Atypical HUS triggered by infection with SARS-CoV2

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.

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Does complement factor B have a role in the pathogenesis of atypical HUS?

Molecular Immunology ◽

10.1016/j.molimm.2005.06.041 ◽

2006 ◽

Vol 43 (7) ◽

pp. 856-859 ◽

Cited By ~ 29

Author(s):

David Kavanagh ◽

Elizabeth J. Kemp ◽

Anna Richards ◽

Rachel M. Burgess ◽

Elizabeth Mayland ◽

...

Keyword(s):

Complement Factor ◽

Factor B ◽

Complement Factor B ◽

Atypical Hus

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7. Thrombotic Microangiopathy: HUS and Atypical HUS

Nihon Naika Gakkai Zasshi ◽

10.2169/naika.104.1959 ◽

2015 ◽

Vol 104 (9) ◽

pp. 1959-1963

Author(s):

Masaomi Nangaku ◽

Yoko Yoshida ◽

Hideki Kato

Keyword(s):

Thrombotic Microangiopathy ◽

Atypical Hus

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P1805UNEXPECTD COMPLEMENT GENES ABNORALITIES IN CHILDREN WITH SECONDARY HEMOLITIC UREMIC SYNDROME

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p1805 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Luigi Cirillo ◽

Francesca Becherucci ◽

Francesco Guzzi ◽

Carmela Errichiello ◽

Elisa Buti ◽

...

Keyword(s):

Next Generation Sequencing ◽

Genetic Background ◽

Case Series ◽

Cobalamin Deficiency ◽

Genetic Defects ◽

Next Generation ◽

Atypical Hus ◽

Uremic Syndrome ◽

Generation Sequencing

Abstract Background and Aims Secondary hemolytic-uremic syndrome (HUS) is currently defined in the absence of genetic defects in complement genes (primary or atypical HUS, aHUS) or Shiga-toxin producing E. Coli infection (STEC-HUS). However, the role of complement genes abnormalities in secondary HUS is still a matter of debate as results coming from studies performed in adults are controversial. Moreover, genetic defects of complement regulation have been recently described in children with STEC-HUS, thus challenging the current HUS classification. The identification of a role of complement genes abnormalities in these patients could have important clinical implications for diagnosis and treatment. In this study, we assessed the presence of complement genes abnormalities in children with secondary HUS. Method We describe a case series of pediatric patients diagnosed with secondary HUS. All patients were screened for the presence of ADAMTS13 auto-antibody and ADAMTS13 deficiency. We performed next-generation sequencing for a panel of complement genes reported in association with aHUS (CFH, CFI, MCP, C3, FB, and THBD). Copy number variations and hybrid genes assessment were included in the analysis. Results Four patients aged 1-4 years with a diagnosis of sporadic secondary HUS were included in the study. HUS was secondary to glomerulopathy, cobalamin deficiency, bone marrow transplantation, and pneumococcal pneumoniae. Two out of four patients showed hypocomplementaemia (both C3 and C4). Diarrhea was a common clinical feature in all patients at onset, and none of these patients showed neurologic involvement. Renal replacement therapy was required in two patients at onset. Only one patient did not recover kidney function, and subsequently underwent kidney transplantation. Next-generation sequencing showed genetic abnormalities in all the patients (Table 1). All but one genetic variants have already been described in association with atypical HUS. Interestingly, haplotypes in CHF and MCP were present in three patients, all of Caucasian ethnicity. Conclusion According to the current HUS classification, complement abnormalities are diagnostic of aHUS. However, results coming from pediatric cohorts of STEC-HUS patients already claimed a role for genetic background also outside the aHUS spectrum, suggesting that the current terminology lacks both specificity and suggestion of cause. In this case series, complement genes abnormalities were present in all patients. Whether confirmed in larger cohorts, these findings would support the role of genetic background even in secondary HUS, suggesting the need for a revision of the current HUS classification, in agreement with the pathogenic mechanisms, in order to tailor the optimal treatment.

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Use of Highly Individualized Complement Blockade Has Revolutionized Clinical Outcomes after Kidney Transplantation and Renal Epidemiology of Atypical Hemolytic Uremic Syndrome

Journal of the American Society of Nephrology ◽

10.1681/asn.2019040331 ◽

2019 ◽

Vol 30 (12) ◽

pp. 2449-2463 ◽

Cited By ~ 13

Author(s):

Julien Zuber ◽

Marie Frimat ◽

Sophie Caillard ◽

Nassim Kamar ◽

Philippe Gatault ◽

...

Keyword(s):

Cohort Study ◽

Hemolytic Uremic Syndrome ◽

Kidney Transplant ◽

Atypical Hemolytic Uremic Syndrome ◽

Population Based ◽

Adult Patients ◽

Transplant Recipients ◽

Risk Of Recurrence ◽

Atypical Hus ◽

Uremic Syndrome

BackgroundAtypical hemolytic uremic syndrome (HUS) is associated with high recurrence rates after kidney transplant, with devastating outcomes. In late 2011, experts in France recommended the use of highly individualized complement blockade–based prophylaxis with eculizumab to prevent post-transplant atypical HUS recurrence throughout the country.MethodsTo evaluate this strategy’s effect on kidney transplant prognosis, we conducted a retrospective multicenter study from a large French nationwide registry, enrolling all adult patients with atypical HUS who had undergone complement analysis and a kidney transplant since January 1, 2007. To assess how atypical HUS epidemiology in France in the eculizumab era evolved, we undertook a population-based cohort study that included all adult patients with atypical HUS (n=397) between 2007 and 2016.ResultsThe first study included 126 kidney transplants performed in 116 patients, 58.7% and 34.1% of which were considered to be at a high and moderate risk of atypical HUS recurrence, respectively. Eculizumab prophylaxis was used in 52 kidney transplants, including 39 at high risk of recurrence. Atypical HUS recurred after 43 (34.1%) of the transplants; in four cases, patients had received eculizumab prophylaxis and in 39 cases they did not. Use of prophylactic eculizumab was independently associated with a significantly reduced risk of recurrence and with significantly longer graft survival. In the second, population-based cohort study, the proportion of transplant recipients among patients with ESKD and atypical HUS sharply increased between 2012 and 2016, from 46.2% to 72.3%, and showed a close correlation with increasing eculizumab use among the transplant recipients.ConclusionsResults from this observational study are consistent with benefit from eculizumab prophylaxis based on pretransplant risk stratification and support the need for a rigorous randomized trial.

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HUS and atypical HUS

Blood ◽

10.1182/blood-2016-11-709865 ◽

2017 ◽

Vol 129 (21) ◽

pp. 2847-2856 ◽

Cited By ~ 102

Author(s):

T. Sakari Jokiranta

Keyword(s):

Shiga Toxin ◽

Complement Activation ◽

Cell Damage ◽

Gastrointestinal Infection ◽

Vicious Cycle ◽

Intravascular Hemolysis ◽

Endothelial Cell Damage ◽

Atypical Hus ◽

Uremic Syndrome ◽

The Common

Abstract Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by intravascular hemolysis, thrombocytopenia, and acute kidney failure. HUS is usually categorized as typical, caused by Shiga toxin–producing Escherichia coli (STEC) infection, as atypical HUS (aHUS), usually caused by uncontrolled complement activation, or as secondary HUS with a coexisting disease. In recent years, a general understanding of the pathogenetic mechanisms driving HUS has increased. Typical HUS (ie, STEC-HUS) follows a gastrointestinal infection with STEC, whereas aHUS is associated primarily with mutations or autoantibodies leading to dysregulated complement activation. Among the 30% to 50% of patients with HUS who have no detectable complement defect, some have either impaired diacylglycerol kinase ε (DGKε) activity, cobalamin C deficiency, or plasminogen deficiency. Some have secondary HUS with a coexisting disease or trigger such as autoimmunity, transplantation, cancer, infection, certain cytotoxic drugs, or pregnancy. The common pathogenetic features in STEC-HUS, aHUS, and secondary HUS are simultaneous damage to endothelial cells, intravascular hemolysis, and activation of platelets leading to a procoagulative state, formation of microthrombi, and tissue damage. In this review, the differences and similarities in the pathogenesis of STEC-HUS, aHUS, and secondary HUS are discussed. Common for the pathogenesis seems to be the vicious cycle of complement activation, endothelial cell damage, platelet activation, and thrombosis. This process can be stopped by therapeutic complement inhibition in most patients with aHUS, but usually not those with a DGKε mutation, and some patients with STEC-HUS or secondary HUS. Therefore, understanding the pathogenesis of the different forms of HUS may prove helpful in clinical practice.

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