From ICU Syndromes to ICU Subphenotypes: Consensus Report and Recommendations for Developing Precision Medicine in the ICU.

Critical care uses syndromic definitions to describe patient groups for clinical practice and research. There is growing recognition that a "precision medicine" approach is required and that integrated biologic and physiologic data identify reproducible subpopulations that may respond differently to treatment. This article reviews the current state of the field and considers how to successfully transition to a precision medicine approach. To impact clinical care, identification of subpopulations must do more than differentiate prognosis. It must differentiate response to treatment, ideally by defining subgroups with distinct functional or pathobiological mechanisms (endotypes). There are now multiple examples of reproducible subpopulations of sepsis, acute respiratory distress syndrome, and acute kidney or brain injury described using clinical, physiological, and/or biological data. Many of these subpopulations have demonstrated the potential to define differential treatment response, largely in retrospective studies, and that the same treatment-responsive subpopulations may cross multiple clinical syndromes (treatable traits). To bring about a change in clinical practice, a precision medicine approach must be evaluated in prospective clinical studies requiring novel adaptive trial designs. Several such studies are underway, but there are multiple challenges to be tackled. Such subpopulations must be readily identifiable and be applicable to all critically ill populations around the world. Subdividing clinical syndromes into subpopulations will require large patient numbers. Global collaboration of investigators, clinicians, industry, and patients over many years will therefore be required to transition to a precision medicine approach and ultimately realize treatment advances seen in other medical fields.

Acute kidney injury in patients with cirrhosis: Acute Disease Quality Initiative (ADQI) and International Club of Ascites (ICA) joint multidisciplinary consensus meeting.

Patients with cirrhosis are prone to developing acute kidney injury (AKI), a complication associated with a markedly increased in-hospital morbidity and mortality, along with a risk of progression to chronic kidney disease. Whereas patients with cirrhosis are at increased risk of developing any phenotype of AKI, hepatorenal syndrome (HRS), a specific form of AKI (HRS-AKI) in patients with advanced cirrhosis and ascites, carries an especially high mortality risk. Early recognition of HRS-AKI is crucial since administration of splanchnic vasoconstrictors may reverse the AKI and serve as a bridge to liver transplantation, the only curative option. In 2023, a joint meeting of the International Club of Ascites (ICA) and the Acute Disease Quality Initiative (ADQI) was convened to develop new diagnostic criteria for HRS-AKI, to provide graded recommendations for the work-up, management and post-discharge follow-up of patients with cirrhosis and AKI, and to highlight priorities for further research.

The Role of Cell Cycle Arrest Biomarkers for Predicting Acute Kidney Injury in Critically Ill COVID-19 Patients: A Multicenter, Observational Study.

OBJECTIVES: Patients with COVID-19-associated acute respiratory distress syndrome (ARDS) have a high risk for developing acute kidney injury (AKI) which is associated with an increased risk of death and persistent renal failure. Early prediction of AKI is crucial in order to implement preventive strategies. The purpose of this study was to investigate the predictive performance of tissue inhibitor of metalloproteinases 2 and insulin like growth factor binding protein 7 (TIMP-2) × (IGFBP7) in critically ill patients with COVID-19-associated ARDS. DESIGN: Multicenter, prospective, observational study. SETTING: Twelve centers across Europe and United Kingdom. PATIENTS: Patients with moderate or severe COVID-19-associated ARDS were included and serial measurements of (TIMP-2) × (IGFBP7) were performed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the development of moderate or severe AKI according to the Kidney Disease: Improving Global Outcomes definition. Three hundred patients were available for the primary analysis, and 39 met the primary endpoint. At enrollment, urinary (TIMP-2) × (IGFBP7) had high predictive value for the primary endpoint with an area under the receiver operating characteristic curve of 0.89 (95% CI, 0.84-0.93). (TIMP-2) × (IGFBP7) was significantly higher in endpoint-positive patients at enrollment and at 12 hours. CONCLUSIONS: Urinary (TIMP-2) × (IGFBP7) predicts the occurrence of AKI in critically ill patients with COVID-19-associated ARDS.

The Role of Erythropoietin Levels in Predicting Long-Term Outcomes following Severe Acute Kidney Injury.

INTRODUCTION: Acute kidney injury (AKI) survivors are at an increased risk of chronic kidney disease, end-stage kidney disease, and mortality. Little is known about the effect of erythropoietin (EPO), a kidney-producing hormone, in post-AKI setting. We aimed to investigate the role of EPO as a predictor of long-term outcomes in post-severe AKI survivors. METHODS: We performed a retrospective analysis of post-AKI cohort conducted between August 2018 and December 2021. Adults who survived severe AKI stages 2-3 were enrolled. Serum EPO was obtained at 1 month after hospital discharge. We explored whether EPO level could predict long-term kidney outcomes at 12 months including mortality, kidney replacement therapy, doubling serum creatinine, and major adverse kidney events at 365 days. RESULTS: One hundred and twelve patients were enrolled. Median EPO level was significantly higher in non-survivors than survivors (28.9 [interquartile range: 16.2-50.7] versus 11.6 mU/mL [7.5-22.3], p = 0.003). The best EPO level cut-off was 16.2 mU/mL (sensitivity 77.8%, specificity 62.1%). Serum EPO predicted 12-month mortality with an area under the curve (AUC) of 0.69. Combining clinical model using age, baseline, and discharge kidney function with serum EPO improved prediction with AUC of 0.74. Multivariable analysis demonstrated that high-level of EPO group had significantly higher mortality compared with low-level EPO group (15.2% vs. 3.0%, p = 0.020). Hematocrit was significantly lower in high-level EPO group compared with low-level EPO group at 12 months (33.4 ± 1.1% vs. 36.0 ± 0.9%, p = 0.038). CONCLUSIONS: Plasma EPO appears to be a useful marker for predicting long-term outcome in post-severe AKI survivors.

Angiotensin II infusion in COVID-19: An international, multicenter, registry-based study.

To expand our understanding of the role of angiotensin II (ANGII) in coronavirus infectious disease 2019 (COVID-19), we conducted an international, multicenter registry study to assess the use of ANGII in patients with COVID-19 compared to patients not receiving ANGII. Critically ill adult patients who were diagnosed with COVID-19 and received ANGII were matched with COVID-19 patients not receiving ANGII according to age, respiratory support, history of hypertension, use of angiotensin-converting enzyme inhibitors and/or ANGII receptor blocker, and date of admission. All outcomes were exploratory in nature and included improvement in oxygenation, duration of organ support, and mortality. In one year, 132 patients were included (65 in the ANGII group and 67 in the control group), and patients were comparable in baseline characteristics. During the first 12 h of infusion, patients in the ANGII had a faster decrease in FiO2  and maintained similar mean arterial pressure levels. Hospital mortality was not statistically significantly different between the groups (53.8% vs. 40.3%; p = 0.226). Within the limitations of such a study design, our findings confirm previous observations of a potentially positive effect of ANGII on blood pressure and FiO2 but no effect on patient-centered outcomes.

Delayed versus early initiation of renal replacement therapy for severe acute kidney injury: a systematic review and individual patient data meta-analysis of randomised clinical trials.

BACKGROUND: The timing of renal replacement therapy (RRT) for severe acute kidney injury is highly debated when no life-threatening complications are present. We assessed whether a strategy of delayed versus early RRT initiation affects 28-day survival in critically ill adults with severe acute kidney injury. METHODS: In this systematic review and individual patient data meta-analysis, we searched MEDLINE (via PubMed), Embase, and the Cochrane Central Register of Controlled Trials for randomised trials published from April 1, 2008, to Dec 20, 2019, that compared delayed and early RRT initiation strategies in patients with severe acute kidney injury. Trials were eligible for inclusion if they included critically ill patients aged 18 years or older with acute kidney injury (defined as a Kidney Disease: Improving Global Outcomes [KDIGO] acute kidney injury stage 2 or 3, or, where KDIGO was unavailable, a renal Sequential Organ Failure Assessment score of 3 or higher). We contacted the principal investigator of each eligible trial to request individual patient data. From the included trials, any patients without acute kidney injury or who were not randomly allocated were not included in the individual patient data meta-analysis. The primary outcome was all-cause mortality at day 28 after randomisation. This study is registered with PROSPERO (CRD42019125025). FINDINGS: Among the 1031 studies identified, one study that met the eligibility criteria was excluded because the recruitment period was not recent enough, and ten (including 2143 patients) were included in the analysis. Individual patient data were available for nine studies (2083 patients), from which 1879 patients had severe acute kidney injury and were randomly allocated: 946 (50%) to the delayed RRT group and 933 (50%) to the early RRT group. 390 (42%) of 929 patients allocated to the delayed RRT group and who had available data did not receive RRT. The proportion of patients who died by day 28 did not significantly differ between the delayed RRT group (366 [44%] of 837) and the early RRT group (355 [43%] of 827; risk ratio 1·01 [95% CI 0·91 to 1·13], p=0·80), corresponding to an overall risk difference of 0·01 (95% CI -0·04 to 0·06). There was no heterogeneity across studies (I2=0%; τ2=0), and most studies had a low risk of bias. INTERPRETATION: The timing of RRT initiation does not affect survival in critically ill patients with severe acute kidney injury in the absence of urgent indications for RRT. Delaying RRT initiation, with close patient monitoring, might lead to a reduced use of RRT, thereby saving health resources. FUNDING: None.

Definitions of acute renal dysfunction: an evolving clinical and biomarker paradigm.

PURPOSE OF REVIEW: The current definition and classification of acute kidney injury (AKI) has limitations and shortcomings, which impact clinical management. The aim of this review is to highlight recent advances in our understanding of the pathophysiology and epidemiology of AKI, which impacts management and offers opportunities. RECENT FINDINGS: Kidney damage varies according to the type of primary insult, secondary effects and mitigating responses and leads to distinct molecular, cellular and functional changes. Different sub-types of AKI with varying clinical phenotypes, recovery patterns and responses to therapeutic interventions have been identified. New tools to identify and characterize these AKI sub-types are available with the potential opportunity for individualized timely aetiology-based management of AKI. SUMMARY: The identification of different sub-phenotypes of AKI based on genetic, molecular, cellular and functional pathophysiological changes following potential nephrotoxic exposures is possible with new technologies. This offers opportunities for personalized management of AKI and supports the call for a refinement of the existing AKI criteria.

Nutritional assessment and support during continuous renal replacement therapy.

Malnutrition is highly prevalent in patients with acute kidney injury, especially in those receiving renal replacement therapy (RRT). For the assessment of nutritional status, a combination of screening tools, anthropometry, and laboratory parameters is recommended rather than a single test. To avoid underfeeding and overfeeding during RRT, energy expenditure should be measured by indirect calorimetry or calculated using predictive equations. Nitrogen balance should be periodically measured to assess the degree of catabolism and to evaluate protein intake. However, there is limited data for nutritional targets specifically for patients on RRT, such as protein intake. The composition of commercial solutions for continuous renal replacement therapy (CRRT) varies. CRRT itself can be associated with both, nutrient losses into the effluent fluid and caloric gain from dextrose, lactate, and citrate. The role of micronutrient supplementation, and potential use of micronutrient enriched CRRT solutions in this setting is unknown, too. This review provides an overview of existing knowledge and uncertainties related to nutritional aspects in patients on CRRT and emphasizes the need for more research in this area.

Acute kidney injury in ECMO patients.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2021. Other selected articles can be found online at  https://www.biomedcentral.com/collections/annualupdate2021 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from  https://link.springer.com/bookseries/8901 .

Clearance of inflammatory cytokines in patients with septic acute kidney injury during renal replacement therapy using the EMiC2 filter (Clic-AKI study).

BACKGROUND: The EMiC2 membrane is a medium cut-off haemofilter (45 kiloDalton). Little is known regarding its efficacy in eliminating medium-sized cytokines in sepsis. This study aimed to explore the effects of continuous veno-venous haemodialysis (CVVHD) using the EMiC2 filter on cytokine clearance. METHODS: This was a prospective observational study conducted in critically ill patients with sepsis and acute kidney injury requiring kidney replacement therapy. We measured concentrations of 12 cytokines [Interleukin (IL) IL-1ß, IL-1α, IL-2, IL-4, IL-6, IL-8, IL-10, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, vascular endothelial growth factor, monocyte chemoattractant protein (MCP)-1, epidermal growth factor (EGF)] in plasma at baseline (T0) and pre- and post-dialyzer at 1, 6, 24, and 48 h after CVVHD initiation and in the effluent fluid at corresponding time points. Outcomes were the effluent and adsorptive clearance rates, mass balances, and changes in serial serum concentrations. RESULTS: Twelve patients were included in the final analysis. All cytokines except EGF concentrations declined over 48 h (p < 0.001). The effluent clearance rates were variable and ranged from negligible values for IL-2, IFN-γ, IL-1α, IL-1ß, and EGF, to 19.0 ml/min for TNF-α. Negative or minimal adsorption was observed. The effluent and adsorptive clearance rates remained steady over time. The percentage of cytokine removal was low for most cytokines throughout the 48-h period. CONCLUSION: EMiC2-CVVHD achieved modest removal of most cytokines and demonstrated small to no adsorptive capacity despite a decline in plasma cytokine concentrations. This suggests that changes in plasma cytokine concentrations may not be solely influenced by extracorporeal removal. TRIAL REGISTRATION: NCT03231748, registered on 27th July 2017.

Comprehensive versus standard care in post-severe acute kidney injury survivors, a randomized controlled trial.

BACKGROUND: Currently, there is a lack of evidence to guide optimal care for acute kidney injury (AKI) survivors. Therefore, post-discharge care by a multidisciplinary care team (MDCT) may improve these outcomes. This study aimed to demonstrate the outcomes of implementing comprehensive care by a MDCT in severe AKI survivors. METHODS: This study was a randomized controlled trial conducted between August 2018 to January 2021. Patients who survived severe AKI stage 2-3 were enrolled and randomized to be followed up with either comprehensive or standard care for 12 months. The comprehensive post-AKI care involved an MDCT (nephrologists, nurses, nutritionists, and pharmacists). The primary outcome was the feasibility outcomes; comprising of the rates of loss to follow up, 3-d dietary record, drug reconciliation, and drug alert rates at 12 months. Secondary outcomes included major adverse kidney events, estimated glomerular filtration rate (eGFR), and the amount of albuminuria at 12 months. RESULTS: Ninety-eight AKI stage 3 survivors were enrolled and randomized into comprehensive care and standard care groups (49 patients in each group). Compared to the standard care group, the comprehensive care group had significantly better feasibility outcomes; 3-d dietary record, drug reconciliation, and drug alerts (p < 0.001). The mean eGFR at 12 months were comparable between the two groups (66.74 vs. 61.12 mL/min/1.73 m2, p = 0.54). The urine albumin: creatinine ratio (UACR) was significantly lower in the comprehensive care group (36.83 vs. 177.70 mg/g, p = 0.036), while the blood pressure control was also better in the comprehensive care group (87.9% vs. 57.5%, p = 0.006). There were no differences in the other renal outcomes between the two groups. CONCLUSIONS: Comprehensive care by an MDCT is feasible and could be implemented for severe AKI survivors. MDCT involvement also yields better reduction of the UACR and better blood pressure control. Trial registration Clinicaltrial.gov: NCT04012008 (First registered July 9, 2019).

Development and validation of point-of-care testing of albuminuria for early screening of chronic kidney disease.

INTRODUCTION: Chronic kidney disease (CKD) is a significant global health issue. As the prevalence of renal replacement therapy (RRT) in Thailand is increasing, early detection and management of CKD is the most important step to prevent CKD progression and the need for RRT. Current diagnostic tests for CKD are non-specific and expensive. We aimed to develop and validate antibody-based-albumin point-of-care testing (POCT) to detect patients with impaired kidney function at early stage. METHODS: The prototype strip test was developed under the concept of competitive lateral flow immunochromatography assay, or strip test. Monoclonal antibodies (MAbs) to human serum albumin (HSA) were harvested from the hybridomas of spleen cells from immunized mice and mouse myeloma cells. Presence of MAbs was detected by enzyme-linked immunosorbent assay (ELISA). Spot urine was obtained from patients with kidney disease, type I, or type II Diabetes Mellitus upon their visit at King Chulalongkorn Memorial Hospital during 2018-2019. All samples were analyzed for urine albumin with our POCT (CU microalbumin) and the other two commercial POCTs (Microalbu PHAN and MICRAL). The results were validated against standard method for urine microalbumin measurement. A urine microalbumin concentration of less than 20 ug/ml was defined as normal. The sensitivity, specificity, and predictive values were calculated in comparison with the standard laboratory method. RESULT: A total of 100 adult patients were included. CU microalbumin had a sensitivity of 86%, a specificity of 94%, and a positive predictive value of 96%. Our POCT showed good correlation with the laboratory results. CONCLUSION: CU microalbumin correlated well with the standard method for quantitative measurement of urine albumin. Therefore, it has the potential for early screening of CKD, especially in primary health care facilities in resource limited settings.

Epidemiology and short-term outcomes of acute kidney injury among patients in the intensive care unit in Laos: a nationwide multicenter, prospective, and observational study.

BACKGROUND: Acute kidney injury (AKI) has become a global health issue. Little is known about the disease burden in Laos. We aimed to evaluate the burden and outcomes of AKI as well as assess the availability of AKI treatment in Laos. METHODS: We performed a multicentric prospective observational study in adult patients who had been admitted to 5 intensive care units (ICU) in Laos. The data was serially collected on the first 28 days of ICU admission. Patients were diagnosed by the KDIGO 2012 criteria for AKI. We used AKI occurrence as the primary outcome and explored risk factors on the development and outcomes of AKI. RESULTS: We enrolled 1480 patients from 5 ICU centers across Laos from January to December 2016. After excluding patients with end-stage renal disease and those with incomplete data, AKI occurred in 508 of the 1460 enrolled patients (34.8%). Overall, the rates of maximum AKI staging were 4% for stage 1, 10.3% for stage 2, and 20.5% for stage 3. Risk factors for AKI were older age, obesity, cardiovascular diseases, respiratory diseases, renal diseases, oncologic diseases, and chronic kidney diseases. Only 1.8% of all participants received RRT. The mortality rate was 28.4% in non-AKI patients compared to 44.5% in AKI patients, which increased according to the stage of AKI (stage 1, 4.9%; stage 2, 28.3%; stage 3 66.8%; P < 0.001). There were 13.6% who were discharged against medical advice. CONCLUSIONS: AKI is a huge burden in Laos with under-recognition and poor outcomes.

The epidemiology and characteristics of acute kidney injury in the Southeast Asia intensive care unit: a prospective multicentre study.

BACKGROUND: Etiologies for acute kidney injury (AKI) vary by geographic region and socioeconomic status. While considerable information is now available on AKI in the Americas, Europe and China, large comprehensive epidemiologic studies of AKI from Southeast Asia (SEA) are still lacking. The aim of this study was to investigate the rates and characteristics of AKI among intensive care unit (ICU) patients in Thailand. METHODS: We conducted the largest prospective observational study of AKI in SEA. The data were serially collected on the first 28 days of ICU admission by registration in electronic web-based format. AKI status was defined by full Kidney Disease: Improving Global Outcome criteria. We used AKI occurrence as the clinical outcome and explored the impact of modifiable and non-modifiable risk factors on the development and progression of AKI. RESULTS: We enrolled 5476 patients from 17 ICU centres across Thailand from February 2013 to July 2015. After excluding patients with end-stage renal disease and those with incomplete data, AKI occurred in 2471 of 4668 patients (52.9%). Overall, the maximum AKI stage was Stage 1 in 7.5%, Stage 2 in 16.5% and Stage 3 in 28.9%. In the multivariable adjusted model, we found that older age, female sex, admission to a regional hospital, medical ICU, high body mass index, primary diagnosis of cardiovascular-related disease and infectious disease, higher Acute Physiology and Chronic Health Evaluation II, non-renal Sequential Organ Failure Assessment scores, underlying anemia and use of vasopressors were all independent risk factors for AKI development. CONCLUSIONS: In Thai ICUs, AKI is very common. Identification of risk factors of AKI development will help in the development of a prognostic scoring model for this population and should help in decision making for timely intervention, ultimately leading to better clinical outcomes.

Precision renal replacement therapy.

PURPOSE OF REVIEW: This article reviews the current evidence supporting the use of precision medicine in the delivery of acute renal replacement therapy (RRT) to critically ill patients, focusing on timing, solute control, anticoagulation and technologic innovation. RECENT FINDINGS: Precision medicine is most applicable to the timing of RRT in critically ill patients. As recent randomized controlled trials have failed to provide consensus on when to initiate acute RRT, the decision to start acute RRT should be based on individual patient clinical characteristics (e.g. severity of the disease, evolution of clinical parameters) and logistic considerations (e.g. organizational issues, availability of machines and disposables). The delivery of a dynamic dialytic dose is another application of precision medicine, as patients may require different and varying dialysis doses depending on individual patient factors and clinical course. Although regional citrate anticoagulation (RCA) is recommended as first-line anticoagulation for continuous RRT, modifications to RCA protocols and consideration of other anticoagulants should be individualized to the patient's clinical condition. Finally, the evolution of RRT technology has improved precision in dialysis delivery through increased machine accuracy, connectivity to the electronic medical record and automated reduction of downtime. SUMMARY: RRT has become a complex treatment for critically ill patients, which allows for the prescription to be precisely tailored to the different clinical requirements.

Net ultrafiltration prescription survey in Europe.

BACKGROUND: Fluid overload is common in patients in the intensive care unit (ICU) and ultrafiltration (UF) is frequently required. There is lack of guidance on optimal UF practice. We aimed to explore patterns of UF practice, barriers to achieving UF targets, and concerns related to UF practice among practitioners working in Europe. METHODS: This was a sub-study of an international open survey with focus on adult intensivists and nephrologists, advanced practice providers, and ICU and dialysis nurses working in Europe. RESULTS: Four hundred eighty-five practitioners (75% intensivists) from 31 countries completed the survey. The most common criteria for UF initiation was persistent oliguria/anuria (45.6%), followed by pulmonary edema (16.7%). Continuous renal replacement therapy was the preferred initial modality (90.0%). The median initial and maximal rate of net ultrafiltration (UFNET) prescription in hemodynamically stable patients were 149 mL/hr. (IQR 100-200) and 300 mL/hr. (IQR 201-352), respectively, compared to a median UFNET rate of 98 mL/hr. (IQR 51-108) in hemodynamically unstable patients and varied significantly between countries. Two-thirds of nurses and 15.5% of physicians reported assessing fluid balance hourly. When hemodynamic instability occurred, 70.1% of practitioners reported decreasing the rate of fluid removal, followed by starting or increasing the dose of a vasopressor (51.3%). Most respondents (90.7%) believed in early fluid removal and expressed willingness to participate in a study comparing protocol-based fluid removal versus usual care. CONCLUSIONS: There was a significant variation in UF practice and perception among practitioners in Europe. Future research should focus on identifying the best strategies of prescribing and managing ultrafiltration in critically ill patients.

The effect of polymyxin B hemoperfusion on modulation of human leukocyte antigen DR in severe sepsis patients.

BACKGROUND: Recent randomized trials have not found that polymyxin B hemoperfusion (PMX-HP) improves outcomes for patients with sepsis. However, it remains unclear whether the therapy could provide benefit for highly selected patients. Monocyte human leukocyte antigen (mHLA-DR) expression, a critical step in the immune response, is decreased during sepsis and leads to worsening sepsis outcomes. One recent study found that PMX-HP increased mHLA-DR expression while another found that the treatment removed HLA-DR-positive cells. METHODS: We conducted a randomized controlled trial in patients with blood endotoxin activity assay (EAA) level ≥ 0.6. Patients in the PMX-HP group received a 2-h PMX-HP treatment plus standard treatment for 2 consecutive days. Patients in the non-PMX-HP group received only standard treatment. The primary outcome compared the groups on median change in mHLA-DR expression between day 3 and baseline. Secondary outcomes compared the groups on the mean or median change in CD11b expression, neutrophil chemotaxis, presepsin, cardiovascular Sequential Organ Failure Assessment (CVS SOFA) score, vasopressor dose, and EAA level between day 3 and baseline. We further compared the groups on mortality, ICU-free days, ventilator-free days, dialysis dependence status, renal recovery, serum creatinine, vasopressor-free days, and major adverse kidney events (MAKE 28), measured on day 28. RESULTS: Fifty-nine patients were randomized to PMX-HP (n = 29) and non-PMX-HP (n = 30) groups. At baseline, mHLA-DR expression, CD11b, neutrophil chemotaxis, and clinical parameters were comparable between groups. The median change in mHLA-DR expression between day 3 and baseline was higher in PMX-HP patients than in patients receiving standard therapy alone (P = 0.027). The mean change in CD11b between day 3 and baseline was significantly lower in the PMX-HP group than in the non-PMX-HP group (P = 0.002). There were no significant changes from baseline in neutrophil chemotaxis, presepsin, CVS SOFA scores, vasopressor doses, or EAA level between groups. On day 28 after enrollment, mortality, ICU-free days, ventilator-free days, dialysis dependence status, renal recovery, serum creatinine, vasopressor-free days, and MAKE 28 were comparable between groups. CONCLUSION: PMX-HP improved mHLA-DR expression in severe sepsis patients. Future studies should examine the potential benefit of PMX-HP in patients with low mHLA-DR expression. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02413541 . Registered on 3 March 2015.

Early versus standard initiation of renal replacement therapy in furosemide stress test non-responsive acute kidney injury patients (the FST trial).

BACKGROUND: The timing of initiation of renal replacement therapy (RRT) in severe acute kidney injury (AKI) remains controversial, with early initiation resulting in unnecessary therapy for some patients while expectant therapy may delay RRT for other patients. The furosemide stress test (FST) has been shown to predict the need for RRT and therefore could be used to exclude low-risk patients from enrollment in trials of RRT timing. We conducted this multicenter pilot study to determine whether FST could be used to screen patients at high risk for RRT and to determine the feasibility of incorporating FST into a trial of early initiation of RRT. METHODS: FST was performed using intravenous furosemide (1 mg/kg in furosemide-naive patients or 1.5 mg/kg in previous furosemide users). FST-nonresponsive patients (urine output less than 200 mL in 2 h) were then randomized to early (initiation within 6 h) or standard (initiation by urgent indication) RRT. RESULTS: FST was completed in all patients (100%). Only 6/44 (13.6%) FST-responsive patients ultimately received RRT while 47/60 (78.3%) nonresponders randomized to standard RRT either received RRT or died (P <  0.001). Among 118 FST-nonresponsive patients, 98.3% in the early RRT arm and 75% in the standard RRT arm received RRT. The adherence to the protocol was 94.8% and 100% in the early and standard RRT group, respectively. We observed no differences in 28-day mortality (62.1 versus 58.3%, P = 0.68), 7-day fluid balance, or RRT dependence at day 28. However, hypophosphatemia occurred more frequently in the early RRT arm (P = 0.002). CONCLUSION: The furosemide stress test appears to be feasible and effective in identifying patients for randomization to different RRT initiation times. Our findings should guide implementation of large-scale randomized controlled trials for the timing of RRT initiation. TRIAL REGISTRATION: clinicaltrials.gov, NCT02730117 . Registered 6 April 2016.