FIRST EXPERIENCE OF USING THE BIOSIMILAR OF ORIGINAL ECULIZUMAB FOR PREVENTION OF ATYPICAL HEMOLYTIC-UREMIC SYNDROME RECURRENCE AFTER RENAL TRANSPLANTATION IN A CHILD

2021 ◽  
Vol 100 (1) ◽  
pp. 293-296
Author(s):  
S.V. Baiko ◽  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Molecular Genetic ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Disease Recurrence ◽  
Regulatory Proteins ◽  
Molecular Genetic Study ◽  
Complement Regulatory Proteins ◽  
Before And After ◽  
Uremic Syndrome ◽  
End Stage

The article presents a clinical case of atypical hemolytic uremic syndrome (аHUS), the debut of which proceeded under the guise of a typical HUS. After 4 months of hemodialysis, the child did not need renal replacement therapy for the next 9 months. The development of end-stage renal failure required a molecular genetic study to clarify the diagnosis. The child has mutations in the genes of the complement regulatory proteins – factor I and MCP. The risk of aHUS recurrence with these genes mutations to a renal transplant without pathogenetic prophylaxis is up to 80%. The use of the Russian biosimilar eculizumab before and after kidney transplantation allowed to prevent the activation of complement and disease recurrence to transplanted organ.

scholarly journals Pediatric Atypical Hemolytic Uremic Syndrome Advances

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3580
Author(s):  
Rupesh Raina ◽  
Nina Vijayvargiya ◽  
Amrit Khooblall ◽  
Manasa Melachuri ◽  
Shweta Deshpande ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Regulatory Proteins ◽  
High Rate ◽  
Complement Factor ◽  
Mortality And Morbidity ◽  
Complement Regulatory Proteins ◽  
Alternate Pathway ◽  
Uremic Syndrome

Atypical hemolytic uremic syndrome (aHUS) is a rare disorder characterized by dysregulation of the alternate pathway. The diagnosis of aHUS is one of exclusion, which complicates its early detection and corresponding intervention to mitigate its high rate of mortality and associated morbidity. Heterozygous mutations in complement regulatory proteins linked to aHUS are not always phenotypically active, and may require a particular trigger for the disease to manifest. This list of triggers continues to expand as more data is aggregated, particularly centered around COVID-19 and pediatric vaccinations. Novel genetic mutations continue to be identified though advancements in technology as well as greater access to cohorts of interest, as in diacylglycerol kinase epsilon (DGKE). DGKE mutations associated with aHUS are the first non-complement regulatory proteins associated with the disease, drastically changing the established framework. Additional markers that are less understood, but continue to be acknowledged, include the unique autoantibodies to complement factor H and complement factor I which are pathogenic drivers in aHUS. Interventional therapeutics have undergone the most advancements, as pharmacokinetic and pharmacodynamic properties are modified as needed in addition to their as biosimilar counterparts. As data continues to be gathered in this field, future advancements will optimally decrease the mortality and morbidity of this disease in children.

scholarly journals Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome

Blood ◽  
2006 ◽  
Vol 108 (4) ◽  
pp. 1267-1279 ◽  
Author(s):  
Jessica Caprioli ◽  
Marina Noris ◽  
Simona Brioschi ◽  
Gaia Pianetti ◽  
Federica Castelletti ◽  
...  
Keyword(s):  
Disease Recurrence ◽  
Factor H ◽  
Response To Therapy ◽  
Regulatory Proteins ◽  
Response To Treatment ◽  
Complement Factor ◽  
Genetic Studies ◽  
Complement Regulatory Proteins ◽  
Uremic Syndrome ◽  
The Impact

Abstract Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy with manifestations of hemolytic anemia, thrombocytopenia, and renal impairment. Genetic studies have shown that mutations in complement regulatory proteins predispose to non–Shiga toxin–associated HUS (non-Stx–HUS). We undertook genetic analysis on membrane cofactor protein (MCP), complement factor H (CFH), and factor I (IF) in 156 patients with non-Stx–HUS. Fourteen, 11, and 5 new mutational events were found in MCP, CFH, and IF, respectively. Mutation frequencies were 12.8%, 30.1%, and 4.5% for MCP, CFH, and IF, respectively. MCP mutations resulted in either reduced protein expression or impaired C3b binding capability. MCP-mutated patients had a better prognosis than CFH-mutated and nonmutated patients. In MCP-mutated patients, plasma treatment did not impact the outcome significantly: remission was achieved in around 90% of both plasma-treated and plasma-untreated acute episodes. Kidney transplantation outcome was favorable in patients with MCP mutations, whereas the outcome was poor in patients with CFH and IF mutations due to disease recurrence. This study documents that the presentation, the response to therapy, and the outcome of the disease are influenced by the genotype. Hopefully this will translate into improved management and therapy of patients and will provide the way to design tailored treatments.

scholarly journals Acute Progression of Adult-Onset Atypical Hemolytic-Uremic Syndrome due to CFH Mutation: A Case Report

2013 ◽  
Vol 2013 ◽  
pp. 1-4
Author(s):  
Bartlomiej Posnik ◽  
Dorota Sikorska ◽  
Krzysztof Hoppe ◽  
Krzysztof Schwermer ◽  
Krzysztof Pawlaczyk ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Late Onset ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Genetic Mutation ◽  
Current Data ◽  
Factor H ◽  
Rapid Progression ◽  
Uremic Syndrome ◽  
Stage Renal Disease ◽  
End Stage

Atypical hemolytic-uremic syndrome (aHUS), unlike typical HUS, is not due to bacteria but rather to an idiopathic or genetic cause that promotes dysregulation of the alternative complement pathway. It leads to hemolytic anemia, thrombocytopenia, and renal impairment. Although aHUS secondary to a genetic mutation is relatively rare, when occurring due to a mutation in Factor H (CFH), it usually presents with younger onset and has a more severe course, which in the majority ends with end-stage renal failure. Paradoxically to most available data, our case features acute aHUS due to a CFH mutation with late onset (38-year-old) and rapid progression to end-stage renal disease. Due to current data indicating a high risk of graft failure in such patients, the diagnosis of aHUS secondary to a genetic cause has disqualified our patient from a living (family) donor renal transplantation and left her with no other option but to begin permanent renal replacement therapy.

scholarly journals Atypical Hemolytic Uremic Syndrome Successfully Treated with Eculizumab

2020 ◽  
Vol 95 (2) ◽  
pp. 124-128
Author(s):  
Jung Hyun Kim ◽  
Won Kyung Han ◽  
Yu Bum Choi ◽  
Hyung Jong Kim ◽  
Jisu Oh ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
End Stage Renal Disease ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Delayed Diagnosis ◽  
Membrane Attack Complex ◽  
Acute Renal Injury ◽  
Humanized Monoclonal Antibody ◽  
Uremic Syndrome ◽  
Stage Renal Disease ◽  
End Stage

Atypical hemolytic uremic syndrome (aHUS) is a rare syndrome characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal injury, which results from uncontrolled complement activation. Delayed diagnosis and treatment of aHUS may result in end-stage renal disease (ESRD) and an associated dependence on dialysis. In extreme cases, it may cause death due to multi-organ failure. Eculizumab, a humanized monoclonal antibody against C5, inhibits the formation of the terminal membrane attack complex and is used to treat aHUS. Here, we report a 46-year-old male patient who suffered from aHUS relapse, despite prior treatment with repeated plasma exchange and hemodialysis. Eculizumab therapy improved his hematologic findings without use of hemodialysis.

scholarly journals Mapping interactions between complement C3 and regulators using mutations in atypical hemolytic uremic syndrome

Blood ◽  
2015 ◽  
Vol 125 (15) ◽  
pp. 2359-2369 ◽  
Author(s):  
Elizabeth C. Schramm ◽  
Lubka T. Roumenina ◽  
Tania Rybkine ◽  
Sophie Chauvet ◽  
Paula Vieira-Martins ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Binding Sites ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Regulatory Proteins ◽  
Complement C3 ◽  
Renal Outcome ◽  
Protein Surface ◽  
Complement Regulation ◽  
Key Points ◽  
Uremic Syndrome

Key Points C3 mutations in aHUS commonly result in impaired complement regulation, C3 consumption, and a poor renal outcome. C3 mutations tend to cluster at the protein surface and facilitate mapping of putative binding sites for the regulatory proteins.

scholarly journals Complement in hemolytic anemia

Blood ◽  
2015 ◽  
Vol 126 (22) ◽  
pp. 2459-2465 ◽  
Author(s):  
Robert A. Brodsky
Keyword(s):  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Reticuloendothelial System ◽  
Immunoglobulin M ◽  
Regulatory Proteins ◽  
Cold Agglutinin Disease ◽  
Complement Regulatory Proteins ◽  
Uremic Syndrome ◽  
Alternative Pathway Of Complement

Abstract Complement is increasingly being recognized as an important driver of human disease, including many hemolytic anemias. Paroxysmal nocturnal hemoglobinuria (PNH) cells are susceptible to hemolysis because of a loss of the complement regulatory proteins CD59 and CD55. Patients with atypical hemolytic uremic syndrome (aHUS) develop a thrombotic microangiopathy (TMA) that in most cases is attributable to mutations that lead to activation of the alternative pathway of complement. For optimal therapy, it is critical, but often difficult, to distinguish aHUS from other TMAs, such as thrombotic thrombocytopenic purpura; however, novel bioassays are being developed. In cold agglutinin disease (CAD), immunoglobulin M autoantibodies fix complement on the surface of red cells, resulting in extravascular hemolysis by the reticuloendothelial system. Drugs that inhibit complement activation are increasingly being used to treat these diseases. This article discusses the pathophysiology, diagnosis, and therapy for PNH, aHUS, and CAD.

scholarly journals Pregnancy-triggered atypical hemolytic uremic syndrome (aHUS): a Global aHUS Registry analysis

2021 ◽  
Author(s):  
Fadi Fakhouri ◽  
Marie Scully ◽  
Gianluigi Ardissino ◽  
Imad Al-Dakkak ◽  
Benjamin Miller ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Clinical Characteristics ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Complement Factor ◽  
Childbearing Age ◽  
History Of ◽  
Uremic Syndrome ◽  
Stage Renal Disease ◽  
End Stage

Abstract Background Atypical hemolytic uremic syndrome (aHUS) is a rare disease in which uncontrolled terminal complement activation leads to systemic thrombotic microangiopathy (TMA). Pregnancy can trigger aHUS and, without complement inhibition, many women with pregnancy-triggered aHUS (p-aHUS) progress to end-stage renal disease (ESRD) with a high risk of morbidity. Owing to relatively small patient numbers, published characterizations of p-aHUS have been limited, thus the Global aHUS Registry (NCT01522183, April 2012) provides a unique opportunity to analyze data from a large single cohort of women with p-aHUS. Methods The demographics and clinical characteristics of women with p-aHUS (n = 51) were compared with those of women of childbearing age with aHUS and no identified trigger (non-p-aHUS, n = 397). Outcome evaluations, including renal survival according to time to ESRD, were compared for patients with and without eculizumab treatment (a complement C5 inhibitor) in both aHUS groups. Results Baseline demographics and clinical characteristics were broadly similar in both groups. The proportion of women with p-aHUS and non-p-aHUS with pathogenic variant(s) in complement genes and/or anti-complement factor H antibodies was similar (45% and 43%, respectively), as was the proportion with a family history of aHUS (12% and 13%, respectively). Eculizumab treatment led to significantly improved renal outcomes in women with aHUS, regardless of whether aHUS was triggered by pregnancy or not: adjusted hazard ratio for time to ESRD was 0.06 (p = 0.006) in the p-aHUS group and 0.20 (p < 0.0001) in the non-p-aHUS group. Conclusion Findings from this study support the characterization of p-aHUS as a complement-mediated TMA. Graphic abstract

scholarly journals New perspectives on the approach to patients with atypical Hemolytic Uremic Syndrome candidates for renal transplantation

2021 ◽  
Vol 35 (3) ◽  
Author(s):  
Ana Figueiredo ◽  
◽  
Nuno Oliveira ◽  
Catarina Romãozinho ◽  
Helena Sá ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Renal Transplantation ◽  
Hemolytic Uremic Syndrome ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Recurrence Risk ◽  
End Stage Kidney Disease ◽  
Post Transplant ◽  
Complement Dysregulation ◽  
Uremic Syndrome ◽  
End Stage

Atypical hemolytic uremic syndrome (aHUS) is one of the most challenging diseases for a nephrologist, with high rates of progression to end- -stage kidney disease (ESKD) and post-transplant recurrence. Complement dysregulation has been found in up to 70% of cases, which can be hereditary or acquired. Over the last few years, knowledge of the pathogenesis of aHUS has greatly increased, with the unravelling of the complement’s role, providing not only the chance for individualized post-transplant recurrence risk assessment, but also the possibility of a highly effective treatment through pharmacological C5-9 blockade with eculizumab. The overall outcome and prognosis of patients with aHUS has dramatically improved since the approval of this drug in 2011, allowing renal transplant to be a much safer option for these patients. Our aim was to present a proposal for the management of patients with aHUS, candidates for renal transplantation, in the light of the most recent studies.

scholarly journals Complement in hemolytic anemia

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 385-391 ◽  
Author(s):  
Robert A. Brodsky
Keyword(s):  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Reticuloendothelial System ◽  
Immunoglobulin M ◽  
Regulatory Proteins ◽  
Cold Agglutinin Disease ◽  
Complement Regulatory Proteins ◽  
Uremic Syndrome ◽  
Alternative Pathway Of Complement

Abstract Complement is increasingly being recognized as an important driver of human disease, including many hemolytic anemias. Paroxysmal nocturnal hemoglobinuria (PNH) cells are susceptible to hemolysis because of a loss of the complement regulatory proteins CD59 and CD55. Patients with atypical hemolytic uremic syndrome (aHUS) develop a thrombotic microangiopathy (TMA) that in most cases is attributable to mutations that lead to activation of the alternative pathway of complement. For optimal therapy, it is critical, but often difficult, to distinguish aHUS from other TMAs, such as thrombotic thrombocytopenic purpura; however, novel bioassays are being developed. In cold agglutinin disease (CAD), immunoglobulin M autoantibodies fix complement on the surface of red cells, resulting in extravascular hemolysis by the reticuloendothelial system. Drugs that inhibit complement activation are increasingly being used to treat these diseases. This article discusses the pathophysiology, diagnosis, and therapy for PNH, aHUS, and CAD.

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