Glomerular Patterns Research Articles

Glomerular Elasticity and Gene Expression Patterns Define Two Phases of Alport Nephropathy.

Early steps in glomerular injury are poorly understood in collagen IV nephropathies. We characterized structural, functional, and biophysical properties of glomerular capillaries and podocytes in Col4α3-/- mice and analyzed kidney cortex transcriptional profiles at various disease stages. We investigated the effects of TUDCA (suppresses ER stress) on these parameters and used human FSGS transcriptomic data to identify pathways rescued by TUDCA. In Col4α3-/- mice, podocyte injury develops by 3 months, with maximum glomerular deformability and 40% podocyte loss at 4 months. This period is followed is followed by glomerular capillary stiffening, proteinuria, reduced renal function, inflammatory infiltrates, and fibrosis. Bulk RNA sequencing at sequential time points revealed progressive increases in inflammatory and injury gene expression, and activation of the TNF pathway. Mapping Podocyte-enriched genes from FSGS patients to mice showed that TUDCA, which mitigated renal injury suppressed molecular pathways associated with podocyte stress, hypertrophy and tubulo-interstitial injury. Col4α3-/- nephropathy progresses in two phases. The first is characterized by podocytopathy, increased glomerular capillary deformability and accelerated podocyte loss, and the second by increased capillary wall stiffening and renal inflammatory and profibrotic pathway activation. The response of podocytes to TUDCA treatment provides insights into signaling pathways in Alport and related nephropathies.

Predictors of glomerular IgA immunostaining patterns and disease progression in IgA nephropathy patients; a 13-year study of clinical and morphological features of renal biopsies

Introduction: IgA nephropathy (IgAN) is a common primary glomerulonephritis with highly heterogeneous clinical and histopathological features. The MEST-C scoring system has been developed to improve prognostic assessment but lacks elements related to immunostaining study. Objectives: This study aimed to investigate the association between the immunofluorescence (IF) deposits’ patterns of IgA (mesangiocapillary versus pure mesangial) with demographic, clinical, biochemical, and morphological parameters of MEST-C classification in IgAN patients. Patients and Methods: This retrospective, cross-sectional study was conducted on 268 biopsy-proven cases of IgAN from July 2009 to July 2022 at a single laboratory in Isfahan in Iran. The demographic, clinical, and laboratory data including age, gender, serum creatinine, and proteinuria were collected from the biopsy request forms. The morphological parameters of MEST-C classification and IF study patterns were collected from the biopsy reports. Results: The average age of all patients was 37.7 ± 13.47 years, with 67% being males. The mean serum creatinine and proteinuria levels were 1.43 mg/dL and 1730.94 mg/day, respectively. MEST-C score analysis revealed that 171 patients (63.8%) had mesangial expansion (M1), while 105 patients (39.2%) exhibited endocapillary hypercellularity (E1). Additionally, segmental glomerulosclerosis (S1) and tubular atrophy/interstitial fibrosis (T1 and T2) was observed in 160 biopsy samples (59.7%). Moreover, crescent (C) formation was noted in 76 (28.4%) of biopsies. Data analysis using univariate logistic regression demonstrated that E, T, and C on morphology, complement C3, IgG, IgM deposits on IF, and the total MEST score were all associated with an increased risk for mesangiocapillary deposits of IgA. However, using the multivariate method, the results indicated that only the total MEST score (OR: 2.4), presence of crescent (OR: 3.22), presence of endocapillary hypercellularity (OR: 4.86), tubular atrophy/interstitial fibrosis grade II (OR: 34.4), and IgG deposition (OR: 3.37) were independent risk factors for mesangiocapillary deposits of IgA. Conclusion: The total MEST score is significantly higher in mesangiocapillary patterns. Furthermore, the presence of E1, T2, and C1-2 morphological parameters of the updated Oxford classification in renal biopsies are independent risk factors for IgA mesangiocapillary deposits. Hyperactivation of immunoglobulins and the complement system appears to contribute to mesangial-capillary proliferation.

Ring-shaped odor coding in the antennal lobe of migratory locusts

The representation of odors in the locust antennal lobe with its >2,000 glomeruli has long remained a perplexing puzzle. We employed the CRISPR-Cas9 system to generate transgenic locusts expressing the genetically encoded calcium indicator GCaMP in olfactory sensory neurons. Using two-photon functional imaging, we mapped the spatial activation patterns representing a wide range of ecologically relevant odors across all six developmental stages. Our findings reveal a functionally ring-shaped organization of the antennal lobe composed of specific glomerular clusters. This configuration establishes an odor-specific chemotopic representation by encoding different chemical classes and ecologically distinct odors in the form of glomerular rings. The ring-shaped glomerular arrangement, which we confirm by selective targeting of OR70a-expressing sensory neurons, occurs throughout development, and the odor-coding pattern within the glomerular population is consistent across developmental stages. Mechanistically, this unconventional spatial olfactory code reflects the locust-specific and multiplexed glomerular innervation pattern of the antennal lobe.

Histological reappraisal of IgA nephropathy: the role of glomerular pattern of injury and mesangial complement deposition

BackgroundThere is a clear need to refine the histological assessment in IgA Nephropathy (IgAN). We sought to investigate the clinical significance of the light microscopy (LM) pattern of glomerular injury and of the intensity of mesangial C3 staining in IgAN.MethodsWe conducted a retrospective, observational study that included all patients with biopsy-proven primary IgAN that had at least 12 months of follow-up. The LM pattern of glomerular injury was reevaluated based on a modified HAAS classification. Mesangial C3 deposition by immunofluorescence (IF) staining was scored semi-quantitatively. The study primary composite endpoint was defined as doubling of serum creatinine or ESRD (dialysis, renal transplant or eGFR < 15 ml/min). The secondary study endpoint was eGFR decline per year.ResultsThis cohort included 214 patients with IgAN (mean age, 41.4 ± 12.6 years), with a mean eGFR and median 24-h proteinuria of 55.2 ± 31.5 ml/min/1.73m2 and 1.5 g/day (IQR:0.8–3.25), respectively. The most frequent LM pattern was the mesangioproliferative (37.4%), followed by the sclerotic (22.5%) and proliferative/necrotizing patterns (21.4%). Regarding the IF findings, mild-moderate and intense mesangial C3 staining was present in 30.6% and 61.1% of patients, respectively. Those with sclerosing and crescentic patterns had the worst renal survival (5-year renal survival of 48.8% and 42.9%) and the highest rate of eGFR change/year (-2.32 ml/min/y and − 2.16 ml/min/y, respectively) compared to those with other glomerular patterns of injury. In addition, those with intense C3 staining reached the composite endpoint more frequently compared to those without intense C3 staining (35.5% vs. 21.4%, p = 0.04). After multivariate adjustment, patients with crescentic and sclerosing patterns had a 3.6-fold and 2.1-fold higher risk for the composite endpoint compared to those with mesangioproliferative pattern, while an intense mesangial C3 deposition being also associated with a worse renal outcome (HR, 3.33; 95%CI, 1.21–9.2).ConclusionsWe have shown that the LM pattern of glomerular injury and the intensity of mesangial C3 deposition might stratify more accurately the renal outcome in patients with IgAN.

Biosensor systems: determination of optimal time parameters of olfactory stimulation

Biosensor systems are improving swiftly and become increasingly important in areas such as defense and security, medical field, especially, cancer screening and detection, environmental quality monitoring, and so forth. The present work describes the development of a biosensor system, based on the use of macrosmatic animal olfactory bulb (OB) visualized by optical imaging of odor-evoked glomerular activity patterns. The difficulties that automatic detection of odor-evoked patterns presents under multiple stimulation are associated with adaptation processes, which are manifested as a reversible change in the sensitivity of the neural structures of the olfactory system. The optimal stimulus duration and interstimulus intervals for stabilizing the glomerular response and getting images of glomerular activity patterns under the multiple odor stimulation with constant accuracy have been experimentally found. The results obtained show the availability of other resource in addition to the existing tools used for the development of biosensor systems.

Hyperfiltration can be detected by transcutaneous assessment of glomerular filtration rate in diabetic obese mice.

We addressed if hyperfiltration can be assessed transcutaneously in male diabetic obese mice (BTBRob/ob) at 12 and 24 wk and how this relates to glomerular parameters indicative for hyperfiltration. Transcutaneous assessment of FITC-Sinistrin clearance [transcutaneous assessment of glomerular filtration rate (tGFR)] was compared against classical plasma clearance. Kidney from SV620C-01-PEI perfused mice were harvested at 24 wk and processed for tissue clearing and classical histology. Perfusion patterns of glomerular capillaries, glomerular size, and vasodilation of the afferent arterioles were assessed. Although at 12 wk FITC-Sinistrin half-life (t1/2) for both tGFR and plasma clearance suggested hyperfiltration, this was not significant anymore at 24 wk. In kidneys of diabetic mice the diameter of the afferent arteriole was significantly larger and positively correlated with glomerular size. Glomerular perfusion pattern in these mice was heterogeneous ranging from non- to well-perfused glomeruli. Nonperfused glomerular areas displayed a strong periodic acid-Schiff's (PAS) positive staining. Collectively our data demonstrate that tGFR is a valid method to detect hyperfiltration. Hyperfiltration occurs early in BTBRob/ob mice and disappears with disease progression as a consequence of a reduced filtration surface. It remains to be assessed if tGFR is also a valid method in diabetic mice with severely compromised renal function.NEW & NOTEWORTHY tGFR measurement is a relatively new method to assess kidney function in conscious rodents, which can be repeated multiple times in the same animal to track the course of the disease and/or the effect of potential treatments. Since the literature was inconclusive on the suitability of this technique in obese mice, we validated it for the first time against classical plasma clearance in the commonly used BTBRob/ob mouse model.

Influence of Hospital Practices on Native Glomerular Pathologic Patterns: Insights from the Largest Kidney Biopsy Cohort in Thailand

Influence of Hospital Practices on Native Glomerular Pathologic Patterns: Insights from the Largest Kidney Biopsy Cohort in Thailand

Assessment of Vulvar Intraepithelial Neoplasia (VIN) Grades Based on Dermoscopic Features: A Diagnostic Study.

Vulvar intraepithelial neoplasia (VIN) is a vulvar skin lesion considered a precursor of vulvar squamous cell carcinoma. No characteristics have been discovered to date that allows us to differentiate between grades of VIN, such as correlating the thickness of involvement of the epithelium (VIN1, VIN2, and VIN3) to the dermoscopic pattern. The aim of this study was to correlate the clinical and dermoscopic features of VIN cases with histopathological findings, with the purpose of identifying dermoscopic characteristics that allow us to differentiate between different grades of VIN. A retrospective study of the clinical and dermoscopic characteristics of VINs was recruited. Clinical and dermoscopic characteristics, as well as histopathology data, were gathered from patients at two Dermatology Units in Italy during the period spanning from January 2020 to December 2021. The study population consisted of 20 patients with a histologically confirmed diagnosis of VIN. The mean age of patients at the time of diagnosis was 55 years. At the dermoscopic level, VIN1 was characterized by a homogeneous erythematous area that completely involved the entire lesion, with a vascular pattern consisting of regular glomerular vessels. VIN3, was characterized by the presence of compact milky white areas that involved almost the entire lesion. VIN2 was characterized by the presence of non-compact white areas that allowed homogeneous erythematous areas to be seen transparently, without other distinguishing aspects. Although a definitive diagnosis and grading of VIN remains confirmed only histopathologically, our study shows how dermoscopy may aid the differential diagnosis between the different grades of VIN; the presence of a compact milky white area that involves nearly the entire lesion should be interpreted as an alarming feature, while homogeneous erythematous areas or a glomerular vascular pattern are more typical of the first stage of this neoplasia.

A Spatially Guided Machine-Learning Method to Classify and Quantify Glomerular Patterns of Injury in Histology Images.

We performed a cross-validated comparison of three modifications of a convolutional neural network (CNN)-based approach for recognition and intraglomerular quantification of nine main glomerular patterns of injury. Reference values provided by two nephropathologists were used for validation. For each glomerular image, visual attention heatmaps were generated with a probability of class attribution for further intraglomerular quantification. The quality of classifier-produced heatmaps was evaluated by intersection over union metrics (IoU) between predicted and ground truth localization heatmaps. A proposed spatially guided modification of the CNN classifier achieved the highest glomerular pattern classification accuracies, with area under curve (AUC) values up to 0.981. With regards to heatmap overlap area and intraglomerular pattern quantification, the spatially guided classifier achieved a significantly higher generalized mean IoU value compared to single-multiclass and multiple-binary classifiers. We propose a spatially guided CNN classifier that in our experiments reveals the potential to achieve high accuracy for the localization of intraglomerular patterns.

The method for assessment of local permutations in the glomerular patterns of the rat olfactory bulb by aligning interindividual odor maps.

The comparison of odor functional maps in rodents demonstrates a high degree of inter-individual variability in glomerular activity patterns. There are substantial methodological difficulties in the interindividual assessment of local permutations in the glomerular patterns, since the position of anatomical extracranial landmarks, as well as the size, shape and angular orientation of olfactory bulbs can vary significantly. A new method for defining anatomical coordinates of active glomeruli in the rat olfactory bulb has been developed. The method compares the interindividual odor functional maps and calculates probabilistic maps of glomerular activity with adjustment. This adjustment involves rotation, scaling and shift of the functional map relative to its expected position in probabilistic map, computed according to the anatomical coordinates. The calculation of the probabilistic map of the odorant-specific response compensates for potential anatoamical errors due to individual variability in olfactory bulb dimensions and angular orientation. We show its efficiency on real data from a large animal sample recorded by two-photon calcium imaging in dorsal surface of the rat olfactory bulb. The proposed method with probabilistic map calculation enables the spatial consistency of the effects of individual odorants in different rats to be assessed and allow stereotypical positions of odor-specific clusters in the glomerular layer of the olfactory bulb to be identified.

Exploring hospital practice types and their impact on glomerular pathologic patterns: Insights from the largest kidney biopsy cohort in Thailand.

This study aims to investigate the influence of different kidney biopsy practices on the prevalence of glomerular pathologic patterns in the largest kidney biopsy registry in Thailand. We conducted a retrospective review of kidney biopsy records from the period between 2000 and 2014. The records were obtained from 2 major institutions: King Chulalongkorn Memorial Hospital, a large university-based hospital, and the Kidney Center Bangkok Hospital, which provides pathology services to hospitals throughout Thailand. The study included native kidney biopsies from all provinces in Thailand, excluding paediatric patients, kidney transplant recipients, and cases of inadequate and repeated biopsies. Patient demographics, indications for biopsy, and final glomerular diagnoses were compared across different hospital practice settings: university (UVH), private (PVH) and public (PBH). A total of 5893 eligible native kidney biopsies were identified from a pool of 7005 biopsies conducted over a 15-year period in 25 provinces throughout Thailand. The 3 most common indications for biopsy were suspected kidney involvement in systemic lupus erythematosus (SLE) (29%), nephrotic syndrome (NS) (29%), and acute glomerulonephritis (AGN)/rapidly progressive glomerulonephritis (RPGN) (13%). The leading indication for biopsy differed across practice types, with suspected kidney involvement in SLE being the primary indication in UVH, while NS took precedence in both PBH and PVH practices. Notably, UVH performed fewer kidney biopsies for asymptomatic urinary abnormalities and diabetes-related indications compared with PVH and PBH. The leading glomerular diagnoses correlated with the biopsy indications, with lupus nephritis (LN) being the most common diagnosis in UVH and PBH practices, whiles immunoglobulin A nephropathy was the predominant diagnosis in PVH practice. Hospital practice types significantly impact the prevalence of glomerular pathologic diagnosis patterns in kidney biopsy data, highlighting the importance of considering this influence in epidemiological comparisons.

Diagnosis and treatment of focal-segmental glomerulosclerosis-2023

The histopathological term focal-segmental glomerulosclerosis comprises different pathogenic processes with the unifying features of ahigh proteinuria and the name-giving glomerular lesion pattern seen on light microscopy. Adifferentiation according to the underlying cause into primary, secondary and genetic forms is therefore of utmost importance. The pathogenesis of primary focal-segmental glomerulosclerosis remains unknown but, like minimal-change disease, an autoimmune-mediated process leading to podocyte damage is assumed. Consequently, the unifying term "podocytopathy" is increasingly being used for both entities. Supportive treatment measures to preserve kidney function are important in all subtypes. In contrast, immunosuppressive treatment is only indicated in primary focal-segmental glomerulosclerosis. Steroid-dependence, steroid-resistance and frequently relapsing disease often complicate disease management and necessitate alternative treatment strategies. Here, the Austrian Society of Nephrology (ÖGN) provides consensus recommendations on how to best diagnose and manage patients with focal-segmental glomerulosclerosis.

IgA Nephropathy Associated with IgA Vasculitis Coexisting with Focal Segmental Glomerulosclerosis Tip Variant: A Case Report

IgA vasculitis (IgAV), previously known as Henoch–Schönlein purpura, is a form of small vessel vasculitis that affects the skin, joints, intestines, and kidneys. The clinical presentation in adults is usually infrequent, more severe, with a worse prognosis and a higher recurrence rate. Due to limited scientific evidence, IgAV is viewed similarly to IgA nephropathy (IgAN), and the renal histopathological lesions are indistinguishable between the two. IgAN is the most prevalent glomerular diseases worldwide. The diagnosis of IgAN is confirmed through a renal biopsy. The most frequently found histopathological lesions are mesangial proliferation and concurrent IgA deposition confirmed by direct immunofluorescence. Focal segmental glomerulosclerosis (FSGS) appears as a glomerular pattern of injury in up to 40% of renal biopsies with IgAN, although there are few reported cases in the international literature where both diseases coexist as primary etiologies. We report a case of a female patient presenting with vasculitic lesions, abdominal pain, and nephrotic syndrome, whose cause is confirmed by a renal biopsy with a diagnosis of IgAN secondary to IgAV and coexistence of FSGS, an unusual presentation with few case reports.

Gain modulation and odor concentration invariance in early olfactory networks.

The broad receptive field of the olfactory receptors constitutes the basis of a combinatorial code that allows animals to detect and discriminate many more odorants than the actual number of receptor types that they express. One drawback is that high odor concentrations recruit lower affinity receptors which can lead to the perception of qualitatively different odors. Here we addressed the contribution that signal-processing in the antennal lobe makes to reduce concentration dependence in odor representation. By means of calcium imaging and pharmacological approach we describe the contribution that GABA receptors play in terms of the amplitude and temporal profiles of the signals that convey odor information from the antennal lobes to higher brain centers. We found that GABA reduces the amplitude of odor elicited signals and the number of glomeruli that are recruited in an odor-concentration-dependent manner. Blocking GABA receptors decreases the correlation among glomerular activity patterns elicited by different concentrations of the same odor. In addition, we built a realistic mathematical model of the antennal lobe that was used to test the viability of the proposed mechanisms and to evaluate the processing properties of the AL network under conditions that cannot be achieved in physiology experiments. Interestingly, even though based on a rather simple topology and cell interactions solely mediated by GABAergic lateral inhibitions, the AL model reproduced key features of the AL response upon different odor concentrations and provides plausible solutions for concentration invariant recognition of odors by artificial sensors.

#4295 SPECTRUM OF GLOMERULAR AND VASCULAR KIDNEY PATHOLOGY ASSOCIATED WITH MYELOPROLIFERATIVE NEOPLASMS

Abstract Background and Aims Myeloproliferative neoplasms (MPN) are chronic blood disorders defined by an overproduction of clonal, differentiated hematopoietic cells. A high prevalence of chronic kidney disease (CKD) is described in patients with MPN. The glomerular histological pattern of MPN-related kidney disease, MPN-related glomerulopathy (MPN-RG), may not account for the entirety of CKD risk in this population, as it appears to be rare and has mostly been reported in patients with myelofibrosis. The inflammatory and prothrombotic state of clonal blood cells has been linked to a systemic vasculopathy in MPN patients, characterized by thromboses and microvascular disease. Thus, we put forward the hypothesis that intrarenal vessel injury may occur during MPN, and that vascular nephrosclerosis may be a common histological pattern in MPN patients presenting with kidney disease. Method We conducted an exhaustive, retrospective, multicenter study of MPN kidney biopsies in four kidney pathology units. All adult patients with a history of MPN who underwent a kidney biopsy were included. We performed a systematic histological review of glomerular and vascular compartments. MPN-RG was defined as mesangial expansion and negative glomerular immunofluorescence studies, with at least one of the following: mesangial hypercellularity, or features of chronic glomerular thrombotic microangiopathy. Hematopoietic cells were detected using anti-glycophorin C, anti-myeloperoxidase, and anti-factor VIII immunohistochemistry (IHC). Chronic vascular lesions were evaluated using the Banff aah and cv lesion definitions and compared to matched adult native kidney biopsies. We used multivariable logistic regression models to assess determinants of vascular lesions, using the number of antihypertensive drugs as a proxy for hypertension severity. Results We included 47 MPN patients who underwent a kidney biopsy, including 16 patients with chronic myeloid leukemia, 14 with polycythemia vera, 10 with essential thrombocythemia and 7 with primary myelofibrosis. 14 cases (29.8%) met our definition of MPN-RG. MPN-RG was strongly associated with myelofibrosis (primary or secondary, P = 0.021) and poorer ESRD-free survival (P = 0.007). Positive IHC for circulating cells in the glomerular capillaries was not associated with glomerular injury but was positively correlated with blood leukocyte count (P = 0.004). Thirty-three patients (75.0%) had moderate-to-severe arteriosclerosis; 39 patients (84.8%) had moderate-to-severe arteriolar hyalinosis. Multivariable models including 188 control kidney biopsies revealed an association between MPN and chronic kidney vascular damage, which was independent of established risk factors such as age, diabetes mellitus and hypertension (Table 1 and Table 2). Conclusion We demonstrate the strong association between MPN-RG and myelofibrosis and confirm its poor renal prognosis. We argue that the finding of glomerular intracapillary hematopoietic cells should not be considered in the diagnosis of MPN-RG. Most notably, our results show that MPN represent a novel, independent risk factor for vascular nephrosclerosis, and establish a new link between MPN and CKD. These findings raise new hypotheses regarding the pathophysiology of vascular nephrosclerosis in the general population.

A Cross-Sectional Study on Histological Pattern of Primary Glomerular Diseases among Adult Patients

Background and Aims: Primary glomerulonephritis (GN) is the major cause for end-stage renal disease (ESRD) and considered to contribute in 52% cases. Kidney biopsy is an essential tool in nephrologists' clinical practice for determining diagnosis, prognosis, and therapy of a variety of glomerular conditions. The purpose of the present study was to determine the primary glomerular diseases histopathological pattern among adult patients. Patients and Methods: A total of 94 suspected primary glomerular disease (GD) patients were investigated in this cross-sectional study conducted in the Nephrology Unit of Medicine department of Mayo Hospital, Lahore from 21st January 2021 to 20th February 2022. Individual’s demographic details, diagnostic tests, clinical presentation, kidney biopsy indications, and post-biopsy complications were recorded on pre-designed questionnaire/pro-forma. Data analysis was done using SPSS version 27. Results: Out of 94 patients, about 76 (80.9%) patients had primary glomerular disease diagnosed on native kidney biopsies. The overall mean age was 38.4± 6.2 years. Out of 94 primary glomerular disease patients, there were 48 (51.1%) male and 46 (48.9%) females. The incidence of nephrotic syndrome and unexplained renal parameters elevations were 47.4% (n=36) and 31.6% (n=24) respectively. The prevalence of Primary focal segmental glomerulosclerosis (FSGS), membrano-proliferative glomerulonephritis (MPGN), minimal change disease, and IgA nephropathy was 30.3% (n=23), 25% (n=19), 17.1% (n=13), and 6.6% (n=5) respectively. Kidney biopsy post-complications were found in 8 (10.5%) cases. Conclusion: The present study observed that MPGN and FSDS were the most prime causes for primary glomerular disease. The most prevalent indication of kidney biopsy was nephrotic syndrome. Keywords: Glomerular disease, kidney biopsy, histopathological pattern, adult patients

Proteinuria and Electrophoretic Pattern in Dogs with Comorbidities Associated with Chronic Kidney Disease.

In animals with chronic pathologies, the detection of proteinuria via the proteinuria: creatininuria ratio (UPC) and urinary protein electrophoresis allows for the early diagnosis of chronic kidney disease (CKD). The objective of this work was to identify and determine the magnitude of proteinuria and its electrophoretic pattern characterization in dogs with chronic diseases pathophysiologically related to proteinuria. With the studied patients, five groups were formed. The control group (CG) contained non-proteinuric cases. The cases with proteinuria were classified into four groups according to the concurrent disease: chronic inflammatory diseases (IG), neoplasms (NG), heart diseases (HG), and endocrine diseases (EG). For the statistical analysis, descriptive statistics and non-parametric tests were used. Data from 264 dogs were obtained; in the disease groups, proteinuria was observed in more than 30% as the only finding of kidney disease, evidencing a greater risk factor for proteinuria in the HG group (OR 4.047, CI 1.894-8.644, p < 0.0001). In the HG, NG, and EG groups, a higher frequency of glomerular pattern (GEP) related to glomerular hypertension was observed; in the IG, a higher frequency of mixed pattern (MEP) was observed. These findings are secondary to the hyperfiltration process that affects the glomerulus and the renal tubule.

Robust odor identification in novel olfactory environments in mice

Relevant odors signaling food, mates, or predators can be masked by unpredictable mixtures of less relevant background odors. Here, we developed a mouse behavioral paradigm to test the role played by the novelty of the background odors. During the task, mice identified target odors in previously learned background odors and were challenged by catch trials with novel background odors, a task similar to visual CAPTCHA. Female wild-type (WT) mice could accurately identify known targets in novel background odors. WT mice performance was higher than linear classifiers and the nearest neighbor classifier trained using olfactory bulb glomerular activation patterns. Performance was more consistent with an odor deconvolution method. We also used our task to investigate the performance of female Cntnap2-/- mice, which show some autism-like behaviors. Cntnap2-/- mice had glomerular activation patterns similar to WT mice and matched WT mice target detection for known background odors. However, Cntnap2-/- mice performance fell almost to chance levels in the presence of novel backgrounds. Our findings suggest that mice use a robust algorithm for detecting odors in novel environments and this computation is impaired in Cntnap2-/- mice.

Digital Spatial Profiling of Glomerular Gene Expression in Pauci-Immune Focal Necrotizing Glomerulonephritis.

Pauci-immune focal necrotizing glomerulonephritis (piFNGN) involves asynchronous onset and progression of injurious lesions in biopsies. Pathologists can describe this heterogeneity within a biopsy, but translating the information into prognostic or expression analyses is challenging. Understanding the underlying molecular processes could improve treatment; however, bulk or single-cell transcriptomic analyses of dissociated tissue disregard the heterogeneity of glomerular injury. We characterize protein and mRNA expression of individual glomeruli in 20 biopsies from 18 patients with antineutrophil cytoplasmic antibody-associated piFNGN using the NanoString digital spatial profiling (DSP) platform. For this purpose, circular annotations of glomeruli were analyzed using protein, immuno-oncology RNA, and Cancer Transcriptome Atlas panels (n=120, 72, and 48 glomeruli, respectively). Histologic evaluation of glomerular patterns of injury was performed in adjacent serial sections. Expression data were processed by log2 transformation, quantile normalization, and batch adjustment. DSP revealed distinct but overlapping gene expression profiles relating to the morphological evolution of injurious lesions, including dynamic expression of various immune checkpoint regulators. Enrichment analysis indicated deregulated pathways that underline known and highlight novel potential mechanisms of disease. Moreover, by capturing individual glomeruli, DSP describes heterogeneity between and within biopsies. We demonstrate the benefit of spatial profiling for characterization of heterogeneous glomerular injury, indicating novel molecular correlates of glomerular injury in piFNGN.

Digital spatial profiling of glomerular gene expression in pauci-immune focal necrotizing glomerulonephritis

Introduction: Pauci-immune focal necrotizing glomerulonephritis (piFNGN) involves asynchronous onset and progression of injurious lesions in biopsies. Pathologists describe this heterogeneity within a biopsy, but translating the information into prognostic or expression analyses is challenging. Understanding the underlying molecular processes could improve treatment; however, bulk or single cell transcriptomic analyses of dissociated tissue disregard the heterogeneity of glomerular injury. Methods: We characterize protein and mRNA expression of individual glomeruli in 20 biopsies from 18 patients with anti-neutrophil cytoplasmic antibody-associated piFNGN using the Nanostring digital spatial profiling (DSP) platform. For this purpose, circular annotations of glomeruli were analyzed using protein, immuno-oncology RNA, and cancer transcriptome atlas panels (n=120, 72, and 48 glomeruli, respectively). Histological evaluation of glomerular patterns of injury was performed in adjacent serial sections. Expression data was processed by log2 transformation, quantile normalization and batch adjustment. Results: DSP revealed distinct but overlapping gene expression profiles relating to the morphological evolution of injurious lesions, including dynamic expression of various immune checkpoint regulators. Enrichment analysis indicated deregulated pathways that underline known and highlight novel potential mechanisms of disease. Moreover, by capturing individual glomeruli, DSP describes heterogeneity between and within biopsies. Conclusions: We demonstrate the benefit of spatial profiling for characterization of heterogeneous glomerular injury, indicating novel molecular correlates of glomerular injury in piFNGN.