Behind the scenes: Key lessons learned from the RELIEVE-AKI clinical trial.

Continuous kidney replacement therapy (CKRT) is commonly used to manage critically ill patients with severe acute kidney injury. While recent trials focused on the correct dosing and timing of CKRT, our understanding regarding the optimum dose of net ultrafiltration is limited to retrospective data. The Restrictive versus Liberal Rate of Extracorporeal Volume Removal Evaluation in Acute Kidney Injury (RELIEVE-AKI) trial has been conducted to assess the feasibility of a prospective randomized trial in determining the optimum net ultrafiltration rate. This paper outlines the relevant challenges and solutions in implementing this complex ICU-based trial. Several difficulties were encountered, starting with clinical issues related to conducting a trial on patients with rapidly changing hemodynamics, low patient recruitment rates, increased nursing workload, and the enormous volume of data generated by patients undergoing prolonged CKRT. Following several brainstorming sessions, several points were highlighted to be considered, including the need to streamline the intervention, add more flexibility in the trial protocols, ensure comprehensive a priori planning, particularly regarding nursing roles and their compensation, and enhance data management systems. These insights are critical for guiding future ICU-based dynamically titrated intervention trials, leading to more efficient trial management, improved data quality, and enhanced patient safety.

Magnesium Derangement among Critically Ill Patients with Acute Kidney Injury: An Association with Acute Kidney Disease.

INTRODUCTION: The association between magnesium level and progression to acute kidney disease (AKD) in acute kidney injury (AKI) patients was not well studied. With AKI transition to AKD, the burden of the disease on mortality, morbidity, and healthcare costs increases. Serum magnesium disturbances are linked with a decline in renal function and increased risk of death in CKD and hemodialysis patients. This study aims to assess the significance of magnesium derangements as a risk factor for the progression of AKI to AKD in critically ill patients. METHODS: This study was conducted among patients with AKI admitted to the intensive care units at Mayo Clinic from 2007 to 2017. Serum magnesium at AKI onset was categorized into five groups of <1.7, 1.7-1.9, 1.9-2.1, 2.1-2.3, and ≥2.3 mg/dL, with 1.9-2.1 mg/dL as the reference group. AKD was defined as AKI that persisted >7 days following the AKI onset. Logistic regression was used to evaluate the association between magnesium and AKD. RESULTS: Among 20,198 critically ill patients with AKI, the mean age was 66 ± 16 years, and 57% were male. The mean serum magnesium at AKI onset was 1.9 ± 0.4 mg/dL. The overall incidence of AKD was 31.4%. The association between serum magnesium and AKD followed a U-shaped pattern. In multivariable analysis, serum magnesium levels were associated with increased risk of AKD with the odds ratio of 1.17 (95% CI: 1.07-1.29), 1.13 (95% CI: 1.01-1.26), and 1.65 (95% CI: 1.48-1.84) when magnesium levels were <1.7, 2.1-2.3, and ≥2.3 mg/dL, respectively. CONCLUSION: Among patients with AKI, magnesium level derangement was an independent risk for AKD in critically ill AKI patients. Monitoring serum magnesium and proper correction in critically ill patients with AKI should be considered an AKD preventive intervention in future trials.

Development and validation of a preliminary multivariable diagnostic model for identifying unusual infections in hospitalized patients.

Diagnostic delay leads to poor outcomes in infections, and it occurs more often when the causative agent is unusual. Delays are attributable to failing to consider such diagnoses in a timely fashion. Using routinely collected electronic health record (EHR) data, we built a preliminary multivariable diagnostic model for early identification of unusual fungal infections and tuberculosis in hospitalized patients. We conducted a two-gate case-control study. Cases encompassed adult patients admitted to 19 Mayo Clinic enterprise hospitals between January 2010 and March 2023 diagnosed with blastomycosis, cryptococcosis, histoplasmosis, mucormycosis, pneumocystosis, or tuberculosis. Control groups were drawn from all admitted patients (random controls) and those with community-acquired infections (ID-controls). Development and validation datasets were created using randomization for dividing cases and controls (7:3), with a secondary validation using ID-controls. A logistic regression model was constructed using baseline and laboratory variables, with the unusual infections of interest outcome. The derivation dataset comprised 1043 cases and 7000 random controls, while the 451 cases were compared to 3000 random controls and 1990 ID-controls for validation. Within the derivation dataset, the model achieved an area under the curve (AUC) of 0.88 (95% confidence interval [CI]: 0.87-0.89) with a good calibration accuracy (Hosmer-Lemeshow P = 0.623). Comparable performance was observed in the primary (AUC = 0.88; 95% CI: 0.86-0.9) and secondary validation datasets (AUC = 0.84; 95% CI: 0.82-0.86). In this multicenter study, an EHR-based preliminary diagnostic model accurately identified five unusual fungal infections and tuberculosis in hospitalized patients. With further validation, this model could help decrease time to diagnosis.

Temporal Relationship and Clinical Outcomes of Acute Kidney Injury Following Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis.

OBJECTIVES: Conduct a systematic review and meta-analysis to assess prevalence and timing of acute kidney injury (AKI) development after acute respiratory distress syndrome (ARDS) and its association with mortality. DATA SOURCES: Ovid MEDLINE(R), Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Ovid PsycINFO database, Scopus, and Web of Science thought April 2023. STUDY SELECTION: Titles and abstracts were screened independently and in duplicate to identify eligible studies. Randomized controlled trials and prospective or retrospective cohort studies reporting the development of AKI following ARDS were included. DATA EXTRACTION: Two reviewers independently extracted data using a pre piloted abstraction form. We used Review Manager 5.4 software (Cochrane Library, Oxford, United Kingdom) and Open Meta software (Brown University, Providence, RI) for statistical analyses. DATA SYNTHESIS: Among the 3646 studies identified and screened, 17 studies comprising 9359 ARDS patients met the eligibility criteria and were included in the meta-analysis. AKI developed in 3287 patients (40%) after the diagnosis of ARDS. The incidence of AKI at least 48 hours after ARDS diagnosis was 20% (95% CI, 0.18-0.21%). The pooled risk ratio (RR) for the hospital (or 30-d) mortality among ARDS patients who developed AKI was 1.93 (95% CI, 1.71-2.18). AKI development after ARDS was identified as an independent risk factor for mortality in ARDS patients, with a pooled odds ratio from multivariable analysis of 3.69 (95% CI, 2.24-6.09). Furthermore, two studies comparing mortality between patients with late vs. early AKI initiation after ARDS revealed higher mortality in late AKI patients with RR of 1.46 (95% CI, 1.19-1.8). However, the certainty of evidence for most outcomes was low to very low. CONCLUSIONS: While our findings highlight a significant association between ARDS and subsequent development of AKI, the low to very low certainty of evidence underscores the need for cautious interpretation. This systematic review identified a significant knowledge gap, necessitating further research to establish a more definitive understanding of this relationship and its clinical implications.

Acetazolamide for acute kidney injury in patients undergoing high dose methotrexate therapy: a systematic review and meta-analysis.

BACKGROUND: Urine alkalization is one of the standard treatments to prevent acute kidney injury in patients receiving high-dose methotrexate. Carbonic anhydrase inhibitors are promising adjuvants/substitutes with advantages such as faster urine alkalization time and prevention of fluid overload. However, there is limited and contradictory evidence on its efficacy and safety. We aimed to compare the efficacy and safety of carbonic anhydrase inhibitors to standard treatments in adult patients receiving high-dose methotrexate. METHODS: The protocol was registered at PROSPERO (CRD42022352802) in August 2021. We evaluated the use of carbonic anhydrase inhibitors in combination with standard treatment compared to standard treatment alone. We excluded articles irrelevant to the efficacy and safety of acetazolamide in patients receiving high dose methotrexate and/or did not provide sufficient data regarding doses, recruitment criteria, and follow-up period. Two authors performed the data extraction independently. RESULTS: Among 198 articles retrieved, six observational studies met all eligibility criteria. Four studies with five datasets (totaling 558 patients/cycles) had enough data to be included in the meta-analysis. We independently report the results from the two remaining studies. The results did not show a significant difference between acetazolamide versus standard treatment in acute kidney injury (AKI) rate (OR = 0.79, 95% CI 0.48-1.29, P = 0.34, I2 = 0%). Regarding the time to urine pH goal, there was no significant time difference between the two groups (Mean Difference = 0.07, 95% CI - 1.9 to 2.04, P = 0.95, I2 = 25%). Furthermore, our meta-analysis showed that acetazolamide did not reduce length of stay (Mean Difference = 0.75, 95% CI - 0.8 to 2.31, P = 0.34, I2 = 0%). In one study, the only reported side effect of acetazolamide was hypokalemia (nearly 50% in the acetazolamide group). CONCLUSIONS: This systematic review showed no significant difference between acetazolamide and standard care treatment regarding urine alkalinization time and AKI rate in adult patients receiving high dose methotrexate. We suggest performing a large blinded, randomized, controlled trial to evaluate the potential benefits of this low-cost medication.

Restrictive versus Liberal Rate of Extracorporeal Volume Removal Evaluation in Acute Kidney Injury (RELIEVE-AKI): a pilot clinical trial protocol.

INTRODUCTION: Observational studies have linked slower and faster net ultrafiltration (UFNET) rates during kidney replacement therapy (KRT) with mortality in critically ill patients with acute kidney injury (AKI) and fluid overload. To inform the design of a larger randomised trial of patient-centered outcomes, we conduct a feasibility study to examine restrictive and liberal approaches to UFNET during continuous KRT (CKRT). METHODS AND ANALYSIS: This study is an investigator-initiated, unblinded, 2-arm, comparative-effectiveness, stepped-wedged, cluster randomised trial among 112 critically ill patients with AKI treated with CKRT in 10 intensive care units (ICUs) across 2 hospital systems. In the first 6 months, all ICUs started with a liberal UFNET rate strategy. Thereafter, one ICU is randomised to the restrictive UFNET rate strategy every 2 months. In the liberal group, the UFNET rate is maintained between 2.0 and 5.0 mL/kg/hour; in the restrictive group, the UFNET rate is maintained between 0.5 and 1.5 mL/kg/hour. The three coprimary feasibility outcomes are (1) between-group separation in mean delivered UFNET rates; (2) protocol adherence; and (3) patient recruitment rate. Secondary outcomes include daily and cumulative fluid balance, KRT and mechanical ventilation duration, organ failure-free days, ICU and hospital length of stay, hospital mortality and KRT dependence at hospital discharge. Safety endpoints include haemodynamics, electrolyte imbalance, CKRT circuit issues, organ dysfunction related to fluid overload, secondary infections and thrombotic and haematological complications. ETHICS AND DISSEMINATION: The University of Pittsburgh Human Research Protection Office approved the study, and an independent Data and Safety Monitoring Board monitors the study. A grant from the United States National Institute of Diabetes and Digestive and Kidney Diseases sponsors the study. The trial results will be submitted for publication in peer-reviewed journals and presented at scientific conferences. TRIAL REGISTRATION NUMBER: This trial has been prospectively registered with clinicaltrials.gov (NCT05306964). Protocol version identifier and date: 1.5; 13 June 2023.

The role of medicinal products in the treatment of inflammatory bowel diseases (IBD) through inhibition of TLR4/NF-kappaB pathway.

Inflammatory bowel disease (IBD) is a lifelong and recurrent disease of the gastrointestinal tract that afflicts many people in the world. Growing evidence has currently indicated that dysfunction of immune system, particularly toll-like receptors 4 (TLR4) signaling pathway dysfunction plays a pivotal part in the pathogenesis of IBD. TLR4 signaling is involved both in the pathogenesis and in the efficacy of treatment of IBD. There are some medicinal products and herbal medicines, which their role in the treatment of IBD through modulation of TLR4 signaling has been implicated. The purpose of this review article is to summarize those medicinal products and herbal medicines.