Early, Individualized Recommendations for Hospitalized Patients With Acute Kidney Injury: A Randomized Clinical Trial.

Importance: Acute kidney injury (AKI) is a common complication during hospitalization and is associated with adverse outcomes. Objective: To evaluate whether diagnostic and therapeutic recommendations sent by a kidney action team through the electronic health record improve outcomes among patients hospitalized with AKI compared with usual care. Design, Setting, and Participants: Randomized clinical trial conducted at 7 hospitals in 2 health systems: in New Haven, Bridgeport, New London, and Waterbury, Connecticut, and Westerly, Rhode Island; and in Baltimore, Maryland. Hospitalized patients with AKI were randomized between October 29, 2021, and February 8, 2024. Final follow-up occurred February 22, 2024. Intervention: An alert about AKI was sent to the kidney action team, consisting of a study physician and study pharmacist, which sent personalized recommendations through the electronic health record in 5 major categories (diagnostic testing, volume, potassium, acid base, and medications) within 1 hour of AKI detection. The note was immediately visible to anyone with access to the electronic health record. Randomization to the intervention or usual care occurred after the recommendations were generated, but the note was only delivered to clinicians of patients randomized to the intervention group. Main Outcomes and Measures: The primary outcome was a composite outcome consisting of AKI progression to a higher stage of AKI, dialysis, or mortality occurring while the patient remained hospitalized and within 14 days from randomization. Results: Of the 4003 patients randomized (median age, 72 years [IQR, 61-81 years), 1874 (47%) were female and 931 (23%) were Black patients. The kidney action team made 14 539 recommendations, with a median of 3 (IQR, 2-5) per patient. The primary outcome occurred in 19.8% of the intervention group and in 18.4% in the usual care group (difference, 1.4%, 95% CI, -1.1% to 3.8,% P = .28). Of 6 secondary outcomes, only 1 secondary outcome, rates of recommendation implementation, significantly differed between the 2 groups: 2459 of 7270 recommendations (33.8%) were implemented in the intervention group and 1766 of 7269 undelivered recommendations (24.3%) were implemented in the usual care group within 24 hours (difference, 9.5%; 95% CI, 8.1% to 11.0%). Conclusions and Relevance: Among patients hospitalized with AKI, recommendations from a kidney action team did not significantly reduce the composite outcome of worsening AKI stage, dialysis, or mortality, despite a higher rate of recommendation implementation in the intervention group than in the usual care group. Trial Registration: ClinicalTrials.gov Identifier: NCT04040296.

The Global Turbidity Current Pump and Its Implications for Organic Carbon Cycling.

Submarine turbidity currents form the largest sediment accumulations on Earth, raising the question of their role in global carbon cycles. It was previously inferred that terrestrial organic carbon was primarily incinerated on shelves and that most turbidity current systems are presently inactive. Turbidity currents were thus not considered in global carbon cycles, and the burial efficiency of global terrestrial organic carbon was considered low to moderate (∼10-44%). However, recent work has shown that burial of terrestrial organic carbon by turbidity currents is highly efficient (>60-100%) in a range of settings and that flows occur more frequently than once thought, although they were far more active at sea-level lowstands. This leads to revised global estimates for mass flux (∼62-90 Mt C/year) and burial efficiency (∼31-45%) of terrestrial organic carbon in marine sediments. Greatly increased burial fluxes during sea-level lowstands are also likely underestimated; thus, organic carbon cycling by turbidity currents could play a role in long-term changes in atmospheric CO2 and climate.

Incidence and outcomes of acute kidney injury including hepatorenal syndrome in hospitalized patients with cirrhosis in the US.

BACKGROUND & AIMS: Acute kidney injury (AKI) in cirrhosis is common and associated with high morbidity, but the incidence rates of different etiologies of AKI are not well described in the US. We compared incidence rates, practice patterns, and outcomes across etiologies of AKI in cirrhosis. METHODS: We performed a retrospective cohort study of 11 hospital networks, including consecutive adult patients admitted with AKI and cirrhosis in 2019. The etiology of AKI was adjudicated based on pre-specified clinical definitions (prerenal/hypovolemic AKI, hepatorenal syndrome [HRS-AKI], acute tubular necrosis [ATN], other). RESULTS: A total of 2,063 patients were included (median age 62 [IQR 54-69] years, 38.3% female, median MELD-Na score 26 [19-31]). The most common etiology was prerenal AKI (44.3%), followed by ATN (30.4%) and HRS-AKI (12.1%); 6.0% had other AKI, and 7.2% could not be classified. In our cohort, 8.1% of patients received a liver transplant and 36.5% died by 90 days. The lowest rate of death was observed in patients with prerenal AKI (22.2%; p <0.001), while death rates were higher but not significantly different from each other in those with HRS-AKI and ATN (49.0% vs. 52.7%; p = 0.42). Using prerenal AKI as a reference, the adjusted subdistribution hazard ratio (sHR) for 90-day mortality was higher for HRS-AKI (sHR 2.78; 95% CI 2.18-3.54; p <0.001) and ATN (sHR 2.83; 95% CI 2.36-3.41; p <0.001). In adjusted analysis, higher AKI stage and lack of complete response to treatment were associated with an increased risk of 90-day mortality (p <0.001 for all). CONCLUSION: AKI is a severe complication of cirrhosis. HRS-AKI is uncommon and is associated with similar outcomes to ATN. The etiology of AKI, AKI stage/severity, and non-response to treatment were associated with mortality. Further optimization of vasoconstrictors for HRS-AKI and supportive therapies for ATN are needed. IMPACT AND IMPLICATIONS: Acute kidney injury (AKI) in cirrhosis carries high morbidity, and management is determined by the etiology of injury. However, a large and well-adjudicated multicenter database from US centers that uses updated AKI definitions is lacking. Our findings demonstrate that acute tubular necrosis and hepatorenal syndrome have similar outcomes (∼50% mortality at 90 days), though hepatorenal syndrome is uncommon (12% of all AKI cases). These findings represent practice patterns at US transplant/tertiary centers and can be used as a baseline, presenting the situation prior to the adoption of terlipressin in the US.

Personalised recommendations for hospitalised patients with Acute Kidney Injury using a Kidney Action Team (KAT-AKI): protocol and early data of a randomised controlled trial.

INTRODUCTION: Although studies have examined the utility of clinical decision support tools in improving acute kidney injury (AKI) outcomes, no study has evaluated the effect of real-time, personalised AKI recommendations. This study aims to assess the impact of individualised AKI-specific recommendations delivered by trained clinicians and pharmacists immediately after AKI detection in hospitalised patients. METHODS AND ANALYSIS: KAT-AKI is a multicentre randomised investigator-blinded trial being conducted across eight hospitals at two major US hospital systems planning to enrol 4000 patients over 3 years (between 1 November 2021 and 1 November 2024). A real-time electronic AKI alert system informs a dedicated team composed of a physician and pharmacist who independently review the chart in real time, screen for eligibility and provide combined recommendations across the following domains: diagnostics, volume, potassium, acid-base and medications. Recommendations are delivered to the primary team in the alert arm or logged for future analysis in the usual care arm. The planned primary outcome is a composite of AKI progression, dialysis and mortality within 14 days from randomisation. A key secondary outcome is the percentage of recommendations implemented by the primary team within 24 hours from randomisation. The study has enrolled 500 individuals over 8.5 months. Two-thirds were on a medical floor at the time of the alert and 17.8% were in an intensive care unit. Virtually all participants were recommended for at least one diagnostic intervention. More than half (51.6%) had recommendations to discontinue or dose-adjust a medication. The median time from AKI alert to randomisation was 28 (IQR 15.8-51.5) min. ETHICS AND DISSEMINATION: The study was approved by the ethics committee of each study site (Yale University and Johns Hopkins institutional review board (IRB) and a central IRB (BRANY, Biomedical Research Alliance of New York). We are committed to open dissemination of the data through clinicaltrials.gov and sharing of data on an open repository as well as publication in a peer-reviewed journal on completion. TRIAL REGISTRATION NUMBER: NCT04040296.

The Lymphatic System in Kidney Disease.

The high-capacity vessels of the lymphatic system drain extravasated fluid and macromolecules from nearly every part of the body. However, far from merely a passive conduit for fluid removal, the lymphatic system also plays a critical and active role in immune surveillance and immune response modulation through the presentation of fluid, macromolecules, and trafficking immune cells to surveillance cells in regional draining lymph nodes before their return to the systemic circulation. The potential effect of this system in numerous disease states both within and outside of the kidney is increasingly being explored for their therapeutic potential. In the kidneys, the lymphatics play a critical role in both fluid and macromolecule removal to maintain oncotic and hydrostatic pressure gradients for normal kidney function, as well as in shaping kidney immunity, and potentially in balancing physiological pathways that promote healthy organ maintenance and responses to injury. In many states of kidney disease, including AKI, the demand on the preexisting lymphatic network increases for clearance of injury-related tissue edema and inflammatory infiltrates. Lymphangiogenesis, stimulated by macrophages, injured resident cells, and other drivers in kidney tissue, is highly prevalent in settings of AKI, CKD, and transplantation. Accumulating evidence points toward lymphangiogenesis being possibly harmful in AKI and kidney allograft rejection, which would potentially position lymphatics as another target for novel therapies to improve outcomes. However, the extent to which lymphangiogenesis is protective rather than maladaptive in the kidney in various settings remains poorly understood and thus an area of active research.

Longest sediment flows yet measured show how major rivers connect efficiently to deep sea.

Here we show how major rivers can efficiently connect to the deep-sea, by analysing the longest runout sediment flows (of any type) yet measured in action on Earth. These seafloor turbidity currents originated from the Congo River-mouth, with one flow travelling >1,130 km whilst accelerating from 5.2 to 8.0 m/s. In one year, these turbidity currents eroded 1,338-2,675 [>535-1,070] Mt of sediment from one submarine canyon, equivalent to 19-37 [>7-15] % of annual suspended sediment flux from present-day rivers. It was known earthquakes trigger canyon-flushing flows. We show river-floods also generate canyon-flushing flows, primed by rapid sediment-accumulation at the river-mouth, and sometimes triggered by spring tides weeks to months post-flood. It is demonstrated that strongly erosional turbidity currents self-accelerate, thereby travelling much further, validating a long-proposed theory. These observations explain highly-efficient organic carbon transfer, and have important implications for hazards to seabed cables, or deep-sea impacts of terrestrial climate change.

Mortality after acute kidney injury and acute interstitial nephritis in patients prescribed immune checkpoint inhibitor therapy.

BACKGROUND: In patients receiving immune checkpoint inhibitor (ICI) therapy, acute kidney injury (AKI) is common, and can occur either from kidney injury unrelated to ICI use or from immune activation resulting in acute interstitial nephritis (AIN). In this study, we test the hypothesis that occurrence of AIN indicates a favorable treatment response to ICI therapy and therefore among patients who develop AKI while on ICI therapy, those with AIN will demonstrate greater survival compared with others with AKI. METHODS: In this observational cohort study, we included participants initiated on ICI therapy between 2013 and 2019. We tested the independent association of AKI and estimated AIN (eAIN) with mortality up to 1 year after therapy initiation as compared with those without AKI using time-varying Cox proportional hazard models controlling for demographics, comorbidities, cancer type, stage, and therapy, and baseline laboratory values. We defined eAIN as those with a predicted probability of AIN >90th percentile derived from a recently validated diagnostic model. RESULTS: Of 2207 patients initiated on ICIs, 617 (28%) died at 1 year and 549 (25%) developed AKI. AKI was independently associated with higher mortality (adjusted HR, 2.28 (95% CI 1.90 to 2.72)). Those AKI patients with eAIN had more severe AKI as reflected by a higher peak serum creatinine (3.3 (IQR 2.1-6.1) vs 1.4 (1.2-1.9) mg/dL, p<0.001) but exhibited lower mortality than those without eAIN in univariable analysis (HR 0.43 (95% CI 0.21 to 0.89)) and after adjusting for demographics, comorbidities, and cancer type and severity (adjusted HR 0.44 (95% CI 0.21 to 0.93)). CONCLUSION: In patients treated with ICI, mortality was higher in those with AKI unrelated to ICI but lower in those where the underlying etiology was AIN. Future studies could evaluate the association of biopsy-proven or biomarker-proven AIN with mortality in those receiving ICI therapy.

Integrating field and laboratory approaches for ripple development in mixed sand-clay-EPS.

The shape and size of sedimentary bedforms play a key role in the reconstruction of sedimentary processes in modern and ancient environments. Recent laboratory experiments have shown that bedforms in mixed sand-clay develop at a slower rate and often have smaller heights and wavelengths than equivalent bedforms in pure sand. This effect is generally attributed to cohesive forces that can be of physical origin, caused by electrostatic forces of attraction between clay minerals, and of biological origin, caused by 'sticky' extracellular polymeric substances (EPS) produced by micro-organisms, such as microalgae (microphytobenthos) and bacteria. The present study demonstrates, for the first time, that these laboratory experiments are a suitable analogue for current ripples formed by tidal currents on a natural mixed sand-mud-EPS intertidal flat in a macrotidal estuary. Integrated hydrodynamic and bed morphological measurements, collected during a spring tide under weak wave conditions near Hilbre Island (Dee Estuary, north-west England, UK), reveal a statistically significant decrease in current ripple wavelength for progressively higher bed mud and EPS contents, and a concurrent change from three-dimensional linguoid to two-dimensional straight-crested ripple planform morphology. These results agree well with observations in laboratory flumes, but the rate of decrease of ripple wavelength as mud content increased was found to be substantially greater for the field than the laboratory. Since the formation of ripples under natural conditions is inherently more complex than in the laboratory, four additional factors that might affect current ripple development in estuaries, but which were not accounted for in laboratory experiments, were explored. These were current forcing, clay type, pore water salinity and bed EPS content. These data illustrate that clay type alone cannot explain the difference in the rate of decrease in ripple wavelength, because the bed clay contents were too low for clay type to have had a measurable effect on bedform development. Accounting for the difference in current forcing between the field and experiments, and therefore the relative stage of development with respect to equilibrium ripples, increases the difference between the ripple wavelengths. The presence of strongly cohesive EPS in the current ripples on the natural intertidal flat might explain the majority of the difference in the rate of decrease in ripple wavelength between the field and the laboratory. The effect of pore water salinity on the rate of bedform development cannot be quantified at present, but salinity is postulated herein to have had a smaller influence on the ripple wavelength than bed EPS content. The common presence of clay and EPS in many aqueous sedimentary environments implies that a re-assessment of the role of current ripples and their primary current lamination in predicting and reconstructing flow regimes is necessary, and that models that are valid for pure sand are an inappropriate descriptor for more complex mixed sediment. This study proposes that this re-assessment is necessary at all bed clay contents above 3%.