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

BACKGROUND: 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). MATERIALS AND METHODS: 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 < 60 mL/minute per 1.73 m2. RESULTS: 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 60 mL/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 59 mL/minute exhibited a measured CrCI ≥ 60 mL/minute. CONCLUSIONS: 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 40-59 mL/minute.

Prevalence of renal insufficiency and factors associated among selected cancer patients on chemotherapy at Ocean Road Cancer Institute in Tanzania: a cross-sectional study.

BACKGROUND: Cancer is among the leading cause of death worldwide. Chemotherapy is commonly used in cancer management and among the challenges in managing cancer patients is renal insufficiency (RI), which can be due to cancer or anticancer treatment and can be potentiated by different factors. Data regarding the prevalence of RI and associated factors in Tanzania is scanty. This study aims to assess the prevalence of RI and associated factors among selected cancer patients on chemotherapy. METHODS: This analytical cross-sectional study was conducted at Ocean Road Cancer Institute (ORCI) in Dar es Salaam, Tanzania, from March to May 2023. The study included cancer patients on chemotherapy. Data was collected using semi-structured questionnaires whereby socio-demographics, clinical and laboratory data were recorded. Data was analyzed by using STATA version 15. Categorical data was presented as frequencies and percentages, and continuous data was summarized using means. A modified Poisson regression model was used to assess factors associated with RI. The p-values ≤ 0.05 was considered statistically significant. RESULTS: Out of 354 patients, the majority (76.6%) were female. The enrolled patients' mean age was 53 ± 13.19 years. The proportion of cancer patients with RI was 62.2% with most (60%) having stage 2 and stage 3 (37.7%). Age, hypertension (HTN), human immunodeficiency virus (HIV), diabetes mellitus (DM) and non-steroidal anti-inflammatory drugs (NSAIDs) use were significantly associated with increased risk of RI (p ≤ 0.05). CONCLUSION: This study showed that RI is common among cancer patients on chemotherapy. Age, HTN, DM, HIV and NSAIDS use were associated with RI. Close monitoring of kidney function is necessary for cancer patients with other factors associated with RI. Use of creatinine clearance (CrCl) rather than serum creatinine in estimating kidney function is important.

Enhanced renal clearance impacts levetiracetam concentrations in patients with traumatic brain injury with and without augmented renal clearance.

BACKGROUND: The purpose of this study was to examine the impact of ARC on levetiracetam concentrations during the first week following acute TBI. The hypothesis was levetiracetam concentrations are significantly lower in TBI patients with augmented renal clearance (ARC) compared to those with normal renal clearance. METHODS: This is a prospective cohort pharmacokinetic study of adults with moderate to severe TBI treated with levetiracetam during the first week after injury. Serial blood collections were performed daily for analysis of levetiracetam, cystatin C, and 12-hr creatinine clearance (CrCl) determinations. Patients were divided into two cohorts: with (CrCl ≥130 ml/min/1.73 m2) and without ARC. RESULTS: Twenty-two patients with moderate to severe TBI were included. The population consisted primarily of young male patients with severe TBI (mean age 40 years old, 68% male, median admission GCS 4). Each received levetiracetam 1000 mg IV every 12 h for the study period. ARC was present in 77.3% of patients, with significantly lower levetiracetam concentrations in ARC patients and below the conservative therapeutic range (< 6mcg/mL) for all study days. In patients without ARC, the serum concentrations were also below the expected range on all but two study days (Days 4 and 5). Four of the 22 (18.2%) patients exhibited seizure activity during the study period (two of these patients exhibited ARC). Cystatin C concentrations were significantly lower in patients with ARC, though the mean for all patients was within the typical normal range. CONCLUSIONS: ARC has a high prevalence in patients with moderate to severe TBI. Levetiracetam concentrations after standard dosing were low in all TBI patients, but significantly lower in patients with ARC. This study highlights the need to consider personalized drug dosing in TBI patients irrespective of the presence of ARC. CLINICAL TRIAL REGISTRATION: This study was registered at cliicaltrials.gov (NCT02437838) Registered on 08/05/2015, https://clinicaltrials.gov/ct2/show/NCT02437838 .

Abbreviated Urine Collection Compared With 24-Hour Urine Collection for Measuring Creatinine Clearance in Adult Critically Ill Patients: A Systematic Review.

OBJECTIVE: To evaluate the accuracy of abbreviated urine collection (≤12 hours) compared with 24-hour urine collection for measuring creatinine clearance (CrCl) in critically ill adult patients. DATA SOURCES: We searched PubMed, Embase, Web of Science, Google Scholar, and ProQuest Dissertations and Thesis Global; screened reference lists of included studies; and contacted the authors when needed. English studies only were considered with no restriction on dates. STUDY SELECTION AND DATA EXTRACTION: After duplicate removal, 2 reviewers screened titles/abstracts, reviewed full-text articles, and extracted data independently. Studies that compared abbreviated versus 24-hour urine collection for measuring CrCl were included. We assessed the risk of bias using the QUADAS-2 tool. We extracted correlation coefficients, mean prediction errors (ME)-as a measure of bias, and root mean squared prediction errors (RMSE)-as a measure of precision. DATA SYNTHESIS: Five studies were included, comprising 528 adult critically ill adults from surgical, medical, and trauma intensive care units (ICUs). Three studies had high risk of bias, and 2 had low risk. The studies evaluated different durations of urine collection, including 30-minute, 2-hour, 4-hour, 6-hour, and 12-hour. Mean 24-hour CrCl ranged from 57 mL/min/1.73 m2 to 103 mL/min. Abbreviated urine collection led to CrCl that correlated well with the 24-hour measured CrCl (correlation coefficient ranged from 0.8 to 0.95). Mean prediction error ranged from 5 mL/min/1.73 m2 to 16 mL/min (from 8% to 25% of the 24-hour CrCl). Root mean squared prediction error calculated from 1 study was 30.5 mL/min/1.73 m2. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Abbreviated urine collection is used to measure CrCl for renal drug dosing in critically ill patients, but its accuracy is not well-established. CONCLUSIONS: Abbreviated urine collection may overestimate CrCl compared with 24-hour urine collection. Larger, well-conducted studies are needed to evaluate the accuracy of CrCl measured using different durations of urine collection in critically ill patients.

Creatinine clearance/eGFR ratio: a simple index for muscle mass related to mortality in ICU patients.

INTRODUCTION: In patients admitted to the intensive care unit (ICU), muscle mass is inversely associated with mortality. Although muscle mass can be estimated with 24-h urinary creatinine excretion (UCE), its use for risk prediction in individual patients is limited because age-, sex-, weight- and length-specific reference values for UCE are lacking. The ratio between measured creatinine clearance (mCC) and estimated glomerular filtration rate (eGFR) might circumvent this constraint. The main goal was to assess the association of the mCC/eGFR ratio in ICU patients with all-cause hospital and long-term mortality. METHODS: The mCC/eGFR ratio was determined in patients admitted to our ICU between 2005 and 2021 with KDIGO acute kidney injury (AKI) stage 0-2 and an ICU stay ≥ 24 h. mCC was calculated from UCE and plasma creatinine and indexed to 1.73 m2. mCC/eGFR was analyzed by categorizing patients in mCC/eGFR quartiles and as continuous variable. RESULTS: Seven thousand five hundred nine patients (mean age 61 ± 15 years; 38% female) were included. In-hospital mortality was 27% in the lowest mCC/eGFR quartile compared to 11% in the highest quartile (P < 0.001). Five-year post-hospital discharge actuarial mortality was 37% in the lowest mCC/eGFR quartile compared to 19% in the highest quartile (P < 0.001). mCC/eGFR ratio as continuous variable was independently associated with in-hospital mortality in multivariable logistic regression (odds ratio: 0.578 (95% CI: 0.465-0.719); P < 0.001). mCC/eGFR ratio as continuous variable was also significantly associated with 5-year post-hospital discharge mortality in Cox regression (hazard ratio: 0.27 (95% CI: 0.22-0.32); P < 0.001). CONCLUSIONS: The mCC/eGFR ratio is associated with both in-hospital and long-term mortality and may be an easily available index of muscle mass in ICU patients.

Population Pharmacokinetic of Vancomycin Administered by Continuous Infusion in Critically Ill Patients.

INTRODUCTION: Administration of vancomycin dose by continuous infusion (CI) according to population pharmacokinetic (Pop Pk) models is highly recommended in critically ill patients who exhibit pathophysiological changes. OBJECTIVE: The objective of this study was to develop and validate a Pop Pk model of vancomycin administered by CI in critically ill patients with normal and impaired renal functions. METHODS: The Pop Pk study was performed using a nonparametric approach (Pmetrics*). The influence of covariates (gender, age, weight, height, and creatinine clearance [Cr-Cl]) was tested on the model's Pk parameters. The performance of the final model was assessed using an external dataset. RESULTS: A one-compartment model (volume of distribution [Vd], elimination from compartment [Ke]) was found to show a good prediction performance. The influence of covariates has shown that age and Cr-Cl affected significantly Vd and Ke, respectively. The distribution of simulated vancomycin clearance (CLv) according to different renal function levels showed a negative correlation between CLv and the severity of the renal impairment. The internal validation of the final model showed that the plot of individual-predicted concentration versus observed concentration resulted in r2 = 0.86 in the final model. The external validation of the final model showed an acceptable predictive performance. CONCLUSION: We developed a Pop Pk model for vancomycin administered by CI in critically ill patients. A significant impact of Cr-Cl and different stages of renal failure on CLv has been demonstrated. The establishment of an individualized proposal dose based on this model may be helpful to achieve the target range which is critical in optimizing the efficacy and safety of this antibiotic.

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.

Screening for pre-existing renal function disorders has become a routine clinical assessment for initiating TDF-containing antiretroviral treatment or pre-exposure prophylaxis in adults including pregnant women. Pregnancy inherently increases renal function, hence normal reference standards for non-pregnant adults cannot be used for pregnant women. In a secondary analysis of data from a healthy pregnant population not living with HIV who participated in a PrEP clinical trial, we established reference intervals for serum creatinine (sCr) concentration and creatinine clearance (CrCl) during pregnancy and postpartum in an African population. Using sCr and CrCl values for 249 healthy pregnant African women, we can confirm that the upper limit of normal for sCr in pregnancy is 20% lower than that for the 6-month postnatal period and recommend an upper limit of 57 umol/l and 60 umol/l in the second and third trimesters respectively to determine normal renal function in pregnant African women.We further determined the lower limit of normal for creatinine clearance using two methods of calculation, which was 35% higher than that of the postnatal period. Using the modification of diet in renal disease calculation, we recommend a lower limit of 129 and 119 ml/min/1.73m² for the second and third trimesters respectively. Using the Cockcroft­Gault calculation, we recommend a lower limit of 120 and 123 ml/min/1.73m² for the second and third trimesters respectively. Using current standard cut-off values estimated for adults may lead to underreporting of abnormal renal function in African pregnant women.

Retrospective Study of Factors Affecting the Accuracy of Predicting Vancomycin Concentrations in Patients Aged 75 Years and Above.

Background and Objectives: The predicted serum concentrations of vancomycin are determined using population pharmacokinetic parameters. However, the accuracy of predicting vancomycin serum concentrations in the older population remains unclear. Therefore, this study aimed to investigate the accuracy of predicting vancomycin serum concentrations and identifying elements that diminish the prediction accuracy in older people. Materials and Methods: A total of 144 patients aged 75 years or older were included. The serum vancomycin concentrations in the patients were predicted based on population pharmacokinetic parameters common in Japan. We examined the accuracy of serum vancomycin concentration prediction in elderly individuals by comparing the predicted and measured serum vancomycin concentrations in each patient. The prediction accuracy was evaluated using the mean prediction error (ME) and mean absolute error of prediction (MAE) calculated from the measured and predicted serum vancomycin concentrations in each patient. Results: The ME for all patients was 0.27, and the 95% CI included 0, indicating that the predicted values were not significantly biased compared to the measured values. However, the predicted serum concentrations in the <50 kg body weight and serum creatinine (Scr) < 0.6 mg/dL groups were significantly biased compared to the measured values. The group with a history of intensive care unit (ICU) admission showed the largest values for the ME and MAE. Conclusions: Our prediction accuracy was satisfactory but tended to be lower in underweight patients, those with low creatinine levels, and patients admitted to the ICU. Patients with multiple of these factors may experience a greater degree of decreased predictive accuracy.

Peritoneal Dialysis Prescription and Adequacy in Clinical Practice: Core Curriculum 2023.

As the global prevalence of peritoneal dialysis (PD) continues to grow, practitioners must be equipped with prescribing strategies that focus on the needs and preferences of patients. PD is an effective form of kidney replacement therapy that offers numerous benefits to patients, including more flexibility in schedules compared with in-center hemodialysis (HD). Additional benefits of PD include salt and water removal without significant changes in patient hemodynamics. This continuous yet gentle removal of solutes and fluid is associated with better-preserved residual kidney function. Unfortunately, sometimes these advantages are overlooked at the expense of an emphasis on achieving small solute clearance targets. A more patient-centered approach emphasizes the importance of individualized treatment, particularly when considering incremental PD and other prescriptions that align with lifestyle preferences. In shifting the focus from small solute clearance targets to patient needs and clinical goals, PD remains an attractive, patient-centered form of kidney replacement therapy.

Carboplatin dosing in the treatment of ovarian cancer: An NRG oncology group study.

OBJECTIVE: To determine the effects of using National Comprehensive Cancer Network (NCCN) guidelines to estimate renal function on carboplatin dosing and explore adverse effects associated with a more accurate estimation of lower creatinine clearance (CrCl). METHODS: Retrospective data were obtained for 3830 of 4312 patients treated on GOG182 (NCT00011986)-a phase III trial of platinum-based chemotherapy for advanced-stage ovarian cancer. Carboplatin dose per patient on GOG182 was determined using the Jelliffe formula. We recalculated CrCl to determine dosing using Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (with/without NCCN recommended modifications) formulas. Associations between baseline CrCl and toxicity were described using the area under the receiver operating characteristic curve (AUC). Sensitivity and positive predictive values described the model's ability to discriminate between subjects with/without the adverse event. RESULTS: AUC statistics (range, 0.52-0.64) showed log(CrClJelliffe) was not a good predictor of grade ≥3 adverse events (anemia, thrombocytopenia, febrile neutropenia, auditory, renal, metabolic, neurologic). Of 3830 patients, 628 (16%) had CrCl <60 mL/min. Positive predictive values for adverse events ranged from 1.8%-15%. Using the Cockcroft-Gault, Cockcroft-Gault with NCCN modifications, and MDRD (instead of Jelliffe) formulas to estimate renal function resulted in a >10% decrease in carboplatin dosing in 16%, 32%, and 5.2% of patients, respectively, and a >10% increase in carboplatin dosing in 41%, 9.6% and 12% of patients, respectively. CONCLUSION: The formula used to estimate CrCl affects carboplatin dosing. Estimated CrCl <60 mL/min (by Jelliffe) did not accurately predict adverse events. Efforts continue to better predict renal function. Endorsing National Cancer Institute initiatives to broaden study eligibility, our data do not support a minimum threshold CrCl <60 mL/min as an exclusion criterion from clinical trials.

Estimated glomerular filtration rate with and without race for drug dosing: Cystatin C vs. serum creatinine.

The goal of this study was to use a model kidney function clearance-dependent drug (vancomycin) to understand the gain or loss of precision in dosing with use of serum creatinine (Scr ), serum cystatin C (Scys ) and race and nonrace-based equations of the estimated glomerular filtration rate (eGFR). In this study of hospitalized patients, we compared Scr , Scys and their combination to estimate kidney function and vancomycin clearance. The nonrace-based Scys eGFR model outperformed other clearance models and improved the probability of target attainment by 15%. When Scys is not available, we show that the new 2021 CKD-EPI eGFRcr equation (no race factor) performs as well as the current conventional approach. This improvement in model performance does not negate the need for individualized dosing but exemplifies the need to remove race as a factor of kidney-function dose adjustment.

Optimizing carboplatin dosing by an improved prediction of carboplatin clearance using a CT-enhanced estimate of renal function.

AIMS: Carboplatin is generally dosed based on a modified Calvert formula, in which the Cockcroft-Gault-based creatinine clearance (CRCL) is used as proxy for the glomerular filtration rate (GFR). The Cockcroft-Gault formula (CG) overpredicts CRCL in patients with an aberrant body composition. The CT-enhanced estimate of RenAl FuncTion (CRAFT) was developed to compensate for this overprediction. We aimed to evaluate whether carboplatin clearance is better predicted by CRCL based on the CRAFT compared to the CG. METHODS: Data of four previously conducted trials was used. The CRAFT was divided by serum creatinine to derive CRCL. The difference between CRAFT- and CG-based CRCL was assessed by population pharmacokinetic modelling. Furthermore, the difference in calculated carboplatin dose was assessed in a heterogeneous dataset. RESULTS: In total, 108 patients were included in the analysis. Addition of the CRAFT- and CG-based CRCL as covariate on carboplatin clearance led, respectively, to an improved model fit with a 26-point drop in objective function value and a worsened model fit with an increase of 8 points. In 19 subjects with serum creatinine <50 µmol/L, the calculated carboplatin dose was 233 mg higher using the CG. CONCLUSIONS: Carboplatin clearance is better predicted by CRAFT vs. CG-based CRCL. In subjects with low serum creatinine, the calculated carboplatin dose using CG exceeds the dose using CRAFT, which might explain the need for dose capping when using the CG. Therefore, the CRAFT might be an alternative for dose capping while still dosing accurately.

Development and validation of the creatinine clearance predictor machine learning models in critically ill adults.

BACKGROUND: In critically ill patients, measured creatinine clearance (CrCl) is the most reliable method to evaluate glomerular filtration rate in routine clinical practice and may vary subsequently on a day-to-day basis. We developed and externally validated models to predict CrCl one day ahead and compared them with a reference reflecting current clinical practice. METHODS: A gradient boosting method (GBM) machine-learning algorithm was used to develop the models on data from 2825 patients from the EPaNIC multicenter randomized controlled trial database. We externally validated the models on 9576 patients from the University Hospitals Leuven, included in the M@tric database. Three models were developed: a "Core" model based on demographic, admission diagnosis, and daily laboratory results; a "Core + BGA" model adding blood gas analysis results; and a "Core + BGA + Monitoring" model also including high-resolution monitoring data. Model performance was evaluated against the actual CrCl by mean absolute error (MAE) and root-mean-square error (RMSE). RESULTS: All three developed models showed smaller prediction errors than the reference. Assuming the same CrCl of the day of prediction showed 20.6 (95% CI 20.3-20.9) ml/min MAE and 40.1 (95% CI 37.9-42.3) ml/min RMSE in the external validation cohort, while the developed model having the smallest RMSE (the Core + BGA + Monitoring model) had 18.1 (95% CI 17.9-18.3) ml/min MAE and 28.9 (95% CI 28-29.7) ml/min RMSE. CONCLUSIONS: Prediction models based on routinely collected clinical data in the ICU were able to accurately predict next-day CrCl. These models could be useful for hydrophilic drug dosage adjustment or stratification of patients at risk. TRIAL REGISTRATION: Not applicable.

Glomerular filtration rate in critically ill neonates and children: creatinine-based estimations versus iohexol-based measurements.

BACKGROUND: Acute kidney injury (AKI) and augmented renal clearance (ARC), both alterations of the glomerular filtration rate (GFR), are prevalent in critically ill children and neonates. AKI and ARC prevalence estimates are based on estimation of GFR (eGFR) using serum creatinine (SCr), which is known to be inaccurate. We aimed to test our hypothesis that AKI prevalence will be higher and ARC prevalence will be lower in critically ill children when using iohexol-based measured GFR (mGFR), rather than using eGFR. Additionally, we aimed to investigate the performance of different SCr-based eGFR methods. METHODS: In this single-center prospective study, critically ill term-born neonates and children were included. mGFR was calculated using a plasma disappearance curve after parenteral administration of iohexol. AKI diagnosis was based on the KDIGO criteria, SCr-based eGFR, and creatinine clearance (CrCL). Differences between eGFR and mGFR were determined using Wilcoxon signed-rank tests and by calculating bias and accuracy (percentage of eGFR values within 30% of mGFR values). RESULTS: One hundred five children, including 43 neonates, were included. AKI prevalence was higher based on mGFR (48%), than with KDIGO or eGFR (11-40%). ARC prevalence was lower with mGFR (24%) compared to eGFR (38-51%). eGFR equations significantly overestimated mGFR (60-71 versus 41 ml/min/1.73 m2, p < 0.001-0.002). Accuracy was highest with eGFR equations based on age- and sex-dependent equations (up to 59%). CONCLUSION: Iohexol-based AKI prevalence was higher and ARC prevalence lower compared to standard SCr-based eGFR methods. Age- and sex-dependent equations for eGFR (eGFR-Smeets for neonates and eGFR-Pierce for children) best approached measured GFR and should preferably be used to optimize diagnosis of AKI and ARC in this population. A higher resolution version of the Graphical abstract is available as Supplementary information.

Machine Learning-Based Prediction of Digoxin Toxicity in Heart Failure: A Multicenter Retrospective Study.

Digoxin toxicity (plasma digoxin concentration ≥0.9 ng/mL) is associated with worsening heart failure (HF). Decision tree (DT) analysis, a machine learning method, has a flowchart-like model where users can easily predict the risk of adverse drug reactions. The present study aimed to construct a flowchart using DT analysis that can be used by medical staff to predict digoxin toxicity. We conducted a multicenter retrospective study involving 333 adult patients with HF who received oral digoxin treatment. In this study, we employed a chi-squared automatic interaction detection algorithm to construct DT models. The dependent variable was set as the plasma digoxin concentration (≥ 0.9 ng/mL) in the trough during the steady state, and factors with p < 0.2 in the univariate analysis were set as the explanatory variables. Multivariate logistic regression analysis was conducted to validate the DT model. The accuracy and misclassification rates of the model were evaluated. In the DT analysis, patients with creatinine clearance <32 mL/min, daily digoxin dose ≥1.6 µg/kg, and left ventricular ejection fraction ≥50% showed a high incidence of digoxin toxicity (91.8%; 45/49). Multivariate logistic regression analysis revealed that creatinine clearance <32 mL/min and daily digoxin dose ≥1.6 µg/kg were independent risk factors. The accuracy and misclassification rates of the DT model were 88.2 and 46.2 ± 2.7%, respectively. Although the flowchart created in this study needs further validation, it is straightforward and potentially useful for medical staff in determining the initial dose of digoxin in patients with HF.

Creatinine clearance in selection of living kidney donor among the Malaysian population: is it safe?

BACKGROUND: Assessment of donor renal function is made by the measurement of Glomerular Filtration Rate (GFR). Exogenous markers are preferred over creatinine clearance and are widely used for measuring GFR. However, they are difficult to obtain, costly and laborious. This is a study to look into the safety and accuracy of creatinine clearance for renal assessment among the living kidney donors in the Malaysian population. METHODS: This is a retrospective, single-centre study comprising 105 living kidney donor candidates from the year 2007 to 2020. By comparing against 51-Chromium ethylenediamine-tetraacetic acid (51Cr-EDTA), we analysed creatinine clearance for correlation, bias, precision and accuracy. RESULTS: The study group had a mean age of 45.68 ± 10.97 years with a mean serum creatinine of 64.43 ± 17.68 µmol/L and a urine volume of 2.06 ± 0.83 L. Mean measured GFR from 51Cr-EDTA was 124.37 ± 26.83 ml/min/1.73m2 whereas mean creatinine clearance was 132.35 ± 38.18 ml/min/1.73m2. Creatinine clearance overestimated 51Cr-EDTA significantly with a correlation coefficient of 0.48 (p < 0.001) and an accuracy of 78.10% and 64.0% within 30% and 20% respectively of 51Cr-EDTA. CONCLUSION: Creatinine clearance is an acceptable and affordable alternative for donor renal assessment in the absence of exogenous markers with an emphasis on adequate urine collection followed by using measured GFR in selected cases.

Population Pharmacokinetic Modeling to Inform Sertraline Dosing Optimization in Patients with Depression.

Sertraline is one of the most prescribed antidepressants, but its pharmacokinetic (PK) properties are still not completely characterized. Using nonlinear mixed-effects modeling, we examined factors influencing sertraline PK variability in outpatients with major depressive disorder. Blood samples from 53 male and female adults treated with sertraline orally were collected at a steady state. Various demographic and clinical covariates were tested by stepwise regression procedure. We found that sertraline clearance is significantly influenced by serum concentrations of its main metabolite N-desmethylsertraline, whereas clearance of N-desmethylsertraline is affected by both creatinine clearance and drug daily dose. These results were confirmed by the reduction of points dispersion in goodness-of-fit plots for their predicted versus measured concentrations and with bootstrapping analyses. This finding can serve to inform sertraline dosing optimization, especially when changes in kidney function occur in treated individuals, to prevent adverse drug reactions and maximize therapeutic benefits.

Residual Renal Phosphate Clearance in Patients Receiving Hemodialysis or Hemodiafiltration.

OBJECTIVES: Substantial levels of residual renal clearance and urine output may occur in patients treated with hemodialysis or hemodiafiltration. However, the relationships among residual renal urea, creatinine, and phosphate clearances, respectively, and between clearances and urine volume have not been well described. METHODS: We performed a prospective, cross-sectional study which enrolled hemodialysis and hemodiafiltration patients with a urine volume of >100 mL/day, in whom at least 2 residual renal clearances were obtained over a 6-month observation period. Urine was collected for 24 hours prior to the midweek treatment session and concentrations of urea, creatinine, and phosphate were measured. RESULTS: Thirty-eight patients (24 men, 14 women) with a mean age of 70.4 ± 12.4 (SD) years were included in this analysis. All patients were dialyzed 3 times per week with mean treatment duration of 243 ± 7.89 minutes. Twenty patients were undergoing hemodiafiltration and 18 patients high-flux hemodialysis. In total, 102 dialysis sessions, of which 52 were hemodiafiltration, and urine collections were analyzed. Mean urine volume was 457 ± 254 mL per 24 hours. Residual renal clearance rates of urea (Kr Urea), creatinine (Kr Cr), and phosphate (Kr Phos) were 1.60 ± 0.979, 4.69 ± 3.79, and 1.98 ± 1.36 mL/minute, respectively. Mean ratios of Kr Cr/Kr Urea, Kr Phos/Kr Urea, and Kr Phos/Kr Cr were 2.83 ± 1.21, 1.23 ± 0.387, and 0.477 ± 0.185, respectively. There was a modest correlation between Kr Phos and daily urine volume (r = 0.605, P = .001). CONCLUSIONS: In maintenance hemodialysis and hemodiafiltration patients, residual renal phosphate clearance is approximately 23% higher than residual renal urea clearance. Urine volume is a modestly accurate surrogate for estimating residual renal phosphate clearance, but only when urine volume is <300 mL/day.

Creatinine Clearance in Acute Brain Injury: A Comparison of Methods.

BACKGROUND: Currently, the measurement of glomerular filtration rate is very complex and costly, so its daily evaluation is performed using endogenous markers, of which creatinine is the most frequently used. It allows the estimation of glomerular filtration rate by means of its clearance or by formulas based on its serum and urine concentration. Augmented renal clearance (ARC) is frequent among critically ill patients and is defined as creatinine clearance (CrCl) > 130 ml/min/1.73 m2. The aim of this study was to compare measured CrCl (MCC) and estimated CrCl obtained with the Cockcroft-Gault formula (CG), the Modification of Diet in Renal Disease Study equation (MDRD), and the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) in patients with severe traumatic brain injury and nontraumatic subarachnoid hemorrhage. The second aim was to assess the incidence of ARC in this population of neurocritical patients. METHODS: This was a prospective, observational, single center study from a cohort of 74 patients admitted to the neurocritical intensive care unit due to traumatic brain injury or subarachnoid hemorrhage. Serum creatinine (at 7 a.m.) and a 6-h urine collection were analyzed, and CrCl was measured and estimated by using CG, MDRD, and CKD-EPI. The intraclass correlation coefficient (ICC) was evaluated for each pair, and Bland-Altman plots were used to assess clinical significance. RESULTS: Among 74 patients, the median age was 53 (interquartile range [IQR] 36-65), and the median Glasgow Coma Scale score at admission was 6. The median MCC at admission was 176 (IQR 135-214). The medians of CG, MDRD and CKD-EPI were, respectively, 129 ml/min/1.73 m2 (IQR 95-176), 158 (IQR 115-202), and 116 (97-132). An ICC was applied to evaluate the correlation between MCC and estimated methods and showed a weak correlation between MCC and estimated CrCl obtained with the three different methods. The strongest ICC statistical correlation was found between MCC and MDRD, and the weakest correlation was found between MCC and CKD-EPI. Bland-Altman plots showed that differences between each pair were not clinically acceptable. ARC was present in 78% of measurements, using MCC. A weak correlation was observed between MCC and calculated CrCl. CG, MDRD, and CKD-EPI overestimated MCC when MCC ≤ 130 ml/min/1.73 m2 and underestimated it when MCC > 130 ml/min/1.73 m2. CONCLUSIONS: In this population, there was a weak statistical correlation between measured and estimated methods. In patients with ARC, formulas underestimated MCC. MCC should probably be the preferred methodology for renal function assessment in the clinical setting to better adjust drug dosage and guarantee drug effectiveness.

Augmented Renal Clearance in Patients with Acute Ischemic Stroke: A Prospective Observational Study.

BACKGROUND: Augmented renal clearance (ARC) is a phenomenon that has been demonstrated in many subsets of critically ill patients and is characterized by a creatinine clearance (CrCl) > 130 mL/min. Prior research has examined ARC prevalence in the presence of sepsis, traumatic brain injury, subarachnoid hemorrhage, and intracranial hemorrhage. However, to our knowledge, no studies have examined whether this phenomenon occurs in patients suffering from an acute ischemic stroke (AIS). The objective of this study was to evaluate whether patients experiencing an AIS exhibit ARC, identify potential contributing factors, and examine the precision of current renal clearance estimation methods in patients with AIS experiencing ARC. METHODS: This was a single-center prospective observational study conducted in adult patients admitted to a neurocritical intensive care unit (ICU) at a community hospital. Once consent was gained, patients with an admitting diagnosis of an AIS underwent a 24-h urine collection to assess measured CrCl. The primary end point assessed for ARC, defined as a measured CrCl > 130 mL/min. The secondary end point evaluated length of stay in the neurocritical ICU. RESULTS: Twenty-eight patients met enrollment criteria, and data was analyzed for 20 patients. ARC was present in 35% of enrolled patients. Mathematical estimations of renal function were inadequate in detecting ARC manifestation. Patients experiencing ARC were associated with nonsignificantly shorter ICU length of stay. CONCLUSIONS: ARC appears to manifest in patients with AIS inconsistently. Patients experiencing ARC were associated with nonsignificantly shorter ICU length of stay.