%) sensitivity for detecting patients showing kidney function decline crossing clinically significant thresholds (e.g. a 25% decline in function). Consequently, the additional cost of monitoring kidney function annually using a cystatin C-based equation could not be justified (incremental cost per patient over 10 years = £43.32). Modelling data showed association between higher albuminuria and faster decline in measured and creatinine-estimated glomerular filtration rate. Reference change values for measured glomerular filtration rate (%, positive/negative) were 21.5/-17.7, with lower reference change values for estimated glomerular filtration rate. Recruitment of people from South Asian and African-Caribbean backgrounds was below the study target. Prospective studies of the value of cystatin C as a risk marker in chronic kidney disease should be undertaken. Inclusion of cystatin C in glomerular filtration rate-estimating equations marginally improved accuracy but not detection of disease progression. Our data do not support cystatin C use for monitoring of glomerular filtration rate in stage 3 chronic kidney disease. This trial is registered as ISRCTN42955626. This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/103/01) and is published in full in Health Technology Assessment; Vol. 28, No. 35. See the NIHR Funding and Awards website for further award information.

Creatinine-based formulas are not ideal to estimate glomerular filtration rate in selected pediatric patients: data from a tertiary pediatric nephrology center.

Evaluating glomerular filtration rate (GFR) remains challenging in pediatrics; new formulas were developed to increase performance of GFR estimation (eGFR). We aimed to evaluate the recently published formulas as applied to another pediatric population. A retrospective study was conducted in a cohort of 307 patients with a "kidney risk" (mean age 12.1 ± 4.5 years, sex ratio 1/1) assessed in a tertiary pediatric nephrology center and a mean measured GFR (mGFR) using plasma iohexol clearance of 85.5 ± 25.3 mL/min/1.73 m2; creatinine levels were measured by IDMS-standardized enzymatic method and cystatin C by immunonephelometry. The following eGFRs were calculated: Schwartz2009, Schwartz-Lyon, CKiDU25creat, and EKFC for eGFR using creatinine (eGFR-creat), CKiDU25cys and FAScys for eGFR using cystatin (eGFR-cys) as well as combined SchwartzCreat-Cys, average (CKiDU25creat-CKiDU25cys), and average (EKFC-FAScys) for eGFR using both biomarkers. The performance of the different formulas was evaluated compared to mGFR by absolute bias measurement and accuracy (p10%, p30%). Results are expressed as mean ± SD. Creatinine-based formulas and especially the new CKiDU25 and EKFC overestimate GFR, even in children with normal kidney function. However, the bias is constant with these two formulas whatever the age group or gender, contrary to the previously published formulas. In contrast, cystatin C-based equations and combined formulas showed good performance in all age groups and all medical conditions with an acceptable bias and p30%. In our pediatric population, the performance of all creatinine-based formulas is inadequate with significant GFR overestimation, mainly in subjects with mGFR > 75 mL/min/1.73 m2. Conversely, cystatin C-based or combined formulas have acceptable performance in patients followed in a tertiary pediatric nephrology unit.

#771 Estimating glomerular filtration rate: does the diabetic status influence the performances of current equations?

Abstract Background and Aims Diabetes is the first cause of chronic kidney disease (CKD) worldwide. The estimation of glomerular filtration rate (GFR) is one main tool to detect CKD. The most used biomarker remains serum creatinine and the European Kidney Function Consortium (EKFCcrea) equations is the most validated in Europe. More recently, another renal biomarker, cystatin C, has been proposed. In the current analysis, we studied the performances of the EKFC equations in a large cohort of subjects according to their diabetic status. Method Four cohorts from the EKFC dataset were considered in which the diabetic status was available: Lund, Sweden (n = 2,780), Berlin, Germany (n = 654), Créteil, France (n = 466), and Paris, France (n = 2,258). Serum creatinine and cystatin C were measured with calibrated assays. GFR was measured by plasma clearances (mGFR) (iohexol in Lund, Berlin and Créteil and 51Cr-EDTA in Paris). The performance of the equations was assessed by calculating bias, precision (IQR) and P30 (percentage of eGFR-values within ±30% of mGFR). As the characteristics of diabetic patients were different, we matched diabetic and non-diabetic patients using the following matching criteria: age (±3 years), sex (equal), mGFR (±3 mL/min/1.73 m²), and BMI (±2.5 kg/m²). Results In the whole population (n = 6,158), median [IQR] age was 61 [47; 72] years, with 45.8% of women. Mean measured GFR (mGFR) was 60 [39; 82] mL/min/1.73 m². Compared to non-diabetic subjects (n = 5,124), diabetic patients (n = 1,034) were older, more frequently males, heavier, had lower mGFR (45 vs 64 mL/min/1.73 m²), and higher creatinine (1.44 vs 1.06 mg/dL; p &amp;lt; 0.0001) and cystatin C (1.67 vs 1.20 mg/L) concentrations. The performance of the EKFCcys equation was similar to EKFCcrea, but the EKFCcrea+cys had better P30 than single-biomarker equations. Globally, P30 were substantially lower in diabetic patients than in non-diabetic patients (Table). We could match data for 289 females and 546 males. The results in the matched cohorts were quite similar between diabetics and non-diabetics subjects, and this is true for every equation. Conclusion In conclusion, in a large dataset of patients including diabetics and non-diabetics, we showed that the EKFC equations are accurate in diabetic and non-diabetic patients. Combining the creatinine and cystatin C-based equations presents an added value. If accuracy of all equations seems better in non-diabetic than in diabetic subjects, it is probably more due to differences in age and (still more) in GFR levels than to the diabetic status.

Utility of Cystatin C-based Equation for the Estimation of Glomerular Filtration Rate in a Pediatric Population.

The accurate assessment of kidney function is vital for the early detection of kidney damage. The estimated glomerular filtration rate GFR (eGFR) from serum cystatin C (CysC) and creatinine-based equations are commonly used in clinical practice as an alternative to the invasive measured glomerular filtration rate (mGFR), which is the usually accepted overall best index of kidney function in health and disease. Recently the CKiD under 25 (CkiD U25) equations have been shown to perform well in children and young adults with chronic kidney disease (CKD). In this focused report, we evaluated the performance of the CkiD U25 equations alongside 3 non-race-corrected (NRC) eGFR equations commonly used in pediatrics in our cohort. mGFR measured following the intravenous injection of tracer Tc-99mDTPA was retrospectively compared with eGFR from these equations in 57 patients (6 months to 22 years) from different races/ethnicities. Ordinary least squares regression analyses were used to assess correlation between the mGFRs and eGFRs. The average mGFR for this cohort was 84.1 mL/min/1.73 m2. The NRC creatinine equations overestimated eGFR across all groups, with the lowest bias for CKiD U25-creatinine (22.59 mL/min/1.73 m2). The best correlations to mGFR, P30, and lowest biases were the CKiD U25-CysC (0.6281, 80.7%, 3.72 mL/min/1.73 m2) and Schwartz CysC (0.6372, 77.2%, -4.68 mL/min/1.73 m2). Overall, both CKiD U25-CysC and Schwartz CysC provide a good estimation of mGFR with the CKiD U25-CysC having the overall best performance compared to mGFR in our study.

Evaluation of eGFR methods in a sub-Saharan African community-based pediatric population.

Accurate assessment of the estimated glomerular filtration rate (eGFR) plays a pivotal role in the early detection, management, and optimal medication dosing for chronic kidney disease (CKD). However, validation of eGFR, utilizing cystatin C-based equations, is limited in African children and adolescents with CKD. We evaluate the agreement of eGFR equations incorporating both cystatin C and creatinine in this specific population. This community-based study assessed CKD in children (2-15years) using cystatin C and serum creatinine. eGFR agreement with the reference was evaluated with Bland-Altman plots, ROC curves, and Lin's CCC, using the Under-25 serum creatinine-cystatin C equation as the reference standard. Pairwise ROC comparisons assess the statistical differences in estimation equation agreement. Among 666 children (mean age, 7.8 ± 3.8years; 48.6% male), CKD prevalence was 11.6% (95% CI, 9.2-14.2%). Notably, the Chehade equation, using combined biomarkers, aligned best with the reference, displaying the lowest mean deviation (- 0.59; 95% CI, - 1.19 to 0.01), superior agreement (P10, 91.0%; P30, 96.70%), and highest discriminatory power (0.989). In contrast, CKD-EPI 2012 cystatin C had the highest mean deviation (- 35.90) and lowest discriminatory power (0.79). Equations combining creatinine and cystatin C (Schwartz, Chehade, Full Age Spectrum) demonstrated strong positive Lin's CCC with CKiD U25 creatinine-cystatin C, while Bouvet showed a notably weak correlation (Lin's CCC, 0.22). In African children with CKD, the Chehade, CKiD Under 25 creatinine-based equations, and the Full Age Spectrum equations show promise for CKD diagnosis. However, a measured GFR is essential to identifying the most accurate eGFR equation in this population.

New race-free creatinine- and cystatin C-based equations for the estimation of glomerular filtration rate and association with cardiovascular mortality in the AtheroGene study

Renal function is associated with cardiovascular outcomes and mortality. Among equations used to eGFR, CKD–EPI equations show more accurate association with cardiovascular risk and mortality than MDRD. Recently, new CKD–EPI equations were proposed which do not include race and would be considered sufficiently accurate to estimate eGFR in clinical practice. It is unknown if these new race-free equations are comparably well associated with cardiovascular outcomes in high-risk individuals. The analysis was performed in the AtheroGene Study cohort including patients at high cardiovascular risk. eGFR was determined using the established as well as the recently developed formulas which are calculated without the otherwise existing coefficient for black race. The outcome was cardiovascular death. Analyses included Cox-proportional hazard regression and area-under-the-curve calculation. The analysis included 2089 patients followed up for a median of 3.8 years with a maximum of 6.9 years, corresponding to an overall period of 7701 patient-years. Cardiovascular death occurred in 93 (4.45%), corresponding to an annualized rate of 1.2/100 person-years. In all Cox regression analyses, the estimated adjusted GFR was an independent predictor of cardiovascular death. The equations which included cystatin C showed higher C-index compared to those which did not include cystatin C (0.75–0.76 vs. 0.71, respectively). The equations for the estimation of eGFR which include cystatin C are better associated with cardiovascular death compared to the race-free equations which include only creatinine. This finding adds on the related literature which supports the elimination of race in GFR-estimating equations, and promotion of the use of cystatin C.

Assessment of the 2023 European Kidney Function Consortium (EKFC) equations in a Chinese adult population.

The European Kidney Function Consortium (EKFC) developed two novel equations in 2023 for estimating glomerular filtration rate (GFR): one sex-free cystatin C-based equation (EKFCCys) and one creatinine-cystatin C combined equation (EKFCCr-Cys). This study compared their performance with the previous creatinine-based EKFC equation (EKFCCr) and commonly used Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Berlin Initiative Study (BIS) equations in Chinese adults. A total of 2,438 Chinese adults (mean age=53.04 years) who underwent the 99mTc-DTPA renal dynamic imaging for reference GFR (rGFR) were included. Diagnostic value was evaluated using correlation coefficients, sensitivity, specificity, and area under the receiver operating characteristic curve (ROCAUC). Performance was assessed in terms of bias, precision (interquartile range of the median difference [IQR]), accuracy (percentage of estimates ±30 % of rGFR [P30], and root-mean-square error [RMSE]) across age, sex, and rGFR subgroups. Gender differences in bias and P30 were also analyzed. Average rGFR was 73.37 mL/min/1.73 m2. EKFC equations showed stronger correlations and larger AUCs compared to the parallel CKD-EPI equations, with EKFCCr-Cys demonstrating the greatest improvement (R=0.771, ROCAUC=0.913). Concerning bias, precision, and accuracy, EKFC equations consistently outperformed CKD-EPI equations. EKFCCr-Cys and EKFCCr performed acceptably well in the entire population and were equivalent to BIS equations in the elderly. All equations, including EKFCCys, showed similar P30 accuracy across sexes. EKFC equations provided a reasonable alternative for estimating GFR in the Chinese adult population. While EKFCCys did not outperform EKFCCr, EKFCCr-Cys improved the accuracy of single-marker equations.

A Pilot Study for the Kidney Effects of Voxelotor in Sickle Cell Anemia

The kidneys are among the most commonly affected organ systems in sickle cell anemia (SCA) and an estimated 15% of deaths in patients with SCA are attributed to kidney failure (PMID 7993409). Angiotensin converting enzyme-inhibitors and angiotensin receptor blockers have been adopted to treat SCA-related chronic kidney disease (CKD) from the non-SCA literature, although demonstrated efficacy in SCA CKD has been marginal in a limited number of small, short-term studies (PMID 28589652). Therapies that directly target the pathophysiology of SCA-related kidney disease may stabilize or improve kidney function. Both the rate of hemolysis and the degree of anemia are associated with the development and progression of CKD in SCA (PMID 24329963, 21523807). Voxelotor inhibits hemoglobin polymerization in SCA red blood cells in the deoxygenated state, leading to a reduction in the rate of hemolysis and an increase in hemoglobin concentration. We conducted a pilot study to determine whether voxelotor can improve kidney function in adults with SCA (NCT 04335721). SCA (HbSS or HbSβ 0-thalassemia) patients ≥ 18 years old and with urine dipstick-defined hemoglobinuria (+ for blood &amp; ≤ 2 red blood cells/high power field), CKD stage 1 or 2 (urine albumin-to-creatinine ratio [ACR] ≥ 30 mg/g &amp; estimated glomerular filtration rate [eGFR] ≥ 60 mL/min/1.73m 2), and hemoglobin concentrations of 5.5 - 10.5 g/dL were eligible. The eGFR was calculated using the CKD-EPI 2009 creatinine-based equation without the race coefficient and the 2012 cystatin C-based equation. Patients were randomized to voxelotor 1,500mg/day for 48 weeks or standard of care, as defined by their primary SCA provider. First or second void urines were collected for urine ACR measurements. The primary endpoint was the change in urine ACR from the mean values at baseline and screening versus the mean values at 47 and 48 week visits. One patient randomized to standard of care was started on voxelotor at week 24 by his provider to improve his hemoglobin concentration. This patient is included in the voxelotor treatment group in combined analysis; the change in laboratory measures in this patient is based upon changes from the mean of values at week 12 and 24 to week 47 and 48 visits. Median and range values are provided. Between 3/2021 and 6/2022, 8 SCA patients with hemoglobinuria and urine ACR &amp;gt; 30mg/g crt observed during routine clinic visits were screened and 6 met the inclusion criteria. The median age of the enrolled cohort was 36 (27 - 63) years, 4 were male, 4 were on stable doses of hydroxyurea (median dose 1000mg/day; 500 - 1500mg/day) and 2 were on stable doses of lisinopril (5, 20mg/day) for at least 90 days before screening. Two other patients had been on lisinopril in the past but developed hyperkalemia prior to enrollment. The median values of kidney function measures at screening and baseline study visits were as follows: urine ACR, 251 (32 - 3132) and 392 (80 - 3101) mg/g crt; creatinine-based eGFR, 109 (93 - 136) and 115 (88 - 137) mL/min/1.73m 2; and cystatin C-based eGFR, 82 (61 - 141) and 85 (61 - 128) mL/min/1.73m 2, respectively. SCA patients who received voxelotor (n = 4) had a median increase in hemoglobin concentration of +0.9 g/dL (-0.4 - +2.6 g/dL) and reductions in indirect bilirubin concentration of -2.2 mg/dL (0 - -4 mg/dL) and reticulocyte % of -2.7% (-1.2 - -4.9%). Urine ACR (-59%, -21% - -100%) improved in SCA patients treated with voxelotor but worsened in those who received standard of care without voxelotor (n = 2) (+86.3%, 64 - 108%) (P=0.009) (Figure 1A). 24-hour urine protein concentrations also improved in those that received voxelotor (-45%, -25% - -100%) but increased in those who did not receive voxelotor (+122%, 113 - 131%) (P = 0.002) (Figure 1B). Changes in creatinine- and cystatin-C based eGFR from baseline were not significantly different between patients who received voxelotor and those who did not. This pilot study demonstrates that SCA patients with hemoglobinuria and early stages of CKD treated with voxelotor may have significant improvements in urine ACR and proteinuria after 24 - 48 weeks of therapy. These preliminary results support the concept that improving hemolytic anemia could be a targeted therapeutic approach to reduce biomarkers of kidney dysfunction, and they warrant larger, prospective clinical studies.

Diagnostic standard: assessing glomerular filtration rate.

Creatinine-based estimated glomerular filtration rate (eGFR) is imprecise at individual level, due to non-GFR-related serum creatinine determinants, including atypical muscle mass. Cystatin C has the advantage of being independent of muscle mass, a feature that led to the development of race- and sex-free equations. Yet, cystatin C-based equations do not perform better than creatinine-based equations for estimating GFR unless both variables are included together. The new race-free Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation had slight opposite biases between Black and non-Black subjects in the USA, but has poorer performance than that the previous version in European populations. The European Kidney Function Consortium (EKFC) equation developed in 2021 can be used in both children and adults, is more accurate in young and old adults, and is applicable to non-white European populations, by rescaling the Q factor, i.e. population median creatinine, in a potentially universal way. A sex- and race-free cystatin C-based EKFC, with the same mathematical design, has also be defined. New developments in the field of GFR estimation would be standardization of cystatin C assays, development of creatinine-based eGFR equations that incorporate muscle mass data, implementation of new endogenous biomarkers and the use of artificial intelligence. Standardization of different GFR measurement methods would also be a future challenge, as well as new technologies for measuring GFR. Future research is also needed into discrepancies between cystatin C and creatinine, which is associated with high risk of adverse events: we need to standardize the definition of discrepancy and understand its determinants.

Performance of Creatinine and Cystatin C-Based Equations Among Patients with Hematological or Solid Cancers: Real-World Data from a Clinical Cohort

Performance of Creatinine and Cystatin C-Based Equations Among Patients with Hematological or Solid Cancers: Real-World Data from a Clinical Cohort

Estimated glomerular filtration rate among intensive care unit survivors: From the removal of race coefficient to cystatin C-based equations

PurposeBlack race coefficient used in serum creatinine (sCr)-based estimated glomerular filtration rate (eGFR) calculation may perpetuate racial disparities. Among intensive care unit (ICU) survivors, sCr overestimates kidney function due to sarcopenia. Cystatin C (cysC) is a race- and muscle mass-independent eGFR marker. We investigated the impact of removing the race coefficient from sCr-based eGFR and compared cysC- and sCr-based eGFR in ICU survivors. Materials and methodsAmong 30,920 patients from 2 institutions in the Bronx and Boston, eGFR was calculated at hospital discharge using sCr-based equations with and without race coefficient (eGFRsCr2009 and eGFRsCr2021). In a subset with available cysC between ICU admission and 1-year follow-up, sCr- and cysC-based estimates were compared. ResultseGFRsCr2021 was higher than eGFRsCr2009 by a median of 4 ml/min/1.73 m2 among non-Black patients and lower by a median of 8 ml/min/1.73 m2 among Black patients. Removing race coefficient reclassified 12.9% of non-Black subjects and 16.1% of Black subjects to better and worse eGFR category, respectively, and differentially impacted the prevalence of kidney dysfunction between the institutions due to differences in racial composition. Among 51 patients with available cysC (108 measurements), cysC-based estimates were lower than sCr-based estimates (median difference 9 to 16 ml/min/1.73 m2), resulting in reclassification to worse eGFR category in 34% to 53.5% of measurements. ConclusionsAmong ICU survivors, removal of race coefficient leads to lower eGFR in Black patients and may contribute to overestimation of kidney function in non-Black patients. While cysC is rarely used, estimates based on this marker are significantly lower than those based on sCr.

Diagnostic challenges of diabetic kidney disease.

Diabetic kidney disease (DKD) is one of the most common microvascular complications of both type 1 and type 2 diabetes and the most common cause of the end-stage renal disease (ESRD). It has been evidenced that targeted interventions at an early stage of DKD can efficiently prevent or delay the progression of kidney failure and improve patient outcomes. Therefore, regular screening for DKD has become one of the fundamental principles of diabetes care. Long-established biomarkers such as serum-creatinine-based estimates of glomerular filtration rate and albuminuria are currently the cornerstone of diagnosis and risk stratification in routine clinical practice. However, their immanent biological limitations and analytical variations may influence the clinical interpretation of the results. Recently proposed new predictive equations without the variable of race, together with the evidence on better accuracy of combined serum creatinine and cystatin C equations, and both race- and sex-free cystatin C-based equation, have enabled an improvement in the detection of DKD, but also require the harmonization of the recommended laboratory tests, wider availability of cystatin C testing and specific approach in various populations. Considering the complex pathophysiology of DKD, particularly in type 2 diabetes, a panel of biomarkers is needed to classify patients in terms of the rate of disease progression and/or response to specific interventions. With a personalized approach to diagnosis and treatment, in the future, it will be possible to respond to DKD better and enable improved outcomes for numerous patients worldwide.

Effect of Two Cystatin C Reagents and Four Equations on Glomerular Filtration Rate Estimations After Standardization.

Serum cystatin C (cysC), which is less affected by sex, race, and muscle mass than creatinine, is a useful biomarker of the estimated glomerular filtration rate (eGFR). The standardization of cysC measurements remains controversial, although a certified reference material (ERM-DA471/IFCC) is available. Moreover, the effect of combinations of cysC reagents and equations for eGFR is unclear. We conducted a simulation analysis of cysC measured using two reagents standardized against ERM-DA471/IFCC-Gentian cystatin C immunoassay (Gentiancys; GentianAS, Moss, Norway) and Roche Tina-quant Cystatin C Gen.2 (Rochecys; Roche, Mannheim, Germany)-on a Cobas c702 system (Roche) and eGFR generated by eight combinations of four equations: 2012 cystatin C-based Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPIcys); the Caucasian, Asian, pediatric, and adult equation (CAPAeq); full age spectrum equation (FASeq); and 2023 cystatin C-based European Kidney Function Consortium equation (EKFCcys). A total of 148 participants (mean age, 60.5±14.5 years; 43% female) were enrolled. The mean cysC was 1.72±1.44 mg/L for Gentiancys and 1.71±1.35 mg/L for Rochecys. Regression analysis showed concordance between the reagents within 0.85-4.40 mg/L when using ±7.61% total allowable error. Lin's concordance correlation coefficient of eGFR, by combining the measuring system and equation, varied from 0.73 to 1.00. The equivalence of cysC values at low concentrations (<0.85 mg/L) between the two reagents was unsatisfactory. Results obtained with different measurement systems could lead to larger differences in eGFR varying with the combination.

#3207 KIDNEY FUNCTION ESTIMATORS FOR DRUG DOSE ADJUSTMENT OF DIRECT ORAL ANTICOAGULANTS IN OLDER ADULTS WITH ATRIAL FIBRILLATION

Abstract Background and Aims The Food and Drug Administration and the European Medicines Agency (EMA) recommend using the Cockcroft-Gault equation (CG) for drug dose adjustment of direct oral anticoagulant drugs (DOACs) in non-valvular atrial fibrillation (NVAF), whereas Cardiology guidelines recommend using estimated glomerular filtration rate (eGFR). This issue is of great importance in older adults, which are more prone to adverse drug reactions and have higher prevalence of atrial fibrillation as compared to younger adults, and in whom CG has worse diagnostic performance than most eGFR equations. We aimed to assess if prognosis was similar according to drug dose status using different kidney function estimators based on creatinine and/or cystatin C in older adults with NVAF. Method We used data from the Berlin Initiative Study (BIS): a population-based prospective cohort study initiated in 2009, with five biennial study visits. Participants with a history of NVAF (based on ICD-10 codes) and a dispensed prescription of DOAC four months prior to baseline or a follow-up visit according to claims data were included. Drug dose status was defined according to the EMA guidelines. CG, deindexed (in ml/min) creatinine and/or cystatin C-based CKD-EPI, and deindexed BIS 1 (creatinine-based) and BIS 2 (creatinine and cystatin C-based) equations were included. Associations between dosing status and mortality, stroke or systemic embolism, and bleeding events were assessed using marginal structural Cox models with time-varying variables and taking account of various confounders. Subgroup analyses were performed in rivaroxaban and apixaban users, but not in dabigatran and edoxaban users because of too small sample sizes. Results Two hundred twenty four patients treated with DOACs were included in this analysis (median age 87 years, median eGFRCKD-EPIcr 56 ml/min/1.73m², median follow-up length 40 months for the mortality analysis). Of those, 99 (44%) were taking rivaroxaban, 86 (38%) apixaban, 21 (9%) edoxaban, and 18 (8%) dabigatran. Using CG, 154 (69%) had appropriate DOAC dose at baseline, 52 (23%) were underdosed, and 18 (8%) were overdosed. Discrepancies were found by comparing dosing status according to CG and eGFR equations (Figure 1). During the follow-up period, 109 (14.9/100 person-years) participants died, 25 (3.6/100 person-years) experienced a stroke or systemic embolism, and 60 (9.9/100 person-years) experienced a bleeding event. Drug dose status was not significantly associated with mortality and the occurrence of stroke or systemic embolism, whatever equation was used. Underdose status was associated with a significantly lower risk of bleeding events with all the equations but overdose status was not associated with a higher risk of bleeding events (Figure 2). In subgroup analyses, drug dose status was not associated with mortality and bleeding event in apixaban users, whatever equation was used. In rivaroxaban users, underdose status was associated with a significant higher risk of death by using CG, eGFRCKD-EPIcys, and BIS 2, and a lower risk of bleeding event by using eGFRCKD-EPIcr. Conclusion In this population of very old adults with NVAF, drug dose status of DOAC was not associated with mortality or the occurrence of stroke or systemic embolism for any of the studied equations. However, underdose status was associated with bleeding events occurrence regardless of the equation used. These associations differed according to the used drug, but this should be interpreted with cautious due to small sample sizes. Our results do not allow us to provide any guidance which equation to use in this context. A study including a larger group of patients with discrepancy in dose status according to the used equations would be of great interest.