Cockcroft-Gault Estimates Research Articles

PB1820: CD47-BLOCKER TTI-622 COMBINED WITH AZACITIDINE IN PATIENTS WITH TP53-MUTATED ACUTE MYELOID LEUKEMIA (AML) AND WITH AZACITIDINE + VENETOCLAX IN ELDERLY OR UNFIT PATIENTS WITH TP53-WILDTYPE AML

Background: CD47 is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a “don’t eat me” signal to suppress macrophage phagocytosis. TTI-622 is a fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG4. It is designed to enhance phagocytosis and antitumor activity by preventing CD47 from delivering its inhibitory signal as well as generating a moderate pro-phagocytic signal via IgG4 Fc. Importantly, unlike many CD47-blocking agents, TTI-622 does not bind to human red blood cells. Increased expression of CD47 is an adverse prognostic factor in acute myeloid leukemia (AML) due to its association with reduced event-free and overall survival, and blockade of CD47 has shown pre-clinical and clinical activity in AML. In vitro, both azacitidine and venetoclax significantly enhanced the pro-phagocytic effect of TTI-622 on macrophages. Aims: To characterize the safety and preliminary efficacy profile of TTI-622 in combination with azacitidine in newly diagnosed TP53-mutated AML and in combination with azacitidine + venetoclax in elderly or unfit, newly diagnosed TP53-wildtype AML. Pharmacokinetics and immunogenicity of TTI-622 combined with azacitidine ± venetoclax will also be investigated. Primary endpoints include dose-limiting toxicities, incidence of adverse events (AEs) and complete response (CR). Minimal residual disease status will also be evaluated. Methods: As part of an ongoing dose-escalation and expansion trial of TTI-622 (NCT03530683), patients with AML meeting the below key entry criterion are enrolled. Cohort A includes patients with newly diagnosed TP53-mutated AML. Cohort B includes patients with newly diagnosed TP53-wildtype AML who are either elderly (375 years) or unfit. Unfit patients include those < 75 years with one or more of the following comorbidities: Eastern Cooperative Oncology Group (ECOG) performance status of 2, clinically significant heart or lung comorbidities, contraindication to anthracycline therapy, or other comorbidity the investigator regards as incompatible with intensive remission induction chemotherapy. All patients from both cohorts must have documented bone marrow or peripheral blast counts 3 20% and must have received no prior systemic therapy for AML nor hypomethylating agents for any antecedent hematologic disorders prior to transformation to AML. Patients must have no extramedullary disease or leukocytosis >25,000/mL. Renal function must be 330 mL/minute based on Cockcroft-Gault estimate. There are no restrictions based on neutrophil or platelet counts, or hemoglobin level. Patients with AML secondary to antecedent hematologic disorders or therapy induced will not comprise more than 50% of either Cohort. Up to 30 patients will be enrolled into each cohort. In 28-day cycles, patients in both Cohorts will receive TTI-622 8 mg/kg intravenous (IV) infusions weekly combined with azacitidine 75 mg/m2 administered either IV or subcutaneously for 7 consecutive days, repeated approximately every 4 weeks. Patients in Cohort B will also receive venetoclax 100 mg and 200 mg orally on Days 1 and 2, respectively, followed by 400 mg (or equivalent adjusted for azoles) daily thereafter. Safety monitoring includes clinical laboratories and assessments of AEs based on CTCAE v 4.03. Response assessments of both bone marrow and peripheral blood are performed at the end of Cycles 1, 2 and 4; and then every 3 cycles thereafter. Response assessment is per the ELN2017 criteria. Results: Results N/A (trial-in-progress) Summary/Conclusion: Conclusion N/A (trial-in-progress)

Association of Renal Clearance with Cerebral White Matter Vascular Disease in Hospitalized Veterans With and Without Delirium.

To assess the relation between renal function and delirium and to assess and compare the relation between cerebral white matter lesion (WML) and renal function as estimated by three formulas for the estimated glomerular filtration rate (eGFR) in older adult hospitalized veterans with and without delirium. Commonly used formulas to assess renal function-the four-variable Modification of Diet in Renal Disease (MDRD), the six-variable MDRD, and the Cockcroft-Gault eGFR equations-were used to assess renal function in 100 older adult hospitalized veterans with delirium (delirium group) and 100 hospitalized veterans without delirium (nondelirium group) that were age, sex, and race matched. WML location and volumes were assessed using brain computed tomography imaging for each of the 200 veterans in the study. One radiologist, blinded to the diagnoses of the veterans, examined head computed tomography scans for WML in the cortex, subcortex (frontal, temporal, parietal, occipital lobes), basal ganglia (globus pallidus, caudate, putamen), and internal capsule. WML were graded as not present, <1 cm, 1 to 2 cm, or >2 cm. Exploratory χ2 analyses were used to determine the association between the stage of chronic kidney disease and WML. Simple logistic regression analyses were then used to estimate the strength of association between the stages of kidney disease and WML for particular regions of the brain. The mean age of delirium group and nondelirium group veterans was 66 years. χ2 tests revealed no reliable relation between stages of renal disease and delirium. χ2 exploratory analyses of WML in brain regions by renal disease stages demonstrated significant differences in associations among the MDRD-4, MDRD-6, and Cockcroft-Gault formulas for measuring eGFR. The MDRD-4 formula was least associated with the presence or absence of WML. The Cockcroft-Gault estimation of eGFR was most associated with the presence or absence of WML. Simple logistic regressions showed notable increases in the association between stages of renal failure and WMLs in specific areas of the brain, with the MDRD-4 being the least associative with the fewest specific areas and the Cockcroft-Gault formula being the most associative with the most specific areas. The association between stages 2 through 5 of chronic kidney disease and WLM support the role of kidney function as a potential risk factor for WML in older adult military veterans. The Cockcroft-Gault formula is an important renal index of suspected WML and renal stages 2 through 5, superior to the MDRD-6 and MDRD-4, respectively, in association with WML in older adult military veterans.

Correlation of Measured and Estimated Creatinine Clearance in Hospitalized Elderly Patients: A Retrospective Cohort Study.

Background: Accurate assessment of renal function is essential in hospitalized elderly patients. Few studies have examined the accuracy of Cockcroft-Gault (C-G) estimates of creatinine clearance (CrCl) compared with measured clearance in these patients. Objective: The objective of this study was to determine the correlation between C-G estimates of CrCl and measured CrCl in hospitalized elderly patients. Methods: This Institutional Review Board-approved, single-center retrospective observational cohort study included all patients who were 65 years and older admitted to our medical center in January to September 2018 with either an 8- or 24-hour urine collected during admission. The primary outcome was correlation, bias, and precision of C-G estimates of CrCl versus measured CrCl using Pearson correlation, Spearman linear regression, and Bland-Altman analysis. Outliers were determined using a cut-off of ±20%. Data are presented as median (interquartile range) or percentages. Results: A total of 108 urine collections from 90 unique patients were included in the study. The patients were 51% female, median age was 71 (68-77) years, and median body mass index was 26.6 (22.8-31) kg/m2. Most collections were over 24 hours (66.7%), and 38% were performed while patients were in an intensive care unit. Median blood urea nitrogen (BUN) was 24.5 (17-36) mg/dL and median serum creatinine was 0.71 (0.55-1.09) mg/dL. The median C-G estimation was 75.4 (48.2-110.6) mL/min, and the median measured CrCl was 79.1 (38.1-99.5) mL/min, r 2 = .56 (P < .001). Bland-Altman analysis showed large limits of agreement (-75.5-57.7 mL/min), with a bias of -8.9 and precision (standard deviation of bias) of 34 mL/min. Outliers were common, with 38% of C-G estimation values >120% of measured CrCl, and 18% of C-G estimates <80% of measured CrCl. Conclusions: Measured CrCl varied significantly from C-G estimates in hospitalized elderly patients. It is important to recognize characteristics of patients who may benefit from measurement of CrCl. Future studies should examine the impact of this variance on clinical outcomes.

Estimation of Kidney Function in Oncology: Implications for Anticancer Drug Selection and Dosing.

Estimation of kidney function in patients with cancer directly affects drug dosing, agent selection, and eligibility for clinical trials of novel agents. Overestimation of kidney function may lead to overdosing or inappropriate agent selection and corresponding toxicity. Conversely, underestimation of kidney function may lead to underdosing or inappropriate agent exclusion and subsequent therapeutic failure. It would seem obvious that the most accurate estimates of kidney function should be used to reduce variability in decision making and ultimately, the therapeutic outcomes of toxicity and clinical benefit. However, clinical decision making is often more complex. The Cockcroft-Gault formula remains the most universally implemented estimator of kidney function in patients with cancer, despite its relative inaccuracy compared with the Chronic Kidney Disease Epidemiology Collaboration equation. The Chronic Kidney Disease Epidemiology Collaboration equation is a more precise estimator of kidney function; however, many currently used kidney function cutoff values were determined before the development of the Chronic Kidney Disease Epidemiology Collaboration equation and creatinine assay standardization using Cockcroft-Gault estimates. There is a need for additional studies investigating the validity of currently used estimates of kidney function in patients with cancer and the applicability of traditional anticancer dosing and eligibility guidelines to modern and more accurate estimates of kidney function. In this review, we consider contemporary calculation methods used to estimate kidney function in patients with cancer. We discuss the clinical implications of using these various methods, including the potential influence on drug dosing, drug selection, and clinical trial eligibility, using carboplatin and cisplatin as case studies.

Estimating Renal Function in Drug Development: Time to Take the Fork in the Road.

Renal function is the most commonly applied patient-specific quantitative variable used to determine drug doses. Measurement of renal function is not practical in most clinical settings; therefore, clinicians often rely on estimates when making dosing decisions. Similarly, renal function estimates are used to assign subjects in phase 1 pharmacokinetic studies, which inform dosing in late-phase clinical trials and ultimately the product label. The Cockcroft-Gault estimate of creatinine clearance has been the standard renal function metric; however, this paradigm is shifting toward the Modification of Diet in Renal Diseases (MDRD) estimate of the glomerular filtration rate (GFR). The proportion of approved new drug labels with dosing recommendations based on the MDRD equation was 16.7% in 2015, 70.0% in 2016, and 46.7% in 2017. Disharmonious recommendations from the United States Food and Drug Administration and the European Medicines Agency will continue to increase this heterogeneity in the assessment of renal function in drug development and negatively impact industry, health systems, and clinicians. In this review, we discuss the current regulatory guidance for the conduct of renal impairment pharmacokinetic studies and review the implications of this guidance across the medication use system with 3 recently approved antibiotics: ceftazidime/avibactam, delafloxacin, and meropenem/vaborbactam. Finally, we suggest measuring GFR in phase 1 studies and employing the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation to integrate data across clinical trials. This will help to harmonize CKD staging, population pharmacokinetic analyses, and dosing by estimated renal function.

Use of Estimating Equations for Dosing Antimicrobials in Patients with Acute Kidney Injury Not Receiving Renal Replacement Therapy.

Acute kidney injury (AKI) can potentially lead to the accumulation of antimicrobial drugs with significant renal clearance. Drug dosing adjustments are commonly made using the Cockcroft-Gault estimate of creatinine clearance (CLcr). The Modified Jelliffe equation is significantly better at estimating kidney function than the Cockcroft-Gault equation in the setting of AKI. The objective of this study is to assess the degree of antimicrobial dosing discordance using different glomerular filtration rate (GFR) estimating equations. This is a retrospective evaluation of antimicrobial dosing using different estimating equations for kidney function in AKI and comparison to Cockcroft-Gault estimation as a reference. Considering the Cockcroft-Gault estimate as the criterion standard, antimicrobials were appropriately adjusted at most 80.7% of the time. On average, kidney function changed by 30 mL/min over the course of an AKI episode. The median clearance at the peak serum creatinine was 27.4 (9.3–66.3) mL/min for Cockcroft Gault, 19.8 (9.8–47.0) mL/min/1.73 m2 for MDRD and 20.5 (4.9–49.6) mL/min for the Modified Jelliffe equations. The discordance rate for antimicrobial dosing ranged from a minimum of 8.6% to a maximum of 16.4%. In the event of discordance, the dose administered was supra-therapeutic 100% of the time using the Modified Jelliffe equation. Use of estimating equations other than the Cockcroft Gault equation may significantly alter dosing of antimicrobials in AKI.

Serum Cystatin C as an Endogenous Marker of Renal Function in Patients with Chronic Kidney Disease (CKD)

Background: Cystatin C is being considered as a potential replacement for serum creatinine as a filtration marker.Objectives: This present study was conducted to determine the validity of Cystatin C as a renal function test and to compare the Cystatin C and serum creatinine level between the CKD cases and person not having CKD.Methodology: The present case control study was conducted in the department of Nephrology of Dhaka Medical College Hospital during the period of January 2009 to December 2009 with the aim to find out the serum Cystatin C as diagnostic markers of chronic kidney disease. In the present study total 100 respondents were included. Among them 50 were CKD patients and another 50 were without CKD. Results: It was an age and sex matched study. Out of 50 patients with CKD, 29 (58.0%) were in the stage IV followed by 15 (30.0%) were in the stage III and rest 6 (12.0%) were in the stage V. In CKD group 31 (62.0%) had glomerulonephritis, 18 (36.0%) had HTN, 11 (22.0%) had DM and 3 (6.0%) had obstructive uropathy. In without CKD group 9 (18.0%) had HTN, 6 (12.0%) had DM. Mean±SD of Serum Creatinine in CKD and without CKD groups were 5.73±2.69 and 0.85±0.11mg/dl respectively. Mean±SD of Serum Cystatin C in CKD and without CKD groups were 3.59±1.21 and 0.71±0.09 mg/dl respectively. In all patients sensitivity of Cystatin C to diagnose CKD was 100.0% and specificity also100.0%. Sensitivity of serum creatinine to diagnose CKD was 88.0% and specificity was 100.0%.Conclusions: Cystatin C proved more reliable than creatinine and was comparable to plasma creatinine and Cockcroft-Gault estimation. Serum Cystatin C had higher diagnostic accuracy with high sensitivity and specificity to detect renal function and is a reliable marker of renal function. Journal of Current and Advance Medical Research 2017;4(1):3-12

Estimated glomerular filtration rate leads to higher drug dose recommendations in the elderly compared with creatinine clearance.

The elderly are at risk for adverse drug events because of inappropriate dosing of renally eliminated medications. The purpose of this study was to evaluate differences in estimates of kidney function and recommended doses of select medications in the elderly using the Modification of Diet in Renal Disease (MDRD) or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations compared with the Cockcroft-Gault (CG) equation. Patients 65 years of age and older were included in this retrospective, observational analysis. Kidney function was estimated by CG, MDRD and CKD-EPI equations for all patients and by age category (65-69, 70-79, 80-89 and 90-100 years). Differences in estimates and dosing of allopurinol, enoxaparin, gabapentin, piperacillin/tazobactam and sulfamethoxazole/trimethoprim using the MDRD and CKD-EPI compared with the CG were assessed. In the 4160 patients (98% male, mean age 74 ± 7 years), the MDRD and CKD-EPI estimates were significantly higher than CG estimates for all patients and by age category (p < 0.001). Dosing discordance was predominantly because of a higher dose recommended by MDRD and CKD-EPI estimates compared with CG. Discordance was highest with gabapentin (27%), the medication with the greatest number of dosing stratifications by estimated kidney function, and increased by 66% from the youngest to the oldest age category. Until newer equations are used uniformly to develop dosing nomograms, it is prudent to adopt a process for drug dosing in the elderly that is more conservative than eGFR based dosing, but that considers the potential for underestimating kidney function with the CG equation.

Matching “Engine and Chassis” in ECD Kidney Transplantation Using a Novel Creatinine Clearance Match Ratio (CCMR) Is Associated With Improved Outcomes.

BACKGROUND: To improve outcomes of expanded criteria donor (ECD) kidneys, prior studies matched donors to recipients according to recipient weight or donor kidney size. This study hypothesizes that matching donors to recipients based on Cockcroft-Gault estimates of creatinine clearance can improve outcomes in ECD kidney transplants compared to predictions based on size matching or donor creatinine clearance alone. METHODS: Recipients of ECD kidneys in the Scientific Registry of Transplant Recipients (SRTR) who were transplanted from October 1, 1987 to August 31, 2011 were included. The estimated creatinine clearance ratio (CCMR) was calculated as the estimated recipient creatinine clearance based on manipulations of the Cockcroft-Gault equation utilizing donor creatinine clearance at the time of transplant. Univariate and multivariate analyses predicted the hazard ratio of graft failure and the odds ratio of requiring dialysis within the first week. The CCMR was compared to the kidney donor risk index (KDRI) and recipient-to-donor weight and age ratios using discrimination analyses. RESULTS: 25,640 ECD kidney transplants were analyzed. On multivariate analysis, higher CCMR was associated with increased graft failure and odds of requiring dialysis within the first week (comparing highest ratio quintile versus lowest ratio quintile: HR 1.53, p<0.001; OR 2.18, p<0.001). CCMR was found to be superior in prediction and discrimination ability as compared to donor creatinine clearance, recipient/donor age ratio, and recipient/donor weight ratio. CONCLUSION: ECD kidneys have improved outcomes when the donor/recipient creatinine clearance match ratio is optimal.

ESTIMATING GLOMERULAR FILTRATION RATE IN PALLIATIVE CARE PATIENTS: COMPARISON OF THE COCKROFT- GAULT AND ABBREVIATED MODIFICATION OF DIET IN RENAL DISEASE FORMULAS-IS IT RELEVANT TO CLINICAL PRACTICE?

BackgroundThe National Kidney Foundation, Kidney Disease Outcomes Quality Initiative recommends the Cockcroft Gault (CG) or abbreviated modified diet in renal disease (aMDRD) formulas for estimating Glomerular Filtration Rate (GFR). Clinical...

New algorithm for valganciclovir dosing in pediatric solid organ transplant recipients

CMV infections are common after SOT. v-GCV is increasingly used in children. The aim of this study was to evaluate presently used dosing algorithms. Data from 104 pediatric SOT recipients (kidney, liver, and heart) aged 0.3–16.9 yr and receiving v-GCV once a day were used for model development and validation with the Pmetrics package for R. Monte Carlo simulations were performed to compare the probability of a GCV AUC 40–60 mg*h/L with the different algorithms across a range of ages, weights, and GFRs. GCV pharmacokinetics was well described by the non-parametric model. Clearance was dependent on GFR and Cockcroft-Gault estimates improved the model fit over Schwartz. Simulations showed that our new algorithm, where v-GCV dose is: Weight [kg]*(0.07*GFR [mL/min]+k), where k = 5 for GFR ≤ 30 mL/min, k = 10 for GFR > 30 mL/min and weight > 30 kg and k = 15 for GFR > 30 mL/min and weight ≤ 30 kg, outperformed the other algorithms. Thirty-three percent of all patients achieve an exposure above and 21% within the therapeutic window. We propose a simple algorithm for initial v-GCV dosing that standardizes plasma drug exposure better than current algorithms. Subsequent TDM is strongly suggested to achieve individual drug levels within the therapeutic window.

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Introduction: Estimation of renal function is essential in antimicrobial dosing. The Cockcroft-Gault (CG) equation is used as a gold standard, but it is not validated in AKI and changing renal function. Estimation methods by Jelliffe, Chiou, and Brater have been proposed in AKI, but not studied for drug dosing. Hypothesis: The objective of this study is to compare creatinine clearance (CrCl) estimates using the CG equation with estimates using the Jelliffe, Chiou, and Brater equations in patients with AKI. We hypothesize that these estimates will result in differences in antimicrobial dosing. Methods: In this retrospective study, discharge records were screened to identify patients with a diagnosis of AKI. A sample size of 300 patients provided 80% power to detect a 10ml/min difference in CrCl. Data points collected were age, height, weight, gender, race, and serum creatinine measures. Peak serum creatinine and two values pre/post peak measures were collected. CrCl estimates for the Jelliffe, Chiou, and Brater equations with worsening and improving renal function were compared to CG estimates using the Wilcoxon matched-pairs signed-ranks test. Dosing recommendations for piperacillin/tazobactam were calculated with each estimate. Results: 314 patients were included; average age was 61.4 years and 162 subjects were male. For improving renal function, the average difference between the CG and each equation was: Jelliffe 18ml/min (p<0.0001); Chiou 18ml/min (p<0.0001); and Brater 17ml/min (p=0.0614). For worsening renal function, average difference between CG and each equation was: Jelliffe 14ml/min (p=0.003); Chiou 13ml/min; and Brater 15ml/min (p=0.318). Variations in estimates resulted in different dosing recommendations for piperacillin/tazobactam in 55% of patients with the Jelliffe equation and 43% with the Chiou equation. Conclusions: Significant differences in renal function estimates exist between the CG equation (current standard) and the Jelliffe and Chiou equations for estimation in AKI. These may impact dosing for piperacillin/tazobactam, a commonly used antimicrobial. Further studies with laboratory measurements to determine CrCl are needed to optimize antimicrobial dosing regimens.

Comparison between the Three Most Popular Formulae to Estimate Renal Function, in Subjects 75 Years of Age or Older

The aim of the study was to compare the accuracy of three formulae that estimate creatinine clearance (CL(CR)), in elderly hospitalized patients: the Cockcroft-Gault (CG) formula and the Modification of Diet in Renal Disease formulae with 4 and 6 variables (MDRD4 and MDRD6). A prospective, cross-sectional, observational study was conducted in four hospital geriatric wards. Consecutive patients admitted to the wards who were aged ≥75 years and had an indwelling urinary catheter for the purpose of care were eligible for enrolment. CL(CR) was determined via four methods: measurement of CL(CR) from plasma and urine creatinine plus 24-h urine volume; the CG formula; and the MDRD4 and MDRD6 formulae. Moderate and severe renal impairments were defined as a CL(CR) of 30.0-59.9 and <30.0 mL/min, respectively. A total of 157 patients were included. Their mean age (±SD) was 86.5 ± 6.1 (range 75-105) years and 46.5 % were male. The median values and interquartile ranges (IQRs) (in mL/min) were 44.0 (IQR 32.1-64.5) for measured CL(CR), 42.1 (IQR 31.3-56.3) for CG-estimated CL(CR), 64.3 (IQR 49.8-81.7) for MDRD4-estimated CL(CR) and 49.3 (IQR 37.4-63.4) for MDRD6-estimated CL(CR) (respectively, p < 0.05, p < 0.001 and p = 0.44 compared with measured CL(CR)). Biases (±SD) for CG, MDRD4 and MDRD6 CL(CR) estimates were -3.6 (±22.2), 19.3 (±26.4) and 2.4 (±22.5) mL/min, respectively. When estimated CL(CR) values were assessed against the measured value, it was found that misclassification of renal impairment (absent/moderate/severe) occurred in 41 % of patients when using the CG, in 40 % when using the MDRD6, and in 45 % when using the MDRD4. The 30 % accuracies of the three formulae were 63 % for CG, 37 % for MDRD4 and 59 % for MDRD6. In elderly hospitalized patients, CG and MDRD6 gave better predictions for measured CL(CR) than MDRD4, with no significant difference between them.

Comparative Evaluation of the Cockcroft‐Gault Equation and the Modification of Diet in Renal Disease (MDRD) Study Equation for Drug Dosing: An Opinion of the Nephrology Practice and Research Network of the American College of Clinical Pharmacy

Accurate assessment of kidney function is an important component of determining appropriate drug dosing regimens. Nearly all manufacturer-recommended dosage adjustments are based on creatinine clearance ranges derived from clinical pharmacokinetic studies performed during the drug development process. The Cockcroft-Gault (CG) equation provides an estimate of creatinine clearance and is the equation most commonly used to determine drug dosages in patients with impaired kidney function. The Modification of Diet in Renal Disease (MDRD) study equation has also been proposed for this purpose. Published studies report that drug dosages determined by the two equations do not agree in 10-40% of cases. However, interpretation and comparison of these studies are complicated by the variable creatinine methods used for calculating CG and MDRD estimates, the patient populations studied, and a lack of outcomes data demonstrating the clinical significance of dosing discrepancies. Moreover, the impact of reporting standardized serum creatinine values on the accuracy of the CG equation and corresponding drug dosing regimens have been questioned. Currently, no prospective pharmacokinetic studies have been conducted with use of the MDRD equation to generate dosing recommendations, and limited data are available to support its use in some patient populations representing demographic extremes. Collectively, these issues have resulted in considerable confusion among clinicians and have fueled a healthy debate on whether or not to use the MDRD equation to determine drug dosages. Each of these issues is reviewed, and a proposed algorithm for using creatinine-based kidney function assessments in drug dosing is provided. Knowledge of the advantages, limitations, and clinical role of each equation will facilitate their safe and effective use in drug dosing.

Use of estimated glomerular filtration rate for drug dosing in the chronic kidney disease patient

Assessment of kidney function is necessary to stage chronic kidney disease (CKD) and appropriately dose medications. The Cockcroft-Gault equation provides an estimate of creatinine clearance (eClCr) and is the method commonly referenced in pharmacokinetic studies. The Modification of Diet in Renal Disease (MDRD) and CKD-Epidemiology Collaboration (EPI) equations provide an estimate of glomerular filtration rate (eGFR), with the MDRD eGFR now automatically reported by most clinical laboratories. This review describes the differences in the Cockcroft-Gault, MDRD, and CKD-EPI equations and considerations when applying estimates from these equations for drug dosing. Studies evaluating drug-dosing regimens using eClCr and eGFR differ in their results depending on the population in which the equation is applied, the adjustment factors used to account for body size, and the number of dosing levels for a particular medication. The largest study to evaluate drug regimen design by method concluded that either the eGFR or Cockcroft-Gault estimates could be used for drug dosing. Differences in methodology among studies are a key factor in evaluating these results and will be highlighted in this review. The Cockcroft-Gault, MDRD, and CKD-EPI equations provide reasonable estimates of kidney function; however, clinicians must understand the limitations when using these estimates for drug regimen design.

Gentamicin pharmacokinetics in old age and frailty

Frailty, a syndrome of decreased physiological reserve that is prevalent in old age, impacts on clinical pharmacology. The aims of the study were to (1) determine whether frailty affects the pharmacokinetics of gentamicin and (2) assess the accuracy of different estimates of body size and renal clearance as estimates of gentamicin pharmacokinetics in older inpatients. This was an observational study of gentamicin pharmacokinetics in a cohort of Australian hospital inpatients aged ≥65 years, who were administered prophylactic intravenous gentamicin. Of the 31 participants, 14 were frail and 17 non frail on the Reported Edmonton Frail Scale. The mean volume of distribution of gentamicin was 14.8 ± 1.4 l in frail participants and 15.3 ± 2.2 l in non frail (NS). Volume of distribution correlated best with lean bodyweight. Gentamicin clearance was significantly lower in frail participants (46.6 ± 10.7 ml min(-1)) than in non frail (58.2 ± 12.4 ml min(-1), P=0.01). The Cockcroft Gault estimate of creatinine clearance calculated using ideal bodyweight gave the best estimate of gentamicin clearance (mean error -0.15 ml min(-1), 95% CI -2.67, 2.39). The Cockcroft Gault creatinine clearance calculated using actual bodyweight and the estimated glomerular filtration rate from the modified diet in renal disease equation overestimated gentamicin clearance, with mean errors of -10.15 ml min(-1) (95%CI -13.60, -6.71) and -18.86 ml min(-1) (95% CI -22.45, -15.27), respectively. The Cockcroft Gault creatinine clearance calculated using lean bodyweight underestimated gentamicin clearance (mean error 6.54 ml min(-1), 95% CI 4.18, 8.90). Frail older people have significantly lower gentamicin clearance than non frail. The best estimate of gentamicin clearance is obtained from the Cockcroft Gault creatinine clearance calculated using ideal bodyweight.

A comparison of estimates of glomerular filtration in critically ill patients with augmented renal clearance

IntroductionIncreasingly, derived estimates of glomerular filtration, such as the modification of diet in renal disease (MDRD) equation and Cockcroft-Gault (CG) formula are being employed in the intensive care unit (ICU). To date, these estimates have not been rigorously validated in those with augmented clearances, resulting in potentially inaccurate drug prescription.MethodsPost-hoc analysis of prospectively collected data in two tertiary level ICU's in Australia and Portugal. Patients with normal serum creatinine concentrations manifesting augmented renal clearance (ARC) (measured creatinine clearance (CLCR) > 130 ml/min/1.73 m2) were identified by chart review. Comparison between measured values and MDRD and CG estimates were then undertaken. Spearman correlation coefficients (rs) were calculated to determine goodness of fit, and precision and bias were assessed using Bland-Altman plots.ResultsEighty-six patients were included in analysis. The median [IQR] measured CLCR was 162 [145-190] ml/min/1.73 m2, as compared to 135 [116-171], 93 [83-110], 124[102-154], and 108 [87-135] ml/min/1.73 m2 estimated by CG, modified CG, 4-variable MDRD and 6-variable MDRD formulae. All of the equations significantly under-estimated the measured value, with CG displaying the smallest bias (39 ml/min/1.73 m2). Although a moderate correlation was noted between CLCR and CG (rs = 0.26, P = 0.017) and 4-variable MDRD (rs = 0.22, P = 0.047), neither had acceptable precision for clinical application in this setting. CG estimates had the highest sensitivity for correctly identifying patients with ARC (62%).ConclusionsDerived estimates of GFR are inaccurate in the setting of ARC, and should be interpreted with caution by the physician. A measured CLCR should be performed to accurately guide drug dosing.

The Practical Implications of Using Estimated GFR as the Presumed Reference Variable to Estimate Transplant Chronic Kidney Disease

We determined the proportions of matched kidney transplant isotope GFRs (iGFRs) to the estimated functions (eGFRs) calculated from Isotope Dilution Mass Spectrometry (IDMS), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), and Cockcroft-Gault (CG) equations. One thousand four hundred and three iGFR/eGFR pairs on 390 kidney transplant patients were compared considering the iGFR or eGFR as the reference or test variable. Conformity of iGFR to CG estimates demonstrated the least bias of 1.3±18.4 mL/min/1.73 m2 (compared to 1.5±19.4 and - 2.2±19.2 for IDMS and CKDI-EPI, P&lt;0.05) and CKD-EPI estimates the highest precision of 4.1±41.8 (compared to 11.3±43.9 for IDMS and 5.7±37.3 for CG; P&lt;0.05). IDMS eGFR cut off less than 60 and less than 30 mL/min/1.73m2 were correctly matched by iGFR in 79.4% and 49.1% of the times, while CKD-EPI was matched by iGFR in 83.5% and 52.5%. CG was matched in 78.3% and 53.6%. IGFR cut off levels of less than 60, and less than 30 mL/min/1.73m2 were predicted by IDMS in 83.8% and 64.0% of the times. CKD-EPI was correct in 77.8% and 59.0% and CG in 82.5% and 41.6%, respectively. Transplant eGFR results obtained by CKD-EPI or CG are likely to be more precise and less biased than IDMS.

Weighing the Evidence: The Challenge of Developing Evidence-Based Renal Dosing Strategies

Evaluating drug dosing to account for patient renal function is one of the primary review functions of a hospital pharmacist. Available estimates of renal function have known limitations, but laboratory and medical advances have improved the detection and classification of kidney disease. How do new, more accurate methods of classifying renal disease apply to the interpretation of drug dose recommendations derived by other, less accurate methods? The application of these new strategies to medication dose evaluation lacks clarity. The Cockcroft-Gault estimation of creatinine clearance (CrCl) was introduced in 1976 and has been a standard consideration for drug dose evaluation in adult patients with renal impairment. Although it has been routinely used, this method has recognized limitations. For example, the standard modification to account for female gender in the Cockcroft-Gault equation is theoretical; the original study population did not include female patients. The Modification of Diet in Renal Disease (MDRD) estimation of glomerular filtration rate (GFR) was introduced in 1999 and generally provides a more accurate assessment of renal function than traditional estimates in adult patients. Because the MDRD equation was not available or generally accepted as a method for classifying kidney function during the development of most marketed drugs, clinicians may be unsure about how to apply estimated GFR to drug dose evaluation. Both Cockcroft-Gault and MDRD estimates are based on studies in patients with stable renal function. In contrast, hospitalized patients often demonstrate dynamic renal function due to changing clinical status and comorbidities. National Kidney Disease Education Program (NKDEP) guidance on drug dosing recognizes this limitation and acknowledges that available estimates do not account for all factors that affect serum creatinine concentrations. Available estimates lack accuracy for patients with body size or muscle mass extremes. Some clinicians using the Cockcroft-Gault equation round the low serum creatinine values in elderly patients to another value, such as 1 mg/dL, or utilize ideal body weight to overcome these limitations. However, these approaches are not evidence-based, and researchers have demonstrated that these modifications are less accurate. 2-5 A standardized technique to calibrate serum creatinine assays introduced several years ago is now expected to be fully implemented nationally. Standardization minimizes variation of serum creatinine assay results between clinical laboratories and should lead to more consistent dosing for drugs eliminated renally. Changes to serum creatinine reference ranges would have been expected at most facilities upon implementation. Standardization has generally resulted in higher CrCl values as estimated by the CockcroftGault equation. According to the NKDEP, because the original study samples are no longer available and the creatinine assay method used to derive the CockcroftGault equation is no longer utilized, the equation cannot be re-expressed to the new standardized creatinine values. In contrast, standardized calibration of serum creatinine assays increases the accuracy of estimating GFR by the MDRD method. Current US Food and Drug Administration (FDA) guidance for the industry on pharmacokinetics published in 1998 acknowledges measured serum creatinine concentrations or estimated CrCl as recognized methods to classify kidney function for drug dosing. Draft guidance posted for review in 2010 reflects the significant changes in the body of knowledge in classifying renal disease and incorporates MDRD as well as Cockcroft-Gault estimates of kidney function. According to the NKDEP, clinicians should use either the MDRD equation or the Cockcroft-Gault equation to estimate kidney function for drug dosing.

Evaluation of the Chronic Kidney Disease Epidemiology Collaboration Equation for Dosing Antimicrobials

Since the derivation of the Modification of Diet in Renal Disease (MDRD) equation for estimating glomerular filtration rate (GFR), investigators determined that it cannot be used for drug dosing. In 2009, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) derived an equation that was more accurate than the MDRD estimation of GFR. Therefore, questions exist about which method should be preferred in making dosage adjustments for renally eliminated antimicrobials. To determine whether a difference exists when making antimicrobial dosage adjustments in patients with CKD based on estimation of GFR using the CKD-EPI and Cockcroft-Gault equations. A database of 409 patients with CKD admitted to a tertiary care facility was used. GFR was calculated using both the CKD-EPI equation(s) and the Cockcroft-Gault equation and compared using correlation and Bland-Altman methodology. Dosage discordance rates of antimicrobials were determined. Average GFRs for all patients using the Cockcroft-Gault and CKD-EPI equations were 34.8 +/- 12 mL/min and 39.9 +/- 13 mL/min, respectively (5.09 [95% CI 4.60 to 5.59]; p < 0.001). The correlation coefficient between the 2 estimations was high (r = 0.91). The Bland-Altman plot yielded limits of agreement of 15.3 and -5.1; thus, the CKD-EPI estimation may range from 5.1 mL/min below to 15.3 mL/min above the Cockcroft-Gault estimation for 95% of the cases. A discordance rate of 15-25% existed among the recommended dosing adjustments of the selected antimicrobials when comparing the Cockcroft-Gault and CKD-EPI estimations. Though this study did not determine which equation should be selected to dose adjust antimicrobials, it demonstrated statistically significant differences between the Cockcroft-Gault and CKD-EPI equations. The clinical significance of these differences is uncertain in the absence of data assessing clinical outcomes that result from the use of the discordant doses. Clinical judgment should be employed when making renal dosage adjustments of antimicrobials.