Faculty Bibliography

Rationale & Objective: Acute kidney injury (AKI) is a heterogeneous clinical syndrome with varying causes, pathophysiology, and outcomes. We incorporated plasma and urine biomarker measurements to identify AKI subgroups (subphenotypes) more tightly linked to underlying pathophysiology and long-term clinical outcomes. Study Design: Multicenter cohort study. Setting & Participants: 769 hospitalized adults with AKI matched with 769 without AKI, enrolled from December 2009 to February 2015 in the ASSESS-AKI Study. Predictors: 29 clinical, plasma, and urinary biomarker parameters used to identify AKI subphenotypes. Outcome: Composite of major adverse kidney events (MAKE) with a median follow-up period of 4.7 years. Analytical Approach: Latent class analysis (LCA) and k-means clustering were applied to 29 clinical, plasma, and urinary biomarker parameters. Associations between AKI subphenotypes and MAKE were analyzed using Kaplan-Meier curves and Cox proportional hazard models. Results: Among 769 AKI patients both LCA and k-means identified 2 distinct AKI subphenotypes (classes 1 and 2). The long-term risk for MAKE was higher with class 2 (adjusted HR, 1.41 [95% CI, 1.08-1.84]; P = 0.01) compared with class 1, adjusting for demographics, hospital level factors, and KDIGO stage of AKI. The higher risk of MAKE among class 2 was explained by a higher risk of long-term chronic kidney disease progression and dialysis. The top variables that were different between classes 1 and 2 included plasma and urinary biomarkers of inflammation and epithelial cell injury; serum creatinine ranked 20th out of the 29 variables for differentiating classes. Limitations: A replication cohort with simultaneously collected blood and urine sampling in hospitalized adults with AKI and long-term outcomes was unavailable. Conclusions: We identify 2 molecularly distinct AKI subphenotypes with differing risk of long-term outcomes, independent of the current criteria to risk stratify AKI. Future identification of AKI subphenotypes may facilitate linking therapies to underlying pathophysiology to prevent long-term sequalae after AKI.

INTRODUCTION: Mortality and morbidity associated with COVID-19 acute respiratory distress syndrome (ARDS) has been associated with pulmonary vasculopathy, which has been hypothesized to increase pulmonary dead space (VD/ VT). However, VD/VT is rarely measured at the bedside. As a result, multiple proxy estimates have been developed. Our hypothesis was proxy estimates for VD/VT would have differing utilities in prognostication of COVID-19 ARDS.
METHOD(S): We conducted a retrospective cohort study of patients admitted to an intensive care unit with SARSCoV- 2 ARDS who required invasive mechanical ventilation. Ventilation parameters were collected 2-8 hours after intubation. The VD/Vt proxies examined were 1) ventilatory ratio (VR), 2) estimation of VD/VT using the Harris-Benedict equation for energy expenditure (VD/VT-HB), 3) direct estimation of VD/VT using Beitler et. al.'s formula (VD/VTDir), and 4) corrected minute ventilation (VECorr). For each proxy, subjects were dichotomized using the median value. Comparisons were performed using the Wilcoxon rank-sum test with alpha=0.05.
RESULT(S): For 139 subjects, mean VR was 2.08 (SD+/-0.80), mean VD/VT-HB was 0.614 (+/-0.15), mean VD/VT-Dir was 0.657 (+/-0.08), and mean VECorr was 12.2 (+/-4.6) L/min. All four proxies had strong inter-measure correlation (Pearson's r 0.748-0.881, p< 0.001 for all comparisons). No proxy was predictive of 30-day hospital mortality. High VR and VECorr were associated with increased morbidity using a composite endpoint of death or organ failure (defined as requiring renal dialysis or extracorporeal membrane oxygenation) with both having an odds ratio of 2.20 (95% CI: 1.12-4.33, p=0.022), while VD/VT-HB (p=0.552) and VD/VT-Dir (p=0.554) were not significantly associated. Of all proxies, only VR was significantly associated with increased sequential organ failure assessment (SOFA) score at 10+/-4 days post-intubation (6.2 vs. 4.8, p=0.024) and more ventilatorfree days within the 30 days after intubation (3.2 vs. 1.8, p=0.029).
CONCLUSION(S): Ventilatory ratio and corrected minute volume appear to have stronger associations with morbidity in COVID-19 ARDS compared to other VD/VT estimates. Ventilatory ratio is also associated with ventilator-free days and delayed SOFA score

Rationale: Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is characterized by global developmental impairment and early-onset, refractory seizures. In a recent placebo-controlled study, ganaxolone reduced major motor seizure frequency (MMSF) in patients with CDD. Here we report further data at a minimum of 1-year in the open-label extension (OLE).
Method(s): Patients with CDD (aged 2-19 years) who completed the double-blind phase were eligible to receive ganaxolone in the OLE. Assessments included changes in MMSF from pre-randomization baseline to 3-month intervals in the OLE, responder rates (>=50% and >=75% MMSF reductions), Clinical Global Impression of Improvement (CGI-I), safety, and tolerability.
Result(s): Eighty-eight patients (87.1%; median age of 5; 79.5% female) continued into the OLE (101 were randomized to the double-blind study). Median baseline 28-day MMSF was 50.6. The 1-year retention rate was 70.5% with 26 discontinuations. At the time of analysis, 34 participants had discontinued due to lack of efficacy (n = 12), adverse event (n = 10), or withdrawal by caregiver (n = 10) as the most common reasons. During months 1-3, 4-6, 7-9, and 10-12, patients experienced a median reduction in MMSF of 24.7%, 32.1%, 30.0%, and 42.2%, respectively. During months 13-24, MMSF reductions ranged from 44.2% to 56.1%. At 1 year, 46.3% and 23.9% of patients experienced a >=50% and >=75% reduction in MMSF, respectively. In the OLE, clinicians and caregivers rated 60.6% and 72.5% of the patients, respectively, as improved at 1 year. The most commonly reported adverse events were seizure (22.7%), somnolence (20.5%), vomiting (18.2%), and pyrexia (17.0%). There was one death reported due to sepsis, but it was deemed unrelated to study treatment.
Conclusion(s): Reductions in MMSF at 1 year and beyond provide supportive evidence for the maintenance of effect of ganaxolone in seizures associated with CDD. Ganaxolone was generally well-tolerated in the OLE with safety findings consistent with the double-blind phase

INTRODUCTION: Ventilatory ratio (VR) is a simple bedside index of carbon dioxide removal. VR correlates well with physiologic dead space fraction (VD/VT) and clinical outcomes in patients with acute respiratory distress syndrome (ARDS). We hypothesized that high VR would identify COVID-19 ARDS patients with higher risk for death and organ failure.
METHOD(S): We conducted a retrospective cohort study of patients admitted to a single hospital in New York, NY, USA from March-July 2020 who had PCR-confirmed SARS-CoV-2 infection, met the Berlin criteria for ARDS, and required tracheostomy for prolonged invasive mechanical ventilation (MV). MV parameters were collected 2-8 hours after intubation. Based on prior studies, a VR>2 was considered to be abnormally elevated. Comparisons were performed using the Wilcoxon rank-sum test or z-test for difference in proportions with alpha=0.05. The primary outcome was 30- day mortality and the secondary outcome was a composite endpoint of death or organ failure defined as requiring renal replacement or extracorporeal membrane oxygenation (ECMO) during the hospitalization.
RESULT(S): Of 139 subjects enrolled, 67 (48.2%) had a VR>2. Low and high VR groups had similar baseline characteristics, including age (mean 58 years, SD +/-15.2), body mass index (30.1+/-6.69 kg/m2), simplified acute physiology score II (35.4+/-12.4), sequential organ failure assessment (SOFA) score (5.7+/-2.5), and a 19-point review of systemic disease history. High VR was not significantly associated with mortality (OR 0.92, p=0.827). However, high VR was associated with increased risk for the composite endpoint (OR 1.96, p=0.049) and independently identified patients with a higher risk of organ failure (OR 2.03, p=0.047). High VR was also associated with longer hospital length-of-stay for subjects who survived to discharge (52 vs. 43, p=0.035), more MV-free days within the 30 days after intubation (3.2 vs. 1.8, p=0.029), and higher SOFA score at 10+/-4 days post-intubation (6.2 vs. 4.8, p=0.024).
CONCLUSION(S): Ventilatory ratio identifies COVID-ARDS ventilated patients with increased risk for organ failure requiring advanced intervention, as well as patients who may require prolonged mechanical ventilation and hospitalization

Cardiovascular morbidity and mortality occur with an extraordinarily high incidence in the hemodialysis-dependent end-stage kidney disease population. There is a clear need to improve identification of those individuals at the highest risk of cardiovascular complications in order to better target them for preventative therapies. Twelve-lead electrocardiograms are ubiquitous and use inexpensive technology that can be administered with minimal inconvenience to patients and at a minimal burden to care providers. The embedded waveforms encode significant information on the cardiovascular structure and function that might be unlocked and used to identify at-risk individuals with the use of artificial intelligence techniques like deep learning. In this review, we discuss the experience with deep learning-based analysis of electrocardiograms to identify cardiovascular abnormalities or risk and the potential to extend this to the setting of dialysis-dependent end-stage kidney disease.

UNLABELLED:Cather-directed therapies (CDTs) are an evolving therapeutic option for patients with intermediate-risk pulmonary embolism (PE). Although many techniques have been studied, there is limited evidence for the impact of timing of intervention on patient outcomes. Our objective was to assess the association between time to CDT in patients presenting with PE on patient-related outcomes such as length of stay (LOS) and mortality. DESIGN/METHODS:Retrospective cohort study. SETTING/METHODS:Single academic center. PATIENTS/METHODS:We identified patients for which the PE response team had been activated from January 2014 to October 2021. Patients were split into two cohorts depending on whether they went to CDT less than 24 hours from admission (early) versus greater than 24 hours (late). INTERVENTIONS/METHODS:None. MEASUREMENTS AND MAIN RESULTS/RESULTS:= 0.523). CONCLUSIONS:Patients who underwent CDT within 24 hours of admission were more likely to have shorter hospital and ICU LOS. The magnitude of change in LOS between the two cohorts was not fully explained by the difference in time to CDT. There were modest improvements in pulmonary hemodynamics in the patients who underwent CDT earlier.

UNLABELLED:Vascular dysfunction and capillary leak are common in critically ill COVID-19 patients, but identification of endothelial pathways involved in COVID-19 pathogenesis has been limited. Angiopoietin-like 4 (ANGPTL4) is a protein secreted in response to hypoxic and nutrient-poor conditions that has a variety of biological effects including vascular injury and capillary leak. OBJECTIVES/OBJECTIVE:To assess the role of ANGPTL4 in COVID-19-related outcomes. DESIGN SETTING AND PARTICIPANTS/METHODS:Two hundred twenty-five COVID-19 ICU patients were enrolled from April 2020 to May 2021 in a prospective, multicenter cohort study from three different medical centers, University of Washington, University of Southern California and New York University. MAIN OUTCOMES AND MEASURES/METHODS:Plasma ANGPTL4 was measured on days 1, 7, and 14 after ICU admission. We used previously published tissue proteomic data and lung single nucleus RNA (snRNA) sequencing data from specimens collected from COVID-19 patients to determine the tissues and cells that produce ANGPTL4. RESULTS:single-nuclear RNA gene expression was significantly increased in pulmonary alveolar type 2 epithelial cells and fibroblasts in COVID-19 lung tissue compared with controls. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:ANGPTL4 is expressed in pulmonary epithelial cells and fibroblasts and is associated with clinical prognosis in critically ill COVID-19 patients.

INTRODUCTION: Ventilatory ratio (VR) is a bedside index of impaired ventilation that can be used as a surrogate marker for pulmonary dead space fraction (VD/VT). Vasculopathy is hypothesized to increase VD/VT in patients with acute respiratory distress syndrome (ARDS) due to COVID-19. The purpose of this study was to investigate associations between VR and markers of inflammation in critically ill COVID-ARDS patients.
METHOD(S): We conducted a retrospective study of patients admitted to an intensive care unit due to SARS-CoV-2 infection. All subjects required invasive mechanical ventilation and met the Berlin criteria for ARDS. Clinical lab values were collected at two timepoints: 2-8 hours after intubation (T1) and 2-24 hours before tracheostomy (T2). VR was split into high (VR>2) and low (VR< 2) groups. Comparisons were performed using student's t, Mann-Whitney, and z tests for difference in proportions with alpha=0.05.
RESULT(S): Of the 139 subjects enrolled at T1, 67 (48%) had high VR (>2), with an overall mean VR of 2.08. High VR was significantly associated with leukocyte count (WBC) (13.3 vs. 10.6 x10^9/L, p=0.004), and platelet count (284 vs 248 x10^9/L, p=0.003). There was no association between VR status and procalcitonin (p=0.08), d-dimer (p=0.73), fibrinogen (p=0.38), CRP (p=0.22), and ferritin (p=0.33). Since certain markers had non-Gaussian distributions, we determined threshold values. D-dimer over 500 ng/mL was associated with higher VR (2.3 vs. 1.8, p=0.004) and procalcitonin over 0.5 ng/mL was moderately associated with higher VR (2.2 vs 1.9, p=0.052). CRP >181 mug/mL (the median) and ferritin values >1.5x the upper limit of normal were not associated with VR (p=0.30 and p=0.26, respectively). To enrich the dataset, we pooled data from T1 and T2 and treated each as an independent sample. In this pooled analysis, high VR was associated with higher platelet count (282 vs. 253, p=0.046), and higher procalcitonin (3.464 vs. 0.964, p=0.032). There were no significant associations with VR and d-dimer (p=0.88), fibrinogen (p=0.54), CRP (p=0.20), and ferritin (p=0.76) in the pooled data.
CONCLUSION(S): Ventilatory ratio appears to be associated with higher levels of some inflammatory markers including WBC, platelets, d-dimer, and procalcitonin in COVID-ARDS patients