Small Vessels Research Articles

Clinical Predictors of Postmortem Amyloid and Nonamyloid Cerebral Small Vessel Disease in Middle-Aged to Older Adults.

Sporadic cerebral small vessel disease (CSVD) is a class of important pathologic processes known to affect the aging brain and to contribute to cognitive impairment. We aimed to identify clinical risk factors associated with postmortem CSVD in middle-aged to older adults. We developed and tested risk models for their predictive accuracy of a pathologic diagnosis of nonamyloid CSVD and cerebral amyloid angiopathy (CAA) in a retrospective sample of 160 autopsied cases from the Edinburgh Brain Bank. Individuals aged 40 years and older covering the spectrum of healthy aging and common forms of dementia (i.e., highly-prevalent etiologies such as Alzheimer disease (AD), vascular cognitive impairment (VCI), and mixed dementia) were included. We performed binomial logistic regression models using sample splitting and cross-validation methods. Demographics, lifestyle habits, traditional vascular risk factors, chronic medical conditions, APOE4, and cognitive status were assessed as potential predictors. Forty percent of our sample had a clinical diagnosis of dementia (AD = 33, VCI = 26 and mixed = 5) while others were cognitively healthy (n = 96). The mean age at death was 73.8 (SD 14.1) years, and 40% were female. The presence of none-to-mild vs moderate-to-severe nonamyloid CSVD was predicted by our model with good accuracy (area under the curve [AUC] = 0.84, sensitivity [SEN] = 72%, specificity [SPE] = 95%), with the most significant clinical predictors being age, history of cerebrovascular events, and cognitive impairment. The presence of CAA pathology was also predicted with high accuracy (AUC = 0.86, SEN = 93%, SPE = 79%). Significant predictors included alcohol intake, history of cerebrovascular events, and cognitive impairment. In a subset of atypical dementias (n = 24), our models provided poor predictive performance for both nonamyloid CSVD (AUC = 0.50) and CAA (AUC = 0.43). CSVD pathology can be predicted with high accuracy based on clinical factors in patients within the spectrum of AD, VCI, and normal aging. Whether this prediction can be enhanced by the addition of fluid and neuroimaging biomarkers warrants additional study. Improving our understanding of clinical determinants of vascular brain health may lead to novel strategies in the prevention and treatment of vascular etiologies contributing to cognitive decline. This study provides Class II evidence that selected clinical factors accurately distinguish between middle-aged to older adults with and without cerebrovascular small vessel disease (amyloid and nonamyloid) pathology.

Clutter evalution of unmanned surface vehicles for maritime traffic monitoring

A traditional maritime radar system is utilized for ship detection and tracking through onshore transmitters and receivers. However, it faces challenges when it comes to detecting small boats. In contrast, unmanned surface vehicles (USVs) have been designed to monitor maritime traffic. They excel in detecting vessels of various sizes and enhance the capabilities and resolution of maritime radar systems. Nevertheless, just like conventional radar systems, USVs encounter difficulties due to environmental interference and clutter, affecting the accuracy of target signal detection. This research proposes a comprehensive numerical assessment to tackle the clutter issue associated with USVs. This involves gathering clutter signal data, performing numerical analysis, and employing distribution fitting techniques that leverage mathematical distributions to unravel data complexity. The root mean square error (RMSE) is applied in this analysis to validate the efficacy of the distribution model. The results of this study aim to formulate a clutter model that can enhance radar performance in detecting small vessels within cluttered environments.

3D printing and bioprinting in the battle against diabetes and its chronic complications

Diabetes is a metabolic disorder characterized by high blood sugar. Uncontrolled blood glucose affects the circulatory system in an organism by intervening blood circulation. The high blood glucose can lead to macrovascular (large blood vessels) and microvascular (small blood vessels) complications. Due to this, the vital organs (notably brain, eyes, feet, heart, kidneys, lungs and nerves) get worsen in diabetic patients if not treated at the earliest. Therefore, acquiring treatment at an appropriate time is very important for managing diabetes and other complications that are caused due to diabetes. The root cause for the occurrence of various health complications in diabetic patients is the uncontrolled blood glucose levels. This review presents a consolidated account of the applications of various types of three-dimensional (3D) printing and bioprinting technologies in treating diabetes as well as the complications caused due to impaired blood glucose levels. Herein, the development of biosensors (for the diagnosis), oral drug formulations, transdermal drug carriers, orthotic insoles and scaffolds (for the treatment) are discussed. Next to this, the fabrication of 3D bioprinted organs and cell-seeded hydrogels (pancreas engineering for producing insulin and bone engineering for managing bone defects) are explained. As the final application, 3D bioprinting of diabetic disease models for high-throughput screening of ant-diabetic drugs are discussed. Lastly, the challenges and future perspective associated with the use of 3D printing and bioprinting technologies against diabetes and its related chronic complications have been put forward.

Gastric ischemia as an under-reported cause of death in older people.

Acute gastric ischemia is a rare condition due to the rich vascular supply of the stomach. Here we present a case of fatal gastric ischemia associated with bowel ischemia, only diagnosed at autopsy, which was requested for the suspicion of medical liability. A complete post-mortem examination was conducted, along with a macroscopic analysis of the superior mesenteric artery and detailed histological analyses. Past clinical data was also reviewed. The macroscopic blackish discoloration of the stomach and the bowel, coupled with the presence of neutrophils in the mucosa and submucosal non-occlusive thrombi, were consistent with gastric and bowel ischemia, despite the presence of confounding putrefactive changes. The unique aspect of this case resides in the ante-mortem peculiar vascularization of the stomach, supplied by small collateral vessels. No mechanical occlusion was identified, and the cause of the ischemia was deemed as non-occlusive, likely due to systemic hypoperfusion. The analysis of clinical data and documentation of associated comorbidities are strongly recommended, especially when a rare cause of death is suspected. With the aging population, especially among women, and the prevalence of risk factors, the forensic pathologist could increasingly encounter rare cases of gastric ischemia.

Association of NOTCH3 Variant Risk Category With 2-Year Clinical and Radiologic Small Vessel Disease Progression in Patients With CADASIL.

Pathogenic variants in NOTCH3 are the main cause of hereditary cerebral small vessel disease (SVD). SVD-associated NOTCH3 variants have recently been categorized into high risk (HR), moderate risk (MR), or low risk (LR) for developing early-onset severe SVD. The most severe NOTCH3-associated SVD phenotype is also known as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aimed to investigate whether NOTCH3 variant risk category is associated with 2-year progression rate of SVD clinical and neuroimaging outcomes in CADASIL. A single-center prospective 2-year follow-up study was performed of patients with CADASIL. Clinical outcomes were incident stroke, disability (modified Rankin Scale), and executive function (Trail Making Test B given A t-scores). Neuroimaging outcomes were mean skeletonized mean diffusivity (MSMD), normalized white matter hyperintensity volume (nWMHv), normalized lacune volume (nLV), and brain parenchymal fraction (BPF). Cox regression and mixed-effect models, adjusted for age, sex, and cardiovascular risk factors, were used to study 2-year changes in outcomes and differences in disease progression between patients with HR-NOTCH3 and MR-NOTCH3 variants. One hundred sixty-two patients with HR (n = 90), MR (n = 67), and LR (n = 5) NOTCH3 variants were included. For the entire cohort, there was 2-year mean progression for MSMD (β = 0.20, 95% CI 0.17-0.23, p = 7.0 × 10-24), nLV (β = 0.13, 95% CI 0.080-0.19, p = 2.1 × 10-6), nWMHv (β = 0.092, 95% CI 0.075-0.11, p = 8.8 × 10-20), and BPF (β = -0.22, 95% CI -0.26 to -0.19, p = 3.2 × 10-22), as well as an increase in disability (p = 0.002) and decline of executive function (β = -0.15, 95% CI -0.30 to -3.4 × 10-5, p = 0.05). The HR-NOTCH3 group had a higher probability of 2-year incident stroke (hazard ratio 4.3, 95% CI 1.4-13.5, p = 0.011), and a higher increase in MSMD (β = 0.074, 95% CI 0.013-0.14, p = 0.017) and nLV (β = 0.14, 95% CI 0.034-0.24, p = 0.0089) than the MR-NOTCH3 group. Subgroup analyses showed significant 2-year progression of MSMD in young (n = 17, β = 0.014, 95% CI 0.0093-0.019, p = 1.4 × 10-5) and premanifest (n = 24, β = 0.012, 95% CI 0.0082-0.016, p = 1.1 × 10-6) individuals. In a trial-sensitive time span of 2 years, we found that patients with HR-NOTCH3 variants have a significantly faster progression of major clinical and neuroimaging outcomes, compared with patients with MR-NOTCH3 variants. This has important implications for clinical trial design and disease prediction and monitoring in the clinic. Moreover, we show that MSMD is a promising outcome measure for trials enrolling premanifest individuals.

Antineutrophil cytoplasmic antibody-associated vasculitis.

This review focuses on latest developments in managing antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV), a systemic autoimmune condition characterized by inflammation and necrosis of small blood vessels due to circulating autoantibodies that target neutrophilic granules. Our understanding of AAV pathogenesis has evolved in the past decades highlighting the central pathogenic roles of autoantibodies and complement activation. In parallel, the appreciation for glucocorticoid toxicity has led the research on crucial steroid-sparing therapeutic alternatives. Complement inhibitors (like avacopan) that have emerged are associated with better preservation of kidney function in AAV patients with severe kidney impairment. The role of plasma-exchange (PLEX) was revisited in updated guidelines that recommended its potential use in the context of diffuse alveolar hemorrhage associated hypoxia and severe kidney involvement, particularly with a serum creatinine level above 3.4 mg/dl. The ANCA Kidney Risk Score risk prediction and Glucocorticoid Toxicity Index score aid in identifying high-risk patients and individualizing management plans. Kidney involvement in AAV requires prompt diagnosis and initiation of immunosuppression to prevent irreversible nephron loss. Newer therapeutic targets are on the horizon and offer hope for personalized treatment strategies.

Peripheral inflammatory response in people after acute ischaemic stroke and isolated spontaneous cervical artery dissection.

The systemic inflammatory response following acute ischaemic stroke remains incompletely understood. We characterised the circulating inflammatory profile in 173 acute ischaemic stroke patients by measuring 65 cytokines and chemokines in plasma. Participants were grouped based on their inflammatory response, determined by high-sensitivity C-reactive protein levels in the acute phase. We compared stroke patients' profiles with 42 people experiencing spontaneous cervical artery dissection without stroke. Furthermore, variations in cytokine levels among stroke aetiologies were analysed. Follow-up samples were collected in a subgroup of ischaemic stroke patients at three and twelve months. Ischaemic stroke patients had elevated plasma levels of HGF and SDF-1α, and lower IL-4 levels, compared to spontaneous cervical artery dissection patients without stroke. Aetiology-subgroup analysis revealed reduced levels of nine cytokines/chemokines (HGF, SDF-1α, IL-2R, CD30, TNF-RII, IL-16, MIF, APRIL, SCF), and elevated levels of IL-4 and MIP-1β, in spontaneous cervical artery dissection (with or without ischaemic stroke as levels were comparable between both groups) compared to other aetiologies. The majority of cytokine/chemokine levels remained stable across the study period. Our research indicates that stroke due to large artery atherosclerosis, cardioembolism, and small vessel occlusion triggers a stronger inflammatory response than spontaneous cervical artery dissection.

Recurrent cerebrovascular events after recent small subcortical infarction.

Recent small subcortical infarcts (RSSI) are the neuroimaging hallmark feature of small vessel disease (SVD)-related acute lacunar stroke. Long-term data on recurrent cerebrovascular events including their aetiology after RSSI are scarce. This retrospective study included all consecutive ischaemic stroke patients with an MRI-confirmed RSSI (in the supply area of a small single brain artery) at University Hospital Graz between 2008 and 2013. We investigated associations between clinical and SVD features on MRI (STRIVE criteria) and recurrent cerebrovascular events, using multivariable Cox regression adjusted for age, sex, vascular risk factors and MRI parameters. We analysed 332 consecutive patients (mean age 68years, 36% women; median follow-up time 12years). A recurrent ischaemic cerebrovascular event occurred in 70 patients (21.1%; 54 ischaemic strokes, 22 transient ischaemic attacks) and was mainly attributed to SVD (68%). 26 patients (7.8%) developed intracranial haemorrhage. In multivariable analysis, diabetes (HR 2.43, 95% CI 1.44-3.88), severe white matter hyperintensities (HR 1.97, 95% CI 1.14-3.41), and cerebral microbleeds (HR 1.89, 95% CI 1.32-3.14) on baseline MRI were related to recurrent ischaemic stroke/TIA, while presence of cerebral microbleeds increased the risk for intracranial haemorrhage (HR 3.25, 95% CI 1.39-7.59). A widely used SVD summary score indicated high risks of recurrent ischaemic (HR 1.22, 95% CI 1.01-1.49) and haemorrhagic cerebrovascular events (HR 1.57, 95% CI 1.11-2.22). Patients with RSSI have a substantial risk for recurrent cerebrovascular events-particularly those with coexisting chronic SVD features. Recurrent events are mainly related to SVD again.

Behavior of PCDD/Fs and PCBs from Wastewater Treatment Plants during Sewage Sludge Composting: Study of Semi-Anaerobic Conditions and Different Stages of the Process

Composting is a common treatment for the high amounts of sewage sludge produced in wastewater treatment plants, and the product is used in agriculture. Composting reduces the levels of biodegradable organic pollutants, although other compounds present in wastewater and not eliminated previously by conventional physical–chemical and chemical treatments, such as polychorodibenzo-p-dioxins/furans (PCDD/Fs) and polychlorinated biphenyls (PCBs), have been found in the final compost at higher levels than those observed in the initial sludge. Their formation was studied during composting under unfavorable aeration conditions and paying attention to different stages of the process. Experiments were carried out in small vessels inside a controlled oven for three types of sewage sludge. Pentachlorophenol was previously added as a dioxin precursor. A clear formation of PCDD/Fs was found, especially during the maturation stage for two experiments. Mainly octachlorodibenzo-p-dioxin (OCDD) and 1234678-heptachlorodibenzo-p-dioxin (1234678-HpCDD) to a lesser extent were formed. OCDD levels in the final samples were around 10 times higher than those of the initial mixture after removing the concentration effect. No clear formation nor degradation of PCBs was observed. The toxicity values due to PCDD/Fs and PCBs found in the initial mixtures were 1.20–2.46 ng WHO-TEQ/kg, and those from the final samples were 2.30–7.86 ng WHO-TEQ/kg. Although the toxicity values are below the most restrictive limits found in Europe in this case, toxicity could increase considerably with the presence and concentration of other precursors. Compost from sewage sludge is an ecological product, but the operating conditions must be controlled to avoid PCDD/F formation and facilitate degradation of persistent organic pollutants.

Clinical characteristics of cerebral amyloid angiopathy and risk factors of cerebral amyloid angiopathy related intracerebral hemorrhage.

There is limited understanding of the differences between cerebral amyloid angiopathy (CAA) with and without intracerebral hemorrhage (ICH). This article aimed to describe the characteristics of CAA and identify the risk factors of CAA-ICH in a multicenter cohort. Patients consecutively enrolled in the national multicenter prospective Cerebral Small Vessel Disease Cohort Study who met the Boston diagnostic criteria for CAA or CAA-related inflammation were included in this study. The demographic characteristics and clinical data were collected. The clinical and radiographic differences between CAA with and without ICH were compared to identify the risk factors for CAA-ICH. A total of 219 CAA patients were included, with an average age of 67.12 ± 9.93. Of all patients, 26.0% were CAA with ICH. Univariate analysis showed that CAA-ICH is associated with carrying more APOE ε2 allele, less lobar cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), lower Fazekas scale, a tendency of gait disorder, and acute onset (P < 0.05). The generalized linear mixed model yielded statistically significant associations between CAA with ICH and carrying the APOE ε2 allele, cSS, the lower number of lobar CMBs, and the lower Fazekas scale (P < 0.05). It is meaningful to classify CAA with and without ICH, as there may be different mechanisms between the two. CAA with ICH has a susceptibility to carrying APOE ε2, cSS, and a relatively small number of CMBs. Fewer CMBs do not mean lower susceptibility to ICH in CAA. Larger prospective cohort studies are necessary to further clarify these conclusions.

P.030 Remote ischemic conditioning in acute ischemic stroke and small vessel disease – a feasibility study

Background: We tested the hypothesis that delivering remote ischemic conditioning (RIC) with an adjunct tissue reflectance sensor (TRS) device may be feasible in patients with acute ischemic stroke (AIS) and cerebral small vessel disease (cSVD). Methods: AIS patients with neurological deficits within 7 days of symptom onset were screened for moderate to severe cSVD. Eligible patients were randomized 2:1 to receive intervention RIC or sham RIC (7 days). The primary outcome measure was intervention feasibility. It was assessed as an intervention-related comfort by a 5-point Likert scale during each session (1-very uncomfortable, 5-very comfortable). The secondary outcome measure was assessment of TRS derived dermal blood concentration and blood oxygenation changes during RIC. Results: Forty-seven (32 intervention, 15 sham) patients were enrolled at a median (IQR) 39.7 (25-64) hours after symptom onset, with mean±SD age of 75±12 years, 22 (46.8%) were females and median baseline NIHSS of 5(3-7). The Likert scale was 3.5 (3-4) in the intervention group and 4 (4-5) in the sham group. The TRS derived blood concentration and blood oxygenation changes were proportionate in the intervention arm and absent in the sham arm. Conclusions: RIC treatment with TRS is feasible in patients with AIS+cSVD. The efficacy of RIC needs further assessment.

Heterogeneous blood-brain barrier dysfunction in cerebral small vessel diseases.

We explored how blood-brain barrier (BBB) leakage rate of gadolinium chelates (Ktrans) and BBB water exchange rate (kw) varied in cerebral small vessel disease (cSVD) subtypes. Thirty sporadic cSVD, 40 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and 13 high-temperature requirement factor A serine peptidase 1 (HTRA) -related cSVD subjects were investigated parallel to 40 healthy individuals. Subjects underwent clinical, cognitive, and MRI assessment. In CADASIL, no difference in Ktrans, but lower kw was observed in multiple brain regions. In sporadic cSVD, no difference in kw, but higher Ktrans was found in the whole brain and normal-appearing white matter. In HTRA1-related cSVD, both higher Ktrans in the whole brain and lower kw in multiple brain regions were observed. In each patient group, the altered BBB measures were correlated with lesion burden or clinical severity. In cSVD subtypes, distinct alterations of kw and Ktrans were observed. The combination of Ktrans and kw can depict the heterogeneous BBB dysfunction. We measured BBB leakage to gadolinium-based contrast agent (Ktrans) and water exchange rate (kw) across BBB in three subtypes of cSVD. CADASIL is characterized by lower kw, HTRA1-related cSVD exhibits both higher Ktrans and lower kw, while sporadic cSVD is distinguished by higher Ktrans. There are distinct alterations in kw and Ktrans among subtypes of cSVD, indicating the heterogeneous nature of BBB dysfunction.

The neuropathological landscape of small vessel disease and Lewy pathology in a cohort of Hispanic and non-Hispanic White decedents with Alzheimer disease

Cerebrovascular and α-synuclein pathologies are frequently observed alongside Alzheimer disease (AD). The heterogeneity of AD necessitates comprehensive approaches to postmortem studies, including the representation of historically underrepresented ethnic groups. In this cohort study, we evaluated small vessel disease pathologies and α-synuclein deposits among Hispanic decedents (HD, n = 92) and non-Hispanic White decedents (NHWD, n = 184) from three Alzheimer’s Disease Research Centers: Columbia University, University of California San Diego, and University of California Davis. The study included cases with a pathological diagnosis of Intermediate/High AD based on the National Institute on Aging– Alzheimer’s Association (NIA-AA) and/or NIA-Reagan criteria. A 2:1 random comparison sample of NHWD was frequency-balanced and matched with HD by age and sex. An expert blinded to demographics and center origin evaluated arteriolosclerosis, cerebral amyloid angiopathy (CAA), and Lewy bodies/Lewy neurites (LBs/LNs) with a semi-quantitative approach using established criteria. There were many similarities and a few differences among groups. HD showed more severe Vonsattel grading of CAA in the cerebellum (p = 0.04), higher CAA density in the posterior hippocampus and cerebellum (ps = 0.01), and increased LBs/LNs density in the frontal (p = 0.01) and temporal cortices (p = 0.03), as determined by Wilcoxon’s test. Ordinal logistic regression adjusting for age, sex, and center confirmed these findings except for LBs/LNs in the temporal cortex. Results indicate HD with AD exhibit greater CAA and α-synuclein burdens in select neuroanatomic regions when compared to age- and sex-matched NHWD with AD. These findings aid in the generalizability of concurrent arteriolosclerosis, CAA, and LBs/LNs topography and severity within the setting of pathologically confirmed AD, particularly in persons of Hispanic descent, showing many similarities and a few differences to those of NHW descent and providing insights into precision medicine approaches.

#2291 ANCA negative vasculitis—the unmet need within small vessel vasculitis

Abstract Background and Aims ANCA negative small vessel vasculitis with renal involvement has been described in a number of cohorts. Though comprehensive studies comparing these individuals to ANCA positive patients are lacking and they are routinely excluded from clinical trials. Whilst the numbers are smaller than those with ANCA positivity, they still make up a large proportion of small vessel vasculitidies (Fig. 1). The absence of detectable circulating ANCA is thought to indicate a distinct spectrum of the disease. There remains unanswered questions regarding the pathophysiology, diagnosis and management of patients with seronegative AAGN. We present data from Croatian referral center. Method Study included 106 AAV patients with biopsy proven renal involvement in the period from 2007-2017. Category variables were analysed with Fisher Exact test and continuous with Kruskal-Wallis test. Statistical difference was then analysed post hoc with Chi-square test. Kaplan Meyer survival analysis and multivariate Cox proportional hazard regression analysis were used to explore difference between clinical phenotypes and finding significant predictors regarding outcomes which were defined as combined outcome end-stage renal disease and death (ESRDD), ESRD alone, the death outcome alone and relapse rate. Results 106 AAV patients with renal involvement were included: 66 (61.1%) MPA, 20 (18.5%) GPA, 20 (18.5%) RLV. 14 (13%) were PR3-ANCA positive, 57 (52.8%) MPO ANCA positive, 5 (4.6%) PR3-ANCA+MPO-ANCA and 32 (29.6%) ANCA negative patients. ANCA negative patients were comparatively younger (p = 0.02) and presented with more renal limited vasculitis (RLV; p &amp;lt; 0.001), lower BVAS (p = 0.003) and lower CRP (p = 0.001). ANCA negative patients usually presented with nephrotic syndrome compared to positive ones which presented with rapid progressive nephritic syndrome or acute nephritic syndrome (p = 0.027). 24-hour proteinuria levels were higher in ANCA negative group (p = 0.003). Though statistical difference was not reached, there was tendency for ANCA negatives to receive less plasmapheresis (p = 0.074). Histologically there were no differences between ANCA positive and ANCA-negative patients. On sub analysis ANCA negatives versus individual seropositive groups, there was tendency that ANCA negatives and MPO-ANCA patients had lower percentage of glomerular crescents (p = 0.092) but more acute tubular damage (p = 0.087). There were no differences in clinical outcomes between the groups. Conclusion ANCA negative vasculitis form a large proportion of small vessel vasculitidies and present with different clinical laboratory and histological (renal) characteristics than ANCA positive ones. More often than not disease seems to be renal limited and patients tend to be younger. Due to the rarity of the disease, there remains unanswered questions regarding the pathophysiology, diagnosis and management of these patients. This study highlights noteworthy distinctions between the two groups. Whether these differences warrant adjustments in treatment algorithms or a reconsideration of the classification of small vessel vasculitis remains to be determined. Further investigation into the pathogenetic mechanisms of seronegative AAVs is essential.

#3068 Fibrosis and CD-163+ macrophages: making a difference between MPO-AAV and PR3-AAV

Abstract Background and Aims Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a necrotizing vasculitis characterized by inflammation of small blood vessels, with the kidney being one of the most affected organs. Its pathogenesis is a complex, multifactorial process involving inflammation and fibrosis in which macrophages play a crucial role. Macrophages are plastic cells that can change their phenotype in response to their environment. Infiltration of CD163+ macrophages (anti-inflammatory) in the interstitium and glomeruli is observed in AAV patients. Clinical and demographic differences between PR3-AAV and MPO-AAV were observed. We observed that interstitial fibrosis (IFTA) is more pronounced in MPO-AAV than in PR3-AAV. We aimed to investigate the differences in CD163+ macrophage infiltration and interstitial fibrosis between PR3-AAV and MPO-AAV. Method Retrospective single-center study of 80 AAV patients (66 MPO-AAV and 14 PR3-AAV) diagnosed by renal biopsy with at least 1 year of follow-up. Clinical and laboratory variables, ANCA type and renal/patient survival were evaluated. 26 human kidney tissue samples (13 MPO-AAV and 13 PR3-AAV) were stained for CD163+ by immunohistochemistry and immunofluorescence, and trichrome-stained biopsy slides were used to measure the degree of fibrosis. Histomorphometric quantification was performed using MetaMorph® software in both cases. Data analysis was performed under standard conditions. Statistical significance was defined as P values less than 0.05. All P values were 2-sided. Results CD163+ macrophages infiltration in the interstitial space was greater in MPO-AAV than PR3-AAV with statistical significance (p &amp;lt; 0.001), observing an average infiltration area of 0.333% in MPO-AAV than 0.116% in PR3-AAV. Furthermore, IFTA was higher at diagnosis in MPO-AAV (35.35%) than in PR3-AAV (31.21%) at the diagnosis with a p = 0.03. However, a correlation between IF and CD163+ macrophages infiltration was not possible to stablish. Conclusion We have observed an increased macrophage infiltrate with an anti-inflammatory and reparative phenotype that is higher at diagnosis in ANCAS-MPO compared to ANCAS-PR3, the same difference occurs with respect to interstitial fibrosis. Since the study population is small, no correlations between fibrosis and CD163 macrophage infiltration have yet been found.

#2699 Rare glomerular microangiopathy: clinicopathological characteristics and prognosis

Abstract Background and Aims Different from the typical histologic changes of thrombotic microangiopathy (TMA), we identified a group of patients whose pathology with glomerular involvement without blood vessel lesions, which was rare and known as glomerular microangiopathy (GMA). Method In Peking Union Medical College Hospital, a total of 33 patients were diagnosed as GMA with proliferation and swelling of glomerular endothelial cells, fragmented red blood cells, fibrin or platelet thrombi in the capillary lumen, thickening of the basement membrane, stenosis or occlusion of capillary lumen, but no abnormalities in the endothelium of renal small vessels. The pathology and clinical data were from the medical records and analyzed. Results The patients were 66.7% male with a mean of 45 years (14 to 74 years). The primary diseases were Castleman's disease (CD, 30.3%), POEMS syndrome (21.2%), cancer patients receiving agents targeting vascular endothelial growth factor (21.2%), and others. All the patients showed various degrees of proteinuria, with an average 24-hour urinary protein of 2.66 g/d, hematuria (63.6%), and acute kidney injury (AKI, 39.4%). The median serum creatinine (SCr) was 142 (107.5, 169) μmol/L. The AKI patients had lower Alb (P &amp;lt; 0.0001), PLT (P = 0.0192), higher high-sensitivity C-reactive protein (hs-CRP) (P = 0.0199), and reduction of IgA (P = 0.0021). There is no significant difference in SCr and proteinuria among patients with different etiologies. The CD patients exhibited higher hs-CRP and D-Dimer. Treatment included targeting therapy of underlying hematological disorders, glucocorticoid combination with or without immunosuppressant, and supportive treatment. After treatment, we observed proteinuria remission (66.7%), partial improvement (27.3%), or complete recovery (45.5%) of renal function. Conclusion In Castleman's disease, POEMS syndrome, and patients receiving agents targeting VEGF, initial attention to GMA might improve the prognosis and shed light on the study of the mechanisms.

#2183 Does thrombotic microangiopathy drive the occurrence and pattern of cerebrovascular disease in malignant hypertension?

Abstract Background and Aims Malignant hypertension (MHT) is characterized by diffuse microvascular damage caused by severe hypertension, often presenting with multiple organ involvement. Cerebrovascular injury, occurring in both acute and chronic forms, stands as a hallmark of the disease, being identified in up to half of patients. Thrombotic microangiopathy (TMA), defined as the association of mechanical hemolytic anemia with thrombocytopenia, also emerges as a frequent complication in MHT patients. However, the potential contribution of TMA to cerebrovascular disease remains unexplored. The secondary objective of this study was to provide a comprehensive description of the patterns of cerebrovascular injury occurring in MHT, with a focus on acute ischemic strokes (AIS). Method We retrospectively assessed the brain MRI of patients admitted to the kidney intensive care unit at Tenon hospital for malignant hypertension during the 2017-2023 period. Brain MRIs were performed on a systematic basis regardless of neurological symptoms and were independently reviewed by two trained specialists in a blinded fashion. Patterns of acute cerebrovascular disease, defined as AIS, intracerebral hematoma (ICH) or posterior reversible encephalopathy syndrome (PRES), were systematically assessed. Number of AIS lesions, their size and localization were recorded. Underlying chronic cerebral small vessel disease (CSVD) was defined as presence of lacunes, white matter hyperintensities, cerebral microbleeds or perivascular spaces. Severity of the chronic cerebrovascular disease was measured using a validated CSVD score. Results A total of 60 patients were admitted for malignant hypertension, with a mean age of 42.9 years. 40 patients (66.7%) presented with severe acute kidney injury. Cerebrovascular disease, either acute or chronic, was found in 42 patients (70.0%). Underlying chronic CSVD was present in 33 patients (55.0%). Acute patterns of injury occurred in 27 patients (45.0%). AIS was the most frequent (33.3%), followed by PRES (21.7%). Only one patient presented with ICH. Among patients with AIS, 14 (70%) presented with multiple simultaneous lesions. Of note, most patients with AIS exhibited diffuse encephalopathy syndrome (60.0%) rather than focal deficit (40.0%). Systemic TMA was present at admission in 34 patients (56.7%). In an exploratory data analysis, presence of AIS on brain MRI was associated with the presence of underlying CVSD (p = 0.013), but not with the presence of TMA at admission (p = 0.79). No association was found between TMA and PRES (p = 0.22). Conclusion Our study confirmed the high incidence of cerebrovascular disease during MHT. Most notably, 1 in 3 patients presented with AIS. TMA did not appear to increase the incidence nor to influence the pattern of brain injury.

#823 Effect of dapsone on the treatment of refractory IgA vasculitis

Abstract Background and Aims IgA vasculitis (IgAV), previously known as Henoch-Schönlein purpura, is a systemic IgA-mediated vasculitis of the small vessels commonly seen in children. The natural history of IgAV is generally self-limiting. However, one-third of patients experience symptom recurrence and a refractory course. We performed this study to examine the use of dapsone (4,4'-sulfonyldianiline or diaminodiphenyl sulfone) in refractory IgAV cases. Method A literature search of PubMed databases retrieved 16 articles published until May 31, 2023. A total of 38 patients with IgAV were recruited. Results A palpable purpura persisted in nearly all the patients with refractory course, followed by joint pain (25 of 38 patients; 69.2%). Hematuria and proteinuria were noted in 11 (28.9%) and 7 (18.4%) of the patients, respectively. Treatment response within 1-2 days was obtained in 12 of 38 patients (31.6%), compared to within ≥3 days in 22 patients (57.9%). Relapse after treatment discontinuation was reported in 21 patients (55.3%) but not in 11 patients (28.9 %). Twelve of the 38 patients (31.6%) reported adverse effects of dapsone, including arthralgia (5.3%), rash (5.3%), dapsone hypersensitivity syndrome (2.6%), methemoglobinemia (21%), and hemolysis (15.8%). These findings indicate that dapsone may have a beneficial effect on refractory IgAV. Conclusion It is observed that in spite of several adverse effects, dapsone treatment exerts a beneficial effect in IgAV patients with prolonged cutaneous manifestation refractory to corticosteroid. Close renal monitoring may be needed to discover renal involvement of IgAV. Multicenter randomized placebo-controlled trials are necessary to determine the standard dosage of dapsone at initial or tapering of treatment in IgAV patients.

Shenfu injection alleviate gut ischemia/reperfusion injury after severe hemorrhagic shock through improving intestinal microcirculation in rats

BackgroundShenfu (SF) injection, a traditional Chinese medication, would improve microcirculation in cardiogenic shock and infectious shock. This study was aimed to explore the therapeutic potential of the SF injection in gut ischemia-reperfusion (I/R) injury after severe hemorrhagic shock (SHS) and resuscitation. Furthermore, we also investigated the optimal adm？ inistration timing. MethodsTwenty-four male SD rats were randomly divided into four groups: Sham group (sham, n = 6), Control group (n = 6), SF injection group (SF, n = 6), and Delayed Shenfu injection administration group (SF-delay, n = 6). In SHS and resuscitation model, rats were induced by blood draw to a mean arterial pressure (MAP) of 40 ± 5 mmHg within 1 h and then maintained for 40 min; HR, MAP ‘were recorded, microcirculation index [De Backer score, perfused small vessel density (PSVD), total vessel density (TVD), microcirculation flow index score (MFI), flow heterogeneity index (HI)] were analyzed. The blood gas index was detected, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), diamine oxidase (DAO), malondialdehyde (MDA) were measured by ELISA; ZO-1, and claudin-1 were measured by Western blotting. In addition, hematoxylin-eosin (HE) and periodic acid schiff (PAS) staining pathological sections of the intestinal mucosal tissues were also performed. ResultsSF injection increased the MAP, relieved the metabolic acidosis degree associated with the hypoperfusion, and improved the intestinal microcirculatory density and perfusion quality after I/R injury. The expression of DAO, MDA in intestinal tissue, and plasma IL-6, TNF-α significantly decreased in the SF injection group compared to the control group. The concentration of ZO-1 and claudin-1 is also higher in the SF injection group. In addition, the HE and PAS staining results also showed that SF injection could decrease mucosal damage and maintain the structure. In the SF-delay group, the degree of intestinal tissue damage was intermediate between that of the control group and SF injection group. ConclusionsSF injection protect the intestine from I/R injury induced by SHS and resuscitation, the mechanism of which might be through improving intestinal microcirculation, reducing the excessive release of inflammatory factors and increasing intestinal mucosal permeability. Furthermore, the protection effect is more pronounced if administration during the initial resuscitation phase.

#1782 Clinicopathological study of renal limited pauci-immune vasculitis and its short-term outcome: a single centre observational study

Abstract Background and Aims Pauci immune crescentic glomerulonephritis, is a leading cause of RPGN. The majority of patients with PICGN have glomerular diseases as a part of a systemic small vessel vasculitis, a minority may present as renal-limited vasculitis. In north-east India, there are still no major studies in this group of patients. Therefore, our study involving north-east Indian population constitutes an effort to prospectively study the clinico-pathological feature of patients with PICGN and assess the short-term outcome. Method This single-centre, prospective, observational, study was conducted over 12 months at the Department of Nephrology, Gauhati Medical College. All renal biopsy-proven patients with pauci-immune renal vasculitis were included, excluding those with secondary vasculitis. Baseline characteristics and laboratory data were recorded, and disease activity was assessed using the Birmingham Vasculitis Activity Score. The ANCA tests were performed using a standardised essay for both indirect immunofluorescence assay and antigen-specific ELISA. The renal biopsy specimen obtained was evaluated by light microscopy and direct immunofluorescence. The sample size was calculated based on the prevalence of pauci-immune glomerulonephritis, and data were analysed using SPSS. Results The study involved 24 patients, predominantly females (70.83%), aged 14-65 years, presenting predominantly with pedal oedema and oliguria. Laboratory findings showed varying levels of haemoglobin, total count, platelet count, creatinine, and 24-hour urine protein. 50% of the patients were (MPO) positive, 33.3% were (PR3) positive while 16% were ANCA negative. Renal biopsy analysis showed a majority with mixed class according to the Berden classification. Treatment involved induction with Methylprednisolone and Cyclophosphamide, with dialysis administered to 58.3% of patients. At six months, 36.3% had a stable GFR, and 50% were on maintenance hemodialysis. Factors predicting renal loss included oliguria, dialysis at presentation, and fibrous/fibrocellular crescents. The best predictor of renal outcome was serum creatinine at presentation. Conclusion Pauci-immune CrGN is a severe disease affecting a wide age range. Early diagnosis and treatment initiation are crucial for better outcomes, including lower ESRD risk and relapse rates. Prognostic factors include baseline serum creatinine levels and fibrous crescents. Optimising treatment regimens may improves outcomes.