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Aim: The aim of this study was to investigate the association of hyperoncotic (20%) human albumin solution (HAS) with outcomes among critically ill patients receiving continuous renal replacement therapy (RRT)., Methods: Analysis of the Randomized Evaluation of Normal versus Augmented Level (RENAL) RRT trial data., Results: Of 1,508 patients, 771 (51%) received albumin. Of these, 345 (45%) received 4% HAS only, 155 (20%) received 20% HAS only, and 271 (35%) received both. Patients who received combined 4% and 20% HAS were more severely ill, received more days of RENAL trial therapy and required mechanical ventilation for longer. Mean daily fluid balance was -288 mL (-904 to 261) with 20% HAS only versus 245 mL (-248 to 1,050) with 4% HAS only (p < 0.001). On Cox proportional hazards regression, 20% HAS exposure was not associated with greater 90-day mortality (odds ratio 1.12, 95% confidence interval [CI]: 0.77-1.62; p = 0.55) or longer recovery to RRT independence (sub-hazard ratio 1.04, 95% CI: 0.84-1.30; p = 0.70) compared to those who received 4% HAS only., Conclusions: RENAL trial patients commonly received albumin in varying concentrations. The administration of 20% HAS was associated with a more negative fluid balance but was not independently associated with increased mortality or RRT dependence when compared to 4% HAS only., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Background: Acute kidney injury requiring renal replacement therapy (AKI-RRT) is strongly associated with mortality after cardiac surgery; however, options for early identification of patients at high risk for AKI-RRT are extremely limited. Early after cardiac surgery, the predictive ability for AKI-RRT even of one of the most extensively evaluated novel urinary biomarkers, neutrophil gelatinase-associated lipocalin (NGAL), appears to be only moderate. We aimed to determine whether the NGAL/hepcidin-25 ratio (urinary concentrations of NGAL divided by that of hepcidin-25) early after surgery may compare favorably to NGAL for identification of high-risk patients after cardiac surgery., Methods: This is a prospective substudy of the BICARBONATE trial, a multicenter parallel-randomized controlled trial comparing perioperative bicarbonate infusion for AKI prevention to usual patient care. At a tertiary referral center, 198 patients at increased kidney risk undergoing cardiac surgery with cardiopulmonary bypass were included into the present study. The primary outcome measure was defined as AKI-RRT. Secondary outcomes were in-hospital mortality and long-term mortality. We compared area under the curve of the receiver operating characteristic (AUC-ROC) of urinary NGAL with that of the urinary NGAL/hepcidin-25 ratio within 60 minutes after end of surgery. We compared adjusted AUC and performed cross-validated reclassification statistics of the (logarithmic) urinary NGAL/hepcidin-25 ratio adjusted to Cleveland risk score/EuroScore, cross-clamp time, age, volume of packed red blood cells, and (logarithmic) urinary NGAL concentration. The association of the NGAL/hepcidin-25 ratio with long-term patient survival was assessed using Cox proportional hazard regression analysis adjusting for EuroScore, aortic cross-clamp time, packed red blood cells and urinary NGAL., Results: Patients with AKI-RRT (n = 13) had 13.7-times higher NGAL and 3.3-times lower hepcidin-25 concentrations resulting in 46.9-times higher NGAL/hepcidin-25 ratio early after surgery compared to patients without AKI-RRT. The NGAL/hepcidin-25 ratio had higher AUC-ROC compared with NGAL for risk of AKI-RRT and in-hospital mortality (unadjusted AUC-ROC difference 0.087, 95% confidence interval [CI], 0.036-0.138, P < .001; 0.082, 95% CI, 0.018-0.146, P = .012). For AKI-RRT, the NGAL/hepcidin-25 ratio increased adjusted category-free net reclassification improvement (cfNRI; 0.952, 95% CI, 0.437-1.468; P < .001) and integrated discrimination improvement (IDI; 0.040, 95% CI, 0.008-0.073; P = .016) but not AUC difference. For in-hospital mortality, the ratio improved AUC of the reference model (AUC difference 0.056, 95% CI, 0.003-0.108; P = .037) and cfNRI but not IDI. The urinary NGAL/hepcidin-25 ratio remained significantly associated with long-term mortality after adjusting for the model covariates., Conclusions: The urinary NGAL/hepcidin-25 ratio appears to early identify high-risk patients and outperform NGAL after cardiac surgery. Confirmation of our findings in other cardiac surgery centers is now needed., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2021 International Anesthesia Research Society.)

Over the last 40 years, acute renal replacement therapy (RRT) in the intensive care units (ICUs) of high-income countries has transitioned from the predominant use of intermittent hemodialysis (and the much less common use of peritoneal dialysis) to the almost exclusive use of continuous renal replacement therapy (CRRT). Accordingly, CRRT has become the most common form of vital organ support delivered to critically ill patients. A series of clinical and technical advances has enabled the transformation of basic CRRT machines into highly sophisticated and customized devices. Recent work has focused on using evidence from clinical trials to enhance the application of CRRT with regard to timing of initiation, choice of modality, dose, and anticoagulation. However, many questions remain unanswered. Uncertainty surrounding volume control and the utility of strategies to minimize circulatory stress are key areas for future development. Advances in membrane technology, combination with other extracorporeal therapies, and personalization of CRRT delivery may provide additional benefit to certain subgroups. Development of quality metrics and use of data analytics to audit and benchmark could provide important insight into practice, while biofeedback and automated CRRT prescription could increase safety. In this review, we summarize the evolution of CRRT and highlight several future areas for development., (© 2021 Wiley Periodicals LLC.)

Objectives: The optimal time to initiate renal replacement therapy in critically ill patients with acute kidney injury is controversial. We investigated the effect of such earlier versus later initiation of renal replacement therapy on the primary outcome of 28-day mortality and other patient-centered secondary outcomes., Design: We searched MEDLINE (via PubMed), EMBASE, and Cochrane databases to July 17, 2020, and included randomized controlled trials comparing earlier versus later renal replacement therapy., Setting: Multiple centers involved in eight trials., Patients: Total of 4,588 trial participants., Intervention: Two independents investigators screened and extracted data using a predefined form. We selected randomized controlled trials in critically ill adult patients with acute kidney injury and compared of earlier versus later initiation of renal replacement therapy regardless of modality., Measurements and Main Results: Overall, 28-day mortality was similar between earlier and later renal replacement therapy initiation (38.43% vs 38.06%, respectively; risk ratio, 1.01; [95% CI, 0.94-1.09]; I2 = 0%). Earlier renal replacement therapy, however, shortened hospital length of stay (mean difference, -2.14 d; [95% CI, -4.13 to -0.14]) and ICU length of stay (mean difference, -1.18 d; [95% CI, -1.95 to -0.42]). In contrast, later renal replacement therapy decreased the use of renal replacement therapy (relative risk, 0.69; [95% CI, 0.58-0.82]) and lowered the risk of catheter-related blood stream infection (risk ratio, 0.50, [95% CI, 0.29-0.86). Among survivors, renal replacement therapy dependence at day 28 was similar between earlier and later renal replacement therapy initiation (risk ratio, 0.98; [95% CI, 0.66-1.40])., Conclusions: Earlier or later initiation of renal replacement therapy did not affect mortality. However, earlier renal replacement therapy was associated with significantly shorter ICU and hospital length of stay, whereas later renal replacement therapy was associated with decreased use of renal replacement therapy and decreased risk of catheter-related blood stream infection. These findings can be used to guide the management of critically ill patients with acute kidney injury., Competing Interests: Dr. Neto reported receiving lecture fee from Drager outside the submitted work. Dr. Yanase reported receiving scholarship for PhD course in Monash University from Japan Student Services Organization and Endeavour Scholarship. Dr. Wald reports receiving speaker fees and unrestricted research funding from Baxter. Dr. Bagshaw reported receiving fees for scientific advisory and grants from Baxter; he reported receiving fees for scientific advisory from Diagnostics and Spectral Medical, Canada, all outside the submitted work; he is supported by a Canada Research Chair in Critical Care Nephrology. Dr. Bellomo reported receiving grants from Baxter International outside the submitted work. The remaining authors have disclosed that they have no potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Neutrophil gelatinase-associated lipocalin (NGAL) and hepcidin-25 are involved in catalytic iron-related kidney injury after cardiac surgery with cardiopulmonary bypass. We explored the predictive value of plasma NGAL, plasma hepcidin-25, and the plasma NGAL:hepcidin-25 ratio for major adverse kidney events (MAKE) after cardiac surgery., Methods: We compared the predictive value of plasma NGAL, hepcidin-25, and plasma NGAL:hepcidin-25 with that of serum creatinine (Cr) and urinary output and protein for primary-endpoint MAKE (acute kidney injury [AKI] stages 2 and 3, persistent AKI >48 hours, acute dialysis, and in-hospital mortality) and secondary-endpoint AKI in 100 cardiac surgery patients at intensive care unit (ICU) admission. We performed ROC curve, logistic regression, and reclassification analyses., Results: At ICU admission, plasma NGAL, plasma NGAL:hepcidin-25, plasma interleukin-6, and Cr predicted MAKE (area under the ROC curve [AUC]: 0.77, 0.79, 0.74, and 0.74, respectively) and AKI (0.73, 0.89, 0.70, and 0.69). For AKI prediction, plasma NGAL:hepcidin-25 had a higher discriminatory power than Cr (AUC difference 0.26 [95% CI 0.00-0.53]). Urinary output and protein, plasma lactate, C-reactive protein, creatine kinase myocardial band, and brain natriuretic peptide did not predict MAKE or AKI (AUC <0.70). Only plasma NGAL:hepcidin-25 correctly reclassified patients according to their MAKE and AKI status (category-free net reclassification improvement: 0.82 [95% CI 0.12-1.52], 1.03 [0.29-1.77]). After adjustment to the Cleveland risk score, plasma NGAL:hepcidin-25 ≥0.9 independently predicted MAKE (adjusted odds ratio 16.34 [95% CI 1.77-150.49], P =0.014)., Conclusions: Plasma NGAL:hepcidin-25 is a promising marker for predicting postoperative MAKE.

Over the past decade, new insights into epidemiology, pathophysiology and biomarkers have modified our understanding of acute kidney dysfunction and damage, and their association with subsequent chronic kidney disease. The concept of acute kidney injury (AKI), which has relied on established but nonetheless flawed biomarkers of solute clearance (serum creatinine levels and urinary output), has been challenged by the identification of novel biomarkers of tubular stress and/or damage. The expression of some of these novel biomarkers precedes changes in conventional biomarkers or can increase their predictive power, and might therefore enhance the clinical accuracy of the definition of AKI. In addition, the need to consider AKI recurrence, duration and progression to chronic kidney disease within the clinical and epidemiological framework of AKI led to the emergence of the concept of acute kidney disease. New definitions of acute syndromes of kidney impairment and injury are needed.

Purpose: We compared a restrictive fluid management strategy to usual care among critically ill patients with acute kidney injury (AKI) who had received initial fluid resuscitation., Methods: This multicenter feasibility trial randomized 100 AKI patients 1:1 in seven ICUs in Europe and Australia. Restrictive fluid management included targeting negative or neutral daily fluid balance by minimizing fluid input and/or enhancing urine output with diuretics administered at the discretion of the clinician. Fluid boluses were administered as clinically indicated. The primary endpoint was cumulative fluid balance 72 h from randomization., Results: Mean (SD) cumulative fluid balance at 72 h from randomization was - 1080 mL (2003 mL) in the restrictive fluid management arm and 61 mL (3131 mL) in the usual care arm, mean difference (95% CI) - 1148 mL (- 2200 to - 96) mL, P = 0.033. Median [IQR] duration of AKI was 2 [1-3] and 3 [2-7] days, respectively (median difference - 1.0 [- 3.0 to 0.0], P = 0.071). Altogether, 6 out of 46 (13%) patients in the restrictive fluid management arm and 15 out of 50 (30%) in the usual care arm received renal replacement therapy (RR 0.42; 95% CI 0.16-0.91), P = 0.043. Cumulative fluid balance at 24 h and 7 days was lower in the restrictive fluid management arm. The dose of diuretics was not different between the groups. Adverse events occurred more frequently in the usual care arm., Conclusions: In critically ill patients with AKI, a restrictive fluid management regimen resulted in lower cumulative fluid balance and less adverse events compared to usual care. Larger trials of this intervention are justified.

Objectives: Mannitol and hypertonic saline are used to treat raised intracerebral pressure in patients with traumatic brain injury, but their possible effects on kidney function and mortality are unknown., Design: A post hoc analysis of the erythropoietin trial in traumatic brain injury (ClinicalTrials.gov NCT00987454) including daily data on mannitol and hypertonic saline use., Setting: Twenty-nine university-affiliated teaching hospitals in seven countries., Patients: A total of 568 patients treated in the ICU for 48 hours without acute kidney injury of whom 43 (7%) received mannitol and 170 (29%) hypertonic saline., Interventions: None., Measurements and Main Results: We categorized acute kidney injury stage according to the Kidney Disease Improving Global Outcome classification and defined acute kidney injury as any Kidney Disease Improving Global Outcome stage-based changes from the admission creatinine. We tested associations between early (first 2 d) mannitol and hypertonic saline and time to acute kidney injury up to ICU discharge and death up to 180 days with Cox regression analysis. Subsequently, acute kidney injury developed more often in patients receiving mannitol (35% vs 10%; p < 0.001) and hypertonic saline (23% vs 10%; p < 0.001). On competing risk analysis including factors associated with acute kidney injury, mannitol (hazard ratio, 2.3; 95% CI, 1.2-4.3; p = 0.01), but not hypertonic saline (hazard ratio, 1.6; 95% CI, 0.9-2.8; p = 0.08), was independently associated with time to acute kidney injury. In a Cox model for predicting time to death, both the use of mannitol (hazard ratio, 2.1; 95% CI, 1.1-4.1; p = 0.03) and hypertonic saline (hazard ratio, 1.8; 95% CI, 1.02-3.2; p = 0.04) were associated with time to death., Conclusions: In this post hoc analysis of a randomized controlled trial, the early use of mannitol, but not hypertonic saline, was independently associated with an increase in acute kidney injury. Our findings suggest the need to further evaluate the use and choice of osmotherapy in traumatic brain injury., Competing Interests: Dr. Skrifvars reports having received a research grant from GE Healthcare, travel reimbursements, and lecture fees from BARD Medical (Ireland), and he received personal research funding from Medicinska Understodsforeningen Liv och Halsa, Finska Läkaresallskapet, Sigrid Juselius Stiftelse, and Svenska Kulturfonden. Dr. Presneill’s institution received funding from the Australian National Health and Medical Research Council (NHMRC) (project grant ID 545902); he received support from the Victorian Transport Accident Commission (project grant ID D162); and he disclosed off-label product use of erythropoietin trial in traumatic brain injury. Dr. Nichol has received support from the Health Research Board of Ireland. Dr. Little received support for article research from the NHMRC, and she also disclosed off-label product use of Epoetin alfa. Drs. McArthur’s and Cooper’s institutions received funding from the NHMRC. Dr. Cooper’s institution received funding from the Transport Accident Commission and Pressura Neuro. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Introduction: Acute kidney injury (AKI) during critical illness increases the risk of subsequent chronic kidney disease. Guidelines recommend inpatient nephrology assessment and review at 3 months., Objectives: To quantify the prevalence and predictors of inpatient and outpatient nephrology follow-up of AKI patients admitted to critical care areas within a tertiary hospital., Methods: Retrospective study of all critically ill adults with AKI between January 1, 2012 and December 31, 2016 with a baseline estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m 2 and alive and independent of renal replacement therapy for 30 days after hospital discharge. We used logistic regression models to examine the primary outcome of nephrology review at 3 months. Secondary outcomes included inpatient nephrology review, renal recovery at discharge and the development of a major adverse kidney event (MAKE) at 1 year., Results: Of 702 critically ill patients with AKI (mean age 66 years, 64% male, baseline eGFR 78 mL/min/1.73 m 2 ), 43 patients (6%) received nephrology follow-up at 3 months and 63 patients (9%) at 1 year. Nephrology follow-up occurred more frequently in patients with a higher baseline creatinine, a higher discharge creatinine and greater severity of AKI. Seventy patients (10%) underwent inpatient nephrology review. Overall, 414 (59%) had recovery of renal function by the time of discharge and 239 (34%) developed a MAKE at 12 months., Conclusion: Inpatient and outpatient nephrology follow-up of AKI patients after admission to a critical care area was uncommon although one-third developed a MAKE. These findings provide the rationale for controlled studies of nephrology follow-up., (© 2020 Asian Pacific Society of Nephrology.)

Management of fluid overload is one of the most challenging problems in the care of critically ill patients with oliguric acute kidney injury. Various clinical practice guidelines support fluid removal using ultrafiltration during kidney replacement therapy. However, ultrafiltration is associated with considerable risks. Emerging evidence from observational studies suggests that both slow and fast rates of net fluid removal (that is, net ultrafiltration (UF NET )) during continuous kidney replacement therapy are associated with increased mortality compared with moderate UF NET rates. In addition, fast UF NET rates are associated with an increased risk of cardiac arrhythmias. Experimental studies in patients with kidney failure who were treated with intermittent haemodialysis suggest that fast UF NET rates are also associated with ischaemic injury to the heart, brain, kidney and gut. The UF NET rate should be prescribed based on patient body weight in millilitres per kilogramme per hour with close monitoring of patient haemodynamics and fluid balance. Dialysate cooling and sodium modelling may prevent haemodynamic instability and facilitate large volumes of fluid removal in patients with kidney failure who are treated with intermittent haemodialysis, but the effects of this strategy on organ injury are less well studied in critically ill patients treated with continuous kidney replacement therapy. Randomized trials are required to examine whether moderate UF NET rates are associated with a reduced risk of haemodynamic instability, organ injury and improved outcomes in critically ill patients.

Objective: To develop a simple model for the prediction of acute kidney injury (AKI) and renal replacement therapy (RRT) that could be used in clinical or research risk stratification., Design: Retrospective analysis., Setting: Multi-institutional., Participants: All cardiac surgery patients from September 2016 to December 2018., Interventions: Observational., Measurements and Main Results: The study cohort was divided into a development set (75%) and validation set (25%). The following 2 data epochs were used: preoperative data and immediate postoperative data (within 4 h of intensive care unit admission). Univariate statistics were used to identify variables associated with AKI or RRT. Stepwise logistic regression was used to develop a parsimonious model. Model discrimination and calibration were evaluated in the test set. Models were compared with previously published models and with a more comprehensive model developed using the least absolute shrinkage and selection operator. The study included 22,731 patients at 33 hospitals. The incidences of AKI (any stage) and RRT for the present analysis were 5,829 patients (25.6%) and 488 patients (2.1%), respectively. Models were developed for AKI, with an area under the receiver operating curve (AU-ROC) of 0.67 and 0.69 preoperatively and postoperatively, respectively. Models for RRT had an AU-ROC of 0.77 and 0.80 preoperatively and postoperatively, respectively. These models contained between 3 and 5 variables. Comparatively, comprehensive least absolute shrinkage and selection operator models contained between 21 and 26 variables, with an AU-ROC of 0.71 and 0.72 for AKI and 0.84 and 0.87 for RRT respectively., Conclusion: In the present study, simple, clinically applicable models for predicting AKI and RRT preoperatively and immediate postoperatively were developed. Even though AKI prediction remained poor, RRT prediction was good with a parsimonious model., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In sepsis-induced acute kidney injury, kidney blood flow may increase despite decreased glomerular filtration. Normally, angiotensin-II reduces kidney blood flow to maintain filtration. We hypothesized that sepsis reduces angiotensin type-1 receptor (AT1R) expression to account for this observation and tested this hypothesis in a patient case-control study and studies in mice. Seventy-three mice underwent cecal ligation and puncture (a sepsis model) or sham operation. Additionally, 94 septic mice received losartan (selective AT1R antagonist), angiotensin II without or with losartan, or vehicle. Cumulative urine output, kidney blood flow, blood urea nitrogen, and creatinine were measured. AT1R expression was assessed using ELISA, qPCR, and immunofluorescence. A blinded pathologist evaluated tissue for ischemic injury. AT1R expression was compared in autopsy tissue from seven patients with sepsis to that of the non-involved portion of kidney from ten individuals with kidney cancer and three non-infected but critically ill patients. By six hours post ligation/puncture, kidney blood flow doubled, blood urea nitrogen rose, and urine output fell. Concurrently, AT1R expression significantly fell 2-fold in arterioles and the macula densa. Creatinine significantly rose by 24 hours and sham operation did not alter measurements. Losartan significantly exacerbated ligation/puncture-induced changes in kidney blood flow, blood urea nitrogen, creatinine, and urine output. There was no histologic evidence of cortical ischemia. Significantly, angiotensin II prevented changes in kidney blood flow, creatinine, and urine output compared to vehicle. Co-administering losartan with angiotensin-II reversed this protection. Relative to both controls, patients with sepsis had low AT1R expression in arterioles and macula densa. Thus, murine cecal ligation/puncture and clinical sepsis decrease renal AT1R expression. Angiotensin II prevents functional changes while AT1R-blockade exacerbates them independent of ischemia in mice., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Critically ill patients with COVID-19 may develop multiple organ dysfunction syndrome, including acute kidney injury (AKI). We report the incidence, risk factors, associations, and outcomes of AKI and renal replacement therapy (RRT) in critically ill COVID-19 patients., Methods: We performed a retrospective cohort study of adult patients with COVID-19 diagnosis admitted to the intensive care unit (ICU) between March 2020 and May 2020. Multivariable logistic regression analysis was applied to identify risk factors for the development of AKI and use of RRT. The primary outcome was 60-day mortality after ICU admission., Results: 101 (50.2%) patients developed AKI (72% on the first day of invasive mechanical ventilation [IMV]), and thirty-four (17%) required RRT. Risk factors for AKI included higher baseline Cr (OR 2.50 [1.33-4.69], p = 0.005), diuretic use (OR 4.14 [1.27-13.49], p = 0.019), and IMV (OR 7.60 [1.37-42.05], p = 0.020). A higher C-reactive protein level was an additional risk factor for RRT (OR 2.12 [1.16-4.33], p = 0.023). Overall 60-day mortality was 14.4% {23.8% (n = 24) in the AKI group versus 5% (n = 5) in the non-AKI group (HR 2.79 [1.04-7.49], p = 0.040); and 35.3% (n = 12) in the RRT group versus 10.2% (n = 17) in the non-RRT group, respectively (HR 2.21 [1.01-4.85], p = 0.047)}., Conclusions: AKI was common among critically ill COVID-19 patients and occurred early in association with IMV. One in 6 AKI patients received RRT and 1 in 3 patients treated with RRT died in hospital. These findings provide important prognostic information for clinicians caring for these patients., (© 2020 S. Karger AG, Basel.)

Aims: To study the impact of early human albumin solution (HAS) in continuous renal replacement therapy (RRT) patients., Methods: Analysis of Randomized Evaluation of Normal versus Augmented Level (RENAL) RRT trial data., Results: Of 1,464 patients, 500 (34%) received early albumin. These patients had higher illness severity scores, greater use of mechanical ventilation, and 90-day mortality (51 vs. 41%; p < 0.001). However, early albumin carried similar RRT dependence risk among survivors at day 90 (4.9 vs. 5.8%; p = 0.62). On Cox proportional hazards regression, with standardized inverse probability of treatment weighting, early albumin was not associated with increased mortality (hazard ratio [HR]: 1.23, 95% CI: 0.97-1.55; p = 0.09) or recovery to RRT independence (HR: 0.92, 95% CI: 0.78-1.10; p = 0.38)., Conclusions: Early albumin was administered to one-third of RENAL trial patients and in those with greater illness severity. Early albumin was not independently associated with mortality risk or rate of recovery to RRT independence., (© 2020 S. Karger AG, Basel.)

Background: There is no information on acute kidney injury (AKI) and continuous renal replacement therapy (CRRT) among invasively ventilated coronavirus disease 2019 (COVID-19) patients in Western healthcare systems., Objective: To study the prevalence, characteristics, risk factors and outcome of AKI and CRRT among invasively ventilated COVID-19 patients., Methods: Observational study in a tertiary care hospital in Milan, Italy., Results: Among 99 patients, 72 (75.0%) developed AKI and 17 (17.7%) received CRRT. Most of the patients developed stage 1 AKI (33 [45.8%]), while 15 (20.8%) developed stage 2 AKI and 24 (33.4%) a stage 3 AKI. Patients who developed AKI or needed CRRT at latest follow-up were older, and among CRRT treated patients a greater proportion had preexisting CKD. Hospital mortality was 38.9% for AKI and 52.9% for CRRT patients., Conclusions: Among invasively ventilated COVID-19 patients, AKI is very common and CRRT use is common. Both carry a high risk of in-hospital mortality., (© 2020 S. Karger AG, Basel.)

Glomerular filtration rate (GFR) is acutely increased following a high-protein meal or systemic infusion of amino acids. The mechanisms underlying this renal functional response remain to be fully elucidated. Nevertheless, they appear to culminate in preglomerular vasodilation. Inhibition of the tubuloglomerular feedback signal appears critical. However, nitric oxide, vasodilator prostaglandins, and glucagon also appear important. The increase in GFR during amino acid infusion reveals a "renal reserve," which can be utilized when the physiological demand for single nephron GFR increases. This has led to the concept that in subclinical renal disease, before basal GFR begins to reduce, renal functional reserve can be recruited in a manner that preserves renal function. The extension of this concept is that once a decline in basal GFR can be detected, renal disease is already well progressed. This concept likely applies both in the contexts of chronic kidney disease and acute kidney injury. Critically, its corollary is that deficits in renal functional reserve have the potential to provide early detection of renal dysfunction before basal GFR is reduced. There is growing evidence that the renal response to infusion of amino acids can be used to identify patients at risk of developing either chronic kidney disease or acute kidney injury and as a treatment target for acute kidney injury. However, large multicenter clinical trials are required to test these propositions. A renewed effort to understand the renal physiology underlying the response to amino acid infusion is also warranted.

Rationale & Objective: The usefulness of measures of neutrophil gelatinase-associated lipocalin (NGAL) in urine or plasma obtained on clinical laboratory platforms for predicting acute kidney injury (AKI) and AKI requiring dialysis (AKI-D) has not been fully evaluated. We sought to quantitatively summarize published data to evaluate the value of urinary and plasma NGAL for kidney risk prediction., Study Design: Literature-based meta-analysis and individual-study-data meta-analysis of diagnostic studies following PRISMA-IPD guidelines., Setting & Study Populations: Studies of adults investigating AKI, severe AKI, and AKI-D in the setting of cardiac surgery, intensive care, or emergency department care using either urinary or plasma NGAL measured on clinical laboratory platforms., Selection Criteria for Studies: PubMed, Web of Science, Cochrane Library, Scopus, and congress abstracts ever published through February 2020 reporting diagnostic test studies of NGAL measured on clinical laboratory platforms to predict AKI., Data Extraction: Individual-study-data meta-analysis was accomplished by giving authors data specifications tailored to their studies and requesting standardized patient-level data analysis., Analytical Approach: Individual-study-data meta-analysis used a bivariate time-to-event model for interval-censored data from which discriminative ability (AUC) was characterized. NGAL cutoff concentrations at 95% sensitivity, 95% specificity, and optimal sensitivity and specificity were also estimated. Models incorporated as confounders the clinical setting and use versus nonuse of urine output as a criterion for AKI. A literature-based meta-analysis was also performed for all published studies including those for which the authors were unable to provide individual-study data analyses., Results: We included 52 observational studies involving 13,040 patients. We analyzed 30 data sets for the individual-study-data meta-analysis. For AKI, severe AKI, and AKI-D, numbers of events were 837, 304, and 103 for analyses of urinary NGAL, respectively; these values were 705, 271, and 178 for analyses of plasma NGAL. Discriminative performance was similar in both meta-analyses. Individual-study-data meta-analysis AUCs for urinary NGAL were 0.75 (95% CI, 0.73-0.76) and 0.80 (95% CI, 0.79-0.81) for severe AKI and AKI-D, respectively; for plasma NGAL, the corresponding AUCs were 0.80 (95% CI, 0.79-0.81) and 0.86 (95% CI, 0.84-0.86). Cutoff concentrations at 95% specificity for urinary NGAL were>580ng/mL with 27% sensitivity for severe AKI and>589ng/mL with 24% sensitivity for AKI-D. Corresponding cutoffs for plasma NGAL were>364ng/mL with 44% sensitivity and>546ng/mL with 26% sensitivity, respectively., Limitations: Practice variability in initiation of dialysis. Imperfect harmonization of data across studies., Conclusions: Urinary and plasma NGAL concentrations may identify patients at high risk for AKI in clinical research and practice. The cutoff concentrations reported in this study require prospective evaluation., (Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale: There are no prospective observational studies exploring the relationship between relative hypotension and adverse kidney-related outcomes among critically ill patients with shock. Objectives: To investigate the magnitude of relative hypotension during vasopressor support among critically ill patients with shock and to determine whether such relative hypotension is associated with new significant acute kidney injury (AKI) or major adverse kidney events (MAKE) within 14 days of vasopressor initiation. Methods: At seven multidisciplinary ICUs, 302 patients, aged ≥40 years and requiring ≥4 hours of vasopressor support for nonhemorrhagic shock, were prospectively enrolled. We assessed the time-weighted average of the mean perfusion pressure (MPP) deficit (i.e., the percentage difference between patients' preillness basal MPP and achieved MPP) during vasopressor support and the percentage of time points with an MPP deficit > 20% as key exposure variables. New significant AKI was defined as an AKI-stage increase of two or more (Kidney Disease: Improving Global Outcome creatinine-based criteria). Measurements and Main Results: The median MPP deficit was 19% (interquartile range, 13-25), and 54% (interquartile range, 19-82) of time points were spent with an MPP deficit > 20%. Seventy-three (24%) patients developed new significant AKI; 86 (29%) patients developed MAKE. For every percentage increase in the time-weighted average MPP deficit, multivariable-adjusted odds of developing new significant AKI and MAKE increased by 5.6% (95% confidence interval, 2.2-9.1; P  = 0.001) and 5.9% (95% confidence interval, 2.2-9.8; P  = 0.002), respectively. Likewise, for every one-unit increase in the percentage of time points with an MPP deficit > 20%, multivariable-adjusted odds of developing new significant AKI and MAKE increased by 1.2% (0.3-2.2; P  = 0.008) and 1.4% (0.4-2.4; P  = 0.004), respectively. Conclusions: Vasopressor-treated patients with shock are often exposed to a significant degree and duration of relative hypotension, which is associated with new-onset, adverse kidney-related outcomes.Study registered with Australian New Zealand Clinical Trial Registry (ACTRN 12613001368729).

Objectives: To compare the effects of restoring mean arterial pressure with vasopressin or norepinephrine on systemic hemodynamics, renal blood flow, intrarenal perfusion and oxygenation, and renal function in ovine septic acute kidney injury., Design: Interventional Study., Setting: Research Institute., Subjects: Adult Merino ewes., Interventions: Flow probes were implanted on the pulmonary and renal arteries (and the mesenteric artery in sheep that received vasopressin). Fiber-optic probes were implanted in the renal cortex and medulla to measure tissue perfusion and oxygen tension (PO2). Conscious sheep were administered Escherichia coli to induce septic acute kidney injury. Vasopressin (0.03 IU/min [0.03-0.05 IU/min]; n = 7) or norepinephrine (0.60 μg/kg/min [0.30-0.70 μg/kg/min]; n = 7) was infused IV and titrated to restore baseline mean arterial pressure during 24-30 hours of sepsis., Measurements and Main Results: Ovine septic acute kidney injury was characterized by reduced mean arterial pressure (-16% ± 2%) and creatinine clearance (-65% ± 9%) and increased renal blood flow (+34% ± 7%) but reduced renal medullary perfusion (-44% ± 7%) and PO2 (-47% ± 10%). Vasopressin infusion did not significantly affect renal medullary perfusion or PO2 and induced a sustained (6 hr) ~2.5-fold increase in creatinine clearance. Vasopressin reduced sepsis-induced mesenteric hyperemia (+61 ± 13 to +9% ± 6%). Norepinephrine transiently (2 hr) improved creatinine clearance (by ~3.5-fold) but worsened renal medullary ischemia (to -64% ± 7%) and hypoxia (to -71% ± 6%)., Conclusions: In ovine septic acute kidney injury, restoration of mean arterial pressure with vasopressin induced a more sustained improvement in renal function than norepinephrine, without exacerbating renal medullary ischemia and hypoxia or reducing mesenteric blood flow below baseline values.

Acute kidney injury after cardiac surgery (AKICS) is common. Previous studies examining the role that mean arterial pressure (MAP) during cardiopulmonary bypass (CPB) may have on AKICS have not taken into account how baseline central venous pressure (CVP) and mean perfusion pressure (MPP) (i.e. MAP - CVP) can influence its evolution. To assess whether the change in MPP to the kidneys (i.e. delta MPP or DMPP) during CPB compared to baseline is an independent predictor of AKICS. After ethical approval, a retrospective observational study was performed on all patients undergoing CPB between October 2013 and June 2015 at a university-affiliated hospital. Known risk factors for the development of AKICS were recorded, as were the MPP values at baseline and during CPB. From this, statistical modelling was performed to identify predictors of postoperative AKICS. 664 patients were identified. Analysis was performed on 513 patients after exclusion. On logistic regression, significant and independent predictors of AKICS included: d20DMPP (cumulative duration of MPP values during CPB that were 20% below baseline and exceeded three consecutive minutes) (P = 0.010); baseline CVP; age; pre-operative creatinine level; and left ventricular (LV) dysfunction (ejection fraction (EF) < 45%). On alternative modelling, the cumulative number of MPP values during CPB that were 10% below baseline was also independently associated with AKICS (P = 0.003). Modelling without taking into account CVP also supported this association. The duration of differences in perfusion pressure to the kidneys during CPB compared to baseline is an independent predictor of AKICS.

Aim: Acute kidney injury (AKI) is associated with poor short-term and long-term clinical outcomes. The role of nephrology follow-up in post-AKI management remains uncertain., Methods: A systematic review and meta-analysis were performed examining all randomized controlled trials and observational studies assessing the effect of nephrology follow-up on patients' clinical outcomes. The primary outcome was all-cause mortality. The secondary outcomes were renal outcomes, which were defined as a composite of requirement of permanent dialysis and recurrent AKI. Pooled analysis was performed using a random-effect model., Results: We identified six studies (8972 patients, mean follow-up of 49 months). Five were retrospective cohort studies and one was a prospective cohort study. Risk of bias was a concern with all studied. Only four studies reported primary and/or secondary outcomes and were included. Compared with patients without nephrology follow-up, patients with nephrology follow-up had significantly reduced mortality by 22% (three studies, 3240 patients, relative risk [RR] = 0.78, 95% confidence interval [CI] = 0.70-0.88, I 2 = 0.0%). Nephrology follow-up did not improve composite renal outcomes with high heterogeneity due to significant differences in reported renal outcomes and follow-up period (two studies, 2537 patients, RR = 1.72, 95% CI = 0.49-6.05, I 2 = 90.1%)., Conclusion: Current evidence from observational studies is biased. It suggests long-term survival benefits with post-discharge nephrology follow-up in AKI patients. However, due to its low quality, such evidence is only hypothesis-generating. Nonetheless, it provides a rationale for future randomized controlled trials of nephrology follow-up in AKI patients. SUMMARY AT A GLANCE The present meta-analysis assessed the effect of nephrology follow-up on patients' clinical outcomes, and suggested long-term survival benefits in acute kidney injury (AKI) survivors. Although the study inherently comprises potential risks of bias due to paucity of available data, the results provide a rationale for future randomized controlled trials., (© 2020 Asian Pacific Society of Nephrology.)

In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) published a guideline on the classification and management of acute kidney injury (AKI). The guideline was derived from evidence available through February 2011. Since then, new evidence has emerged that has important implications for clinical practice in diagnosing and managing AKI. In April of 2019, KDIGO held a controversies conference entitled Acute Kidney Injury with the following goals: determine best practices and areas of uncertainty in treating AKI; review key relevant literature published since the 2012 KDIGO AKI guideline; address ongoing controversial issues; identify new topics or issues to be revisited for the next iteration of the KDIGO AKI guideline; and outline research needed to improve AKI management. Here, we present the findings of this conference and describe key areas that future guidelines may address., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Acute kidney injury is common in critically ill patients, many of whom receive renal-replacement therapy. However, the most effective timing for the initiation of such therapy remains uncertain., Methods: We conducted a multinational, randomized, controlled trial involving critically ill patients with severe acute kidney injury. Patients were randomly assigned to receive an accelerated strategy of renal-replacement therapy (in which therapy was initiated within 12 hours after the patient had met eligibility criteria) or a standard strategy (in which renal-replacement therapy was discouraged unless conventional indications developed or acute kidney injury persisted for >72 hours). The primary outcome was death from any cause at 90 days., Results: Of the 3019 patients who had undergone randomization, 2927 (97.0%) were included in the modified intention-to-treat analysis (1465 in the accelerated-strategy group and 1462 in the standard-strategy group). Of these patients, renal-replacement therapy was performed in 1418 (96.8%) in the accelerated-strategy group and in 903 (61.8%) in the standard-strategy group. At 90 days, death had occurred in 643 patients (43.9%) in the accelerated-strategy group and in 639 (43.7%) in the standard-strategy group (relative risk, 1.00; 95% confidence interval [CI], 0.93 to 1.09; P = 0.92). Among survivors at 90 days, continued dependence on renal-replacement therapy was confirmed in 85 of 814 patients (10.4%) in the accelerated-strategy group and in 49 of 815 patients (6.0%) in the standard-strategy group (relative risk, 1.74; 95% CI, 1.24 to 2.43). Adverse events occurred in 346 of 1503 patients (23.0%) in the accelerated-strategy group and in 245 of 1489 patients (16.5%) in the standard-strategy group (P<0.001)., Conclusions: Among critically ill patients with acute kidney injury, an accelerated renal-replacement strategy was not associated with a lower risk of death at 90 days than a standard strategy. (Funded by the Canadian Institutes of Health Research and others; STARRT-AKI ClinicalTrials.gov number, NCT02568722.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: Fluid accumulation frequently coexists with acute kidney injury (AKI) and is associated with increased risk for AKI progression and mortality. Among septic shock patients, restricted use of resuscitation fluid has been reported to reduce the risk of worsening of AKI. Restrictive fluid therapy, however, has not been studied in the setting of established AKI. Here, we present the protocol and statistical analysis plan of the REstricted fluid therapy VERsus Standard trEatment in Acute Kidney Injury-the REVERSE-AKI trial that compares a restrictive fluid therapy regimen to standard therapy in critically ill patients with AKI., Methods: REVERSE-AKI is an investigator-initiated, multinational, open-label, randomized, controlled, feasibility pilot trial conducted in seven ICUs in five countries. We aim to randomize 100 critically ill patients with AKI to a restrictive fluid treatment regimen vs standard management. In the restrictive fluid therapy regimen, the daily fluid balance target is neutral or negative. The primary outcome is the cumulative fluid balance assessed after 72 hours from randomization. Secondary outcomes include safety, feasibility, duration, and severity of AKI, and outcome at 90 days (mortality and dialysis dependence)., Conclusions: This is the first multinational trial investigating the feasibility and safety of a restrictive fluid therapy regimen in critically ill patients with AKI., Trial Registration: clinical.trials.gov NCT03251131., (© 2020 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Background: Plasma creatinine (Cr) is a marker of kidney function and typically measured once daily. We hypothesized that Cr measured by point-of-care technology early after ICU admission would be a good predictor of acute kidney injury (AKI) the next day in critically ill patients., Methods: We conducted a retrospective database audit in a single tertiary ICU database. We included patients with normal first admission Cr (Cr F ) and identified a Cr value (Cr P ) obtained within 6-12 hours from ICU admission. We used their difference converted into percentage (delta-Cr-%) to predict subsequent AKI (based on Cr and/or need for renal replacement therapy) the next day. We assessed predictive value by calculating area under the receiver characteristic curve (AUC), logistic regression models for AKI with and without delta-Cr-%, and the category-free net reclassifying index (cfNRI)., Results: We studied 780 patients. Overall, 70 (9.0%) fulfilled the Cr AKI definition by Cr P measurement. On day 2, 148 patients (19.0%) were diagnosed with AKI. AUC (95% CI) for delta-Cr-% to predict AKI on day 2 was 0.82 (95% CI 0.78-0.86), and 0.74 (95% CI 0.69-0.80) when patients with AKI based on the Cr P were excluded. Using a cut-off of 17% increment, the positive likelihood ratio (95% CI) for delta-Cr-% to predict AKI was 3.5 (2.9-4.2). The cfNRI was 90.0 (74.9-106.1)., Conclusions: Among patients admitted with normal Cr, early changes in Cr help predict AKI the following day., (© 2020 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: Frequent assessment of urine output (UO), serum creatinine (sCr) and urinary cell cycle arrest biomarkers (CCAB) may improve acute kidney injury (AKI) prediction., Objective: To study the performance of UO, short term sCr changes and urinary CCAB to predict severe AKI., Methods: We measured 6 hours of UO, 6-hourly sCr changes, and urinary CCABs in all critically ill patients with cardiovascular or respiratory failure or early signs of renal stress between February and October 2018. We studied the association of such measurements, and their combination, with the development of AKI Stage 2 or 3 of the Kidney Disease: Improving Global Outcomes (KDIGO) definition at 12 hours. We evaluated predictive performance with logistic regression, area under the receiver operating characteristic (AUROC) curve, and net reclassification indices. We computed an optimal cut-off value for each biomarker., Results: We assessed 622 patients and, as per the exclusion criteria, we enrolled 105 critically ill patients. After 12 hours of enrolment, AKI occurred in 32 patients (30%). UO, sCr change over 6 hours and CCABs were significantly associated with severe AKI at 12 hours, with all variables achieving an AUROC > 0.7 after adjustment. Combination of any of the two or three variables achieved an AUROC > 0.7 for subsequent severe AKI at 12 hours. The optimal predictive high specificity cut-off values were ≤ 0.4 mL/kg/h for UO, variation of +15 μmol/L over 6 hours in sCr, and ≥ 1.5 (ng/mL) 2 /1000 for CCABs., Conclusion: In this prospective study, an integrative approach using UO, short term sCr change and/or urinary CCABs showed a satisfactory performance for the prediction of severe AKI development at 12 hours.

Objective: Hyperammonaemia contributes to complications in acute liver failure (ALF) and may be treated with continuous renal replacement therapy (CRRT), but current practice is poorly understood., Design: We retrospectively analysed data for baseline characteristics, ammonia concentration, CRRT use, and outcomes in a cohort of Australian and New Zealand patients with ALF., Setting: All liver transplant ICUs across Australia and New Zealand., Participants: Sixty-two patients with ALF., Main Outcome Measures: Impact of CRRT on hyperammonaemia and patient outcomes., Results: We studied 62 patients with ALF. The median initial (first 24 h) peak ammonia was 132 μmol/L (interquartile range [IQR], 91-172), median creatinine was 165 μmol/L (IQR, 92-263) and median urea was 6.9 mmol/L (IQR, 3.1-12.0). Most patients (43/62, 69%) received CRRT within a median of 6 hours (IQR, 2-12) of ICU admission. At CRRT commencement, three-quarters of such patients did not have Stage 3 acute kidney injury (AKI): ten patients (23%) had no KDIGO creatinine criteria for AKI, 12 (28%) only had Stage 1, and ten patients (23%) had Stage 2 AKI. Compared with non-CRRT patients, those treated with CRRT had higher ammonia concentrations (median, 141 μmol/L [IQR, 102-198] v 91 μmol/L [IQR, 54-115]; P = 0.02), but a nadir Day 1 pH of only 7.25 (standard deviation, 0.16). Prevention of extreme hyperammonaemia (> 140 μmol/L) after Day 1 was achieved in 36 of CRRT-treated patients (84%) and was associated with transplant-free survival (55% v 13%; P = 0.05)., Conclusion: In Australian and New Zealand patients with ALF, CRRT is typically started early, before Stage 3 AKI or severe acidaemia, and in the presence hyperammonaemia. In these more severely ill patients, CRRT use was associated with prevention of extreme hyperammonaemia, which in turn, was associated with increased transplant-free survival.

Background: The ability of urinary biomarkers to complement established clinical risk prediction models for postoperative adverse kidney events is unclear. We assessed the effect of urinary biomarkers linked to suspected pathogenesis of cardiac surgery-induced acute kidney injury (AKI) on the performance of the Cleveland Score, a risk assessment model for postoperative adverse kidney events., Methods: This pilot study included 100 patients who underwent open-heart surgery. We determined improvements to the Cleveland Score when adding urinary biomarkers measured using clinical laboratory platforms (neutrophil gelatinase-associated lipocalin [NGAL], interleukin-6) and those in the preclinical stage (hepcidin-25, midkine, alpha-1 microglobulin), all sampled immediately post-surgery. The primary endpoint was major adverse kidney events (MAKE), and the secondary endpoint was AKI. We performed ROC curve analysis, assessed baseline model performance (odds ratios [OR], 95% CI), and carried out statistical reclassification analyses to assess model improvement., Results: NGAL (OR [95% CI] per 20 concentration-units wherever applicable): (1.07 [1.01-1.14]), Interleukin-6 (1.51 [1.01-2.26]), midkine (1.01 [1.00-1.02]), 1-hepcidin-25 (1.08 [1.00-1.17]), and NGAL/hepcidin-ratio (2.91 [1.30-6.49]) were independent predictors of MAKE and AKI (1.38 [1.03-1.85], 1.08 [1.01-1.15], 1.01 [1.00-1.02], 1.09 [1.01-1.18], and 3.45 [1.54-7.72]). Category-free net reclassification improvement identified interleukin-6 as a model-improving biomarker for MAKE and NGAL for AKI. However, only NGAL/hepcidin-25 improved model performance for event- and event-free patients for MAKE and AKI., Conclusions: NGAL and interleukin-6 measured immediately post cardiac surgery may complement the Cleveland Score. The combination of biomarkers with hepcidin-25 may further improve diagnostic discrimination., Competing Interests: CA has received honoraria speaking for Siemens Healthineers. MH has received honoraria speaking for Abbott Diagnostics, Alere, Biosite Inc., and Siemens Healthineers, AA has received honoraria speaking for Abbott Diagnostics. All companies are involved in the development and marketing of renal biomarkers., (© The Korean Society for Laboratory Medicine.)

Renal medullary hypoxia may contribute to the pathophysiology of acute kidney injury, including that associated with cardiac surgery requiring cardiopulmonary bypass (CPB). When performed under volatile (isoflurane) anesthesia in sheep, CPB causes renal medullary hypoxia. There is evidence that total intravenous anesthesia (TIVA) may preserve renal perfusion and renal oxygen delivery better than volatile anesthesia. Therefore, we assessed the effects of CPB on renal perfusion and oxygenation in sheep under propofol/fentanyl-based TIVA. Sheep ( n = 5) were chronically instrumented for measurement of whole renal blood flow and cortical and medullary perfusion and oxygenation. Five days later, these variables were monitored under TIVA using propofol and fentanyl and then on CPB at a pump flow of 80 mL·kg -1 ·min -1 and target mean arterial pressure of 70 mmHg. Under anesthesia, before CPB, renal blood flow was preserved under TIVA (mean difference ± SD from conscious state: -16 ± 14%). However, during CPB renal blood flow was reduced (-55 ± 13%) and renal medullary tissue became hypoxic (-20 ± 13 mmHg versus conscious sheep). We conclude that renal perfusion and medullary oxygenation are well preserved during TIVA before CPB. However, CPB under TIVA leads to renal medullary hypoxia, of a similar magnitude to that we observed previously under volatile (isoflurane) anesthesia. Thus use of propofol/fentanyl-based TIVA may not be a useful strategy to avoid renal medullary hypoxia during CPB.

Objectives: To assess the attitudes of practitioners with respect to net ultrafiltration prescription and practice among critically ill patients with acute kidney injury treated with renal replacement therapy., Design: Multinational internet-assisted survey., Setting: Critical care practitioners involved with 14 societies in 80 countries., Subjects: Intervention: MEASUREMENT AND MAIN RESULTS:: Of 2,567 practitioners who initiated the survey, 1,569 (61.1%) completed the survey. Most practitioners were intensivists (72.7%) with a median duration of 13.2 years of practice (interquartile range, 7.2-22.0 yr). Two third of practitioners (71.0%; regional range, 55.0-95.5%) reported using continuous renal replacement therapy with a net ultrafiltration rate prescription of median 80.0 mL/hr (interquartile range, 49.0-111.0 mL/hr) for hemodynamically unstable and a maximal rate of 299.0 mL/hr (interquartile range, 200.0-365.0 mL/hr) for hemodynamically stable patients, with regional variation. Only a third of practitioners (31.5%; range, 13.7-47.8%) assessed hourly net fluid balance during continuous renal replacement therapy. Hemodynamic instability was reported in 20% (range, 20-38%) of patients and practitioners decreased the rate of fluid removal (70.3%); started or increased the dose of a vasopressor (51.5%); completely stopped fluid removal (35.8%); and administered a fluid bolus (31.6%), with significant regional variation. Compared with physicians, nurses were most likely to report patient intolerance to net ultrafiltration (73.4% vs 81.3%; p = 0.002), frequent interruptions (40.4% vs 54.5%; p < 0.001), and unavailability of trained staff (11.9% vs 15.6%; p = 0.04), whereas physicians reported unavailability of dialysis machines (14.3% vs 6.1%; p < 0.001) and costs associated with treatment as barriers (12.1% vs 3.0%; p < 0.001) with significant regional variation., Conclusions: Our study provides new knowledge about the presence and extent of international practice variation in net ultrafiltration. We also identified barriers and specific targets for quality improvement initiatives. Our data reflect the need for evidence-based practice guidelines for net ultrafiltration.

Background: Continuous renal replacement therapy (CRRT) technique may affect circuit lifespan. A shorter circuit life may reduce CRRT efficacy and increase costs., Methods: In a before-and-after study, we compared circuit median survival time during continuous venovenous hemofiltration (CVVH) versus continuous venovenous hemodialysis (-CVVHD). We performed log-rank mixed effects univariate analysis and Cox mixed effect regression modeling to define predictors of circuit lifespan., Results: We compared 197 -CVVHD and 97 CVVH circuits in 39 patients. There was no overall difference in circuit lifespan. When no anticoagulation was used, median circuit survival time was shorter for CVVH circuits (5 h, 95% CI 3-7 vs. 10 h, 95% CI 8-13, p < 0.01). Moreover, CVVHD, lower platelets levels, and longer activated partial thromboplastin time independently predicted longer circuit median survival time., Conclusions: CVVHD is associated with longer circuit median survival time than CVVH when no anticoagulation is used and is an independent predictor of circuit survival., (© 2020 S. Karger AG, Basel.)

Acute kidney injury (AKI) is defined by a rapid increase in serum creatinine, decrease in urine output, or both. AKI occurs in approximately 10-15% of patients admitted to hospital, while its incidence in intensive care has been reported in more than 50% of patients. Kidney dysfunction or damage can occur over a longer period or follow AKI in a continuum with acute and chronic kidney disease. Biomarkers of kidney injury or stress are new tools for risk assessment and could possibly guide therapy. AKI is not a single disease but rather a loose collection of syndromes as diverse as sepsis, cardiorenal syndrome, and urinary tract obstruction. The approach to a patient with AKI depends on the clinical context and can also vary by resource availability. Although the effectiveness of several widely applied treatments is still controversial, evidence for several interventions, especially when used together, has increased over the past decade., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Renal tissue hypoxia has been implicated as a critical mediatory factor in multiple forms of acute kidney injury (AKI), including in sepsis. In sepsis, whole-kidney measures of macrocirculatory flow and oxygen delivery appear to be poor predictors of microcirculatory abnormalities. Studies in experimental hyperdynamic septic AKI have shown that the renal medulla is particularly susceptible to hypoxia early in sepsis, even in the presence of increased global renal blood flow and oxygen delivery. It has been proposed that an early onset of progressive renal medullary hypoxia, leading to oxidative stress and inflammation, can initiate a downward spiral of cellular injury culminating in AKI. Recent experimental studies have shown that clinical therapies for septic AKI, including, fluids, vasopressors, and diuretics, have distinct effects on renal macrocirculation and microcirculation. Herein, we review the clinical and experimental evidence of alterations in global and regional kidney perfusion and oxygenation during septic AKI and associated therapies. We justify the need for investigation of the effects of therapies on renal microcirculatory perfusion and oxygenation. We propose that interventions that do not worsen the underlying renal pathophysiologic and reparative processes in sepsis will reduce the development and/or progression of AKI more effectively., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: To study hemodynamic changes within continuous renal replacement therapy circuits and evaluate their relationship with continuous renal replacement therapy longevity., Design: Analysis of downloaded variables recorded by continuous renal replacement therapy machines during multiple episodes of clinical care., Setting: Tertiary ICU in Melbourne, Australia., Patients: Cohort of 149 ICU patients: 428 episodes of continuous renal replacement therapy., Interventions: None., Measurements and Main Results: Indices of continuous renal replacement therapy function representing 554,991 minutes were assessed including blood flow, access pressure, effluent pressure, prefilter pressure, and return pressure. We defined three patterns of artificial kidney failure: early (≤ 12 hr), intermediate (> 12-24 hr), and late (> 24 hr) in 35%, 31%, and 34% of circuits, respectively. Mean access pressure in late artificial kidney failure was 7.5 mm Hg (7.1-7.9 mm Hg) less negative than early failing circuits and pressures demonstrated lower variability in such late failing circuits. Access dysfunction, defined as access pressure less than or equal to -200 mm Hg occurred in the first 4 hours in 118 circuits (27%) which had a shorter (median [interquartile range]) life at 12.9 hr [5.5-21.3 hr]) hours than access dysfunction-free circuits (18.8 hr [10.1-33.4 hr]; p < 0.0001). Multivariate analysis found the first occurrence of access dysfunction (as a time-varying covariate) was independently associated with increased hazard of subsequent failure (hazard ratio, 1.75; 1.36-2.26). Classification and regression tree analysis of summary pressure indices in the first 2 hours confirmed minimum access pressure to be a significant predictor, as well as indices of transmembrane pressure and return pressure. A pressure-based predictor correctly identified early and late failing circuits (86.2% and 93.6% specificity, respectively)., Conclusions: Access dysfunction is a predictor of continuous renal replacement therapy circuit failure. Future monitoring of continuous renal replacement therapy hemodynamics may facilitate remedial actions to improve circuit function.

Norepinephrine exacerbates renal medullary hypoxia in experimental septic acute kidney injury. Here we examined whether dexmedetomidine, an α2-adrenergic agonist, can restore vasopressor responsiveness, decrease the requirement for norepinephrine and attenuate medullary hypoxia in ovine gram-negative sepsis. Sheep were instrumented with pulmonary and renal artery flow probes, and laser Doppler and oxygen-sensing probes in the renal cortex and medulla. Conscious sheep received an infusion of live Escherichia coli for 30 hours. Eight sheep in each group were randomized to receive norepinephrine, norepinephrine with dexmedetomidine, dexmedetomidine alone or saline vehicle, from 24-30 hours of sepsis. Sepsis significantly reduced the average mean arterial pressure (84 to 67 mmHg), average renal medullary perfusion (1250 to 730 perfusion units), average medullary tissue pO 2 (40 to 21 mmHg) and creatinine clearance (2.50 to 0.78 mL/Kg/min). Norepinephrine restored baseline mean arterial pressure (to 83 mmHg) but worsened medullary hypoperfusion (to 330 perfusion units) and medullary hypoxia (to 9 mmHg). Dexmedetomidine (0.5 μg/kg/h) co-administration significantly reduced the norepinephrine dose (0.8 to 0.4 μg/kg/min) required to restore baseline mean arterial pressure, attenuated medullary hypoperfusion (to 606 perfusion units), decreased medullary tissue hypoxia (to 29 mmHg), and progressively increased creatinine clearance (to 1.8 mL/Kg/min). Compared with vehicle time-control, dexmedetomidine given alone significantly prevented the temporal reduction in mean arterial pressure, but had no significant effects on medullary perfusion and oxygenation or creatinine clearance. Thus, in experimental septic acute kidney injury, dexmedetomidine reduced norepinephrine requirements, attenuated its adverse effects on the renal medulla, and maintained renal function., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Mortality in intensive care unit (ICU) patients with acute kidney injury (AKI) remains high. Previous studies have explored the role of HMG-CoA reductase inhibitors (statins) with variable findings., Methods: The Randomized Evaluation of Normal versus Augmented Level Replacement Therapy (RENAL) Study recruited 1508 participants requiring dialysis in ICU between 2006 and 2009. Statin use was recorded at study baseline. Multivariate Cox modelling was used to assess associations of such statin use and all-cause mortality. Propensity score analysis was performed for sensitivity analysis. The primary outcome was all-cause mortality at 90 days., Results: Of the 1462 participants with the available data on statin usage, 187 (12.8%) received statin therapy at baseline. Participants who receiving statins were older (P < 0.001), less likely to have sepsis or require mechanical ventilation (P < 0.001). Multivariable analysis showed statin use did not have significant associations with mortality at both day 28 (hazard ratio (HR) = 1.053, 95% confidence interval (CI) = 0.784-1.415, P = 0.730) and day 90 (HR = 1.091, 95% CI = 0.836-1.424, P = 0.520). Propensity score analysis confirmed the lack of association between statin use and mortality at day 90 (HR = 1.042, 95% CI = 0.734-1.479, P = 0.819). However, in septic patients, multivariable analysis suggested statin therapy was associated with a trend to higher mortality at day 90 (HR = 1.688, 95% CI = 1.132-2.519, P = 0.010) and continuation of statins was associated with higher mortality (HR = 2.160, 95% CI = 1.296-3.599, P = 0.003), compared with statin withdrawal., Conclusion: In the RENAL study cohort, baseline statin use was not associated with mortality. Our findings do not support a protective role of statins in ICU patients with severe AKI. Clinical Trials registration number for the RENAL study: NCT00221013, the date of registration: September 14, 2005., (© 2019 Asian Pacific Society of Nephrology.)

In experimental sepsis, the rapid development of renal medullary hypoxia precedes the development of acute kidney injury (AKI) and may contribute to its pathogenesis. We investigated whether inhibiting active sodium transport and oxygen consumption in the medullary thick ascending limb with furosemide attenuates the medullary hypoxia in experimental septic AKI. Sheep were instrumented with flow probes on the pulmonary and renal arteries and fiber optic probes to measure renal cortical and medullary perfusion and oxygen tension (Po 2 ). Sepsis and AKI were induced by infusion of live Escherichia coli . At 24 h of sepsis there were significant decreases in renal medullary tissue perfusion (1,332 ± 233 to 698 ± 159 blood perfusion units) and Po 2 (44 ± 6 to 19 ± 6 mmHg) (both P < 0.05). By 5 min after intravenous administration of furosemide (20 mg), renal medullary Po 2 increased to 43 ± 6 mmHg and remained at this normal level for 8 h. Furosemide caused transient increases in fractional excretion of sodium and creatinine clearance, but medullary perfusion, renal blood flow, and renal oxygen delivery were unchanged. Urinary F 2 -isoprostanes, an index of oxidative stress, were not significantly changed at 24 h of sepsis but tended to transiently decrease after furosemide treatment. In septic AKI, furosemide rapidly restored medullary Po 2 to preseptic levels. This effect was not accompanied by changes in medullary perfusion or renal oxygen delivery but was accompanied by a transient increase in fractional sodium excretion, implying decreased oxygen consumption as a mechanism.

Purpose: We assessed the incidence, characteristics, outcomes and associations of small, short-term point-of-care creatinine increases in critically ill patients., Methods: We prospectively identified the first episode of small (>1 μmol/L/h) short-term (3-4 h) point-of-care creatinine increase between two sequential arterial blood gas measurements. We followed patients for the subsequent development of Kidney Disease: Improving Global Outcomes (KDIGO) defined acute kidney injury (AKI) in the intensive care unit (ICU)., Results: Of 387 patients, 279 (72.1%) developed an episode of small short-term point-of-care creatinine increase and 212 (54.8%) developed AKI. Such episodes occurred at a median of 5 (IQR 2-10) hours after ICU admission, while AKI occurred at a median of 15 (IQR 9-28) hours after admission. Patients with such episodes were more likely to be mechanically ventilated on admission (83.9 vs. 44.4%; p < .001) and had higher hospital mortality (10.9 vs. 3.7%, p = .03). Creatinine increase episodes had a sensitivity of 86% (95% CI 78-95) and specificity of 31% (95% CI 26-36) for subsequent AKI stages 2 and 3 in 24 h., Conclusions: Small, short-term point-of-care creatinine increase episodes are common. They are associated with illness severity, occur early, precede AKI by 10 h and are sensitive rather than specific markers of AKI., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Importance: Net ultrafiltration (NUF) is frequently used to treat fluid overload among critically ill patients, but whether the rate of NUF affects outcomes is unclear., Objective: To examine the association of NUF with survival among critically ill patients with acute kidney injury being treated with continuous venovenous hemodiafiltration., Design, Setting, and Participants: The Randomized Evaluation of Normal vs Augmented Level (RENAL) of Renal Replacement Therapy trial was conducted between December 30, 2005, and November 28, 2008, at 35 intensive care units in Australia and New Zealand among critically ill adults with acute kidney injury who were being treated with continuous venovenous hemodiafiltration. This secondary analysis began in May 2018 and concluded in January 2019., Exposures: Net ultrafiltration rate, defined as the volume of fluid removed per hour adjusted for patient body weight., Main Outcomes and Measures: Risk-adjusted 90-day survival., Results: Of 1434 patients, the median (interquartile range) age was 67.3 (56.9-76.3) years; 924 participants (64.4%) were male; median (interquartile range) Acute Physiology and Chronic Health Evaluation III score was 100 (84-118); and 634 patients (44.2%) died. Using tertiles, 3 groups were defined: high, NUF rate greater than 1.75 mL/kg/h; middle, NUF rate from 1.01 to 1.75 mL/kg/h; and low, NUF rate less than 1.01 mL/kg/h. The high-tertile group compared with the low-tertile group was not associated with death from day 0 to 6. However, death occurred in 51 patients (14.7%) in the high-tertile group vs 30 patients (8.6%) in the low-tertile group from day 7 to 12 (adjusted hazard ratio [aHR], 1.51; 95% CI, 1.13-2.02); 45 patients (15.3%) in the high-tertile group vs 25 patients (7.9%) in the low-tertile group from day 13 to 26 (aHR, 1.52; 95% CI, 1.11-2.07); and 48 patients (19.2%) in the high-tertile group vs 29 patients (9.9%) in the low-tertile group from day 27 to 90 (aHR, 1.66; 95% CI, 1.16-2.39). Every 0.5-mL/kg/h increase in NUF rate was associated with increased mortality (3-6 days: aHR, 1.05; 95% CI, 1.00-1.11; 7-12 days: aHR, 1.08; 95% CI, 1.02-1.15; 13-26 days: aHR, 1.11; 95% CI, 1.04-1.18; 27-90 days: aHR, 1.13; 95% CI, 1.05-1.22). Using longitudinal analyses, increase in NUF rate was associated with lower survival (β = .056; P < .001). Hypophosphatemia was more frequent among patients in the high-tertile group compared with patients in the middle-tertile group and patients in the low-tertile group (high: 308 of 477 patients at risk [64.6%]; middle: 293 of 472 patients at risk [62.1%]; low: 247 of 466 patients at risk [53.0%]; P < .001). Cardiac arrhythmias requiring treatment occurred among all groups: high, 176 patients (36.8%); middle: 175 patients (36.5%); and low: 147 patients (30.8%) (P = .08)., Conclusions and Relevance: Among critically ill patients, NUF rates greater than 1.75 mL/kg/h compared with NUF rates less than 1.01 mL/kg/h were associated with lower survival. Residual confounding may be present from unmeasured risk factors, and randomized clinical trials are required to confirm these findings., Trial Registration: ClinicalTrials.gov identifier: NCT00221013.

Background: The association between intraoperative oliguria during major abdominal surgery and the subsequent development of postoperative acute kidney injury (AKI) remains poorly defined. We hypothesised that, in such patients, intraoperative oliguria would be an independent predictor of subsequent AKI., Methods: We performed a post hoc analysis of data from the Restrictive versus Liberal Fluid Therapy in Major Abdominal Surgery (RELIEF) trial of conservative vs liberal fluid therapy during and after major abdominal surgery. We used χ 2 , logistic regression, and fractional polynomials to study the association between intraoperative oliguria defined as a urinary output <0.5 ml kg -1 h -1 and the development of postoperative AKI defined by the Kidney Disease Improving Global Outcomes consensus criteria., Results: We included 2444 of 2983 patients from the RELIEF trial in this study. A total of 889 patients (36%) met oliguric criteria intraoperatively. Oliguria occurred in 35% of those without AKI, and 44%, 48%, and 45% of those who developed postoperative AKI Stages 1-3, respectively (P<0.001 for trend). Intraoperative oliguria was associated with an increased risk of AKI, risk ratio: 1.38 (95% confidence interval: 1.14-1.44; P<0.001), but greater intensity of oliguria (urine output <0.3 ml kg -1 h -1 ) did not increase this risk further. Most patients with oliguria did not develop AKI; the positive predictive value of oliguria was 25.5%, and the negative predictive value was 81.6%., Conclusions: Intraoperative oliguria, defined as urine output <0.5 ml kg -1 h -1 , was relatively common and was associated with postoperative AKI. However, the predictive utility of oliguria for AKI was low, whilst its absence had a good predictive value for an AKI-free postoperative course., Clinical Trial Registration: NCT01424150., (Copyright © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Renal medullary hypoxia may contribute to cardiac surgery-associated acute kidney injury (AKI). However, the effects of cardiopulmonary bypass (CPB) on medullary oxygenation are poorly understood. Here we tested whether CPB causes medullary hypoxia and whether medullary oxygenation during CPB can be improved by increasing pump flow or mean arterial pressure (MAP). Twelve sheep were instrumented to measure whole kidney, medullary, and cortical blood flow and oxygenation. Five days later, under isoflurane anesthesia, CPB was initiated at a pump flow of 80 mL kg -1 min -1 and target MAP of 70 mm Hg. Pump flow was then set at 60 and 100 mL kg -1 min -1 , while MAP was maintained at approximately 70 mm Hg. MAP was then increased by vasopressor (metaraminol, 0.2-0.6 mg/min) infusion at a pump flow of 80 mL kg -1 min -1 . CPB at 80 mL kg -1 min -1 reduced renal blood flow (RBF), -61% less than the conscious state, perfusion in the cortex (-44%) and medulla (-40%), and medullary Po 2 from 43 to 27 mm Hg. Decreasing pump flow from 80 to 60 mL kg -1 min -1 further decreased RBF (-16%) and medullary Po 2 from 25 to 14 mm Hg. Increasing pump flow from 80 to 100 mL kg -1 min -1 increased RBF (17%) and medullary Po 2 from 20 to 29 mm Hg. Metaraminol (0.2 mg/min) increased MAP from 63 to 90 mm Hg, RBF (47%), and medullary Po 2 from 19 to 39 mm Hg. Thus, the renal medulla is susceptible to hypoxia during CPB, but medullary oxygenation can be improved by increasing pump flow or increasing target MAP by infusion of metaraminol., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether a continuous intravenous infusion of standard amino acids could preserve kidney function after on-pump cardiac surgery., Methods: Adult patients scheduled to receive cardiac surgery lasting longer than 1 hour on-pump were randomized to standard care (n = 36) or an infusion of amino acids initiated immediately after induction of anesthesia (n = 33). The study's primary outcome measurements assessed renal function. These assessments included duration of renal dysfunction, duration and severity of acute kidney injury (AKI), estimated glomerular filtration rate (eGFR) over time, urine output, and use of renal-replacement therapy. Complications and other measures of morbidity were also assessed., Results: Sixty-nine patients (mean age 71.5 [standard deviation 9.2] years; 19 of 69 women) were enrolled and randomized. Patients received coronary artery bypass graft surgery (37/69), valve surgery (24/69), coronary artery bypass graft and valve surgery (6/69), or other procedures (2/69). Mean on-pump time was 268 [standard deviation 136] minutes. Duration of renal dysfunction did not differ between the groups (relative risk, 0.86; 95% confidence interval [CI], 0.19-3.79, P = .84). However, patients who received the amino acid infusion had a reduced duration of AKI (relative risk, 0.02; 95% CI, 0.005-0.11, P < .0001) and greater eGFR (+10.8%; 95% CI, 1.0%-20.8%, P = .033). Daily mean urine output was also significantly greater in patients who received the amino acid infusion (1.4 ± 0.5 vs 1.7 ± 0.9 L/d; P = .046)., Conclusions: Commencing an infusion of standard amino acids immediately after the induction of anesthesia did not alter duration of renal dysfunction; however, other key measures of renal function (duration of AKI, eGFR and urine output) were significantly improved. These results warrant replication in multicenter clinical trials., (Copyright © 2018 The American Association for Thoracic Surgery. All rights reserved.)

Aim: To evaluate the prognostic value of baseline SOFA coagulation score (SOFA-CS) and change in platelet counts in patients with severe acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT)., Methods: We performed a secondary analysis from the Randomized Evaluation of Normal versus Augmented Level of RRT (RENAL) study. The primary endpoint was all-cause mortality at 90 days after randomization. The association between baseline SOFA-CS, changes in platelet counts, process of care, and clinical outcomes were analyzed using multivariate Cox model adjusted for baseline variables., Results: The complete SOFA-CS data were available in 1454 out of 1508 patients from the RENAL study. Among them, 708 patients had an abnormal SOFA-CS (defined as SOFA-CS ≥ 1), while 746 patients had normal SOFA-CS at baseline (SOFA-CS = 0). An abnormal SOFA-CS was independently associated with an increased risk of death at 90 days (HR = 1.27, 95% CI = 1.05-1.53, P = 0.015). An abnormal SOFA-CS was associated with prolonged length of ICU stay and duration of mechanical ventilation as well. Furthermore, there was no significant association between changes in platelet counts in patients who survived beyond 4 days and 90 day mortality (HR = 1.26, 95% CI = 0.29-5.56, P = 0.76). However, on multivariable analysis a decline of ≥60% (HR = 1.93, 95% CI = 1.23-3.05, P = 0.004) was associated with 90 day mortality in patients who survived beyond the first 4 days., Conclusions: In the RENAL study, thrombocytopaenia is a common phenomenon in patients with severe AKI receiving CRRT. An abnormal baseline SOFA-CS and reductions in platelet counts were associated with increased mortality at 90 days., (© 2018 Asian Pacific Society of Nephrology.)

Introduction: Supra-clinical doses of clonidine appear beneficial in experimental sepsis, but there is limited understanding of the effects of clonidine at clinically relevant doses., Methods: In conscious sheep, with implanted renal and pulmonary artery flow probes, sepsis was induced by infusion of live Escherichia coli. At 24 h, a high clinical dose of clonidine (HCDC) [1.0 μg/kg/h], a low clinical dose of clonidine (LCDC) [0.25 μg/kg/h] or vehicle, was infused for 8 h., Results: Animals developed hyperdynamic, hypotensive sepsis with acute kidney injury. The HCDC decreased heart rate (153 ± 6 to 119 ± 7 bpm) and cardiac output (5.6 ± 0.4 to 5.0 ± 0.4 L/min), with no reduction in mean arterial pressure (MAP). In contrast, LCDC increased cardiac output with peripheral vasodilatation. Both doses induced a large transient increase in urine output, an increase in plasma osmolality and, with the high dose, an increase in plasma arginine vasopressin. Sepsis increased plasma interleukin-6 (IL-6) and IL-10 and clonidine further increased IL-10 (1.6 ± 0.1 to 3.3 ± 0.7 ng/mL), but not IL-6. Clonidine reduced rectal temperature. During recovery from sepsis, MAP returned to baseline values more rapidly in the HCDC group (P < 0.001)., Conclusions: In hyperdynamic, hypotensive sepsis, the effects of clonidine at clinically relevant doses are complex and dose dependent. HCDC attenuated sepsis-related increases in heart rate and cardiac output, with little effect on arterial pressure. It also induced a water diuresis, increased AVP, reduced body temperature, and had an anti-inflammatory action. Low-dose clonidine had similar but less pronounced effects, except that it induced moderate vasodilatation and increased cardiac output.

Purpose: To investigate the relationship between sex and mortality and whether menopause or the intensity of renal replacement therapy (RRT) modify this relationship in patients with severe septic acute kidney injury (AKI)., Materials and Methods: Post-hoc analysis of patients with sepsis included in the Randomized Evaluation of Normal versus Augmented Level renal replacement therapy (RENAL) trial., Results: Of 724 patients, 458 (63.3%) were male and 266 (36.7%) were female. The mean delivered effluent flow rate was 25.6 ± 7.4 ml/kg/h (80 ± 15% of prescribed dose) in males and 27.4 ± 7.6 ml/kg/h (83 ± 15% of prescribed dose) in females (p = .01). A total of 237 (51.7%) males and 118 (44.5%) females died within 90 days of randomization (p = .06). The adjusted hazard ratio (HR) for 90-day mortality was significantly decreased in females as compared with males (HR 0.74, 95% CI 0.57 to 0.96, p = .02). The relationship between sex and mortality was not significantly altered by menopausal status (adjusted P value for interaction 0.99) or by RRT intensity allocation (adjusted P value for interaction 0.27)., Conclusions: In a cohort of patients with sepsis and severe AKI, female sex was associated with improved survival. The relationship between sex and survival was not altered by menopausal status or RRT intensity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

AKI is a common complication of sepsis and is significantly associated with mortality. Sepsis accounts for more than 50% of the cases of AKI, with a mortality rate of up to 40%. The pathogenesis of septic AKI is complex, but there is emerging evidence that, at least in the first 48 hours, the defects may be functional rather than structural in nature. For example, septic AKI is associated with an absence of histopathological changes, but with microvascular abnormalities and tubular stress. In this context, renal medullary hypoxia due to redistribution of intra-renal perfusion is emerging as a critical mediator of septic AKI. Clinically, vasopressor drugs remain the cornerstone of therapy for maintenance of blood pressure and organ perfusion. However, in septic AKI, there is insensitivity to vasopressors such as norepinephrine, leading to persistent hypotension and organ failure. Vasopressin, angiotensin II, and, paradoxically, α 2 -adrenergic receptor agonists (clonidine and dexmedetomidine) may be feasible adjunct therapies for catecholamine-resistant vasodilatory shock. In this review, we outline the recent progress made in understanding how these drugs may influence the renal microcirculation, which represents a crucial step toward developing better approaches for the circulatory management of patients with septic AKI., (© 2018 John Wiley & Sons Ltd.)