Chronic Kidney Disease Epidemiology Collaboration eGFR Research Articles

Assessing the Reliability of Creatinine-Estimated Glomerular Filtration Rate in Living Kidney Donor Candidates: Does it Measure up to the Measured Rate?

Abstract A living donor kidney transplant is the best therapy option for patients with end stage renal disease (ESRD); however, it is associated with an increased risk of ESRD development in the donor. Thorough evaluation of the donor candidate’s kidney function status is essential for the appropriate selection of candidates with minimal risk of post-donation kidney dysfunction. In this study, glomerular filtration rate (GFR) values measured by iohexol plasma clearance (mGFR) and estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) creatinine equations (eGFR), with and without the race factor (2009 and 2021 CKD-Epi equations, respectively), were compared in a cohort of 303 kidney donor candidates. GFR values were analyzed using Bland-Altman plots, linear regression, Mann-Whitney U tests, and p10 and p30 values. Bland-Altman analysis revealed a lack of agreement between the 2009 and 2021 CKD-Epi eGFR and corresponding mGFR values, with both equations showing a negative bias of 10 – 11 mL/min/1.73m2 and indicating an underestimation of creatinine-eGFR. eGFR underestimation was confirmed by Mann-Whitney U analysis; median GFR values were significantly lower for both CKD-Epi equations as compared to corresponding iohexol-measured values (2009: 85.86; 2021: 87.29; mGFR: 96.58). Despite the overall underestimation, over 14% of donor candidates with eGFR >90 mL/min/1.73m2 had an mGFR value <90 mL/min/1.73m2. Conversely, 36% - 38% of donors with normal kidney function of >90 mL/min/1.73m2 as determined by iohexol-mGFR had corresponding eGFR values <90 mL/min/1.73m2. eGFR showed a significant but poor correlation with mGFR, with R2 values of 0.2775 and 0.2803, respectively. While the 2021 eGFR equation had better accuracy as compared to the 2009 equation (p30 of 81% versus 76%), it displayed low overall accuracy with a p10 of <43%. Separate analysis of Black donor candidates’ eGFR and mGFR values revealed similar trends as observed for the total cohort. While exclusion of the race factor in the 2021 CKD-Epi equation slightly improved accuracy (p30 of 77% versus 72%), the correlation with mGFR remained poor for both equations (R2: 0.1455 and 0.1377 for the 2009 and 2021 equations, respectively). The results of this study confirmed that creatinine-eGFR values, regardless of the race factor, differ significantly from iohexol-mGFR. Our data shows that even potential kidney donors with eGFR >90 mL/min/1.73m2 cannot be presumed to have normal kidney function, while eGFR <90 mL/min/1.73m2 cannot accurately exclude donor candidates. We conclude that creatinine-eGFR cannot reliably serve as a substitute for mGFR in the context of living donor kidney function evaluation.

OR31-06 Gender-Affirming Hormone Therapy Affects Serum Cystatin C-based eGFR In Transgender Individuals

Abstract Disclosure: S.A. van Eeghen: None. C. Wiepjes: None. N. Nokoff: None. P. Bjornstad: None. M. Den Heijer: None. D. van Raalte: None. Background: Previous studies in transgender individuals have shown that masculinizing (testosterone) hormone therapy increases and feminizing (estradiol combined with anti-androgen) hormone therapy decreases serum creatinine. Translating this into estimated glomerular filtration rate (eGFR) according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, eGFR increases in transwomen and decreases in transmen during gender-affirming hormone therapy (GAHT). However, serum creatinine is significantly correlated with lean body mass (LBM), which also changes during GAHT, with transmen gaining and transwomen loosing muscle mass. Thus changes in creatinine-derived eGFR during hormone therapy may not reflect true changes in GFR. Another manner to estimate GFR, which is not affected by body composition, is by measuring plasma cystatin C concentrations. Therefore, we studied the effects of GAHT on serum cystatin C, a sex-independent marker for GFR. Methods: In this prospective, observational sub study of the European Network for the Investigation of Gender Incongruence (ENIGI), serum cystatin C was measured in 266 transwomen and 285 transmen before and at 12 months of GAHT. Transwomen received feminizing hormone therapy, consisting of oral (n= 122) or transdermal administration (n= 144) of estrogen in combination with the oral anti-androgen cyproteroneacetate. Transmen received masculinizing hormone therapy, which consisted of intramuscular (n= 144) or transdermal (n= 141) administration of testosterone. Serum cystatin C-based eGFR was calculated according to the full-age-spectrum equation (FAScysC; mL/min/1.73m2). Linear regression was used to assess the means. Results: In transwomen (baseline characteristics; median age 29 (IQR 23-43) years; median BMI 22.9 (IQR 20.8-26.4) kg/m2; creatinine 78.6 ± 9.9 μmol/L; creatinine-based CKD-EPI eGFR 110 ± 14 mL/min/1.73m2), cystatin C decreased by 0.07 (95% CI, 0.05 to 0.09) mg/L; from 0.94 ± 0.17 mg/L before GAHT to 0.87 ± 0.15 mg/L during GAHT. This corresponds with an increase in FAScysC of 7 (95% CI, 5 to 9) mL/min/1.73m2; from 93 ± 17 to 100 ± 18 mL/min/1.73m2. On the contrary, in transmen (baseline characteristics; median age 22 (IQR 20-28) years; median BMI 24.7 (IQR 21.4-30.1) kg/m2; creatinine 66.8 ± 9.3 μmol/L; creatinine-based CKD-EPI eGFR 110 ± 15 mL/min/1.73m2) cystatin C increased by 0.05 (95% CI, 0.03 to 0.07) mg/L; from 0.89 ± 0.17 mg/L before GAHT to 0.95 ± 0.16 mg/L during 12 months of GAHT. This is consistent with a decrease in FASCysC of 6 (95% CI, 4 to 8) mL/min/1.73m2; from 101 ± 19 to 94 ± 15 mL/min/1.73m2. Conclusions: In this large-sized cohort of transgender individuals, cystatin C-based eGFR increased with feminizing hormone therapy and decreased with masculinizing hormone therapy, indicating true biological effects of sex hormones on kidney physiology, which warrants further investigation. Presentation: Sunday, June 18, 2023

A-369 Evaluation of a Point-of-Care Whole Blood Creatinine Assay and eGFR Concordance using the CKD-EPI 2021 Equation

Abstract Background Estimated glomerular filtration rate (eGFR) from serum creatinine is considered a better assessment of renal function than serum creatinine alone. Patients with chronic kidney disease have a higher risk of developing contrast-induced nephropathy (CIN). GEM Premier ChemSTAT (Instrumentation Laboratory, Bedford, USA) whole blood (WB) creatinine assay along with eGFR reporting capability per the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 eGFR equation is now available and could provide a quick point-of-care (POC) screening test alternative to the lab assay for patient risk management. Currently the CKD-EPI 2009 formula for non-AA population has been used to estimate eGFR in our institution. Recently the CKD-EPI 2021 equation without race adjustment has been recommended by multiple professional societies. The goal of this clinical evaluation was to compare the analytical performance of the ChemSTAT WB creatinine assay and the clinical concordance of eGFR to an established lab method by CKD-EPI 2021 equation. Methods Remnant heparinized WB samples along with age and gender were obtained. The WB samples were analyzed on the GEM Premier ChemSTAT and the plasma assayed on an Architect analyzer (Abbott Laboratories, Lake Forest, USA) as the reference method. The eGFR based on the CKD-EPI 2009 equation were obtained for both WB and plasma creatinine. The eGFR based on CKD-EPI 2021 equation were retrospectively calculated based on WB and plasma creatinine, age and gender. The clinical concordance of categorizing patients with abnormal kidney function (eGFR < 60 ml/min/1.73 m2) and overall concordance of patients (eGFR < 60 + eGFR≥60) was assessed for WB vs plasma eGFR. Error grid analysis was performed for eGFR as described by Snaith et al. (1) to identify the impact of discordant results between WB and plasma eGFRs. Results A total of 60 patient samples were analyzed, median age (SD) = 68.5 (15.2), 53.3% female. The WB ChemSTAT creatinine assay correlated well with the Architect across the tested ranges with regression results of: ChemSTAT_Creatinine (μmol/L) = 1.1099*Architect_Creatinine – 16.0, r = 0.990. A small mean bias (SD) of -3.0 (22.6) μmol/L was observed between ChemSTAT and Architect from the Bland-Altman analysis. When identifying patients with abnormal kidney function (eGFR < 60), ChemSTAT WB eGFR showed 84% (21/25) concordance against the plasma eGFR. An overall clinical eGFR concordance of 88% (53/60) was observed for ChemSTAT. The error grid analysis indicated 100% (60/60) of ChemSTAT WB eGFRs (Zones A and B combined) had no implication to clinical management. Mean biases (SD) from reported CKD-EPI eGFR 2021 vs 2009 equation of 3 (1.6) and 2 (2.6) were observed from Architect plasma creatinine and ChemSTAT WB creatinine, respectively. Conclusions Strong correlations were observed between the ChemSTAT WB POC creatinine assay and eGFR versus the lab method. Based on the high clinical concordance of WB eGFR with CKD-EPI 2021 equation and low mean bias, GEM Premier ChemSTAT demonstrated good performance as POC method for rapid and lab quality renal function assessment.

A-091 Assessing the Reliability of Creatinine-Estimated Glomerular Filtration Rate in Living Kidney Donor Candidates: Does it Measure up to the Measured Rate?

Abstract Background A living donor kidney transplant is the best therapy option for patients with end stage renal disease (ESRD); however, it is associated with an increased risk of ESRD development in the donor. Thorough evaluation of the donor candidate’s kidney function status is essential for the appropriate selection of candidates with minimal risk of post-donation kidney dysfunction. Methods Glomerular filtration rate (GFR) values measured by iohexol plasma clearance (mGFR) and estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) creatinine equations (eGFR), with and without the race factor (2009 and 2021 CKD-Epi equations, respectively), were compared in a cohort of 303 kidney donor candidates. GFR values were analyzed using Bland-Altman plots, linear regression, Mann–Whitney U-tests, and p10 and p30 values. Results Bland-Altman analysis revealed a lack of agreement between the 2009 and 2021 CKD-Epi eGFR and corresponding mGFR values, with both equations showing a negative bias of 10–11 mL/min/1.73 m2 and indicating an underestimation of creatinine-eGFR. eGFR underestimation was confirmed by Mann Whitney U analysis; median GFR values were significantly lower for both CKD-Epi equations as compared to corresponding iohexol-measured values (2009: 85.86; 2021: 87.29; mGFR: 96.58). Despite the overall underestimation, over 14% of donor candidates with eGFR >90 mL/min/1.73 m2 had an mGFR value <90 mL/min/1.73 m2. Conversely, 36%–38% of donors with normal kidney function of >90 mL/min/1.73 m2 as determined by iohexol-mGFR had corresponding eGFR values <90 mL/min/1.73 m2. eGFR showed a significant but poor correlation with mGFR, with R2 values of 0.2775 and 0.2803, respectively. While the 2021 eGFR equation had better accuracy as compared to the 2009 equation (p30 of 81% vs 76%), it displayed low overall accuracy with a p10 of <43%. Separate analysis of Black donor candidates’ eGFR and mGFR values revealed similar trends as observed for the total cohort. While exclusion of the race factor in the 2021 CKD-Epi equation slightly improved accuracy (p30 of 77% vs 72%), the correlation with mGFR remained poor for both equations (R2: 0.1455 and 0.1377 for the 2009 and 2021 equations, respectively). Conclusion The results of this study confirmed that creatinine-eGFR values, regardless of the race factor, differ significantly from iohexol-mGFR. Our data shows that even potential kidney donors with eGFR >90 mL/min/1.73 m2 cannot be presumed to have normal kidney function, while eGFR <90 mL/min/1.73 m2 cannot accurately exclude donor candidates. We conclude that creatinine-eGFR cannot reliably serve as a substitute for mGFR in the context of living donor kidney function evaluation.

Performance of Creatinine and Cystatin C-Based Equations to Estimate Kidney Function in Renal Transplant Recipients

Background: Numerous equations are applied in order to estimate the glomerular filtration rate (GFR). Objectives: This study aimed to spot the optimal equation that accurately estimates GFR and, therefore, the chronic kidney disease (CKD) stage in renal transplant patients. Methods: This cross-sectional study was conducted on 58 renal transplant patients. Their venous blood samples were obtained for serum creatinine and cystatin C determination used to calculate estimated GFR (eGFR). The average contrast of GFR in each equation was calculated using the Bland-Altman method. The correlation, bias, imprecision, and 10% and 30% accuracy were compared between the eGFR cystatin C and creatinine. Concordance between both equations for CKD staging was assessed. The classification of patients was also investigated. Results: Bland-Altman plots and bias demonstrated that eGFR by the abbreviated modification of diet in renal disease (Ab-MDRD) was the most accurate compared with chronic kidney disease epidemiology collaboration (CKD-EPI) cystatin C, followed by CKD-EPI eGFR creatinine. With reference to CKD-EPI cystatin C, the imprecision of the equations was approximately similar to Ab-MDRD, and CKD-EPI creatinine is still better than the Cockcroft-gault (CG) formula. They also showed good 30% accuracy. Finally, our finding suggested that Ab-MDRD and CKD-EPI eGFR creatinine might be the best-performing equation in the classification of the CKD stages in a cutoff of 60 mL/min/1.73 m2. Conclusions: Due to the high cost and potential delay in measuring cystatin C, it would be much more appropriate to measure Ab-MDRD; after that, CKD-EPI eGFR creatinine as an alternative approach in order to facilitate rapid clinical decision in renal transplant patients.

New analysis of the comparative diagnostic performances of five different eGFR equations: The revised 2021 CKD-EPI eGFR, and the four older equations

Purpose: In 2021, the CKD-EPI-creatinine and CKD-EPI-creatinine-cystatin-C combined equations were revised again by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and the National Institute of Diabetes & Digestive and Kidney Diseases (NIDDK) and it was reported that its accuracy was increased. The main object of this study is to compare the diagnostic accuracy and performance of 2009 CKD-EPI eGFRcr, 2012 CKD-EPI eGFRCysC, 2012 CKD-EPI eGFRcr-CysC, MDRD, and revised 2021 CKD-EPI to provide a better estimation.
 Materials and Methods: The study design was prospective. The sample consisted of 111 CKD patients and 35 healthy individuals who applied to the nephrology clinic. All participants were evaluated by a nephrologist. The participants were divided into study groups according to their KDIGO classification. Five variables were used: age, race, gender, serum creatinine, and serum cystatin-C.
 Results: 2012 CKD-EPI eGFR cystatin-C out performed existing equations in terms of accuracy, specificity, and sensitivity (AUC:0.988). Furthermore, when both creatinine and cystatin-C are included in an equation, it consistently improves diagnostic values over formulas containing only creatinine (2009CKD-EPI eGFRcr AUC:0.953, 2012CKD-EPI eGFRcr-CysC AUC: 0.985, 2021CKD-EPI eGFRcr AUC:0.954, MDRD AUC: 0.953, 2021CKD-EPI eGFRcr-CysC AUC: 0.985).
 Conclusion: The new formula has not been confirmed to be superior to other equations in its ability to estimate eGFR values, particularly at higher levels of chronic kidney disease. When compared with existing equations, 2012 CKD-EPI eGFRCysC had higher specificity and sensitivity. Combined formulas containing both blood tests had higher diagnostic values than equations containing only creatinine. Our results can help inform which equations to use for better estimation in renal function screening.

Removing race and body surface area indexation for estimated kidney function based drug dosing: Aminoglycosides as justification of these principles.

The use of race in medicine can contribute to health inequity. Updated equations for estimated glomerular filtration rate (eGFR) without race have been published. Likewise, de-indexation of eGFR to body surface area (BSA) has been recommended by regulatory guidance for drug dosing in renal impairment. Clinical data justifying these recommendations for drug dosing are sparse. We examined the gain or loss of precision in drug dosing with estimated creatinine clearance (eCLcr) and eGFR using serum creatinine (eGFRcr) with and without race and BSA indexation by evaluating the population pharmacokinetics of the aminoglycosides as a classic drug class to probe kidney function. Medical records from adult patients treated with gentamicin or tobramycin over a 13-year period were queried. Population pharmacokinetic analyses were performed using a 1-compartment base structural model. Models compared body size descriptors as covariates of the volume of distribution (V). Estimated creatinine clearance and eGFRcr using multiple contemporary equations with and without BSA indexation were tested as covariates of clearance (CL). The final data set included 2968 patients treated with either gentamicin (20.2%) or tobramycin (79.8%). Patients self-identified as Caucasian (82%), African-American (10%), or other. The median [5th, 95th percentile] weight and BSA were 80.5 [49.4, 136]kg and 1.94 [1.48, 2.56]m2 , respectively. Models of eCLcr and eGFRcr without indexation to BSA had a better model fit than eGFRcr indexed to BSA for aminoglycoside CL. The 2021 Chronic Kidney Disease Epidemiology collaboration (CKD-EPI) eGFRcr equation (no race, no BSA indexation) provided a comparable model fit to the 2009 CKD-EPI eGFRcr equation (with race, no BSA indexation) for aminoglycoside CL. Race is not a relevant covariate of aminoglycoside CL. The 2021 CKD-EPI eGFR equation without race and BSA indexation is a better method for gentamicin and tobramycin CL estimation. Confirmation of these results for other drugs can support the harmonization of dosing by kidney function.

18 F]PSMA-1007 renal uptake parameters: Reproducibility and relationship to estimated glomerular filtration rate.

Scintigraphy with technetium-99m-labelled dimercaptosuccinic acid ([99m Tc]Tc-DMSA) is widely used for renal cortical imaging. Uptake of [99m Tc]Tc-DMSA has been shown to correlate with glomerular filtration rate (GFR). Prostate-specific membrane antigen (PSMA) radiopharmaceuticals used for positron emission tomography (PET) show high renal uptake and are being investigated for renal imaging. [68 Ga]Ga-PSMA-11 PET parameters have been shown to correlate with estimated GFR (eGFR). The aim of this study was to investigate the relationship between renal [18 F]PSMA-1007 uptake and eGFR. Hundred and eighty-five patients underwent PET imaging at 1 and 2 h after injection of 4.0 ± 0.2 MBq [18 F]PSMA-1007. Serum creatinine levels were measured and GFR estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations. Fifteen patients were excluded due to missing or incorrect data. Thus, data from 170 patients were analyzed. Kidneys were segmented in the PET images using a convolutional neural network with manual correction. For each kidney, mean standardized uptake value (SUVmean ) and segmentation volume in millilitres were measured. Linear regression analyses were performed with eGFR as the outcome variable. Variation in the eGFR values was explained to a significant degree by SUVmean and renal segmentation volume in both the 1and 2 himages. This correlation was stronger for CKD-EPI eGFR (1 h R2 = 0.64; 2 h R2 = 0.64) than for MDRD eGFR (1 h R2 = 0.47; 2 h R2 = 0.45). Renal [18 F]PSMA-1007 uptake parameters correlate with eGFR and are indicative of renal cortical function.

An Endorsement of the Removal of Race From GFR Estimation Equations: A Position Statement From the National Kidney Foundation Kidney Disease Outcomes Quality Initiative

An Endorsement of the Removal of Race From GFR Estimation Equations: A Position Statement From the National Kidney Foundation Kidney Disease Outcomes Quality Initiative

Performance of the 2021 Race-Free CKD-EPI Creatinine- and Cystatin C–Based Estimated GFR Equations Among Kidney Transplant Recipients

Race-free estimated glomerular filtration rate (eGFR) equations incorporating creatinine with and without cystatin C were recently developed and recommended for routine use. However, the performance of these equations among kidney transplant recipients (KTRs) remains unknown. Cross-sectional study to validate the 2021 race-free Chronic Kidney Disease (CKD) Epidemiology Collaboration (CKD-EPI) eGFR equation based on creatinine alone (eGFRcr) or based on creatinine and cystatin C (eGFRcr-cys) among KTRs. KTRs in stable condition (N= 415) from Canada and New Zealand with same-day measurements of creatinine, cystatin C, and glomerular filtration rate (GFR) usingradiolabeled diethylenetriaminepentaacetic acid. The 2009 CKD-EPI eGFRcr, 2021 CKD-EPI eGFRcr, 2012 CKD-EPI eGFRcr-cys, 2021 CKD-EPI eGFRcr-cys, 2012 CKD-EPI eGFRcys, and Modification of Diet in Renal Disease (MDRD) Study eGFR equations were compared with measured GFR. Bias, precision, accuracy, and correct classification by CKD stage. Bias was defined as the difference between estimated and measured GFR. Precision was represented by the interquartile range. Accuracy was defined as the percentages of participants with eGFRs within 10%/20%/30% (P10/P20/P30) of measured GFR, root mean square error, and mean absolute error. 87% of patients studied were White, 3% Black, and 10% other races. Mean measured GFR was 53 ± 19 (SD) mL/min/1.73 m2. The 2009 and 2021 CKD-EPI eGFRcr equations demonstrated similar median bias (-2.3 vs-0.2 mL/min/1.73 m2, respectively), precision (14.5 vs 14.9 mL/min/1.73 m2), and accuracy (P10/P20/P30, 32%/65%/84% vs 33%/63%/84%). The 2012 and 2021 CKD-EPI eGFRcr-cys equations also demonstrated similar median bias (-3.6 vs 0.3 mL/min/1.73 m2, respectively), precision (13.3 vs 14.3 mL/min/1.73 m2), and accuracy (P10/P20/P30, 32%/63%/80% vs 32%/67%/83%). No clear difference in performance was detected between the 2021 CKD-EPI eGFRcr and eGFRcr-cys equations among KTRs. The proportion of correct classification by CKD stage was similar across all eGFR equations. Moderate sample size, few patients had a GFR<30 mL/min/1.73 m2, and the large majority of patients were White. Among KTRs, the 2021 race-free CKD-EPI eGFR equations perform similarly to the previous CKD-EPI equations that included race correction terms. No significant difference in performance was observed between the 2021 CKD-EPI eGFRcr and eGFRcr-cys equations in the kidney transplant population.

Utilizing Longitudinal Within-Individual Changes of Serum Creatinine, Cystatin C, and/or eGFR to Optimize Clinical Sensitivity and Eliminate Race and Gender Corrections.

The recent recommendation by the American Society of Nephrology/National Kidney Foundation task force to immediately eliminate the “race” factor in the estimated glomerular filtration rate (eGFR) equation (1) is a much-needed and long-overdue correction of the original Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR equations. While the primary and continual goal of the MDRD, CKD-EPI, and other eGFR equations has been to agree with measured GFR (mGFR), we believe this was misguided as shown by the necessity of updating to the CKD-EPI (2021) equation to improve its clinical ability to detect and monitor changes in kidney function for all persons. This new emphasis will enhance the role of the eGFR as a clinical guide for determining chronic kidney disease (CKD) stage and possible referral to nephrology. Because eGFR is calculated from serum creatinine (sCr) and/or cystatin C (sCysC), which are reliable measurements, we propose that these measurements and eGFRs calculated from them are actually more clinically useful, more reliable, and far more used than mGFRs, which have much greater analytical and physiological variation (2–5). Indeed, it was the variability of the mGFR, not the more reliable sCr, that required both the MDRD and CKD-EPI equations to accept wide error tolerances of ±30%, with 81% of the MDRD eGFRs and 84% of CKD-EPI eGFRs within the 30% error tolerance.

Correction: The Kidney Failure Risk Equation for prediction of end stage renal disease in UK primary care: An external validation and clinical impact projection cohort study

[This corrects the article DOI: 10.1371/journal.pmed.1002955.].

An Evaluation of Baseline Kidney Function in the REPRIEVE Trial of Pitavastatin in Human Immunodeficiency Virus.

Chronic kidney disease is a common comorbid condition among persons living with human immunodeficiency virus (PWH). We characterized baseline kidney function in the REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) trial cohort. REPRIEVE enrolled PWH with low to moderate cardiovascular risk based on traditional risk factors to evaluate the effect of statin therapy on cardiovascular events. We determined baseline estimated glomerular filtration rate (eGFR) with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease, and Cockcroft-Gault equations, and we evaluated baseline factors associated with eGFR <90 mL/min/1.73 m2 by logistic regression. We performed Bland-Altman plots and scatterplots to assess agreement between equations. Among 7770 participants enrolled, the median age was 50 years, 31% were female (natal sex), 43% black or African American and 15% Asian, the median body mass index (calculated as calculated as weight in kilograms divided by height in meters squared) was 25.8, and the median CD4 cell count 620/µL. The median CKD-EPI eGFR was 97 mL/min/1.73 m2, and 38% had an eGFR <90 mL/min/1.73 m2. In the adjusted model, factors associated with eGFR <90 mL/min/1.73 m2 included white race, older age, higher body mass index, high-income region of enrollment, hypertension, and tenofovir disoproxil fumarate. The CKD-EPI and Modification of Diet in Renal Disease equations demonstrated strong agreement, particularly at lower eGFR values. Overall, there was 56% concordance between the 3 equations (categories <60, 60 to <90, ≥90 mL/min), improving to 73% after accounting for individual body surface area. REPRIEVE enrolled a diverse cohort including a substantial number of PWH with reduced kidney function. Factors associated with reduced eGFR included traditional risk factors and tenofovir disoproxil fumarate exposure. Three commonly used equations have only fair agreement, with potential implications for both clinical care and epidemiologic studies. NCT02344290.

Validation of equations to estimate glomerular filtration rate in South Africans of mixed ancestry.

The Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations are two commonly used formulae to estimate glomerular filtration rate (GFR) in adults. The CKD-EPI equation is recommended in current international and local guidelines for the diagnosis and management of chronic kidney disease (CKD), unless an alternative equation has been shown to have superior accuracy. Validation and comparison of the equations in local populations are therefore required. Previous studies have reported on the accuracy of these prediction equations in black South Africans and those of Indian ancestry. To evaluate the MDRD and CKD-EPI equations in South African (SA) adults of mixed ancestry. In all participants, GFR was measured (mGFR) from plasma clearance of 99mTc-diethylenetetraaminepenta-acetic acid (99mTc-DTPA), using a standardised technique. Serum creatinine assays were isotope dilution mass spectrometry traceable. GFR was estimated (eGFR) using the MDRD and CKD-EPI equations, with and without the black ethnicity factor. The agreement, bias, precision and accuracy of each equation was determined. Eighty adults were included (30 male, median age 39 years, median GFR 59 mL/min/1.73 m2). Sixty-eight had a diagnosis of CKD, 10 were potential kidney donors, and 2 were healthy volunteers. Both equations, without the black ethnicity factor, had good agreement with measured GFR. The equations tended to overestimate GFR, with bias of 1.6 and 7.9 mL/min/1.73 m2 for the MDRD and CKD-EPI equations, respectively. The interquartile ranges of the differences were 15.9 and 20.2 mL/min/1.73 m2, and as a measure of accuracy, the percentages of estimates that fell within 30% of the mGFR (P30) were 80% and 72.5% (p=0.18). For identification of individuals with a GFR &lt;60 mL/min/1.73 m2, the sensitivity of MDRD eGFR was 97.3% and that of CKD-EPI eGFR was 97.1%. The MDRD and CKD-EPI equations have shown satisfactory and comparable performance in this SA mixed-ancestry adult population, with the MDRD equation marginally less biased than the CKD-EPI.

Uric Acid Lowering and Biomarkers of Kidney Damage in CKD Stage 3: A Post Hoc Analysis of a Randomized Clinical Trial

Rationale & ObjectiveHyperuricemia is associated with chronic kidney disease (CKD) progression. We evaluated whether lowering serum uric acid levels improves levels of biomarkers of kidney damage.Study DesignPost hoc analysis of clinical trial participants.Setting & ParticipantsA double-blind randomized placebo-controlled study designed to lower serum uric acid levels. 80 patients with stage 3 CKD and asymptomatic hyperuricemia were randomly assigned to allopurinol treatment or placebo (300 mg/d) for 12 weeks.Exposure/PredictorAllopurinol treatment versus placebo.Outcomes & MeasuresWe evaluated the change from baseline for the following urinary biomarkers of kidney damage: albumin-creatinine ratio (ACR), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), and transforming growth factor β1 (TGF-β1). Additionally, we evaluated CKD Epidemiology Collaboration (CKD-EPI)-estimated glomerular filtration rate (eGFR) and cystatin C eGFR.Analytical ApproachGeneralized linear mixed modeling was used.ResultsAfter 12 weeks, allopurinol (compared to placebo) significantly lowered serum uric acid levels with an estimate of −3.3 mg/dL (95% CI, −4.1 to −2.5 mg/dL; P < 0.001). Estimates for the change for allopurinol versus placebo over time were 1.09 (95% CI, 0.77-1.54) for ACR, 0.77 (95% CI, 0.36-1.63) for NGAL, and 2.36 (95% CI, 0.97-5.70) for TGF-β1. The model did not converge for KIM-1, but Wilcoxon signed rank test showed no significant difference in change from baseline between study groups. There was no significant change observed in CKD-EPI eGFR or cystatin C eGFR.LimitationsPost hoc analysis and short duration of the study.ConclusionsUric acid–lowering with allopurinol is not associated with improvement in levels of biomarkers of kidney damage in patients with asymptomatic hyperuricemia and stage 3 CKD.FundingThe study was funded by the National Institutes of Health through a career development award, K23DK088833, and the Clinical and Translational Science Award UL1TR002537.Trial RegistrationNCT01228903.

Population Pharmacokinetics of Imipenem in Critically Ill Patients: A Parametric and Nonparametric Model Converge on CKD-EPI Estimated Glomerular Filtration Rate as an Impactful Covariate.

BackgroundPopulation pharmacokinetic (popPK) models for antibiotics are used to improve dosing strategies and individualize dosing by therapeutic drug monitoring. Little is known about the differences in results of parametric versus nonparametric popPK models and their potential consequences in clinical practice. We developed both parametric and nonparametric models of imipenem using data from critically ill patients and compared their results.MethodsTwenty-six critically ill patients treated with intravenous imipenem/cilastatin were included in this study. Median estimated glomerular filtration rate (eGFR) measured by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was 116 mL/min/1.73 m2 (interquartile range 104–124) at inclusion. The usual dosing regimen was 500 mg/500 mg four times daily. On average, five imipenem levels per patient (138 levels in total) were drawn as peak, intermediate, and trough levels. Imipenem concentration-time profiles were analyzed using parametric (NONMEM 7.2) and nonparametric (Pmetrics 1.5.2) popPK software.ResultsFor both methods, data were best described by a model with two distribution compartments and the CKD-EPI eGFR equation unadjusted for body surface area as a covariate on the elimination rate constant (Ke). The parametric population parameter estimates were Ke 0.637 h−1 (between-subject variability [BSV]: 19.0% coefficient of variation [CV]) and central distribution volume (Vc) 29.6 L (without BSV). The nonparametric values were Ke 0.681 h−1 (34.0% CV) and Vc 31.1 L (42.6% CV).ConclusionsBoth models described imipenem popPK well; the parameter estimates were comparable and the included covariate was identical. However, estimated BSV was higher in the nonparametric model. This may have consequences for estimated exposure during dosing simulations and should be further investigated in simulation studies.Electronic supplementary materialThe online version of this article (10.1007/s40262-020-00859-1) contains supplementary material, which is available to authorized users.

The value of kinetic glomerular filtration rate estimation on medication dosing in acute kidney injury.

BackgroundIn acute kidney injury (AKI), medication dosing based on Cockcroft-Gault creatinine clearance (CrCl) or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rates (eGFR) are not valid when serum creatinine (SCr) is not in steady state. The aim of this study was to determine the impact of a kinetic estimating equation that incorporates fluctuations in SCrs on drug dosing in critically ill patients.MethodsWe used data from participants enrolled in the NIH Acute Respiratory Distress Syndrome Network Fluid and Catheters Treatment Trial to simulate drug dosing category changes with the application of the kinetic estimating equation developed by Chen. We evaluated whether kinetic estimation of renal function would change medication dosing categories (≥60, 30–59, 15–29, and <15mL/min) compared with the use of CrCl or CKD-EPI eGFR.ResultsThe use of kinetic CrCl and CKD-EPI eGFR resulted in a large enough change in estimated renal function to require medication dosing recategorization in 19.3% [95 CI 16.8%–21.9%] and 23.4% [95% CI 20.7%–26.1%] of participants, respectively. As expected, recategorization occurred more frequently in those with AKI. When we examined individual days for those with AKI, dosing discordance was observed in 8.5% of total days using the CG CrCl and 10.2% of total days using the CKD-EPI equation compared with the kinetic counterparts.ConclusionIn a critically ill population, use of kinetic estimates of renal function impacted medication dosing in a substantial proportion of AKI participants. Use of kinetic estimates in clinical practice should lower the incidence of medication toxicity as well as avoid subtherapeutic dosing during renal recovery.

The Kidney Failure Risk Equation for prediction of end stage renal disease in UK primary care: An external validation and clinical impact projection cohort study.

BackgroundThe Kidney Failure Risk Equation (KFRE) uses the 4 variables of age, sex, urine albumin-to-creatinine ratio (ACR), and estimated glomerular filtration rate (eGFR) in individuals with chronic kidney disease (CKD) to predict the risk of end stage renal disease (ESRD), i.e., the need for dialysis or a kidney transplant, within 2 and 5 years. Currently, national guideline writers in the UK and other countries are evaluating the role of the KFRE in renal referrals from primary care to secondary care, but the KFRE has had limited external validation in primary care. The study’s objectives were therefore to externally validate the KFRE’s prediction of ESRD events in primary care, perform model recalibration if necessary, and assess its projected impact on referral rates to secondary care renal services.Methods and findingsIndividuals with 2 or more Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR values < 60 ml/min/1.73 m2 more than 90 days apart and a urine ACR or protein-to-creatinine ratio measurement between 1 December 2004 and 1 November 2016 were included in the cohort. The cohort included 35,539 (5.6%) individuals (57.5% female, mean age 75.9 years, median CKD-EPI eGFR 51 ml/min/1.73 m2, median ACR 3.2 mg/mmol) from a total adult practice population of 630,504. Overall, 176 (0.50%) and 429 (1.21%) ESRD events occurred within 2 and 5 years, respectively. Median length of follow-up was 4.7 years (IQR 2.8 to 6.6). Model discrimination was excellent for both 2-year (C-statistic 0.932, 95% CI 0.909 to 0.954) and 5-year (C-statistic 0.924, 95% 0.909 to 0.938) ESRD prediction. The KFRE overpredicted risk in lower (<20%) risk groups. Reducing the model’s baseline risk improved calibration for both 2- and 5-year risk for lower risk groups, but led to some underprediction of risk in higher risk groups. Compared to current criteria, using referral criteria based on a KFRE-calculated 5-year ESRD risk of ≥5% and/or an ACR of ≥70 mg/mmol reduced the number of individuals eligible for referral who did not develop ESRD, increased the likelihood of referral eligibility in those who did develop ESRD, and referred the latter at a younger age and with a higher eGFR. The main limitation of the current study is that the cohort is from one region of the UK and therefore may not be representative of primary care CKD care in other countries.ConclusionsIn this cohort, the recalibrated KFRE accurately predicted the risk of ESRD at 2 and 5 years in primary care. Its introduction into primary care for referrals to secondary care renal services may lead to a reduction in unnecessary referrals, and earlier referrals in those who go on to develop ESRD. However, further validation studies in more diverse cohorts of the clinical impact projections and suggested referral criteria are required before the latter can be clinically implemented.

Diagnostic performance of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation at estimating glomerular filtration rate in adults with diabetes mellitus: a systematic review and meta-analysis protocol

IntroductionTimely detection leading to the implementation of reno-protective measures reduces the progression of diabetic kidney disease. Estimated glomerular filtration rate (eGFR) is a major surrogate of kidney function. The Chronic...

Performance of creatinine-based equations for estimating glomerular filtration rate changes over time.

Glomerular filtration rate (GFR) is commonly used to monitor chronic kidney disease (CKD) progression, but its validity for evaluating kidney function changes over time has not been comprehensively evaluated. We assessed the performance of creatinine-based equations for estimating GFR slope according to patient characteristics and specific CKD diagnosis. In the NephroTest cohort study, we measured GFR 5324 times by chromium 51-labeled ethylenediamine tetraacetic acid renal clearance in 1955 adult patients with CKD Stages 1-4 referred to nephrologists (Stages 1-2, 19%) and simultaneously estimated GFR with both the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations for isotope dilution mass spectrometry traceable creatinine; absolute and relative GFR slopes were calculated using a linear mixed model. Over a median follow-up of 3.4 [interquartile range (IQR) 2.0-5.6] years, the decline in mean absolute and relative measured GFR (mGFR) and CKD-EPI and MDRD estimated GFR (eGFR) was 1.6 ± 1.2, 1.5 ± 1.4 and 1.3 ± 1.3 mL/min/1.73 m2/year and 5.9 ± 5.3, 5.3 ± 5.3 and 4.8 ± 5.2%/year, respectively; 52% and 55% of the patients had MDRD and CKD-EPI eGFR slopes within 30% of mGFR slopes. Both equations tended to overestimate the GFR slope in the youngest patients and underestimate it in the oldest, thus producing inverse associations between age and mGFR versus eGFR slope. Other patient characteristics and specific CKD diagnoses had little effect on the performance of the equations in estimating associations. This study shows little bias, but poor precision in GFR slope estimation for both MDRD and CKD-EPI equations. Importantly, bias strongly varied with age, possibly due to variations in muscle mass over time, with implications for clinical care and research.