Diffuse Microangiopathy Research Articles

The amplification of CNS damage in Alzheimer's disease due to SARS-CoV2 infection

Pre-existing Alzheimer's disease is a risk factor for severe/fatal COVID-19 and infection by SARS-CoV2 virus has been associated with an increased incidence of un-masked Alzheimer's disease. The molecular basis whereby SARS-CoV2 may amplify Alzheimer's disease is not well understood. This study analyzed the molecular changes in autopsy brain tissues from people with pre-existing dementia who died of COVID-19 (n = 5) which was compared to equivalent tissues of people who died of COVID-19 with no history of dementia (n = 8), Alzheimer's disease pre-COVID-19 (n = 10) and aged matched controls (n = 10) in a blinded fashion. Immunohistochemistry analyses for hyperphosphorylated tau protein, α-synuclein, and β-amyloid-42 confirmed the diagnoses of Alzheimer's disease (n = 4), and Lewy body dementia (n = 1) in the COVID-19 group. The brain tissues from patients who died of COVID-19 with no history of dementia showed a diffuse microangiopathy marked by endocytosis of spike subunit S1 and S2 in primarily CD31+ endothelia with strong co-localization with ACE2, Caspase-3, IL6, TNFα, and Complement component 6 that was not associated with SARS-CoV2 RNA. Microglial activation marked by increased TMEM119 and MCP1 protein expression closely paralleled the endocytosed spike protein. The COVID-19 tissues from people with no pre-existing dementia showed, compared to controls, 5-10× fold increases in expression of neuronal NOS and NMDAR2 as well as a marked decrease in the expression of proteins whose loss is associated with worsening Alzheimer's disease: MFSD2a, SHIP1, BCL6, BCL10, and BACH1. In COVID-19 tissues from people with dementia the widespread spike-induced microencephalitis with the concomitant microglial activation co-existed in the same areas where neurons had hyperphosphorylated tau protein suggesting that the already dysfunctional neurons were additionally stressed by the SARS-CoV2 induced microangiopathy. ACE2+ human brain endothelial cells treated with high dose (but not vaccine equivalent low dose) spike S1 protein demonstrated each of the molecular changes noted in the in vivo COVID-19 and COVID-19/Alzheimer's disease brain tissues. It is concluded that fatal COVID-19 induces a diffuse microencephalitis and microglial activation in the brain due to endocytosis of circulating viral spike protein that amplifies pre-existing dementia in at least two ways: 1) modulates the expression of proteins that may worsen Alzheimer's disease and 2) stresses the already dysfunctional neurons by causing an acute proinflammatory/hypercoagulable/hypoxic microenvironment in areas with abundant hyperphosphorylated tau protein and/or βA-42.

Peripheral Microangiopathy Changes in Pulmonary Arterial Hypertension Related to Systemic Sclerosis: Data From a Multicenter Observational Study

Systemic sclerosis (SSc) is a connective tissue disease characterized by immune-system alterations, fibrosis involving the skin and internal organs and diffuse microangiopathy. Pulmonary arterial hypertension (PAH) is a severe complication of SSc affecting about 10–15% of the patients and it is a leading cause of mortality. Due to the devastating nature of SSc-PAH, there is a clear need to systematically adopt appropriate screening programs. Nail fold videocapillaroscopy (NVC) studies have shown a more severe peripheral microvascular dysfunction in SSc patients with PAH suggesting that abnormalities in peripheral microcirculation may correlate with pulmonary microangiopathy. This is a cross-sectional study involving four tertiary University Rheumatology Units in the Center-North of Italy. Seventy patients, 35 adults with SSc and PAH confirmed by RHC (F/M 34/1; median age 65.2 ± 8.9 SD yrs), and 35 SSc patients without PAH were enrolled (F/M 3471; median age 63.3 ± 10.3 SD yrs). Clinical, laboratoristic and instrumental data were collected and NVC was performed in all patient. Specific NVC parameters were evaluated and a semi-quantitative rating scale was adopted to score these changes. Finally, patients were distributed into the suitable NVC pattern belonging to the scleroderma pattern. Our aim was to compare the peripheral microangiopathy changes in SSc patients with and without PAH, and to investigate the relationship between NVC findings and the main hemodynamic parameters of pulmonary vasculopathy. Patients with SSc-PAH+ showed a significant higher frequency of interstitial lung disease (ILD). No significant differences regarding clinical and laboratoristic parameters were observed. NVC abnormalities, avascular areas were more frequent in SSc patients with PAH, respect to those without (p = 0.03), and capillary density was significantly lower when considering grade 3 (p = 0.02). A higher NVC semiquantitative mean was found in SSc-PAH+ patients and a greater rate of the “late” pattern was detected in SSc-PAH+ subjects in respect to PAH- (57.1% vs. 25.7%) (p = 0.03). A significant correlations between pulmonary pressure values (sPAP by TTE and mPAP by RHC) and the capillary density (Spearman's rho 0.35, p = 0.04 for both). Our findings provide additional evidence to the literature data, confirming that a higher degree of peripheral nailfold microangiopathy is more common in SSc-PAH patients, and further strengthening the concept that NVC changes may run parallel with similar abnormalities inside pulmonary microcirculation.

PB2194: ISCHEMIC STROKE IN PATIENTS WITH THROMBOCYTOPENIA AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION

Background: Hematopoietic stem cell transplantation (HSCT) is a critical strategy in the treatment of hematopoietic diseases, but it is not free of complications. Those occurring in the central nervous system (CNS) exhibit potential severity and poor prognosis, the most frequent being infection and hemorrhagic stroke secondary to thrombocytopenia. Up to 3% of transplant recipients develop a stroke; however, despite the relationship between thrombocytopenia and bleeding at any level, ischemic strokes have also been described in patients with thrombocytopenia. Aims: The aim of our study was to review the development ischemic stroke following allogeneic HSCT and to identify possible associated risk factors. Methods: A total of 4 patients developed ischemic stroke after allogeneic HSCT in a single center in 2019, 75% male and 25% female, aged between 43 and 70 years. Fifty percent had cardiovascular risk factors prior to transplantation (smoking, dyslipidemia, obesity and hypertension), without previous structural heart disease, arrhythmias, thrombotic or ischemic pathology. Only one patient had a positive lupus anticoagulant. All received allogeneic HSCT from related donors (50% haploidentical, 50% identical) as consolidation treatment for malignant disease without CNS infiltration. The source of progenitors was bone marrow 50% and peripheral blood 50%. 75% were performed with reduced-intensity conditioning and 25% myeloablative. None received total body irradiation. Results: Seventy-five percent of the episodes took place in the immediate post-transplantation period (first 100 days), only one occurred later (day +2142). Seventy-five percent had localized ischemic stroke and 25% had cerebral diffuse microangiopathy (Fazekas 3). 75% had no graft-versus-recipient disease (GVHD) at the time of the event, whereas 25% suffered from chronic grade 3 GVHD with pulmonary, renal, and cutaneous involvement. 50% presented the episode in the setting of thrombotic microangiopathy, or suspicion of it. Only 50% were receiving immunosuppressive treatment based on calcineurin inhibitors or corticosteroids. In 75% the episode was followed by a concurrent hemorrhagic event (hemorrhagic cystitis, sublingual hematoma). Concomitant infections were detected in 50% of the patients, of which 50% presented pneumonia caused by Aspergillusspp and Respiratory Syncytial Virus, 25% bacteremia caused by S. Parasanguinisand 25% pneumococcal pneumonia. In half of the cases there was coexistence of more than one microorganism at pulmonary level. Cytomegalovirus was positivized in blood in 50% of the cases, with no evidence of proven disease. Thrombocytopenia was present in all patients, with under 47x109/L platelets in 50% and under 20x109/L platelets in 25%. Hemoglobin was under 9 g/dL in 75%. Image:Summary/Conclusion: In summary, the development of ischemic stroke after allogeneic HSCT is infrequent; however, there are factors that favor their appearance, such as cardiovascular risk factors prior to transplantation, treatments used and intercurrent complications, including thrombotic microangiopathy, which can cause ischemia due to induced endothelial damage. In most cases the events occur in an infectious background. Thrombocytopenia does not in itself constitute a protective factor. In addition, long-term or acute bleeding has been related to thrombotic and ischemic phenomena. However, given the scarcity of case reports, further studies are needed to establish the relationship between allogeneic HSCT and the presence of ischemic events in CNS.

The Effect of Grapex on Wounds Healing in Patients with Scleroderma: A Randomized Controlled Clinical Trial

Background and Aim: Scleroderma (SC) is a connective tissue disease, characterized by diffuse microangiopathy and excessive production of collagen. The current study aimed to investigate the effectiveness of Grapex extract in improving the wound of patients with scleroderma. Methods: This randomized controlled double-blind clinical trial was performed from 2018 to 2019 on patients with scleroderma referred to Golestan Hospital in Ahvaz, Iran. Forty patients with active SC were selected and randomly divided into two groups. Patients applied the ointment twice a day for 4 weeks on the surface of their wounds. After four weeks of using the cream, the rate of wound healing was determined by clinical examination of the wounds. Results: 6 people were excluded from the study due to the lack of referral and final analyzes were performed on 34 patients (16 patients in the control group and 18 patients in the case group). The results of this study showed that there was a significant difference between the two groups in terms of response to treatment (p <0.0001). At the end of the fourth week, 88.89% of the patients in the case group (16 of the 18 patients) achieved complete healing of the wounds in comparison with 18.75% of the control group (3 of the 16 patients). Neither the control group nor the case group had a significant association between response to treatment with age and gender of patients, type of scleroderma, duration of illness, and symptoms. Conclusion: This study showed the effectiveness of Grapex cream ointment in healing scleroderma wounds. Therefore, Grapex cream is an effective, inexpensive, safe, and available medicine that can be used to accelerate wound healing in patients with scleroderma. *Corresponding Authors: Elham Rajaei, Email: elhamrj@gmail.com Please cite this article as: Hemmati AA, Deris Zayeri Z, Rajaei E, Ghanavati M. The Effect of Grapex on Wounds Healing in Patients with Scleroderma: A Randomized Controlled Clinical Trial. Arch Med Lab Sci. 2021;7:1-10 (e1). https://doi.org/10.22037/amls.v7.31059

Kidney allograft infarction associated with transplant renal artery stenosis in a COVID-19 kidney transplant recipient

Kidney allograft infarction is rare, but an urgent condition that requires prompt intervention to avoid allograft loss. Renal artery thrombosis is the leading cause of infarction. Apart from traditional risk factors for thrombosis, emerging SARS-CoV-2 predisposes patients to thrombotic diseases both in arterial and venous vasculatures. We report a case of kidney transplant recipient with known transplant renal artery stenosis (TRAS) status post angioplasty with severe COVID-19, complicated by oliguric acute kidney injury requiring continuous renal replacement therapy (CRRT). She did not have a history of thromboembolic disease. The hospital course was complicated by new-onset atrial and ventricular fibrillation and cardiac arrest requiring multiple rounds of cardiopulmonary resuscitation. She had no signs of renal recovery, and an abdominal CT scan showed evidence of allograft infarcts. She underwent an allograft nephrectomy. Pathology revealed diffuse thrombotic microangiopathy involving glomeruli, arterioles, and arteries associated with diffuse cortical infarction with negative SARS-CoV-2 immunostain and in situ hybridization. This is the first case of kidney allograft infarct with a history of TRAS in a COVID-19 patient. Underlying TRAS and COVID-19-associated thrombosis in this patient are unique and likely play a key role in allograft infarction from arterial thrombosis. Recognizing risk factors and early therapy for allograft infarction may improve transplant outcomes.

Острое повреждение почек при COVID-19: клинико-морфологические сопоставления на основании данных аутопсийных исследований

Severe Acute Respiratory Syndrome (SARS-CoV-2) has spread rapidly throughout the world, causing high morbidity and mortality Analysis of clinical and autopsy data may allow to understand this disease The results of pulmonary and renal autopsies in 37 deceased patients from COVID-19 are presented Materials and methods An autopsy was performed in Moscow in 37 deceased patients aged from 28 to 94 years The microscopic features of the lungs and kidneys were examined using hematoxylin and eosin staining Results Important findings include diffuse alveolar injury, pulmonary thrombosis and microangiopathy, as well as acute kidney injury in all cases, varying in severity Conclusions We report the presence of acute kidney injury in all cases, which requires correction of renal function in patients with SARS-CoV-2, with control of serum creatinine levels, urine volume, proteinuria and hematuria Тяжелый острый респираторный синдром (SARS-CoV-2) быстро распространился по всему миру, вызвав высокую заболеваемость и смертность Анализ клинических данных и данных аутопсии может помочь нам разобраться в данной болезни Мы представляем результаты легочной и почечной аутопсии у 37 умерших от COVID-19 пациентов Материалы и методы В Москве произведена аутопсия 37 умершим пациентам в возрасте от 28 до 94 лет Были исследованы микроскопические особенности легких и почек с помощью окрашивания гематоксилином и эозином Результаты Важные результаты включают диффузное альвеолярное повреждение, тромбоз и микроангиопатию в легких, а также острое повреждение почек во всех случаях различной степени тяжести Выводы Мы сообщаем о наличии острого повреждения почек во всех исследуемых случаях, что требует коррекции функции почек у больных SARS-CоV-2 с контролем уровня креатинина в плазме крови, объема мочи, наличия протеинурии и гематурии

COVID-19 pathology: experience of 2000 autopsies

Background: Pathological anatomy, patogenesis and the morphogenesis of manifestations and complications of COVID-19 remain insufficiently studied. The fullest information on structural bases of organs and tissues alterations by new coronavirus disease can be obtained as a result of autopsies.&#x0D; Aims: The aim of the study was to study the morphological changes of lungs and other organs of the autopsies of COVID-19 deceased persons. Results of 2000 autopsies of people who died of a severe form of COVID-19 in Moscow, consisting of 1212 men and 788 women, from March 20 to May 22, 2020 (a ratio 1.54:1) aged from 20 to 99 years (on average 68.515.63 years) were presented. This experience was previously generalized in the Atlas COVID-19 pathology. Autopsies were made in the converted interstationary pathoanatomical offices at strict observance of rules of biosafety according to standard and legal documents of WHO, Russian Ministry of Health and Rospotrebnadzor.&#x0D; Results: Morphological changes of lungs with varying severity and extent were detected in all examined cases; however, damage to other organs was also common, which in some cases prevailed over pulmonary changes and was the cause of death. The main morphological changes in lungs were diffuse alveolar damage and microangiopathy, alveolar hemorrhage syndrome, thrombosis, and thromboembolism.&#x0D; Conclusion: The involvement of the lungs, other organs, and vascular system in the pathological process is a result of multiple factors. It is advisable to implement clinical and morphological masks of COVID-19.

Cardiovascular manifestations of COVID-19: An evidence-based narrative review.

The recent outbreak of coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization on March 11, 2020. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, primarily involves the respiratory system with viral pneumonia as a predominant manifestation. In addition, SARS-CoV-2 has various cardiovascular manifestations which increase morbidity and mortality in COVID-19. Patients with underlying cardiovascular diseases and conventional cardiovascular risk factors are predisposed for COVID-19 with worse prognosis. The possible mechanisms of cardiovascular injury are endothelial dysfunction, diffuse microangiopathy with thrombosis and increased angiotensin II levels. Hyperinflammation in the myocardium can result in acute coronary syndrome, myocarditis, heart failure, cardiac arrhythmias and sudden death. The high level of cardiac troponins and natriuretic peptides in the early course of COVID-19 reflects an acute myocardial injury. The complex association between COVID-19 and cardiovascular manifestations requires an in-depth understanding for appropriate management of these patients. Till the time a specific antiviral drug is available for COVID-19, treatment remains symptomatic. This review provides information on the cardiovascular risk factors and cardiovascular manifestations of COVID-19.

AB0563 AORTIC ROOT DILATION IN ASSOCIATED WITH THE REDUCTION OF CAPILLARY DENSITY OBSERVED AT NAILFOLD CAPILLAROSCOPY IN SSC PATIENTS

Background:Systemic sclerosis (SSc) in a chronic autoimmune disease characterized by endothelial dysfunction and diffuse microangiopathy, leading to tissue ischemia and inducing fibrosis of skin and visceral organs. Furthermore, it was demonstrated the impairment of wall elasticity of large-medium vessels, such as aorta and its branches (1). SSc-related microangiopathy of vasa vasorum of the aortic wall could also be supposed. However no data on this hypothesis are available in literature.SSc microangiopathy may be easily studied at the nailfold by means of videocapillaroscopy. Indeed, capillaroscopic findings are representative of the microvascular damage caused by SSc troughout the body.Objectives:we aimed to investigate the presence of aortic root dilation, classical sign of aortic wall damage, in a cohort of SSc patients, and to correlate these findings with the capillaroscopic patterns (early, active, and late, according to Cutolo’s classification (2)).Methods:we recruited 125 SSc patients (M/F: 14/111, mean age 55+/-12.7 years, median disease duration 11 years) in 3 Rheumatology Centres in Sicily, Italy, from January to December 2019.Transthoracic echocardiogram with aortic root diameter measurement was carried out in all patients. Moreover, videocapillaroscopy with identification of early, active, or late SSc patterns was performed in the whole case series. Patients with early SSc pattern formed the subgroup 1, while those with the active or late patterns (both characterized by the reduction of capillary density) the subgroup 2.Results:we identified 8 (6.4%) SSc patients with aortic root dilation (diameter &gt; 35 mm). Their age and their frequencies of cardiovascular risk factors were similar to the whole series. Moreover, videocapillaroscopy showed 62 (49.6%) early, 47 (37.6%) active, and 16 (12.8%) late SSc patterns.Aortic root dilation was observed in only one patient in the subgroup 1 (1/62, 1.6%), and in 7 cases of the subgroup 2 (7/63, 11.1%); p=0.03.Conclusion:in this multicentre study, we found that aortic root dilation is significantly associated with the reduction of capillary density at nailfold capillaroscopy (active or late SSc patterns). On the basis of these findings, we might argue that SSc-related microangiopathy of vasa vasorum could contribute to aortic wall damage, at least in a subset of SSc patients.

The Science Underlying COVID-19: Implications for the Cardiovascular System.

The coronavirus disease 2019 (COVID-19) pandemic has affected health and economy worldwide on an unprecedented scale. Patients have diverse clinical outcomes, but those with preexisting cardiovascular disease, hypertension, and related conditions incur disproportionately worse outcome. The high infectivity of severe acute respiratory syndrome coronavirus 2 is in part related to new mutations in the receptor binding domain, and acquisition of a furin cleavage site in the S-spike protein. The continued viral shedding in the asymptomatic and presymptomatic individuals enhances its community transmission. The virus uses the angiotensin converting enzyme 2 receptor for internalization, aided by transmembrane protease serine 2 protease. The tissue localization of the receptors correlates with COVID-19 presenting symptoms and organ dysfunction. Virus-induced angiotensin converting enzyme 2 downregulation may attenuate its function, diminish its anti-inflammatory role, and heighten angiotensin II effects in the predisposed patients. Lymphopenia occurs early and is prognostic, potentially associated with reduction of the CD4+ and some CD8+ T cells. This leads to imbalance of the innate/acquired immune response, delayed viral clearance, and hyperstimulated macrophages and neutrophils. Appropriate type I interferon pathway activation is critical for virus attenuation and balanced immune response. Persistent immune activation in predisposed patients, such as elderly adults and those with cardiovascular risk, can lead to hemophagocytosis-like syndrome, with uncontrolled amplification of cytokine production, leading to multiorgan failure and death. In addition to the airways and lungs, the cardiovascular system is often involved in COVID-19 early, reflected in the release of highly sensitive troponin and natriuretic peptides, which are all extremely prognostic, in particular, in those showing continued rise, along with cytokines such as interleukin-6. Inflammation in the vascular system can result in diffuse microangiopathy with thrombosis. Inflammation in the myocardium can result in myocarditis, heart failure, cardiac arrhythmias, acute coronary syndrome, rapid deterioration, and sudden death. Aggressive support based on early prognostic indicators with expectant management can potentially improve recovery. Appropriate treatment for heart failure, arrhythmias, acute coronary syndrome, and thrombosis remain important. Specific evidence-based treatment strategies for COVID-19 will emerge with ongoing global collaboration on multiple approaches being evaluated. To protect the wider population, antibody testing and effective vaccine will be needed to make COVID-19 history.

Systemic sclerosis: Recent insight in clinical management.

Systemic sclerosis (SSc) is a connective tissue disease characterized by diffuse microangiopathy and immune dysregulation which ultimately result in widespread fibrosis of skin and internal organs. Although the 2013 EULAR/ACR criteria have allowed to improve the sensitivity for SSc diagnosis, it has recently come to light that the traditional subclassification into limited and diffuse cutaneous forms does not appear to fully capture the different phenotypes of the scleroderma spectrum. In this regard, a recent large cluster analysis-based study and other ongoing projects are trying to achieve a better stratification of SSc patients, as the disease course remains largely unpredictable to date. Recent preclinical studies and randomized controlled trials have yielded encouraging results with new drugs targeting inflammatory/immunological and fibrotic pathways. One of the main unmet needs in SSc remains the early identification of patients at high mortality risk, for whom aggressiveness of therapies ought to be determined and weighed against disease prognosis. Furthermore, lung and cardiac transplantation may also be taken into account in some carefully selected patients. Though the prognosis of SSc remains poor, an optimized stratification of patients along with the recent and ongoing advances in therapies could greatly impact the natural course of the disease in the near future. Moreover, it is envisioned that there will be an increasing need in the future to further develop combination therapies to better fight against this complex disease. In this review we discussed new insights into organ involvements and therapeutic options.

Diffuse Lymph-Nodes Microangiopathy as Concurrent Cause of Immunodeficiency in Long-Term Insulin-Dependent Diabetic Patients

Immune abnormalities have been demonstrated in vitro models in genetic (type1) autoimmune (type 2) and metabolic (type 1 and type 2) Insulin-Dependent Diabetes Mellitus (IDDM). However, the precise reason for increased susceptibility to frequent and protracted infections in diabetic patients is still unclear, despite a multitude of in vitro studies which have focused on the metabolic and functional modifications of immune cells Diabetes microangiopathy, which is a peculiar alteration of the disease, has been extensively described in the retina, renal glomeruli, skin, skeletal muscles, peripheral nerves, and other organs but not in lymph nodes. We report our histological and immunohistochemical observations in lymph-nodes removed in multiple sites during autopsy from four patients with long-term IDDM, severe lymphocytpenia and several infectious diseases during their life. The peculiar microangiopathic modifications made by presence of hyaline substance thickening basal membrane of thin vessels and capillaries appear concurrent with lymphodepletion of B and T cells dependent areas of lymph-nodes and with jointed marked reduction of Follicular Dendritic Reticulum Cells (FDRC). Indeed microangiopathy further compromise the traffic and diapedesis of T and B lymphocytes may prevent the transformation of endothelial cells into FDRC with severe immune failure of lymphoid follicles. The histological and immunohistochemical data in this study could provide additional insights into the complex problem of the immunodeficiency in diabetic patients.

The significance of smoking as a risk factor for the disorder of the obstructive pulmonary pattern in the patients with systemic sclerosis

Background/Aim. Systemic sclerosis (SSc) is a chronic systemic disease of the connective tissue. It is characterized by diffuse microangiopathy, increased activity and creating deposits of collagen in the skin and internal organs. Involvement of the lung function disturbances in SSc is a bad prognostic sign. The aim of our study was to investigate the association between smoking habits and lung function disorder in the SSc patients. Methods. The testing was conducted at the Clinic for Rheumatology and Immunology of the Military Medical Academy in 2016. In this study, we included 42 patients with the newly diagnosed SSc and the patients whose disease had been diagnosed earlier. Results. The patients were classified according to the smoking habits, 14 (33.3%) patients were nonsmokers, while 28 (66.7%) patients were current (23 patients) or ex-smokers (5 patients). We found no significant differences in examined parameters among smokers and nonsmokers. In addition, distribution of the patients with the obstructive pulmonary pattern revealed by spirometry was uniform between smokers and nonsmokers. The concentrations of C reactive protein (CRP) were significantly higher in the SSc patients with the obstructive pulmonary pattern. The patients with the obstructive pattern on spirometry had significantly lower values of forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), FEV1/FVC ratio, diffusing lung capacity for carbon monoxide (DLCO) and FVC/DLCO ratio. Conclusion. In our study, we concluded that in the SSc patients with the obstructive pulmonary pattern revealed by spirometry, there were no significant differences between smokers and nonsmokers. CRP is a significant predictor of the lung involvement existence in the SSc patients.

P041 Renal allograft hyperacute rejection: Reviewing the role of hla and non–hla antibodies

A 35 y/o Caucasian female with bilateral nephrectomies due to Von Hippel-Lindeau disease received a first right kidney transplant from a 14 y/o male deceased donor. At 0.5 day post kidney transplant (POD), ultrasound suggested renal vein thrombosis. Allograft biopsy at the time of thrombectomy showed extensive endothelial injury with diffuse thrombotic angiopathy and microangiopathy. There was moderate microvascular inflammation, though C4d was negative. Overall findings were suggestive of hyperacute rejection. Despite thrombectomy and apheresis, the allograft was not viable and was removed on POD 2. We retrospectively re-analyzed HLA donor specific antibody (DSA) and cross-match (XM) results. Additional retrospective testing included endothelial cell XM using surrogate endothelial cell lines (1.5-fold > negative control as +), non–HLA auto-antibodies (AuAb) against different targets associated with allograft rejection (1.5-fold > negative control as +), and angiotensin II type-I receptor antibody (AT1R-Ab) > 17 U/ml as positive and 10–17 U/ml as borderline positive. Pre-kidney transplant HLA-B7 DSA was 3000 mean fluorescence intensity, but both T/B cell flow cytometry XMs were negative. HLA-B7 DSA reduced to 2100 mean fluorescence intensity at POD 1. Pre- kidney transplant AT1R-Ab was positive, but also declined to borderline positive at POD 1. Both pre and post-kidney transplant endothelial cell XM were consistently positive. Six endothelial targets and 1 chronic kidney disease related AuAbs were positive pre- transplant, but 6 out of 7 decreased to borderline level POD 1 (Table 1). Positive endothelial cell XM combined with weak HLA- B7 DSA and multiple strong direct/indirect endothelial target antigen specificities suggest the possible involvement of AuAbs in severe acute endothelial injury related allograft dysfunction.

ABNORMAL NAILFOLD VIDEOCAPILLAROSCOPY IN PATIENTS WITH ANTISYNTHETASE SYNDROME: CASE REPORTS AND REVIEW OF THE LITERATURE

Classified as a distinct subset of idiopathic inflammatory myopathies, anti-synthetase syndrome is an orphan autoimmune disease characterized by the presence of anti-aminoacyl-tRNA synthetase antibodies associated with a spectrum of clinical features including interstitial lung disease, myositis or dermatomyositis, chronic polyarthritis, fever, mechanic‘s hands and Raynaud‘s phenomenon. The main objective of our study was to evaluate nailfold capillary abnormalities in a series of cases diagnosed with anti-synthetase syndrome, aiming to describe capillaroscopy findings and to identify potential relation with clinical and functional outcomes. Irrespective of clinical and serological disease subtype, significant capillaroscopic changes may help diagnosis and identify negative prognostic factors, advancing the role of routine capillaroscopy in the decisional algorithm of anti-synthetase syndrome. Nailfold videocapillaroscopy is able to provide valuable information in patients with anti-tRNA synthetase myositis, suggesting that diffuse microangiopathy represents an early pathobiologic event.

Teaching NeuroImages: Adult-onset leukoencephalopathy with intracranial calcifications and cysts (Labrune syndrome).

A 42-year-old woman was admitted for a complex partial seizure. At age 18 years, she had transient diplopia, which was considered a simple strabismus. Current examination revealed a left VI cranial nerve palsy and right arm hyperreflexia. Neuroimaging showed multiple intraparenchymal cystic lesions in white matter (figure), multiple calcifications in basal ganglia, and extensive bilateral leukoencephalopathy. Lack of extraneurologic involvement and genetic testing ( CTC1 gene) ruled out other disorders (mainly Coats plus syndrome). Leukoencephalopathy with intracranial calcifications and cysts is considered a diffuse microangiopathy affecting children.1 Adult-onset patients may present a heterogeneous and milder clinical picture, with slow progression.2

Nailfold capillaroscopic changes in dermatomyositis and polymyositis.

Inflammatory myopathies (IM) are a group of muscle diseases occurring both in children and adults. Nailfold videocapillaroscopy (NVC) alterations are described in IM, but available data are discordant, including differences between polymyositis (PM) and dermatomyositis (DM). The aim of this study was to describe the capillaroscopic differences between PM and DM patients and possible correlation with clinical and serological features. We analyzed 52 unselected patients with IM in a cross-sectional study in a 6-month period. NVC findings of 29 DM and 23 PM patients were compared with those of 52 patients with primary Raynaud's phenomenon. Tortuosities, capillary loss, enlarged and giant capillaries, microhemorrhages, and ramified capillaries were scored by a semiquantitative rating; disorganization of the vascular array, avascular areas, and scleroderma pattern were scored as presence/absence. Sex, mean age, and mean disease duration were similar in both groups. Disorganization of the vascular array, enlarged and giant capillaries, capillary loss, and scleroderma-like pattern were observed almost only in IM patients. Significant differences were observed between PM and DM with higher frequency and mean score of NVC changes in DM. In DM patients with disease duration ≤6 months (14/29 patients), capillary density was significantly reduced (P = 0.039) and giant capillaries more frequent (P = 0.027), compared with patients with longer disease duration, while a scleroderma pattern tended to be more frequent in patients with a disease duration of less than 6 months. On the contrary, no differences were observed for ramified capillaries with regard to disease duration. Capillaroscopic alterations are identified only in DM patients as expression of diffuse microangiopathy; surprisingly, more severe changes were associated with shorter disease duration, while persistence of ramified capillaries with long-standing disease.

SAT0298 Nailfold Capillaroscopic Alterations in Dermatomyositis and Polymyositis

BackgroundInflammatory myopathies (IM) are a group of acquired muscle diseases with heterogeneous features occurring both in children and adults. Nailfold capillaroscopy (NVC) alterations are described in IM, but their frequency,...

Adjuvant spinal cord stimulation improves wound healing of peripheral tissue loss due to steal syndrome of the hand: clinical challenge treating a difficult case

Hand ischaemia due to arterial steal syndrome is an infrequent, but potentially serious complication of arteriovenous fistula (AVF) for haemodialysis. We present a case of hand ischaemia caused by steal syndrome in a 69-year-old haemodialysis patient, 10 months after a brachiobasilic fistula creation. The patient underwent multiple operations without resolution of hand pain and tissue loss. The implantation of an adjuvant cervical spinal cord stimulator allowed the patient to obtain complete hand pain relief and wound healing. Probably, the diffuse microangiopathy typical of haemodialysis patients could be responsible for the persistence of ischaemic signs and symptoms after a surgical revascularisation. The effect of sympathetic blockade and the subsequent improvement of the arterial blood flow and tissue oxygenation because of spinal cord stimulation (SCS) can be useful to achieve complete ischaemic pain relief in order to enhance wound healing and to limit the tissue loss. In conclusion, the association of cervical spinal cord stimulation and surgical revascularisation could represent a valid option to treat a critical upper limb ischaemia following steal syndrome due to AVF.

AB0396 Plasma ghrelin levels in patients with systemic sclerosis

BackgroundSystemic sclerosis (SSc) is a systemic connective tissue disease characterised by immune system changes, fibrosis of the skin and internal organs involvement and diffuse microangiopathy. Ghrelin, a 28 amino acid...