New biomarkers in acute kidney injury.

Acute kidney injury (AKI) is a commonly encountered clinical syndrome. Although it often complicates community acquired illness, it is more common in hospitalized patients, particularly those who are critically ill or who have undergone major surgery. Approximately 20% of hospitalized adult patients develop an AKI during their hospital care, and this rises to nearly 60% in the critically ill, depending on the population being considered. In general, AKI is more common in older adults, in those with preexisting chronic kidney disease and in those with known risk factors for AKI (including diabetes and hypertension). The development of AKI is associated with an increase in both mortality and morbidity, including the development of post-AKI chronic kidney disease. Currently, AKI is defined by a rise in serum creatinine from either a known or derived baseline value and/or oliguria or anuria. However, clinicians may fail to recognize the initial development of AKI because of a delay in the rise of serum creatinine or because of inaccurate urine output monitoring. This, in turn, delays any putative measures to treat AKI or to limit its degree. Consequently, efforts have focused on new biomarkers associated with AKI that may allow early recognition of this syndrome with the intent that this will translate into improved patient outcomes. Here we outline current biomarkers associated with AKI and explore their potential in aiding diagnosis, understanding the pathophysiology and directing therapy.

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

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

Vitamin D metabolism in critically ill patients with acute kidney injury: a prospective observational study.

BACKGROUND: Vitamin D deficiency in critically ill patients is associated with poor outcomes, and vitamin D supplementation is recommended for patients with chronic kidney disease. Whether acute kidney injury (AKI) is associated with altered Vitamin D metabolism is unknown. We aimed to compare the longitudinal profiles of serum 25(OH)D and 1,25(OH)2D concentrations in critically ill patients with and without moderate to severe AKI and explore the impact of renal recovery and parathyroid hormone (PTH). METHODS: In this prospective, observational study in two centres in the UK, critically ill patients with and without AKI underwent serial measurement of serum 25(OH)D and 1,25(OH)2D and plasma PTH concentrations for 5 days. Linear mixed model analysis and sensitivity analyses were performed. RESULTS: Serial data of 137 patients were analysed. Seventy-one patients had AKI stage II/III of whom 23 recovered kidney function during the 5-day study period; 66 patients did not have AKI at enrolment of whom 14 developed new AKI. On day of enrolment, patients' serum 25(OH)D concentrations were low (median 18 nmol/L) but there was no significant difference between patients with and without AKI. Median serum 1,25(OH)2D levels were significantly lower in patients with AKI II/III (41 pmol/L [IQR 26, 58]) compared to similarly unwell patients without AKI (54 pmol/L [IQR 33, 69]) during the 5-day period. Recovery of kidney function in patients with AKI was associated with a rise in 1,25(OH)2D concentrations. Plasma PTH results were impacted by serum calcium and magnesium levels but not associated with 1,25(OH)2D levels. CONCLUSIONS: Critically ill patients with moderate-to-severe AKI have significantly lower serum 1,25(OH)2D concentrations than similarly sick patients without AKI but there was no difference in serum 25(OH)D concentrations. Recovery of AKI was associated with a rise in serum 1,25(OH)2D concentrations. More research is needed to investigate the health benefits and safety of supplementation with active vitamin D in critically ill patients with moderate-to-severe AKI. Trial registration Clinicaltrials.gov (NCT02869919), registered on 16 May 2016.

CCL14 Predicts Oliguria and Dialysis Requirement in Patients with Moderate to Severe Acute Kidney Injury.

INTRODUCTION: AKI is a frequent complication of critical illness and portends poor outcome. CCL14 is a validated predictor of persistent severe AKI in critically ill patients. We examined the association of CCL14 with urine output within 48 h. METHODS: In pooled data from 2 studies of critically ill patients with KDIGO stage 2-3 AKI, CCL14 was measured by NEPHROCLEAR™ CCL14 Test on the Astute 140® Meter (low, intermediate, and high categories [1.3 and 13 ng/mL]). Average hourly urine output over 48 h, stage 3 AKI per urine output criterion on day 2, and composite of dialysis or death within 7 days were examined using multivariable mixed and logistic regression models. RESULTS: Of the 497 subjects with median age of 65 (56-74) years, 49% (242/497) were on diuretics. CCL14 concentration was low in 219 (44%), intermediate in 217 (44%), and high in 61 (12%) patients. In mixed regression analysis, hourly urine output over time was different within each CCL14 risk category based on diuretic use due to significant three-way interaction (p < 0.001). In logistic regression analysis, CCL14 risk category was independently associated with low urine output on day 2 per KDIGO stage 3 (adjusted for diuretic use and baseline clinical variables), and composite of dialysis or death within 7 days (adjusted for urine output within 48 h of CCL14 measurement). CONCLUSIONS: CCL14 measured in patients with moderate to severe AKI is associated with urine output trajectory within 48 h, oliguria on day 2, and dialysis within 7 days.

Assessing the role of Chemokine (C-C motif) ligand 14 in AKI: a European consensus meeting.

BACKGROUND: Urinary Chemokine (C-C motif) ligand 14 (CCL14) is a biomarker associated with persistent severe acute kidney injury (AKI). There is limited data to support the implementation of this AKI biomarker to guide therapeutic actions. METHODS: Sixteen AKI experts with clinical CCL14 experience participated in a Delphi-based method to reach consensus on when and how to potentially use CCL14. Consensus was defined as ≥ 80% agreement (participants answered with 'Yes', or three to four points on a five-point Likert Scale). RESULTS: Key consensus areas for CCL14 test implementation were: identifying challenges and mitigations, developing a comprehensive protocol and pairing it with a treatment plan, and defining the target population. The majority agreed that CCL14 results can help to prioritize AKI management decisions. CCL14 levels above the high cutoff (> 13 ng/mL) significantly changed the level of concern for modifying the AKI treatment plan (p < 0.001). The highest level of concern to modify the treatment plan was for discussions on renal replacement therapy (RRT) initiation for CCL14 levels > 13 ng/mL. The level of concern for discussion on RRT initiation between High and Low, and between Medium and Low CCL14 levels, showed significant differences. CONCLUSION: Real world urinary CCL14 use appears to provide improved care options to patients at risk for persistent severe AKI. Experts believe there is a role for CCL14 in AKI management and it may potentially reduce AKI-disease burden. There is, however, an urgent need for evidence on treatment decisions and adjustments based on CCL14 results.

Predicting the Development of Renal Replacement Therapy Indications by Combining the Furosemide Stress Test and Chemokine (C-C Motif) Ligand 14 in a Cohort of Postsurgical Patients.

OBJECTIVES: Optimal timing of renal replacement therapy (RRT) initiation in severe acute kidney injury (AKI) remains controversial. Initiation of treatment early in the course of AKI may lead to some patients undergoing unnecessary RRT, whereas delayed treatment is associated with increased mortality. This study aims to investigate whether the combination of the furosemide stress test (FST) and AKI-associated biomarkers can predict the development of indications for RRT. DESIGN: Single-center, prospective, observational study. SETTING: University Hospital of Muenster, Germany. PATIENTS: Critically ill, postoperative patients with moderate AKI (Kidney Disease: Improving Global Outcomes stage 2) and risk factors for further progression (vasopressors and/or mechanical ventilation) receiving an FST. INTERVENTIONS: Sample collection and measurement of different biomarkers (chemokine [C-C motif] ligand 14 [CCL14], neutrophil gelatinase-associated lipocalin, dipeptidyl peptidase 3). MEASUREMENT AND MAIN RESULTS: The primary endpoint was the development of greater than or equal to one predefined RRT indications (hyperkalemia [≥ 6 mmol/L], diuretic-resistant hypervolemia, high urea serum levels [≥ 150 mg/dL], severe metabolic acidosis [pH ≤ 7.15], oliguria [urinary output < 200 mL/12 hr], or anuria). Two hundred eight patients were available for the primary analysis with 108 having a negative FST (urine output < 200 mL in 2 hr following FST). Ninety-eight patients (47%) met the primary endpoint, 82% in the FST negative cohort. At the time of inclusion, the combination of a negative FST test and high urinary CCL14 levels had a significantly higher predictive value for the primary endpoint with an area under the receiver operating characteristic curve (AUC) of 0.87 (95% CI, 0.82-0.92) compared with FST or CCL14 alone (AUC, 0.79; 95% CI, 0.74-0.85 and AUC, 0.83; 95% CI, 0.77-0.89; p < 0.001, respectively). Other biomarkers showed lower AUCs. CONCLUSIONS: The combination of the FST with the renal biomarker CCL14 predicts the development of indications for RRT.

Real-World Use of AKI Biomarkers: A Quality Improvement Project Using Urinary Tissue Inhibitor Metalloprotease-2 and Insulin-Like Growth Factor Binding Protein 7 ([TIMP-2]*[IGFBP7]).

INTRODUCTION: Novel urinary biomarkers, including tissue inhibitor metalloprotease-2 and insulin-like growth factor binding protein 7 ([TIMP-2]*[IGFBP7]), have been developed to identify patients at risk for acute kidney injury (AKI). We investigated the "real-world" clinical utility of [TIMP-2]*[IGFBP7] in preventing AKI. METHODS: We performed a before and after single-center quality improvement study of intensive care unit (ICU) patients at risk for severe (KDIGO stage 2 or 3) AKI. In the prospective cohort, ICU providers were allowed to order [TIMP-2]*[IGFBP7] for patients at their discretion, then offered AKI practice recommendations based on the results. Outcomes were compared to a historical cohort in which biomarker values were not reported to clinical teams. RESULTS: There was no difference in 7-day progression to severe AKI between the prospective (n = 116) and historical cohorts (n = 63) when [TIMP-2]*[IGFBP7] ≥0.3 (24 [28%] versus 8 [21%], p = 0.38) despite more stage 1 AKI at time of biomarker measurement in the prospective cohort (58 [67%] versus 9 [23%], p < 0.001). In the prospective cohort, patients with higher [TIMP-2]*[IGFBP7] values were more likely to receive a nephrology consult. Early consultation (within 24 h of biomarker measurement, n = 20) had a nonsignificant trend toward net negative volume balance (-1,787 mL [6,716 mL] versus + 4,974 mL [15,540 mL]) and more diuretic use (19 [95%] versus 8 [80%]) and was associated with less severe AKI (9 [45%] versus 10 [100%], p = 0.004) and inpatient dialysis (2 [10%] versus 7 [70%], p = 0.002) compared to delayed consultation (n = 10). CONCLUSIONS: Despite the prospective cohort having more preexisting stage 1 AKI, there were equal rates of progression to severe AKI in the prospective and historical cohorts. In the setting of [TIMP-2]*[IGFBP7] reporting, there were more nephrology consults in response to elevated biomarker levels. Early nephrology consultation resulted in improved volume balance and favorable outcomes compared to delayed consultation.

When to discontinue renal replacement therapy. what do we know?

PURPOSE OF REVIEW: Acute kidney injury is common in intensive care patients. Supportive care involves the use of renal replacement therapies as organ support. Initiation of renal replacement therapy has been the subject of much interest over the last few years with several randomised controlled studies examining the optimal time to commence treatment. In contrast to this, little evidence has been generated regarding cessation of therapy. Given that this treatment is complex, not without risk and expensive it seems timely that efforts should be expended at examining this vexing issue. RECENT FINDINGS: Although several studies have been reported examining the successful discontinuation of renal replacement therapies all studies reported to-date are observational in nature. Conventional biochemical criteria have been used as well as physiological parameters including urine output. More recently, more novel biomarkers of renal function have been studied. Although to-date no optimal variable nor threshold for discontinuation can be established. SUMMARY: Several variables have been described which may have a role in determining which patients may be successfully weaned from renal replacement therapy. However, few have been exposed to vigorous examination and evidence is sparse in support of any potential approach although urine output currently is the most often described. More recently novel biomarkers have also been examined but again are limited by study design and heterogeneity. Further research is clearly needed focussing on proposed variables preferably in multivariate models to improve predictive ability and successful cessation of therapy.

Renal function in very old critically ill patients.

PURPOSE OF REVIEW: Current demographic change leads to higher number of elderly patients admitted to an ICU. Among other organs also the kidneys show age-related changes, which are associated with a decline in various aspects of renal function. The purpose of this review is to provide an overview of structural and functional changes in elderly and also to specifically address the increased risk of acute kidney injury (AKI) in this population. RECENT FINDINGS: Ageing in the kidneys is affected by many different factors, such as low grade chronic inflammation, called inflammageing, and various comorbidities. Nevertheless, a decrease of glomerular filtration rate (GFR) occurs independent of the presence of comorbidities and a steady decline of GFR has been reported in both healthy men and women. Pharmacodynamic of many drugs is altered by these changes. Additionally the rate of diuretic resistance appears to be increased. The cause of AKI occurrence in older age is, multifactorial and includes preventable triggers (hypovolemia, hypotension, nephrotoxins) as well as changes associated with aging. SUMMARY: Age-related alterations of the kidneys were found at microscopic and macroscopic levels of the cell. These changes lead to a reduced renal reserve and subsequently to an increased vulnerability of aged kidneys when an additional stressor is added. Age is an independent risk factor for developing AKI. Physicians should take into account the altered renal function in elderly patients and take renal protective measures at an early stage.

Proenkephalin as a biomarker correlates with acute kidney injury: a systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Proenkephalin A 119-159 (PENK) is freely filtered in the glomerulus with plasma levels correlating with glomerular filtration rate. Therefore, PENK has been proposed as an early indicator of acute kidney injury (AKI) although its performance is dependent on the clinical setting. This meta-analysis aimed to investigate the correlation between PENK levels and the development of AKI. METHODS: We conducted a comprehensive search on the PubMed, Embase, Cochrane databases, the website ClinicalTrials.gov and Cnki.net until June 26, 2023. Summary receiver operating characteristic (SROC) curves were used to amalgamate the overall test performance. Diagnostic odds ratio (DOR) was employed to compare the diagnostic accuracy of PENK with other biomarkers. Quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria. RESULTS: We incorporated 11 observational studies with 3969 patients with an incidence of AKI of 23.4% (929 out of 3969 patients) with the best optimal cutoff value of PENK for early detection of AKI being 57.3 pmol/L. The overall sensitivity and specificity of PENK in identifying AKI were 0.69 (95% CI 0.62-0.75) and 0.76 (95% CI 0.68-0.82), respectively. The combined positive likelihood ratio (LR) stood at 2.83 (95% CI 2.06-3.88), and the negative LR was 0.41 (95% CI 0.33-0.52). The SROC curve showcased pooled diagnostic accuracy of 0.77 (95% CI 0.73-0.81). Interestingly, patients with a history of hypertension or heart failure demonstrated a lower specificity of PENK in correlating the development of AKI. CONCLUSION: Our results indicate that PENK possesses significant potential as a biomarker for the early detection of the development of AKI, using a cutoff point of 57.3 pmol/L for PENK.

Standardization of Nomenclature for the Mechanisms and Materials Utilized for Extracorporeal Blood Purification.

In order to develop a standardized nomenclature for the mechanisms and materials utilized during extracorporeal blood purification, a consensus expert conference was convened in November 2022. Standardized nomenclature serves as a common language for reporting research findings, new device development, and education. It is also critically important to support patient safety, allow comparisons between techniques, materials, and devices, and be essential for defining and naming innovative technologies and classifying devices for regulatory approval. The multidisciplinary conference developed detailed descriptions of the performance characteristics of devices (membranes, filters, and sorbents), solute and fluid transport mechanisms, flow parameters, and methods of treatment evaluation. In addition, nomenclature for adsorptive blood purification techniques was proposed. This report summarizes these activities and highlights the need for standardization of nomenclature in the future to harmonize research, education, and innovation in extracorporeal blood purification therapies.

RAND appropriateness panel to determine the applicability of UK guidelines on the management of acute respiratory distress syndrome (ARDS) and other strategies in the context of the COVID-19 pandemic.

BACKGROUND: COVID-19 has become the most common cause of acute respiratory distress syndrome (ARDS) worldwide. Features of the pathophysiology and clinical presentation partially distinguish it from 'classical' ARDS. A Research and Development (RAND) analysis gauged the opinion of an expert panel about the management of ARDS with and without COVID-19 as the precipitating cause, using recent UK guidelines as a template. METHODS: An 11-person panel comprising intensive care practitioners rated the appropriateness of ARDS management options at different times during hospital admission, in the presence or absence of, or varying severity of SARS-CoV-2 infection on a scale of 1-9 (where 1-3 is inappropriate, 4-6 is uncertain and 7-9 is appropriate). A summary of the anonymised results was discussed at an online meeting moderated by an expert in RAND methodology. The modified online survey comprising 76 questions, subdivided into investigations (16), non-invasive respiratory support (18), basic intensive care unit management of ARDS (20), management of refractory hypoxaemia (8), pharmacotherapy (7) and anticoagulation (7), was completed again. RESULTS: Disagreement between experts was significant only when addressing the appropriateness of diagnostic bronchoscopy in patients with confirmed or suspected COVID-19. Adherence to existing published guidelines for the management of ARDS for relevant evidence-based interventions was recommended. Responses of the experts to the final survey suggested that the supportive management of ARDS should be the same, regardless of a COVID-19 diagnosis. For patients with ARDS with COVID-19, the panel recommended routine treatment with corticosteroids and a lower threshold for full anticoagulation based on a high index of suspicion for venous thromboembolic disease. CONCLUSION: The expert panel found no reason to deviate from the evidence-based supportive strategies for managing ARDS outlined in recent guidelines.

Subphenotypes of acute kidney injury in adults.

PURPOSE OF REVIEW: Acute kidney injury is a heterogeneous syndrome and as such is associated with multiple predisposing conditions and causes all of which affect outcomes. Such heterogeneity may conceal the potential benefit of therapies when generally applied to patients with acute kidney injury (AKI). The discovery of pathophysiology-based subphenotypes could be of benefit in allocating current and future therapies to specific groups. RECENT FINDINGS: Clinical subphenotypes group patients into categories according to predisposing factors, disease severity, and trajectory. These may be helpful in assessing patient outcomes. Analyses of existing databases have revealed biological subphenotypes that are characterized by levels of biomarkers indicative of hyperinflammation and endothelial injury. Patients with increased levels of these biomarkers display higher mortality rates compared with those with lower levels and there is potential that this group might respond differently to therapies. However, challenges remain in the validation, generalizability, and application of these subphenotypes. SUMMARY: Subphenotyping may help reduce heterogeneity under the umbrella term of acute kidney injury. Despite challenges remain, the identification of AKI subphenotypes has opened the potential of AKI research focused on better targeted therapies.

Blood Purification Studies in the ICU: What Endpoints Should We Use?

The potential for treatment of the critically ill using blood purification techniques has been discussed for several decades. However, since the first attempts at applying extracorporeal techniques to patients with sepsis were described, there has been considerable hesitancy towards the widespread adoption of such methods, given the lack of mortality benefit observed and indeed the paucity of randomized controlled studies. However, this is not unique so far as studies on the critically ill are concerned where there is a dearth of studies providing a positive finding to influence clinical practice. Consequently, as well as targeted patient selection, it is perhaps time to consider endpoints other than mortality in studies on the critically ill, particularly in blood purification studies where, to-date, such heterogeneous groups of patients have been studied.

Management of acute kidney injury associated with Covid-19: what have we learned?

PURPOSE OF REVIEW: Although initially kidney involvement in COVID-19 infection was felt to occur relatively infrequently, this has proved not to be the case. In critically ill patients with COVID-19, multiorgan failure including acute kidney injury (AKI) is common and is associated with an increased risk of mortality and morbidity. This review focuses briefly on the epidemiology and pathophysiology of COVID-19 associated AKI as well as options for management. RECENT FINDINGS: The risk factors for AKI are common to both noncovid-related AKI and COVID-19 associated AKI. Kidney injury in COVID-19 associated AKI may arise through several mechanisms, including not only direct effects on the kidney leading to tubular injury but also through the effects of treatment of multiorgan failure complicating infection. During surge conditions, the use of kidney replacement therapy has embraced all modalities including the use of peritoneal dialysis. The use of blood purification techniques has been proposed, but to date, the results are variable. SUMMARY: COVID-19 associated AKI is common, affecting approximately a quarter of patients hospitalized with COVID-19. Glomerular injury can occur, but in the main tubular injury seems most likely leading to AKI, which should be managed following clinical pathways informed by accepted guidelines.

Prevention of Cardiac Surgery-Associated Acute Kidney Injury by Implementing the KDIGO Guidelines in High-Risk Patients Identified by Biomarkers: The PrevAKI-Multicenter Randomized Controlled Trial.

BACKGROUND: Prospective, single-center trials have shown that the implementation of the Kidney Disease: Improving Global Outcomes (KDIGO) recommendations in high-risk patients significantly reduced the development of acute kidney injury (AKI) after surgery. We sought to evaluate the feasibility of implementing a bundle of supportive measures based on the KDIGO guideline in high-risk patients undergoing cardiac surgery in a multicenter setting in preparation for a large definitive trial. METHODS: In this multicenter, multinational, randomized controlled trial, we examined the adherence to the KDIGO bundle consisting of optimization of volume status and hemodynamics, functional hemodynamic monitoring, avoidance of nephrotoxic drugs, and prevention of hyperglycemia in high-risk patients identified by the urinary biomarkers tissue inhibitor of metalloproteinases-2 [TIMP-2] and insulin growth factor-binding protein 7 [IGFBP7] after cardiac surgery. The primary end point was the adherence to the bundle protocol and was evaluated by the percentage of compliant patients with a 95% confidence interval (CI) according to Clopper-Pearson. Secondary end points included the development and severity of AKI. RESULTS: In total, 278 patients were included in the final analysis. In the intervention group, 65.4% of patients received the complete bundle as compared to 4.2% in the control group (absolute risk reduction [ARR] 61.2 [95% CI, 52.6-69.9]; P < .001). AKI rates were statistically not different in both groups (46.3% intervention versus 41.5% control group; ARR -4.8% [95% CI, -16.4 to 6.9]; P = .423). However, the occurrence of moderate and severe AKI was significantly lower in the intervention group as compared to the control group (14.0% vs 23.9%; ARR 10.0% [95% CI, 0.9-19.1]; P = .034). There were no significant effects on other specified secondary outcomes. CONCLUSIONS: Implementation of a KDIGO-derived treatment bundle is feasible in a multinational setting. Furthermore, moderate to severe AKI was significantly reduced in the intervention group.

Heparin 2.0: A New Approach to the Infection Crisis.

In April 2020, the US Food and Drug Administration granted emergency use authorization for certain medical devices to be used in patients with coronavirus disease 2019 (CO-VID-19). This included extracorporeal blood purification devices. This narrative review will give a brief overview regarding some of the extracorporeal devices that could be used to treat COVID-19 patients, including the Seraph® 100 Microbind® Affinity Blood Filter, produced by ExThera Medical (Martinez, CA, USA), first licensed in the European Economic Area in 2019. The Seraph® 100 contains ultrahigh molecular weight polyethylene beads with end point-attached heparin and is approved for the reduction of pathogens from the bloodstream either as a single agent or as an adjunct to conventional anti-infective agents. Bacteria, viruses, fungi, and toxins have been shown to bind to the immobilized heparin in a similar way to the interaction with heparan sulfate on the cell surface. This binding is nonreversible and as such, the pathogens are removed from the bloodstream. In this review, we describe the pathophysiological basis and rationale for using heparin for pathogen removal from the blood as well as exploring the technology behind the adaptation of heparin to deprive it of its systemic anticoagulant activity. In addition, we summarize the in vitro data as well as the available preclinical testing and published clinical reports. Finally, we discuss the enormous potential of this technology in an era of increasing antibiotic resistance and high mortality associated with sepsis and consider the application of this as a possible treatment option for COVID-19.

Renin and Survival in Patients Given Angiotensin II for Catecholamine-Resistant Vasodilatory Shock. A Clinical Trial.

Rationale: Exogenous angiotensin II increases mean arterial pressure in patients with catecholamine-resistant vasodilatory shock (CRVS). We hypothesized that renin concentrations may identify patients most likely to benefit from such therapy.Objectives: To test the kinetic changes in renin concentrations and their prognostic value in patients with CRVS.Methods: We analyzed serum samples from patients enrolled in the ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock) trial for renin, angiotensin I, and angiotensin II concentrations before the start of administration of angiotensin II or placebo and after 3 hours.Measurements and Main Results: Baseline serum renin concentration (normal range, 2.13-58.78 pg/ml) was above the upper limits of normal in 194 of 255 (76%) study patients with a median renin concentration of 172.7 pg/ml (interquartile range [IQR], 60.7 to 440.6 pg/ml), approximately threefold higher than the upper limit of normal. Renin concentrations correlated positively with angiotensin I/II ratios (r = 0.39; P < 0.001). At 3 hours after initiation of angiotensin II therapy, there was a 54.3% reduction (IQR, 37.9% to 66.5% reduction) in renin concentration compared with a 14.1% reduction (IQR, 37.6% reduction to 5.1% increase) with placebo (P < 0.0001). In patients with renin concentrations above the study population median, angiotensin II significantly reduced 28-day mortality to 28 of 55 (50.9%) patients compared with 51 of 73 patients (69.9%) treated with placebo (unstratified hazard ratio, 0.56; 95% confidence interval, 0.35 to 0.88; P = 0.012) (P = 0.048 for the interaction).Conclusions: The serum renin concentration is markedly elevated in CRVS and may identify patients for whom treatment with angiotensin II has a beneficial effect on clinical outcomes.Clinical trial registered with www.clinicaltrials.gov (NCT02338843).

Understanding Lactatemia in Human Sepsis. Potential Impact for Early Management.

Rationale: Hyperlactatemia in sepsis may derive from a prevalent impairment of oxygen supply/demand and/or oxygen use. Discriminating between these two mechanisms may be relevant for the early fluid resuscitation strategy.Objectives: To understand the relationship among central venous oxygen saturation (ScvO2), lactate, and base excess to better determine the origin of lactate.Methods: This was a post hoc analysis of baseline variables of 1,741 patients with sepsis enrolled in the multicenter trial ALBIOS (Albumin Italian Outcome Sepsis). Variables were analyzed as a function of sextiles of lactate concentration and sextiles of ScvO2. We defined the "alactic base excess," as the sum of lactate and standard base excess.Measurements and Main Results: Organ dysfunction severity scores, physiologic variables of hepatic, metabolic, cardiac, and renal function, and 90-day mortality were measured. ScvO2 was lower than 70% only in 35% of patients. Mortality, organ dysfunction scores, and lactate were highest in the first and sixth sextiles of ScvO2. Although lactate level related strongly to mortality, it was associated with acidemia only when kidney function was impaired (creatinine >2 mg/dl), as rapidly detected by a negative alactic base excess. In contrast, positive values of alactic base excess were associated with a relative reduction of fluid balance.Conclusions: Hyperlactatemia is powerfully correlated with severity of sepsis and, in established sepsis, is caused more frequently by impaired tissue oxygen use, rather than by impaired oxygen transport. Concomitant acidemia was only observed in the presence of renal dysfunction, as rapidly detected by alactic base excess. The current strategy of fluid resuscitation could be modified according to the origin of excess lactate.

Use of Cell Cycle Arrest Biomarkers in Conjunction With Classical Markers of Acute Kidney Injury.

OBJECTIVES: Decreased urine output and/or increased serum creatinine may herald the development of acute kidney injury or reflect normal physiology. In this secondary analysis of the Sapphire study, we examined biomarkers of cell cycle arrest in the settings of oliguria and/or azotemia to improve risk assessment when used with conventional indices in predicting severe acute kidney injury (Kidney Disease: Improving Global Outcomes 3 defined by the need for renal replacement therapy or changes in urine output, serum creatinine or both) or death. DESIGN: Prospective, international, Sapphire study. SETTING: Academic Medical Center. PATIENTS: Patients without acute kidney injury Kidney Disease: Improving Global Outcomes stage 2 or 3. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary endpoint being development of severe acute kidney injury or death within 1 week. Secondary analysis examined the relationship between tissue inhibitor of metalloproteinases-2 ([TIMP-2]) and insulin growth factor binding protein 7 ([IGFBP7]) and 9-month death or dialysis conditioned on progression to stage 2-3 acute kidney injury within 1 week. Seventy-nine patients reached the primary endpoint and were more likely to be surgical, with higher nonrenal Acute Physiology and Chronic Health Evaluation III scores and more chronic kidney disease. Stage 1 urine output, serum creatinine, and urinary [TIMP-2]•[IGFBP7] greater than 2.0 were all predictive of progression to the primary endpoint independent from nonrenal Acute Physiology and Chronic Health Evaluation III score. Combinations of predictors increased the hazard ratios considerably (from 2.17 to 4.14 to 10.05, respectively). In the presence of acute kidney injury (stage 1), [TIMP-2]•[IGFBP7] greater than 2.0 leads to an increased risk of death or dialysis at 9 months even in the absence of progression of acute kidney injury (stage 2-3) within 7 days. CONCLUSIONS: Cell cycle arrest biomarkers, TIMP-2 and IGFBP7, improve risk stratification for severe outcomes in patients with stage 1 acute kidney injury by urine output, serum creatinine or both, with risk increasing with each acute kidney injury indicator. Longer term outcomes demonstrate that the associated risks of a [TIMP-2]•[IGFBP7] greater than 2.0 is equivalent to acute kidney injury progression even where no progression from stage 1 acute kidney injury is observed.