Hemoadsorption: Consensus report of the 30th Acute Disease Quality Initiative workgroup.

Adsorption-based extracorporeal therapies have been subject to technical developments and clinical application for close to five decades. More recently, new technological developments in membrane and sorbent manipulation have made it possible to deliver more biocompatible extracorporeal adsorption therapies to patients with a variety of conditions. There are several key rationales based on physicochemical principles and clinical considerations that justify the application and investigation of such therapies as evidenced by multiple ex-vivo, experimental, and clinical observations. Accordingly, unspecific adsorptive extracorporeal therapies have now been applied to the treatment of a wide array of conditions from poisoning to drug overdoses, to inflammatory states and sepsis, and acute or chronic liver and kidney failure. In response to the rapidly expanding knowledge base and increased clinical evidence, we convened an Acute Disease Quality Initiative (ADQI) consensus conference dedicated to such treatment. The data show that hemoadsorption has clinically acceptable short-term biocompatibility and safety, technical feasibility, and experimental demonstration of specified target molecule removal. Pilot studies demonstrate potentially beneficial effects on physiology and larger studies of endotoxin-based hemoadsorption have identified possible target phenotypes for larger randomized controlled trials (RCTs). Moreover, in a variety of endogenous and exogenous intoxications, removal of target molecules has been confirmed in vivo. However, some studies have raised concerns about harm or failed to deliver benefits. Thus, despite many achievements, modern hemoadsorption remains a novel and experimental intervention with limited data, and a large research agenda.

The Influence of Body Mass Index on Clinical Interpretation of Established and Novel Biomarkers in Acute Heart Failure.

BACKGROUND: Body mass index (BMI) is a known confounder for natriuretic peptides, but its influence on other biomarkers is less well described. We investigated whether BMI interacts with biomarkers' association with prognosis in patients with acute heart failure (AHF). METHODS AND RESULTS: B-type natriuretic peptide (BNP), high-sensitivity cardiac troponin I (hs-cTnI), galectin-3, serum neutrophil gelatinase-associated lipocalin (sNGAL), and urine NGAL were measured serially in patients with AHF during hospitalization in the AKINESIS (Acute Kidney Injury Neutrophil gelatinase-associated lipocalin Evaluation of Symptomatic Heart Failure) study. Cox regression analysis was used to determine the association of biomarkers and their interaction with BMI for 30-day, 90-day and 1-year composite outcomes of death or HF readmission. Among 866 patients, 21.2%, 29.7% and 46.8% had normal (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2) or obese (≥ 30 kg/m2) BMIs on admission, respectively. Admission values of BNP and hs-cTnI were negatively associated with BMI, whereas galectin-3 and sNGAL were positively associated with BMI. Admission BNP and hs-cTnI levels were associated with the composite outcome within 30 days, 90 days and 1 year. Only BNP had a significant interaction with BMI. When BNP was analyzed by BMI category, its association with the composite outcome attenuated at higher BMIs and was no longer significant in obese individuals. Findings were similar when evaluated by the last-measured biomarkers and BMIs. CONCLUSIONS: In patients with AHF, only BNP had a significant interaction with BMI for the outcomes, with its association attenuating as BMI increased; hs-cTnI was prognostic, regardless of BMI.

Galectin-3, Acute Kidney Injury and Myocardial Damage in Patients With Acute Heart Failure.

BACKGROUND: Galectin-3, a biomarker of inflammation and fibrosis, can be associated with renal and myocardial damage and dysfunction in patients with acute heart failure (AHF). METHODS AND RESULTS: We retrospectively analyzed 790 patients with AHF who were enrolled in the AKINESIS study. During hospitalization, patients with galectin-3 elevation (> 25.9 ng/mL) on admission more commonly had acute kidney injury (assessed by KDIGO criteria), renal tubular damage (peak urine neutrophil gelatinase-associated lipocalin [uNGAL] > 150 ng/dL) and myocardial injury (≥ 20% increase in the peak high-sensitivity cardiac troponin I [hs-cTnI] values compared to admission). They less commonly had ≥ 30% reduction in B-type natriuretic peptide from admission to last measured value. In multivariable linear regression analysis, galectin-3 was negatively associated with estimated glomerular filtration rate and positively associated with uNGAL and hs-cTnI. Higher galectin-3 was associated with renal replacement therapy, inotrope use and mortality during hospitalization. In univariable Cox regression analysis, higher galectin-3 was associated with increased risk for the composite of death or rehospitalization due to HF and death alone at 1 year. After multivariable adjustment, higher galectin-3 levels were associated only with death. CONCLUSIONS: In patients with AHF, higher galectin-3 values were associated with renal dysfunction, renal tubular damage and myocardial injury, and they predicted worse outcomes.

Prevention and management of antibiotic associated acute kidney injury in critically ill patients: new insights.

PURPOSE OF REVIEW: Drug associated kidney injury (D-AKI) occurs in 19-26% of hospitalized patients and ranks as the third to fifth leading cause of acute kidney injury (AKI) in the intensive care unit (ICU). Given the high use of antimicrobials in the ICU and the emergence of new resistant organisms, the implementation of preventive measures to reduce the incidence of D-AKI has become increasingly important. RECENT FINDINGS: Artificial intelligence is showcasing its capabilities in early recognition of at-risk patients for acquiring AKI. Furthermore, novel synthetic medications and formulations have demonstrated reduced nephrotoxicity compared to their traditional counterparts in animal models and/or limited clinical evaluations, offering promise in the prevention of D-AKI. Nephroprotective antioxidant agents have had limited translation from animal studies to clinical practice. The control of modifiable risk factors remains pivotal in avoiding D-AKI. SUMMARY: The use of both old and new antimicrobials is increasingly important in combating the rise of resistant organisms. Advances in technology, such as artificial intelligence, and alternative formulations of traditional antimicrobials offer promise in reducing the incidence of D-AKI, while antioxidant medications may aid in minimizing nephrotoxicity. However, maintaining haemodynamic stability using isotonic fluids, drug monitoring, and reducing nephrotoxic burden combined with vigilant antimicrobial stewardship remain the core preventive measures for mitigating D-AKI while optimizing effective antimicrobial therapy.

Moving toward a contemporary classification of drug-induced kidney disease.

Drug-induced kidney disease (DIKD) accounts for about one-fourth of all cases of acute kidney injury (AKI) in hospitalized patients, especially in critically ill setting. There is no standard definition or classification system of DIKD. To address this, a phenotype definition of DIKD using expert consensus was introduced in 2015. Recently, a novel framework for DIKD classification was proposed that incorporated functional change and tissue damage biomarkers. Medications were stratified into four categories, including "dysfunction without damage," "damage without dysfunction," "both dysfunction and damage," and "neither dysfunction nor damage" using this novel framework along with predominant mechanism(s) of nephrotoxicity for drugs and drug classes. Here, we briefly describe mechanisms and provide examples of drugs/drug classes related to the categories in the proposed framework. In addition, the possible movement of a patient's kidney disease between certain categories in specific conditions is considered. Finally, opportunities and barriers to adoption of this framework for DIKD classification in real clinical practice are discussed. This new classification system allows congruencies for DIKD with the proposed categorization of AKI, offering clarity as well as consistency for clinicians and researchers.

Urinary biomarkers predict progression and adverse outcomes of acute kidney injury in critical illness.

BACKGROUND: Acute kidney injury (AKI) is common in hospitalized patients and is associated with high morbidity and mortality. The Dublin Acute Biomarker Group Evaluation study is a prospective cohort study of critically ill patients (n = 717). We hypothesized that novel urinary biomarkers would predict progression of AKI and associated outcomes. METHODS: The primary (diagnostic) analysis assessed the ability of biomarkers levels at the time of early Stage 1 or 2 AKI to predict progression to higher AKI stage, renal replacement therapy (RRT) or death within 7 days of intensive care unit admission. In the secondary (prognostic) analysis, we investigated the association between biomarker levels and RRT or death within 30 days. RESULTS: In total, 186 patients had an AKI within 7 days of admission. In the primary (diagnostic) analysis, 8 of the 14 biomarkers were independently associated with progression. The best predictors were cystatin C [adjusted odds ratio (aOR) 5.2; 95% confidence interval (CI) 1.3-23.6], interleukin-18 (IL-18; aOR 5.1; 95% CI 1.8-15.7), albumin (aOR 4.9; 95% CI 1.5-18.3) and neutrophil gelatinase-associated lipocalin (NGAL; aOR 4.6; 95% CI 1.4-17.9). Receiver-operating characteristics and net reclassification index analyses similarly demonstrated improved prediction by these biomarkers. In the secondary (prognostic) analysis of Stages 1-3 AKI cases, IL-18, NGAL, albumin and monocyte chemotactic protein-1 were also independently associated with RRT or death within 30 days. CONCLUSIONS: Among 14 novel urinary biomarkers assessed, cystatin C, IL-18, albumin and NGAL were the best predictors of Stages 1-2 AKI progression. These biomarkers, after further validation, may have utility to inform diagnostic and prognostic assessment and guide management of AKI in critically ill patients.

EDTAKI: a Nephrology and Public Policy Committee platform call for more European involvement in acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is an often neglected but crucial element of clinical nephrology. The aim of the Nephrology and Public Policy Committee (NPPC) of the European Renal Association-European Dialysis and Transplant Association is to promote several key aspects of European nephrology. One of the targets proposed by the NPPC was to advance European nephrology involvement in AKI. METHODS: We undertook a literature analysis to define the current position of European nephrology in the field of AKI compared with other regions and to determine how different European countries compare with each other. RESULTS: It appeared that vis-à-vis countries with a comparable socio-economic status (the USA, Australia, New Zealand and Canada), the European contribution was almost 50% less. Within Europe, Central and Eastern Europe and countries with a lower gross domestic product showed lower scientific output. Nephrologists contributed to less than half of the output. There was no trend of a change over the last decade. CONCLUSIONS: There is room to improve the contribution of European nephrology in the field of AKI. We propose a model on how to promote clinical collaboration on AKI across Europe and the creation of a pan-European nephrology network of interested units to improve clinical outcomes, increase nephrologist involvement and awareness outside nephrology and stimulate research on AKI in Europe. Accordingly, we also propose a list of research priorities and stress the need for more European funding of AKI research.

Intermittent Convective Therapies in Patients with Acute Kidney Injury: A Systematic Review with Meta-Analysis.

INTRODUCTION: In critically ill patients requiring intermittent renal replacement therapy (RRT), the benefits of convective versus diffusive clearance remain uncertain. We conducted a systematic review and meta-analysis to determine the safety, clinical efficacy, and clearance efficiency of hemofiltration (HF) and hemodiafiltration (HDF) compared to hemodialysis (HD) in patients with acute kidney injury (AKI) receiving intermittent RRT. METHOD: We searched Medline, Embase, Cochrane Library, and PROSPERO. We included clinical trials and observational studies that reported the use of intermittent HF or HDF in adult patients with AKI. The following outcomes were included: mortality, renal recovery, clearance efficacy, intradialytic hemodynamic stability, circuit loss, and inflammation modulation. RESULTS: A total of 3,169 studies were retrieved and screened. Four randomized controlled trials and 4 observational studies were included (n: 615 patients). Compared with conventional HD, intermittent convective therapies had no effect on in-hospital mortality (relative risk, 1.23; 95% confidence interval (CI), 0.76-1.99), renal recovery at 30 days (RR, 0.98; 95% CI, 0.82-1.16), time-to-renal recovery (mean difference [MD], 0.77; 95% CI, -6.56 to 8.10), and number of dialysis sessions until renal recovery (MD, -1.34; 95% CI, -3.39 to 0.72). The overall quality of included studies was low, and dialysis parameters were suboptimal for all included studies. CONCLUSION: This meta-analysis suggests that there is no significant difference in short-term mortality and renal recovery in patients with severe AKI when treated with intermittent HF or HDF compared to conventional HD. This systematic review emphasizes the need for further trials evaluating optimal convective parameters in AKI patients treated with intermittent dialysis.

Potential Utility of Cardiorenal Biomarkers for Prediction and Prognostication of Worsening Renal Function in Acute Heart Failure.

BACKGROUND: Multiple different pathophysiologic processes can contribute to worsening renal function (WRF) in acute heart failure. METHODS AND RESULTS: We retrospectively analyzed 787 patients with acute heart failure for the relationship between changes in serum creatinine and biomarkers including brain natriuretic peptide, high sensitivity cardiac troponin I, galectin 3, serum neutrophil gelatinase-associated lipocalin, and urine neutrophil gelatinase-associated lipocalin. WRF was defined as an increase of greater than or equal to 0.3 mg/dL or 50% in creatinine within first 5 days of hospitalization. WRF was observed in 25% of patients. Changes in biomarkers and creatinine were poorly correlated (r ≤ 0.21) and no biomarker predicted WRF better than creatinine. In the multivariable Cox analysis, brain natriuretic peptide and high sensitivity cardiac troponin I, but not WRF, were significantly associated with the 1-year composite of death or heart failure hospitalization. WRF with an increasing urine neutrophil gelatinase-associated lipocalin predicted an increased risk of heart failure hospitalization. CONCLUSIONS: Biomarkers were not able to predict WRF better than creatinine. The 1-year outcomes were associated with biomarkers of cardiac stress and injury but not with WRF, whereas a kidney injury biomarker may prognosticate WRF for heart failure hospitalization.

Nephrotoxicity from Vancomycin Combined with Piperacillin-Tazobactam: A Comprehensive Review.

BACKGROUND: Recent studies have identified the combination of vancomycin with piperacillin-tazobactam (VPT) to be associated with increased nephrotoxicity. Multiple, large cohort studies have found this widely used combination to have a higher risk of nephrotoxicity than other regimens in a variety of populations. SUMMARY: This review summarizes the epidemiology and clinical features of VPT-associated acute kidney injury (AKI). Potential mechanisms involved in the pathogenesis of this phenomenon are also discussed. Key Message: VPT-associated nephrotoxicity is a recently recognized clinical entity. Clinical strategies to minimize the risk of toxicity in this setting include antimicrobial stewardship, monitoring of kidney function, and emerging data supporting the potential role for novel biomarkers in predicting and managing AKI.

Temporal trends in acute kidney injury across health care settings in the Irish health system: a cohort study.

BACKGROUND: Complete ascertainment of the true rates of acute kidney injury (AKI) and emerging trends are essential for planning of preventive strategies within health systems. METHODS: We conducted a retrospective cohort study from 2005 to 2014 using data from regional laboratory information systems to determine incidence rates of AKI and severity Stages 1-3 in the Irish health system. Multivariable models were developed to explore annual trends and the contributions of demographic factors, clinical measures, geographic factors and location of medical supervision expressed as adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: From 2005 to 2014, incidence rates of AKI increased from 6.1% (5.8-6.3) to 13.2% (12.7-13.8) per 100 patient-years in men and from 5.0% (4.8-5.2) to 11.5% (11.0-12.0) in women, P < 0.001. Stage 1 AKI accounted for the greatest growth in incidence, from 4.4% (95% CI 4.3-4.6) in 2005 to 10.1% (95% CI 9.8-10.5) in 2014 (P < 0.001 for trend). Compared with 2005, patients in 2014 were more likely to experience AKI [OR 4.53 (95% CI 4.02-5.1) for Stage 1, OR 5.22 (4.16-6.55) for Stage 2 and OR 4.11 (3.05-5.54) for Stage 3], adjusting for changing demographic and clinical profiles. Incidence rates of AKI increased in all locations of medical supervision during the period of observation, but were greatest for inpatient [OR 19.11 (95% CI 17.69-20.64)] and emergency room settings [OR 5.97 (95% CI 5.56-6.42)] compared with a general practice setting (referent). CONCLUSION: Incidence rates of AKI have increased substantially in the Irish health system, which were not accounted for by changing demographic patterns, clinical profiles or location of medical supervision.

New drugs for acute kidney injury.

PURPOSE OF REVIEW: To describe recent advances in the development of therapeutic agents for acute kidney injury (AKI). RECENT FINDINGS: Traditional care for AKI is mostly supportive. At present, no specific therapy has been developed to prevent or treat AKI. However, based on a better understanding of the pathophysiology of AKI, various potential compounds have been recently identified and tested. A variety of pathways has been targeted, including oxidative and mitochondrial stress, cellular metabolism and repair, inflammation, apoptosis and hemodynamics. Many of these potential agents are currently ongoing early-phase clinical trials, and the purpose of this review is to provide a summary of those with the most potential. SUMMARY: Despite the lack of therapies specifically approved for AKI, many interesting potential agents are entering clinical trials, with the potential to transform the care of patients with AKI.

Utility of Urine Neutrophil Gelatinase-Associated Lipocalin for Worsening Renal Function during Hospitalization for Acute Heart Failure: Primary Findings of the Urine N-gal Acute Kidney Injury N-gal Evaluation of Symptomatic Heart Failure Study (AKINESIS).

BACKGROUND: Worsening renal function (WRF) during acute heart failure (AHF) occurs frequently and has been associated with adverse outcomes, though this association has been questioned. WRF is now evaluated by function and injury. We evaluated whether urine neutrophil gelatinase-associated lipocalin (uNGAL) is superior to creatinine for prediction and prognosis of WRF in patients with AHF. METHODS AND RESULTS: We performed a multicenter, international, prospective cohort of patients with AHF requiring IV diuretics. The primary outcome was whether uNGAL predicted development of WRF, defined as a sustained increase in creatinine of 0.5 mg/dL or ≥50% above first value or initiation of renal replacement therapy, within the first 5 days. The main secondary outcome was a composite of in-hospital adverse events. We enrolled 927 patients (mean 68.5 years of age, 62% men). The primary outcome occurred in 72 patients (7.8%). The first, peak and the ratio of uNGAL to urine creatinine (area under curves (AUC) ≤ 0.613) did not have diagnostic utility over the first creatinine (AUC 0.662). There were 235 adverse events in 144 patients. uNGAL did not predict (AUCs ≤ 0.647) adverse clinical events better than creatinine (AUC 0.695). CONCLUSIONS: uNGAL was not superior to creatinine for predicting WRF or adverse in-hospital outcomes and cannot be recommended for WRF in AHF.

Biomarker Predictors of Adverse Acute Kidney Injury Outcomes in Critically Ill Patients: The Dublin Acute Biomarker Group Evaluation Study.

BACKGROUND: The Dublin Acute Biomarker Group Evaluation (DAMAGE) Study is a prospective 2-center observational study investigating the utility of urinary biomarker combinations for the diagnostic and prognostic assessment of acute kidney injury (AKI) in a heterogeneous adult intensive care unit (ICU) population. The objective of this study is to evaluate whether serial urinary biomarker measurements, in combination with a simple clinical model, could improve biomarker performance in the diagnostic prediction of severe AKI and clinical outcomes such as death and need for renal replacement therapy (RRT). METHODS: Urine was collected daily from patients admitted to the ICU, for a total of 7 post-admission days. Urine biomarker concentrations (neutrophil gelatinase-associated lipocalin [NGAL], α-glutathione S-transferase [GST], π-GST, kidney injury molecule-1 [KIM-1], liver-type fatty acid-binding protein [L-FABP], Cystatin C, creatinine, and albumin) were measured. Urine biomarkers were combined with a clinical prediction of AKI model, to determine ability to predict AKI (any stage, within 2 days or 7 days of ICU admission), or a -30-day composite clinical outcome (RRT - or death). RESULTS: A total of 257 (38%) patients developed AKI within 7 days of ICU admission. Of those who developed AKI, 106 (41%) patients met stage 3 AKI within 7 days of ICU admission and 208 patients of the entire study cohort (31%) met the composite clinical endpoint of in-hospital mortality or RRT within 30 days of ICU admission. The addition of urinary NGAL/albumin to the clinical model modestly improved the prediction of AKI, in particular severe stage 3 AKI (area under the curve [AUC] of 0.9 from 0.87, p = 0.369) and the prediction of 30-day RRT or death (AUC 0.83 from 0.79, p = 0.139). CONCLUSION: A clinical model incorporating severity of illness, patient demographics, and chronic illness with currently available clinical biomarkers of renal function was strongly predictive of development of AKI and associated clinical outcomes in a heterogeneous adult ICU population. The addition of urinary NGAL/albumin to this simple clinical model improved the prediction of severe AKI, need for RRT and death, but not at a statistically or clinically significant level, when compared to the clinical model alone.

The role of goal-directed therapy in the prevention of acute kidney injury after major gastrointestinal surgery: Substudy of the OPTIMISE trial.

BACKGROUND: Acute kidney injury (AKI) is an important adverse outcome after major surgery. Peri-operative goal-directed haemodynamic therapy (GDT) may improve outcomes by reducing complications such as AKI. OBJECTIVE: To determine if GDT was associated with a reduced incidence of postoperative AKI according to specific renal biomarkers. DESIGN: Prospective substudy of the OPTIMISE trial, a multicentre randomised controlled trial comparing peri-operative GDT to usual patient care. SETTING: Four UK National Health Service hospitals. PATIENTS: A total of 287 high-risk patients aged at least 50 years undergoing major gastrointestinal surgery. OUTCOME MEASURES: The primary outcome measure was AKI defined as urinary neutrophil gelatinase-associated lipase (NGAL) at least 150 ng ml 24 and 72 h after surgery. Secondary outcomes were between-group differences in NGAL measurements and NGAL : creatinine ratios 24 and 72 h after surgery and AKI stage 2 or greater according to Kidney Disease Improving Global Outcomes (KDIGO) criteria within 30 days of surgery. RESULTS: In total, 20 of 287 patients (7%) experienced postoperative AKI of KDIGO grade 2 or 3 within 30 days. The proportion of patients with urinary NGAL at least 150 ng ml 24 or 72 h after surgery was similar in the two groups [GDT 31/144 (21.5%) patients vs. usual patient care 28/143 (19.6%) patients; P = 0.88]. Absolute values of urinary NGAL were also similar at 24 h (GDT 53.5 vs. usual patient care 44.1 ng ml; P = 0.38) and 72 h (GDT 45.1 vs. usual patient care 41.1 ng ml; P = 0.50) as were urinary NGAL : creatinine ratios at 24 h (GDT 45 vs. usual patient care 43 ng mg; P = 0.63) and 72 h (GDT 66 vs. usual patient care 63 ng mg; P = 0.62). The incidence of KDIGO-defined AKI was also similar between the groups [GDT 9/144 (6%) patients vs. usual patient care 11/143 (8%) patients; P = 0.80]. CONCLUSION: In this trial, GDT did not reduce the incidence of AKI amongst high-risk patients undergoing major gastrointestinal surgery. This may reflect improving standards in usual patient care. TRIAL REGISTRATION: OPTIMISE Trial Registration ISRCTN04386758.

Drug management in acute kidney disease - Report of the Acute Disease Quality Initiative XVI meeting.

AIMS: To summarize and extend the main conclusions and recommendations relevant to drug management during acute kidney disease (AKD) as agreed at the 16th Acute Disease Quality Initiative (ADQI) consensus conference. METHODS: Using a modified Delphi method to achieve consensus, experts attending the 16th ADQI consensus conference reviewed and appraised the existing literature on drug management during AKD and identified recommendations for clinical practice and future research. The group focussed on drugs with one of the following characteristics: (i) predominant renal excretion; (ii) nephrotoxicity; (iii) potential to alter glomerular function; and (iv) presence of metabolites that are modified in AKD and may affect other organs. RESULTS: We recommend that medication reconciliation should occur at admission and discharge, at AKD diagnosis and change in AKD phase, and when the patient's condition changes. Strategies to avoid adverse drug reactions in AKD should seek to minimize adverse events from overdosing and nephrotoxicity and therapeutic failure from under-dosing or incorrect drug selection. Medication regimen assessment or introduction of medications during the AKD period should consider the nephrotoxic potential, altered renal and nonrenal elimination, the effects of toxic metabolites and drug interactions and altered pharmacodynamics in AKD. A dynamic monitoring plan including repeated serial assessment of clinical features, utilization of renal diagnostic tests and therapeutic drug monitoring should be used to guide medication regimen assessment. CONCLUSIONS: Drug management during different phases of AKD requires an individualized approach and frequent re-assessment. More research is needed to avoid drug associated harm and therapeutic failure.

Cytokine Clearances in Critically Ill Patients on Continuous Renal Replacement Therapy.

BACKGROUND/AIMS: We sought to quantify any differences in cytokine clearance between continuous venovenous hemofiltration (CVVH-convective) compared to continuous venovenous hemodialysis (CVVHD-diffusive). METHODS: We conducted a 20 patient, multicenter, prospective, open-label randomized trial (CVVH or CVVHD) at continuous renal -replacement therapy (CRRT) initiation. Blood, urine, and effluent were collected at 0, 4, 24, and 48 h after initiation of CRRT. Serum electrolytes, cytokines levels, and clearances were measured. Cytokines studies included IL-1ß, IL-1RA, IL-6, IL-10, and TNFα. RESULTS: We randomized 20 patients to receive CRRT. After 4 h of CRRT there was no difference in total cytokine levels or change in cytokine concentrations across the 2 groups. With the exception of IL-1 RA, all cytokines levels decreased across patient groups regardless of modality. There was no significant difference in cytokine concentration across CRRT modality for any time point. CONCLUSION: Within the first 4 h of CRRT initiation, there is no significant difference between cytokine or solute clearance between CVVH and CVVHD.

Effect of Human Recombinant Alkaline Phosphatase on 7-Day Creatinine Clearance in Patients With Sepsis-Associated Acute Kidney Injury: A Randomized Clinical Trial.

Importance: Sepsis-associated acute kidney injury (AKI) adversely affects long-term kidney outcomes and survival. Administration of the detoxifying enzyme alkaline phosphatase may improve kidney function and survival. Objective: To determine the optimal therapeutic dose, effect on kidney function, and adverse effects of a human recombinant alkaline phosphatase in patients who are critically ill with sepsis-associated AKI. Design, Setting, and Participants: The STOP-AKI trial was an international (53 recruiting sites), randomized, double-blind, placebo-controlled, dose-finding, adaptive phase 2a/2b study in 301 adult patients admitted to the intensive care unit with a diagnosis of sepsis and AKI. Patients were enrolled between December 2014 and May 2017, and follow-up was conducted for 90 days. The final date of follow-up was August 14, 2017. Interventions: In the intention-to-treat analysis, in part 1 of the trial, patients were randomized to receive recombinant alkaline phosphatase in a dosage of 0.4 mg/kg (n = 31), 0.8 mg/kg (n = 32), or 1.6 mg/kg (n = 29) or placebo (n = 30), once daily for 3 days, to establish the optimal dose. The optimal dose was identified as 1.6 mg/kg based on modeling approaches and adverse events. In part 2, 1.6 mg/kg (n = 82) was compared with placebo (n = 86). Main Outcomes and Measures: The primary end point was the time-corrected area under the curve of the endogenous creatinine clearance for days 1 through 7, divided by 7 to provide a mean daily creatinine clearance (AUC1-7 ECC). Incidence of fatal and nonfatal (serious) adverse events ([S]AEs) was also determined. Results: Overall, 301 patients were enrolled (men, 70.7%; median age, 67 years [interquartile range {IQR}, 59-73]). From day 1 to day 7, median ECC increased from 26.0 mL/min (IQR, 8.8 to 59.5) to 65.4 mL/min (IQR, 26.7 to 115.4) in the recombinant alkaline phosphatase 1.6-mg/kg group vs from 35.9 mL/min (IQR, 12.2 to 82.9) to 61.9 mL/min (IQR, 22.7 to 115.2) in the placebo group (absolute difference, 9.5 mL/min [95% CI, -23.9 to 25.5]; P = .47). Fatal adverse events occurred in 26.3% of patients in the 0.4-mg/kg recombinant alkaline phosphatase group; 17.1% in the 0.8-mg/kg group, 17.4% in the 1.6-mg/kg group, and 29.5% in the placebo group. Rates of nonfatal SAEs were 21.0% for the 0.4-mg/kg recombinant alkaline phosphatase group, 14.3% for the 0.8-mg/kg group, 25.7% for the 1.6-mg/kg group, and 20.5% for the placebo group. Conclusions and Relevance: Among patients who were critically ill with sepsis-associated acute kidney injury, human recombinant alkaline phosphatase compared with placebo did not significantly improve short-term kidney function. Further research is necessary to assess other clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02182440.

Biomarkers of drug-induced kidney injury.

PURPOSE OF REVIEW: Drug-induced kidney injury (DIKI) is an important and potentially modifiable cause of acute kidney injury (AKI). The reliance on traditional markers of kidney injury to diagnose DIKI impedes early detection. Biomarkers of DIKI that facilitate early diagnosis and the identification of high-risk patients are essential to ameliorate the clinical burden of this complication. RECENT FINDINGS: Recent progress in this area supports the potential utility of several biomarkers for the diagnosis of DIKI, for the prediction of outcomes and also for monitoring responses to potential nephrotoxic or beneficial therapies. Data regarding the impact of clinically relevant factors, such as chronic kidney disease, on biomarker levels represents a further recent advancement. Emerging novel biomarkers include microRNAs, which are showing promise as markers of drug-induced tubular damage. They may also have a role in elucidating the molecular mechanisms of AKI. SUMMARY: There is compelling evidence to support the use of biomarkers for the early detection of DIKI. Ongoing research is required to delineate their role in prognostication and for the prediction of outcomes. The inclusion of biomarkers in more clinical studies of DIKI would be a welcome advance, which may accelerate their integration into clinical diagnostics.