Structures of LRP2 reveal a molecular machine for endocytosis.

The low-density lipoprotein (LDL) receptor-related protein 2 (LRP2 or megalin) is representative of the phylogenetically conserved subfamily of giant LDL receptor-related proteins, which function in endocytosis and are implicated in diseases of the kidney and brain. Here, we report high-resolution cryoelectron microscopy structures of LRP2 isolated from mouse kidney, at extracellular and endosomal pH. The structures reveal LRP2 to be a molecular machine that adopts a conformation for ligand binding at the cell surface and for ligand shedding in the endosome. LRP2 forms a homodimer, the conformational transformation of which is governed by pH-sensitive sites at both homodimer and intra-protomer interfaces. A subset of LRP2 deleterious missense variants in humans appears to impair homodimer assembly. These observations lay the foundation for further understanding the function and mechanism of LDL receptors and implicate homodimerization as a conserved feature of the LRP receptor subfamily.

Tocilizumab for the treatment of chronic antibody mediated rejection in kidney transplant recipients.

BACKGROUND: Chronic active antibody-mediated rejection (CAAMR) constitutes a dominant form of late allograft failure. Several treatment strategies directed at CAAMR have been attempted but proven ineffective at delaying kidney function decline or reducing donor-specific antibodies (DSA). We describe our single-center experience using tocilizumab in patients with CAAMR. METHODS: This is a retrospective analysis using electronic medical records. 38 kidney transplant recipients at Columbia University Irving Medical Center who had been prescribed tocilizumab and followed for at least 3 months between August 2013 through December 2019 were included. RESULTS: Tocilizumab use was associated with a decrease in the rate of estimated glomerular filtration rate (eGFR) decline in the 6 months following treatment initiation as compared to the 3 months before tocilizumab was initiated (difference between slopes before and after initiation of treatment = 2.6 mL/min/1.73 m2 (SE = .8, p = .002) per month for up to 6 months following Tocilizumab initiation). Allograft biopsies showed significant improvement in interstitial inflammation scores (score 1(0,1) to 0 (0,1), p = .03) while other histologic scores remained stable. There was no significant change in proteinuria or DSA titers post-treatment with tocilizumab. CONCLUSIONS: Treatment of CAAMR with tocilizumab was associated with a decrease in the rate of eGFR decline and a reduction in interstitial inflammation scores in patients with CAAMR.

Latent Class Analysis Reveals COVID-19-related Acute Respiratory Distress Syndrome Subgroups with Differential Responses to Corticosteroids.

Rationale: Two distinct subphenotypes have been identified in acute respiratory distress syndrome (ARDS), but the presence of subgroups in ARDS associated with coronavirus disease (COVID-19) is unknown. Objectives: To identify clinically relevant, novel subgroups in COVID-19-related ARDS and compare them with previously described ARDS subphenotypes. Methods: Eligible participants were adults with COVID-19 and ARDS at Columbia University Irving Medical Center. Latent class analysis was used to identify subgroups with baseline clinical, respiratory, and laboratory data serving as partitioning variables. A previously developed machine learning model was used to classify patients as the hypoinflammatory and hyperinflammatory subphenotypes. Baseline characteristics and clinical outcomes were compared between subgroups. Heterogeneity of treatment effect for corticosteroid use in subgroups was tested. Measurements and Main Results: From March 2, 2020, to April 30, 2020, 483 patients with COVID-19-related ARDS met study criteria. A two-class latent class analysis model best fit the population (P = 0.0075). Class 2 (23%) had higher proinflammatory markers, troponin, creatinine, and lactate, lower bicarbonate, and lower blood pressure than class 1 (77%). Ninety-day mortality was higher in class 2 versus class 1 (75% vs. 48%; P < 0.0001). Considerable overlap was observed between these subgroups and ARDS subphenotypes. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RT-PCR cycle threshold was associated with mortality in the hypoinflammatory but not the hyperinflammatory phenotype. Heterogeneity of treatment effect to corticosteroids was observed (P = 0.0295), with improved mortality in the hyperinflammatory phenotype and worse mortality in the hypoinflammatory phenotype, with the caveat that corticosteroid treatment was not randomized. Conclusions: We identified two COVID-19-related ARDS subgroups with differential outcomes, similar to previously described ARDS subphenotypes. SARS-CoV-2 PCR cycle threshold had differential value for predicting mortality in the subphenotypes. The subphenotypes had differential treatment responses to corticosteroids.

Presentation and Outcomes of Patients with ESKD and COVID-19.

BACKGROUND: The relative immunosuppression and high prevalence of comorbidities in patients with ESKD on dialysis raise concerns that they may have an elevated risk of severe coronavirus disease 2019 (COVID-19), but outcomes for COVID-19 in such patients are unclear. METHODS: To examine presentation and outcomes of COVID-19 in patients with ESKD on dialysis, we retrospectively collected clinical data on 59 patients on dialysis who were hospitalized with COVID-19. We used Wilcoxon rank sum and Fischer exact tests to compare patients who died versus those still living. RESULTS: Two of the study's 59 patients were on peritoneal dialysis, and 57 were on hemodialysis. Median age was 63 years, with high prevalence of hypertension (98%) and diabetes (69%). Patients who died were significantly older than those still living (median age, 75 versus 62 years) and had a higher median Charlson comorbidity index (8 versus 7). The most common presenting symptoms were fever (49%) and cough (39%); initial radiographs most commonly showed multifocal or bilateral opacities (59%). By end of follow-up, 18 patients (31%) died a median 6 days after hospitalization, including 75% of patients who required mechanical ventilation. Eleven of those who died had advanced directives against intubation. The remaining 41 patients (69%) were discharged home a median 8 days after admission. The median initial white blood cell count was significantly higher in patients who died compared with those still living (7.5 versus 5.7×103/µl), as was C-reactive protein (163 versus 80 mg/L). CONCLUSIONS: The association of COVID-19 with high mortality in patients with ESKD on dialysis reinforces the need to take appropriate infection control measures to prevent COVID-19 spread in this vulnerable population.

Ineffective cardiac resynchronization pacing is associated with poor outcomes in a nationwide cohort analysis.

BACKGROUND: Delivery of cardiac resynchronization therapy (CRT) requires left ventricular myocardial capture to achieve clinical benefits. OBJECTIVE: We sought to determine whether ineffective pacing affects survival. METHODS: Ineffective ventricular pacing (VP) was defined as the difference between the percentage of delivered CRT (%VP) and the percentage of EffectivCRT in CRT devices. Using the Optum de-identified electronic health record data set and Medtronic CareLink data warehouse, we identified patients implanted with applicable devices with at least 30 days of follow-up. Kaplan-Meier and Cox proportional hazards models assessed the effect of %VP and % ineffective VP on survival. RESULTS: Among 7987 patients with 2.1 ± 1.0 years of follow-up, increasing ineffective VP was associated with decreasing survival: the highest observed survival was in the quartile with <0.08% ineffective VP and the lowest survival was in the quartile with >1.47% ineffective VP (85.1% vs 75.7% at 3 years; P < .001). As expected, patients with more than the median %VP of 97.7% had better survival than did patients with <97.7% VP (84.2% vs 77.8%; P < .001). However, patients who had >97.7% VP but >2% ineffective VP had similar survival to patients with <97.7% VP but ≤2% ineffective VP (81.6% vs 79.4%; P = .54). A multivariable Cox proportional hazards model demonstrated that <97.7% VP (adjusted hazard ratio 1.29; 95% confidence interval 1.14-1.46; P < .001) and >2% ineffective VP (hazard ratio 1.35; 95% confidence interval 1.18-1.54; P < .001) were both significantly associated with decreased survival. CONCLUSION: Ineffective VP is associated with decreased survival. In addition to maximizing the percentage of delivered CRT pacing, every effort should be made to minimize ineffective VP.

Ethylene Glycol Intoxication Requiring ECMO Support.

Ethylene glycol is commonly used in antifreeze, and ingestion of even a small amount can result in acute kidney injury, severe metabolic acidosis, and neurological injury. When cases are recognized early, treatment involves administration of alcohol dehydrogenase inhibitors to prevent conversion to toxic metabolites of glycolate, glyoxolate, and oxalate. In later presentations with more severe renal injury, hemodialysis may be required for clearance of toxic metabolites and supportive care for renal failure. We present the first reported case of severe ethylene glycol intoxication requiring support of extracorporeal membrane oxygenation (ECMO) due to refractory cardiopulmonary collapse.

Number of Donor Renal Arteries and Early Outcomes after Deceased Donor Kidney Transplantation.

Background: Anatomic abnormalities increase the risk of deceased donor kidney discard, but their effect on transplant outcomes is understudied. We sought to determine the effect of multiple donor renal arteries on early outcomes after deceased donor kidney transplantation. Methods: For this retrospective cohort study, we identified 1443 kidneys from 832 deceased donors with ≥1 kidney transplanted at our center (2006-2016). We compared the odds of delayed graft function and 90-day graft failure using logistic regression. To reduce potential selection bias, we then repeated the analysis using a paired-kidney cohort, including kidney pairs from 162 donors with one single-artery kidney and one multiartery kidney. Results: Of 1443 kidneys included, 319 (22%) had multiple arteries. Multiartery kidneys experienced longer cold ischemia time, but other characteristics were similar between groups. Delayed graft function (50% multiartery versus 45% one artery, P=0.07) and 90-day graft failure (3% versus 3%, P=0.83) were similar between groups before and after adjusting for donor and recipient characteristics. In the paired kidney analysis, cold ischemia time was significantly longer for multiartery kidneys compared with single-artery kidneys from the same donor (33.5 versus 26.1 hours, P<0.001), but delayed graft function and 90-day graft failure were again similar between groups. Conclusions: Compared with single-artery deceased donor kidneys, those with multiple renal arteries are harder to place, but experience similar delayed graft function and early graft failure.

Characterising the long-term clinical outcomes of 1190 hospitalised patients with COVID-19 in New York City: a retrospective case series.

OBJECTIVE: To characterise the long-term outcomes of patients with COVID-19 admitted to a large New York City medical centre at 3 and 6 months after hospitalisation and describe their healthcare usage, symptoms, morbidity and mortality. DESIGN: Retrospective cohort through manual chart review of the electronic medical record. SETTING: NewYork-Presbyterian/Columbia University Irving Medical Center, a quaternary care academic medical centre in New York City. PARTICIPANTS: The first 1190 consecutive patients with symptoms of COVID-19 who presented to the hospital for care between 1 March and 8 April 2020 and tested positive for SARS-CoV-2 on reverse transcriptase PCR assay. MAIN OUTCOME MEASURES: Type and frequency of follow-up encounters, self-reported symptoms, morbidity and mortality at 3 and 6 months after presentation, respectively; patient disposition information prior to admission, at discharge, and at 3 and 6 months after hospital presentation. RESULTS: Of the 1190 reviewed patients, 929 survived their initial hospitalisation and 261 died. Among survivors, 570 had follow-up encounters (488 at 3 months and 364 at 6 months). An additional 33 patients died in the follow-up period. In the first 3 months after admission, most encounters were telehealth visits (59%). Cardiopulmonary symptoms (35.7% and 28%), especially dyspnoea (22.1% and 15.9%), were the most common reported symptoms at 3-month and 6-month encounters, respectively. Additionally, a large number of patients reported generalised (26.4%) or neuropsychiatric (24.2%) symptoms 6 months after hospitalisation. Patients with severe COVID-19 were more likely to have reduced mobility, reduced independence or a new dialysis requirement in the 6 months after hospitalisation. CONCLUSIONS: Patients hospitalised with SARS-CoV-2 infection reported persistent symptoms up to 6 months after diagnosis. These results highlight the long-term morbidity of COVID-19 and its burden on patients and healthcare resources.

Outcomes for Patients With COVID-19 and Acute Kidney Injury: A Systematic Review and Meta-Analysis.

INTRODUCTION: There are limited data on the association of kidney dysfunction with prognosis in coronavirus disease 2019 (COVID-19), and the extent to which acute kidney injury (AKI) predisposes patients to severe illness and inferior outcomes is unclear. We aim to assess the incidence of AKI among patients with COVID-19 and examine their associations with patient outcomes as reported in the available literature thus far. METHODS: We systematically searched MEDLINE, EMBASE, SCOPUS, and MedRxiv databases for full-text articles available in English published from December 1, 2019 to May 24, 2020. Clinical information was extracted and examined from 20 cohorts that met inclusion criteria, covering 13,137 mostly hospitalized patients confirmed to have COVID-19. Two authors independently extracted study characteristics, results, outcomes, study-level risk of bias, and strength of evidence across studies. Neither reviewer was blind to journal titles, study authors, or institutions. RESULTS: Median age was 56 years, with 55% male patients. Approximately 43% of patients had severe COVID-19 infection, and approximately 11% died. Prevalence of AKI was 17%; 77% of patients with AKI experienced severe COVID-19 infection, and 52% died. AKI was associated with increased odds of death among COVID-19 patients (pooled odds ratio, 15.27; 95% CI 4.82-48.36), although there was considerable heterogeneity across studies and among different regions in the world. Approximately 5% of all patients required use of renal replacement therapy (RRT). CONCLUSIONS: Kidney dysfunction is common among patients with COVID-19, and patients who develop AKI have inferior outcomes. Additional research into management and potential mechanisms of this association is needed.

High rate of renal recovery in survivors of COVID-19 associated acute renal failure requiring renal replacement therapy.

INTRODUCTION: A large proportion of patients with COVID-19 develop acute kidney injury (AKI). While the most severe of these cases require renal replacement therapy (RRT), little is known about their clinical course. METHODS: We describe the clinical characteristics of COVID-19 patients in the ICU with AKI requiring RRT at an academic medical center in New York City and followed patients for outcomes of death and renal recovery using time-to-event analyses. RESULTS: Our cohort of 115 patients represented 23% of all ICU admissions at our center, with a peak prevalence of 29%. Patients were followed for a median of 29 days (2542 total patient-RRT-days; median 54 days for survivors). Mechanical ventilation and vasopressor use were common (99% and 84%, respectively), and the median Sequential Organ Function Assessment (SOFA) score was 14. By the end of follow-up 51% died, 41% recovered kidney function (84% of survivors), and 8% still needed RRT (survival probability at 60 days: 0.46 [95% CI: 0.36-0.56])). In an adjusted Cox model, coronary artery disease and chronic obstructive pulmonary disease were associated with increased mortality (HRs: 3.99 [95% CI 1.46-10.90] and 3.10 [95% CI 1.25-7.66]) as were angiotensin-converting-enzyme inhibitors (HR 2.33 [95% CI 1.21-4.47]) and a SOFA score >15 (HR 3.46 [95% CI 1.65-7.25). CONCLUSIONS AND RELEVANCE: Our analysis demonstrates the high prevalence of AKI requiring RRT among critically ill patients with COVID-19 and is associated with a high mortality, however, the rate of renal recovery is high among survivors and should inform shared-decision making.