scholarly journals The experience of using the Russian biosimilar of the original drug eculizumab for the treatment of patients with atypical hemolytic-uremic syndrome

2020 ◽  
Vol 92 (6) ◽  
pp. 76-80
Author(s):  
Yulia V. Lavrishcheva ◽  
Alexander A. Yakovenko ◽  
Dmitrii A. Kudlai
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Thrombotic Microangiopathy ◽  
High Efficiency ◽  
Systemic Disease ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Adult Patients ◽  
Alternative Complement Pathway ◽  
Complement Pathway ◽  
Alternative Complement ◽  
Uremic Syndrome

Atypical hemolytic-uremic syndrome (aHUS) is a chronic systemic disease of a genetic nature, which is based on uncontrolled activation of the alternative complement pathway, leading to generalized thrombosis in the vessels of the microvasculature (complement-mediated thrombotic microangiopathy). To date, therapy with eculizumab is the most effective and pathogenetically substantiated method of treating patients with ASH. Using the example of three clinical cases of patients with a verified diagnosis of aHUS, the high efficiency and safety of the worlds first bioanalogue of eculizumab in the treatment of adult patients with aHUS (complement-mediated thrombotic microangiopathy) was demonstrated.

ADAMTS13 Variants in Atypical Hemolytic Uremic Syndrome

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 490-490
Author(s):  
Shuju Feng ◽  
Stephen J. Eyler ◽  
Yuzhou Zhang ◽  
Tara K. Maga ◽  
Michael H. Kroll ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Genetic Variants ◽  
Functional Activity ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Alternative Complement Pathway ◽  
Hek293 Cells ◽  
Complement Pathway ◽  
Alternative Complement ◽  
Uremic Syndrome

Abstract Abstract 490 Atypical hemolytic uremic syndrome (aHUS) is a clinically defined thrombotic microangiopathic anemia (TMA) characterized by the symptom triad of renal failure, thrombocytopenia and microangiopathic hemolytic anemia in the absence of Shiga-toxin-producing bacteria as a triggering factor. Its pathogenesis is linked to dysregulation of the alternative pathway of the complement cascade, with loss-of-function mutations reported in complement regulators like factor H (CFH), membrane cofactor protein (MCP), factor I (CHI) and thrombomodulin (THBD), and gain-of-function mutations in complement activators like factor B (CFB) and complement component 3 (C3). In nearly 40% of patients, however, mutations are not identified in these genes raising the possibility of unrecognized contributory genetic causes. Genetic variants in ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motifs) have been causally related to thrombotic thrombocytopenic purpura (TTP), another TMA characterized by the pentad of neurologic symptoms, fever, kidney failure, thrombocytopenia and microangiopathichemolytic anemia. The phenotypic similarities between aHUS and TTP can at times lead to difficulty in their clinical distinction. On this basis, we hypothesized that partial deficiency in ADAMTS13 function may coexist with abnormalities in the alternative complement pathway in patients with aHUS. To test this hypothesis, we measured ADAMTS13 functional activity in 26 patients with aHUS by fluorescence resonance energy transfer substrate-von Willebrandfactor 73mer (FRETS-VWF73) and recombinant VWF A2 domain cleavage assay. We also genotyped all patients for ADAMTS13 and alternative complement pathway genes. We transiently expressed 10 different ADAMTS13 missense variants in HEK293 cells to analyze activity and secretion of each recombinant protein. The ADAMTS13 functional activity was partially reduced (< 60%) in serum from 20 patients (77%) as measured by FRETS-VWF73 and recombinant VWF A2 cleavage assays. Genetic variants in ADAMTS13 were identified in 21 patients (81%) and included R386C, Q448E, A900V, V832M, R1060W, R7W/Q448E, A900V/Q448E, R1096H/A747V, R7W/A1033T, R7W/P618A/Q448E, R7W/P618A/A900V/Q448E, R7W/P618A/A732V/Q448E. The coexistence of both ADAMTS13 deficiency and excessive complement functional activity was present in 13 patients (50%). Activity of recombinant ADAMTS13 proteins containing the following variants was normal: R386C, Q448E, P618A, A732V, A747V, V832M, A900V, A1033T and R1060H. The R1096H variant of ADAMTS13 was associated with a reduction in functional activity by 50%. The secretion of recombinant proteins with the following variants was severely reduced: P618A, R1060H (<1%), R386C, R1096H (<10%), and A1033T (<50%) (Figures 1 and 2). This study implicates ADAMTS13 in the pathogenesis of aHUS and mandates the evaluation of ADAMTS13 in aHUS patients. Defining the role of ADAMTS13 in aHUS may aid in the development of new treatments and/or assist in clarifying whether long-term treatment with currently available anti-complement therapy is required for this disease. Disclosures: Kroll: Aplagon: Membership on an entity's Board of Directors or advisory committees; Optimer: Consultancy; Leo: Honoraria, Travel Expenses, Travel Expenses Other.

Use of eculizumab in pregnancy-associated atypical hemolytic uremic syndrome

2018 ◽  
Vol 7 (1) ◽  
Author(s):  
Meenal Misal ◽  
Megha Gupta ◽  
Lawrence D. Platt ◽  
Neil S. Silverman ◽  
Christina S. Han
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Clinical Evaluation ◽  
Thrombotic Microangiopathy ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Complement Factor ◽  
Complement Inhibitor ◽  
Complement Pathway ◽  
Uremic Syndrome ◽  
Terminal Complement

Abstract Pregnancy-associated atypical hemolytic uremic syndrome (p-aHUS) is a rare disorder, with an estimated incidence of 1 in 25,000 pregnancies [Fakhouri F, Roumenina L, Provot F, Sallee M, Caillard S, Couzi L, et al. Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J Am Soc Nephrol. 2010;21:859–67.]. Unlike classic hemolytic uremic syndrome (HUS), aHUS is not related to Escherichia coli 0157:H7 infections. Rather, it arises from uncontrolled alternative complement pathway activation leading to diffuse endothelial damage. The formation of the resulting fibrin and platelet microthrombi in the vasculature leads to hemolysis, thrombocytopenia and ischemic end-organ damage in the form of acute kidney injury [Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676–87; Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368:2169–81; Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60; Shen YM. Clinical evaluation of thrombotic microangiopathy: identification of patients with suspected atypical hemolytic uremic syndrome. Thromb J. 2016;14(Suppl 1):19.]. Triggers for hyperactivation of the complement pathway include infection, inflammation, malignancy, endothelium-affecting drugs, maternal-fetal hemorrhage and pre-eclampsia [Shen YM. Clinical evaluation of thrombotic microangiopathy: identification of patients with suspected atypical hemolytic uremic syndrome. Thromb J. 2016;14(Suppl 1):19.]. Thirty percent of individuals with aHUS are found to have mutations in the genes encoding complement regulatory proteins, such as protein factor H, complement factor I and complement 3 [Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676–87; Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60.]. Outcomes of an untreated aHUS are poor: up to 50% of patients with aHUS progress to end-stage renal disease within a year and 25% die during the acute phase [Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60; Laurence J, Haller H, Mannucci PM, Nangaku M, Praga M, Rodriguez de Cordoba S. Atypical hemolytic uremic syndrome (aHUS): essential aspects of an accurate diagnosis. Clin Adv Hematol Oncol. 2016;14(Suppl 11):2–15.]. We present an unusual case of a 37-year-old primigravida who developed p-aHUS in the setting of hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. She was successfully treated with a relatively novel medication; eculizumab, a terminal complement inhibitor. In contrast to previous reports of long-term treatment, she received a total of six doses of eculizumab and remained in remission at 12 months postpartum.

scholarly journals Retrospective and Systematic Analysis of Causes and Outcomes of Thrombotic Microangiopathies in Routine Clinical Practice: An 11-Year Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Nicolas Henry ◽  
Chloé Mellaza ◽  
Nicolas Fage ◽  
François Beloncle ◽  
Franck Genevieve ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Hemolytic Uremic Syndrome ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Routine Clinical Practice ◽  
Complement Pathway ◽  
Thrombotic Microangiopathies ◽  
Thrombocytopenic Purpura ◽  
Multiple Factors ◽  
Alternative Complement ◽  
Uremic Syndrome

Background: Thrombotic microangiopathies (TMAs) are highly suspected in patients showing mechanical hemolytic anemia, thrombocytopenia, and haptoglobin consumption. Primary [thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome] and secondary TMA are considered. Even if ADAMTS13 measurements and alternative complement pathway explorations have greatly improved the ability to identify primary TMA, their diagnosis remains difficult, and their frequency relative to that of secondary TMA is undetermined. The objectives of the present study were, therefore, to describe the etiologies, management, and the outcomes of patients presenting with TMA in real-life clinical practice.Methods: We conducted a retrospective study between 01/01/2008 and 31/12/2018 that included all consecutive patients presenting with biological TMA syndrome at admission or developing during hospitalization. Patients were identified from the laboratory databases, and their medical files were reviewed to confirm TMA diagnosis, to determine etiology, and to analyze their therapeutic management and outcomes.Results: During this period, 239 patients with a full TMA biological syndrome were identified, and the TMA diagnosis was finally confirmed in 216 (90.4%) after the cases were reviewed. Primary TMAs (thrombotic thrombocytopenic purpura or atypical hemolytic uremic syndrome) were diagnosed in 20 of 216 patients (9.3%). Typical HUS was diagnosed in eight patients (3.7%), and the most frequent secondary TMAs were HELLP syndrome (79/216, 36.6%) and active malignancies (30/219, 13.9%). ADAMTS13 measurements and alternative complement pathway analyses were performed in a minority of patients. Multiple factors identified as TMA triggers were present in most patients, in 55% of patients with primary TMA, vs. 44.7% of patients with secondary TMA (p = 0.377). Death occurred in 57 patients (23.4%) during follow-up, and dialysis was required in 51 patients (23.6%). Active malignancies [odds ratio (OR) 13.7], transplantation (OR 4.43), male sex (OR 2.89), and older age (OR 1.07) were significantly associated with death.Conclusion: Secondary TMAs represent many TMA causes in patients presenting a full TMA biological syndrome during routine clinical practice. Multiple factors favoring TMA are present in about half of primary or secondary TMA. ADAMTS13 and complement pathway were poorly explored in our cohort. The risk of death is particularly high in patients with malignancies as compared with patients with other TMA.

scholarly journals Efficacy and safety of the long-acting C5 inhibitor ravulizumab in patients with atypical hemolytic uremic syndrome triggered by pregnancy: a subgroup analysis

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Anja Gäckler ◽  
Ulf Schönermarck ◽  
Vladimir Dobronravov ◽  
Gaetano La Manna ◽  
Andrew Denker ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Multicenter Trial ◽  
Efficacy And Safety ◽  
Meningococcal Infections ◽  
Phase 3 ◽  
Alternative Complement ◽  
Uremic Syndrome ◽  
Long Acting ◽  
Inhibitor Treatment

Abstract Background Atypical hemolytic uremic syndrome (aHUS) triggered by pregnancy is a rare disease caused by dysregulation of the alternative complement pathway that occurs in approximately 1 in 25,000 pregnancies. The 311 phase 3 trial (NCT02949128) showed that ravulizumab, a long-acting C5 inhibitor obtained through selective modifications to eculizumab, is efficacious in inhibiting complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. In this analysis, we report outcomes in a subgroup of patients from the 311 study who developed TMA postpartum. Methods This was a phase 3, multicenter trial evaluating efficacy and safety of ravulizumab in adults (≥18 years of age) with aHUS naïve to complement inhibitor treatment. The primary endpoint was complete TMA response (simultaneous platelet count normalization [≥150 × 109/L], lactate dehydrogenase normalization [≤246 U/L] and 25% improvement in serum creatinine) through the 183-day initial evaluation period. Additional efficacy endpoints included time to complete TMA response, hematologic normalization, and dialysis requirement status. Results Eight patients presenting with TMA postpartum (median age of 37.7 [range; 22.1–45.2] years) were diagnosed with aHUS and received ≥1 dose of ravulizumab. Five patients (63%) were on dialysis at baseline. Complete TMA response was achieved in 7/8 patients (87.5%) in a median time of 31.5 days. Hematologic normalization was observed in all patients. All patients on dialysis at baseline discontinued dialysis within 21 days after treatment with ravulizumab. All patients showed continued improvements in the estimated glomerular filtration rate from baseline to Day 183. Three possible treatment-related adverse events were observed in 2 patients (arthralgia and nasopharyngitis [both non-severe]; urinary tract infection). No deaths or meningococcal infections occurred. Conclusions Treatment with ravulizumab provided immediate and complete C5 inhibition, resulting in rapid clinical and laboratory improvements and complete TMA response through 183 days in patients with aHUS triggered by pregnancy. The safety profile observed in this subset of patients analysed is consistent with the 311 study investigating ravulizumab in patients with aHUS naïve to complement treatment. Trial registration Clinical trial identifier:NCT02949128.

scholarly journals Case Report: Lipoprotein Glomerulopathy Complicated by Atypical Hemolytic Uremic Syndrome

2021 ◽  
Vol 8 ◽  
Author(s):  
Lara Kollbrunner ◽  
Patricia Hirt-Minkowski ◽  
Javier Sanz ◽  
Elena Bresin ◽  
Thomas J. Neuhaus ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Complement Factor ◽  
Inherited Disease ◽  
Lipoprotein Glomerulopathy ◽  
Gene Encoding ◽  
Alternative Complement ◽  
Uremic Syndrome ◽  
The Complement System

Lipoprotein glomerulopathy (LPG) is a rare inherited disease caused by mutations in the APOE gene, encoding apolipoprotein E (apoE). Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) characterized by overactivation of the alternative complement pathway. Here we report the case of a 21-year-old man with LPG who developed aHUS. A functional complement assay demonstrated an overactivation of the complement system. Complementary genetic analysis revealed a homozygous aHUS risk allele for complement factor-H related 1 (CFHR1), CFHR1*B. To the best of our knowledge, this is the first report of an aHUS in a patient with LPG.

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

2019 ◽  
Vol 30 (12) ◽  
pp. 2449-2463 ◽  
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.

scholarly journals A Challenging Case of Atypical Hemolytic Uremic Syndrome in a Young African American Patient

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4225-4225
Author(s):  
Urwat Til Vusqa ◽  
Palash Asawa ◽  
Yazan Samhouri ◽  
Rama Bhagavatula ◽  
Robert B. Kaplan
Keyword(s):  
Blood Pressure ◽  
African American ◽  
Hemolytic Uremic Syndrome ◽  
Thrombotic Microangiopathy ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Malignant Hypertension ◽  
Coagulation Cascade ◽  
Complement Factors ◽  
Uremic Syndrome ◽  
Terminal Complement

Abstract Background It is known that malignant hypertension (mHTN) and thrombotic microangiopathy (TMA) commonly coexist. Deciding which phenomenon preceded the other remains a clinical dilemma, specifically in African American patients. However, making that determination is of utmost importance because the management will be different, and that can have dramatic effects on prognosis and outcomes. Herein, we report a case of atypical hemolytic uremic syndrome (aHUS) presenting as mHTN. Case Presentation A 35-year-old African American male with known history of hypertension, presented with nausea, vomiting, and diarrhea for four days. He also reported fatigue and exertional shortness of breath. Upon presentation, his blood pressure was 260/160 mmHg, otherwise physical exam was unremarkable. Initial work up showed hemoglobin of 8.8 g/dL (baseline 13.5), platelet count of 21,000/mL (baseline 250,000), serum creatinine of 16.99 mg/dL (baseline 0.99), MCV (84 fl), increased reticulocyte production index (3.58), increased LDH (1709 U/L), undetectable haptoglobin, and numerous schistocytes on peripheral blood smear. He was admitted as a case of hypertensive emergency and TMA. IV labetalol and hemodialysis were started. Given his gastrointestinal symptoms; stool for Shigella and E.Coli O157:H7 were checked and they were negative. Given the severity of his hematologic derangements and difficult to control blood pressure, we decided to proceed with renal biopsy to rule out primary aHUS which showed thrombotic microangiopathy, global glomerulosclerosis, moderate interstitial fibrosis and tubular atrophy suggestive of aHUS or rheumatologic disorders like systemic sclerosis and arguing against malignant HTN as the sole player. ANA and anti-Scl-70 antibodies were negative. Final impression was aHUS by exclusion, and patient received meningococcal vaccines (Menactra and Bexsero) in preparation to start eculizumab. aHUS genetic panel was sent which came back equivocal as it showed mutations of unknown significance (homozygous missense mutation in the MASP2 gene and 2 heterozygous mutations in the C2 gene). He was started on eculizumab 900 mg weekly for 4 weeks then 1200 mg biweekly starting week 5. He was seen in the office 2 months after initial presentation and receiving 5 doses of Eculizumab. His kidney function showed improvement with &gt; 2 liters of urine output daily, blood pressure was better controlled. A decision by nephrology was made to give him a break from dialysis and remains dialysis-free a year later. Discussion aHUS is a rare disorder with an estimated prevalence of seven per one million children in Europe. It causes uninhibited activation of complement factors that leads to renal endothelial damage and activation of coagulation cascade leading to TMA. The diagnosis of aHUS requires the fulfillment of the classical triad (microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure) with a positive gene mutation or antibodies to complement factors. However, absence of these mutations or antibodies, as in the presented case, do not exclude the diagnosis. The early diagnosis of aHUS is necessary for treatment with eculizumab, a monoclonal antibody against C5 to block the terminal complement cascade. Kidney biopsy can be helpful in equivocal cases especially if it shows only the typical changes of malignant hypertension which essentially rules out aHUS. Hypertension with concurrent TMA is treated with strict BP control which is often enough to resolve TMA features and restores renal function, at least partially. On the contrary, aHUS causing severe HTN needs more sophisticated testing and blockade of the terminal complement component to improve outcome; that's why the distinction of which one is the primary process is of utmost importance. Our case emphasizes the importance of having low threshold for testing for aHUS in patients with mHTN and TMA, especially in African American patients where malignant HTN is known to happen more commonly, and to notice the subtle hints that may help in this distinction, such as profound hemolysis or thrombocytopenia out of proportion to what one would expect from mHTN alone. Early recognition of aHUS may save a patient's kidney. Disclosures No relevant conflicts of interest to declare.

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