scholarly journals Complement-Mediated Thrombotic Microangiopathy Associated with Lupus Nephritis Treated with Eculizumab: A Case Report

2021 ◽  
pp. 95-102
Author(s):  
Everardo Arias Torres ◽  
Yongen Chang ◽  
Sheetal Desai ◽  
Ian Chang ◽  
Jonathan E. Zuckerman ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Homozygous Deletion ◽  
Multiple Organ ◽  
Thrombotic Microangiopathies ◽  
Clinical Criteria ◽  
Organ Systems ◽  
Oral Steroids ◽  
Uremic Syndrome

Thrombotic microangiopathies (TMAs) involve multiple organ systems due to the presence of microangiopathic hemolysis. One such condition, atypical hemolytic uremic syndrome (aHUS), is a complement-mediated process that is part of a spectrum of disorders that have underlying complement dysfunction of the alternative pathway due to overactivity or decreased self-nonself discrimination by innate immunity. Complement-amplifying conditions such as pregnancy may unmask a diagnosis of aHUS. We present an important case of a pregnant 23-year-old Hispanic female who presented in mid-gestation (21 weeks) with an initial diagnosis of systemic lupus erythematosus (SLE) complicated by aHUS. She met clinical criteria for aHUS on presentation and was found to have a pathogenic CFHR1–3 homozygous deletion. She has been treated with intravenous and oral steroids, cyclophosphamide, subsequently also with plasma exchange, and finally with eculizumab with partial improvement in renal function. This case adds to the emerging literature showing that SLE and aHUS (or complement-mediated TMA) can be successfully treated with C5 blockade.

scholarly journals ISCHEMIC COLITIS IN AN ADULT PATIENT WITH ATYPICAL HEMOLYTIC UREMIC SYNDROME (case report)

2019 ◽  
Vol 18 (2) ◽  
pp. 82-89
Author(s):  
O. S. Ozerova ◽  
E. A. Poltorykhina ◽  
A. V. Vardanyan ◽  
O. A. Maynovskaya ◽  
V. V. Veselov ◽  
...  
Keyword(s):  
Case Report ◽  
Hemolytic Uremic Syndrome ◽  
Ischemic Colitis ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Multiple Organ ◽  
Complement Components ◽  
Organ Systems ◽  
Threatening Condition ◽  
Uremic Syndrome

Atypical hemolytic uremic syndrome (aHUS) is a rare life-threatening condition caused by uncontrolled complement activation due to mutations in the alternative pathway of complement components. aHUS is characterized by microangiopathic hemolytic anemia, thrombocytopenia, acute renal failure and affecting multiple organ systems. Extra-renal manifestations of aHUS take place in 20% of patients including involvement of the central nervous system, cardiovascular system, lungs, skin and gastrointestinal tract. This case report describes a severe course of atypical hemolytic uremic syndrome in a 21-year-old female, developed ischemic colitis.

P0403INNATE DEFECTS OF COMPLEMENT ALTERNATIVE PATHWAY AMONG LUPUS PATIENTS WITH AND WITHOUT THROMBOTIC MICROANGIOPATHY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Cai Yue ◽  
Quexian Cui ◽  
Xuemei Li
Keyword(s):  
Lupus Erythematosus ◽  
Thrombotic Microangiopathy ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Malignant Hypertension ◽  
Complement Alternative Pathway ◽  
College Hospital ◽  
Medical College ◽  
Significant Difference ◽  
Uremic Syndrome

Abstract Background and Aims Thrombotic microangiopathy (TMA) is a rare and severe complication of systemic lupus erythematosus (SLE). The pathogenesis of TMA among lupus patients is not fully understood yet. The aim of the study was to evaluated innate complement alternative pathway (AP) defects among patients with SLE-TMA. Method 15 consecutive lupus patients with clinically or pathologically diagnosed TMA from Peking Union Medical College Hospital through Jan 2017 to Dec 2019 were enrolled. Lupus patients with TMA secondary to antiphospholipid antibodies, ADAMTS13 inhibitor, overlap syndrome, infection, malignant hypertension and medications were excluded. The exonic regions of 13 genes including CFH, CFI, CFB, C3, CFHR1-5, MCP, THBD, DGKE, PLG were analysed with next generation sequencing. Mutations were interpreted according to ACMG 2015 guideline. Patients with atypical hemolytic uremic syndrome (aHUS) (n=2), lupus nephritis (LN) without TMA (n=8), and malignant hypertension (n=6) were set as control. Results Six AP mutations rated as VUS or likely pathogenic were detected among 5/15 (33.3%) patients with SLE-TMA, while three were detected among 3/8 (37.5%) of patients with LN, one among 1/6 (16.7%) patients with malignant hypertension, and three among 2/2 (100%) of patients with aHUS. There was no significant difference regarding mutation rate among the groups. Conclusion There is no significant difference regarding AP mutations among lupus patients with and without TMA. Mechanisms other than innate AP abnormality may be involved in the pathogenesis of TMA among lupus patients.

scholarly journals Atypical hemolytic uremic syndrome secondary to lupus nephritis, responsive to eculizumab

2016 ◽  
Vol 8 (3) ◽  
Author(s):  
Alexander G. Raufi ◽  
Shruti Scott ◽  
Omar Darwish ◽  
Kevin Harley ◽  
Kanwarpal Kahlon ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Hemolytic Uremic Syndrome ◽  
Lupus Erythematosus ◽  
Multidisciplinary Approach ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Organ Damage ◽  
Atypical Hus ◽  
First Line Therapy ◽  
Autoimmune Attack ◽  
Uremic Syndrome

Among the spectrum of disease manifestations associated with systemic lupus erythematosus, lupus nephritis is particularly concerning due to the potential for renal failure. This autoimmune attack may not, however, be limited to the kidney and is increasingly being recognized as a trigger for atypical Hemolytic Uremic Syndrome (aHUS). Atypical HUS falls under the spectrum of the thrombotic microangiopathies (TMAs) – a group of disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end organ damage. Although plasma exchange is considered first-line therapy for thrombotic thrombocytopenic purpura – a TMA classically associated with autoimmune depletion of ADAMTS-13 – aHUS demonstrates less reliable responsiveness to this modality. Instead, use of the late complement inhibitor Eculizumab has emerged as an effective modality for the management of such patients. Diagnosis of aHUS, however, is largely clinically based, relying heavily upon a multidisciplinary approach. Herein we present the case of a patient with atypical HUS successfully treated with Eculizumab in the setting of Class IV-G (A) lupus nephritis and hypocomplementemia.

scholarly journals Leukoencephalopathy and cerebral edema as the presenting manifestations of SLE in an ANA-negative adolescent female: A case report and review of literature.

2020 ◽  
Author(s):  
Alexandra Theisen ◽  
Paroma Bose ◽  
Christina Knight ◽  
Melissa Oliver
Keyword(s):  
Cerebral Edema ◽  
Lupus Erythematosus ◽  
Primary Care Physicians ◽  
Neuropsychiatric Symptoms ◽  
Clinical Manifestations ◽  
Central Nervous System Involvement ◽  
Multiple Organ ◽  
Small Subset ◽  
Adolescent Female ◽  
Organ Systems

Abstract Background: Systemic lupus erythematosus (SLE) is an autoimmune disease with various clinical manifestations involving multiple organ systems. Neuropsychiatric manifestations of SLE has been associated with increased morbidity and mortality, thus it is important to recognize and diagnosis the disease entity and treat early. When neuropsychiatric symptoms are involved, typically there are many other systemic features to aid in the diagnosis of SLE. Many autoantibodies have been discovered and are used to help diagnose SLE. The antibody present in most cases of pediatric SLE, as well as in many other rheumatic diseases, is the nonspecific antinuclear antibody (ANA), making it a commonly used screening tool by primary care physicians when evaluating a patient with a possible rheumatic disorder. However, a small subset of SLE patients, 1-5%, present with a negative ANA, and it is important to keep SLE on the differential diagnosis in specific instances when a thorough infectious and neurological workup has been completed and proven to be inconclusive. Case Presentation: This case involves a Hispanic adolescent female with a negative ANA who presented with diffuse cerebral edema secondary to leukoencephalopathy due to SLE with central nervous system involvement. She had an extensive workup while inpatient involving metabolism, infectious disease, rheumatology, and neurology prior to obtaining the diagnosis of SLE. She was treated with both cyclophosphamide and rituximab and showed improvement. Conclusions: A review of the literature revealed 8 cases with SLE presenting with or developing diffuse cerebral edema and/or leukoencephalopathy. Our patient’s case differs in that she was also ANA negative despite other autoantibody positivity. While she did have low complements and transient leukopenia, she did not present with other signs of organ involvement, which made the diagnosis of SLE with neuropsychiatric involvement quite challenging. We discuss the importance of keeping SLE on the differential despite a negative ANA in complex cases without any other cause and to consider initial screening with not only the ANA but also dsDNA and complements to avoid missed diagnoses.

scholarly journals C5a and C5aR1 are key drivers of microvascular platelet aggregation in clinical entities spanning from aHUS to COVID-19

2021 ◽  
Author(s):  
Sistiana Aiello ◽  
Sara Gastoldi ◽  
Miriam Galbusera ◽  
Piero Luigi Ruggenenti ◽  
Valentina Portalupi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Bacterial Infections ◽  
Viral Infections ◽  
Ex Vivo ◽  
Inflammatory Diseases ◽  
Thrombus Formation ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Uremic Syndrome

Unrestrained activation of the complement system till the terminal products, C5a and C5b-9, plays a pathogenetic role in acute and chronic inflammatory diseases. In endothelial cells, complement hyperactivation may translate into cell dysfunction, favoring thrombus formation. The aim of this study was to investigate the role of the C5a/C5aR1 axis as opposite to C5b-9 in inducing endothelial dysfunction and loss of anti-thrombogenic properties. In vitro and ex vivo assays with serum from patients with atypical hemolytic uremic syndrome (aHUS) -a prototype rare disease of complement-mediated microvascular thrombosis due to genetically determined alternative pathway dysregulation- and cultured microvascular endothelial cells, demonstrated that the C5a/C5aR1 axis is a key player of endothelial thromboresistance loss. C5a added to normal human serum, fully recapitulated the pro-thrombotic effects of aHUS serum. Mechanistic studies showed that C5a caused RalA-mediated exocytosis of vWF and P-selectin from Weibel-Palade bodies, which favored further vWF binding on the endothelium and platelet adhesion and aggregation. In patients with severe COVID-19 -who suffered from acute activation of complement triggered by SARS-CoV-2 infection- we found the same C5a-dependent pathogenic mechanisms. These results highlight C5a/C5aR1 as a common pro-thrombogenic effector spanning from genetic rare diseases to viral infections, and may have clinical implications. Selective C5a/C5aR1 blockade could have advantages over C5 inhibition, since the former preserves the formation of C5b-9 that is critical to control bacterial infections that often develop as comorbidities in severely ill patients. (Clinicaltrials.gov identifier NCT02464891)

scholarly journals Biologics in the Treatment of Lupus Erythematosus: A Critical Literature Review

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Dominik Samotij ◽  
Adam Reich
Keyword(s):  
Clinical Trials ◽  
Lupus Erythematosus ◽  
Unmet Need ◽  
Clinical Manifestations ◽  
Immunosuppressive Drugs ◽  
Multiple Organ ◽  
Biologic Agents ◽  
Drug Induced ◽  
Treatment Regimes ◽  
Organ Systems

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease affecting multiple organ systems that runs an unpredictable course and may present with a wide variety of clinical manifestations. Advances in treatment over the last decades, such as use of corticosteroids and conventional immunosuppressive drugs, have improved life expectancy of SLE sufferers. Unfortunately, in many cases effective management of SLE is still related to severe drug-induced toxicity and contributes to organ function deterioration and infective complications, particularly among patients with refractory disease and/or lupus nephritis. Consequently, there is an unmet need for drugs with a better efficacy and safety profile. A range of different biologic agents have been proposed and subjected to clinical trials, particularly dedicated to this subset of patients whose disease is inadequately controlled by conventional treatment regimes. Unfortunately, most of these trials have given unsatisfactory results, with belimumab being the only targeted therapy approved for the treatment of SLE so far. Despite these pitfalls, several novel biologic agents targeting B cells, T cells, or cytokines are constantly being evaluated in clinical trials. It seems that they may enhance the therapeutic efficacy when combined with standard therapies. These efforts raise the hope that novel drugs for patients with refractory SLE may be available in the near future. This article reviews the current biological therapies being tested in the treatment of SLE.

Treatment of Atypical Hemolytic Uremic Syndrome and Thrombotic Microangiopathies: A Focus on Eculizumab

2013 ◽  
Vol 61 (2) ◽  
pp. 289-299 ◽  
Author(s):  
Jan Schmidtko ◽  
Sven Peine ◽  
Youssef El-Housseini ◽  
Manuel Pascual ◽  
Pascal Meier
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Thrombotic Microangiopathies ◽  
Uremic Syndrome

scholarly journals Complement Activation and Thrombotic Microangiopathies

2019 ◽  
Vol 14 (12) ◽  
pp. 1719-1732 ◽  
Author(s):  
Marta Palomo ◽  
Miquel Blasco ◽  
Patricia Molina ◽  
Miquel Lozano ◽  
Manuel Praga ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Hemolytic Uremic Syndrome ◽  
Acute Phase ◽  
Complement Activation ◽  
Hellp Syndrome ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Malignant Hypertension ◽  
Clinical Relapse ◽  
Thrombotic Microangiopathies ◽  
Uremic Syndrome

Background and objectivesAtypical hemolytic uremic syndrome is a form of thrombotic microangiopathy caused by dysregulation of the alternative complement pathway. There is evidence showing complement activation in other thrombotic microangiopathies. The aim of this study was to evaluate complement activation in different thrombotic microangiopathies and to monitor treatment response.Design, setting, participants, & measurementsComplement activation was assessed by exposing endothelial cells to sera or activated-patient plasma—citrated plasma mixed with a control sera pool (1:1)—to analyze C5b-9 deposits by immunofluorescence. Patients with atypical hemolytic uremic syndrome (n=34) at different stages of the disease, HELLP syndrome (a pregnancy complication characterized by hemolysis, elevated liver enzymes, and low platelet count) or severe preeclampsia (n=10), and malignant hypertension (n=5) were included.ResultsAcute phase atypical hemolytic uremic syndrome–activated plasma induced an increased C5b-9 deposition on endothelial cells. Standard and lower doses of eculizumab inhibited C5b-9 deposition in all patients with atypical hemolytic uremic syndrome, except in two who showed partial remission and clinical relapse. Significant fibrin formation was observed together with C5b-9 deposition. Results obtained using activated-plasma samples were more marked and reproducible than those obtained with sera. C5b-9 deposition was also increased with samples from patients with HELLP (all cases) and preeclampsia (90%) at disease onset. This increase was sustained in those with HELLP after 40 days, and levels normalized in patients with both HELLP and preeclampsia after 6–9 months. Complement activation in those with malignant hypertension was at control levels.ConclusionsThe proposed methodology identifies complement overactivation in patients with atypical hemolytic uremic syndrome at acute phase and in other diseases such as HELLP syndrome and preeclampsia. Moreover, it is sensitive enough to individually assess the efficiency of the C5 inhibition treatment.

scholarly journals Modified Ham test for atypical hemolytic uremic syndrome

Blood ◽  
2015 ◽  
Vol 125 (23) ◽  
pp. 3637-3646 ◽  
Author(s):  
Eleni Gavriilaki ◽  
Xuan Yuan ◽  
Zhaohui Ye ◽  
Alexander J. Ambinder ◽  
Satish P. Shanbhag ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Cell Lines ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Cell Killing ◽  
Thrombotic Microangiopathies ◽  
Gpi Anchor ◽  
Deficient Cell ◽  
Key Points ◽  
Uremic Syndrome

Key Points GPI-anchor–deficient cell lines are more vulnerable to complement C5b-9 deposition and cell killing from aHUS serum. PIGA-null reagent cell lines can be used to rapidly and reliably distinguish aHUS from other thrombotic microangiopathies.

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