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In January 2020, Novel Coronavirus Disease 2019 (COVID-19) resulted in a global pandemic, creating uncertainty towards the management of Liver Transplantation (LT) programmes. Lombardy has been the most affected region in Italy: The current mortality rate of COVID-19 patients is 18,3% (10022 deaths) (April 10th) with hospitals in Lombardy having to expand the total number of ICU beds from 724 to 1381 to accommodate infected patients. There has been a drastic decrease in liver donors. From February 23rd until April 10th, 17 LTs were performed in Lombardy. Mean donor age was 49 years (range 18-74) whereas mean recipient age was 55 (13-69); mean MELD Score was 12 (6-24). All donors underwent screening for SARS CoV-2 prior to LT. Two patients tested positive after LT, and one patient died for COVID on POD 30. 16 patients are alive after an average of 30 days post LT (range 3-46). 10 patients have been discharged. This study has found no specific reason concerning the safety of recipients, to stop liver transplantation programmes. Several Key-lessons from our experience are reported. However, due to the complex circumstances which surround the viral outbreak, the cessation or a reduction in LT activity is a pragmatic requirement.

As the COVID-19 pandemic has continued to spread, studies have shown that hospitalized COVID-19 patients are at significant risk for developing acute kidney injury (AKI), which can cause increased morbidity, the need for dialysis treatment, chronic kidney diseases, and even death. In this paper, we present a proof-of-concept study for the utilization of combination therapeutic-loaded dual-targeted biodegradable nanoparticles (NPs) to treat concurrent AKI and COVID-19 in patients by delivering the therapeutics across the gut epithelial barrier and to the kidney, in order to lower the viral load as well as reduce the symptoms of AKI. Despite recent vaccination efforts and the end of the COVID-19 pandemic in sight, problems related to the long-term effects of COVID-19 will continue to persist, including impacts on patients suffering from AKI and other chronic renal conditions. Therefore, the dual-targeted blended polymeric NP developed in this study to treat concurrent COVID-19 infection and AKI is a useful proof-of-concept nanoplatform for future treatments of these complications.

Impaired cellular cholesterol efflux is a key factor in the progression of renal, cardiovascular, and autoimmune diseases. Here we describe a class of 5-arylnicotinamide compounds, identified through phenotypic drug discovery, that upregulate ABCA1-dependent cholesterol efflux by targeting Oxysterol Binding Protein Like 7 (OSBPL7). OSBPL7 was identified as the molecular target of these compounds through a chemical biology approach, employing a photoactivatable 5-arylnicotinamide derivative in a cellular cross-linking/immunoprecipitation assay. Further evaluation of two compounds (Cpd A and Cpd G) showed that they induced ABCA1 and cholesterol efflux from podocytes in vitro and normalized proteinuria and prevented renal function decline in mouse models of proteinuric kidney disease: Adriamycin-induced nephropathy and Alport Syndrome. In conclusion, we show that small molecule drugs targeting OSBPL7 reveal an alternative mechanism to upregulate ABCA1, and may represent a promising new therapeutic strategy for the treatment of renal diseases and other disorders of cellular cholesterol homeostasis., This study describes a class of small molecule compounds that promote ABCA1-dependent cholesterol efflux via a non-transcriptional mechanism, the identification of the molecular target by a chemical biology approach, and the potential of these agents for the treatment of chronic kidney diseases and potentially other diseases where lipid accumulation drives disease progression.

Daniel H. Mintz Fig. 1 was born in Far Rockaway, New York, in 1930 to European Jewish parents, Jacob and Fanny, and grew up on Long Island, New York, where his parents immigrated in the early 1900s. In his youth he excelled both in sports (basketball) and academically; he was accepted as a premed student at St. Bonaventure College, where he completed his Bachelor’s degree cum laude. He entered New York Medical College, which had no quotas for Jewish students (unlike many other schools at that time), and completed his medical training in 1956. (Fig. 2) While serving his internship at Henry Ford Hospital in Detroit, Michigan, he met his future wife, Dawn, a hospital nurse. In 1961, Dan entered residency at Georgetown University School of Medicine and joined the faculty, initiating his research career under the mentorship of Dr. Larry Kyle, Chairman of Medicine, studying parathyroid and bone disorders (1). Daniel Mintz in 2006. Daniel Mintz as a young student, and with his parents and sister at his medical graduation ceremony, New York Medical College, 1956. Dan’s first love was clinical medicine, so it is no surprise that he was appointed Chief of Medicine at the then District of Columbia General Hospital in 1964. He once recounted the story that kept him in academic medicine after planning to start a private practice in Leesburg, Northern Virginia. Dr. Kyle called him into his office and told him in no uncertain terms that he was making a mistake and should remain in academia. As Dan recalled years later, “In those days you did what your boss told you to do!” This career-changing decision was a testament to Dan’s primary reason for entering medicine—to be a healer of the sick. His capacity for responding to people in need strongly influenced his …

Chronic Kidney Disease (CKD) represents the 9th most common cause of death in the U.S(1), but despite this large health burden, treatment options for affected patients remain limited. To remedy this, several relevant pathways have been identified that may lead to novel therapeutic options. Among them, altered renal lipid metabolism, first described in 1982, has been recognized as a common pathway in clinical and experimental CKD of both metabolic and non-metabolic origin. This observation has led many researchers to investigate the cause of this renal parenchyma lipid accumulation and its downstream effect on renal structure and function. Among key cellular components of the kidney parenchyma, podocytes are terminally differentiated cells that cannot be easily replaced when lost. Clinical and experimental evidence supports a role of reduced podocyte number in the progression of CKD. Given the importance of the podocytes in the maintenance of the glomerular filtration barrier and the accumulation of triglyceride and cholesterol-rich lipid droplets in the podocyte and glomerulus in kidney diseases that cause CKD, understanding the upstream cause and downstream consequences of lipid accumulation in podocytes may lead to novel therapeutic opportunities. In this review we hope to consolidate our understanding of the causes and consequences of dysregulated renal lipid metabolism in CKD development and progression, with a major focus on podocytes.

Background: Liver bleeding secondary to haemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome is uncommon, but a life-threatening peripartum condition that needs a prompt multidisciplinary approach.Case Presentation: In this study, we presented a case of 28-year-old pregnant woman, who was presented to the obstetrics department with signs of preeclampsia and foetal growth restriction. An emergency caesarean section was performed, and the patient developed a HELLP syndrome complicated by spontaneous liver rupture. After radiological and surgical procedures, liver failure became evident and liver transplantation was successfully performed. The patient and her daughter are now alive.Conclusions: Despite the rarity of this disease, liver complications due to HELLP syndrome must be properly diagnosed and treated given the gravity of the possible evolution in young women. After diagnosis, the patients must be treated in specialised centres with gynaecological, liver surgery, and transplant skills.

Background: Lupus membranous nephropathy (LMN) is a rare disease, usually associated with nephrotic syndrome. Methods: We reviewed the literature by searching for the following terms on Pubmed.gov: lupus nephritis, membranous nephropathy (MN), lupus membranous nephropathy, nephrotic syndrome, and Class V lupus nephritis. Results: The histology of LMN at light microscopy is similar to that of primary MN. Cases of MN associated with focal or diffuse proliferation are not considered LMN by the International Society of Nephrology/Renal Pathology Society classification. Immunofluorescence study of LMN shows deposits of all immunoglobulins and complement. Tubulo-reticular structures, extraglomerular deposits, subepithelial, and scanty subendothelial deposits can be seen on electron microscopy. Phospholipase A2 receptor deposits are usually but not necessarily absent in LMN. The pathogenesis is still not completely understood. The inflammatory milieu of lupus may favor the development of autoantigens and intraglomerular assembly of immune complexes. These are more often associated with mesangial or endocapillary hypercellular lesions. Alternatively, autoantibodies may bind autoantigens in the glomerular subepithelium, triggering a signaling cascade leading to LMN. A central role in the development of podocyte injury and proteinuria is played by the components of complement C5b-C9. CKD progression in LMN is slow but may be accelerated by the frequency of renal flares. Persistent nephrotic syndrome and/or the frequent use of corticosteroids may lead to a series of life-threatening complications. Discussion: Treatment of arterial hypertension, dyslipidemia, and diabetes are of paramount importance. Besides specific therapies of these complications, hydroxychloroquine and vitamin D supplementation are recommended. Immunosuppression should be limited to patients with nephrotic proteinuria. The most frequently used drugs are corticosteroids, calcineurin inhibitors, cyclophosphamide, mycophenolate, and rituximab, alone or combined. Early detection and treatment of renal flares is of paramount importance to prevent CKD progression.

Background: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1’s natural absence in laboratory animals makes studying its pathobiology challenging. Methods: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes. Results: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR

Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. Besides glycemic and blood pressure control, environmental factors such as cigarette smoking (CS) adversely affect the progression of DN. The effects of CS on DN progression have been attributed to combustion-generated molecules without consideration to the role of nicotine (NIC), responsible for the addictive properties of both CS and electronic cigarettes (ECs). Podocytes are essential to preserve the structure and function of the glomerular filtration barrier, and strong evidence indicates that early podocyte loss promotes DN progression. We performed experiments in human podocytes and in a mouse model of diabetes that develops nephropathy resembling human DN. We determined that NIC binding to podocytes in concentrations achieved with CS and ECs activated NADPH oxidase, which sets in motion a dysfunctional molecular network integrated by cyclooxygenase 2, known to induce podocyte injury; downregulation of AMP-activated protein kinase, important for maintaining cellular energy stores and antioxidation; and upregulation of CD36, which increased lipid uptake and promoted apoptosis. In diabetic mice, NIC increased proteinuria, a recognized marker of chronic kidney disease progression, accompanied by reduced glomerular podocyte synaptopodin, a crucial stabilizer of the podocyte cytoskeleton, and increased fibronectin expression. This novel study critically implicates NIC itself as a contributor to DN progression in CS and EC users. NEW & NOTEWORTHY In this study, we demonstrate that nicotine increases the production of reactive oxygen species, increases cyclooxygenase-2 expression, and upregulates Cd36 while inducing downregulation of AMP-activated protein kinase. In vivo nicotine increases proteinuria and fibronectin expression in diabetic mice. This study demonstrates that effects of nicotine on podocytes are responsible, at least in part, for the deleterious effects of smoking in the progression of chronic kidney disease, including diabetic nephropathy.

The application of deep learning for automated segmentation (delineation of boundaries) of histologic primitives (structures) from whole slide images can facilitate the establishment of novel protocols for kidney biopsy assessment. Here, we developed and validated deep learning networks for the segmentation of histologic structures on kidney biopsies and nephrectomies. For development, we examined 125 biopsies for Minimal Change Disease collected across 29 NEPTUNE enrolling centers along with 459 whole slide images stained with Hematoxylin & Eosin (125), Periodic Acid Schiff (125), Silver (102), and Trichrome (107) divided into training, validation and testing sets (ratio 6:1:3). Histologic structures were manually segmented (30048 total annotations) by five nephropathologists. Twenty deep learning models were trained with optimal digital magnification across the structures and stains. Periodic Acid Schiff-stained whole slide images yielded the best concordance between pathologists and deep learning segmentation across all structures (F-scores: 0.93 for glomerular tufts, 0.94 for glomerular tuft plus Bowman's capsule, 0.91 for proximal tubules, 0.93 for distal tubular segments, 0.81 for peritubular capillaries, and 0.85 for arteries and afferent arterioles). Optimal digital magnifications were 5X for glomerular tuft/tuft plus Bowman's capsule, 10X for proximal/distal tubule, arteries and afferent arterioles, and 40X for peritubular capillaries. Silver stained whole slide images yielded the worst deep learning performance. Thus, this largest study to date adapted deep learning for the segmentation of kidney histologic structures across multiple stains and pathology laboratories. All data used for training and testing and a detailed online tutorial will be publicly available.

A critical link between metabolic disorders and a form of low-grade systemic and chronic inflammation has been recently established and named 'Metaflammation'. Metaflammation has been recognized as a key mediator of both microvascular and macrovascular complications of diabetes and as a significant contributor to the development of diabetic kidney disease (DKD). The goal of this review is to summarize the contribution of diabetes-induced inflammation and the related signaling pathways to diabetic complications, with a particular focus on how innate immunity and lipid metabolism influence each other.

Defective cholesterol metabolism primarily linked to reduced ATP-binding cassette transporter A1 (ABCA1) expression is closely associated with the pathogenesis and progression of kidney diseases, including diabetic kidney disease and Alport Syndrome. However, whether the accumulation of free or esterified cholesterol contributes to progression in kidney disease remains unclear. Here, we demonstrate that inhibition of sterol-O-acyltransferase-1 (SOAT1), the enzyme at the endoplasmic reticulum that converts free cholesterol to cholesterol esters, which are then stored in lipid droplets, effectively reduced cholesterol ester and lipid droplet formation in human podocytes. Furthermore, we found that inhibition of SOAT1 in podocytes reduced lipotoxicity-mediated podocyte injury in diabetic kidney disease and Alport Syndrome in association with increased ABCA1 expression and ABCA1-mediated cholesterol efflux. In vivo, Soat1 deficient mice did not develop albuminuria or mesangial expansion at 10-12 months of age. However, Soat1 deficiency/inhibition in experimental models of diabetic kidney disease and Alport Syndrome reduced cholesterol ester content in kidney cortices and protected from disease progression. Thus, targeting SOAT1-mediated cholesterol metabolism may represent a new therapeutic strategy to treat kidney disease in patients with diabetic kidney disease and Alport Syndrome, like that suggested for Alzheimer's disease and cancer treatments.

National data on patient characteristics, treatment, and outcomes of critically ill coronavirus disease 2019 (COVID-19) solid organ transplant (SOT) patients are limited. We analyzed data from a multicenter cohort study of adults with laboratory-confirmed COVID-19 admitted to intensive care units (ICUs) at 68 hospitals across the United States from March 4 to May 8, 2020. From 4153 patients, we created a propensity score matched cohort of 386 patients, including 98 SOT patients and 288 non-SOT patients. We used a binomial generalized linear model (log-binomial model) to examine the association of SOT status with death and other clinical outcomes. Among the 386 patients, the median age was 60 years, 72% were male, and 41% were black. Death within 28 days of ICU admission was similar in SOT and non-SOT patients (40% and 43%, respectively; relative risk [RR] 0.92; 95% confidence interval [CI]: 0.70-1.22). Other outcomes and requirement for organ support including receipt of mechanical ventilation, development of acute respiratory distress syndrome, and receipt of vasopressors were also similar between groups. There was a trend toward higher risk of acute kidney injury requiring renal replacement therapy in SOT vs. non-SOT patients (37% vs. 27%; RR [95% CI]: 1.34 [0.97-1.85]). Death and organ support requirement were similar between SOT and non-SOT critically ill patients with COVID-19.

Introduction: Prior cross-sectional studies suggest that health-related quality of life (HRQOL) worsens with more severe glomerular disease. This longitudinal analysis was conducted to assess changes in HRQOL with changing disease status. Methods: Cure Glomerulonephropathy (CureGN) is a cohort of patients with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA vasculitis, or IgA nephropathy. HRQOL was assessed at enrollment and follow-up visits 1 to 3 times annually for up to 5 years with the Patient-Reported Outcomes Measurement Information System (PROMIS). Global health, anxiety, and fatigue domains were measured in all; mobility was measured in children; and sleep-related impairment was measured in adults. Linear mixed effects models were used to evaluate HRQOL responsiveness to changes in disease status. Results: A total of 469 children and 1146 adults with PROMIS scores were included in the analysis. HRQOL improved over time in nearly all domains, though group-level changes were modest. Edema was most consistently associated with worse HRQOL across domains among children and adults. A greater number of symptoms also predicted worse HRQOL in all domains. Sex, age, obesity, and serum albumin were associated with some HRQOL domains. The estimated glomerular filtration rate (eGFR) was only associated with fatigue and adult physical health; proteinuria was not associated with any HRQOL domain in adjusted models. Conclusion: HRQOL measures were responsive to changes in disease activity, as indicated by edema. HRQOL over time was not predicted by laboratory-based markers of disease. Patient-reported edema and number of symptoms were the strongest predictors of HRQOL, highlighting the importance of the patient experience in glomerular disease. HRQOL outcomes inform understanding of the patient experience for children and adults with glomerular diseases.

Introduction Glomerular diseases are characterized by variable disease activity over many years. We aimed to analyze the relationship between clinical disease activity and duration of glomerular disease. Methods Disease activity in adults with chronic minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy (IgAN; first diagnostic biopsy >5 years before enrollment; Of Longstanding Disease [OLD] cohort, n = 256) followed at Columbia University Medical Center (CUMC), was compared with disease activity of an internal and external cohort of patients with first diagnostic biopsy, Graphical abstract

There is growing evidence that migraine is associated with attentional abnormalities, both during and outside migraine attacks, which would impact the cognitive processing of sensory stimulation. However, these attention alterations are poorly characterized and their neurophysiological basis is still unclear. Nineteen migraineurs without aura and nineteen healthy participants were recruited to perform a task which used visually-cued auditory targets and distracting sounds to evaluate conjointly top-down and bottom-up attention mechanisms. Magnetoencephalography (MEG) signals were recorded. We investigated anticipatory alpha activity (power increase and decrease) and distractor-induced gamma activity as markers for top-down (inhibition and facilitation) and bottom-up attention, respectively. Compared to healthy participants, migraineurs presented a significantly less prominent alpha power increase in visual areas in anticipation of the auditory target, indexing a reduced inhibition of task-irrelevant visual areas. However, there was no significant group difference regarding the alpha power decrease in the relevant auditory cortices in anticipation of the target, nor regarding the distractor-induced gamma power increase in the ventral attention network. These results in the alpha band suggest that top-down inhibitory processes in the visual cortices are deficient in migraine but there is no clear evidence supporting a disruption of top-down facilitatory attentional processes. This relative inability to suppress irrelevant sensory information may be underlying the self-reported increased distractibility and contribute to sensory disturbances in migraine.

Background: In the absence of a histological diagnosis, persistent albuminuria is globally accepted as the main diagnostic criteria for diabetic kidney disease (DKD). Methods: In the present retrospective study, we evaluated data from an Italian cohort of 42 deceased diabetic donors (mainly with type 2 diabetes). Using the kidney biopsies obtained at the time of donation to evaluate single or double allocation based on Karpinski score, we determined the prevalence of histological lesions attributable to diabetes. Results: All 42 donors presented with proteinuria in the normal range and an estimated glomerular filtration rate (eGFR) (chronic kidney disease [CKD]-EPI) >60 mL/min/1.73 m2. A kidney biopsy was available for 36 patients; of these, one was not interpretable and 32 showed histopathological lesions consistent with DKD and encompassing all histological classes. Thus, we found a relatively high proportion of histologically proven DKD that had been clinically undiagnosed, as none of the patient had significant proteinuria and eGFR 2. Conclusions: The data we present here support the need to implement routine kidney biopsies in normoalbuminuric diabetic subjects in the early stages of CKD. Such strategy may help to improve risk stratification in diabetic patients and guide therapeutic decisions during the early stages of the disease.

Alport syndrome is characterized by hematuria, sensorineural hearing loss, and ocular abnormalities. It was first described by Cecil Alport in 1927, who connected kidney disease and deafness as coexpressed hereditary traits. The molecular basis of Alport syndrome was identified in the 1990s with the

Alport syndrome (AS) is a genetic disorder involving mutations in the genes encoding collagen IV α3, α4 or α5 chains, resulting in the impairment of glomerular basement membrane. Podocytes are responsible for production and correct assembly of collagen IV isoforms; however, data on the phenotypic characteristics of human AS podocytes and their functional alterations are currently limited. The evident loss of viable podocytes into the urine of patients with active glomerular disease enables their isolation in a non-invasive way. Here we isolated, immortalized, and subcloned podocytes from the urine of three different AS patients for molecular and functional characterization. AS podocytes expressed a typical podocyte signature and showed a collagen IV profile reflecting each patient's mutation. Furthermore, RNA-sequencing analysis revealed 348 genes differentially expressed in AS podocytes compared with control podocytes. Gene Ontology analysis underlined the enrichment in genes involved in cell motility, adhesion, survival, and angiogenesis. In parallel, AS podocytes displayed reduced motility. Finally, a functional permeability assay, using a podocyte-glomerular endothelial cell co-culture system, was established and AS podocyte co-cultures showed a significantly higher permeability of albumin compared to control podocyte co-cultures, in both static and dynamic conditions under continuous perfusion. In conclusion, our data provide a molecular characterization of immortalized AS podocytes, highlighting alterations in several biological processes related to extracellular matrix remodelling. Moreover, we have established an in vitro model to reproduce the altered podocyte permeability observed in patients with AS. © 2020 The Authors. The Journal of Pathology published by John WileySons Ltd on behalf of Pathological Society of Great Britain and Ireland..

Introduction Much of the higher risk for end-stage kidney disease (ESKD) in African American individuals relates to ancestry-specific variation in the apolipoprotein L1 gene (APOL1). Relative to kidneys from European American deceased-donors, kidneys from African American deceased-donors have shorter allograft survival and African American living-kidney donors more often develop ESKD. The National Institutes of Health (NIH)–sponsored APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) is prospectively assessing kidney allograft survival from donors with recent African ancestry based on donor and recipient APOL1 genotypes. Methods APOLLO will evaluate outcomes from 2614 deceased kidney donor-recipient pairs, as well as additional living-kidney donor-recipient pairs and unpaired deceased-donor kidneys. Results The United Network for Organ Sharing (UNOS), Association of Organ Procurement Organizations, American Society of Transplantation, American Society for Histocompatibility and Immunogenetics, and nearly all U.S. kidney transplant programs, organ procurement organizations (OPOs), and histocompatibility laboratories are participating in this observational study. APOLLO employs a central institutional review board (cIRB) and maintains voluntary partnerships with OPOs and histocompatibility laboratories. A Community Advisory Council composed of African American individuals with a personal or family history of kidney disease has advised the NIH Project Office and Steering Committee since inception. UNOS is providing data for outcome analyses. Conclusion This article describes unique aspects of the protocol, design, and performance of APOLLO. Results will guide use of APOL1 genotypic data to improve the assessment of quality in deceased-donor kidneys and could increase numbers of transplanted kidneys, reduce rates of discard, and improve the safety of living-kidney donation., Graphical abstract

Kidney disease is common in patients with multiple myeloma. Patients often present with acute kidney failure most commonly the result of light chain cast nephropathy. Presentation can also be in the form of nephrotic syndrome associated with immunoglobulin light chain amyloidosis or monoclonal immunoglobulin deposition disease and tubulopathy as in acquired light chain Fanconi syndrome. We present a case of a 56-year-old male with multiple myeloma who presented with chronic kidney disease and uric acid stones. Chemical analysis of the nephrolithiasis showed it to be entirely composed of uric acid. Fractional excretion of uric acid was elevated at 35.9%. Kidney biopsy was consistent with light chain proximal tubulopathy. Bone marrow biopsy showed 30% kappa light chain–restricted plasma cells. Genetic sequencing identified the light chain to be from the Vk1-33 subgroup. The patient was treated with bortezomib, cyclophosphamide, and dexamethasone, with improvement of his kidney function. This case illustrates a rare presentation of multiple myeloma.

Fibroblast growth factor (FGF) 21, a hormone that increases insulin sensitivity, has shown promise as a therapeutic agent to improve metabolic dysregulation. Here we report that FGF21 directly targets cardiac myocytes by binding β-klotho and FGF receptor (FGFR) 4. In combination with high glucose, FGF21 induces cardiac myocyte growth in width mediated by extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. While short-term FGF21 elevation can be cardio-protective, we find that in type 2 diabetes (T2D) in mice, where serum FGF21 levels are elevated, FGFR4 activation induces concentric cardiac hypertrophy. As T2D patients are at risk for heart failure with preserved ejection fraction (HFpEF), we propose that induction of concentric hypertrophy by elevated FGF21-FGFR4 signaling constitutes a novel mechanism promoting T2D-associated HFpEF and that FGFR4 blockade might serve as a cardio-protective therapy in T2D. In addition, potential adverse cardiac effects of FGF21 mimetics currently in clinical trials should be investigated.

BackgroundClassification of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies. This approach does not reflect underlying disease biology, limiting the ability to predict progression or treatment response.MethodsSystems biology approaches were used to categorize patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) based on kidney biopsy tissue transcriptomics across three cohorts and assessed association with clinical outcomes. Patient-level tissue pathway activation scores were generated using differential gene expression. Then, functional enrichment and non-invasive urine biomarker candidates were identified. Biomarkers were validated in kidney organoid models and single nucleus RNA-seq (snRNAseq) from kidney biopsies.ResultsTranscriptome-based categorization identified three subgroups of patients with shared molecular signatures across independent North American, European and African cohorts. One subgroup demonstrated worse longterm outcomes (HR 5.2, p = 0.001) which persisted after adjusting for diagnosis and clinical measures (HR 3.8, p = 0.035) at time of biopsy. This subgroup’s molecular profile was largely (48%) driven by tissue necrosis factor (TNF) activation and could be predicted based on levels of TNF pathway urinary biomarkers TIMP-1 and MCP-1 and clinical features (correlation 0.63, p ConclusionsMolecular profiling identified a patient subgroup within nephrotic syndrome with poor outcome and kidney TNF pathway activation. Clinical trials using non-invasive biomarkers of pathway activation to target therapies are currently being evaluated.Significance StatementMechanistic, targeted therapies are urgently needed for patients with nephrotic syndrome. The inability to target an individual’s specific disease mechanism using currently used diagnostic parameters leads to potential treatment failure and toxicity risk. Patients with focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) were grouped by kidney tissue transcriptional profiles and a subgroup associated with poor outcomes defined. The segregation of the poor outcome group was driven by tumor necrosis factor (TNF) pathway activation and could be identified by urine biomarkers, MCP1 and TIMP1. Based on these findings, clinical trials utilizing non-invasive biomarkers of pathway activation to target therapies, improve response rates and facilitate personalized treatment in nephrotic syndrome have been initiated.

Variation in hospital mortality has been described for coronavirus disease 2019 (COVID-19), but the factors that explain these differences remain unclear.Our objective was to utilize a large, nationally representative dataset of critically ill adults with COVID-19 to determine which factors explain mortality variability.In this multicenter cohort study, we examined adults hospitalized in intensive care units with COVID-19 at 70 United States hospitals between March and June 2020. The primary outcome was 28-day mortality. We examined patient-level and hospital-level variables. Mixed-effects logistic regression was used to identify factors associated with interhospital variation. The median odds ratio (OR) was calculated to compare outcomes in higher- vs. lower-mortality hospitals. A gradient boosted machine algorithm was developed for individual-level mortality models.A total of 4,019 patients were included, 1537 (38%) of whom died by 28 days. Mortality varied considerably across hospitals (0-82%). After adjustment for patient- and hospital-level domains, interhospital variation was attenuated (OR decline from 2.06 [95% CI, 1.73-2.37] to 1.22 [95% CI, 1.00-1.38]), with the greatest changes occurring with adjustment for acute physiology, socioeconomic status, and strain. For individual patients, the relative contribution of each domain to mortality risk was: acute physiology (49%), demographics and comorbidities (20%), socioeconomic status (12%), strain (9%), hospital quality (8%), and treatments (3%).There is considerable interhospital variation in mortality for critically ill patients with COVID-19, which is mostly explained by hospital-level socioeconomic status, strain, and acute physiologic differences. Individual mortality is driven mostly by patient-level factors. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Summary: Many US states published crisis standards of care (CSC) guidelines for allocating scarce critical care resources during the COVID-19 pandemic. However, the performance of these guidelines in maximizing their population benefit has not been well tested. In 2,272 adults with COVID-19 requiring mechanical ventilation drawn from the Study of the Treatment and Outcomes in Critically Ill Patients with COVID-19 (STOP-COVID) multicenter cohort, we test the following three approaches to CSC algorithms: Sequential Organ Failure Assessment (SOFA) scores grouped into ranges, SOFA score ranges plus comorbidities, and a hypothetical approach using raw SOFA scores not grouped into ranges. We find that area under receiver operating characteristic (AUROC) curves for all three algorithms demonstrate only modest discrimination for 28-day mortality. Adding comorbidity scoring modestly improves algorithm performance over SOFA scores alone. The algorithm incorporating comorbidities has modestly worse predictive performance for Black compared to white patients. CSC algorithms should be empirically examined to refine approaches to the allocation of scarce resources during pandemics and to avoid potential exacerbation of racial inequities.

Hypercoagulability may be a key mechanism of death in patients with COVID-19. This cohort study evaluated the incidence of venous thromboembolism and major bleeding in critically ill patients with COVID-19 and examined the observational effect of early therapeutic anticoagulation on survival., Visual Abstract. Early Anticoagulation in COVID-19 Hypercoagulability may be a key mechanism of death in patients with COVID-19. This cohort study evaluated the incidence of venous thromboembolism and major bleeding in critically ill patients with COVID-19 and examined the observational effect of early therapeutic anticoagulation on survival. Visual Abstract. Early Anticoagulation in COVID-19 Hypercoagulability may be a key mechanism of death in patients with COVID-19. This cohort study evaluated the incidence of venous thromboembolism and major bleeding in critically ill patients with COVID-19 and examined the observational effect of early therapeutic anticoagulation on survival., Background: Hypercoagulability may be a key mechanism of death in patients with coronavirus disease 2019 (COVID-19). Objective: To evaluate the incidence of venous thromboembolism (VTE) and major bleeding in critically ill patients with COVID-19 and examine the observational effect of early therapeutic anticoagulation on survival. Design: In a multicenter cohort study of 3239 critically ill adults with COVID-19, the incidence of VTE and major bleeding within 14 days after intensive care unit (ICU) admission was evaluated. A target trial emulation in which patients were categorized according to receipt or no receipt of therapeutic anticoagulation in the first 2 days of ICU admission was done to examine the observational effect of early therapeutic anticoagulation on survival. A Cox model with inverse probability weighting to adjust for confounding was used. Setting: 67 hospitals in the United States. Participants: Adults with COVID-19 admitted to a participating ICU. Measurements: Time to death, censored at hospital discharge, or date of last follow-up. Results: Among the 3239 patients included, the median age was 61 years (interquartile range, 53 to 71 years), and 2088 (64.5%) were men. A total of 204 patients (6.3%) developed VTE, and 90 patients (2.8%) developed a major bleeding event. Independent predictors of VTE were male sex and higher D-dimer level on ICU admission. Among the 2809 patients included in the target trial emulation, 384 (11.9%) received early therapeutic anticoagulation. In the primary analysis, during a median follow-up of 27 days, patients who received early therapeutic anticoagulation had a similar risk for death as those who did not (hazard ratio, 1.12 [95% CI, 0.92 to 1.35]). Limitation: Observational design. Conclusion: Among critically ill adults with COVID-19, early therapeutic anticoagulation did not affect survival in the target trial emulation. Primary Funding Source: None.

Lipid dysmetabolism is one of the main features of diabetes mellitus and manifests by dyslipidemia as well as the ectopic accumulation of lipids in various tissues and organs, including the kidney. Research suggests that impaired cholesterol metabolism, increased lipid uptake or synthesis, increased fatty acid oxidation, lipid droplet accumulation and an imbalance in biologically active sphingolipids (such as ceramide, ceramide-1-phosphate and sphingosine-1-phosphate) contribute to the development of diabetic kidney disease (DKD). Currently, the literature suggests that both quality and quantity of lipids are associated with DKD and contribute to increased reactive oxygen species production, oxidative stress, inflammation, or cell death. Therefore, control of renal lipid dysmetabolism is a very important therapeutic goal, which needs to be archived. This article will review some of the recent advances leading to a better understanding of the mechanisms of dyslipidemia and the role of particular lipids and sphingolipids in DKD.

The kidney is a radiosensitive late-responding normal tissue. Injury is characterized by radiation nephropathy and decline of glomerular filtration rate (GFR). The current study aimed to compare two rapid and cost-effective methodologies of assessing GFR against more conventional biomarker measurements.C57BL/6 mice were treated with bilateral focal X-irradiation (1x14Gy or 5x6Gy). Functional measurements of kidney injury were assessed 20 weeks post-treatment. GFR was estimated using a transcutaneous measurement of fluorescein-isothiocyanate conjugated (FITC)-sinistrin renal excretion and also dynamic contrast-enhanced CT imaging with a contrast agent (ISOVUE-300 Iopamidol).Hematoxylin and eosin (HE) and Periodic acid-Schiff staining identified comparable radiation-induced glomerular atrophy and mesangial matrix accumulation after both radiation schedules, respectively, although the fractionated regimen resulted in less diffuse tubulointerstitial fibrosis. Albumin-to-creatinine ratios (ACR) increased after irradiation (1x14Gy: 100.4 ± 12.2 µg/mg; 6x5Gy: 80.4 ± 3.02 µg/mg) and were double that of nontreated controls (44.9 ± 3.64 µg/mg). GFR defined by both techniques was negatively correlated with BUN, mesangial expansion score, and serum creatinine. The FITC-sinistrin transcutaneous method was more rapid and can be used to assess GFR in conscious animals, dynamic contrast-enhanced CT imaging technique was equally safe and effective.This study demonstrated that GFR measured by dynamic contrast-enhanced CT imaging is safe and effective compared to transcutaneous methodology to estimate kidney function.

Although olfactory disorders (OD) are among the most significant symptoms of COVID-19, recovery time from COVID-19-related OD and their consequences on the quality of life remain poorly documented. We investigated the characteristics and behavioral consequences of COVID-19-related OD using a large-scale study involving 3111 French respondents (78% women) to an online questionnaire over a period of 9 months covering different epidemic waves (from 8 April 2020 to 13 January 2021). In the patients who subjectively recovered from COVID-19-related OD (N = 609), recovery occurred on average after 16 days and most of the time within 1 month (“normal” recovery range); 49 subjectively recovered in 1–2.5 months, and several cases took up to 6.5 months. Among the patients with ongoing OD (N = 2502), 974 were outside the “normal” recovery range (persistent OD) and reported OD for 1–10 months. Developing a persistent OD was more likely with increasing age and in women and was more often associated with parosmia and phantosmia. The deleterious impact of COVID-19-related OD on the quality of life was significantly aggravated by OD duration and was more pronounced in women. Because persistent OD is not infrequent after COVID-19, has deleterious consequences on the quality of life, and receives few solutions from the health practitioners, it would be beneficial to implement screening and treatment programs to minimize the long-term behavioral consequences of COVID-19-related OD.

Deep learning based object detectors are commonly deployed on mobile devices to solve a variety of tasks. For maximum accuracy, each detector is usually trained to solve one single specific task, and comes with a completely independent set of parameters. While this guarantees high performance, it is also highly inefficient, as each model has to be separately downloaded and stored. In this paper we address the question: can task-specific detectors be trained and represented as a shared set of weights, plus a very small set of additional weights for each task? The main contributions of this paper are the following: 1) we perform the first systematic study of parameter-efficient transfer learning techniques for object detection problems; 2) we propose a technique to learn a model patch with a size that is dependent on the difficulty of the task to be learned, and validate our approach on 10 different object detection tasks. Our approach achieves similar accuracy as previously proposed approaches, while being significantly more compact.

IMPORTANCE: Therapies that improve survival in critically ill patients with coronavirus disease 2019 (COVID-19) are needed. Tocilizumab, a monoclonal antibody against the interleukin 6 receptor, may counteract the inflammatory cytokine release syndrome in patients with severe COVID-19 illness. OBJECTIVE: To test whether tocilizumab decreases mortality in this population. DESIGN, SETTING, AND PARTICIPANTS: The data for this study were derived from a multicenter cohort study of 4485 adults with COVID-19 admitted to participating intensive care units (ICUs) at 68 hospitals across the US from March 4 to May 10, 2020. Critically ill adults with COVID-19 were categorized according to whether they received or did not receive tocilizumab in the first 2 days of admission to the ICU. Data were collected retrospectively until June 12, 2020. A Cox regression model with inverse probability weighting was used to adjust for confounding. EXPOSURES: Treatment with tocilizumab in the first 2 days of ICU admission. MAIN OUTCOMES AND MEASURES: Time to death, compared via hazard ratios (HRs), and 30-day mortality, compared via risk differences. RESULTS: Among the 3924 patients included in the analysis (2464 male [62.8%]; median age, 62 [interquartile range {IQR}, 52-71] years), 433 (11.0%) received tocilizumab in the first 2 days of ICU admission. Patients treated with tocilizumab were younger (median age, 58 [IQR, 48-65] vs 63 [IQR, 52-72] years) and had a higher prevalence of hypoxemia on ICU admission (205 of 433 [47.3%] vs 1322 of 3491 [37.9%] with mechanical ventilation and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of

Microphysiological systems, also known as organs-on-chips, are microfluidic devices designed to model human physiology in vitro. Polydimethylsiloxane (PDMS) is the most widely used material for organs-on-chips due to established microfabrication methods, and properties that make it suitable for biological applications such as low cytotoxicity, optical transparency, gas permeability. However, absorption of small molecules and leaching of uncrosslinked oligomers might hinder the adoption of PDMS-based organs-on-chips for drug discovery assays. Here, we have engineered a modular, PDMS-free microphysiological system that is capable of recapitulating biologic barrier functions commonly demonstrated in PDMS-based devices. Our microphysiological system is comprised of a microfluidic chip to house cell cultures and pneumatic microfluidic pumps to drive flow with programmable pressure and shear stress. The modular architecture and programmable pumps enabled us to model multiple in vivo microenvironments. First, we demonstrate the ability to generate cyclic strain on the culture membrane and establish a model of the alveolar air-liquid interface. Next, we utilized three-dimensional finite element analysis modeling to characterize the fluid dynamics within the device and develop a model of the pressure-driven filtration that occurs at the glomerular filtration barrier. Finally, we demonstrate that our model can be used to recapitulate sphingolipid induced kidney injury. Together, our results demonstrate that a multifunctional and modular microphysiological system can be deployed without the use of PDMS. Further, the bio-inert plastic used in our microfluidic device is amenable to various established, high-throughput manufacturing techniques, such as injection molding. As a result, the development plastic organs-on-chips provides an avenue to meet the increasing demand for organ-on-chip technology.

Sphingolipids are well-recognized as major players in the pathogenesis of many human diseases, including chronic kidney disease. The kidney is a very sensitive organ to alterations in sphingolipid metabolism. The critical issues to be addressed in this review relate to the role of sphingolipids and enzymes involved in sphingolipid metabolism in the pathogenesis of glomerular diseases with a special focus on podocytes, a key cellular component of the glomerular filtration barrier. Among several sphingolipids, we will highlight the role of ceramide, sphingosine, sphingosine-1-phosphate and ceramide-1-phosphate. Additionally, we will summarize the current knowledge with regard to the use of sphingolipids as therapeutic agents for the treatment of podocyte injury in kidney disease.

Rationale & Objective The current classification system for focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) does not fully capture the complex structural changes in kidney biopsies, nor the clinical and molecular heterogeneity of these diseases. Study Design Prospective observational cohort study. Setting & Participants N=221 MCD and FSGS patients enrolled in the Nephrotic Syndrome Study Network (NEPTUNE). Exposures The NEPTUNE Digital Pathology Scoring System (NDPSS) was applied to generate scores for 37 glomerular descriptors. Outcomes Time from biopsy to complete proteinuria remission, time from biopsy to kidney disease progression (40% eGFR decline or kidney failure), and eGFR over time. Analytical Approach Cluster analysis was used to group patients with similar morphologic characteristics. Glomerular descriptors and patient clusters were assessed for associations with outcomes using adjusted Cox models and linear mixed models. Messenger RNA from glomerular tissue was used to assess differentially expressed genes between clusters and identify genes associated with individual descriptors driving cluster membership. Results Three clusters were identified: X (N=56), Y (N=68), and Z (N=97). Clusters Y and Z had higher probabilities of proteinuria remission (HR [95% CI]= 1.95 [0.99, 3.85] and 3.29 [1.52, 7.13], respectively), lower hazards of disease progression 0.22 [0.08, 0.57] and 0.11 [0.03, 0.45], respectively), and lower loss of eGFR over time compared with X. Cluster X had 1920 differentially expressed genes compared to Y+Z, which reflected activation of pathways of immune response and inflammation. Six descriptors driving the clusters individually correlated with clinical outcomes and gene expression. Limitations Low prevalence of some descriptors and biopsy at a single time point. Conclusions The NDPSS allows for categorization of FSGS/MCD patients into clinically and biologically relevant subgroups, and uncovers histologic parameters associated with clinical outcomes and molecular signatures not included in current classification systems.

Background and aim Liver grafts from donors with chronic and active history of alcohol abuse are usually immediately ruled out for use in liver transplantation (LT). The aim of our study is to evaluate the use of those grafts. Methods From 2011 to 2016, a study group (Group 1) composed of 5 adult LT patients transplanted with livers from donors with alcohol abuse, was compared with a control group (Group 2) of 10 randomly matched patients who received liver transplants. Preoperative, intraoperative, and postoperative data were compared. Results Among donors, serum gamma-glutamyl transferase values were significantly higher in Group 1. In recipients, post-LT laboratory exams showed significantly higher peak values of aspartate transaminase and alanine transaminase in Group 1; higher values of aspartate aminotransferase, alanine aminotransferase, and total bilirubin in Group 1 were also recorded on day 0. Early allograft dysfunction occurred at higher rates in Group 1 (80% vs 20%, P = .025), with no differences in early rejection episodes or early surgical repeat interventions. All patients from both groups were alive after 20 ± 10 (range 6–35) months from LT. Conclusion Despite higher rates of early allograft dysfunction, selected liver grafts from donors with alcohol abuse can be accepted for LT with good clinical results.

Background Understanding the relationship between clinical and patient-reported outcomes (PROs) will help support clinical care and future clinical trial design of novel therapies for focal segmental glomerulosclerosis (FSGS). Methods FSGS patients ≥8 years of age enrolled in the Nephrotic Syndrome Study Network completed Patient-Reported Outcomes Measurement Information System PRO measures of health-related quality of life (HRQoL) (children: global health, mobility, fatigue, pain interference, depression, anxiety, stress and peer relationships; adults: physical functioning, fatigue, pain interference, sleep impairment, mental health, depression, anxiety and social satisfaction) at baseline and during longitudinal follow-up for a maximum of 5 years. Linear mixed-effects models were used to determine which demographic, clinical and laboratory features were associated with PROs for each of the eight children and eight adults studied. Results There were 45 children and 114 adult FSGS patients enrolled that had at least one PRO assessment and 519 patient visits. Multivariable analyses among children found that edema was associated with global health (−7.6 points, P = 0.02) and mobility (−4.2, P = 0.02), the number of reported symptoms was associated with worse depression (−2.7 per symptom, P = 0.009) and anxiety (−2.3, P = 0.02) and the number of emergency room (ER) visits in the prior 6 months was associated with worse mobility (−2.8 per visit, P Conclusions PROs provide important information about HRQoL for persons with FSGS that is not captured solely by the examination of laboratory-based markers of disease. However, it is critical that instruments capture the patient experience and FSGS clinical trials may benefit from a disease-specific instrument more sensitive to within-patient changes.

The goal of this review is to review the role that renal parenchymal lipid accumulation plays in contributing to diabetic kidney disease (DKD), specifically contributing to the mitochondrial dysfunction observed in glomerular renal cells in the context of DKD development and progression. Mitochondrial dysfunction has been observed in experimental and clinical DKD. Recently, Ayanga et al. demonstrate that podocyte-specific deletion of a protein involved in mitochondrial dynamics protects from DKD progression. Furthermore, our group has recently shown that ATP-binding cassette A1 (a protein involved in cholesterol and phospholipid efflux) is significantly reduced in clinical and experimental DKD and that genetic or pharmacological induction of ABCA1 is sufficient to protect from DKD. ABCA1 deficiency in podocytes leads to mitochondrial dysfunction observed with alterations of mitochondrial lipids, in particular, cardiolipin (a mitochondrial-specific phospholipid). However, through pharmacological reduction of cardiolipin peroxidation DKD progression is reverted. Lipid metabolism is significantly altered in the diabetic kidney and renders cellular components, such as the podocyte, susceptible to injury leading to worsened DKD progression. Dysfunction of the lipid metabolism pathway can also lead to mitochondrial dysfunction and mitochondrial lipid alteration. Future research aimed at targeting mitochondrial lipids content and function could prove to be beneficial for the treatment of DKD.

Alport syndrome is experiencing a remarkable increase in preclinical investigations. To proactively address the needs of the Alport syndrome community, as well as offer clarity for future clinical research sponsors, the Alport Syndrome Foundation hosted a workshop to generate consensus recommendations for prospective trials for conventional drugs. Opinions of key stakeholders were carefully considered, including those of the biopharmaceutical industry representatives, academic researchers, clinicians, regulatory agency representatives, and—most critically—patients with Alport syndrome. Recommendations were established for preclinical researchers, the use and selection of biomarkers, standards of care, clinical trial designs, trial eligibility criteria and outcomes, pediatric trial considerations, and considerations for patient engagement, recruitment, and treatment. This paper outlines their recommendations.

Renal imaging is widely used in the assessment of surrogate markers of nephron mass correlated to renal function. Autopsy studies have tested the validity of various imaging modalities in accurately estimating "true" nephron mass. However, in vivo assessment of nephron mass has been largely limited to kidney volume determination by ultrasonography (US) in pediatric populations. Practical limitations and risks create challenges in incorporating more precise 3D volumetric imaging, like magnetic resonance imaging (MRI), and computed tomography (CT) technologies, compared to US for routine kidney volume assessment in children. Additionally, accounting for structural anomalies such as hydronephrosis when estimating renal parenchymal area in congenital anomalies of the kidney and urinary tract (CAKUT) is important, as it correlates with chronic kidney disease (CKD) progression. 3D imaging using CT and MRI has been shown to be superior to US, which has traditionally relied on 2D measurements to estimate kidney volume using the ellipsoid calculation. Recent innovations using 3D and contrast-enhanced US (CEUS) provide improved accuracy with low risk. Indexing kidney volume to body surface area in children is an important standard that may allow early detection of CKD progression in high-risk populations. This review highlights current understanding of various imaging modalities in assessing nephron mass, discusses applications and limitations, and describes recent advances in the field of imaging and kidney disease. Although renal imaging has been a long-standing, essential tool in assessing kidney disease, innovation and new applications of established technologies provide important tools in the study and management of kidney disease in children.

Focal segmental glomerulosclerosis (FSGS) accounts for about 40% of all nephrotic syndrome cases in adults. The presence of several potential circulating factors has been suggested in patients with primary FSGS and particularly in patients with recurrent disease after transplant. Irrespectively of the nature of the circulating factors, this study was aimed at identifying early glomerular/podocyte-specific pathways that are activated by the sera of patients affected by FSGS. Kidney biopsies were obtained from patients undergoing kidney transplantation due to primary FSGS. Donor kidneys were biopsied pre-reperfusion (PreR) and a subset 1-2 hours after reperfusion of the kidney (PostR). Thirty-one post reperfusion (PostR) and 36 PreR biopsy samples were analyzed by microarray and gene enrichment KEGG pathway analysis. Data were compared to those obtained from patients with incident primary FSGS enrolled in other cohorts as well as with another cohort to correct for pathways activated by ischemia reperfusion. Using an ex-vivo cell-based assay in which human podocytes were cultured in the presence of sera from patients with recurrent and non recurrent FSGS, the molecular signature of podocytes exposed to sera from patients with REC was compared to the one established from patients with NON REC. We demonstrate that inflammatory pathways, including the TNF pathway, are primarily activated immediately after exposure to the sera of patients with primary FSGS, while phagocytotic pathways are activated when proteinuria becomes clinically evident. The TNF pathway activation by one or more circulating factors present in the sera of patients with FSGS supports prior experimental findings from our group demonstrating a causative role of local TNF in podocyte injury in FSGS. Correlation analysis with clinical and histological parameters of disease was performed and further supported a possible role for TNF pathway activation in FSGS. Additionally, we identified a unique set of genes that is specifically activated in podocytes when cultured in the presence of serum of patients with REC FSGS. This clinical translational study supports our prior experimental findings describing a potential role of the TNF pathway in the pathogenesis of FSGS. Validation of these findings in larger cohorts may lay the ground for the implementation of integrated system biology approaches to risk stratify patients affected by FSGS and to identify novel pathways relevant to podocyte injury.

Diabetic kidney disease (DKD) affects ∼40% of patients with diabetes and is associated with high mortality rates. Among different cellular targets in DKD, podocytes, highly specialized epithelial cells of the glomerular filtration barrier, are injured in the early stages of DKD. Both clinical and experimental data support the role of preserved insulin signaling as a major contributor to podocyte function and survival. However, little is known about the key modulators of podocyte insulin signaling. This review summarizes the novel knowledge that intracellular lipids such as cholesterol and sphingolipids are major determinants of podocyte insulin signaling. In particular, the implications of these lipids on DKD development, progression, and treatment will be addressed.

Background Attention is the process which enables to preferentially select salient or relevant stimuli and to attenuate the response to irrelevant incoming stimuli. Migraine is characterized by both attentional alterations and an abnormal sensory processing to external stimulations. The aim of the study was to investigate potential interactions between self-perceived attentional difficulties and sensory hypersensitivity in migraine patients. Methods Forty-six episodic migraineurs without aura and 46 healthy controls filled out questionnaires on self-perceived attention difficulties and self-reported sensitivity to visual, auditory and olfactory stimulations. Results Compared to controls, migraineurs reported significantly higher levels of attention difficulty and sensory sensitivity. Sensory hypersensitivity correlated significantly with self-perceived attentional difficulties in migraineurs (P = 0.002), but not with migraine disability or levels of anxiety or depression. Ictal and interictal sensory sensitivities were significantly correlated in migraineurs within visual (P Conclusion This study shows for the first time an association between self-reported attentional difficulties and multimodal sensory hypersensitivity. Studies combining behavioral and physiological measures of sensory processing and attention processes are necessary to further understand the peculiar vulnerability of migraineurs to sensory stimuli.

Diabetic kidney disease (DKD) is the major contributor to the mortality and the financial burden of diabetes, accounting for approximately 50% of the cases of end‐stage renal disease (ESRD) in the developed world. Several studies have already demonstrated that achieving blood pressure targets in DKD with agents blocking the renin‐angiotensin system confer superior renoprotection when compared to other agents. However, the effects on renal outcomes of antihyperglycaemic agents in these patients have not been reported or studied broadly until recent years. The intent of this article is to review the available data on safety, efficacy, impact on renal outcomes and pathophysiology implications of the most utilized antihyperglycaemic agents in DKD/ESRD.

Although dyslipidemia is associated with chronic kidney disease (CKD), it is more common in nephrotic syndrome (NS), and guidelines for the management of hyperlipidemia in NS are largely opinion-based. In addition to the role of circulating lipids, an increasing number of studies suggest that intrarenal lipids contribute to the progression of glomerular diseases, indicating that proteinuric kidney diseases may be a form of “fatty kidney disease” and that reducing intracellular lipids could represent a new therapeutic approach to slow the progression of CKD. In this review, we summarize recent progress made in the utilization of lipid-modifying agents to lower renal parenchymal lipid accumulation and to prevent or reduce kidney injury. The agents mentioned in this review are categorized according to their specific targets, but they may also regulate other lipid-relevant pathways.

Association of thoracic and abdominal injuries in patients with major trauma is common. Under emergency conditions, it is often difficult to promptly perform a certain diagnosis and identify treatment priorities of life-threatening lesions. We present the case of a young man with combined thoracic and abdominal injuries after a motorcycle accident. Primary evaluation through echography and X-ray showed fluid within the hepatorenal recess and an enlarged mediastinum. Volume load, blood transfusions, and vasoactive agents were initiated to sustain circulation. Despite hemodynamic instability, we decided to perform computed tomographic angiography (CTA) scan that revealed a high-grade traumatic aortic pseudoaneurysm, multiple and severe areas of liver contusion, and a small amount of hemoperitoneum, without active bleeding spots. The patient was successfully submitted to thoracic endovascular aortic repair (TEVAR). Immediately after the end of the successful TEVAR, signs of massive abdominal bleeding revealed. Immediate explorative laparotomy was performed showing massive hepatic hemorrhage. After liver packing and Pringle's maneuver, control of bleeding was lastly obtained with hemostatic devices and selective cross-clamping of the right hepatic artery. The patient was then transferred to intensive care unit where, despite absence of further hemorrhage, hemodynamic instability, anuria, severe lactic acidosis together with liver necrosis indices appeared. A new CTA demonstrated massive parenchymal disruption within the right lobe of the liver and multiple hematomas in the left lobe. Considering the high-grade lesions of the hepatic vascular tree and liver failure, patient was listed for emergency liver transplantation (LT). LT occurred few hours later, and patient's clinical conditions rapidly improved even if the subsequent clinical course was characterized by a severe fungal infection because of immunosuppression. Evaluation of life-threatening lesions and treatment priorities, availability of different excellence skills, and multidisciplinary collaboration have a key role to achieve clinical success in such severe cases.

Background: Bowel and/or mesentery injuries represent the third most common injury among patients with blunt abdominal trauma. Delayed diagnosis increases morbidity and mortality. The aim of our study was to evaluate the role of clinical signs along with CT findings as predictors of early surgical repair. Material and methods: Between March 2014 and February 2017, charts and CT scans of consecutive patients treated for blunt abdominal trauma in two different trauma centers were reread by two experienced radiologists. We included all adult patients who underwent contrast-enhanced CT of the abdomen and pelvis with CT findings of blunt bowel and/or mesenteric injury (BBMI). We divided CT findings into two groups: the first included three highly specific CT signs and the second included six less specific CT signs indicated as “minor CT findings.” The presence of abdominal guarding and/or abdominal pain was considered as “clinical signs.” Reference standards included surgically proven BBMI and clinical follow-up. Association was evaluated by the chi-square test. A logistic regression model was used to estimate odds ratio (OR) and confidence intervals (CI). Results: Thirty-four (4.1%) out of 831 patients who sustained blunt abdominal trauma had BBMI at CT. Twenty-one out of thirty-four patients (61.8%) underwent surgical repair; the remaining 13 were treated conservatively. Free fluid had a significant statistical association with surgery (p = 0.0044). The presence of three or more minor CT findings was statistically associated with surgery (OR = 8.1; 95% CI, 1.2–53.7). Abdominal guarding along with bowel wall discontinuity and extraluminal air had the highest positive predictive value (100 and 83.3%, respectively). Conclusion: In patients without solid organ injury (SOI), the presence of free fluid along with abdominal guarding and three or more “minor CT findings” is a significant predictor of early surgical repair. The association of bowel wall discontinuity with extraluminal air warrants exploratory laparotomy.

The prevalence of diabetes around the world has reached epidemic proportions and is projected to increase to 642 million people by 2040. Diabetes is already the leading cause of end-stage kidney disease (ESKD) in most developed countries, and the growth in the number of people with ESKD around the world parallels the increase in diabetes. The presence of kidney disease is associated with a markedly elevated risk of cardiovascular disease and death in people with diabetes. Several new therapies and novel investigational agents targeting chronic kidney disease patients with diabetes are now under development. This conference was convened to assess our current state of knowledge regarding optimal glycemic control, current antidiabetic agents and their safety, and new therapies being developed to improve kidney function and cardiovascular outcomes for this vulnerable population.