Cystatin C-Based Equation to Estimate GFR without the Inclusion of Race and Sex.

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.).

New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race.

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 m2 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 m2; 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 m2; 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 m2; 95% CI, 1.8 to 5.5) and overestimated measured GFR in non-Blacks (median, 3.9 ml per minute per 1.73 m2; 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.).

Race, Genetic Ancestry, and Estimating Kidney Function in CKD.

BACKGROUND: The inclusion of race in equations to estimate the glomerular filtration rate (GFR) has become controversial. Alternative equations that can be used to achieve similar accuracy without the use of race are needed. METHODS: In a large national study involving adults with chronic kidney disease, we conducted cross-sectional analyses of baseline data from 1248 participants for whom data, including the following, had been collected: race as reported by the participant, genetic ancestry markers, and the serum creatinine, serum cystatin C, and 24-hour urinary creatinine levels. RESULTS: Using current formulations of GFR estimating equations, we found that in participants who identified as Black, a model that omitted race resulted in more underestimation of the GFR (median difference between measured and estimated GFR, 3.99 ml per minute per 1.73 m2 of body-surface area; 95% confidence interval [CI], 2.17 to 5.62) and lower accuracy (percent of estimated GFR within 10% of measured GFR [P10], 31%; 95% CI, 24 to 39) than models that included race (median difference, 1.11 ml per minute per 1.73 m2; 95% CI, -0.29 to 2.54; P10, 42%; 95% CI, 34 to 50). The incorporation of genetic ancestry data instead of race resulted in similar estimates of the GFR (median difference, 1.33 ml per minute per 1.73 m2; 95% CI, -0.12 to 2.33; P10, 42%; 95% CI, 34 to 50). The inclusion of non-GFR determinants of the serum creatinine level (e.g., body-composition metrics and urinary excretion of creatinine) that differed according to race reported by the participants and genetic ancestry did not eliminate the misclassification introduced by removing race (or ancestry) from serum creatinine-based GFR estimating equations. In contrast, the incorporation of race or ancestry was not necessary to achieve similarly statistically unbiased (median difference, 0.33 ml per minute per 1.73 m2; 95% CI, -1.43 to 1.92) and accurate (P10, 41%; 95% CI, 34 to 49) estimates in Black participants when GFR was estimated with the use of cystatin C. CONCLUSIONS: The use of the serum creatinine level to estimate the GFR without race (or genetic ancestry) introduced systematic misclassification that could not be eliminated even when numerous non-GFR determinants of the serum creatinine level were accounted for. The estimation of GFR with the use of cystatin C generated similar results while eliminating the negative consequences of the current race-based approaches. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

Toward Equitable Kidney Function Estimation in Critical Care Practice: Guidance From the Society of Critical Care Medicine's Diversity, Equity, and Inclusion in Renal Clinical Practice Task Force.

OBJECTIVES: Accurate glomerular filtration rate (GFR) assessment is essential in critically ill patients. GFR is often estimated using creatinine-based equations, which require surrogates for muscle mass such as age and sex. Race has also been included in GFR equations, based on the assumption that Black individuals have genetically determined higher muscle mass. However, race-based GFR estimation has been questioned with the recognition that race is a poor surrogate for genetic ancestry, and racial health disparities are driven largely by socioeconomic factors. The American Society of Nephrology and the National Kidney Foundation (ASN/NKF) recommend widespread adoption of new "race-free" creatinine equations, and increased use of cystatin C as a race-agnostic GFR biomarker. DATA SOURCES: Literature review and expert consensus. STUDY SELECTION: English language publications evaluating GFR assessment and racial disparities. DATA EXTRACTION: We provide an overview of the ASN/NKF recommendations. We then apply an Implementation science methodology to identify facilitators and barriers to implementation of the ASN/NKF recommendations into critical care settings and identify evidence-based implementation strategies. Last, we highlight research priorities for advancing GFR estimation in critically ill patients. DATA SYNTHESIS: Implementation of the new creatinine-based GFR equation is facilitated by low cost and relative ease of incorporation into electronic health records. The key barrier to implementation is a lack of direct evidence in critically ill patients. Additional barriers to implementing cystatin C-based GFR estimation include higher cost and lack of test availability in most laboratories. Further, cystatin C concentrations are influenced by inflammation, which complicates interpretation. CONCLUSIONS: The lack of direct evidence in critically ill patients is a key barrier to broad implementation of newly developed "race-free" GFR equations. Additional research evaluating GFR equations in critically ill patients and novel approaches to dynamic kidney function estimation is required to advance equitable GFR assessment in this vulnerable population.

Biomarkers vs Machines: The Race to Predict Acute Kidney Injury.

BACKGROUND: Acute kidney injury (AKI) is a serious complication affecting up to 15% of hospitalized patients. Early diagnosis is critical to prevent irreversible kidney damage that could otherwise lead to significant morbidity and mortality. However, AKI is a clinically silent syndrome, and current detection primarily relies on measuring a rise in serum creatinine, an imperfect marker that can be slow to react to developing AKI. Over the past decade, new innovations have emerged in the form of biomarkers and artificial intelligence tools to aid in the early diagnosis and prediction of imminent AKI. CONTENT: This review summarizes and critically evaluates the latest developments in AKI detection and prediction by emerging biomarkers and artificial intelligence. Main guidelines and studies discussed herein include those evaluating clinical utilitiy of alternate filtration markers such as cystatin C and structural injury markers such as neutrophil gelatinase-associated lipocalin and tissue inhibitor of metalloprotease 2 with insulin-like growth factor binding protein 7 and machine learning algorithms for the detection and prediction of AKI in adult and pediatric populations. Recommendations for clinical practices considering the adoption of these new tools are also provided. SUMMARY: The race to detect AKI is heating up. Regulatory approval of select biomarkers for clinical use and the emergence of machine learning algorithms that can predict imminent AKI with high accuracy are all promising developments. But the race is far from being won. Future research focusing on clinical outcome studies that demonstrate the utility and validity of implementing these new tools into clinical practice is needed.

Kidney Function Measures and Mortality: A Mendelian Randomization Study.

RATIONALE & OBJECTIVE: Individuals with a low estimated glomerular filtration rate (eGFR) are at a high risk of death. However, the causes underpinning this association are largely uncertain. This study aimed to assess the causal relationship of low eGFR with all-cause and cause-specific mortality. STUDY DESIGN: Retrospective cohort study incorporating Mendelian randomization (MR). SETTING & PARTICIPANTS: Individual-level data from 436,214 White participants (54.3% female; aged 56.8±8.0 years) included in the UK Biobank. EXPOSURES: eGFR estimated using cystatin C (eGFRcyst). OUTCOMES: The outcomes of interest included all-cause mortality, cardiovascular mortality, cancer mortality, infection mortality, and other-cause mortality. ANALYTICAL APPROACH: Cox proportional hazards analysis for the conventional observational analyses; linear and nonlinear MR analyses implemented using genetic allele scores as instrumental variables representing kidney function to estimate the effect of kidney function on the survival outcomes. RESULTS: During a median follow-up of 12.1 years, there were 30,489 deaths, 6,098 of which were attributed to cardiovascular events, 15,538 to cancer, 1,516 to infection, and 7,227 to other events. In the conventional observational analysis, eGFRcyst exhibited a nonlinear association with all the outcomes. MR analysis suggested that a genetically predicted lower eGFRcyst was linearly associated with a higher rate of cardiovascular mortality (HR, 1.43; 95% CI, 1.18-1.75) across the entire measurement range (every 10-mL/min/1.73m2 decrement). Nonetheless, no causal associations between eGFRcyst and all-cause mortality (HR, 1.07; 95% CI, 0.98-1.17) or any types of noncardiovascular mortality were detected. LIMITATIONS: Potential misclassification of the actual cause of death, a nonrepresentative sample, and potential error in the interpretation of the magnitude of associations generated in MR analyses. CONCLUSIONS: These findings suggest a potential causal association between low eGFR and cardiovascular mortality in the general population, but no causal relationship with all-cause mortality or noncardiovascular mortality was observed. Further studies in other populations are warranted to confirm these findings. PLAIN-LANGUAGE SUMMARY: This study investigated the existence of a causal relationship between lower kidney function and death of different causes. Using data from 436,214 people in the United Kingdom, we applied conventional statistical analyses and those incorporating genetic data to implement Mendelian randomization, an approach that estimates causal associations. The observational analysis showed a nonlinear association between kidney function and various types of mortality outcomes. However, Mendelian randomization analysis suggested a linear increase in the risk of cardiovascular mortality with lower kidney function, but no causal link between the level of kidney function and all-cause or noncardiovascular mortality was identified. Managing kidney health may help reduce cardiovascular mortality, but caution is needed in interpreting the magnitudes of these results. Further validation in other populations and in those with advanced kidney failure is needed.

Difference Between Estimated GFR Based on Cystatin C Versus Creatinine and Incident Atrial Fibrillation: A Cohort Study of the UK Biobank.

RATIONALE & OBJECTIVE: The difference between cystatin C-based and creatinine-based estimated glomerular filtration rate (eGFRdiff) has been suggested to reflect factors distinct from kidney function that are associated with cardiovascular risk. However, the association between eGFRdiff and atrial fibrillation (AF) risk has not been extensively evaluated. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Using data from the UK Biobank, this study included 363,494 participants with measured serum creatinine and cystatin C levels and without a prior diagnosis of AF or a history of related procedures. EXPOSURE: Estimated GFRdiff, calculated as cystatin C-based eGFR minus creatinine-based eGFR. Estimated GFRdiff was also categorized as negative (<-15mL/min/1.73m2), midrange (-15 to 15mL/min/1.73m2), or positive (≥15mL/min/1.73m2). OUTCOME: Incident AF. ANALYTICAL APPROACH: Subdistribution hazard models were fit, treating death that occurred before development of AF as a competing event. RESULTS: During the median follow-up period of 11.7 years, incident AF occurred in 18,994 (5.2%) participants. In the multivariable-adjusted model, participants with a negative eGFRdiff had a higher risk of incident AF (subdistribution HR [SHR], 1.25 [95% CI, 1.20-1.30]), whereas participants with a positive eGFRdiff had a lower risk of AF (SHR, 0.81 [95% CI, 0.77-0.87]) compared with those with a midrange eGFRdiff. When eGFRdiff was treated as a continuous variable in the adjusted model, every 10mL/min/1.73m2 higher eGFRdiff was associated with a 0.90-fold decrease in the risk of incident AF. LIMITATIONS: A single measurement of baseline serum creatinine and cystatin C levels. CONCLUSIONS: The difference between cystatin C- and creatinine-based eGFRs was associated with the risk of AF development. A higher eGFRdiff was associated with a lower risk of AF. These findings may have implications for the management of patients at risk of incident AF. PLAIN-LANGUAGE SUMMARY: The difference between cystatin C-based estimated glomerular filtration rate (eGFR) and creatinine-based eGFR has recently gained attention as a potential indicator of cardiovascular outcomes influenced by factors other than kidney function. This study investigated the association between the differences in 2 eGFRs (cystatin C-based eGFR minus creatinine-based eGFR) and incident atrial fibrillation (AF) among>340,000 participants from the UK Biobank Study. Compared with those with a near zero eGFR difference, participants with a negative eGFR difference had a higher risk of AF, while those with a positive eGFR difference had a lower risk. These findings suggest that measuring eGFR differences may help identify individuals at a higher risk of developing AF.

Association of cardiac biomarkers with long-term cardiovascular events in a community cohort.

MATERIALS AND METHODS: The study assessed major adverse cardiac events (MACE) (myocardial infarction, coronary artery bypass graft, percutaneous intervention, stroke, and death. Cox proportional hazards models assessed apolipoprotein AI (ApoA1), apolipoprotein B (ApoB), ceramide score, cystatin C, galectin-3 (Gal3), LDL-C, Non-HDL-C, total cholesterol (TC), N-terminal B-type natriuretic peptide (NT proBNP), high-sensitivity cardiac troponin (HscTnI) and soluble interleukin 1 receptor-like 1. In adjusted models, Ceramide score was defined by from N-palmitoyl-sphingosine [Cer(16:0)], N-stearoyl-sphingosine [Cer(18:0)], N-nervonoyl-sphingosine [Cer(24:1)] and N-lignoceroyl-sphingosine [Cer(24:0)]. Multi-biomarker models were compared with C-statistics and Integrated Discrimination Index (IDI). RESULTS: A total of 1131 patients were included. Adjusted NT proBNP per 1 SD resulted in a 31% increased risk of MACE/death (HR = 1.31) and a 31% increased risk for stroke/MI (HR = 1.31). Adjusted Ceramide per 1 SD showed a 13% increased risk of MACE/death (HR = 1.13) and a 29% increased risk for stroke/MI (HR = 1.29). These markers added to clinical factors for both MACE/death (p = 0.003) and stroke/MI (p = 0.034). HscTnI was not a predictor of outcomes when added to the models. DISCUSSION: Ceramide score and NT proBNP improve the prediction of MACE and stroke/MI in a community primary prevention cohort.

In a community cohort, where a wide range of biomarkers were evaluated, Ceramide score provided additive value over traditional cardiac risk factors alone for predicting stroke/MI. NT ProBNP provided additive value in prediction of MACE/death. Other biomarkers failed to improve the discrimination of these models.

An LC-MS/MS method for serum cystatin C quantification and its comparison with two commercial immunoassays.

OBJECTIVES: The standardization of cystatin C (CysC) measurement has received increasing attention in recent years due to its importance in estimating glomerular filtration rate (GFR). Mass spectrometry-based assays have the potential to provide an accuracy base for CysC measurement. However, a precise, accurate and sustainable LC-MS/MS method for CysC is still lacking. METHODS: The developed LC-MS/MS method quantified CysC by detecting signature peptide (T3) obtained from tryptic digestion. Stable isotope labeled T3 peptide (SIL-T3) was spiked to control matrix effects and errors caused by liquid handling. The protein denaturation, reduction and alkylation procedures were combined into a single step with incubation time of 1 h, and the digestion lasted for 3.5 h. In the method validation, digestion time-course, imprecision, accuracy, matrix effect, interference, limit of quantification (LOQ), carryover, linearity, and the comparability to two routine immunoassays were evaluated. RESULTS: No significant matrix effect or interference was observed with the CysC measurement. The LOQ was 0.21 mg/L; the within-run and total imprecision were 1.33-2.05 % and 2.18-3.90 % for three serum pools (1.18-5.34 mg/L). The LC-MS/MS method was calibrated by ERM-DA471/IFCC and showed good correlation with two immunoassays traceable to ERM-DA471/IFCC. However, significant bias was observed for immunoassays against the LC-MS/MS method. CONCLUSIONS: The developed LC-MS/MS method is robust and simpler and holds the promise to provide an accuracy base for routine immunoassays, which will promote the standardization of CysC measurement.

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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Comparison of cystatin C-based estimated glomerular filtration rate with measured glomerular filtration rate in a pediatric cohort of patients with chronic kidney disease.

BACKGROUND: It is essential to have an accurate assessment of the renal function of patients with chronic kidney disease to monitor, treat, and predict further development of the condition. Measurement of renal function in terms of glomerular filtration rate (GFR) requires either urine or blood sampling, but especially in children, more simple methods of measurement are preferable. The main objective of this study was to examine if the estimated GFR (eGFR) calculated with different cystatin-C-based equations was comparable to the GFR measured by a radiotracer (mGFR) in pediatric patients. METHODS: In this retrospective study, 28 pediatric patients contributed with 73 pairs of measurements collected within 5 years. Bland-Altman Limits of Agreement were used to evaluate the performance and accuracy of two different cystatin-C-based estimates, the CKiDCrea-CysC and the CKiDU25 respectively, compared to an mGFR based on plasma clearance of technetium-99m-diethylenetriaminepentaacetic acid or chromium-51-ethylenediaminetetraacetic acid. RESULTS: Using the CKiDCrea-CysC equation, 58.9% of the datasets were within P10 and 87.7% were within P30. The mean difference was 4.8 mL/min/1.73m2 (standard deviation: 8.5 mL/min/1.73m2) and tended to overestimate GFR and thereby overrate the kidney function within the entire GFR range. Using the CKiDU25 equation, 53.4% were within P10 and 93.2% within P30. The mean difference was -2.9 mL/min/1.73m2 (standard deviation: 8.4 mL/min/1.73m2), but the difference varied with the GFR value. CONCLUSIONS: A cystatin-C-based eGFR provides a viable substitute for monitoring renal function in pediatric patients with chronic kidney disease. However, it has a lower accuracy than mGFR and can therefore not replace mGFR in clinical use.

Measurement of Glomerular Filtration Rate in Patients Undergoing Renal Surgery for Cancer: Estimated Glomerular Filtration Rate versus Measured Glomerular Filtration Rate in the Era of Precision Medicine.

BACKGROUND: In the era of precision medicine, determining reliable renal function assessment remains a critical and debatable issue, especially in nephrology and oncology. SUMMARY: This paper delves into the significance of accurately measured glomerular filtration rate (mGFR) in clinical practice, highlighting its essential role in guiding medical decisions and managing kidney health, particularly in the context of renal cancer (RC) patients undergoing nephrotoxic anti-cancer drugs. The limitations and advantages of traditional glomerular filtration rate (GFR) estimation methods, primarily using serum biomarkers like creatinine and cystatin C, are discussed, emphasizing their possible inadequacy in cancer patients. Specifically, newer formulae designed for GFR estimation in cancer patients may not perform at best in RC patients. The paper explores various methods for direct GFR measurement, including the gold standard inulin clearance and alternatives like iohexol plasma clearance. KEY MESSAGE: Despite the logistical challenges of these methods, their implementation is crucial for accurate renal function assessment. The paper concludes by emphasizing the need for continued research and innovation in GFR measurement methodologies to improve patient outcomes, particularly in populations with complex medical needs.

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

BACKGROUND: 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. METHODS: This community-based study assessed CKD in children (2-15 years) 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. RESULTS: Among 666 children (mean age, 7.8 ± 3.8 years; 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). CONCLUSION: 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.

Comparison of estimated GFR using cystatin C versus creatinine in pediatric kidney transplant recipients.

BACKGROUND: An accurate, rapid estimate of glomerular filtration rate (GFR) in kidney transplant patients affords early detection of transplant deterioration and timely intervention. This study compared the performance of serum creatinine (Cr) and cystatin C (CysC)-based GFR equations to measured GFR (mGFR) using iohexol among pediatric kidney transplant recipients. METHODS: CysC, Cr, and mGFR were obtained from 45 kidney transplant patients, 1-18 years old. Cr- and CysC-estimated GFR (eGFR) was compared against mGFR using the Cr-based (Bedside Schwartz, U25-Cr), CysC-based (Gentian CysC, CAPA, U25-CysC), and Cr-CysC combination (CKiD Cr-CysC, U25 Cr-CysC) equations in terms of bias, precision, and accuracy. Bland-Altman plots assessed the agreement between eGFR and mGFR. Secondary analyses evaluated the formulas in patients with biopsy-proven histological changes, and K/DOQI CKD staging. RESULTS: Bias was small with Gentian CysC (0.1 ml/min/1.73 m2); 88.9% and 37.8% of U25-CysC estimations were within 30% and 10% of mGFR, respectively. In subjects with histological changes on biopsy, Gentian CysC had a small bias and U25-CysC were more accurate-both with 83.3% of and 41.7% of estimates within 30% and 10% mGFR, respectively. Precision was better with U25-CysC, CKiD Cr-CysC, and U25 Cr-CysC. Bland-Altman plots showed the Bedside Schwartz, Gentian CysC, CAPA, and U25-CysC tend to overestimate GFR when > 100 ml/min/1.72 m2. CAPA misclassified CKD stage the least (whole cohort 24.4%, histological changes on biopsy 33.3%). CONCLUSIONS: In this small cohort, CysC-based equations with or without Cr may have better bias, precision, and accuracy in predicting GFR.

Diagnostic test accuracy of serum creatinine and cystatin C-based index for sarcopenia: a systematic review and meta-analysis.

BACKGROUND: Sarcopenia is an important prognostic factor, but its optimal screening methods remain challenging. Several new indices developed based on serum creatinine (Cr) and cystatin C (CysC) have been proposed to be diagnostic biomarkers for sarcopenia screening. OBJECTIVE: This review aimed to evaluate the diagnostic accuracy of serum Cr- and CysC-based indices for sarcopenia diagnosis. METHODS: We systematically searched MEDLINE, EMBASE, SCIE and SCOPUS from inception to 2 April 2023. Methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. A bivariate random-effects model was used to synthesise the pooled sensitivity, specificity and area under the curves of the summary receiver operating characteristic (SROC-AUC). RESULTS: We retrieved 936 publications and included 16 studies with 5,566 participants (mean age ranged: 51.0-78.4 years, 50.2% men). The prevalence of sarcopenia ranged from 7.8 to 69.5%. All included studies presented a moderate to high risk of bias. The serum Cr- and CysC-based indices showed moderate diagnostic accuracy for sarcopenia (pooled sensitivity: 0.67, 95% CI 0.57-0.75; pooled specificity: 076, 95% CI 0.67-0.83; pooled SROC-AUC: 0.78, 95% CI 0.74-0.81). The Cr/CysC ratio is the most widely studied index, followed by the Cr × eGFRcys index. Overall, both indicators had satisfactory and comparable performance in screening sarcopenia. CONCLUSION: Serum Cr- and CysC-based indices showed moderate diagnostic accuracy for sarcopenia. The most studied indices-the Cr/CysC ratio and Cr × eGFRcys index-had comparable diagnostic accuracy for evaluating sarcopenia and may serve as surrogate markers for sarcopenia. However, further validation is required to verify these findings.

A multi-center randomized controlled trial to investigate potential effects of exercise therapy on renal function stratified by renal disorders and renal pathology: beneficial or harmful effect in immunoglobulin a nephropathy.

BACKGROUND: The effects of exercise therapy (ET) on renal function in chronic kidney disease (CKD) remain unclear. METHODS: In a randomized controlled trial (UMIN-CTR number: UMIN000038415), we investigated whether ET affects renal function in CKD; eligible patients had undergone renal biopsy in the past 3 months. We stratified patients by disease (immunoglobulin A [IgA] nephropathy, n = 16; diabetic nephropathy, n = 4; benign nephrosclerosis, n = 13; and other CKD types, n = 13) and randomized them to 12 weeks' observation and 24 weeks' ET comprising home-based aerobic exercise 3×/week and resistance training 2×/week (intervention group) or usual care (non-intervention group). Primary endpoint was creatinine-based estimated glomerular filtration rate (eGFR) or serum cystatin C-based eGFR (eGFRcys). Secondary endpoints included urinary protein and exercise tolerance. RESULTS: Seventy patients were enrolled, 50 fulfilled the inclusion criteria, but 4 discontinued before randomization. No items significantly differed between week 0 to 24 in either group (intervention group, n = 23; non-intervention group, n = 23) or between groups at week 24 (intention-to-treat population) in the total study population. The eGFRcys slope showed no significant intergroup difference in the observation period, but eGFRcys improved significantly in IgA nephropathy patients (n = 16) in the intervention group (stratified comparison; week 0, 48.3 ± 18.2; week 24, 51.6 ± 17.6; p = 0.043). In these patients, urinary protein was significantly worse at week 24 in the non-intervention group (p = 0.046) and worsened significantly less in the intervention group (p = 0.039). CONCLUSION: ET did not improve renal function overall in CKD patients but might help maintain renal function in patients with IgA nephropathy.

A study of size-selective renal elimination using a novel human model.

The recently discovered selective glomerular hypofiltration syndromes have increased interest in the actual elimination of molecules in the human kidney. In the present study, a novel human model was introduced to directly measure the single-pass renal elimination of molecules of increasing size. Plasma concentrations of urea, creatinine, C-peptide, insulin, pro-BNP, ß2-microglobulin, cystatin C, troponin-T, orosomucoid, albumin, and IgG were analysed in arterial and renal venous blood from 45 patients undergoing Transcatheter Aortic Valve Implantation (TAVI). The renal elimination ratio (RER) was calculated as the arteriovenous concentration difference divided by the arterial concentration. Estimated glomerular filtration rate (eGFR) was calculated by the CKD-EPI equations for both creatinine and cystatin C. Creatinine (0.11 kDa) showed the highest RER (21.0 ± 6.3%). With increasing molecular size, the RER gradually decreased, where the RER of cystatin C (13 kDa) was 14.4 ± 5.3% and troponin-T (36 kDa) was 11.3 ± 4.6%. The renal elimination threshold was found between 36 and 44 kDa as the RER of orosomucoid (44 kDa) was -0.2 ± 4.7%. The RER of creatinine and cystatin C showed a significant and moderate positive linear relationship with eGFR (r = 0.48 and 0.40). In conclusion, a novel human model was employed to demonstrate a decline in renal elimination with increasing molecular size. Moreover, RERs of creatinine and cystatin C were found to correlate with eGFR, suggesting the potential of this model to study selective glomerular hypofiltration syndromes.

Impact of the serum creatinine and cystatin C ratio for prediction of sarcopenia and prognosis in biliary tract cancer.

BACKGROUND: Sarcopenia is a poor prognostic factor in cancer patients. In recent years, there have been reports that serum creatinine and cystatin C (Cr/CysC) ratio is associated with sarcopenia. However, the prognostic value of the Cr/CysC ratio in biliary tract cancer is unclear. We evaluated the impact of the Cr/CysC ratio on sarcopenia and prognosis in biliary tract cancer. METHODS: We retrospectively reviewed the records of 190 patients with biliary tract cancer who had undergone surgical resection from January 2017 to March 2023. Frozen serum samples collected at the time of surgery were used to measure CysC. We calculated the Cr/CysC ratio and investigated the relationship with sarcopenia and the prognostic significance. RESULTS: We calculated the cutoff value of the Cr/CysC ratio for low skeletal muscle index (SMI) (< 42 cm2/m2 for males and < 38 cm2/m2 for females). The optimal cutoff value of the Cr/CysC ratio was 0.848. The low Cr/CysC ratio group was significantly associated with higher preoperative CRP and lower albumin, lower SMI, lower handgrip strength, and higher intramuscular adipose tissue content. In multivariate analysis, patients with a low Cr/CysC ratio showed poorer overall survival (hazard ratio 2.60, 95% confidence interval 1.07-6.29, p = 0.033), which was significantly worse than in those with a high Cr/CysC ratio. CONCLUSIONS: In patients with biliary tract cancer, the Cr/CysC ratio showed weak correlation with sarcopenic indicators. However, the Cr/CysC ratio could be strong prognostic factor in biliary tract cancer.

The clinical utility of cystatin C based eGFR in assessing renal function among HIV/AIDs patients on ART at Mildmay Uganda.

BACKGROUND: In clinical practice, Measurement of estimated glomerular filtration rates (eGFR) is the gold standard assessing renal function the glomerular filtration rate often estimated from plasma creatinine. Several studies have shown Cystatin C based eGFR (Cys C) to be a better parameter for the diagnosis of impaired renal function. Cystatin C based eGFR has been proposed as a potential renal function marker but its use in HIV&AIDS patients has not been well evaluated. METHODS: A cross sectional study was carried out on 914 HIV&AIDS patients on antiretroviral therapy (ART) attending Mildmay Uganda for care and treatment between January to March 2015. Serum Cystatin C based eGFR was measured using the particle enhanced immunoturbidimetric assay. Creatinine was analyzed using enzymatic Creatinine PAP method and creatinine clearance was calculated according to C&G. RESULTS: The sensitivity of Cystatin C based eGFR was 15.1% (95% CI = 8.4, 24) with specificity 99.3% (95% CI = 98- 99.7). The positive and negative predictive values were 70.0% (95% CI 45.7-88.1) and 91.2% (95% CI 98.11-92.94) respectively. The positive likelihood ratio was 18.81 and negative likelihood ratio was 0.85. Cystatin C based eGFR had diagnostic accuracy of 90.7 and area under curve was 0.768. CONCLUSION: Cystatin C based eGFR exhibited a high specificity and a high positive likelihood ratio in diagnosis of kidney disease among HIV&AIDS patients. Cystatin C based eGFR can be used as a confirmatory test.

Assessment of renal function in persons with motor complete spinal cord injury-cystatin C as an accurate single marker.

STUDY DESIGN: Observational cohort. AIM: To show that Cystatin C is an accurate single marker to estimate GFR in motor complete persons with SCI. OBJECTIVES: To assess if Cystatin C is an accurate for estimating GFR in persons with SCI with no preserved motor power. To study if use of Serum creatinine for estimation of GFR in this population significantly overestimates GFR, thereby inaccurate. SETTING: Tertiary care hospital and Medical College, Vellore, South India. METHODS: 30 persons with SCI (ASIA A and B) fulfilling the inclusion criteria were recruited. Serum Creatinine and Serum Cystatin C values were obtained, and eGFR was calculated based on available formulae. 24-h urine for urine creatinine clearance-based eGFR was used as a reference value. RESULTS: Analysis with a Bland-Atman plot showed that eGFR estimated with Serum Cystatin C was more accurate than Serum Creatinine, using 24-h urine creatinine as a reference value. eGFR using Serum Creatinine significantly overestimated GFR by over 50.6%. Estimated GFR using Serum Cystatin C showed a meager mean difference of 0.5% from the reference 24-h urine creatinine clearance (mean difference of -2.56%). CONCLUSION: Serum Cystatin C is a much more accurate marker for estimating GFR in SCI, compared to serum Creatinine which overestimates GFR.