Higher CrCl Research Articles

Renal function and its impact on the concentration of ceftazidime-avibactam: A cross-sectional study

ObjectiveThis study measured the effect of renal function on the plasma concentrations of ceftazidime and avibactam in critically ill patients. We also sought to measure the concentration ratio of ceftazidime to avibactam. MethodsThis was a cohort study at a tertiary referral centre in Italy, on patients treated with continuous infusion of ceftazidime-avibactam (CAZ-AVI) between November 2019 and December 2023. The association between creatine clearance (CrCl) and free plasma ceftazidime and avibactam concentration, as well as CAZ-AVI ratio was explored to assess correlation and potential risk to fail to achieve target therapeutic concentration. ResultsFifty-two patients, predominantly male (75%), with a median age of 68.5 y were included. Our analyses provided strong evidence for inverse correlation between CrCl and both free-CAZ (r = -0.627; R2 = 0.3936; P < 0.001) and free-AVI plasma concentration (r = -0.619; R2 = 0.3832; P < 0.001). Overall CrCl alone could explain about 40% of overall variation of either free-CAZ and free-AVI. Linear models suggest that free-CAZ and free-AVI concentration drop of about 7.31% and 9.23% for each 10 point increase of CrCl, respectively. Assessment of the CAZ-AVI ratio supports a direct linear association with CrCl suggesting that free-AVI concentration is more affected by CrCl variation than free-CAZ concentration. Patients with CrCl ≥130 mL/min showed a significantly higher risk of suboptimal drug exposure (i.e., less than 4 times the MIC) both to CAZ and AVI. ConclusionThe findings emphasise the need for individualised dosing strategies of CAZ-AVI based on renal function, for antibiotics used in critically ill patients. The study suggests that underdosing in patients with high CrCl is likely to be common and as such could affect drug effectiveness.

Abstract 15692: Clinical Outcomes in TAVR Patients Receiving Oral Anticoagulation Stratified by Baseline Creatinine Clearance Levels: A Subanalysis of the ENVISAGE-TAVI AF Trial

Introduction: The ENVISAGE-TAVI AF (NCT02943785) trial compared edoxaban (EDO) vs vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) after successful transcatheter aortic valve replacement (TAVR). The effect of baseline creatinine clearance (CrCl) on efficacy and safety of EDO vs VKA in these patients is not well understood. Hypothesis: The efficacy and safety of EDO vs VKA in patients with AF undergoing TAVR will vary across the range of baseline CrCl. Methods: In this post-hoc analysis from the ENVISAGE-TAVI AF trial, we stratified patients by oral anticoagulation (OAC) strategy (EDO vs VKA) and CrCl (CrCl ≥90 mL/min, CrCl 60-89 mL/min, CrCl 45-59 mL/min, CrCl 30-44 mL/min, CrCl ≤29 mL/min). Results: Of 1426 patients included, 46.3% (n = 676) had CrCl from 60 to 89 mL/min. Patients with lower CrCl trended older in age than those with higher CrCl ( Table 1 ). The annualized event rates for all outcomes tended to increase with decreasing CrCl ( Table 2 ). Across the range of CrCl, patients receiving EDO vs VKA had higher rates of major bleeding and major gastrointestinal bleeding but lower rates of non-cardiovascular death. Major bleeding did not translate into increased all-cause death. Rates of intracranial hemorrhage were higher with EDO vs VKA in patients with CrCl ≥90 mL/min but lower in all other patients. For all-cause death, differences between EDO and VKA were numerical and did not reach statistical significance. Conclusions: In this ENVISAGE-TAVI AF subanalysis, decrements of CrCl appeared to correlate with rates of adverse outcome parameters more than OAC strategy. Due to low event rates in some outcomes, these results should be interpreted with caution.

Obesity, Hyperfiltration, and Early Kidney Damage: A New Formula for the Estimation of Creatinine Clearance.

Glomerular hyperfiltration may represent a direct pathogenetic link between obesity and kidney disease. The most widely used methods to estimate creatine clearance such as Cockroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) have not been validated in subjects with obesity. The performance of prediction formulas was compared with measured creatinine clearance (mCrCl) in subjects with obesity. The study population included 342 patients with obesity (mean BMI 47.6 kg/m2) without primary kidney disease. A urine collection was performed over 24 hours for measurement of CrCl. mCrCl increased with body weight. The CG formula showed an overestimation at high CrCl, whereas an underestimation resulted from CKD-EPI and MDRD. To improve the accuracy of estimated CrCl (eCrCl), a new CG-based formula was developed:53+0.7×(140-Age)×Weight/(96xSCr)×(0.85iffemale)A cut-off point for BMI of 32 kg/m2 was identified, at which the new formula may be applied to improve eCrCl. In patients with obesity the glomerular filtration rate increases with body weight, and it is associated with the presence of albuminuria, suggesting an early kidney injury. We propose a novel formula that improves the accuracy of eCrCl to avoid missed diagnoses of hyperfiltration in patients with obesity.

High mean arterial pressure target to improve sepsis-associated acute kidney injury in patients with prior hypertension: a feasibility study

BackgroundThe optimal mean arterial pressure (MAP) in cases of septic shock is still a matter of debate in patients with prior hypertension. An MAP between 75 and 85 mmHg can improve glomerular filtration rate (GFR) but its effect on tubular function is unknown. We assessed the effects of high MAP level on glomerular and tubular renal function in two intensive care units of a teaching hospital. Inclusion criteria were patients with a history of chronic hypertension and developing AKI in the first 24 h of septic shock. Data were collected during two 6 h periods of MAP regimen administered consecutively after haemodynamic stabilisation in an order depending on the patient's admission unit: a high-target period (80–85 mmHg) and a low-target period (65–70 mmHg). The primary endpoint was the creatinine clearance (CrCl) calculated from urine and serum samples at the end of each MAP period by the UV/P formula.Results26 patients were included. Higher urine output (+0.2 (95%:0, 0.4) mL/kg/h; P = 0.04), urine sodium (+6 (95% CI 0.2, 13) mmol/L; P = 0.04) and lower serum creatinine (− 10 (95% CI − 17, − 3) µmol/L; P = 0.03) were observed during the high-MAP period as compared to the low-MAP period, resulting in a higher CrCl (+25 (95% CI 11, 39) mL/mn; P = 0.002). The urine creatinine, urine–plasma creatinine ratio, urine osmolality, fractional excretion of sodium and urea showed no significant variation. The KDIGO stage at inclusion only interacted with serum creatinine variation and low level of sodium excretion at inclusion did not interact with these results.ConclusionsIn the early stage of sepsis-associated AKI, a high-MAP target in patients with a history of hypertension was associated with a higher CrCl, but did not affect the kidneys' ability to concentrate urine, which may reflect no effect on tubular function.

Clinical Characteristics Associated With Higher Enoxaparin Dosing Requirements for Venous Thromboembolism Prophylaxis in Trauma Patients.

Enoxaparin dosed by an anti-Xa trough level is effective at reducing venous thromboembolism (VTE) in trauma patients. We identified the patient characteristics associated with higher enoxaparin dosing based on anti-Xa trough levels. A retrospective review was conducted on trauma patients admitted between August 2014 and February 2018 who received enoxaparin dosed by the anti-Xa trough level. Patients who received enoxaparin < 50mg every 12hours were compared to those who required ≥ 50mg every 12hours. Of the 246 patients included, 32 (13.0%) required enoxaparin ≥ 50mg every 12hours to achieve the prophylactic trough level. Factors associated with a higher dose of enoxaparin were male (96.8% vs. 3.2%, P < .01), younger age (39.5 vs. 52.7years, P < .01), higher creatinine clearance (CrCl) (125.9 vs. 93.7mL/min, P < .01), higher body surface area (2m2 vs. 1.8m2, P < .01), and higher injury severity score (18.4 vs. 10.8, P < .01). Height, weight, and body mass index were not significant factors. On regression analysis, CrCl was the only independent predictor for higher enoxaparin dose. There was an increased deep venous thrombosis rate in the higher dose cohort (12.5% vs. 0, P < .01) but no significant differences in transfusion rates. Trauma patients who require higher enoxaparin doses to achieve prophylactic anti-Xa trough levels have a higher CrCl. Patients with high CrCl may benefit from an initial higher dose of enoxaparin to achieve a target anti-Xa level in a shorter time interval to decrease VTE risk.

Baseline characteristics and follow-up outcomes in routine clinical practice patients categorised by renal function in the ETNA-AF-Europe registry

Abstract Background Edoxaban is an oral factor Xa inhibitor anticoagulant with 50% renal clearance, and proven efficacy and safety in patients (pts) with atrial fibrillation (AF). The post-authorisation, observational, ETNA-AF-Europe registry (NCT02944019) assessed the risks and benefits of edoxaban in pts with AF from 10 European countries. Purpose Evaluate baseline characteristics and event rates in pts categorised by creatinine clearance (CrCl) at 1-year follow-up of the ETNA-AF-Europe registry. Methods In this analysis, pts were divided into three groups according to CrCl: ≤50 ml/min (I), 50–80 mL/min (II) and ≥80 mL/min (III) (calculated using Cockcroft-Gault). Outcomes were descriptively analysed. Results Pts with the lowest CrCl (Group I) were mostly females, and had a higher mean age, lower body weight, higher stroke and bleeding risk scores and were considered more frail than those with higher CrCl (Groups II and III) (Table). Group I experienced higher rates of stroke or SEE, major or CRNM bleeding, cardiovascular death, and had a higher total mortality (Figure). Rates of intracranial haemorrhage (ICH) and haemorrhagic stroke (intracerebral and subarachnoid haemorrhage) were low and similar in pts across the range of CrCl. Conclusions Those with lower CrCl had more comorbidities and higher event rates than those with higher CrCl, with the exception of ICH and haemorrhagic stroke. A steep rise in the proportion of pts perceived as frail and in overall mortality in the lowest renal function tertile, raises the question whether low renal function is a determinant or a correlate of mortality. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Daiichi Sankyo Europe GmbH, Munich, Germany

Low Pre-Treatment Hemoglobin and Creatinine Clearance Correlate with Worse Overall Survival, Treatment-Related Mortality, and Regimen-Related Toxicities in Patients Undergoing a Reduced-Intensity Allogeneic Stem Cell Transplantation with Fludarabine and Melphalan

The reduced-intensity conditioning (RIC) regimen consisting of fludarabine and melphalan 140 mg/m2 (Flu/Mel140) prior to allogeneic hematopoietic stem cell transplant (HSCT) has been widely adopted in clinical practice. However, pharmacokinetic (PK) studies report up to a 10-fold interpatient variability in melphalan exposure (AUC). Specifically, melphalan binds to proteins in the red blood cell membrane, leading to higher plasma concentrations in patients with lower hemoglobin. Likewise, since renal elimination contributes significantly to melphalan clearance (~ 40%), the presence of renal impairment also leads to higher concentrations. We previously identified lower hemoglobin and/or creatinine clearance as strong predictors of survival and toxicities after high dose melphalan and autologous transplant. Given this, we hypothesized that clinical variables, in particular, pre-treatment hemoglobin, could predict for outcomes after Flu/Mel140 and HSCT. We analyzed 67 consecutive patients who received Flu/Mel140. In addition to standard clinical parameters, hemoglobin (Hgb) and creatinine clearance (CrCl) on day -6 were obtained. Hemoglobin was grouped as low or high relative to the median (&lt;9.5 or ≥ 9.5 g/dL), and CrCl was divided into two groups (&lt; 60 or ≥ 60 ml/min). In the entire cohort, the median age was 57 (21-73) years, with most patients being female (n=37; 55.2%) and white (n=27; 40.3%) or African-American (n=16; 23.9%). Most patients were diagnosed with AML/MDS (n=27; 40.3%) or idiopathic myelofibrosis (n=14; 20.9%), and the median lines of prior therapy was 2 (0-7). Prior to HSCT, 36 (53.7%) patients presented with intermediate disease risk index (DRI) and 19 (28.4%) with high DRI, while 31 (62%) patients had a high hematopoietic cell transplantation-specific comorbidity index (HCT-CI) score. Thirty (45.5%) patients received a matched related donor transplant, while 31 (47%) received a matched unrelated donor transplant. The median time to neutrophil and platelet engraftment was 15 (9-26) and 16 (8-104) days, respectively. The median overall survival (OS) was significantly shorter in patients with a lower Hgb (113 vs. 2536 days; p=0.004). This difference was attributed to an increased rate of transplant-related mortality (TRM) in patients with a lower Hgb (n=26; 81.3%) versus a higher Hgb (n=11; 36.7%) (p=0.0005). Time to relapse between patients with a lower and higher Hgb was not different (p=0.89). The median OS in patients with a lower CrCl was significantly worse (75 vs. 317 days; p=0.003). The rate of TRM was also found to be significantly worse in patients with a lower CrCl (n=10; 90.1%) compared to patients with a higher CrCl (n=27; 52.9%) (p=0.0023). Time to relapse was not different between patients with a lower and higher Cr Cl (p=0.29). Patients with both a low Hgb and CrCl experienced a shorter median OS (75 days vs. not reached; p&lt;0.0001; Figure 1). Multivariate Cox proportional hazards model with adjustment for clinical and prognostic factors found that a higher Hgb strongly predicted for better OS (HR 0.12, 95% CI 0.03-0.52; p=0.004) and less TRM (HR 0.13, 95% CI 0.03-0.53; p=0.004). The combination of a higher Hgb and CrCl ≥ 60 ml/min predicted for better OS (HR 0.08, 95% CI 0.01-0.63; p=0.017) and trended towards a decreased rate of TRM (HR 0.16, 95% CI 0.02-1.43; p=0.102). We then analyzed regimen-related toxicities among patients with a lower and higher Hgb and lower and higher CrCl. In patients with a lower hemoglobin, the median duration of hospitalization (35 vs. 29 days; p=0.02) and the mean duration of diarrhea (14.6 vs. 7.2 days; p=0.008) were significantly longer. In patients with a lower CrCl, the median duration of hospitalization (40 vs. 29 days; p=0.06) and the mean duration of diarrhea (20.9 vs. 8.6 days; p=0.0009) were longer, and the rate of infection was higher (90.9% vs. 49.1%; p=0.02). We show for the first time that pre-treatment Hgb and CrCl represent important determinants of clinical outcomes after Flu/Mel140 and HSCT. A lower hemoglobin in particular was strongly associated with a shorter OS and TRM. This is consistent with PK studies showing increased melphalan exposure in patients with low Hgb and CrCl. We conclude that consideration of clinical factors that affect melphalan exposure and implementation of PK-directed dosing may be beneficial in achieving optimal outcomes in patients receiving FluMel140 and HSCT. Figure Disclosures Galvin: Incyte: Consultancy. Patel:Celgene: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Speakers Bureau.

Therapeutic drug monitoring-guided continuous infusion of piperacillin/tazobactam significantly improves pharmacokinetic target attainment in critically ill patients: a retrospective analysis of four years of clinical experience

PurposeStandard dosing and intermittent bolus application (IB) are important risk factors for pharmacokinetic (PK) target non-attainment during empirical treatment with β-lactams in critically ill patients, particularly in those with sepsis and septic shock. We assessed the effect of therapeutic drug monitoring-guided (TDM), continuous infusion (CI) and individual dosing of piperacillin/tazobactam (PIP) on PK-target attainment in critically ill patients.MethodsThis is a retrospective, single-center analysis of a database including 484 patients [933 serum concentrations (SC)] with severe infections, sepsis and septic shock who received TDM-guided CI of PIP in the intensive care unit (ICU) of an academic teaching hospital. The PK-target was defined as a PIP SC between 33 and 64 mg/L [fT > 2–4 times the epidemiological cutoff value (ECOFF) of Pseudomonas aeruginosa (PSA)].ResultsPK-target attainment with standard dosing (initial dose) was observed in 166 patients (34.3%), whereas only 49 patients (10.1%) demonstrated target non-attainment. The minimum PK-target of ≥ 33 mg/L was overall realized in 89.9% (n = 435/484) of patients after the first PIP dose including 146 patients (30.2%) with potentially harmful SCs ≥ 100 mg/L. Subsequent TDM-guided dose adjustments significantly enhanced PK-target attainment to 280 patients (62.4%) and significantly reduced the fraction of potentially overdosed (≥ 100 mg/L) patients to 4.5% (n = 20/449). Renal replacement therapy (RRT) resulted in a relevant reduction of PIP clearance (CLPIP): no RRT CLPIP 6.8/6.3 L/h (median/IQR) [SCs n = 752, patients n = 405], continuous veno-venous hemodialysis (CVVHD) CLPIP 4.3/2.6 L/h [SCs n = 160, n = 71 patients], intermittent hemodialysis (iHD) CLPIP 2.6/2.3 L/h [SCs n = 21, n = 8 patients]). A body mass index (BMI) of > 40 kg/m2 significantly increased CLPIP 9.6/7.7 L/h [SC n = 43, n = 18 patients] in these patients. Age was significantly associated with supratherapeutic PIP concentrations (p < 0.0005), whereas high CrCL led to non-target attainment (p < 0.0005). Patients with target attainment (33–64 mg/L) within the first 24 h exhibited the lowest hospital mortality rates (13.9% [n = 23/166], p < 0.005). Those with target non-attainment demonstrated higher mortality rates (≤ 32 mg/L; 20.8% [n = 10/49] ≥ 64 mg/L; 29.4% [n = 79/269]).ConclusionTDM-guided CI of PIP is safe in critically ill patients and improves PK-target attainment. Exposure to defined PK-targets impacts patient mortality while lower and higher than intended SCs may influence the outcome of critically ill patients. Renal function and renal replacement therapy are main determinants of PK-target attainment. These results are only valid for CI of PIP and not for prolonged or intermittent bolus administration of PIP.

Identifying Clinical Predictors of Switching From Direct Oral Anticoagulants to Warfarin

Purpose: Direct oral anticoagulants (DOACs) have been shown to be as effective or superior to warfarin, but warfarin use remains constant. Knowledge regarding the patient population who have switched from a DOAC to warfarin is limited. The objective of this study was to identify clinical predictors which may influence a patient’s likelihood of switching from a DOAC to warfarin for atrial fibrillation (AF) or venous thromboembolism (VTE). Methods: In this single-center, case-control study, patients who switched from a DOAC to warfarin were compared with patients who remained on a DOAC. Baseline demographics were compared between the switch and control groups. Independent factors that increased the likelihood of switching from a DOAC to warfarin were analyzed using logistic regression. Results: A total of 150 patients were included in the control (n = 100) and switch (n = 50) groups. Patients switched from a DOAC to warfarin had more medications at baseline (9 [7, 13] vs 11 [8, 18], P = 0.009). The presence of heart failure (HF) increased the likelihood of switching (odds ratio [OR] = 3.95, confidence interval [CI] = 1.70-9.21, P = 0.002), and for every 10 mL/min increase in creatinine clearance (CrCl), the likelihood of switching decreased ( R = 0.89 [0.80-0.99], P = 0.026). Patients with pulmonary embolism (PE) were less likely to switch from a DOAC to warfarin (OR = 0.20, CI = 0.05-0.86, P = 0.031). Explicitly listed reasons for switching included left ventricular assist device (LVAD) implantation (20%) and valve replacement procedures (20%). Conclusion: Congestive HF was a clinical predictor associated with an increased likelihood of switching from a DOAC to warfarin. Anticoagulation therapy for PE and higher CrCl was associated with a decreased likelihood in switching from DOAC to warfarin.

Association of Kidney Tissue Barrier Disrupture and Renal Dysfunction in Resuscitated Murine Septic Shock.

Septic shock-related kidney failure is characterized by almost normal morphological appearance upon pathological examination. Endothelial barrier disrupture has been suggested to be of crucial importance for septic shock-induced organ dysfunction. Therefore, in murine resuscitated cecal ligation and puncture (CLP)-induced septic shock, we tested the hypothesis whether there is a direct relationship between the kidney endothelial barrier injury and renal dysfunction. Anesthetized mice underwent CLP, and 15 h later, were anesthetized again and surgically instrumented for a 5-h period of intensive care comprising lung-protective mechanical ventilation, fluid resuscitation, continuous i.v. norepinephrine to maintain target hemodynamics, and measurement of creatinine clearance (CrCl). Animals were stratified according to low or high CrCl. Nitrotyrosine formation, expression of the inducible isoform of the nitric oxide synthase, and blood cytokine (tumor necrosis factor, interleukin-6, interleukin-10) and chemokine (monocyte chemoattractant protein-1, keratinocyte-derived chemokine) levels were significantly higher in animals with low CrCl. When plotted against CrCl and neutrophil gelatinase-associated lipocalin levels, extravascular albumin accumulation, and tissue expression of the vascular endothelial growth factor and angiopoietin-1 showed significant mathematical relationships related to kidney (dys)function. Preservation of the constitutive expression of the hydrogen sulfide producing enzyme cystathione-γ-lyase was associated with maintenance of organ function. The direct quantitative relation between microvascular leakage and kidney (dys)function may provide a missing link between near-normal tissue morphology and septic shock-related renal failure, thus further highlighting the important role of vascular integrity in septic shock-related renal failure.

Therapeutic Dose Monitoring for Linezolid in a Patient with MRSA Pneumonia with Bacteremia in Diabetes Insipidus.

IntroductionFew studies have investigated the effect of increased creatinine clearance (CrCl) on linezolid (LZD) concentration. Herein, we report the pharmacokinetic/pharmacodynamic (PK/PD) profile of LZD used in the management of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia with concomitant bacteremia in a patient with high CrCl caused by diabetes insipidus (DI).Case ReportA 19-year-old man was admitted to the intensive care unit following a traumatic brain injury. After admission, he underwent a craniotomy for the severe brain injury. However, he developed DI after the operation. Despite treatment with vasopressin, his urine output reached 5–6 L/day as a result of the DI, and his CrCl increased to 180–278 mL/min. We were required to administer 6–7 L of fluid a day to compensate for the high urinary fluid output. On day 55, MRSA pneumonia with sepsis was suspected and, consequently, LZD was administrated intravenously (600 mg every 12 h). He was treated with LZD for 14 days. The patient has since successfully recovered from MRSA pneumonia with concomitant bacteremia, and was transferred to the general ward on day 82. Blood LZD levels from days 60–68, which were measured after the patient’s transfer to the general ward, showed that the trough levels were lower than the threshold level of detection. The blood 24-h area under the plasma LZD concentration–time curve (AUC)24/minimum inhibitory concentration (MIC) was 69.3.ConclusionIn spite of the low level of LZD AUC24/MIC caused by the high CrCl with DI, MRSA pneumonia with concomitant bacteremia was successfully treated with LZD.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-015-0100-z) contains supplementary material, which is available to authorized users.

The prognostic value of time needed on dialysis in patients with delayed graft function

We hypothesize that in patients with delayed graft function (DGF), the need for a longer time needed on dialysis (TND) post-kidney transplant is associated with poorer long-term function and an increase in complications. This was a retrospective chart review involving collaboration between Western University (WU) Renal Transplant Program of London, Ontario and the Saskatchewan renal transplant program (SRTP). A total of 774 patients (567 WU and 207 SRTP) received kidney transplants between 2004 and 2011, of which 83 patients with deceased donor transplants (59 WU and 24 SRTP) developed DGF, defined as the need for dialysis in the first week posttransplant. Patients with DGF were divided into three groups depending on TND [group 1: <7 days (n = 52), group 2: 7-14 days (n = 13) and group 3 (n = 18): >14 days]. The creatinine clearance (CrCl) at 30 days (42.5, 33.8, 20.0 cc/min; P < 0.001) and 1 year (56.7, 49.2, 37.3 cc/min, P = 0.031) were significantly different between the three groups. Multivariate regression analysis identified length of TND posttransplant (β = -0.5, P < 0.001) and donation after cardiac death (DCD) donor (β = 19.5, P < 0.001) as the most significant predictors of CrCl at 1 year in these patients with DGF. DCD kidneys with DGF had a higher CrCl at 1 year and fewer readmissions in the first year compared with non-DCD kidneys with DGF. Our study suggests that increased TND is associated with worse CrCl at 1 year. The data also support the hypothesis of a different mechanism for DGF in DCD and non-DCD kidneys.

High creatinine clearance in critically ill patients with community-acquired acute infectious meningitis

BackgroundA high dose of anti-infective agents is recommended when treating infectious meningitis. High creatinine clearance (CrCl) may affect the pharmacokinetic / pharmacodynamic relationships of anti-infective drugs eliminated by the kidneys. We recorded the incidence of high CrCl in intensive care unit (ICU) patients admitted with meningitis and assessed the diagnostic accuracy of two common methods used to identify high CrCl.MethodsObservational study performed in consecutive patients admitted with community-acquired acute infectious meningitis (defined by >7 white blood cells/mm3 in cerebral spinal fluid) between January 2006 and December 2009 to one medical ICU. During the first 7 days following ICU admission, CrCl was measured from 24-hr urine samples (24-hr-UV/P creatinine) and estimated according to Cockcroft-Gault formula and the simplified Modification of Diet in Renal Disease (MDRD) equation. High CrCl was defined as CrCl >140 ml/min/1.73 m2 by 24-hr-UV/P creatinine. Diagnostic accuracy was performed with ROC curves analysis.ResultsThirty two patients were included. High CrCl was present in 8 patients (25%) on ICU admission and in 15 patients (47%) during the first 7 ICU days for a median duration of 3 (1-4) days. For the Cockcroft-Gault formula, the best threshold to predict high CrCl was 101 ml/min/1.73 m2 (sensitivity: 0.96, specificity: 0.75, AUC = 0.90 ± 0.03) with a negative likelihood ratio of 0.06. For the simplified MDRD equation, the best threshold to predict high CrCl was 108 ml/min/1.73 m2 (sensitivity: 0.91, specificity: 0.80, AUC = 0.88 ± 0.03) with a negative likelihood ratio of 0.11. There was no difference between the estimated methods in the diagnostic accuracy of identifying high CrCl (p = 0.30).ConclusionsHigh CrCl is frequently observed in ICU patients admitted with community-acquired acute infectious meningitis. The estimated methods of CrCl could be used as a screening tool to identify high CrCl.

Uromodulin concentrations are not associated with incident CKD among persons with coronary artery disease.

BackgroundA common variant of the UMOD gene was linked with prevalent chronic kidney disease (CKD) in large, genomics consortia. One community-based study found that urine concentrations of the uromodulin protein forecast risk of incident CKD. This study within persons with known coronary artery disease (CAD) evaluated whether uromodulin concentrations could distinguish CKD risk.MethodsIn the Heart and Soul Study, the UMOD snp (12917707) was genotyped in 879 individuals with baseline creatinine clearance (CrCl) measured from a 24-hour urine collection. Uromodulin protein was measured from stored urine specimens among a subset of 120 participants, balanced by genotype. Incident CKD cases (N = 102) were defined by an initial CrCl > 70 ml/min and a 5-year follow-up CrCl <60 ml/min; controls (N = 94) were matched on age, sex, and race.ResultsAmong 527 self-described White participants with DNA, 373 (71%) were homozygous for the dominant allele (G/G), 133 (25%) were heterozygous (G/T) and only 21 (4%) were homozygous for the minor allele (T/T). The T/T genotype had an approximately 11 ml/min higher CrCl than the other 2 groups, but this difference did not reach statistical significance (p = 0.20). The T/T genotype had significantly lower uromodulin levels than the common G/G genotype, and the G/T genotype had intermediate levels. However, uromodulin concentrations were similar between cases and controls (44 vs. 48 mg/dL, p = 0.88).ConclusionsThis study among a cohort of persons with established CAD found no association between urine uromodulin and incident CKD, although UMOD genotype was associated with urine uromodulin concentrations.

Methotrexate (M) area under the curve (AUC) and creatinine clearance (CrCl) as prognostic factors in primary central nervous system lymphoma (PCNSL).

2040 Background: High doses of M are used in chemotherapy for PCNSL to penetrate the blood-brain barrier. However, M clearance may vary significantly among individuals, and a retrospective study suggested that lower M AUC and higher CrCl are associated with worse prognosis. This suggested that fast eliminators may require higher M doses or risk being under-treated. In this study, we seek to characterize inter-individual variability in M AUC and its prognostic implications in a prospective data set, in order to determine whether M AUC should be used to individually tailor M doses. Methods: In a phase II trial, patients with newly diagnosed PCNSL received 5-7 cycles of R-MPV-A: d1 rituximab 500 mg/m2; d2 M 3.5 mg/m2, vincristine 1.4 mg/m2; d1-7 procarbazine 100 mg/m2/d on odd-cycles. This was followed by whole-brain radiotherapy (23.4 Gy to patients in CR; 45 Gy otherwise) and consolidation Ara-C. M AUC and CrCl were calculated from cycle 1 and correlated with progression-free survival (PFS). A subset of this trial has been reported (Shah, JCO 2007). Univariate Cox modeling was used to examine predictors of PFS. Results: Thirty-nine patients were included in this analysis (24 men; 15 women); median age 60, range 30-76; median KPS 70, range 50-100. Objective response rate after R-MPV was 92%; 1 patient died from toxicity. After median followup of 3 years, the 2-year PFS was 81% (95% CI 68-95). There was substantial variation in M AUC during cycle 1; median 157 micromol h/l (range 62-2,580). Unlike in the previous report, the PFS was longer in patients with lower M AUC (HR 0.75, 95% CI 0.19-3.0, p = 0.68) and higher CrCl (HR 0.9, 95% CI 0.94-1; p = 0.06), although results did not reach statistical significance. Conclusions: This regimen achieved excellent PFS, but longer followup is needed to evaluate survival. We were unable to confirm the previously described association between higher M AUC and lower CrCl with better prognosis, although our results are limited by sample size and relatively short follow-up. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Bristol-Myers Squibb, Genentech Genentech, Novartis, Pfizer, Schering-Plough

Glomerular Size in Early Protocol Biopsies is Associated with Graft Outcome

Long-term consequences of glomerular enlargement after transplantation are not well understood. The aim is to evaluate the relationship between glomerular volume (Vg) estimated in protocol biopsies, graft function and graft survival. Vg and Banff chronic damage score were evaluated in protocol biopsies at 4 months. Creatinine clearance (CrCl) was estimated by the Cockroft-Gault formula. Vg estimated in 144 patients was 4.8 +/- 2.0 x 10(6)mu(3). It was associated with donor age (r = 0.23, p < 0.01), recipient body mass index (r = 0.17, p = 0.04), delayed graft function (Vg = 5.9 +/- 2.3 vs. 4.6 +/- 1.9 x 10(6)mu(3), p < 0.01) and CrCl (r = 0.17, p = 0.04). The best cutoff of Vg, Banff chronic damage score and CrCl was determined by Cox regression analysis, being 5.0 x 10(6)mu(3) for Vg (relative risk (RR): 2.4, 95% confidence interval (CI): 1.03-5.6), >2 for chronic damage score (RR: 3.4, 95% CI: 1.03-8.9) and 60 mL/min for CrCl (RR: 3.5, 95% CI: 1.04-11.9). These variables were independent predictors of death-censored graft survival. According to Vg and CrCl, four groups of patients were defined. Patients with small glomeruli and high CrCl had a 95% graft survival while patients with large glomeruli and low CrCl had a 45% graft survival at 15 years (p < 0.01). Large glomerular volume, high Banff chronic score and poor early renal function in stable grafts are independently associated with death-censored graft survival.

A tricontinental view of IgA nephropathy.

The purpose of this retrospective study was to analyse patients from four centres in three continents to determine if differences in long-term outcome of IgA nephropathy (IgAN) are explained by clinical and laboratory features at presentation. The study included 711 adults with biopsy-proven IgAN from Glasgow, UK (n = 112), Helsinki, Finland (n = 204), Sydney, Australia (n = 121) and Toronto, Canada (n = 274). Data collected from time of presentation to a nephrologist were age, gender, 24-h urine protein excretion (UP(0)), mean arterial pressure (MAP(0)) and creatinine clearance (CrCl(0)). Outcomes were slope of creatinine clearance (CrCl) and renal survival. At presentation there was significant vari-ability in baseline clinical features with patients from Helsinki having the lowest median UP(0), lowest MAP(0) and highest CrCl(0), all suggesting milder disease. There was significant variability in renal survival between centres with 10-year actuarial survival of 95.7, 87.0, 63.9 and 61.6% in Helsinki, Sydney, Glasgow and Toronto, respectively (P < 0.0001; log rank). Cox proportional hazards model revealed lower age(0) and lower CrCl(0) were significant independent predictors of reduced renal survival. In addition, patients from Helsinki and Sydney but not Glasgow had significantly longer renal survival than patients from Toronto. Median slope of CrCl varied by region from -1.24 ml/min/year in Helsinki, to -3.99 ml/min/year in Toronto (Kruskal-Wallis H test P < 0.0001). By multivariate analysis older age(0), higher CrCl(0) and lower UP(0) were independently associated with slower progression. Subjects from Helsinki had a significantly slower deterioration independent of the other clinical parameters at presentation. When the 269 patients presenting with CrCl(0) <75 ml/min were analysed separately there was no independent centre effect. The findings are consistent with the hypothesis that geographical variability in long-term outcome of IgAN is explained by lead-time bias and inclusion of milder cases in centres with apparent good outcome, but do not exclude the possibility that some of the variability is due to other factors such as genetics, diet or treatment.

Treatment effects of eptifibatide in planned coronary stent implantation in patients with chronic kidney disease (ESPRIT Trial)

The role of platelet glycoprotein IIb/IIIa inhibitor therapy in patients with mild renal impairment is not well characterized. Our objective was to explore the associations of creatinine clearance (CrCl) with outcomes in a trial of eptifibatide therapy in patients who underwent percutaneous coronary intervention (PCI). We analyzed 48-hour and 30-day outcomes of patients enrolled in the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial. Patients were randomly assigned to placebo or eptifibatide as an adjunct to stent implantation (1,755 with CrCl ≥60 ml/min and 289 with CrCl <60 ml/min). CrCl was calculated using the Cockcroft and Gault formula, and the associations of CrCl with outcomes were evaluated using logistic regression models. Patients with CrCl <60 ml/min were more likely to be older, women, hypertensive, and have a history of coronary artery bypass surgery, stroke, or peripheral vascular disease. The interaction of eptifibatide with CrCl had borderline significance for the 30-day outcome (p = 0.109). Treatment effect trended toward a greater magnitude in patients with lower CrCl (60 ml/min) (odds ratio 0.53, confidence interval 0.34 to 0.83) compared with those with higher CrCl (90 ml/min) (odds ratio 0.68, confidence interval 0.49 to 0.94). An accompanying increase in bleeding risk also was not apparent with lower CrCl. The treatment effect of eptifibatide is realized regardless of renal function and trends toward being greater in patients with mild renal impairment.