Cockcroft-Gault Creatinine Clearance Research Articles

Prospective Comparison of Urinary Measured Creatinine Clearance With eGFR and Cystatin C Based Cis-eGFR, Including Kinetic eGFR in the Immediate Post-transplant Period With Prompt Allograft Function

IntroductioneGFR and KeGFR have not been compared, with urinary measured creatinine clearance (mCrCl) or serum Cystatin C eGFR, soon after kidney transplant with prompt primary function. The study aims to compare post-KTx, urinary mCrCl, and eGFRCysC with eGFR and KeGFR. MethodPost-KTx, urine was collected every 12 hours from 25 of the 34 consenting subjects to calculate mCrCl and compare with MDRD-4, Jelliffe eGFR, Cockcroft-Gault Creatinine-Clearance, and KeGFR by Chen and Brater formulae. Serum CysC levels were also measured in the last 14 subjects to compare with creatinine, mCrCl, and eGFRCysC. FindingsAt 12 to 96 hours post-KTx (n=25), mCrCl was 55.8% to 13.6% higher than MDRD-4 eGFR. The mean CysC level (n=14) was 58% to 14% lower than creatinine for up to 3.0 days post-KTx, with higher MDRD-4 eGFRCysC. Chen and Brater KeGFR were significantly lower than mCrCl and eGFR (figure-1B, table-1). Within three days post KTx, a 50% decrease in creatinine provided ≥ 50 mL/min CrCl in 90% of cases (mean mCrCl 61.7± 22.8). This difference was greater when the initial creatinine was higher with the rapid decrease in creatinine. Conclusion1) Post-KTx eGFR/KeGFR formulae underestimate mCrCl. 2) Serum CysC levels were lower than creatinine, corresponding higher eGFRCysC. 3) A 50% decrease from initial serum creatinine; mean mCrCl was 61.7±22.8 mL/min, and 90% of them have mCrCl > 50 mL/min. Post KTx, until creatinine is stabilized, recipients are often receiving subtherapeutic dosing of renally adjusted medications. More prospective studies are necessary, including radioisotope clearance.

Risk factors for renal impairment after liver transplantation in Mongolia: a retrospective single-center study.

Renal impairment (RI) is a frequent complication of liver cirrhosis and is associated with increased mortality and morbidity. Liver transplantation (LT) serves as an effective treatment method for patients with cirrhosis who have impaired renal function. However, renal function often declines after LT, influenced by various factors. This study aimed to investigate the factors contributing to RI following LT in our cases. We analyzed the demographic data, preoperative and perioperative parameters, and postoperative outcomes of patients who underwent LT at the First Central Hospital of Mongolia from September 2011 to December 2022. Renal function was assessed by measuring the glomerular filtration rate using the Cockcroft-Gault creatinine clearance formula pretransplantation and at 24 hours, 72 hours, 7 days, 14 days, and 28 days post-LT. Several factors increased the risk of RI among recipients. These included female sex (odds ratio [OR], 3.06; 95% confidence interval [CI], 1.58-5.91), Child-Turcotte-Pugh (CTP) scores of B and C (OR, 4.23; 95% CI, 0.92-19.41 and OR, 7.68; 95% CI, 1.67-35.30, respectively), preoperative continuous renal replacement therapy (CRRT; OR, 5.86; 95% CI, 1.1-31.21), and a high graft-to-recipient weight ratio (GRWR; OR, 3.45; 95% CI, 1.23-9.63). Additionally, the survival rates for recipients with RI post-LT were 93.4% at 1 year and 78.1% at 3 years. Female sex, a high CTP score, preoperative CRRT, and high GRWR were identified as risk factors for RI after LT in Mongolia.

Comparison of eGFR Equations to Guide Dosing of Medications for Kidney Transplant Recipients.

Clinicians caring for kidney transplant recipients (KTRs) most commonly use estimated glomerular filtration rate (eGFR) to guide medication dosing as it is the most readily available measure of kidney function. Which eGFR equations provide the most accurate medication dosing guidance for KTRs remains uncertain. We studied 415 stable KTRs in Canada and New Zealand. Participants completed same-day measurements of creatinine and cystatin C and measured GFR (diethylenetriaminepentaacetic acid). Chronic Kidney Disease Epidemiology Collaboration, European Kidney Function Consortium, and transplant-specific eGFR equations were compared with both Cockcroft-Gault creatinine clearance (CrCl) and measured GFR. eGFR equations were assessed both indexed to a standardized body surface area (BSA) of 1.73 m2 (milliliter per minute per 1.73 m2, as is conventional reporting from most clinical laboratories) and nonindexed (milliliter per minute) accounting for actual BSA. The primary outcome was the proportion of medication dosing discordance relative to Cockcroft-Gault CrCl or measured GFR for 8 commonly prescribed medications. Stratified analyses were performed on the basis of obesity status. Nonindexed eGFR equations (milliliter per minute) resulted in substantially lower medication dosing discordance compared with indexed eGFR equations (milliliter per minute per 1.73 m2). These findings were most pronounced among KTRs with obesity, in whom underdosing was frequent. When compared with Cockcroft-Gault CrCl, the lowest proportion of discordance was found with the nonindexed 2023 transplant-specific equation. When compared with measured GFR, the lowest proportion of discordance was found with the nonindexed 2021 Chronic Kidney Disease Epidemiology CollaborationCr/CysC equation. Nonindexed eGFR values accounting for actual BSA should be used by clinicians for medication dosing in KTRs. These findings may inform KT providers about which eGFR equations provide the safest, most accurate medication dosing guidance for KTRs.

Phase 1 study to determine the safety and efficacy of onvansertib, a novel, oral, PLK1 inhibitor in patients with proliferative chronic myelomonocytic leukemia relapsed/refractory or intolerant to available therapies.

TPS7089 Background: Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative overlap neoplasm (MDS/MPN) that can be further divided into MD (WBC < 13 x 109/L) and MP (≥13 x 109/L) subtypes. MP-CMML is enriched in RAS pathway mutations ( NRAS, CBL, KRAS, PTPN11 and NF1), has a shorter median survival (19 vs 36 months), has a higher rate of acute myeloid leukemia (AML) transformation (40% vs 10%) and has a unique transcriptomic and epigenetic composition. These RAS pathway mutations promote selective PLK1 overexpression, a mitotic checkpoint kinase. Given the relative inefficacy of hypomethylating agents (HMA) in MP-CMML and previously demonstrated in vitro and in vivo efficacy data for PLK1 inhibition on MP-CMML with RAS pathway mutations, we designed a phase 1 clinical trial testing the safety of onvansertib, a novel, orally bioavailable, PLK1 inhibitor in relapsed/refractory MP-CMML. Methods: This is an investigator-initiated, prospective, open-label, phase I study of onvansertib in MP-CMML relapsed/refractory (RR) or intolerant to existing therapies including HMA and hydroxyurea. The primary endpoint is characterization of safety. Secondary endpoints include efficacy as defined by the 2015 MDS/MPN International Working Group criteria, volumetric spleen response and symptom response via assessment with MPN-SAF-TSS. Inclusion criteria include MP-CMML RR following hydroxyurea or at least 4-cycles of HMA or intolerance of treatment with either, platelets ≥ 20,000/m3 and Cockcroft-Gault creatinine clearance ≥ 60 mL/min/m2. Hydroxyurea may continue for the first 28 days on study. Onvansertib will be given orally on days 1 through 21 of a 28-day cycle with a Bayesian optimal interval design to assess the safety and recommended phase II dose. Exploratory end points include targeting efficacy, impact of PLK1 and KMT2A expression and interactions with ASXL1 and TET2 mutations. Twenty-five patients will be enrolled at Mayo Clinic in Minnesota, with enrollment open since November 2022. Clinical trial information: NCT05549661 .

Tinzaparin for venous thromboembolism in patients with renal impairment: a single-centre, prospective pilot study.

Low molecular weight heparins (LMWH) are used extensively for prophylaxis and treatment of venous thromboembolism (VTE), bridging therapy for warfarin and standard of care in cancer-associated VTE (CA-VTE). Tinzaparin has the highest molecular weight of all LMWH and relies least on renal clearance to Cockcroft-Gault creatinine clearance (CrCl) of 20 mL/min. Previous pharmacological studies have demonstrated safety and effectiveness in elderly patients. Prospective clinical trials have confirmed these findings to CrCl 20 mL/min and in CA-VTE. We describe the pilot program developed at Concord Repatriation General Hospital for tinzaparin. We aim to confirm the deliverability of tinzaparin in patients with renal insufficiency. Twenty patients were established on tinzaparin as therapeutic anticoagulation with CrCl or CKD-EPI estimated glomerular filtration rate (eGFR) 20-50 mL/min with an indication for anticoagulation. Tinzaparin was given as a subcutaneous injection at 175 units/kg as a single daily dose, rounded to the nearest vial size. Tinzaparin anti-Xa levels were tested at Days 2, 7 and 14 (±1 day) and transition to oral anticoagulants were allowed at clinician discretion. No accumulation of tinzaparin was seen into Day 14. Two patients required dose-adjustment, five patients had bleeding complications (two major, three minor) and four patients died during follow-up, all attributable to patients' comorbidities. CrCl and body surface area-standardised CrCl were significantly correlated with tinzaparin anti-Xa level only on Day 2, and this effect was lost when patients with CrCl >50 mL/min were excluded. Data from our cohort confirm the deliverability of therapeutic tinzaparin in patients with CrCl or CKD-EPI eGFR 20-50 mL/min. Bleeding and death outcomes were also comparable to other trials using tinzaparin in CA-VTE. For patients with renal insufficiency, tinzaparin represents an attractive alternative anticoagulant with once-daily administration in a range of potential indications.

Abstract 9317: Variability in Non-Vitamin K Oral Anticoagulant Dose Adjustment According to Renal Formulae and Clinical Outcomes in Atrial Fibrillation Patients: Insights From ORBIT-AF II

Background: Non-Vitamin K Oral Anticoagulants (NOACs) require dose adjustment based on kidney function. Glomerular filtration rate (eGFR) is most commonly used in clinical practice, but product monographs recommend the use of Cockcroft-Gault creatinine clearance equation (eCrCl) for dose adjustment. We sought to evaluate misclassification of NOAC renal dosing using eGFR versus eCrCl. Methods: We included patients enrolled in the ORBIT-AF II trial. eGFR was calculated using both the MDRD and CKD-EPI formulae. Dose adjustments and eligibility were based on landmark trials. Dosing was considered inappropriate when use of eGFR resulted in a lower (under-treatment) or higher (over-treatment) dose than that recommended by eCrCl. Agreement in NOAC dosing between eCrCl and eGFR was assessed. The primary outcome of major adverse cardiovascular and neurological events (MACNE) was a composite of cardiovascular death, stroke or systemic embolism, and myocardial infarction. Sensitivity analysis was performed for the subgroup of patients with CKD (eCrCl<60 ml/min). Results: Among 8,727 in the overall cohort, agreement between CrCl and eGFR was observed in 93.5-93.8% of patients. Among 2,184 patients with CKD, the agreement between eCrCl and eGFR was 79.9-80.7%. Dosing misclassification was observed in 11.5% of rivaroxaban and 1.1% of dabigatran and apixaban treated patients. Patients receiving an inappropriate NOAC dose had a lower mean eCrCl and eGFR. Undertreated patients were older and of lower body weight compared to overtreated and appropriately dosed patients. Dosing misclassification was more frequent in the CKD population (41.9% of rivaroxaban, 5.7% of dabigatran and 4.6% apixaban patients). At one-year, undertreated patients in the CKD group had significantly greater MACNE [adjusted HR 2.90 (1.09-7.75) compared to appropriate NOAC dosing group p = 0.03]. Conclusions: The prevalence of NOAC dosing misclassification NOACs was high when using eGFR, particularly among those with CKD. Among patients with CKD, potential undertreatment due to inappropriate and off-label renal formulae may result in worse clinical outcomes. These findings highlight the importance of using eCrCl, and not eGFR, for dose-adjustment in all AF patients receiving NOACs.

VARIABILITY IN NOAC DOSE ELIGIBILITY AND ADJUSTMENT ACCORDING TO RENAL FORMULAE AND CLINICAL OUTCOMES IN AF PATIENTS WITH AND WITHOUT CKD: INSIGHTS FROM ORBIT AF II

Non-Vitamin K Oral Anticoagulants (NOACs) are used for prevention of thromboembolism in patients with atrial fibrillation (AF). Guidelines recommend dose adjustment based on kidney function.The most common estimates of kidney function employed in clinical practice are derived from glomerular filtration rate (eGFR), however, product monographs recommend the use of the Cockcroft-Gault creatinine clearance equation (eCrCl) for dose adjustment. We sought to evaluate misclassification of NOAC renal dosing using eGFR versus eCrCl.

Impact of Recent Acute Kidney Injury on Creatinine Clearance Estimation in Critically Ill Patients Undergoing Cardiac Surgery.

Acute kidney injury (AKI), often present in critically ill patients and patients with cardiac dysfunction, may alter estimates of renal function. The impact of recent AKI on the accuracy of the Cockcroft-Gault creatinine clearance equation (CG-CrCl) before cardiac surgery is unknown. This single-center, retrospective study included patients who underwent cardiac surgery from 1 January 2006 through 30 June 2012 and whose 24-hour urine creatinine clearance (24hr-CrCl) was measured in the intensive care unit before surgery. We evaluated CG-CrCl accuracy by calculating absolute differences between 24hr-CrCl and CG-CrCl estimates. Clinical impact was signified by discrepancies in United States Food and Drug Administration (FDA) renal impairment stage indicated by 24hr-CrCl versus CG-CrCl estimates. Acute kidney injury was evaluated by using Kidney Disease: Improving Global Outcomes criteria. Of 161 patients, 93 (58%) had recent AKI: stage 1, 31 (33%); stage 2, 39 (42%); and stage 3, 23 (25%). In mL/min, the CG-CrCl overestimated 24hr-CrCl (absolute difference: total, -10 ± 25; no AKI, -7 ± 26; stage 1, -8 ± 17; stage 2, -16 ± 28; and stage 3, -10 ± 26; P=0.29). Renal impairment stages assigned by CG-CrCl did not match 24hr-CrCl in 70 (43%) of the 161 patients, especially those with recent AKI: no AKI, 24/68 (35%); stage 1, 13/31 (42%); stage 2, 23/39 (59%); and stage 3, 10/23 (43%). The CG-CrCl consistently overestimated 24hr-CrCl in critically ill patients before cardiac surgery. Clinicians should use the CG-CrCl cautiously when estimating renal function and medication dosages in this population.

Prognostic value of glomerular function estimated by Cockcroft-Gault creatinine clearance, MDRD-4, CKD-EPI and European Kidney Function Consortium equations in patients with acute coronary syndromes

BackgroundIt remains unknown which equation used to assess the glomerular function is better for risk stratification in patients with acute coronary syndrome (ACS). MethodsThis study included 3985 patients with ACS. Glomerular function was assessed using 4 equations: the Cockcroft-Gault creatinine clearance (C-GCrCl), Modification of Diet in Renal Disease-4 (MDRD-4), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and European Kidney Function Consortium (EKFC) equations. The primary outcome was one-year all-cause mortality. ResultsFor each 30 ml/min decrement, the adjusted hazard ratio [HR] with 95% confidence interval [CI] for one-year mortality was 1.67 [1.27–2.25] for C-GCrCl, 1.45 [1.16–1.81] for MDRD-4, 1.76 [1.35–2.30] for CKD-EPI and 1.94 [1.44–2.63] for EKFC equation. Area under the receiver operating characteristic curve (AUC) for one-year mortality was 0.748 [0.709–0.788] for C-GCrCl, 0.670 [0.621–0.718] for estimated glomerular filtration rate (eGFR) calculated by MDRD-4 equation, 0.725 [0.684–0.765] for eGFR calculated by CKD-EPI equation and 0.741 [0.703–0.779] for eGFR calculated by EKFC equation (P = 0.342 for C-GCrCl, vs. EKFC equation and P ≤ 0.009 for all other AUC comparisons). ConclusionsIn patients with ACS, C-GCrCl and EKFC equations showed a similar discriminatory power regarding prediction of one-year mortality. Both equations were better than MDRD-4 and CKD-EPI equations for risk discrimination for mortality.Clinical Trial Registration: NCT01944800.

Renal Protective Effect of Everolimus in Liver Transplantation: A Prospective Randomized Open-Label Trial.

This was a prospective, randomized, open-label trial comparing EVR and mycophenolic acid (MPA) with CNI and MPA immunosuppression. An Investigational New Drug Application (IND # 113882) was obtained with the Food and Drug Administration as EVR is only approved for use with low-dose tacrolimus. Serum creatinine, 24-hour urine creatinine clearance, iothalamate clearance, Cockcroft-Gault creatinine clearance (CrCl), and Modification of Diet in Renal Disease estimated glomerular filtration rate were prospectively measured at 4 study visits. Nonparametric statistical tests were used for analyses, including the Mann-Whitney U test for continuous outcomes and Pearson's chi-square test for binary outcomes. Effect size was measured using Cohen's d. Patients also completed quality of life surveys using the FACT-Hep instrument at each study visit. Comparison between the 2 groups was performed using the Student t test. Each arm had 12 subjects; 4 patients dropped out in the EVR arm and 1 in the CNI arm by 24 months. Serum creatinine (P = 0.015), Modification of Diet in Renal Disease estimated glomerular filtration rate (P = 0.013), and 24-hour urine CrCL (P = 0.032) were significantly better at 24 months with EVR. Iothalamate clearance showed significant improvement at 12 months (P = 0.049) and a trend toward better renal function (P = 0.099) at 24 months. There was no statistical significance with Cockcroft-Gault CrCl. Adverse events were not significantly different between the 2 arms. The EVR group also showed significantly better physical, functional, and overall self-reported quality of life (P = 0.01) at 24 months. EVR with MPA resulted in significant long-term improvement in renal function and quality of life at 24 months after liver transplantation compared with standard CNI with MPA immunosuppression.

Population Pharmacokinetics and Dose Optimization of Ceftazidime and Imipenem in Patients with Acute Exacerbations of Chronic Obstructive Pulmonary Disease.

Background: Ceftazidime and imipenem have been increasingly used to treat Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD) due to their extended-spectrum covering Pseudomonas aeruginosa. This study aims to describe the population pharmacokinetic (PK) and pharmacodynamic (PD) target attainment for ceftazidime and imipenem in patients with AECOPD. Methods: We conducted a prospective PK study at Bach Mai Hospital (Viet Nam). A total of 50 (ceftazidime) and 44 (imipenem) patients with AECOPD were enrolled. Population PK analysis was performed using Monolix 2019R1 and Monte Carlo simulations were conducted to determine the optimal dose regimen with respect to the attainment of 60% and 40% fT>MIC for ceftazidime and imipenem, respectively. A dosing algorithm was developed to identify optimal treatment doses. Results: Ceftazidime and imipenem PK was best described by a one-compartment population model with a volume of distribution and clearance of 23.7 L and 8.74 L/h for ceftazidime and 15.1 L and 7.88 L/h for imipenem, respectively. Cockcroft–Gault creatinine clearance represented a significant covariate affecting the clearance of both drugs. Increased doses with prolonged infusion were found to cover pathogens with reduced susceptibility. Conclusions: This study describes a novel and versatile three-level dosing algorithm based on patients’ renal function and characteristic of the infective pathogen to explore ceftazidime and imipenem optimal regimen for AECOPD.

P0656FULL AGE SPECTRUM EQUATION IN THE ESTIMATION OF GLOMERULAR FILTRATION RATE IN RUSSIAN ADULT PATIENTS WITH CHRONIC KIDNEY DISEASE

Abstract Background and Aims Glomerular filtration rate (GFR) is the most important and accurate parameter of kidney function in the course of chronic kidney disease (CKD). Renal or plasma inulin, diethylenetriaminepentaacetate (DTPA), ethylenediaminetetraacetate (EDTA), radiocontrast agents (iohexol, iothalamate) and some other substances clearances are the reference methods for determining GFR. However, these methods cannot be applied routinely because of the inconvenience. Several available methods have been developed to estimate GFR in a simpler manner and at low costs. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is widely used to evaluate the GFR in practice. However, this equation is not accurate for the full age spectrum. In 2016, the new equation, full age spectrum equation, based on the serum creatinine (FAScr), was developed and can be applicable to all ages. However, data on the benefits of using the FAScr-method in different populations are contradictory. In particular, it is unclear whether the FAScr provides any advantages over the CKD-EPI method in adults. In this regards, we attempted to compare data obtained FAScr method with results some non-reference and reference methods in adult Russian population. Method We examined 120 Caucasian patients (M:F - 52:68; age 18-76 year) with CKD 1 - 5 stages. Patients with nephrotic syndrome and congestive heart failure were excluded. GFR (reference method) measured by plasma clearance of 99mTc-DTPA (CDTPA). CDTPA determined by one- compartment model 2-4 h method using a Chantler-Barratt linear correction. Estimation GFRs (eGFR) were established by Cockcroft-Gault creatinine clearance (CG), CKD-EPI (creatinine), FAScr and Modification of Diet in Renal Disease (MDRD) methods. Also, renal creatinine clearance (Ccr; UV/P method) was measured. Only GFRs values corrected on 1.73 m2 body surface area had been use. Results The values of GFR (Mean(SEM)) are: CDTPA 67.0(2.46); FAS 69.7(2.50); CKD-EPI 64.3(2.54); MDRD 60.9(2.62); CG 77.6(3.31); Ccr 85.2(3.40), мл/мин/1.73 m2. MDRD was significantly lower (paired Student t-test with correction on multiply comparison by Benjamini-Hochberg method) than CDTPA (P=0.0024), CG (P=0.0001) or Ccr (P<0.0001) were significantly higher. The bias (CDTPA minus non reference GFR) were: FAS -2.67(1.71); CKD-EPI 2.72(1.58); MDRD 6.12(1.78); CG -10.57(2.51); Ccr -18.22(2.26), ml/min. All biases are significantly differ between themselves (P from 0.00064 to <0.000001). The percentage of P30 of the FAS 81.6(3.5) was not significant differ from P30 of CKD-EPI (78.3(3.8); P=0.524) or MDRD (71.7(4.1); P=0.071). However, P30 of CG (67.5(4.3),%; P=0.01) or Ccr (54.2(5.42),%; P<0,001) were significant lower, than P30 of FAS. There were significant comparable direct correlations between CDTPA and FAS (r=0.764), CKD-EPI (r=0.801), MDRD (r=0.756), CG (r=0.656), Ccr (r=0.749); P<0.00001 in all cases. Conclusion In adult Russian population FAScr-method of GFR estimation had not any advantage over CKD-EPIcr-method.

Concordance of Vancomycin Population-Predicted Pharmacokinetics with Patient-Specific Pharmacokinetics in Adult Hospitalized Patients: A Case Series.

BackgroundVancomycin empiric therapy is commonly dosed using clinical algorithms adapted from population-predicted pharmacokinetic parameters. However, precise dosing of vancomycin can be designed using patient-specific pharmacokinetic calculations.ObjectiveThe objective of this study is to assess the correlational fit between vancomycin population-predicted and patient-specific pharmacokinetic parameters [elimination rate constant (Ke) and half-life (t1/2)] in a case series of adult hospitalized patients.MethodsThis is a single-center case series of hospitalized adult patients who received vancomycin, had creatinine clearance calculation for derivation of population-predicted pharmacokinetic parameters, and had two vancomycin concentrations for calculation of patient-specific pharmacokinetic parameters. The primary objective of this case series is to evaluate the correlation between population-predicted and patient-specific pharmacokinetic parameters. The secondary objectives of this study are to evaluate the mean bias and precision between the population-predicted and patient-specific pharmacokinetic parameters and to assess the correlation between population-predicted and patient-specific pharmacokinetic parameters in special population subgroups (obese patients with body mass index ≥ 30 kg/m2 and patients with renal dysfunction). All correlation analyses were performed on the population-predicted pharmacokinetics using diverse methods of estimating renal function (Salazar–Corcoran and Cockcroft–Gault methods using either ideal, actual, or adjusted body weights). All significance testing was set at an α of < 0.05. IBM SPSS Statistics version 25 and SAS version 9.4 were used to conduct all statistical analyses.ResultsA total of 30 patients were included in the study; 33.3% (10/30) of the patients were obese and 56.7% (17/30) had renal dysfunction. In all patients in the study, the calculated population-predicted Ke and t1/2 using all four creatinine clearance estimation methods were each significantly correlated with patient-specific Ke and t1/2 (all Pearson correlation coefficients [r]: > + 0.7, p < 0.001). The population-predicted Ke and t1/2 calculated using Cockcroft–Gault creatinine clearance using adjusted body weight showed the strongest association with patient-specific Ke and t1/2. In the subgroup analyses, all the population-predicted Ke and t1/2 using four creatinine clearance estimation methods were each significantly correlated with patient-specific Ke and t1/2. The exception was the population-predicted t1/2 derived from Cockcroft–Gault creatinine clearance using actual body weight that did not show a significant correlation with patient-specific t1/2 in obese patients.ConclusionsIn this case series, population-predicted pharmacokinetic parameters were strongly correlated with patient-specific pharmacokinetic parameters. The vancomycin population-predicted pharmacokinetic formula can be used safely to predict a patient’s vancomycin pharmacokinetic disposition and can be maintained as an empiric dosing strategy in various hospitalized adult patients.

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.

Long-term vancomycin use had low risk of ototoxicity.

Vancomycin is a commonly used antibiotic with potent activity against Gram-positive organisms, but prolonged use and high doses can lead to toxicity. While vancomycin-associated nephrotoxicity is widely reported, few cases of ototoxicity have been described. The objective of this study was to determine the prevalence of negative changes in audiograms in patients receiving long-term intravenous (IV) vancomycin and to identify high-risk patients who need audiogram monitoring. This was an IRB approved, cross-sectional study performed at an academic medical center from 1/2012-3/2019. Patients who were prescribed IV vancomycin for ≥ 14 days and had baseline and follow-up weekly audiometry were included. All data was extracted from the electronic medical record. The primary endpoint was worsening audiogram while on vancomycin. Descriptive and bivariate statistics were used to describe the patient population. 424 patients were screened for inclusion; 92 received at least two audiograms while on vancomycin. Fifty-three percent of patients were men, the median (IQR) patient age was 44 (34-58) years, and 8% of patients had an estimated Cockcroft-Gault creatinine clearance ≤ 30 mL/min or received hemodialysis. The median (IQR) vancomycin exposure up until the last recorded audiogram was 30 (17-42) days. Vancomycin indications were: 53 (58%) bone and joint infections, 17 (18%) infective endocarditis, 10 (11%) bacteremia, 12 (13%) other infections. Seven (8%) patients experienced a worsening change in hearing from baseline, two (2%) of them suffered mild loss, two (2%) had mild to moderate loss, and three (3%) developed moderate-to-severe hearing loss. In bivariate analyses, no variables were found to be associated with a worsening change in audiogram, including baseline abnormal audiogram, age ≥ 40 years, elevated serum vancomycin levels, or vancomycin doses ≥ 4 grams/day. The prevalence of negative changes in audiograms among patients receiving long-term intravenous vancomycin was low. The utility of routine audiogram testing in this population remains questionable except in high-risk patients; however, larger prospective studies with controls may be warranted to further explore the risk of ototoxicity.

Development of a dosing algorithm for meropenem in critically ill patients based on a population pharmacokinetic/pharmacodynamic analysis

Effective antibiotic dosing is vital for therapeutic success in critically ill patients. This work aimed to develop an algorithm to identify appropriate meropenem dosing in critically ill patients. Population pharmacokinetic (PK) modelling was performed in NONMEM®7.3 based on densely sampled meropenem serum samples (npatients = 48; nsamples = 1376) and included a systematic analysis of 27 pre-selected covariates to identify factors influencing meropenem exposure. Using Monte Carlo simulations newly considering the uncertainty of PK parameter estimates, standard meropenem dosing was evaluated with respect to attainment of the pharmacokinetic/pharmacodynamic (PK/PD) target and was compared with alternative infusion regimens (short-term, prolonged, continuous; daily dose, 2000-6000 mg). Subsequently, a dosing algorithm was developed to identify appropriate dosing regimens. The two-compartment population PK model included three factors influencing meropenem pharmacokinetics: the Cockcroft-Gault creatinine clearance (CLCRCG) on meropenem clearance; and body weight and albumin on the central and peripheral volume of distribution, respectively; of these, only CLCRCG was identified as a vital influencing factor on PK/PD target attainment. A three-level dosing algorithm was developed (considering PK parameter uncertainty), suggesting dosing regimens depending on renal function and the level (L) of knowledge about the infecting pathogen (L1, pathogen unknown; L2, pathogen known; L3(-MIC), pathogen and susceptibility known; L3(+MIC), MIC known). Whereas patients with higher CLCRCG and lower pathogen susceptibility required mainly intensified dosing regimens, lower than standard doses appeared sufficient for highly susceptible pathogens. In conclusion, a versatile meropenem dosing algorithm for critically ill patients is proposed, indicating appropriate dosing regimens based on patient- and pathogen-specific information.

Use of renal risk drugs in a nation-wide Polish older adult population: an analysis of PolSenior database

BackgroundNumerous medications should be avoided, or require dose adjustment in subjects with impaired kidney function. We aimed to assess the prevalence of potentially inappropriate use of renal risk drugs in a nation-wide, community-dwelling Polish older adult population.MethodsWe analysed regular intake of 38 medications that should be avoided, requiring dose modification, increase the risk of pre-renal kidney injury, or may cause potassium retention in subjects with moderately to severely impaired renal function in the PolSenior data base (N = 4514, mean age 76 ± 11 yrs). Kidney function was assessed with short Modification of Diet in Renal Disease formula estimated glomerular filtration rate (sMDRD) and Cockcroft-Gault creatinine clearance (CC).ResultsThere were 855 (19%) individuals with sMDRD < 60 ml/min/1.73m2, and 1734 (38%) with CC < 60 ml/min. Among drugs that should be avoided, spironolactone (20.4% of patients as classified by sMDRD and 17.5% by CC), non-steroidal anti-inflammatory drugs (13.4 and 11.3%), hydrochlorothiazide (11.1 and 11.0%), and metformin (6.9 and 8.2%) were most frequently used. The most frequently used drugs requiring dose modification were piracetam (13.9% by sMDRD, and 11.9% by CC), digoxin (8.3 and 8.8%), and gliclazide (6.8 and 5.9%). Classification of a drug use as ‘appropriate’ or ‘inappropriate’ was discordant depending on the method of kidney function assessment (sMDRD or CC) in up to 30%.Subgroups with sMDRD < 60 ml/min/1.73m2 and with CC < 60 ml/min were taking ≥2 drugs increasing the risk of pre-renal kidney injury more frequently than individuals with better kidney function (46.6 vs. 23.1 and 33.0% vs. 24.4%, respectively).There were 24.7% of individuals with sMDRD < 60 ml/min/1.73m2 and 18.0% with CC < 60 ml/min taking 2 or more drugs increasing serum potassium level. The proportion of subjects with hyperkalaemia increased with the number of such drugs.ConclusionsUse of drugs that should be avoided or require dose adjustment due to renal impairment, and potentially inappropriate drug combinations is a common problem in older adults in Poland. Assessment of kidney function with sMDRD may result in overlooking of requirements for dose adjustment formulated based on creatinine clearance.Trial registrationNot applicable.

Age-dependent error in creatinine clearance estimated by Cockcroft-Gault equation for the elderly patients in a Japanese hospital: a cross-sectional study.

The aim of this study is to assess the accuracy of creatinine clearance (CCr) calculated by the Cockcroft-Gault (CG) equation for elderly patients in a Japanese hospital. This study was a retrospective chart review of patients aged ≥ 55years with a CCr measurement by a 24-h urine collection (24-h) prior to general surgery in our hospital between April 2009 and March 2017. In total, 1028 Japanese patients were included (mean age 73.0 ± 8.9years). The serum creatinine value was 0.82 ± 0.24mg/dL. The CCr estimated by CG and measured by 24 h was 64.2 ± 20.9mL/min and 71.5 ± 21.0mL/min, respectively. The CG CCr was significantly underestimated in patients aged ≥ 65 years, and the discrepancy exhibited an age-dependent character. The error was reached at 21.7 ± 13.2mL/min in patients aged ≥ 90years (P < 0.001). The age-dependent errors almost completely disappeared when the modified CG equation was used, in which the term of age in the original CG equation was constantly regarded as 65, if the patient was 65years or older. Anesthesiologists and intensivists should pay attention to the potential risk of underestimating kidney function when using the CG equation for Japanese elderly patients.

Measurement of glomerular filtration rate in patients undergoing obesity surgery

BackgroundMost studies on obesity surgery have measured renal function using the estimated GFR. However, due to the reduction of muscle mass, and therefore creatinine that accompanies weight loss, such measures can falsely suggest an improvement in renal function. To balance the risks of surgery versus any potential benefits on renal function, we need to be able to determine renal function using valid and reliable methodologies. In this pilot study we aimed to measure renal function in patients with CKD undergoing obesity surgery using the gold standard 51Cr-EDTA GFR clearance methodology which is independent of measures of muscle mass.MethodsNine consecutive obese patients with CKD underwent obesity surgery. Their renal function was assessed using 51Cr-EDTA GFR, cystatin C and serum creatinine as well as using eGFR equations including MDRD CKD Epi, Cockcroft Gault and CKD Epi cystatin before and 12 months after surgery.ResultsRenal function using the 51Cr-EDTA measured GFR did not change significantly after surgery. Similar results were obtained when Cystatin C, CKD Epi cystatin, CKD Epi cystatin creatinine and adjusted Cockcroft Gault Creatinine clearance methods were used. In contrast there were either trends or significant improvements in renal function measured using the MDRD and CKD Epi equations.ConclusionsIn this pilot study using the gold standard 51Cr-EDTA method we found stabilisation in renal function after obesity surgery. Until further definitive data emerge it is critical to balance the risk and benefits of surgery, especially if renal function may not improve as often as previously suggested.Trial registrationClinicalTrials.gov NCT01507350. Registered June 2011.

Ciprofloxacin in critically ill subjects: considering hepatic function, age and sex to choose the optimal dose.

Pathophysiological changes often result in altered pharmacokinetics of ciprofloxacin in critically ill patients. Although ciprofloxacin clearance (CLCIP) substantially depends on kidney function in healthy volunteers, its relationship to measured creatinine clearance (CLCRM) is weak in critically ill patients. To assess the need for dose reductions in isolated or combined kidney and liver dysfunction in critically ill patients and to re-evaluate relationships between kidney parameters, demographics and ciprofloxacin pharmacokinetics. A population pharmacokinetic model was developed based on 444 ciprofloxacin serum concentrations from 15 critically ill patients with severe infections. CLCIP relationships to parameters reflecting hepatic function, CLCRM, Cockcroft-Gault creatinine clearance (CLCRCG), serum creatinine, sex, weight and age were explored. A simulation study was conducted to integrate knowledge from the new and previously published models. Total bilirubin was identified as a hepatic parameter with a clear relationship to CLCIP. A significant relationship between CLCIP and CLCRCG could be attributed to age and sex only. CLCIP was not associated with CLCRM. The predicted risk of potential overexposure (AUC > 250 mg·h/L) was low even with 1200 mg/day ciprofloxacin daily for patients with reduced CLCRCG (<30 mL/min: risk of 0.7%), while the risk was remarkably higher in elderly female patients with elevated bilirubin (risk of about 20% for 65-year-old women with total bilirubin of 4 mg/dL). Bilirubin, age and sex should be considered to assess the need for dose reductions. For MICs ≤0.25 mg/L, it might be appropriate to reduce the dose to 400 mg/day for elderly female subjects with high bilirubin.