Estimated Creatinine Clearance Research Articles

Potential risks of substituting estimated glomerular filtration rate for estimated creatinine clearance for dosing of direct oral anticoagulants in atrial fibrillation and chronic kidney disease

Abstract Background In the clinical trials with direct oral anticoagulants (DOAC) estimates of creatinine clearance (CrCl) with Cockcroft-Gault equation were used to assess renal functions. Recently, most laboratories report renal function estimated with the Modification of Diet in Renal Disease (MDRD) or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, which may lead to impaired dosing of DOACs by physicians. Purpose To compare estimated glomerular filtration rate and estimated creatinine clearance in a large group of patients with atrial fibrillation and chronic kidney disease. Methods Physicians from 423 institutions in the Czech Republic were asked to enroll 5 consecutive outpatients with atrial fibrillation (AF) treated by a DOAC with stage 3 chronic kidney disease and glomerular filtration rate (eGFR) 30–59 ml/min estimated by MDRD or CKD EPI equations into the registry. Besides eGFR, serum creatinine values were recorded and CrCl calculated by the Cockroft-Gault formula. Results of CrCl and eGFR obtained in individual patients were compared and statistically analyzed using two-sample t-test. Results A total of 2115 patients were enrolled. Mean CrCl was 47.43 ml/min, mean eGFR calculated by MDRD and CKD-EPI was lower 43.88 and 43.53 ml/min (P for difference <0.001 for both). Mean difference between CrCl and eGFR in individual patients calculated by MDRD and CKD-EPI was 8.8 and 9.41 ml/min. A difference beween CrCl and eGFR >10 ml/min was found in 31.5% and 34.8% patients when using MDRD and CKD-EPI formulas. The respective differences between CrCl and eGFR between 4.1 and 10 ml/min were found in 28.5% (MDRD) and 30.8% (CKD-EPI). At CrCl above or below 50 ml/min, 24.0% and 24.2% were misclassified when using eGFR calculated by MDRD and CKD-EPI. At CrCl above or below 30 ml/min, 9.8% (MDRD) and 10.0% (CKD-EPI) patients were misclassified (please see Figures). Conclusions When eGFR estimated by MDRD or CKD-EPI is used to assess renal function and guide DOAC dosing instead of CrCl calculated by the Cockroft-Gault formula in patients with AF and stage 3 CKD, more than a third of patients is misclassified and wrong DOAC dose can be recommended. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Boehringer-Ingelheim Differences between CrCl and CKD-EPIDifferences between CrCl and MDRD

Population Pharmacokinetics and Dosing Simulation of Vancomycin Administered by Continuous Injection in Critically Ill Patient.

Background: Vancomycin is widely used for empirical antimicrobial therapy in critically ill patients with sepsis. Continuous infusion (CI) may provide more stable exposure than intermittent infusion, but optimal dosing remains challenging. The aims of this study were to perform population pharmacokinetic (PK) analysis of vancomycin administered by CI in intensive care unit (ICU) patients to identify optimal dosages. Methods: Patients who received vancomycin by CI with at least one measured concentration in our center over 16 months were included, including those under continuous renal replacement therapy (CRRT). Population PK was conducted and external validation of the final model was performed in a dataset from another center. Simulations were conducted with the final model to identify the optimal loading and maintenance doses for various stages of estimated creatinine clearance (CRCL) and in patients on CRRT. Target exposure was defined as daily AUC of 400–600 mg·h/L on the second day of therapy (AUC24–48 h). Results: A two-compartment model best described the data. Central volume of distribution was allometrically scaled to ideal body weight (IBW), whereas vancomycin clearance was influenced by CRRT and CRCL. Simulations performed with the final model suggested a loading dose of 27.5 mg/kg of IBW. The maintenance dose ranged from 17.5 to 30 mg/kg of IBW, depending on renal function. Overall, simulation showed that 55.8% (95% CI; 47–64%) of patients would achieve the target AUC with suggested dosages. Discussion: A PK model has been validated for vancomycin administered by CI in ICU patients, including patients under CRRT. Our model-informed precision dosing approach may help for early optimization of vancomycin exposure in such patients.

Population pharmacokinetics of cefotaxime in intensive care patients

PurposeTo characterise the pharmacokinetics and associated variability of cefotaxime in adult intensive care unit (ICU) patients and to assess the impact of patient covariates.MethodsThis work was based on data from cefotaxime-treated patients included in the ACCIS (Antibiotic Concentrations in Critical Ill ICU Patients in Sweden) study. Clinical data from 51 patients at seven different ICUs in Sweden, given cefotaxime (1000–3000 mg given 2–6 times daily), were collected from the first day of treatment for up to three consecutive days. In total, 263 cefotaxime samples were included in the population pharmacokinetic analysis.ResultsA two-compartment model with linear elimination, proportional residual error and inter-individual variability (IIV) on clearance and central volume of distribution best described the data. The typical individual was 64 years, with body weight at ICU admission of 92 kg and estimated creatinine clearance of 94 mL/min. The resulting typical value of clearance was 11.1 L/h, central volume of distribution 5.1 L, peripheral volume of distribution 18.2 L and inter-compartmental clearance 14.5 L/h. The estimated creatinine clearance proved to be a significant covariate on clearance (p < 0.001), reducing IIV from 68 to 49%.ConclusionA population pharmacokinetic model was developed to describe cefotaxime pharmacokinetics and associated variability in adult ICU patients. The estimated creatinine clearance partly explained the IIV in cefotaxime clearance. However, the remaining unexplained IIV is high and suggests a need for dose individualisation using therapeutic drug monitoring where the developed model, after evaluation of predictive performance, may provide support.

Identifying risk patterns in older adults with atrial fibrillation by hierarchical cluster analysis: A retrospective approach based on the risk probability for clinical events.

Older adults with atrial fibrillation (AF) have highly diverse risk levels for mortality, heart failure (HF), thromboembolism (TE), and major bleeding (MB), thus an integrated risk-pattern algorithm is warranted. We analyzed 573 AF patients aged≥75years from our single-center cohort (Shinken Database 2010-2018). The 3-year risk scores (risk probability) for mortality (M-score), HF (HF-score), TE (TE-score), and MB (MB-score) were estimated for each patient by logistic regression analysis. Using the four risk scores, cluster analysis was performed with Ward's linkage hierarchical algorithm. Three clusters were identified: Clusters 1 (n=429, 74%), 2 (n=24, 5%), and 3 (n=120, 21%). The clusters were characterized as standard risk (Cluster 1), high TE- and MB-risk (Cluster 2), and high M- and HF-risk (Cluster 3). Oral anticoagulants were prescribed for over 80% of the patients in each cluster. Catheter ablation for AF was performed only in Cluster 1 (8.9%). Compared with Cluster 1, Cluster 2 was more closely associated with males, asymptomatic AF, history of cerebral infarction or transient ischemic attack, history of intracranial hemorrhage, high HAS-BLED score (≥3), and low body mass index (<18.0kg/m2). Cluster 3 was more closely associated with old age, heart failure, and low estimated creatinine clearance (<30mL/min). The cluster analysis identified those at a high risk for all-cause death and HF or a high risk for TE and MB and could support decision making in older adults with AF.

The Prognostic Impact of Estimated Creatinine Clearance by Bioelectrical Impedance Analysis in Heart Failure: Comparison of Different eGFR Formulas.

The estimation of glomerular filtration rate (eGFR) provides prognostic information in patients with heart failure (HF). Bioelectrical impedance analysis may calculate eGFR (Donadio formula). The aim of this study was to evaluate the impact of the Donadio formula in predicting all-cause mortality in patients with HF as compared to Cockroft-Gault, MDRD-4 (Modification of Diet in renal Disease Study), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas. Four-hundred thirty-six subjects with HF (52% men; mean age 75 ± 11 years; 42% acute HF) were enrolled. Ninety-two patients (21%) died during the follow-up (median 463 days, IQR 287–669). The area under the receiver operator characteristic curve for eGFR, as estimated by Cockroft-Gault formula (AUC = 0.75), was significantly higher than those derived from Donadio (AUC = 0.72), MDRD-4 (AUC = 0.68), and CKD-EPI (AUC = 0.71) formulas. At multivariate analysis, all eGFR formulas were independent predictors of death; 1 mL/min/1.73 m2 increase in eGFR—as measured by Cockroft-Gault, Donadio, MDRD-4, and CKD-EPI formulas—provided a 2.6%, 1.5%, 1.2%, and 1.6% increase, respectively, in mortality rate. Conclusions. eGFR, as calculated with the Donadio formula, was an independent predictor of mortality in patients with HF as well as the measurements derived from MDRD4 and CKD-EPI formulas, but less accurate than Cockroft-Gault.

Effect of removing race from glomerular filtration rate-estimating equations on anticancer drug dosing and eligibility: a retrospective analysis of National Cancer Institute phase 1 clinical trial participants.

Kidney function assessment by estimated glomerular filtration rate (eGFR) equations, such as the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation, is important to determine dosing and eligibility for anticancer drugs. Inclusion of race in eGFR equations calculates a higher eGFR at a given serum creatinine concentration for Black patients versus non-Black patients. We aimed to characterise the effect of removing race from the CKD-EPI equation on dosing and eligibility of anticancer drugs with kidney function cutoffs. We did a retrospective analysis of patients enrolled in phase 1 studies sponsored by the Cancer Therapy Evaluation Program between January, 1995, and October, 2010. eGFR based on creatinine (eGFRCr) was calculated by the CKD-EPI equation and a version of the CKD-EPI equation without the race term (CKD-EPIwithout race). Estimated creatinine clearance (eClCr) was calculated by the Cockcroft-Gault equation. Dosing simulations based on each assessment of kidney function were done for ten anticancer drugs with kidney function cutoffs for dosing (oxaliplatin, capecitabine, etoposide, topotecan, fludarabine, and bleomycin) or eligibility (cisplatin, pemetrexed, bendamustine, and mitomycin) based on labelling approved by the US Food and Drug Administration or consensus guidelines. The absolute proportion of patients eligible or in each renal dosing range was calculated for each drug. Eligibility and dosing discordance rates were also calculated. Demographics and laboratory values from 340 Black patients (172 men and 168 women) were used. Median age was 57 years (IQR 47-64), median bodyweight was 78·1 kg (67·0-89·8), median body surface area was 1·91 m2 (1·77-2·09), and median serum creatinine concentration was 0·9 mg/dL (0·8-1·1). Median eGFRCr or eClCr was 103 mL/min (85-122) calculated by CKD-EPI, 89 mL/min (73-105) by CKD-EPIwithout race, and 90 mL/min (72-120) by Cockcroft-Gault. Black patients were recommended to receive dose reductions or were rendered ineligible to receive drug more frequently when using CKD-EPIwithout race than when using CKD-EPI, but at a similar rate as when using Cockcroft-Gault. The number of patients ineligible for therapy or recommended to receive any renal dose adjustment when CKD-EPIwithout race versus CKD-EPI was used increased by 72% (from 25 of 340 to 43 of 340 patients) for cisplatin, by 120% (from five to 11) for pemetrexed, by 67% (from three to five) for bendamustine, by 150% (from ten to 25) for capecitabine, by 150% (from ten to 25) for etoposide, by 67% (from three to five) for topotecan, by 61% (from 74 to 119) for fludarabine, and by 163% (from eight to 21) for bleomycin. Up to 18% of patients had discordant recommendations using CKD-EPIwithout race versus CKD-EPI. Removing race from the CKD-EPI equation will calculate a lower eGFR for Black patients and exclude more patients from receiving anticancer therapy, which could lead to undertreatment of Black patients with cancer and adversely affect their outcomes. National Institutes of Health.

Optimized Dosing Regimens of Meropenem in Septic Children Receiving Extracorporeal Life Support.

Objectives: To develop a population pharmacokinetic model of meropenem in children with sepsis receiving extracorporeal life support (ECLS) and optimize the dosage regimen based on investigating the probability of target attainment (PTA).Methods: The children with sepsis were prospectively enrolled in a pediatric intensive care unit from January 2018 to December 2019. The concentration-time data were fitted using nonlinear mixed effect model approach by NONMEM program. The stochastic simulation considering various scenarios based on proposed population pharmacokinetics model were conducted, and the PTAs were calculated to optimize the dosage regimens.Results: A total of 25 children with sepsis were enrolled, of whom13 received ECMO, 9 received CRRT, and 4 received ECMO combined with CRRT. 12 children received a two-step 3-h infusion and 13 children received 1-h infusion. Bodyweight and creatinine clearance had significant impacts on the PK parameters. ECMO intervention was not related to the PK properties. If 100%T > MIC was chosen as target, children receiving 40 mg/kg q8h over a 3 h-infusion only reached the PTA up to 77.4%. If bacteria with MIC 2 mg/L were to be treated with meropenem and the PTA target was 50%T > MIC, a dose of 40 mg/kg q8h for 1 h infusion would be necessary.Conclusions: The PK properties of meropenem in septic children receiving extracorporeal life support were best described. We recommended the opitimized dosing regimens for septic children receiving ECLS depending on the PTA of PK target 50%T > MIC and 100%T > MIC, for children with sepsis during ECLS with different body weight, estimated creatinine clearance (eCRCL) and MIC of bacteria.

Acute kidney injury after the arterial switch operation: incidence, risk factors, and outcomes.

The aim of this retrospective cohort study was to determine the incidence, potential risk factors, characteristics, and outcomes of acute kidney injury in children following the arterial switch operation for transposition of the great arteries. Retrospective review of children who underwent ASO between 2000 and 2020 in our tertiary children's hospital in the Netherlands. Pre-and post-ASO serum creatinine levels were collected. Severe AKI was defined as 100% serum creatinine rise or estimated creatinine clearance <35ml/min/1.73m2 according to pRIFLE criteria. Logistic regression was used to adjust for confounders. A total of 242 children were included. Fifty-seven (24%) children developed severe AKI after ASO. Four patients with severe AKI were treated with renal replacement therapy. Children with severe AKI had a longer duration of mechanical ventilation 4.5 (1.0-29) versus 3 (1.0-12) days (p = 0.001), longer PICU stay 7 (2-76) versus 5 (1-70) days, (p = 0.001), higher rate of myocardial infarction 5% versus 0.5% (p = 0.001), sepsis 24% versus 9% (p = 0.002), post-operative pulmonary hypertension 19% versus 6% (p = 0.002), post-operative bleeding 9% versus 3% (p = 0.044), longer time to sternal closure 3 (1-19) versus 2 (1-6) days, (p = 0.009), and a higher mortality rate 9.0% versus 0.5% (p = 0.001) compared to children without severe AKI. Sepsis was a risk factor for developing severe AKI. In this single-centre cohort, 24% of our patients developed severe AKI after ASO, which is associated with increased morbidity, longer PICU stay, and higher mortality.

Prevalence and Associated Risk Factors of Hypertension in Adults with Disabilities: A Cross-Sectional Study in Shanghai, China.

BackgroundAlthough hypertension is highly prevalent in China, epidemiologic data of hypertension among people with disabilities remain largely unknown. This study aims to examine the prevalence and associated risk factors of hypertension in patients with disabilities.MethodsA cross-sectional study was carried out among 7348 adults with disabilities from February to December 2018 in Shanghai, and patient data from physical, imageological and routine blood examinations were collected and analyzed. Logistic regression models were performed to determine the associated risk factors of hypertension in adults with disabilities.ResultsAmong the 7348 disabled patients, the prevalence of hypertension, rate of receiving treatment, and blood pressure control were 42.5%, 85.0% and 46.0%, respectively. Increases in the levels of age, physical disability, body mass index (BMI), fasting plasma glucose (FBG), total triglyceride (TG), hyperuricemia (hyper-UA), serum urea (SU), and estimated creatinine clearance (eCrCl <80 μmol/L) were independently correlated with hypertension.ConclusionPatients with physical disabilities have a significantly higher prevalence of hypertension compared to the normal population. Patients with intellectual or mental disabilities have lower rates of blood pressure control compared to other types of disabilities. Assessment of associated risk factors highlights an increased likelihood of potential renal dysfunction among hypertensive disabled patients.

Combination Therapy of Chloramphenicol and Daptomycin for the Treatment of Infective Endocarditis Secondary to Multidrug Resistant Enterococcus faecium.

A 38-years-old female with an aortic valve replacement presented to an outside hospital (OSH) with fevers and malaise. Blood cultures revealed VRE which was resistant to linezolid, resistant to ampicillin, non-susceptible to daptomycin (MIC of 8 mcg/mL), and exhibited susceptibility to gentamicin. The patient was therefore initiated on intravenous (IV) daptomycin 6 mg/kg q24h and gentamicin IV 1 mg/kg q8h. However, after 14 days of therapy with daptomycin and gentamicin, the patient was transferred to our institution for the management of cardiogenic shock and hypoxemic respiratory failure. Given the concern for treatment failure, her antimicrobial regimen was changed to IV chloramphenicol 12.5 mg/kg every 6 hours with IV daptomycin 10 mg/kg every 48 hours given an estimated creatinine clearance of 30 mL/minutes. In vitro susceptibilities for chloramphenicol were performed which confirmed susceptibility. A transesophageal echocardiogram revealed a possible abscess at the left coronary cusp and aortic valve dehiscence. The patient underwent aortic valve replacement with aortic root reconstruction. The aortic valve culture grew VRE susceptible to linezolid but resistant to ampicillin and doxycycline. The patient was deemed clinically cured after 42 days of combination therapy with daptomycin and chloramphenicol. After 6 years of follow-up, the patient has not had a recurrent VRE infection. To our knowledge, this is the first case of endocarditis secondary to VRE that was successfully managed with the combination of daptomycin and chloramphenicol.

Higher neutrophil-to-lymphocyte ratio after the first cycle of the first-line chemotherapy is associated with poor cancer specific survival of upper urinary tract carcinoma patients.

BackgroundInflammatory cytokines and immature myeloid derived suppressor cells (MDSCs), which increase during cancer progression, could lead to a neutrophil increase and lymphocyte reduction. Thus, the neutrophil-lymphocyte ratio (NLR) was used to predict survival of patients suffering from urological cancers including upper urinary tract carcinoma. We further determined whether the NLR during the first cycle of first-line chemotherapy could predict cancer specific survival.MethodsWe recruited patients with locally advanced or metastatic upper urinary tract urothelial carcinoma (UTUC) who received chemotherapy between January 2014 and July 2019. We investigated the impact of various clinical variables, including age, sex, performance status, and estimated creatinine clearance (CCr), and NLR before and after the first cycle of the first-line chemotherapy on prognosis.ResultsA total of 41 patients were included in our study. Cancer specific survival of the patients with lower NLR was significantly better than that of the patients with higher NLR measured after the first cycle of the first-line chemotherapy (log-rank test P=0.005, median 29.2 vs. 11.9 months, respectively). Cox proportional regression analysis showed that higher NLR after the first cycle of the first-line chemotherapy was a significant predictor of cancer specific survival.ConclusionsThe NLR after the first cycle of the first-line chemotherapy could be an indication for patients with locally advanced or metastatic UTUC to maintain their first-line chemotherapy treatment.

Exploring the Clinical Utility of Renal Safety Biomarkers during Iron Chelation Therapy in Patients with β-Thalassemia and Other Anemias

Background: Close monitoring of renal function is recommended before and during treatment with the iron chelators deferasirox and deferoxamine (DFO), by assessment of serum creatinine (SCr) and estimated creatinine clearance. To identify patients at increased risk for acute kidney injury while on therapy, efforts are focused on protein biomarkers to predict changes in renal function before SCr increases and to understand the pathophysiology involved. Alpha-1 microglobulin (alpha1M), beta-2 microglobulin (beta2M), retinol-binding protein (RBP), and (urinary) cystatin C increases may reflect proximal tubular dysfunction. Changes in kidney injury molecule-1 (KIM-1), lipocalin-2 (also called NGAL), N-acetyl-beta-glucosaminidase (NAG), clusterin, osteopontin, and tissue inhibitor of metalloproteinase-1 (TIMP-1) may reflect localized pathological processes in the renal nephron. KIM-1 is upregulated dramatically upon epithelial injury and is specific for the proximal tubule. Urinary total protein, microalbumin, and immunoglobulin G (IgG) may reflect either glomerular or tubular injury. The current exploratory analysis assessed 19 renal protein biomarkers as early indicators for an increased risk of acute renal dysfunction in chelated, transfusion-dependent patients with β-thal or other anemias. Objectives were to explore: 1) changes in biomarker profiles over time; 2) correlations between baseline biomarker levels and changes in SCr during treatment; 3) the correlation of changes in biomarker levels with changes in SCr during treatment; 4) correlations between early biomarker changes during treatment with subsequent changes in serum creatinine.Methods: Archived urine samples collected at baseline and every 3-6 months during two deferasirox clinical trials (comparative 1-year 107 study of β-thal patients randomized to deferasirox or DFO; non-comparative 2-year 108 study including β-thal or other anemia [MDS, DBA, rare anemias] patients, excluding SCD) were used. All patients enrolled were aged ≥2 years, received at least 8 blood transfusions/year, and had LIC ≥2 mg Fe/g dw. No patient had baseline SCr >upper limit normal. Patients at risk of acute renal dysfunction were defined as having SCr increased >33% from baseline on ≥2 consecutive visits during the trials. ROC curves were generated by treatment and by underlying disease to determine whether urinary renal markers at baseline (pre-treatment) or change from baseline could predict an increased risk of acute renal dysfunction.Results: 586 β-thal patient samples were assessed from the comparative trial (n=296 deferasirox, n=290 DFO) and 184 from the non-comparative trial (n=85 β-thal; n=99 other non-β-thal anemias [MDS, n=47; DBA, n=30; other rare anemias, n=22]). No significant progressive changes in any renal biomarkers were observed; including acute renal injury (KIM-1, NGAL) and inflammatory (clusterin, osteopontin) biomarkers. Biomarker levels at baseline showed little/no correlation with changes in SCr. Area under the ROC curve (AUC) values were 0.45-0.60, suggesting limited predictive value for urinary renal biomarkers at baseline (pre-treatment) to predict an increased risk of acute renal dysfunction (1.0 = a perfect test, 0.5 = no better than a random test). Weak, though consistent positive correlations were identified between logged fold-change from baseline for biomarkers of renal protein reabsorption and glomerular filtration (alpha1M, beta2M, RBP, microalbumin, total protein, IgG) versus relative change in SCr from baseline over time (r=0.1-0.3) across patient groups. Better associations were identified in non-β-thal patients. Confirmed increase in SCr had the most association with RBP (Fig 1A) and beta2M (Fig 1B) in deferasirox- and DFO-treated patients, respectively. In the non-comparative trial, AUC values were 0.4-0.6 for β-thal patients; most association with NGAL (Fig 1C). In patients with other anemias, nine renal biomarkers had AUCs >0.6; most association with alpha1M (Fig 1D).Conclusions: Without definitive associations with SCr, findings do not support the clinical utility of any of the 19 renal protein biomarkers assessed for monitoring kidney function. The absence of progressive renal biomarker changes at the population level indicates that chelation therapy with deferasirox or DFO did not lead to acute/chronic or progressive renal dysfunction in these studies. [Display omitted] DisclosuresCappellini:Vifor: Honoraria; Celgene: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding, Speakers Bureau; Novartis: Speakers Bureau. Quebe-Fehling:Novartis: Employment. Dieterle:Novartis: Employment. Porter:Bluebird Bio: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celegene: Consultancy.

Data of Real-Life Anticoagulant Treatment in Patients Diagnosed with Nonvalvular Atrial Fibrillation and Secondary Prevention of Venous Thromboembolic Disease with Edoxaban: Experience in Our Center

INTRODUCTIONAtrial fibrillation (AF) is one the most common disturbance of cardiac rhythm in adults and it is a major healthcare problem as it is associated with the risk of ischemic stroke. The prevalence of AF is estimated to affect at least 1% of the population in developed countries. In patients with AF, the risk of stroke is higher, according to the stroke risk stratification schemes CHADS2 and CHA2DS2-VASc. Oral anticoagulation therapy is a well-established treatment to prevent strokes in patients with AF who are at moderate to high risk of stroke, and the non-vitamin K antagonist oral anticoagulants have been recommended as alternatives to warfarin for stroke prevention in patients with non-valvular atrial fibrillation (NVAF) in various treatment guidelines.Edoxaban (Lixiana®, Daiichi-Sankyo) is an oral, reversible, direct factor Xa inhibitor with a linear and predictable pharmacokinetic. The edoxaban dose regimen consisted of 60 mg/24h, that was reduced to 30 mg/24h for estimated creatinine clearance of 15-50mL/min, body weight <60 kg or concomitant use of potent P-glycoprotein inhibitors. It was found not to be inferior to warfarin for prevention of stroke or systemic embolic events (SEE) in patients with AF and to reduce major bleeding, including a signicant reduction of intracranial haemorrhage and cardiovascular death.OBJECTIVEThe primary objective of the study is to evaluate the efficacy of Edoxaban in the prevention of stroke and Embolism Systemic. Besides, the secondary objective is to assess its safety, in function of the major bleeding defined according to the criteria of the International Society of Thrombosis and Hemostasis (ISTH).METHODSThis is a descriptive study. We have included a total of 102 patients with NVAF and venous thromboembolic disease (TED). The indication for anticoagulation was NVFA with 97 cases and 5 patients for secondary prevention of TED.The risk of stroke is assessed according to the scale CHA2DS2-VASc (average 3,83). Figure 1.We also evaluated the risk of bleeding according to the scale HAS-BLED (average 2.85). Figure 2.We have included 85 cases with doses of 60 mg/24h and 17 cases at a dose of 30 mg/24h. According to sex, it was about 56 women and 46 men, aged between 51 and 88 years old (average 72.2).All patients had received prior treatment with Anti-Vitamin K (AVK). The main reason of suspension of Anti-Vitamin K and its replacement with Edoxaban was because therapeutic time in range (TTR) was <65% (88 patients) and bleeding diathesis caused by anti-vitamin K (AVK) (14 patients). Of the patients included, 18 had presented previous stroke under treatment with AVK.We have evaluated complications in both bleeding and thrombosis during the treatment.The treatment time has been between 1 and 6 months (average of 4 months). Figure 3.RESULTSIt has not been reported any case of Stroke, Systemic Embolism, or Major Bleeding (criteria of ISTH) during the follow-up time of the patients treated.The only complications described were:- 1 case of small bruise on the thigh in a patient treated at a dose of 60 mg/24h. In the follow-up visit we performed a new evaluation of the Creatinine Clearance and we found that the figures were 44 ml/min, which was reduced at the dose of 30 mg/24h, as indicated in the Technical Data Sheet.- 1 patient attended the emergency department due to Delirium, which, after ruling out pathology-related (stroke, ischaemic or haemorrhagic, and TED by means of the relevant studies), or cause-effect relationship with the drug continued with the treatment with Edoxaban.- 1 patient presented self-limited Hemoptysis that did not require suspension of the treatment.During the study, a patient was diagnosed with lung cancer and the anticoagulant treatment was suspended. The patient died later by this oncology pathology.CONCLUSIONThe results obtained confirm the efficacy and safety of using Edoxaban in the prevention of stroke in the NVAF and in the few cases of TED.This is a small sample and with a short time of follow-up, due to the fact that the drug was approved in our country a few months ago.Our experience support the results of the trials. We believe that there is a good alternative to oral anticoagulation in patients with NVAF, being effective in the prevention of stroke and Systemic Embolism. It has a good safety profile with a clinical net benefit mainly at the expense of absence of bleeding.Subsequent studies will provide data confirmation. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

MO199DENOSUMAB: NOVEL APPROACH TO TREATMENT OF OSTEOPOROSIS IN RENAL DISEASE

Abstract Background and Aims Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor kappa-B ligand (RANKL), an osteoclast differentiating factor. It inhibits osteoclast formation, decrease bone resorption, increase bone mineral density (BMD), and reduce the risk of fracture. There is no restriction of its use in patients with renal disease, for whom biphosphonates are considered controindicated. The aim of our study was to evaluate the effectiveness in reducing facture risk and safety of Denosumab in patients with Osteoporosis and renal disease. Method This is a prospective analysis of 17 patients with Osteoporosis (average T-score below -2.5) admitted to our Nephrology Department for CKD in the last four years. in Vasculitis, Renal Allograft Recipients. Patients with severe Hyperparatiroidism were excluded. We estimated creatinine clearance (eGFR) using Cockcroft-Gault and classified levels of kidney function using the modified National Kidney Foundation classification of CKD. All patients were adequately supplemented with calcium and vitamin D before and while taking Denosumab 60 mg every 6 months. The primary endpoint is the change in bone mineral density (BMD) at one and two years. Secondary endpoints include changes in bone mineral metabolism parameters (Ca, P, PTHi, 25-OH VitD), incidence of fractures, and renal/allograft fuction at one and two years. Results The mean age was 52.5±4 years and 8/17 (47%) were females. N.13 patients (76.5%) were renal transplant recipients (RTR) on standard triple immunosoppression including steroids (prednisone 5 mg/day), CNI and MMF, with average eGFR 65.7±12.5 ml/min. N.2 patients (11.75%) were in hemodialysis. N.2 patients (11.75%) with Anca Vasculitis on steroid therapy and average eGFR 35.6±7.2 ml/min. All patients enrolled were with a BMD T-score of greater than -4.0 and less than -2.5. Only 2 patients had a history of fractures confirmed by a radiology report. Baseline parameters: calcium 9.8±0.32 mg/dl, phosphate 3.9±0.8 mg/dl, PTHi 137±91.0 ng/L, 25-OH VitD 18.3±8.9 ng/mL. From baseline at 1 month there were an increase in PTH and a decrease in calcemia in only 2 transplant recipients (CKD II and IV), that improved with an increased dose of Vit D. There were no significant difference in baseline bone mineral metabolism parameters to year 1 and 2 in all other patients. We found no difference in eGFR and proteinuria from baseline to 1 and 2 years in RTR and ANCA vasculitis. Significant improvement in T-score was observed at 1 year and 2 years (&amp;lt; -1) in all patients. No one discontinued therapy for adverse events. Conclusion Denosumab may have advantages in patients with kidney dysfunction, because not excreted by the kidney and there is no need for dose adjustment. This prospective study showed a significant improvement in osteoporosis (at Dexa mean T-score ≤ -1), but particular attention should be paid to ensuring that patients are calcium and Vitamin D replete.

Correlation of Estimated Creatinine Clearance and Glomerular Filtration Rate in Very Elderly Patients and Antibiotic Prescribing Errors: Cohort Study.

Determination of renal function is particularly important when prescribing antibiotics to elderly patients. This study aims to determine the correlation between estimated creatinine clearance and the estimated glomerular filtration rate, for a hospitalized population of very elderly patients, and to audit antibiotic prescribing errors. Retrospective cohort study of all patients ≥ 80 years hospitalized with antibiotic. Creatinine clearance was calculated using Cockcroft-Gault equation and estimated glomerular filtration rate by Modification of Diet in Renal Disease Study and Chronic Kidney Disease Epidemiology Collaboration equations. Dosing errors were determined through adjustment of daily define dose to renal function. The study included 589 patients. The correlation of Cockcroft-Gault with Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration was r = 0.98 and 0.96 for the minimum serum creatinine, and 0.97 and 0.93 for the maximum serum creatinine. Based on Cockcroft-Gault, there were errors in the daily defined dose in 45% in the minimum serum creatinine, and 52% in the maximum serum creatinine day. There was a discrepancy in the recording of errors of 14% to 16% when Cockcroft-Gault was compared with Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration. There was a good correlation of Cockcroft-Gault with the estimated glomerular filtration rate by Modification of Diet in Renal Disease or Chronic Kidney Disease Epidemiology Collaboration. Regardless of the equation used to estimate renal function there was a high rate of antibiotic dosing errors documented in this population. This study supports the maintenance of the Cockcroft-Gault equation for drug dosing in the very elderly population. Further studies are needed to investigate underlying causes of prescribing errors.

SUB-CLINICAL DAMAGE TO THE TARGET ORGANS (TOD) IN HYPERTENSIVE PATIENTS, ABOUT 300 PATIENTS

Objective: HTA is considered to be a silent killer. TOD is an indicator of cardiovascular risk in people with hypertension. The main objective of our study is to describe the sub-clinical TOD in hypertensive patients. Design and method: This is a descriptive study, conducted between October 2016 and October 2019. It included all asymptomatic hypertensive patients over the age of 35 of both sexes. Screening for infraclinical cardiac, vascular and renal damage is carried out with; the evaluation of the left ventricular hypertrophy (LVH) ultrasound and electric. Intima media thickness measurement by 2D carotid ultrasound and screening and evaluation of plaques. The measurement of pulsed pressure. Measuring the ABI for obliterating arterial disease. And finally, the estimate of urinary albumin excretion (UEA) and creatinine clearance according to MDRD. Results: 300 patients included in our series, these are 120 men and 180 women. The average age is 59.75 years. The prevalence of TOD is estimated at 72.3%, the prevalence of electrical LVH is 17.3%, the ultrasound LVH is 29%. Carotid hypertrophy is observed in 34.9% and the presence of stenotic plaques affect 9.1% of patients AOMI is found in 9%. Pathological pulsed pressure is found in 34.3%. UAE is pathological in 23.30% of our patients for A2 and 5.7% for A3. The creatinine clearance is less than 60 ml / min in 11%. The main independent risk factors associated with TOD are the value of SBP and Age. Pulse pressure&gt; 60 mmHg is associated with all TOD and the IMT is correlated with all screening tests for TOD. The SCORE score is predictive only for carotid lesions, it is not predictive for LVH or albuminuria. The SCORE score is not very predictive for AOMI and renal failure. Conclusions: Subclinical TOD is frequent in our series. The major modifiable independent risk factor is the value of SBP. Special attention to pulse pressure as a cardiovascular risk factor and marker of arterial stiffness A strategy for screening for target organ damage coupled with effective therapy targeting SBP is the only way to prevent cardiovascular, neurovascular and renal complications.

POS-475 GRANULOMATOUS INTERTITIAL NEPHRITIS : A SERIE OF FIVE PATIENTS

Granulomatous interstitial nephritis (GIN) is a rare histologic diagnosis.The cause is often difficult to establish and the studies are limited.This serie reported the presenting features, associated conditions, treatment, and outcomes of patients with a diagnosis of GIN. From 2005 to 2020 , we analysed cases of acute intertitial nephritis in the departement of nephrology of Fatouma Bourguiba Monastir University Hospital. From 17 cases of acute intertitial glomerulonephritis, five patients had granulomatous interstitial nephritis : three cases were associated with sarcoidosis, two were idiopathic. All the patients were femele.The median age of patients was 57 years [34- 77 years]. All patients presented with advanced renal failure (median estimated creatinine clearance 9 ml/min) and minimal proteinuria ( the mean was 0.9 g/day ) without hematuria. Hypercalcemia was present in 2 patients. Pulmonary involvement was present in one case, uveitis and pancreatitis were identified respectively in two cases and one case. Renal biopsy revealed granulomatous interstitial nephritis lesions in all patients. Corticosteroid therapy using prednisolone 1 mg/kg per day was used in all patients. Two patients had methylprednisolone pulse before oral corticosteroid therapy. MMF was associated with corticosteroids in one case. All patients improved their renal function. The median estimated creatinine clearance was 25 ml/min after 6 months. Two patients had normalized their renal fonction. Granulomatous interstitial nephritis may be the first manifestation of a systemic disease . Histologic features do not seem to distinguish the underlying cause of GIN. Corticosteroids therapy seems to be efficient and must be introduced early to prevent progression to chronic renal failure and it is associated with a good prognosis.

Rosuvastatin Myotoxicity After Starting Canagliflozin Treatment.

TO THE EDITOR: Brailovski and colleagues (1) attributed their patient's rosuvastatin-induced myotoxicity to a possible rosuvastatin–canagliflozin interaction. The assumed interaction was based on known and speculated factors. The known factors include the roles of organic anion-transporting polypeptides (OATPs) 1B1 and 1B3 in facilitating rosuvastatin uptake into hepatocytes and breast cancer resistance protein (BCRP) in facilitating its intestinal absorption and biliary/renal elimination. Subsequent speculation was that rosuvastatin accumulation resulted from inhibition of the OATPs and BCRP by canagliflozin. However, this speculation is not supported by the cited study. Canagliflozin had less than 50% in vitro inhibition of OATP1B1 and OATP1B3, and canagliflozin in vivo inhibition of the uptake transporters was determined not to be expected according to basic models. Moreover, canagliflozin was not found to be an inhibitor of BCRP at the highest feasible concentration in the used assay (2). We believe that the development of rhabdomyolysis in this case was multifactorial and involved patient and drug characteristics. Patients of Asian descent have been shown to have an approximately 2-fold increase in rosuvastatin exposure compared with White patients at similar doses. Hence, a rosuvastatin dosage of 40 mg/d is contraindicated in Asian patients in Canadian prescribing information (3). Furthermore, this patient's pharmacogenetic testing showed a c421 C>A polymorphism in the ABCG2 gene encoding for BCRP; this could have played a role in this patient's rosuvastatin-altered pharmacokinetics. The baseline plasma rosuvastatin level at which patients can tolerate this medication varies widely on the basis of clinical and pharmacogenetic predictors (4). Change in renal function after canagliflozin initiation also should be considered. In the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial, canagliflozin initiation was associated with an initial short-term reduction in estimated glomerular filtration rate (5). This patient's chronic kidney disease (stage 3B) at baseline predisposed her to a decrease in estimated creatinine clearance to less than 30 mL/min/1.73 m2 after canagliflozin initiation and a potential 3-fold increase in rosuvastatin exposure. The rosuvastatin dosage should not have exceeded 10 mg/d per dosing recommendations (3). In summary, a more plausible explanation for this patient's development of rhabdomyolysis is short-term worsening of renal function secondary to canagliflozin initiation in addition to her predisposing factors (that is, Asian descent, receipt of a rosuvastatin dosage of 40 mg/d, advanced age [76 years], and stage 3B chronic kidney disease) that resulted in rosuvastatin accumulation, subsequent rhabdomyolysis, and associated hepatic injury. Nevertheless, this case remains valuable because it highlights the importance of considering an initial decrease in renal function with canagliflozin, especially in patients with chronic kidney disease. Close monitoring and appropriate dose adjustments are warranted in such patients.

A Novel Creatinine-Based Equation to Estimate Glomerular Filtration Rate in Chinese Population With Chronic Kidney Disease: Implications for DOACs Dosing in Atrial Fibrillation Patients.

Background: Over/under-estimating renal function may increase inappropriate dosing strategy associated adverse outcomes; however, previously reported equations to estimate renal function have limited accuracy in chronic kidney disease (CKD) patients. Consequently, we intended to develop a novel equation to precisely estimate renal function and subsequently guide clinical treatment for CKD patients. Methods: A novel approach, Xiangya-s equation, to estimate renal function for CKD patients was derived by linear regression analysis and validated in 1885 patients with measured glomerular filtration rate (mGFR) < 60 ml/min/1.73 m2 by renal dynamic imaging at three representative hospitals in China, with the performance evaluated by accuracy, bias and precision. In the meanwhile, 2,165 atrial fibrillation (AF) patients who initiated direct oral anticoagulants (DOACs) between December 2015 and December 2018 were identified and renal function was assessed by estimated creatinine clearance (eCrCl). Events per 100 patient-years was calculated. Cox proportional hazards regression was applied to compare the incidence of outcomes of each group. Results: Xiangya-s equation demonstrated higher accuracy, lower bias and improved precision when compared with 12 creatinine-based and 2 CysC-based reported equations to estimate GFR in multi-ethnic Chinese CKD patients. When we applied Xiangya-s equation to patients with AF and CKD prescribed DOACs, wide variability was discovered in eCrCl calculated by the Cockcroft-Gault (CG), Modification of Diet in Renal Disease Study (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Xiangya equation which we had developed for generally patients and Xiangya-s equations, which persisted after grouping by different renal function stages. Equation choice affected drug-dosing adjustments, with the formulas agreeing for only 1.19%, 5.52%, 33.22%, 26.32%, and 36.61% of potentially impacted patients for eCrCl cutoffs of <15, <30, 15–49, 30–49, ≥50 ml/min, respectively. Relative to CG equation, accordance in DOACs dosage was 81.08%, 88.54%, 62.25%, and 47.68% for MDRD, CKD-EPI, Xiangya and Xiangya-s equations for patients with CrCl < 50 ml/min (eCrCl cutoffs of <30, 30–49, ≥50 ml/min), respectively. Reclassification of renal function stages by Xiangya-s equation was significantly associated with stroke or systemic embolism, non-major clinically relevant bleeding and any bleeding events. Conclusion: Xiangya-s equation provides more accurate GFR estimates in Chinese CKD patients who need consecutive monitoring of renal function, which may assist clinicians in choosing appropriate drug dosages.

Outcome of Neonatal Acute Kidney Injury in a Special Care Baby Unit (SCABU)

Background: Acute kidney injury (AKI) is common in neonates admitted in Special Care Baby Unit (SCABU) with high morbidity and mortality.&#x0D; Objective: The present study was intended to see the immediate hospital outcome of neonatal acute kidney injury (AKI) in a Special Care Baby Unit (SCABU).&#x0D; Methods: This observational study was carried out in SCABU, in the Department of Paediatrics, Dhaka Medical College Hospital, from October 2013 to March 2014. A total of 44 neonates (from 3-28 days) with AKI were included in this study. AKI staging was done by using pediatric RIFLE criteria as Risk, Injury, Failure. Patients were managed conservatively and immediate hospital outcome was assessed by SCABU stay, multiorgan failure, resolution of AKI, mortality and dialysis as needed.&#x0D; Results: Demographic profile among the study population the neonate of d”7 days old comprised the main bulk. Majority of the neonates were of average birth weight. The diagnosis was based on estimated creatinine clearance(eCCL) criteria of pRIFLE showed that 40.9% neonates were at risk of AKI, 20.5% have had already injured. Higher proportions of neonates were classified as failure (38.6%).Outcome variables of neonatal AKI predicted by pRIFLE criteria was significantly higher in failure group in respect to SCABU stay (12.1+ 7.9) p value &lt; 0.001, multiorgan failure (41.2 %) p value 0.026 and dialysis needed (88.2 %) p value &lt; 0.001, resolution from AKI (47.1%) p value 0.885, Mortality (41.2%) p value 0.106. Here 43% neonates with AKI were improved with normal renal function and 29% improved with impaired renal function. Increased frequency of death (28%) in this series was due to multiorgan involvement and significantly higher in failure group with adequate dialysis support.&#x0D; Conclusion: From the findings of the study it can be concluded that immediate hospital outcome of neonatal AKI is worst even after adequate dialysis support. Multiorgan involvements, increase length of hospital stay at SCABU, increase need for dialysis, are the important cause of increase mortality and morbidity. So, early detection, prompt referral and immediate supportive therapy could improve the outcome of neonatal AKI.&#x0D; DS (Child) H J 2018; 34(1) : 5-10