Prediction and assessment of acute encephalopathy syndromes immediately after febrile status epilepticus.

OBJECTIVE: This study aimed to predict occurrence of acute encephalopathy syndromes (AES) immediately after febrile status epilepticus in children and to explore the usefulness of electroencephalogram (EEG) in the early diagnosis of AES. METHODS: We reviewed data from 120 children who had febrile status epilepticus lasting >30 min and were admitted to our hospital between 2012 and 2019. AES with reduced diffusion on brain magnetic resonance imaging was diagnosed in 11 of these patients. EEG and serum cytokines were analyzed in AES patients. Clinical symptoms and laboratory data were compared between AES and non-AES patients. Logistic regression analysis was used to identify early predictors of AES. RESULTS: Multivariate logistic regression identified serum creatinine as a risk factor for developing AES. A scoring model to predict AES in the post-ictal phase that included serum creatinine, sodium, aspartate aminotransferase, and glucose was developed, and a score of 2 or more predicted AES with sensitivity of 90.9% and specificity of 71.6%. Post-ictus EEG revealed non-convulsive status epilepticus in four of the seven AES patients. CONCLUSION: Children with febrile status epilepticus may be at risk of developing severe AES with reduced diffusion. Post-ictus EEG and laboratory data can predict the occurrence of severe AES.

Urine volume to hydration volume ratio is associated with pharmacokinetics of high-dose methotrexate in patients with primary central nervous system lymphoma.

High-dose methotrexate (HD-MTX)-based chemotherapy is the first-line treatment for primary central nervous system lymphoma (PCNSL), but is associated with severe adverse effects, including myelosuppression and renal impairment. MTX is primarily excreted by the kidneys. Renal function calculated using serum creatinine (Scr) derived from muscle may be overestimated in elderly PCNSL patients. Therefore, we aimed to construct a population pharmacokinetic model in PCNSL patients and explore the factors associated with MTX clearance. Sixteen PCNSL patients (median age, 66 years) treated with HD-MTX were included, and serum MTX concentrations were measured at 193 points in 49 courses. A population pharmacokinetic analysis was performed using NONMEM. A Monte Carlo simulation was conducted, in which serum MTX concentrations were stratified into three groups of creatine clearance (Ccr) (50, 75, and 100 ml/min) with three groups of the urine volume to hydration volume (UV/HV) ratio (<1, 1-2, and >2). The final model was constructed as follows: MTX clearance = 4.90·(Ccr/94.5)0.456 ·(UV/HV)0.458 . In the Monte Carlo simulation, serum MTX concentrations were below the standard values (10, 1, and 0.1 µM at 24, 48, and 72 h, respectively, after the start of the MTX administration) in most patients with UV/HV >2, even with Ccr of 50 ml/min. Conversely, half of the patients with UV/HV <1 and Ccr of 50 ml/min failed to achieve the standard values. The present results demonstrated that the UV/HV ratio was useful for describing the pharmacokinetics of MTX in PCNSL patients.

Multivariate Longitudinal Assessment of Kidney Function Outcomes on Graft Survival after Kidney Transplantation Using Multivariate Joint Modeling Approach: A Retrospective Cohort Study.

Background: The performance of a transplanted kidney is evaluated by monitoring variations in the value of the most important markers. These markers are measured longitudinally, and their variation is influenced by other factors. The simultaneous use of these markers increases the predictive power of the analytical model. This study aimed to determine the simultaneous longitudinal effect of serum creatinine and blood urea nitrogen (BUN) markers, and other risk factors on allograft survival after kidney transplantation. Methods: In a retrospective cohort study, the medical records of 731 renal transplant patients, dated July 2000 to December 2013, from various transplant centers in Mashhad (Iran) were examined. Univariate and multivariate joint models of longitudinal and survival data were used, and the results from both models were compared. The R package joineRML was used to implement joint models. P values <0.05 were considered statistically significant. Results: Results of the multivariate model showed that allograft rejection occurred more frequently in patients with elevated BUN levels (HR=1.68, 95% CI: 1.24-2.27). In contrast, despite a positive correlation between serum creatinine and allograft rejection (HR=1.49, 95% CI: 0.99-2.22), this relationship was not statistically significant. Conclusion: Results of the multivariate model showed that longitudinal measurements of BUN marker play a more important role in the investigation of the allograft rejection.

Acute Kidney Injury: Lessons from Pericardiectomy.

BACKGROUND: Acute kidney (renal) injury (AKI) is a severe and common complication that occurs in ~40% of patients undergoing cardiac surgery. AKI has been associated with increased mortality and worse prognosis. This prospective study was conducted to determine the risk factors for AKI after pericardiectomy and decrease the operative risk of mortality and morbidity. METHODS: This was a prospective, observational cohort study of patients with constrictive pericarditis undergoing pericardiectomy. All patients underwent pericardiectomy via median sternotomy. Serum creatinine was used as the diagnostic standard of AKI according to Kidney Disease Improving Global Outcomes classification. All survivors were monitored to the end date of the study. RESULTS: Consecutive patients (N = 92) undergoing pericardiectomy were divided into 2 groups: with AKI (n = 25) and without AKI (n = 67). The incidence of postoperative AKI was 27.2% (25/92). Hemodialysis was required for 10 patients (40%), and there were 5 operative deaths. Mortality, intubation time, time in intensive care unit, fresh-frozen plasma, and packed red cells of the group with AKI were significantly higher than those of the group without AKI. Both univariate and multivariate analyses showed that statistically significant independent predictors of AKI include intubation time, chest drainage, fresh-frozen plasma, and packed red cells. The latest follow-up data showed that 85 survivors were New York Heart Association class I (97.7%) and 2 were class II (2.3%). CONCLUSIONS: AKI after pericardiectomy is a serious complication and contributes to significantly increased morbidity and mortality. Prevention of AKI development after cardiac surgery and optimization of pre-, peri-, and postoperative factors that can reduce AKI, therefore, contribute to a better postoperative outcome and leads to lower rates of AKI, morbidity, and mortality.

Estimation of inter-laboratory reference change values from external quality assessment data.

INTRODUCTION: It is common for patients to switch between several healthcare providers. In this context, the long-term follow-up of medical conditions based on laboratory test results obtained from different laboratories is a challenge. The measurement uncertainty in an inter-laboratory context should also be considered in data mining research based on routine results from randomly selected laboratories. As a proof-of-concept study, we aimed at estimating the inter-laboratory reference change value (IL-RCV) for exemplary analytes from publicly available data on external quality assessment (EQA) and biological variation. MATERIALS AND METHODS: External quality assessment data of the Reference Institute for Bioanalytics (RfB, Bonn, Germany) for serum creatinine, calcium, aldosterone, PSA, and of whole blood HbA1c from campaigns sent out in 2019 were analysed. The median CVs of all EQA participants were calculated based on 8 samples from 4 EQA campaigns per analyte. Using intra-individual biological variation data from the EFLM database, positive and negative IL-RCV were estimated with a formula based on log transformation under the assumption that the analytes under examination have a skewed distribution. RESULTS: We estimated IL-RCVs for all exemplary analytes, ranging from 13.3% to 203% for the positive IL-RCV and - 11.8% to - 67.0% for the negative IL-RCV (serum calcium - serum aldosterone), respectively. CONCLUSION: External quality assessment data together with data on the biological variation - both freely available - allow the estimation of inter-laboratory RCVs. These differ substantially between different analytes and can help to assess the boundaries of interoperability in laboratory medicine.

Assessment of the correlation of commonly used laboratory tests with clinical activity, renal involvement and treatment of systemic small-vessel vasculitis with the presence of ANCA antibodies.

BACKGROUND: The aim of the study was to assess the correlation of commonly used laboratory tests with clinical activity, degree of kidney involvement and treatment of systemic small-vessel vasculitis with the presence of ANCA antibodies. METHODS: The study included 28 patients with active AAV (BVAS ≥ 3). The following tests were performed: MPO-ANCA, PR3-ANCA, peripheral blood count, ESR, CRP, procalcitonin, creatinine, GFR, urea, albumin, fibrinogen, d-dimer, components of the C3 and C4 complement systems, urinalysis with sediment evaluation and diurnal proteinuria. The assessments were conducted twice: at study entry (A0) and after 6 months (A6) (BVAS = 0). RESULTS: At the time of inclusion in the study, the mean creatinine concentration was 3.39 mg/dl (GFR 33.17 ml/min/1.73 m²), after achieving remission in 11 patients (39.3 %) GFR remained below 30 ml/min/1.73 m², 4 patients (14.3 %) continued renal replacement therapy, and 3 patients (10.7 %) with advanced renal failure died. Microscopic hematuria occurred in 80.9 % of the studied population, withdrew in most patients, strongly correlated with renal involvement p < 0.001 and was not related to disease severity p = 0.147. CRP, ESR, fibrinogen, d-dimer, albumin and hemoglobin in the peripheral blood showed a strong correlation with the clinical activity of AAV and well identified severe patients. High procalcitonin concentrations correlated with a severe form of the disease, pulmonary involvement with respiratory failure and alveolar hemorrhage (mean 3.41 ng/ml, median 0.91 ng/ml, SD 7.62, p = 0.000), and were associated with the occurrence of infectious complications and the need to administer antibiotic therapy. ANCA antibodies were useful in the evaluation of patients with AAV, the amount of antibodies did not correlate with the severity of vasculitis (p = 0.685) and the results in many patients did not match the expected assumptions. CONCLUSIONS: CRP, ESR, fibrinogen, d-dimers, albumin and hemoglobin in the peripheral blood correlate well with the activity of vasculitis and identify severe patients. The resolution of microscopic hematuria suggests remission of the disease in the renal area. Procalcitonin may be slightly increased in patients with active AAV without infection, high concentrations are strongly associated with infectious complications. ANCA antibodies should always be interpreted in the context of the observed clinical symptoms.

Assessment of Renal Function Status in Steady-State Sickle Cell Anaemic Children Using Urine Human Neutrophil Gelatinase-Associated Lipocalin and Albumin:Creatinine Ratio.

INTRODUCTION: Sickle cell anaemia is characterized by defective haemoglobin synthesis and is associated with both endocrine and metabolic alterations. The effects of this clinical condition on kidney function are multifactorial and often begin early in childhood. This study aims to assess renal function in children with sickle cell anaemia using urine albumin:creatinine ratio (ACR) and urine human neutrophil gelatinase-associated lipocalin (NGAL). METHODS: This case-control study was conducted on 200 children aged 5-15 years in 2 tertiary hospitals in South West Nigeria: 150 were of haemoglobin S genotype and 50 were of haemoglobin A genotype. Serum urea, creatinine, urine albumin, and NGAL were assayed by known standard methods. eGFR, urine ACR, and urine NGAL/creatinine ratio (urine NCR) were calculated. RESULTS: The weight, height, BMI, systolic blood pressure, plasma urea, plasma creatinine, and spot urine creatinine of the HbS genotype children were significantly lower compared to that of the HbA genotype children. The eGFR, spot urine albumin, and urine ACR were significantly higher in the HbS group compared to the HbA group. There was no significant difference in the spot urine NGAL and urine NCR between the 2 groups, though both were higher in the HbS group compared to the HbA group. CONCLUSIONS: Kidney injury probably starts early in childhood in sickle cell individuals as indicated by the higher urine ACR detected in them. We infer that urine NGAL and uNCR are not sensitive markers of kidney disease especially in young sickle cell individuals possibly because of the hyperfiltration present at this age.

Significance of serum FGF-23 for risk assessment of contrast-associated acute kidney injury and clinical outcomes in patients undergoing coronary angiography.

BACKGROUND: Fibroblast growth factor (FGF)-23 levels rise as kidney function declines. Whether elevated FGF-23 levels are associated with an increased risk for contrast-associated acute kidney injury (CA-AKI) and major adverse cardiovascular events (MACE) in patients undergoing coronary angiography remain uncertain. METHODS: In total, 492 patients receiving coronary angiography were enrolled. Their serum FGF-23 levels were measured before administration of contrast media. The occurrence of CA-AKI was defined as a rise in serum creatinine of 0.5 mg/dL or a 25% increase from the baseline value within 48 h after the procedure. All patients were followed up for at least 1 year or until the occurrence of MACE including death, nonfatal myocardial infarction (MI), and ischemic stroke. RESULTS: Overall, CA-AKI occurred in 41 (8.3%) patients. During a median follow-up of 2.6 years, there were 24 deaths, 3 nonfatal MIs, and 7 ischemic strokes. Compared with those in the lowest FGF-23 tertile, individuals in the highest FGF-23 tertile had a significantly higher incidence of CA-AKI (P < 0.001) and lower incidence of MACE-free survival (P = 0.001). In multivariate regression analysis, higher FGF-23 level was found to be independently associated with a graded risk for CA-AKI (OR per doubling, 1.90; 95% CI 1.48-2.44) and MACE (HR per doubling, 1.25; 95% CI 1.02-1.52). CONCLUSIONS: Elevated FGF-23 levels were associated with an increased risk for CA-AKI and future MACE among patients undergoing coronary angiography. FGF-23 may play a role in early diagnosis of CA-AKI and predicting clinical outcomes after coronary angiography.

Population pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing regimens.

PURPOSE: This study aimed to characterize pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing scheme. METHODS: Children treated with ciprofloxacin were included. Pharmacokinetics were described using non-linear mixed-effect modelling and validated with an external dataset. Monte Carlo simulations investigated dosing regimens to achieve a target AUC0-24 h/MIC ratio ≥ 125. RESULTS: A total of 189 children (492 concentrations) were included. A two-compartment model with first-order absorption and elimination best described the data. An allometric model was used to describe bodyweight (BW) influence, and effects of estimated glomerular filtration rate (eGFR) and age were significant on ciprofloxacin clearance. CONCLUSION: The recommended IV dose of 10 mg/kg q8h, not exceeding 400 mg q8h, would achieve AUC0-24 h to successfully treat bacteria with MICs ≤ 0.25 (e.g. Salmonella, Escherichia coli, Proteus, Haemophilus, Enterobacter, and Klebsiella). A dose increase to 600 mg q8h in children > 40 kg and to 15 mg/kg q8h (max 400 mg q8h, max 600 mg q8h if augmented renal clearance, i.e., eGFR > 200 mL/min/1.73 m2) in children < 40 kg would be needed for the strains with highest MIC (16% of Pseudomonas aeruginosa and 47% of Staphylococcus aureus). The oral recommended dose of 20 mg/kg q12h (not exceeding 750 mg) would cover bacteria with MICs ≤ 0.125 but may be insufficient for bacteria with higher MIC and a dose increase according bodyweight and eGFR would be needed. These doses should be prospectively confirmed, and a therapeutic drug monitoring could be used to refine them individually.

Optimization of dosing regimens of vancomycin, teicoplanin, linezolid and daptomycin against methicillin-resistant Staphylococcus aureus in neutropenic patients with cancer by Monte Carlo simulations.

The objective of this study was to evaluate the efficacy of various dosing regimens of vancomycin, teicoplanin, linezolid and daptomycin against methicillin-resistant Staphylococcus aureus (MRSA) in neutropenic patients with cancer. Monte Carlo simulations were conducted using pharmacokinetic parameters and pharmacodynamic data to determine cumulative fraction of response (CFRs) in terms of area under the concentration-time curve/minimum inhibition concentration target. Currently clinical standard dosing regimens of vancomycin, teicoplanin, linezolid and daptomycin were insufficient to provide expected CFRs against MRSA for neutropenic patients with cancer. The high dosing regimens of vancomycin (3500 mg/d), teicoplanin (800 mg/d) and daptomycin (8 mg/kg/d) could provide CFRs of ≥ 80%, showing a higher treatment success. However, the majority of CFRs with linezolid simulated dosing regimens reached < 80% against MRSA. Therefore, a strategy of high dosages of vancomycin, teicoplanin and daptomycin may be needed to attain optimal therapeutic efficacy against MRSA in neutropenic patients with cancer.

Post hoc assessment of the relationship among coronary stenosis, electrocardiography, and ventricular function in patients with heart disease.

Cardiovascular diseases including cardiac arrhythmias lead to fatal events in patients with coronary artery disease; however, clinical associations from echocardiography, electrocardiography (ECG), and biomarkers remain unknown. We sought to identify the factors that may be related to elevated QRS intervals in patients with risk for coronary artery disease. In this study, we performed analysis of clinical data from 503 patients divided into two groups, i.e., patients with either <50% coronary artery stenosis or >50% coronary artery stenosis. We further examined patients with elevated ECG parameters such as QRS > 100 ms and QTc > 440 ms. Patients with >50% coronary artery stenosis exhibited significant increases in age, triglycerides, and troponin levels. Further, ECG parameters demonstrated increased QRS and QTc durations, while echocardiographic parameters highlighted a decrease in ejection fraction (EF) and fractional shortening (FS). Patients with QTc > 440 ms exhibited increased brain natriuretic peptide and creatinine levels with a decrease in estimated glomerular filtration rate clearance rates. Patients with QRS > 100 ms had greater left ventricular (LV) mass and LV internal diameter in systole and diastole. Multimodal logistic regression showed significant relation between QTc, age, and creatinine. These findings suggest that patients with significant coronary stenosis may have lower EF and FS with prolonged QRS intervals, demonstrating greater risk for arrhythmic events.

Assessment of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker on the split renal function in the patients with primary hypertension.

ABSTRACT: Bilateral kidney damage in hypertensive patients is not parallel. Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB), as a commonly used antihypertensive drug, could protect kidney function and delay its deterioration. Most studies focused on overall renal function, but the researches on split renal function (SRF) are rare. We investigated the effects of ACEI/ARB on the SRF in patients with primary hypertension.Patients with primary hypertension (n = 429; male: 213; female: 216) admitted to our department between January 2014 and December 2016 were included in this study. The glomerular filtration rate (GFR) of split and total renal function were determined using diethylenetriaminepentaacetic acid tagged with 99mTc renal dynamic imaging method. For the same patient, the side with high GFR was considered as higher GFR kidney, whereas that with a low GFR was considered as lower GFR kidney. The split function score (Q value) was utilized to evaluate the differences of bilateral renal function. The patients were divided into 3 groups based on the Q values (Group 1, Q value <5%; Group 2, Q value of 5%-10%; Group 3, Q value ≥10%). All the patients received antihypertensive therapy based on ACEI/ARB. The renal dynamic imaging was performed in the 1-year follow-up to investigate the changes of the SRF.Compared with the baseline level, significant decline was noticed in the serum creatinine (Scr) in Group 2 and Group 3 (P < .05). The cystatin C in Group 3 showed significant decline (P < .05). Compared with the baseline, there was significant decline in the Q value in Group 2, whereas the GFR of lower GFR kidney showed significant increase (P < .05). No statistical differences were noticed in the Q value and split GFR in Group 1 and Group 3 (P > .05).In primary hypertension patients, ACEI/ARB therapy could improve the SRF of lower GFR kidney in the presence of certain differences between the SRF. As a result, the SRF difference was reduced. In case of Q value in a range of 5% to 10%, ACEI/ARB could improve the renal function effectively. It may be significant for the design of antihypertensive drugs.

Establishment and assessment of a nomogram model for predicting the risk of fulminant myocarditis: A STROBE compliant cross-sectional study.

ABSTRACT: We aimed to identify potential clinical predictors associated with the risk of fulminant myocarditis, and further to establish and assess a nomogram model based on significant attributes for clinical practicability.This is a retrospective, cross-sectional study, involving 28 patients with fulminant myocarditis and 35 age-, and sex-matched patients with non-fulminant myocarditis. Effect-size estimates are expressed as odds ratio (OR) and 95% confidence interval (CI).Fifteen factors were primarily identified to be associated with the significant risk of fulminant myocarditis after adjusting for confounders. Due to strong correlation, 6 factors were retained, including mean arterial pressure (OR, 95% CI, P: .82, .72-.94, .005), creatinine (2.15, 1.13-4.10, 0.020), blood urea nitrogen (1.45, 1.04-2.02, 0.028), aspartate aminotransferase (2.62, 1.16-5.91, 0.021), troponin I (1.43, 1.07-1.90, 0.015), and ventricular wall motion abnormality (25.81, 2.52-264.69, 0.006). The contribution of the 6 significant factors to predicting fulminant myocarditis risk was significant from multi-angle analyses, and regressing these factors in a nomogram model exhibited good predictive accuracy, as reflected by both C-index (>90%, P < .001).We have identified 6 clinical factors in significant association with fulminant myocarditis, and their prediction capability was more obvious in a nomogram model. Further investigations with larger sample sizes and longer follow-up intervals are warranted.

Assessment of renal function using cystatin C and creatinine in Saudi patients after transplantation.

Background: Rapid and accurate assessment of kidney function in patients after transplantation is of utmost importance. The aim of this study was to compare the relationships of serum creatinine and serum cystatin C with an estimated glomerular filtration rate (eGFR) in kidney transplants Saudi patients after a certain period of transplantation. Materials and Methods: In this prospective study, 127 patients were categorized into three groups based on their length of survival after kidney transplantation; <1 year, from 1 to 5 years, and above 5 years after transplantation. Results of cystatin C and creatinine levels were compared by eGFR derived from estimation equation chronic kidney disease epidemiology collaboration. Results: In the three assessed periods, the mean (standard deviation) cystatin C level was 1.72 (0.57), 1.59 (0.64), and 1.82 (0.82), respectively, being highest after 5 years of transplantation, normal in 9.40%, and elevated in 90.60% of the participants, while creatinine level, decreased from 1.57 (0.53) to 1.52 (0.64) in 1-5 years, then it became the highest at 1.75 (0.69) in more than 5 years. The mean was normal in 21.30% and elevated in 78.70% of the patients. Both serum creatinine and cystatin C levels were negatively correlated with posttransplantation time in kidney transplant patients. Conclusion: The cystatin C level was statistically significantly higher after 5 years of transplantation. It is a better parameter to rule out renal dysfunction after transplantation.

Résumé Une évaluation rapide et précise de la fonction rénale chez les patients après une transplantation est de la plus importance. Le but de cette étude était de comparer les relations de la créatinine et de la cystatine C sérique avec un taux de filtration glomérulaire estimé (DFG) chez des patients saoudiens transplantés rénaux après une certaine période de transplantation. Matériel et méthodes: Dans cette étude prospective, 127 patients ont été classés en trois groupes en fonction de leur durée de survie après une transplantation rénale; <1 an, de 1 à 5 ans et plus de 5 ans après la transplantation. Les résultats des taux de cystatine C et de créatinine ont été comparés par le DFG dérivé de l'équation d'estimation de la collaboration épidémiologique sur les maladies rénales chroniques. Résultats: Au cours des trois périodes évaluées, le taux moyen (écart-type) de cystatine C était de 1,72 (0,57), 1,59 (0,64) et 1,82 (0,82), respectivement, étant le plus élevé après 5 ans de transplantation, normal dans 9,40% et élevé chez 90,60% des participants, tandis que le niveau de créatinine est passé de 1,57 (0,53) à 1,52 (0,64) en 1 à 5 ans, puis il est devenu le plus élevé à 1,75 (0,69) en plus de 5 ans. La moyenne était normale chez 21,30% et élevée chez 78,70% des patients. Les taux sériques de créatinine et de cystatine C étaient corrélés négativement avec le temps post-transplantation chez les patients transplantés rénaux. Discussion: Le taux de cystatine C était significativement plus élevé après 5 ans de transplantation. C'est un meilleur paramètre pour exclure un dysfonctionnement rénal après une transplantation.

An Assessment of the Accuracy of Creatinine Measurements in Guyana

ABSTRACT Background: The incidence of chronic kidney disease (CKD) is relatively high in Guyana. Estimated glomerular filtration rate (eGFR) reporting allows for early-stage CKD identification when therapeutic interventions can prevent CKD progression. Accurate creatinine measurements are essential for valid eGFR calculations. Objective: This study was undertaken to assess the accuracy of creatinine measurements in Guyana prior to implementing routine eGFR reporting. Methods: Sixteen Guyanese laboratories participated in this study. Each laboratory received a common set of blinded human serum samples (n = 3) containing clinically relevant creatinine concentrations, assigned by an international reference method (ID-GCMS). Laboratories performed repeated measurements of creatinine in each sample. These data were used to calculate bias, precision and total error (TE) for each creatinine method. Linear regression was used to compare measured creatinine results to assigned reference sample values and to post-analytically correct calibration bias, a priori, for recent patient results from each laboratory. Patient eGFR profiles were compared before and after bias correction. Results: The mean across samples CV and bias for all labs were 9% (range 2.5%-39.3%) and 11% positive (range 0.4%-29.1%), respectively. The mean TE was 28.6%. If the mean TE from a subset of the better performing laboratories (CV < 7%) was to apply nationally, an 'all stage' eGFR misclassification rate of 36% would result. Conclusion: There is a pressing need to improve the accuracy of creatinine measurements in Guyana as, at this time, routine reporting of eGFR by Guyanese laboratories cannot be recommended based on the accuracy data presented in this study.

Evaluation of Meropenem-Ciprofloxacin Combination Dosage Regimens for the Pharmacokinetics of Critically Ill Patients With Augmented Renal Clearance.

Augmented renal clearance (ARC, creatinine clearance > 130 mL/minute) makes difficult achievement of effective concentrations of renally cleared antibiotics in critically ill patients. This study examined the synergistic killing and resistance suppression for meropenem-ciprofloxacin combination dosage regimens against Pseudomonas aeruginosa isolates within the context of ARC. Clinically relevant meropenem and ciprofloxacin concentrations, alone and in combinations, were studied against three clinical isolates with a range of susceptibilities to each of the antibiotics. Isolate Pa1280 was susceptible to both meropenem and ciprofloxacin, Pa1284 had intermediate susceptibility to meropenem and was susceptible to ciprofloxacin, and CR380 was resistant to meropenem and had intermediate susceptibility to ciprofloxacin. Initially, isolates were studied in 72-hour static-concentration time-kill (SCTK) studies. Subsequently, the pharmacokinetic profiles expected in patients with ARC receiving dosage regimens, including at the highest approved daily doses (meropenem 6 g daily divided and administered as 0.5-hour infusions every 8 hours, or as a continuous infusion; ciprofloxacin 0.4 g as 1-hour infusions every 8 hours), were examined in a dynamic hollow-fiber infection model (HFIM) over 7-10 days. In both SCTK and HFIM, combination regimens were generally synergistic and suppressed growth of less-susceptible subpopulations, these effects being smaller for isolate CR380. The time-courses of total and less-susceptible bacterial populations in the HFIM were well-described by mechanism-based models, which enabled conduct of Monte Carlo simulations to predict likely effectiveness of approved dosage regimens at different creatinine clearances. Optimized meropenem-ciprofloxacin combination dosage regimens may be a viable consideration for P. aeruginosa infections in critically ill patients with ARC.

Noninvasive assessment of radiation-induced renal injury in mice.

PURPOSE: The kidney is a radiosensitive late-responding normal tissue. Injury is characterized by radiation nephropathy and decline of glomerular filtration rate (GFR). The current study aimed to compare two rapid and cost-effective methodologies of assessing GFR against more conventional biomarker measurements. METHODS: C57BL/6 mice were treated with bilateral focal X-irradiation (1x14Gy or 5x6Gy). Functional measurements of kidney injury were assessed 20 weeks post-treatment. GFR was estimated using a transcutaneous measurement of fluorescein-isothiocyanate conjugated (FITC)-sinistrin renal excretion and also dynamic contrast-enhanced CT imaging with a contrast agent (ISOVUE-300 Iopamidol). RESULTS: Hematoxylin and eosin (H&E) and Periodic acid-Schiff staining identified comparable radiation-induced glomerular atrophy and mesangial matrix accumulation after both radiation schedules, respectively, although the fractionated regimen resulted in less diffuse tubulointerstitial fibrosis. Albumin-to-creatinine ratios (ACR) increased after irradiation (1x14Gy: 100.4 ± 12.2 µg/mg; 6x5Gy: 80.4 ± 3.02 µg/mg) and were double that of nontreated controls (44.9 ± 3.64 µg/mg). GFR defined by both techniques was negatively correlated with BUN, mesangial expansion score, and serum creatinine. The FITC-sinistrin transcutaneous method was more rapid and can be used to assess GFR in conscious animals, dynamic contrast-enhanced CT imaging technique was equally safe and effective. CONCLUSION: This study demonstrated that GFR measured by dynamic contrast-enhanced CT imaging is safe and effective compared to transcutaneous methodology to estimate kidney function.

External Validation of the DynPG for Kidney Transplant Recipients.

BACKGROUND: In kidney transplantation, dynamic prediction of patient and kidney graft survival (DynPG) may help to promote therapeutic alliance by delivering personalized evidence-based information about long-term graft survival for kidney transplant recipients. The objective of the current study is to externally validate the DynPG. METHODS: Based on 6 baseline variables, the DynPG can be updated with any new serum creatinine measure available during the follow-up. From an external validation sample of 1637 kidney recipients with a functioning graft at 1-year posttransplantation from 2 European transplantation centers, we assessed the prognostic performance of the DynPG. RESULTS: As one can expect from an external validation sample, differences in several recipient, donor, and transplantation characteristics compared with the learning sample were observed. Patients were mainly transplanted from deceased donors (91.6% versus 84.8%; P < 0.01), were less immunized against HLA class I (18.4% versus 32.7%; P < 0.01) and presented less comorbidities (62.2% for hypertension versus 82.7%, P < 0.01; 25.1% for cardiovascular disease versus 33.9%, P < 0.01). Despite these noteworthy differences, the area under the ROC curve varied from 0.70 (95% confidence interval [CI], 0.64-0.76) to 0.76 (95% CI, 0.64-0.88) for prediction times at 1 and 6 years posttransplantation respectively, and calibration plots revealed reasonably accurate predictions. CONCLUSIONS: We validated the prognostic capacities of the DynPG in terms of both discrimination and calibration. Our study showed the robustness of the DynPG for informing both the patient and the physician, and its transportability for a cohort presenting different features than the one used for the DynPG development.

Biomarker-Guided Risk Assessment for Acute Kidney Injury: Time for Clinical Implementation?

Acute kidney injury (AKI) is a common and serious complication in hospitalized patients, which continues to pose a clinical challenge for treating physicians. The most recent Kidney Disease Improving Global Outcomes practice guidelines for AKI have restated the importance of earliest possible detection of AKI and adjusting treatment accordingly. Since the emergence of initial studies examining the use of neutrophil gelatinase-associated lipocalin (NGAL) and cycle arrest biomarkers, tissue inhibitor metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein (IGFBP7), for early diagnosis of AKI, a vast number of studies have investigated the accuracy and additional clinical benefits of these biomarkers. As proposed by the Acute Dialysis Quality Initiative, new AKI diagnostic criteria should equally utilize glomerular function and tubular injury markers for AKI diagnosis. In addition to refining our capabilities in kidney risk prediction with kidney injury biomarkers, structural disorder phenotypes referred to as "preclinical-" and "subclinical AKI" have been described and are increasingly recognized. Additionally, positive biomarker test findings were found to provide prognostic information regardless of an acute decline in renal function (positive serum creatinine criteria). We summarize and discuss the recent findings focusing on two of the most promising and clinically available kidney injury biomarkers, NGAL and cell cycle arrest markers, in the context of AKI phenotypes. Finally, we draw conclusions regarding the clinical implications for kidney risk prediction.