Investigating quantitative histological characteristics in renal pathology using HistoLens.

HistoLens is an open-source graphical user interface developed using MATLAB AppDesigner for visual and quantitative analysis of histological datasets. HistoLens enables users to interrogate sets of digitally annotated whole slide images to efficiently characterize histological differences between disease and experimental groups. Users can dynamically visualize the distribution of 448 hand-engineered features quantifying color, texture, morphology, and distribution across microanatomic sub-compartments. Additionally, users can map differentially detected image features within the images by highlighting affected regions. We demonstrate the utility of HistoLens to identify hand-engineered features that correlate with pathognomonic renal glomerular characteristics distinguishing diabetic nephropathy and amyloid nephropathy from the histologically unremarkable glomeruli in minimal change disease. Additionally, we examine the use of HistoLens for glomerular feature discovery in the Tg26 mouse model of HIV-associated nephropathy. We identify numerous quantitative glomerular features distinguishing Tg26 transgenic mice from wild-type mice, corresponding to a progressive renal disease phenotype. Thus, we demonstrate an off-the-shelf and ready-to-use toolkit for quantitative renal pathology applications.

Safety and Efficacy of Very Early Conversion to Belatacept in Pediatric Kidney Transplantation with Transplant-Associated Thrombotic Microangiopathy: Case Study and Review of Literature.

The inhibition of co-stimulation during T-cell activation has been shown to provide effective immunosuppression in kidney transplantation (KT). Hence, the conversion from calcineurin inhibitor (CNI) to belatacept is emerging as a potential alternate maintenance immunosuppressive therapy in those with transplant-associated thrombotic microangiopathy (TA-TMA) or in the prevention of TA-TMA. We present a 17-year-old male who presented with biopsy-proven CNI-associated TA-TMA immediately post-KT. The administration of eculizumab led to the reversal of TMA. Tacrolimus was converted to belatacept with excellent efficacy and safety during a short-term follow-up of one year. Further larger controlled studies are required to demonstrate the efficacy of this approach in children who present with early-onset TMA post-KT.

ComPRePS: An Automated Cloud-based Image Analysis tool to democratize AI in Digital Pathology.

Artificial intelligence (AI) has extensive applications in a wide range of disciplines including healthcare and clinical practice. Advances in high-resolution whole-slide brightfield microscopy allow for the digitization of histologically stained tissue sections, producing gigapixel-scale whole-slide images (WSI). The significant improvement in computing and revolution of deep neural network (DNN)-based AI technologies over the last decade allow us to integrate massively parallelized computational power, cutting-edge AI algorithms, and big data storage, management, and processing. Applied to WSIs, AI has created opportunities for improved disease diagnostics and prognostics with the ultimate goal of enhancing precision medicine and resulting patient care. The National Institutes of Health (NIH) has recognized the importance of developing standardized principles for data management and discovery for the advancement of science and proposed the Findable, Accessible, Interoperable, Reusable, (FAIR) Data Principles1 with the goal of building a modernized biomedical data resource ecosystem to establish collaborative research communities. In line with this mission and to democratize AI-based image analysis in digital pathology, we propose ComPRePS: an end-to-end automated Computational Renal Pathology Suite which combines massive scalability, on-demand cloud computing, and an easy-to-use web-based user interface for data upload, storage, management, slide-level visualization, and domain expert interaction. Moreover, our platform is equipped with both in-house and collaborator developed sophisticated AI algorithms in the back-end server for image analysis to identify clinically relevant micro-anatomic functional tissue units (FTU) and to extract image features.

ComPRePS: An Automated Cloud-based Image Analysis tool to democratize AI in Digital Pathology.

Artificial intelligence (AI) has extensive applications in a wide range of disciplines including healthcare and clinical practice. Advances in high-resolution whole-slide brightfield microscopy allow for the digitization of histologically stained tissue sections, producing gigapixel-scale whole-slide images (WSI). The significant improvement in computing and revolution of deep neural network (DNN)-based AI technologies over the last decade allow us to integrate massively parallelized computational power, cutting-edge AI algorithms, and big data storage, management, and processing. Applied to WSIs, AI has created opportunities for improved disease diagnostics and prognostics with the ultimate goal of enhancing precision medicine and resulting patient care. The National Institutes of Health (NIH) has recognized the importance of developing standardized principles for data management and discovery for the advancement of science and proposed the Findable, Accessible, Interoperable, Reusable, (FAIR) Data Principles1 with the goal of building a modernized biomedical data resource ecosystem to establish collaborative research communities. In line with this mission and to democratize AI-based image analysis in digital pathology, we propose ComPRePS: an end-to-end automated Computational Renal Pathology Suite which combines massive scalability, on-demand cloud computing, and an easy-to-use web-based user interface for data upload, storage, management, slide-level visualization, and domain expert interaction. Moreover, our platform is equipped with both in-house and collaborator developed sophisticated AI algorithms in the back-end server for image analysis to identify clinically relevant micro-anatomic functional tissue units (FTU) and to extract image features.

The episodic encoding of spoken words in Hindi.

The discovery that listeners more accurately identify words repeated in the same voice than in a different voice has had an enormous influence on models of representation and speech perception. Widely replicated in English, we understand little about whether and how this effect generalizes across languages. In a continuous recognition memory study with Hindi speakers and listeners (N = 178), we replicated the talker-specificity effect for accuracy-based measures (hit rate and D'), and found the latency advantage to be marginal (p = 0.06). These data help us better understand talker-specificity effects cross-linguistically and highlight the importance of expanding work to less studied languages.

Efficacy and Safety of Eculizumab in Enteroaggregative E. coli Associated Hemolytic Uremic Syndrome.

BACKGROUND: Hemolytic uremic syndrome (HUS) may present atypically without the full triad of classical HUS. Eculizumab has been shown to be efficacious in complement-mediated atypical HUS and some cases of Shiga-toxin (ST) associated HUS. We report the utility of eculizumab in enteroaggregative E. coli (EAEC) associated HUS. CASE SUMMARY: A female toddler presented with hemolytic anemia, oliguric acute kidney injury (AKI) without thrombocytopenia, and peripheral schistocytes. The stool examination for ST was negative but positive for EAEC. She required several hemodialysis sessions and received one dosage of eculizumab with rapid reversal of AKI and hemolytic markers. A kidney biopsy revealed acute tubular injury and segmental glomerular basement membrane splitting. Genetic testing was negative for complement mutations or deficiencies. A follow-up six months later showed persistently normal renal function and hematological markers. CONCLUSION: The clinical and histological manifestations of non-ST-associated diarrheal HUS and the role of eculizumab in this condition warrant future larger studies.

Pharmacologic inhibition of glycolysis prevents the development of lupus by altering the gut microbiome in mice.

Gut dysbiosis has been associated with lupus pathogenesis, and fecal microbiota transfers (FMT) from lupus-prone mice shown to induce autoimmune activation into healthy mice. The immune cells of lupus patients exhibit an increased glucose metabolism and treatments with 2-deoxy-D-glucose (2DG), a glycolysis inhibitor, are therapeutic in lupus-prone mice. Here, we showed in two models of lupus with different etiologies that 2DG altered the composition of the fecal microbiome and associated metabolites. In both models, FMT from 2DG-treated mice protected lupus-prone mice of the same strain from the development of glomerulonephritis, reduced autoantibody production as well as the activation of CD4+ T cells and myeloid cells as compared to FMT from control mice. Thus, we demonstrated that the protective effect of glucose inhibition in lupus is transferable through the gut microbiota, directly linking alterations in immunometabolism to gut dysbiosis in the hosts.

Talker-specificity and token-specificity in recognition memory.

Given any feasible amount of time, a talker would never be able to produce the same word twice in an identical manner. Yet recognition memory experiments have consistently used identical tokens to demonstrate that listeners recognize a word more quickly and accurately when it is repeated by the same talker than by a different talker. These talker-specificity effects have served as the foundation of decades of research in speech perception, but the use of identical tokens introduces a confound: Is it the talker or the physical stimulus that drives these effects? And consequently, to what extent do listeners encode the high-level acoustic characteristics of a talker's voice? We investigate the roles of token and talker repetition in two continuous recognition memory experiments. In Exp. 1, listeners heard the voice of one talker, with either Identical or Novel repeated tokens. In Exp. 2, listeners heard two demographically matched talkers, with same-voice repetitions being either Identical or Novel. Classic talker-specificity effects were replicated in both Identical and Novel tokens, but recognition of Identical tokens was in some cases stronger than recognition of Novel tokens. In addition, recognition memory varied across demographically matched talkers, suggesting stronger episodic encoding for one talker than for the other. We argue that novel tokens should serve as the default design for similar studies and that consideration of talker variation can advance our understanding of encoding and memory differences more broadly.

Does kidney biopsy in pediatric lupus patients "complement" the management and outcomes of silent lupus nephritis? Lessons learned from a pediatric cohort.

BACKGROUND: Silent lupus nephritis (SLN) is systemic lupus erythematosus (SLE) without clinical and laboratory features of kidney involvement but with biopsy-proven nephritis. This study aims to describe and compare the baseline characteristics and outcomes of pediatric SLN with overt LN (OLN) and to identify associated risk factors and biochemical markers. METHODS: In this retrospective, observational study, multivariate logistic regression and receiver operating characteristic (ROC) analyses studied age, sex, race, serum complements, anti-double-stranded-DNA antibody, anti-Smith antibody, eGFR, and proliferative nephritis. RESULTS: In our cohort of 69 patients, 47 were OLN, and 22 were SLN. OLN (OR = 4.9, p = 0.03) and non-African Americans (AA) (OR = 13.0, p < 0.01) had higher odds, and increasing C3 and C4 were associated with lower odds of proliferative nephritis (OR 0.95 and 0.65 per one unit increase in C3 and C4, respectively, p < 0.01). They demonstrated a good discriminative ability to detect proliferative nephritis as assessed by the area under the ROC curve (C3 = 0.78, C4 = 0.78). C3 and C4 in proliferative SLN and OLN were comparable and significantly lower than their non-proliferative counterparts. No association was observed between age, sex, anti-double-stranded-DNA antibody, anti-Smith antibody, eGFR, and proliferative nephritis. Proliferative SLN and OLN patients received similar treatments. Adverse events were identified in the proliferative OLN only. CONCLUSIONS: Lower complement levels are associated with proliferative lesions in pediatric LN-both SLN and OLN. The non-AA population had higher odds of having proliferative nephritis than the AA. Prospective, randomized, long-term follow-up of proliferative SLN patients is needed to ascertain the beneficial effect of early diagnosis and treatment. A higher resolution version of the Graphical abstract is available as Supplementary information.

Kidney tubular epithelial cell ferroptosis links glomerular injury to tubulointerstitial pathology in lupus nephritis.

Ferroptosis is a druggable, iron-dependent form of cell death that is characterized by lipid peroxidation but has received little attention in lupus nephritis. Kidneys of lupus nephritis patients and mice showed increased lipid peroxidation mainly in the tubular segments and an increase in Acyl-CoA synthetase long-chain family member 4, a pro-ferroptosis enzyme. Nephritic mice had an attenuated expression of SLC7A11, a cystine importer, an impaired glutathione synthesis pathway, and low expression of glutathione peroxidase 4, a ferroptosis inhibitor. Lipidomics of nephritic kidneys confirmed ferroptosis. Using nephrotoxic serum, we induced immune complex glomerulonephritis in congenic mice and demonstrate that impaired iron sequestration within the proximal tubules exacerbates ferroptosis. Lupus nephritis patient serum rendered human proximal tubular cells susceptibility to ferroptosis which was inhibited by Liproxstatin-2, a novel ferroptosis inhibitor. Collectively, our findings identify intra-renal ferroptosis as a pathological feature and contributor to tubular injury in human and murine lupus nephritis.

Definition, diagnosis and clinical management of non-obstructive kidney dysplasia: a consensus statement by the ERKNet Working Group on Kidney Malformations.

Kidney dysplasia is one of the most frequent causes of chronic kidney failure in children. While dysplasia is a histological diagnosis, the term 'kidney dysplasia' is frequently used in daily clinical life without histopathological confirmation. Clinical parameters of kidney dysplasia have not been clearly defined, leading to imprecise communication amongst healthcare professionals and patients. This lack of consensus hampers precise disease understanding and the development of specific therapies. Based on a structured literature search, we here suggest a common basis for clinical, imaging, genetic, pathological and basic science aspects of non-obstructive kidney dysplasia associated with functional kidney impairment. We propose to accept hallmark sonographic findings as surrogate parameters defining a clinical diagnosis of dysplastic kidneys. We suggest differentiated clinical follow-up plans for children with kidney dysplasia and summarize established monogenic causes for non-obstructive kidney dysplasia. Finally, we point out and discuss research gaps in the field.

Virus-Derived Chemokine Modulating Protein Pre-Treatment Blocks Chemokine-Glycosaminoglycan Interactions and Significantly Reduces Transplant Immune Damage.

Immune cell invasion after the transplantation of solid organs is directed by chemokines binding to glycosaminoglycans (GAGs), creating gradients that guide immune cell infiltration. Renal transplant is the preferred treatment for end stage renal failure, but organ supply is limited and allografts are often injured during transport, surgery or by cytokine storm in deceased donors. While treatment for adaptive immune responses during rejection is excellent, treatment for early inflammatory damage is less effective. Viruses have developed highly active chemokine inhibitors as a means to evade host responses. The myxoma virus-derived M-T7 protein blocks chemokine: GAG binding. We have investigated M-T7 and also antisense (ASO) as pre-treatments to modify chemokine: GAG interactions to reduce donor organ damage. Immediate pre-treatment of donor kidneys with M-T7 to block chemokine: GAG binding significantly reduced the inflammation and scarring in subcapsular and subcutaneous allografts. Antisense to N-deacetylase N-sulfotransferase1 (ASONdst1) that modifies heparan sulfate, was less effective with immediate pre-treatment, but reduced scarring and C4d staining with donor pre-treatment for 7 days before transplantation. Grafts with conditional Ndst1 deficiency had reduced inflammation. Local inhibition of chemokine: GAG binding in donor organs immediately prior to transplant provides a new approach to reduce transplant damage and graft loss.

Minimal change disease after multiple wasp stings.

Acute renal failure is a well-known but uncommon complication of wasp stings. In rare instances, nephrotic syndrome (NS) has also been reported in association with wasp envenomation. The occurrence of minimal change disease (MCD) as a consequence of wasp stings is even less common, with only 1 case reported to date. We report a case of a 67-year-old man, with previously normal kidney function, presenting with acute renal failure with underlying NS due to biopsy-proven MCD, 1 month following numerous wasp stings. Despite treatment with corticosteroids, the patient required hemodialysis and treatment with loop diuretics and prednisone for 6 months until complete resolution. The patient remains free of NS, with normal renal function 3 years following remission.

LC-MS lipidomics of renal biopsies for the diagnosis of Fabry disease.

INTRODUCTION: Lipidomics analysis or lipid profiling is a system-based analysis of all lipids in a sample to provide a comprehensive understanding of lipids within a biological system. In the last few years, lipidomics has made it possible to better understand the metabolic processes associated with several rare disorders and proved to be a powerful tool for their clinical investigation. Fabry disease is a rare X-linked lysosomal storage disorder (LSD) caused by a deficiency in α-galactosidase A (α-GAL A). This deficiency results in the progressive accumulation of glycosphingolipids, mostly globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3), as well as galabiosylceramide (Ga2) and their isoforms/analogs in the vascular endothelium, nerves, cardiomyocytes, renal glomerular podocytes, and biological fluids. OBJECTIVES: The primary objective of this study was to evaluate lipidomic signatures in renal biopsies to help understand variations in Fabry disease markers that could be used in future diagnostic tests. METHODS: Lipidomic analysis was performed by ultra-high pressure liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) on kidney biopsies that were left over after clinical pathology analysis to diagnose Fabry disease. RESULTS: We employed UHPLC-HRMS lipidomics analysis on the renal biopsy of a patient suspicious for Fabry disease. Our result confirmed α-GAL A enzyme activity declined in this patient since a Ga2-related lipid biomarker was substantially higher in the patient's renal tissue biopsy compared with two controls. This suggests this patient has a type of LSD that could be non-classical Fabry disease. CONCLUSION: This study shows that lipidomics analysis is a valuable tool for rare disorder diagnosis, which can be conducted on leftover tissue samples without disrupting normal patient care.

Incidental Finding of a Large Right Atrial Thrombus in a Patient With Cerebral Lymphoma.

Right atrial (RA) masses are rare, challenging to diagnose, and potentially life-threatening with high mortality if untreated. We present a patient presenting with diffuse large B-cell lymphoma in the brain that was incidentally found to have a large RA mass. For a better definition of the RA mass, extensive workup using multimodality imaging including chest computed tomography, transthoracic echocardiography, transesophageal echocardiography, cardiac magnetic resonance imaging, and left heart catheterization was warranted. The imaging demonstrated a large RA mass extending through the tricuspid valve into the right ventricle and superior and inferior vena cava without a mobile component. The mass was then successfully resected, and further histology examination was performed to rule out lymphoma and rare subtypes of diffuse large B-cell lymphoma. The comprehensive workup proved the RA mass to be a calcified thrombus rather than a direct metastatic spread of lymphoma.

Aim2 Couples With Ube2i for Sumoylation-Mediated Repression of Interferon Signatures in Systemic Lupus Erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) involves kidney damage, and the inflammasome-caspase-1 axis has been demonstrated to promote renal pathogenesis. The present study was designed to explore the function of the Absent in Melanoma 2 (Aim2) protein in SLE. METHODS: Female wild-type Aim2-/- , Aim2-/- Ifnar1-/- , Aim2-/- Rag1-/- , and Asc-/- mice ages 8-10 weeks received 1 intraperitoneal injection of 500 µl pristane or saline, and survival of mice was monitored twice a week for 6 months. RESULTS: The absence of Aim2, but not Asc, led to enhanced SLE in mice that received pristane treatment. Increased immune cell infiltration and type I interferon (IFN) signatures in the kidneys of Aim2-/- mice coincided with severity of lupus, which was alleviated by blockade of Ifnar1-mediated signal. Adaptive immune cells were also involved in the glomerular lesions of Aim2-/- mice after pristane challenge. Importantly, even in the absence of pristane, plasmacytoid dendritic cells in the kidneys of Aim2-/- mice were significantly increased compared to control animals. Accordingly, transcriptome analysis revealed that Aim2 deficiency led to enhanced expression of type I IFN-induced genes in the kidneys even at an early developmental stage. Mechanistically, Aim2 bound ubiquitin-conjugating enzyme 2i (Ube2i), which mediates sumoylation-based suppression of type I IFN expression deficiency of Aim2 decreased cellular sumoylation, resulting in an augmented type I IFN signature and kidney pathogenesis. CONCLUSION: The present study demonstrates a critical role for Aim2 in an optimal Ube2i-mediated sumoylation-based suppression of type I IFN generation and development of SLE. As such, the Aim2-Ube2i axis can thus be a novel target for intervention in SLE.