Cockcroft-Gault Research Articles

Kidney function assessment for eligibility in clinical cancer trials – Data from the European Organisation for Research and Treatment of Cancer

PurposeThere is no consensus on how to estimate kidney function for the assessment of eligibility in clinical cancer trials. Patients and methodsWe recalculated the creatinine clearance (CrCl)/glomerular filtration rate (GFR) at baseline in a total of 1768 patients enrolled in twelve clinical trials using the Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI 2021) and European Kidney Function Consortium (EKFC) formulas. Patients were classified as having renal impairment (RI; CrCl/GFR <60 mL/min) or no renal impairment (NRI; CrCl/GFR ≥60 mL/min) with each of the four formulas, respectively. Furthermore, we analyzed the number of adverse events (AE) per month under study treatment using measures of central tendency, variability and regression models. ResultsUsing CG, EKFC, MDRD and CKD-EPI 2021, 152 (8 %), 140 (8 %), 110 (6 %), and 61 (4 %) patients had RI respectively. Indeed, 47 (3 %) patients had RI using all 4 formulas, while 158 (9 %) had RI by at least one but not all four methods. CG showed the broadest variability and inconsistencies with other methods. All calculation methods performed similarly for excluding patients at risk of severe AE. EKFC demonstrated superior predictive ability for excluding patients at risk of renal and urinary tract AE. ConclusionThis post hoc analysis highlights the importance of choosing accurate and representative methods for kidney function estimation in clinical cancer trials. CG should be replaced by newer methods. While CKD-EPI 2021 may maximize trial accrual, EKFC should be considered for treatment affecting kidney function.

A study on comparison of Tc-99m DTPA renal dynamic imaging with Mayo quadratic, Cockcroft-Gault, MDRD, and CKD-EPI formulas for estimation of glomerular filtration rate among South Indian live-related kidney donors

Introduction: Glomerular filtration rate (GFR) is calculated using various prediction equations. These equations are derived from the Western population, and extrapolating to our population subgroups may yield inaccurate results. Objectives: To study the correlation of measured GFR to estimated GFR using four different equations and to analyse how much proximity lies between the GFR calculated by above formulas correlates with DTPA renal scan among South Indian renal donors. Patients and Methods: An observational study was conducted among prospective renal donors undergoing evaluation. Donors underwent a DTPA scan as per protocol. Downloadable calculators calculated the glomerular filtration rate. Results that were descriptive were presented as mean and standard deviation. Correlation and comparisons were made by calculating Pearson’s correlation coefficient and student’s t test respectively. Results: A total of 151 patients were included; 24.5% were males and 75.5% were females. The majority of donors (37.09%) were in the 45-54 years age group. The mean of measured GFR by DTPA was 105.64 mL/min/1.73 m2 whereas estimated GFR was 100.95, 102.34, 109.35, 97.44 mL/min/1.73 m2 in MDRD, CKD-EPI, Mayo, and Cockcroft Gault (CG) formulae respectively with a maximum mean difference for CG of 8.2. Weighted kappa agreement between measured and estimated GFR shows 82.96% agreement with CKD-EPI compared to 78.09% agreement with the MDRD formula. Overall, CKD-EPI performed better in GFR estimation in our study subjects. Conclusion: We found that the CKD-EPI formula performed better in precision, correlation, and accuracy compared to other formulae in GFR estimation among healthy South Indian renal donors. Therefore, the CKD-EPI formula is best suited to pick-up subnormal GFR in clinical practice, as well as in epidemiological studies among the South Asian population.

Cisplatin eligibility in the neoadjuvant setting of patients with muscle-invasive bladder cancer undergoing radical cystectomy.

To examine the agreement of different calculated estimated glomerular filtration rate (eGFR) formulas and measured creatinine clearance (CrCI) at the primary diagnosis of muscle-invasive bladder cancer (MIBC). We performed a multicenter analysis of patients with MIBC, treated with cisplatin-based neoadjuvant chemotherapy (NAC) and radical cystectomy (RC), or with RC alone, between 2011 and 2021. Baseline eGFR was computed using 4 calculated serum equations including Cockcroft-Gault (CG), MDRD, CKD-EPI 2009, and race-free CKD-EPI 2021. To examine the association between calculated eGFR and measured CrCI, subgroup analyses were performed among patients in whom measured 24-hour urine CrCl was determined. Cisplatin-ineligibility was defined as CrCI and/or eGFR < 60mL/minute per 1.73 m2. Of 956 patients, 30.0%, 33.3%, 31.9%, and 27.7% were found to be cisplatin-ineligible by the CG, MDRD, CKD-EPI, and race-free CKD-EPI equations (P = .052). The concordance between calculated eGFR formulas was rated substantial (Cohen's kappa (k): 0.66-0.95). Among the subgroup (n = 245) with measured CrCl, 37 (15.1%) patients had a CrCI less than 60mL/minute. Concordance between measured CrCl and calculated eGFR was poor (ĸ: 0.29-0.40). All calculated eGFR formulas markedly underestimated the measured CrCI. Specifically, 78%-87.5% of patients with a calculated eGFR between 40 and 59mL/minute exhibited a measured CrCI ≥ 60mL/minute. Comparing calculated eGFR formulas, similar percentages of patients with MIBC were deemed cisplatin-ineligible. However, a significant number of patients could be upgraded by being cisplatin-fit based on measured CrCI, particularly when the calculated eGFR was falling within the gray range of 40-59mL/minute.

Development of normal reference intervals for renal function in pregnancy: a secondary analysis of clinical trial data

Background Due to its potential nephrotoxicity, screening for pre-existing renal function disorders has become a routine clinical assessment for initiating Tenofovir diphosphate fumarate (TDF)-containing antiretroviral treatment (ART) or pre-exposure prophylaxis (PrEP) in pregnant and non-pregnant adults. We aimed to establish reference values for commonly used markers of renal function in healthy pregnant women of African origin. Methods Pregnant women ≥18 years, not living with HIV, and at 14–28 weeks gestation were enrolled in a PrEP clinical trial in Durban, South Africa between September 2017 and December 2019. Women were monitored 4-weekly during pregnancy until six months postpartum. We measured maternal weight and serum creatinine (sCr) at each visit and calculated creatinine clearance (CrCl) rates using the Cockcroft–Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulae. Reference ranges for sCr and CrCl by CG and MDRD calculations were derived from the mean ± 2SD of values for pregnancy and postdelivery. Results Between 14-–and 40 weeks gestation, 249 African women not exposed to TDF-PrEP contributed a total of 1193 renal function values. Postdelivery, 207 of these women contributed to 800 renal function values. The normal reference range for sCr was 30–57 and 32–60 umol/l in the 2nd and 3rd trimesters of pregnancy. Normal reference ranges for CrCl using the MDRD calculation were 129–282 and 119–267 ml/min/1.73m2 for the 2nd and 3rd trimesters, respectively. Using the CG method of calculation, normal reference ranges for CrCl were 120—304 and 123–309 ml/min/1.73m2 for the 2nd and 3rd trimesters respectively. In comparison, the normal reference range for sCr, CrCl by MDRD and CG calculations postpartum was 40–77 umol/l, 92–201, and 90–238 ml/min/1.73m2, respectively. Conclusions In African women, the Upper Limit of Normal (ULN) for sCr in pregnancy is approximately 20% lower than 6 months postnatally. Inversely, the Lower Limit of Normal (LLN) for CrCl using either MDRD or CG equation is approximately 35% higher than 6 months postnatally. We provide normal reference ranges for sCr and CrCl for both methods of calculation and appropriate for the 2nd and 3rd trimesters of pregnancy in African women.

Evaluation of Six eGFR Equations in Predicting Acute Kidney Injury in Patients after Off-Pump Coronary Artery Bypass Grafting: A Case Control Study.

There are six widely used equations to calculate the estimated glomerular filtration rate (eGFR) of patients. We aimed to assess the predictive power of preoperative eGFR calculated by these equations for the occurrence of postoperative acute kidney injury (AKI). Patients who underwent isolated coronary surgery from January 2016 to January 2021 were continuously enrolled. Serum creatinine and cystatin C used to calculate eGFR were both measured within 1 week before surgery. The eGFR was calculated using six equations: Cockcroft Gault (CG) equation, Chinese abbreviated modification of diet in renal disease (MDRD) equation, chronic kidney disease-epidemiology (CKD-EPI) equation, and full age spectrum (FAS) equation. Postoperative AKI was diagnosed by Kidney Disease Improving Global Outcomes criteria (KDIGO) (① urine volume 0.5 mL/kg/h for 6 h; ② an increase in serum creatinine by 26.5 µmol/L within 48 h; ③ an increase in serum creatinine to 1.5 times baseline levels, which is known or presumed to have occurred within the prior 7 days), and the occurrence of AKI within 7 days after surgery was followed. A total of 1428 patients were included, of which 319 patients (25.5%) developed postoperative AKI. After adjustment, all eGFRs (CG OR = 0.983, MDRD OR = 0.983, OR = 0.97, OR = 0.955, OR = 0.978, OR = 0. 941, all p 0.001) were significantly associated with AKI. The area under the receiver operating characteristic curve (AUC) was 0.621 for CG, 0.614 for MDRD, 0.643 for , 0.739 for , 0.643 for , 0.744 for , respectively. There was no difference in predictive power between and (p = 0.33, DeLong's test). Preoperative eGFR calculated by and equations have better performance in predicting AKI after off-pump coronary artery bypass grafting than other equations.

Advanced Oxidative Protein Products Had a Diagnostic Accuracy for Identifying Chronic Kidney Disease in Adult Population.

Chronic Kidney Disease (CKD) is a serious public health problem. Hyperglycemia stimulates the production of reactive oxygen species that cause oxidative damage to proteins. AOPPs constitute a group of oxidized dityrosine-containing proteins that are generated during periods of oxidative stress. They have proved to be a valuable early marker of oxidative tissue damage and active mediators of inflammation associated with the uremic state. To analyze if advanced oxidative protein products (AOPPs) have diagnostic accuracy for identifying chronic kidney disease (CKD) in the adult population. We conducted a diagnostic test validation study in 302 adults ≥20 years old, of both sexes, with and without T2D. After obtaining informed consent, a comprehensive clinical history, anthropometric measurements (weight, BMI) and blood pressure were recorded. Glucose, cholesterol, triglyceride, HDL-c, LDL-c and AOPPs were determinates. Glomerular filtration rate (GFR) was calculated using Cockcroft-Gault (C-G) corrected by body surface area (BSA, mL/min/1.73 m2), CKD-EPI and MDRD equations to identify five stages of CKD. This study follows the Standards for Reporting Diagnostic Accuracy Studies (STARD). The median value of AOPPs was 198.32 µmol/L (minimum-maximum value: 113.48-522.42 µmol/L). The group with patients diagnosed with T2D exhibited higher concentrations (median: 487.39 µmol/L) compared to the non-diabetic group (median: 158.50 µmol/L, p = 0.0001). The selected cut-off point was ≥200 µmol/L using the closest to the median value of AOPPs with sensitivity and specificity as follows: C-G: sensitivity 96.58%; specificity 80%; likelihood ratio: 4.83; CKD-EPI: sensitivity 95.76%; specificity 79.89%; likelihood ratio: 4.76; MDRD: sensitivity 86.55%; specificity: 73.22%; likelihood ratio: 3.23. A difference was observed between AOPPs and chronic kidney disease stage. This study provides evidence that AOPPs ≥ 200 µmol/L have diagnostic accuracy in identifying stage 4-5 CKD by C-G, MDRD and CKD-EPI equations in adults with and without T2D.

De-indexed estimated glomerular filtration rates for the dosing of oral antidiabetic drugs in patients with chronic kidney disease.

Introduction: Adjusting drug dose levels based on equations that standardize the estimated glomerular filtration rate (eGFR) to a body surface area (BSA) of 1.73m2 can pose challenges, especially for patients with extremely high or low body mass index (BMI). The objective of the present study of patients with CKD and diabetes was to assess the impact of deindexing creatinine-based equations on estimates of kidney function and on the frequency of inappropriate prescriptions of oral antidiabetic drugs (OADs). Methods: The prospective CKD-REIN cohort is comprised of patients with eGFR <60mL/min/1.73m2. The inclusion criteria for this study were the use of OADs and the availability of data on weight, height and serum creatinine. We compared data for three BMI subgroups (group 1 <30kg/m2; group 2 30-34.9kg/m2; group 3 ≥35kg/m2). Inappropriate prescriptions (contraindicated or over-dosed drugs) were assessed with regard to the summary of product characteristics and the patient's kidney function estimated with the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, the 2021 CKD-EPI equation, the Modification of Diet in Renal Disease (MDRD) equation, the European Kidney Function Consortium (EKFC) equation, their deindexed estimates, and the Cockcroft-Gault (CG) formula. The impact of deindexing the equations was evaluated by assessing 1) the difference between the indexed and deindexed eGFRs, and 2) the difference in the proportion of patients with at least one inappropriate OAD prescription between the indexed and deindexed estimates. Results: At baseline, 694 patients were receiving OADs. The median BMI was 30.7kg/m2, the mean BSA was 1.98m2, and 90% of patients had a BSA >1.73m2. Deindexing the kidney function estimates led to higher eGFRs, especially in BMI group 3. The proportion of patients with at least one inappropriate prescription differed greatly when comparing indexed and deindexed estimates. The magnitude of the difference increased with the BMI: when comparing BMI group 1 with BMI group 3, the difference was respectively -4% and -10% between deindexed 2021 CKD-EPI and indexed CKD-EPI. Metformin and sitagliptin were the most frequent inappropriately prescribed OADs. Conclusion: We highlight significant differences between the BSA-indexed and deindexed versions of equations used to estimate kidney function, emphasizing the importance of using deindexed estimates to adjust drug dose levels - especially in patients with an extreme BMI.

Methods of Estimating Renal Function for Use in Clinical Trial Eligibility Criteria Widely Vary in Phase II and III Clinical Trials in Acute Myeloid Leukemia

Background Renal function is an important parameter to inform drug-dosing in oncology. In acute myeloid leukemia (AML), commonly used therapies or their metabolites are renally cleared. Several equations are commonly used to estimate renal function, such as Cockcroft-Gault (CG) to estimate creatinine clearance (CrCl) and the Modification of Diet in Renal Disease (MDRD) or Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equations to calculate estimated glomerular filtration rates (eGFR). These equations frequently use endogenous serum markers, such as creatinine (Cr) and cystatin-C due to their ready availability but can have limitations. For example, Cr can be affected by muscle mass, diet, and age. Current ADDIKD international consensus guidelines recommend using the CKD-EPI creatinine formula to calculate eGFR to guide anti-cancer drug dosing unless direct GFR measurement is indicated. Renal function criteria are commonly used in clinical trial eligibility. In this study, we analyzed the types of reported renal eligibility criteria in phase II and III trials in AML and the methodology specified for renal function estimation, which can significantly impact treatment options for patients and potentially confound toxicity evaluation. Methods We examined the clinicaltrials.gov database to review publicly reported renal eligibility criteria for interventional phase II and III clinical trials recruiting adults with AML between 2021 to 2023. Trials including pediatric patients and exclusive phase I studies were excluded. Chi-square tests were used to evaluate for potential associations between eGFR cutoff criteria and disease variables. Results A total of 134 trials met criteria for review, including 84 (63%) trials specifically for AML and 50 (37%) allowing additional diagnoses. Of the total study cohort, 107 trials (80%) were evaluating chemotherapy, small molecule inhibitors, immunotherapy and/or combinations of these whereas 27 (20%) were evaluating primarily cell therapy and/or transplant-based regimens. Among the 134 trials, 21 (16%) did not mention renal or general organ function in eligibility criteria; 16 (12%) mentioned renal or organ function in inclusion/exclusion criteria but did not specify an eGFR cutoff value; and 15 (11%) specified a serum Cr cutoff value without a specific eGFR cutoff value. Among 82 (61%) studies specifying eGFR cutoffs: 18 required eGFR ≥60 ml/min and 64 specified cutoffs between 30 ml/min to 50 ml/min or greater (table 1). We found an association between studies requiring an eGFR of 60 ml/min or greater and studies investigating cell therapy or transplant-based regimens (p&amp;lt;0.01). We did not find associations between eGFR cutoff requirements and trials based on disease status (relapsed/refractory AML versus other AML states, p=0.24). We next evaluated methodologies reported in eligibility criteria to estimate renal function. Among the 113 trials commenting on renal function criteria: 15 (13%) did not report either an eGFR cutoff or methodology of determination; 67 (59%) specified eGFR cutoffs without specifying the methodology of determination and/or provided serum Cr-based cutoffs; and 31 (27%) specified either a method of direct measurement or equations to estimate eGFR (including CG-based in 25, CKD-EPI in 1, MDRD-based in 3 and radioisotope methodology in 1) (table 1). No trials mentioned cystatin-C as part of renal function determination. Conclusion In contemporary phase II/III clinical trials for adult patients with AML, we identified that while most trials include renal function in inclusion/exclusion criteria, there was tremendous heterogeneity in methodologies specified for determination of renal function which may make efficacy and toxicity comparisons challenging and impact patient eligibility across institutions. Several trials specified serum Cr cutoffs which can be impacted by factors besides renal function such as age or muscle mass. This study was limited by what trial criteria were publicly available and additional information specifying methodologies to calculate renal function may be available in full trial protocols. Further research is needed to determine the most suitable method for assessing eGFR in patients with AML to optimize treatment exposures for patients and to help reduce confounding of trial results or trial eligibility by institutional practice variation.

Impact of weight and creatinine adjustments on the accuracy of Cockcroft-gault equation in hematopoietic cell transplant patients.

Hematopoietic cell transplant (HCT) patients undergo pre- transplant renal function evaluation to confirm transplant eligibility and tailor pharmacotherapy. There is limited evidence regarding the most accurate method of estimating creatinine clearance (CrCl) within this patient population and no studies exist that evaluate the weight utilized within the Cockcroft-Gault (CG) equation in HCT patients. This study evaluates different weight and serum creatinine (SCr) adjustments utilized within the CG equation estimating for renal clearance in patients undergoing HCT. This is a retrospective, single center analysis of adult HCT patients who underwent pre-transplant evaluation with a measured CrCl using a 24-h urine creatinine collection. The primary outcome was to evaluate the correlation of various weights used in estimation of CrCl compared to measured CrCl. Key secondary outcomes include evaluation of the impact of various weights on estimated CrCl in subpopulations, evaluation of adjusting SCr to pre-determined limits, and determination of an appropriate obesity threshold to utilize body weight adjustments. Seven-hundred and forty-two patients were included in the study. In the primary analysis, CG utilizing adjusted body weight (ADjBW0.4 ) had a greater correlation (r=.812) to measured CrCl when compared to total or ideal body weight (r=.801 and r=.790 respectively). The threshold of 120% of ideal body weight (IBW) produced less bias and greater accuracy in comparison to the threshold of 140% IBW. In patients 60 years or older, rounding low SCr values up .8 or 1mg/dL resulted in decreased correlation and a greater mean difference in comparison to not rounding SCr. In HCT patients who are overweight or obese, ADjBW .4 is the most accurate weight for the CG equation. In HCT patients who have a total body weight<120% IBW, total body weight is the most accurate weight to utilize. Rounding up low SCr to .8 or 1mg/dL does not improve the accuracy or led to less bias of the CG equation.

DOAC Dosing Discordance Using Different Estimates of Kidney Function and Outcomes.

Direct oral anticoagulants (DOACs) are indicated for the prevention of stroke in non-valvular atrial fibrillation (NVAF). Although FDA labeling for DOACs utilizes estimated creatinine clearance (CrCL) according to the Cockcroft-Gault (C-G) equation, estimated glomerular filtration rate (eGFR) according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is often reported. The objectives of this study were to evaluate DOAC dosing discordance and to determine whether discordance based on various estimates of kidney function is associated with bleeding or thromboembolism. The study was an IRB-approved retrospective analysis of patients at UPMC Presbyterian Hospital from 01/01/2010-12/31/2016. Data were obtained through electronic medical records. Adults who received a medication charge for rivaroxaban or dabigatran, had a diagnosis code for atrial fibrillation, and a serum creatinine (SCr) within 3 days of DOAC initiation were included. Doses were considered discordant if the calculated dose based on CKD-EPI did not match the patient's dose during index admission, if dosed correctly utilizing C-G. Association of discordance with dabigatran, rivaroxaban, and clinical outcomes was determined using odds ratios and 95% confidence intervals. Rivaroxaban discordance was present among 49 of the 644 (8%) patients that were dosed correctly with C-G. Dabigatran discordance was present among 17 of the 590 (3%) patients that were dosed correctly. Discordance with rivaroxaban was found to increase the risk of thromboembolism when utilizing CKD-EPI (OR = 2.83; 95% CI, 1.02to7.79, p = 0.045) versus C-G. Our findings emphasize the need to dose DOACs, specifically rivaroxaban, appropriately in patients with NVAF. This article is protected by copyright. All rights reserved.

The impact of clinical equations on carboplatin dosing: A systematic review to determine appropriate dosing of carboplatin in adult cancer patients.

e15005 Background: The Calvert formula is used to estimate the carboplatin dose needed to achieve the desired Area Under the Curve (AUC) despite little consensus on which estimated Glomerular Filtration Rate (eGFR) equation best reflects renal clearance. Cockcroft-Gault (CG) is often used when calculating estimated Creatinine Clearance (CrCl) for the Calvert formula. Equations like Modification of Diet in Renal Disease or CKD-EPI (based on serum creatinine (SrCr) or cystatin C), take into account parameters such as race, gender, weight. We compared several publications to determine the most effective dosing strategy for carboplatin. Methods: Utilizing PubMed, 19 articles were found with the keywords “carboplatin, dosing, eGFR, measure GFR, creatinine clearance, muscle mass.” Our inclusion criteria consisted of being published within the last 10 years, included carboplatin dosing, and evaluated either measured GFR, measured CrCl, carboplatin clearance or toxicities caused by carboplatin. Studies not meeting these parameters were excluded. Of the 19 articles, 11 articles were identified regarding the accuracy of eGFR and its effects on carboplatin dosing and/or dose limiting toxicities. An extensive literature review of each article was used to find a consensus among the clinical equations used in carboplatin dosing. Results: There remains no consensus on the most accurate eGFR equation. Eight studies evaluated accuracy of varying equations in estimating GFR, creatinine clearance or carboplatin clearance. Two studies created new equations (one measuring GFR and the other measuring CrCl) and compared them to current equations for accuracy. Ultimately, only two studies were in agreement that CKD-EPI was the most viable option when GFR uses SrCr. Based on four studies, CG is an inadequate measurement of eGFR. CG ranked low due to a high mean percent error when compared to measured GFR, indicating a larger discrepancy between measured GFR and the estimated value of CG, as compared to other equations. Three of the studies evaluated for a correlation in skeletal muscle mass and hematological toxicities, indicating that changes in muscle mass could correlate with hematological toxicities. One small study developed a new equation based on muscle mass and SrCr and showed positive results for accuracy when compared to measure CrCl. Conclusions: Although a definitive equation to estimate renal clearance could not be established, equations like CG have limited accuracy due to race, weight, age, and gender. The single study that utilized muscle mass demonstrated the most promise and presents a better option for patients, particularly when muscle mass changes over time. Other studies illustrated that muscle mass is significantly correlated with carboplatin toxicity and should be considered for future studies to determine the safest method for dosing carboplatin.

Comparison of glomerular filtration rate estimating equations in Indian geriatric patients with cancer.

e24025 Background: Accurate estimation of glomerular filtration rate (eGFR) is essential for dose calculation of certain anticancer drugs. It is particularly important in older cancer patients because of age-related compromise in renal function. 99mTc-DTPA plasma clearance for GFR measurement poses practical difficulties in the elderly and is expensive. Therefore, we investigated the predictive accuracy of eight commonly used eGFR equations against 99mTc-DTPA plasma clearance as the gold standard in Indian geriatric oncology population. Methods: A cross-sectional study was conducted in the geriatric oncology clinic of Tata Memorial Hospital, India, from June 2021 to November 2022. Age, sex, weight, BUN and serum creatinine were obtained from the hospital records. Serum cystatin C was estimated using sandwich ELISA (Sigma, Germany). GFR was estimated using Cockcroft-Gault (CG); 6 variable MDRD; 4 variable MDRD; CKD-EPI creatinine; CKD-EPI cystatin; CKD-EPI creatinine-cystatin; BIS 1; and BIS 2 equations. GFR was also measured by 99mTc-DTPA plasma technique (Gates’ method). The agreement between different eGFR methods and the measured GFR was analyzed using Bland-Altman test. Results: Out of 311 enrolled patients, 276 patients having full covariate data required for estimation of eGFR by all eight equations were included in the analysis. Majority were males (N = 214). Median age (range) of the patients was 68 (60 – 88) years. Median of measured GFR using 99mTc-DTPA was 71 (17 – 141) ml/min. The performance i.e., bias and 95% Limit of Agreement (LoA) of eGFR equations against measured GFR is shown in table 1. Overall, the BIS 2 equation with least bias of 0.854 and narrowest 95% LoA (-31.23 to 32.94) had the highest agreement with ‘gold standard’. In fact, BIS 2 performed consistently well across age (60-70, 71-80, 81-90) and BMI (≤18.5, 18.6-24.9, ≥25) groups (data not shown). BIS 2 was followed by CKD-EPIcr-cys and CKD-EPIcys with best estimates of bias and 95% LoA (Table 1). Interestingly, all three equations have cystatin C as a covariate. 4vMDRD had the highest bias (-24.08) and least agreement with DTPA (-86.52 – 38.36). Post hoc analysis showed that 59/115 (51.3%) patients who were cisplatin-ineligible (GFR &lt; 60) based on CG were cisplatin-eligible based on BIS 2, while 19/161 (11.8%) patients who were cisplatin-eligible based on CG were actually ineligible as per BIS 2. Conclusions: Equations derived using cystatin C in general, and BIS 2 in particular, have highest predictive accuracy for GFR estimation in older cancer patients. [Table: see text]

A phase 2 evaluation of daratumumab-based induction therapy in patients with multiple myeloma with severe renal insufficiency.

8057 Background: Myeloma patients (pts) with renal insufficiency (RI) have inferior disease outcomes; up to 50% present with acute kidney injury (AKI). AKI results from light chain-induced cast nephropathy; physicochemical properties (self-association, aggregate formation) may determine severity. Daratumumab has extensive data in myeloma, reduces circulating light chains, preserves renal function in AL amyloidosis, and has non-renal clearance. We hypothesized early therapy with daratumumab and VRD normalize myeloma-induced AKI in a population rarely included in trials. Methods: We used a Simon’s two-stage design in newly diagnosed pts with severe AKI (CrCl &lt;30 mL/min) of 4 x 21-D cycles of daratumumab 16mg/kg IV QW x 3 (C1-3, C4D1 only), bortezomib 1.3 mg/m2 SQ D1, 4, 8, and 11, and dexamethasone 40mg (reduced to 20mg at C2 for ≥75 yrs.) D1-4 (C1 only, D1 only C2-4), 8, and 15, with add-on lenalidomide at C2 (25mg if CrCl ≥30 mL/min). Standard antiviral, antithrombotic, premedications were used. Eligibility criteria were broad (CrCl &lt;30 mL/min, PS 0-2, ANC&gt;1000/mm3, Hgb&gt;7 g/dL, plt&gt;75,000/mm3) with liberal dose reductions for generalizability. Primary objective: determine proportion with renal recovery (CrCl ≥50 mL/min) after 2 cycles; secondary objectives: best response (IMWG), renal function at end of treatment, dose density/tolerability, adverse events (AE), renal function change by estimates [Cockcroft-Gault (C-G), MDRD, 24-hour urine, CKD-EPI], and daratumumab PK. If ≥7 responses seen in the first 11 pts, 14 more would be accrued. These data are the planned analysis of the initial cohort. Results: Thirteen pts enrolled: 8 male, 7 white/6 black, median age 69 yr (46-82), 11 treated/evaluable for the primary endpoint. Median baseline CrCl 13.8 mL/min (4.9-20.2), median serum creatinine (SCr) 4.92 mg/dL (3.53-9.93). One withdrew consent, 1 was inevaluable (rapid disease progression and death). Seven achieved CrCl of ≥50 mL/min (median C3D1 CrCl 61 mL/min, 22-151) after 2 cycles, all had SCr improvement at C3D1. Lenalidomide dose was 25 mg on C2D1 in 9/11 pts. Median (range) dose density (delivered/planned): daratumumab 100% (40-100), bortezomib 100% (25-100), dexamethasone 80% (67-100), lenalidomide 100% (0-100). The overall response rate was 100%, ≥VGPR rate 82%. Best responses were CR (3), VGPR (6), PR (2). Treatment-emergent grade ¾ hematologic AEs: anemia (90.9%), lymphopenia (81.8%), thrombocytopenia (36.4%), neutropenia (9.1%). Conclusions: Early, aggressive therapy with a daratumumab-based induction regimen in myeloma pts with severe AKI improves renal function, with the majority achieving CrCl ≥50 mL/min after 2 cycles; all responded. AEs seen were consistent with prior experience with the 4-drug regimen. Per protocol, 14 additional patients will be accrued in the second stage. Clinical trial information: NCT04352205 .

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.

292 Augmented Renal Clearance in Burn Patients: Incidence and Discordance with Standard Creatinine Clearance Estimation

Abstract Introduction Augmented renal clearance (ARC) is a phenomenon that occurs in some critically ill populations. ARC is associated with drug failure, commonly antimicrobials, due to subtherapeutic drug exposure. Patient specific factors for ARC have not been well described in the burn population. The aim of this study is to describe the incidence and patient characteristics associated with ARC in those admitted to a burn service for a mixed severity of illness. Methods Consecutive adult patients admitted to an ABA verified burn center were screened under an institutional collaborative practice agreement for identification of ARC via a 12-hour urine collection (UC-12). Data was collected retrospectively under an IRB approved protocol. Creatinine clearance (CrCl) was calculated directly from UC-12 whereas Cockcroft-Gault (C-G) was calculated using a standard equation with adjusted body weight when applicable. A UC-12 CrCl greater than 130 mL/min was considered ARC and all values were compared to C-G estimations. Descriptive and inferential analyses were non-parametric using a two-sided alpha value of &amp;lt; 0.05 as significant. Results A total of 53 patients over 8 months completed a UC-12 with a median 2 (range 1-9) collected during hospitalization. The population was largely male (81%), without trauma (91%), median age 43 (interquartile range [IQR] 35.5-58.5), total body surface area (TBSA) 20% (IQR 7.25-23.55), with thermal injuries (91%). Of the 53 patients, ARC was identified during hospitalization in 68%. There were no significant differences in median age, TBSA, proportion of trauma, or thermal burn between patients with ARC and those without (41 vs 48 years, 20.25 vs 13%, 11 vs 6%, and 94 vs 82%, respectively; p &amp;gt;0.1 for all). Of the 117 UC-12 measurements, ARC was identified in 61.5%, occurring a median 9 days (range 0-72) post injury. Overall median UC-12 CrCl was 148 mL/min (IQR 105-199) and C-G estimation was 139 mL/min (IQR 106-162) with a median discordance of 16 mL/min (IQR -14-58). Discordance of 30mL/min or more (positively or negatively) was frequent comparing actual CrCl to estimates using C-G (58%). Conclusions ARC, as directly measured by UC-12, is common in a mixed burn population. Additional research is required to identify patients at increased risk for ARC and subsequent drug dosing strategies to maintain efficacy without undue risk of toxicity. Applicability of Research to Practice Widely accepted estimations of CrCl may result in incorrect drug dosing and commonly underestimates actual CrCl which has implications for drug clearance, and therefore, dosing. Patients with ARC likely require dosing that exceeds FDA recommendations when titration to a dynamic effect or real-time pharmacokinetics are unavailable. Timed urine collection for CrCl calculation should be considered in the burn population.

Comparison of CG, CKD-EPI[AS] and CKD-EPI[ASR] equations to estimate glomerular filtration rate and predict mortality in treatment naïve people living with HIV in Zimbabwe

BackgroundRenal impairment in people living with HIV (PWH) in Sub-Saharan Africa is common and associated with increased morbidity and mortality. The ideal equation to estimate glomerular filtration rate (eGFR) in this population remains unclear. That which best predicts clinical risk may be the most appropriate while validation studies are awaited. Here we compare the Cockcroft-Gault (CG), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI[ASR]) and the CKD-EPI equation with the race coefficient removed (CKD-EPI[AS]), in a population of anti-retroviral therapy (ART) naïve PWH in Zimbabwe to assess which equation best predicts mortality.MethodsA retrospective cohort study of treatment naïve PWH at the Newlands Clinic in Harare, Zimbabwe was completed. The study included all patients commencing ART between 2007 and 2019. Predictors of mortality were assessed by multivariable logistic regression.ResultsA total of 2991 patients were followed-up for a median of 4.6 years. The cohort was 62.1% female, with 26.1% of patients having at least one comorbidity. The CG equation identified 21.6% of patients as having renal impairment compared with 17.6% with CKD-EPI[AS] and 9.3% with CKD-EPI[ASR]. There was a mortality rate of 9.1% across the study period. The highest mortality risk was seen in those with renal impairment as determined by the CKD-EPI[ASR] equation for both eGFR < 90 and eGFR < 60 with OR 2.97 (95%CI 1.86–4.76) and OR 10.6 (95%CI 3.15–18.04) respectively.ConclusionIn treatment naïve PWH in Zimbabwe, the CKD-EPI[ASR] equation identifies patients at highest risk of mortality when compared to the CKD-EPI[AS] and CG equations.

Predictive performance of glomerular filtration rate equations based on cystatin C, creatinine and their combination in critically ill patients

Objective24-hour urine creatinine clearance (ClCr 24 hours) remains the gold standard for estimating glomerular filtration rate (GFR) in critically ill patients; however, simpler methods are commonly used in clinical practice....

Association between renal function and bone mineral density in patients with type 2 diabetes mellitus

BackgroundThis study evaluated the association between renal function, assessed by serum creatinine and estimated glomerular filtration rate (eGFR) according to the Cockcroft–Gault (CG) and Modification of Diet in Renal Disease (MDRD) equations, and bone mineral density (BMD) in Chinese patients with type 2 diabetes mellitus (T2DM). Methods1322 patients with T2DM were included, and their basic clinical information, serum biochemical tests, and BMD at the total hip and femur neck were collected. Multivariate adjusted linear regression, smooth curve fitting and a piecewise linear regression model were used to analyze linear and nonlinear associations. Age, BMI, drinking, smoking, systolic blood pressure and diastolic blood pressure, FBG, HbA1C, course of diabetes, hsCRP, TC, TG, HDL-C, LDL-C, Ca, P, PTH, ALP, OC, P1NP, β-CTX and 25(OH)D were adjusted. ResultsAfter adjusting the variables, no correlation between eGFR CG and eGFR MDRD and femur neck BMD was observed in women, men, or the total population. The eGFR CG and eGFR MDRD had a significant positive association with total hip BMD in men and the total population with T2DM. With a 10-unit decrease in eGFR CG, total hip BMD reduced by 0.012 g/cm2 in men and 0.010 g/cm2 the total population. Total hip BMD reduced by 0.014 g/cm2 in men and 0.022 g/cm2 in the total population with a 10-unit decrease in eGFR MDRD. There was no correlation between eGFR CG or eGFR MDRD and total hip BMD in female participants. ConclusionImpaired renal function was associated with decreased total hip BMD in men and the total population with T2DM. No associated between renal function with femur neck BMD was observed.

Renal function estimating equations performance during pregnancy and postpartum.

The objectives of this study were to evaluate the performance of renal function estimating equations compared to measured creatinine clearance (CrCl) during pregnancy and postpartum and to evaluate which body weight (pre-pregnancy weight (PPW), actual body weight (ABW), and ideal body weight (IBW)) provides the best performance. A retrospective study. Collections tookplace in the University of Washington clinical research unit. Women (n = 166) who completed ≥1 pharmacokinetic (PK) study with a 6-24 h measured CrCl during pregnancy and/or ≥3 months postpartum were included. CrCl was estimated utilizing estimated glomerular filtration rate (eGFR) and CrCl equations with common weight descriptors. Analyses included Bland-Altman, relative accuracies within 10% and 25%, and root mean squared error (RMSE). Overall performance was determined by summation of rank for evaluation parameters. During pregnancy, correlations between measured CrCl and estimated CrCl were between 0.5-0.8; equations with slopes closest to one were Modification of Diet in Renal Disease (MDRD2; PPW and ABW) and Cockcroft-Gault (CG) (PPW); and y-intercept closest to zero was Preeclampsia Glomerular Filtration Rate (PGFR). The lowest bias was seen with CG (ABW), and the highest accuracy within 25% was CG (ABW). CG (PPW) had the lowest RMSE. Postpartum, the best correlation was found with MDRD2 (PPW), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI (ABW)), and CKD-EPI 2021 (PPW). For slopes closest to one, MDRD2 (ABW) was best, whereas the equation with y-intercept closest to zero was CKD-EPI (ABW). CG (PPW) had the highest accuracy within 25%, and 100/serum creatinine (SCr) had the lowest bias. Based on overall performance, CG (PPW) was the best followed by CG (ABW) and PGFR during pregnancy and 100/SCr followed by CG (PPW) and CG (ABW) postpartum. The new CKD-EPI 2021 equation did not perform well during pregnancy. When 24-h CrCls are not available during pregnancy, CG (PPW or ABW) performed the best overall, whereas at 3 months postpartum, 100/SCr performed the best overall.

Clinical Associations with the differences in rivaroxaban dosing in patients with atrial fibrillation stratified by three renal function formulae.

Clinical trials used Cockcroft-Gault (CG) formula to calculate the estimated glomerular filtration rate (eGFR) in order to dose rivaroxaban for patients with atrial fibrillation (AF). The aim of this study is to evaluate rivaroxaban dosing appropriateness in patients with AF with or without renal impairment based on the CG formula and other formulae, including Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and the isotope dilution mass spectrometry (IDMS) traceable Modification of Diet in Renal Disease (MDRD) Study equation and the associated clinical outcomes. A retrospective cohort study conducted at Sultan Qaboos University Hospital (SQUH) from 1st January 2016 to 31st December 2020, included all adult patients (≥ 18 years) treated with rivaroxaban for AF and followed up for one year after starting the treatment. Based on the CG formula, the rivaroxaban dose was inappropriately prescribed in 27% of the patients (21% overdosed and 6% underdosed). Higher baseline creatinine (P=0.0014) and concurrent use of antiplatelet therapy (P<0.001) were associated with the tendency to rivaroxaban overdosing. Higher Body Mass Index (BMI) (P=0.002), female sex (P=0.032), and CKD (P=0.003) were associated with rivaroxaban underdosing. The degree of agreement between the renal function tests when comparing MDRD vs CG and CKD-EPI vs CG in terms of estimated glomerular filtration rate/creatine clearance (eGFR/CrCl) calculation was moderate (κ=0.46) and poor (κ=0.00), respectively, while, in terms of rivaroxaban dose appropriateness was almost perfect (κ=0.82) and substantial (κ=0.77). Clinical outcomes measured by stroke and bleeding events were not significantly different according to the appropriateness of the rivaroxaban dose. This study has shown a relatively high consistency with the gold standard in dosing rivaroxaban in AF patients using CG formula. Treatment efficiency and safety were not affected by the proportion of dose inappropriateness found in this cohort.