|
1
|
Wei X, Liu X, Yu Y, Xie W, Luo W, Tu Y, Bu S, Guo G. Application of eculizumab, a terminal complement inhibitor, in the management of atypical hemolytic uremic syndrome in a 14-month-old Chinese pediatric patient: a case report. Front Pediatr 2024; 12:1404725. [PMID: 39144472 PMCID: PMC11322081 DOI: 10.3389/fped.2024.1404725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 07/16/2024] [Indexed: 08/16/2024] Open
Abstract
Eculizumab, a recombined humanized monoclonal antibody which possesses high affinity for the complement protein C5, is a therapeutic agent utilized in the treatment of atypical hemolytic uremic syndrome (aHUS) by inhibiting the terminal complement complex C5b-9. In a pediatric patient with aHUS of 14 months, the administration of eculizumab therapy was accompanied by the inclusion of meningococcal vaccine as part of the national immunization program. Notably, no other antibiotics were administered prior to or during the course of eculizumab treatment. Moreover, there were no occurrences of infusion reactions or meningococcal infections observed throughout the course of treatment. Due to the presence of anti-factor H antibodies and insufficient recovery, glucocorticoids and eculizumab were administered at week 0 and week 1, followed by the initiation of mycophenolate mofetil (MMF) at a dosage of 250 mg (approximately 548 mg/m2) per day starting from Day 10. Due to the recovered of complement antibody after 8 doses of eculizumab, the therapeutic interval was extended from once every 3 weeks to once a month since 9th administration. We experienced and successfully treated a rare case of aHUS with eculizumab in a 14-month-old Chinese pediatric patient.
Collapse
Affiliation(s)
- Xin Wei
- Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xinzhu Liu
- Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yingying Yu
- Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Wei Xie
- Department of Pediatric Intensive Care Unit, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wentao Luo
- Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ye Tu
- Department of Pharmacy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shuhong Bu
- Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Guimei Guo
- Department of Pediatric Nephrology, Rheumatology and Immunology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| |
Collapse
|
|
2
|
Fakhouri F, Schwotzer N, Frémeaux-Bacchi V. How I diagnose and treat atypical hemolytic uremic syndrome. Blood 2023; 141:984-995. [PMID: 36322940 DOI: 10.1182/blood.2022017860] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 09/19/2022] [Accepted: 10/12/2022] [Indexed: 11/06/2022] Open
Abstract
Our understanding and management of atypical hemolytic uremic syndrome (aHUS) have dramatically improved in the last decade. aHUS has been established as a prototypic disease resulting from a dysregulation of the complement alternative C3 convertase. Subsequently, prospective nonrandomized studies and retrospective series have shown the efficacy of C5 blockade in the treatment of this devastating disease. C5 blockade has become the cornerstone of the treatment of aHUS. This therapeutic breakthrough has been dulled by persistent difficulties in the positive diagnosis of aHUS, and the latter remains, to date, a diagnosis by exclusion. Furthermore, the precise spectrum of complement-mediated renal thrombotic microangiopathy is still a matter of debate. Nevertheless, long-term management of aHUS is increasingly individualized and lifelong C5 blockade is no longer a paradigm that applies to all patients with this disease. The potential benefit of complement blockade in other forms of HUS, notably secondary HUS, remains uncertain.
Collapse
Affiliation(s)
- Fadi Fakhouri
- Department of Medicine, Service of Nephrology and Hypertension, Lausanne University Hospital and Université de Lausanne, Lausanne, Switzerland
| | - Nora Schwotzer
- Department of Medicine, Service of Nephrology and Hypertension, Lausanne University Hospital and Université de Lausanne, Lausanne, Switzerland
| | - Véronique Frémeaux-Bacchi
- Laboratory of Immunology, Paris University, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Paris, France
| |
Collapse
|
|
3
|
Abstract
Dysregulation and accelerated activation of the alternative pathway (AP) of complement is known to cause or accentuate several pathologic conditions in which kidney injury leads to the appearance of hematuria and proteinuria and ultimately to the development of chronic renal failure. Multiple genetic and acquired defects involving plasma- and membrane-associated proteins are probably necessary to impair the protection of host tissues and to confer a significant predisposition to AP-mediated kidney diseases. This review aims to explore how our current understanding will make it possible to identify the mechanisms that underlie AP-mediated kidney diseases and to discuss the available clinical evidence that supports complement-directed therapies. Although the value of limiting uncontrolled complement activation has long been recognized, incorporating complement-targeted treatments into clinical use has proved challenging. Availability of anti-complement therapy has dramatically transformed the outcome of atypical hemolytic uremic syndrome, one of the most severe kidney diseases. Innovative drugs that directly counteract AP dysregulation have also opened new perspectives for the management of other kidney diseases in which complement activation is involved. However, gained experience indicates that the choice of drug should be tailored to each patient's characteristics, including clinical, histologic, genetic, and biochemical parameters. Successfully treating patients requires further research in the field and close collaboration between clinicians and researchers who have special expertise in the complement system.
Collapse
Affiliation(s)
- Erica Daina
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Monica Cortinovis
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| |
Collapse
|
|
4
|
Complement System as a New Target for Hematopoietic Stem Cell Transplantation-Related Thrombotic Microangiopathy. Pharmaceuticals (Basel) 2022; 15:ph15070845. [PMID: 35890144 PMCID: PMC9325021 DOI: 10.3390/ph15070845] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/04/2022] [Accepted: 07/05/2022] [Indexed: 02/07/2023] Open
Abstract
Thrombotic microangiopathy (TMA) is a complication that may occur after autologous or allogeneic hematopoietic stem cell transplantation (HSCT) and is conventionally called transplant-associated thrombotic microangiopathy (TA-TMA). Despite the many efforts made to understand the mechanisms of TA-TMA, its pathogenesis is largely unknown, its diagnosis is challenging and the case-fatality rate remains high. The hallmarks of TA-TMA, as for any TMA, are platelet consumption, hemolysis, and organ dysfunction, particularly the kidney, leading also to hypertension. However, coexisting complications, such as infections and/or immune-mediated injury and/or drug toxicity, together with the heterogeneity of diagnostic criteria, render the diagnosis difficult. During the last 10 years, evidence has been provided on the involvement of the complement system in the pathophysiology of TA-TMA, supported by functional, genetic, and therapeutic data. Complement dysregulation is believed to collaborate with other proinflammatory and procoagulant factors to cause endothelial injury and consequent microvascular thrombosis and tissue damage. However, data on complement activation in TA-TMA are not sufficient to support a systematic use of complement inhibition therapy in all patients. Thus, it seems reasonable to propose complement inhibition therapy only to those patients exhibiting a clear complement activation according to the available biomarkers. Several agents are now available to inhibit complement activity: two drugs have been successfully used in TA-TMA, particularly in pediatric cases (eculizumab and narsoplimab) and others are at different stages of development (ravulizumab, coversin, pegcetacoplan, crovalimab, avacopan, iptacopan, danicopan, BCX9930, and AMY-101).
Collapse
|
|
5
|
Fakhouri F, Schwotzer N, Golshayan D, Frémeaux-Bacchi V. The Rational Use of Complement Inhibitors in Kidney Diseases. Kidney Int Rep 2022; 7:1165-1178. [PMID: 35685323 PMCID: PMC9171628 DOI: 10.1016/j.ekir.2022.02.021] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/15/2022] [Accepted: 02/21/2022] [Indexed: 12/14/2022] Open
Abstract
The development of complement inhibitors represented one of the major breakthroughs in clinical nephrology in the last decade. Complement inhibition has dramatically transformed the outcome of one of the most severe kidney diseases, the atypical hemolytic uremic syndrome (aHUS), a prototypic complement-mediated disorder. The availability of complement inhibitors has also opened new promising perspectives for the management of several other kidney diseases in which complement activation is involved to a variable extent. With the rapidly growing number of complement inhibitors tested in a rapidly increasing number of indications, a rational use of this innovative and expensive new therapeutic class has become crucial. The present review aims to summarize what we know, and what we still ignore, regarding complement activation and therapeutic inhibition in kidney diseases. It also provides some clues and elements of thoughts for a rational approach of complement modulation in kidney diseases.
Collapse
Affiliation(s)
- Fadi Fakhouri
- Service de Néphrologie et d'hypertension, Département de Médecine, Centre Hospitalier Universitaire Vaudois (CHUV), Université de Lausanne, Lausanne, Switzerland
| | - Nora Schwotzer
- Service de Néphrologie et d'hypertension, Département de Médecine, Centre Hospitalier Universitaire Vaudois (CHUV), Université de Lausanne, Lausanne, Switzerland
| | - Déla Golshayan
- Centre de Transplantation d'organes, Département de Médecine, Centre Hospitalier Universitaire Vaudois (CHUV), Université de Lausanne, Lausanne, Switzerland
| | - Véronique Frémeaux-Bacchi
- Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d'Immunologie, Paris University, Paris, France
| |
Collapse
|
|
6
|
Complement gene variant effect on relapse of complement-mediated thrombotic microangiopathy after eculizumab cessation. Blood Adv 2022; 7:340-350. [PMID: 35533258 PMCID: PMC9881046 DOI: 10.1182/bloodadvances.2021006416] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 04/08/2022] [Accepted: 04/08/2022] [Indexed: 02/01/2023] Open
Abstract
Eculizumab is effective for complement-mediated thrombotic microangiopathy (CM-TMA), also known as atypical hemolytic uremic syndrome. Although lifelong therapy had been suggested, discontinuation does not universally lead to relapse. Comprehensive data evaluating risk factors for recurrence following discontinuation are limited. Our aim was to systematically review available literature assessing the role of complement genetic variants in this setting. Reports on CM-TMA and eculizumab withdrawal published before 1 January 2021, were included. Key reasons for patient exclusion were no follow-up after drug withdrawal and patients lacking complement genetic testing. Two-hundred eighty patients from 40 publications were included. Median age was 28 years, and 25 patients had a known history of renal transplant. Complement genetic variants were identified in 60%, most commonly in CFH (n = 59) and MCP/CD46 (n = 38). Of patients with a complement gene variant, 51.3% had ≥1 likely pathogenic/pathogenic variant whereas the remaining had variants of uncertain significance (VUS). Overall relapse rate after therapy discontinuation was 29.6%. Relapse rate was highest among patients with CFH variants and MCP/CD46 variants in canonical splice regions. VUS (P < .001) and likely pathogenic/pathogenic variants (P < .001) were associated with increased relapse. Presence of a renal allograft (P = .009); decreasing age (P = .029); and detection of variants in CFH (P < .001), MCP/CD46 (P < .001), or C3 (P < .001) were all independently associated with relapse after eculizumab discontinuation. Eculizumab discontinuation is appropriate in specific patients with CM-TMA. Caution should be exerted when attempting such a strategy in patients with high risk of recurrence, including a subgroup of patients with MCP/CD46 variants.
Collapse
|
|
7
|
Ravulizumab: Characterization and quantitation of a new C5 inhibitor using isotype specific affinity purification and high-resolution mass spectrometry. J Mass Spectrom Adv Clin Lab 2021; 21:10-18. [PMID: 34820672 PMCID: PMC8601004 DOI: 10.1016/j.jmsacl.2021.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 08/02/2021] [Accepted: 08/05/2021] [Indexed: 11/23/2022] Open
Abstract
Introduction Ravulizumab (RAVUL) is a new complement inhibitor, with a difference of 4 amino acids in the heavy chain from a predecessor compound, eculizumab (ECUL). Objectives First, to utilize mass spectrometry (MS) to characterize RAVUL and verify differences from its predecessor and, second, to validate and implement a lab developed test (LDT) for RAVUL that will allow for quantitative therapeutic monitoring. Methods A time-of-flight mass spectrometer (TOF-MS) was used to characterize and differentiate the molecular weight differences between RAVUL and ECUL by both digest and reduction experiments. In parallel, an LDT for RAVUL was validated and implemented utilizing IgG4 enrichment with light chain detection and quantitation on a high throughput orbitrap MS platform. Results The TOF-MS platform allowed for the mass difference between RAVUL and ECUL to be verified along with providing a proof of concept for a new intact protein quantitation software. An LDT on an orbitrap MS was validated and implemented using intact light chain quantitation, with the limitation that it cannot differentiate between ECUL and RAVUL. The LDT has an analytical measuring range from 5 to 600 mcg/mL, inter-assay imprecision of ≤13% CV (n = 13) and accuracy with <4% error from expected values (n = 20). Conclusion The TOF-MS is a versatile development platform that can be used to characterize and verify the molecular weight differences between the ECUL and RAVUL heavy chains. Routine laboratory testing for RAVUL was viable using an orbitrap-MS to quantitate using the mass of the intact light chain. These two platforms, combined, provide incomparable value in development of LDTs for the clinical laboratory.
Collapse
Key Words
- AMR, analytical measuring range
- C5, complement component 5
- DTT, dithiothreitol
- Da, daltons
- ECUL, eculizumab
- Eculizumab
- Fc, crystallizable fragment
- HPLC, high performance liquid chromatography
- IRB, Institutional Review Board
- IS, internal standard
- Intact light chain
- LC, liquid chromatography
- LDT, lab-developed test
- LLOD, lower limit of detection
- LLOQ, lower limit of quantitation
- LOB, limit of blankMS, mass spectrometry
- MW, molecular weight
- Mass spectrometry
- NHS, normal human serum
- NIVOL, nivolumab
- Orbitrap
- PBS, phosphate buffered saline
- PNH, paroxysmal nocturnal hemoglobinuria
- Q-TOF, quadrupole time-of-flight
- RAVUL, ravulizumab
- Ravulizumab
- Therapeutic monoclonal antibody
- Time of flight
- XIC, extracted ion chromatogram
- aHUS, atypical hemolytic uremic syndrome
- t-mAb, therapeutic monoclonal antibody
Collapse
|
|
8
|
Fakhouri F, Frémeaux-Bacchi V. Thrombotic microangiopathy in aHUS and beyond: clinical clues from complement genetics. Nat Rev Nephrol 2021; 17:543-553. [PMID: 33953366 DOI: 10.1038/s41581-021-00424-4] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/23/2021] [Indexed: 02/02/2023]
Abstract
Studies of complement genetics have changed the landscape of thrombotic microangiopathies (TMAs), particularly atypical haemolytic uraemic syndrome (aHUS). Knowledge of complement genetics paved the way for the design of the first specific treatment for aHUS, eculizumab, and is increasingly being used to aid decisions regarding discontinuation of anti-complement treatment in this setting. Complement genetic studies have also been used to investigate the pathogenic mechanisms that underlie other forms of HUS and provided evidence that contributed to the reclassification of pregnancy- and postpartum-associated HUS within the spectrum of complement-mediated aHUS. By contrast, complement genetics has not provided definite evidence of a link between constitutional complement dysregulation and secondary forms of HUS. Therefore, the available data do not support systematic testing of complement genes in patients with typical HUS or secondary HUS. The potential relevance of complement genetics for distinguishing the underlying mechanisms of malignant hypertension-associated TMA should be assessed with caution owing to the overlap between aHUS and other causes of malignant hypertension. In all cases, the interpretation of complement genetics results remains complex, as even complement-mediated aHUS is not a classical monogenic disease. Such interpretation requires the input of trained geneticists and experts who have a comprehensive view of complement biology.
Collapse
Affiliation(s)
- Fadi Fakhouri
- Service of Nephrology and Hypertension, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
| | - Véronique Frémeaux-Bacchi
- Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d'Immunologie, Paris, France
| |
Collapse
|
|
9
|
Outcomes of a clinician-directed protocol for discontinuation of complement inhibition therapy in atypical hemolytic uremic syndrome. Blood Adv 2021; 5:1504-1512. [PMID: 33683339 DOI: 10.1182/bloodadvances.2020003175] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 01/07/2021] [Indexed: 10/22/2022] Open
Abstract
Terminal complement inhibition is the standard of care for atypical hemolytic uremic syndrome (aHUS). The optimal duration of complement inhibition is unknown, although indefinite therapy is common. Here, we present the outcomes of a physician-directed eculizumab discontinuation and monitoring protocol in a prospective cohort of 31 patients that started eculizumab for acute aHUS (and without a history of renal transplant). Twenty-five (80.6%) discontinued eculizumab therapy after a median duration on therapy of 2.37 (interquartile range: 1.06, 9.70) months. Eighteen patients discontinued per protocol and 7 because of nonadherence. Of these, 5 (20%) relapsed; however, relapse rate was higher in the case of nonadherence (42.8%) vs clinician-directed discontinuation and monitoring (11.1%). Four of 5 patients who relapsed were successfully retreated without a decline in renal function. One patient died because of recurrent aHUS and hypertensive emergency in the setting of nonadherence. Nonadherence to therapy (odds ratio, 8.25; 95% confidence interval, 1.02-66.19; P = .047) was associated with relapse, whereas the presence of complement gene variants (odds ratio, 1.39; 95% confidence interval, 0.39-4.87; P = .598) was not significantly associated with relapse. Relapse occurred in 40% (2 of 5) with a CFH or MCP variant, 33.3% (2 of 6) with other complement variants, and 0% (0 of 6) with no variants (P = .217). There was no decline in mean glomerular filtration rate from the date of stopping eculizumab until end of follow-up. In summary, eculizumab discontinuation with close monitoring is safe in most patients, with low rates of aHUS relapse and effective salvage with eculizumab retreatment in the event of recurrence.
Collapse
|
|
10
|
Eculizumab discontinuation in children and adults with atypical hemolytic-uremic syndrome: a prospective multicenter study. Blood 2021; 137:2438-2449. [PMID: 33270832 DOI: 10.1182/blood.2020009280] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 11/23/2020] [Indexed: 12/21/2022] Open
Abstract
The optimal duration of eculizumab treatment in patients with atypical hemolytic uremic syndrome (aHUS) remains poorly defined. We conducted a prospective national multicenter open-label study to assess eculizumab discontinuation in children and adults with aHUS. Fifty-five patients (including 19 children) discontinued eculizumab (mean treatment duration, 16.5 months). Twenty-eight patients (51%) had rare variants in complement genes, mostly in MCP (n = 12; 22%), CFH (n = 6; 11%), and CFI (n = 6; 10%). At eculizumab discontinuation, 17 (30%) and 4 patients (7%) had stage 3 and 4 chronic kidney disease, respectively. During follow-up, 13 patients (23%; 6 children and 7 adults) experienced aHUS relapse. In multivariable analysis, female sex and presence of a rare variant in a complement gene were associated with an increased risk of aHUS relapse, whereas requirement for dialysis during a previous episode of acute aHUS was not. In addition, increased sC5b-9 plasma level at eculizumab discontinuation was associated with a higher risk of aHUS relapse in all patients and in the subset of carriers with a complement gene rare variant, both by log-rank test and in multivariable analysis. Of the 13 relapsing patients, all of whom restarted eculizumab, 11 regained their baseline renal function and 2 had a worsening of their preexisting chronic kidney disease, including 1 patient who progressed to end-stage renal disease. A strategy of eculizumab discontinuation in aHUS patients based on complement genetics is reasonable and safe. It improves the management and quality of life of a sizeable proportion of aHUS patients while reducing the cost of treatment. This trial was registered at www.clinicaltrials.gov as #NCT02574403.
Collapse
|
|
11
|
Risk of Atypical HUS Among Family Members of Patients Carrying Complement Regulatory Gene Abnormality. Kidney Int Rep 2021; 6:1614-1621. [PMID: 34169201 PMCID: PMC8207326 DOI: 10.1016/j.ekir.2021.03.885] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 03/08/2021] [Accepted: 03/15/2021] [Indexed: 01/06/2023] Open
Abstract
Introduction Atypical hemolytic uremic syndrome (aHUS) is mainly due to complement regulatory gene abnormalities with a dominant pattern but incomplete penetrance. Thus, healthy carriers can be identified in any family of aHUS patients, but it is unpredictable if they will eventually develop aHUS. Methods Patients are screened for 10 complement regulatory gene abnormalities and once a genetic alteration is identified, the search is extended to at-risk family members. The present cohort study includes 257 subjects from 71 families: 99 aHUS patients (71 index cases + 28 affected family members) and 158 healthy relatives with a documented complement gene abnormality. Results Fourteen families (19.7%) experienced multiple cases. Over a cumulative observation period of 7595 person-years, only 28 family members carrying gene mutations experienced aHUS (overall penetrance of 20%), leading to a disease rate of 3.69 events for 1000 person-years. The disease rate was 7.47 per 1000 person-years among siblings, 6.29 among offspring, 2.01 among parents, 1.84 among carriers of variants of uncertain significance, and 4.43 among carriers of causative variants. Conclusions The penetrance of aHUS seems a lot lower than previously reported. Moreover, the disease risk is higher in carriers of causative variants and is not equally distributed among generations: siblings and the offspring of patients have a much greater disease risk than parents. However, risk calculation may depend on variant classification that could change over time.
Collapse
|
|
12
|
Chaturvedi S, Braunstein EM, Brodsky RA. Antiphospholipid syndrome: Complement activation, complement gene mutations, and therapeutic implications. J Thromb Haemost 2021; 19:607-616. [PMID: 32881236 PMCID: PMC8080439 DOI: 10.1111/jth.15082] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 08/21/2020] [Accepted: 08/24/2020] [Indexed: 12/13/2022]
Abstract
Antiphospholipid syndrome (APS) is an acquired thromboinflammatory disorder characterized by the presence of antiphospholipid antibodies as well as an increased frequency of venous or arterial thrombosis and/or obstetrical morbidity. The spectrum of disease varies from asymptomatic to a severe form characterized by widespread thrombosis and multiorgan failure, termed catastrophic APS (CAPS). CAPS affects only about ∼1% of APS patients, often presents as a thrombotic microangiopathy and has a fulminant course with >40% mortality, despite the best available therapy. Animal models have implicated complement in the pathophysiology of thrombosis in APS, with more recent data from human studies confirming the interaction between the coagulation and complement pathways. Activation of the complement cascade via antiphospholipid antibodies can cause cellular injury and promote coagulation via multiple mechanisms. Finally, analogous to classic complement-mediated diseases such as atypical hemolytic uremic syndrome, a subset of patients with APS may be at increased risk for development of CAPS because of the presence of germline variants in genes crucial for complement regulation. Together, these data make complement inhibition an attractive and potentially lifesaving therapy to mitigate morbidity and mortality in severe thrombotic APS and CAPS.
Collapse
Affiliation(s)
- Shruti Chaturvedi
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Evan M Braunstein
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Robert A Brodsky
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| |
Collapse
|
|
13
|
Brambilla M, Ardissino G, Paglialonga F, Testa S, Capone V, Montini G. Haemoglobinuria for the early identification of aHUS relapse: data from the ItalKId-HUS Network. J Nephrol 2021; 35:279-284. [PMID: 33459950 DOI: 10.1007/s40620-021-00965-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 01/01/2021] [Indexed: 10/22/2022]
Abstract
BACKGROUND Atypical haemolytic uremic syndrome (aHUS) is at high risk of relapse at any time, therefore patients require lifelong monitoring. The most appropriate way to monitor patients is not yet clear. Patients could be monitored for relapse by urine dipstick testing for haemoglobinuria based on the hypothesis that thrombotic microangiopathy involving the glomerulus and associated with renal damage (like aHUS) cannot occur without haematuria. METHODS The aim of this retrospective study is to analyse our experience with this approach in aHUS patients who have never previously been treated, who are currently on treatment or who have discontinued C5 inhibition. The records of all aHUS patients (children and adults) managed by or referred to our Centre from January 2009 to March 2020 were included and the analysis for the presence of haemoglobinuria was restricted to the period following primary remission. A positive test was defined as haemoglobin ≥ 1 + . Patients reporting positive urine dipstick tests underwent laboratory investigations to rule in or out the diagnosis of aHUS relapse. RESULTS Eighty-four patients were included with 1517 determinations of haemoglobinuria during a cumulative observation period of 8904 patient-months. Haemoglobinuria for the early diagnosis of ongoing aHUS relapse shows a sensitivity of 100% and a specificity of 87.4% with a positive predictive value (PPV) of 10.5% and a negative predictive value (NPV) of 100%. The accuracy of the test was 87.6%. CONCLUSION Haemoglobinuria is a very sensitive and acceptably specific marker of aHUS relapse. This finding and its validation may have a positive impact on patients' quality of life and on the outcome of this life threatening disease via early diagnosis of relapse.
Collapse
Affiliation(s)
- Marta Brambilla
- Dialysis and Transplant Unit, Center for HUS Prevention Control and Management at the Pediatric Nephrology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Via della Commenda 9, 20122, Milan, Italy.
| | - Gianluigi Ardissino
- Dialysis and Transplant Unit, Center for HUS Prevention Control and Management at the Pediatric Nephrology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Via della Commenda 9, 20122, Milan, Italy
| | - Fabio Paglialonga
- Dialysis and Transplant Unit, Center for HUS Prevention Control and Management at the Pediatric Nephrology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Via della Commenda 9, 20122, Milan, Italy
| | - Sara Testa
- Dialysis and Transplant Unit, Center for HUS Prevention Control and Management at the Pediatric Nephrology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Via della Commenda 9, 20122, Milan, Italy
| | - Valentina Capone
- Dialysis and Transplant Unit, Center for HUS Prevention Control and Management at the Pediatric Nephrology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Via della Commenda 9, 20122, Milan, Italy
| | - Giovanni Montini
- Dialysis and Transplant Unit, Center for HUS Prevention Control and Management at the Pediatric Nephrology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Via della Commenda 9, 20122, Milan, Italy.,Giuliana and Bernardo Caprotti, Chairs of Pediatrics, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| |
Collapse
|
|
14
|
Wijnsma KL, Duineveld C, Volokhina EB, van den Heuvel LP, van de Kar NCAJ, Wetzels JFM. Safety and effectiveness of restrictive eculizumab treatment in atypical haemolytic uremic syndrome. Nephrol Dial Transplant 2019; 33:635-645. [PMID: 29106598 DOI: 10.1093/ndt/gfx196] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 04/10/2017] [Indexed: 11/12/2022] Open
Abstract
Background Atypical haemolytic uremic syndrome (aHUS) is a rare but severe form of thrombotic microangiopathy as a consequence of complement dysregulation. aHUS has a poor outcome with high mortality and >50% of patients developing end-stage renal disease. Since the end of 2012, these outcomes have greatly improved with the introduction of eculizumab. Currently the duration of treatment is debated. Most guidelines advise lifelong treatment. However, there is no hard evidence to support this advice. Historically, a substantial number of aHUS patients were weaned of plasma therapy, often without disease recurrence. Moreover, the long-term consequences of eculizumab treatment are unknown. In this retrospective study we describe 20 patients who received a restrictive treatment regimen. Methods All aHUS patients who presented in the Radboud University Medical Center, Nijmegen, The Netherlands, between 2012 and 2016 and who received eculizumab are described. Clinical, diagnostic and follow-up data were gathered and reviewed. Results Twenty patients (14 adults, 6 children) with aHUS have received eculizumab. Eculizumab was tapered in all and stopped in 17 patients. aHUS recurrence occurred in five patients. Due to close monitoring, recurrence was detected early and eculizumab was restarted. No clinical sequela such as proteinuria or progressive kidney dysfunction was detected subsequently. In total, eculizumab has been discontinued in 13 patients without aHUS recurrence, of which 5 are event free for >1 year. With this strategy ∼€11.4 million have been saved. Conclusions A restrictive eculizumab regimen in aHUS appears safe and effective. Prospective studies should further evaluate the most optimal treatment strategy.
Collapse
Affiliation(s)
- Kioa L Wijnsma
- Department of Pediatric Nephrology, Radboud University Medical Center Amalia Children's Hospital, Nijmegen, The Netherlands
| | - Caroline Duineveld
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Elena B Volokhina
- Department of Pediatric Nephrology, Radboud University Medical Center Amalia Children's Hospital, Nijmegen, The Netherlands.,Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Lambertus P van den Heuvel
- Department of Pediatric Nephrology, Radboud University Medical Center Amalia Children's Hospital, Nijmegen, The Netherlands.,Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Pediatrics, University Hospital Leuven, Leuven, Belgium
| | - Nicole C A J van de Kar
- Department of Pediatric Nephrology, Radboud University Medical Center Amalia Children's Hospital, Nijmegen, The Netherlands
| | - Jack F M Wetzels
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| |
Collapse
|
|
15
|
Atypical and secondary hemolytic uremic syndromes have a distinct presentation and no common genetic risk factors. Kidney Int 2019; 95:1443-1452. [DOI: 10.1016/j.kint.2019.01.023] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 01/01/2019] [Accepted: 01/04/2019] [Indexed: 12/28/2022]
|
|
16
|
Abbas F, El Kossi M, Kim JJ, Shaheen IS, Sharma A, Halawa A. Complement-mediated renal diseases after kidney transplantation - current diagnostic and therapeutic options in de novo and recurrent diseases. World J Transplant 2018; 8:203-219. [PMID: 30370231 PMCID: PMC6201327 DOI: 10.5500/wjt.v8.i6.203] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 08/09/2018] [Accepted: 08/28/2018] [Indexed: 02/05/2023] Open
Abstract
For decades, kidney diseases related to inappropriate complement activity, such as atypical hemolytic uremic syndrome and C3 glomerulopathy (a subtype of membranoproliferative glomerulonephritis), have mostly been complicated by worsened prognoses and rapid progression to end-stage renal failure. Alternative complement pathway dysregulation, whether congenital or acquired, is well-recognized as the main driver of the disease process in these patients. The list of triggers include: surgery, infection, immunologic factors, pregnancy and medications. The advent of complement activation blockade, however, revolutionized the clinical course and outcome of these diseases, rendering transplantation a viable option for patients who were previously considered as non-transplantable cases. Several less-costly therapeutic lines and likely better efficacy and safety profiles are currently underway. In view of the challenging nature of diagnosing these diseases and the long-term cost implications, a multidisciplinary approach including the nephrologist, renal pathologist and the genetic laboratory is required to help improve overall care of these patients and draw the optimum therapeutic plan.
Collapse
Affiliation(s)
- Fedaey Abbas
- Nephrology Department, Jaber El Ahmed Military Hospital, Safat 13005, Kuwait
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
| | - Mohsen El Kossi
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Doncaster Royal Infirmary, Doncaster DN2 5LT, United Kingdom
| | - Jon Jin Kim
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Nottingham Children Hospital, Nottingham NG7 2UH, United Kingdom
| | - Ihab Sakr Shaheen
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Royal Hospital for Children, Glasgow G51 4TF, United Kingdom
| | - Ajay Sharma
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Royal Liverpool University Hospitals, Liverpool L7 8XP, United Kingdom
| | - Ahmed Halawa
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Sheffield Teaching Hospitals, Sheffield S57AU, United Kingdom
| |
Collapse
|
|
17
|
Abbas F, El Kossi M, Kim JJ, Sharma A, Halawa A. Thrombotic microangiopathy after renal transplantation: Current insights in de novo and recurrent disease. World J Transplant 2018; 8:122-141. [PMID: 30211021 PMCID: PMC6134269 DOI: 10.5500/wjt.v8.i5.122] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2018] [Revised: 06/26/2018] [Accepted: 07/10/2018] [Indexed: 02/05/2023] Open
Abstract
Thrombotic microangiopathy (TMA) is one of the most devastating sequalae of kidney transplantation. A number of published articles have covered either de novo or recurrent TMA in an isolated manner. We have, hereby, in this article endeavored to address both types of TMA in a comparative mode. We appreciate that de novo TMA is more common and its prognosis is poorer than recurrent TMA; the latter has a genetic background, with mutations that impact disease behavior and, consequently, allograft and patient survival. Post-transplant TMA can occur as a recurrence of the disease involving the native kidney or as de novo disease with no evidence of previous involvement before transplant. While atypical hemolytic uremic syndrome is a rare disease that results from complement dysregulation with alternative pathway overactivity, de novo TMA is a heterogenous set of various etiologies and constitutes the vast majority of post-transplant TMA cases. Management of both diseases varies from simple maneuvers, e.g., plasmapheresis, drug withdrawal or dose modification, to lifelong complement blockade, which is rather costly. Careful donor selection and proper recipient preparation, including complete genetic screening, would be a pragmatic approach. Novel therapies, e.g., purified products of the deficient genes, though promising in theory, are not yet of proven value.
Collapse
Affiliation(s)
- Fedaey Abbas
- Nephrology Department, Jaber El Ahmed Military Hospital, Safat 13005, Kuwait
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
| | - Mohsen El Kossi
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Doncaster Renal Unit, Doncaster Royal Infirmary, Doncaster DN2 5LT, United Kingdom
| | - Jon Jin Kim
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Nottingham Children Hospital, Nottingham NG7 2UH, United Kingdom
| | - Ajay Sharma
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Transplant Surgery, Royal Liverpool University Hospitals, Liverpool UK L7 8XP, United Kingdom
| | - Ahmed Halawa
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Department of Transplantation Surgery, Sheffield Teaching Hospitals, Sheffield S57AU, United Kingdom
| |
Collapse
|
|
18
|
The impact of eculizumab on routine complement assays. J Immunol Methods 2018; 460:63-71. [DOI: 10.1016/j.jim.2018.06.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 05/05/2018] [Accepted: 06/14/2018] [Indexed: 01/18/2023]
|
|
19
|
Menne J, Delmas Y, Fakhouri F, Kincaid JF, Licht C, Minetti EE, Mix C, Provôt F, Rondeau E, Sheerin NS, Wang J, Weekers LE, Greenbaum LA. Eculizumab prevents thrombotic microangiopathy in patients with atypical haemolytic uraemic syndrome in a long-term observational study. Clin Kidney J 2018; 12:196-205. [PMID: 30976396 PMCID: PMC6452204 DOI: 10.1093/ckj/sfy035] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Indexed: 01/25/2023] Open
Abstract
Background Eculizumab, a terminal complement inhibitor, is approved for atypical haemolytic uraemic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA). Methods In five parent studies, eculizumab effectively prevented TMA and improved renal and haematologic outcomes in patients with aHUS; therefore, these patients could enrol in this long-term, prospective, observational and multicentre study. The primary endpoint was the TMA manifestation rate off and on eculizumab post-parent study. Post hoc analyses evaluated rates during labelled versus non-labelled dosing regimens, and in those with versus without identified complement abnormalities. Serious targeted treatment-emergent adverse events (TEAEs) were evaluated. Results Of 87 patients in the current study, 39 and 76 had off- and on-treatment periods, respectively; 17 (44%) with off periods reinitiated eculizumab. TMA manifestation rate per 100 patient-years was 19.9 off and 7.3 on treatment [hazard ratio (HR), 4.7; P = 0.0008]; rates were highest off treatment and lowest during labelled regimens. TMA manifestations with hospitalizations/serious AEs occurred more frequently off versus on treatment. TMA rates were higher among patients with identified complement abnormalities (HR, 4.5; P = 0.0082). Serious targeted TEAEs occurred at similar rates off and on treatment. Conclusions As expected, patients with aHUS have increased risk of TMA manifestations after discontinuation of eculizumab or in the setting of non-labelled eculizumab dosing. Collectively, results show that maintaining eculizumab treatment minimizes risk of TMA, particularly in patients with identified complement abnormalities. Future studies are needed to further characterize TMA and longer term outcomes on labelled or non-labelled eculizumab regimens and after discontinuation of treatment.
Collapse
Affiliation(s)
- Jan Menne
- Klinik für Nieren- und Hochdruckerkrankungen, Hannover, Germany
| | | | | | | | | | | | - Chris Mix
- Alexion Pharmaceuticals, Inc., New Haven, CT, USA
| | | | - Eric Rondeau
- Hôpital Tenon and Université Paris VI, Paris, France
| | - Neil S Sheerin
- Institute of Cellular Medicine, University of Newcastle upon Tyne, Newcastle upon Tyne, UK
| | - Jimmy Wang
- Alexion Pharmaceuticals, Inc., New Haven, CT, USA
| | | | - Larry A Greenbaum
- Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA
| |
Collapse
|
|
20
|
Abstract
Atypical hemolytic uremic syndrome (aHUS) is a disease characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury. The histopathologic lesions of aHUS include thrombotic microangiopathy involving the glomerular capillaries and thrombosis involving arterioles or interlobar arteries. Extra-renal manifestations occur in up to 20% of patients. The majority of aHUS is caused by complement system defects impairing ordinary regulatory mechanisms. Activating events therefore lead to unbridled, ongoing complement activity producing widespread endothelial injury. Pathologic mutations include those resulting in loss-of-function in a complement regulatory gene (CFH, CFI, CD46 or THBD) or gain-of-function in an effector gene (CFB or C3). Treatment with the late complement inhibitor, eculizumab – a monoclonal antibody directed against C5 – is effective.
Collapse
Affiliation(s)
- Kuixing Zhang
- Department of Pathology and Laboratory Medicine, University of California, Orange, CA, USA
| | - Yuxin Lu
- Department of Pathology and Laboratory Medicine, University of California, Orange, CA, USA
| | - Kevin T Harley
- Department of Internal Medicine, Division of Nephrology and Hypertension, Irvine School of Medicine, University of California, Orange, CA, USA
| | - Minh-Ha Tran
- Department of Pathology and Laboratory Medicine, University of California, Orange, CA, USA
| |
Collapse
|
|
21
|
Volokhina E, Wijnsma K, van der Molen R, Roeleveld N, van der Velden T, Goertz J, Sweep F, Brüggemann RJ, Wetzels J, van de Kar N, van den Heuvel L. Eculizumab Dosing Regimen in Atypical HUS: Possibilities for Individualized Treatment. Clin Pharmacol Ther 2017; 102:671-678. [DOI: 10.1002/cpt.686] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 03/03/2017] [Accepted: 03/08/2017] [Indexed: 01/30/2023]
Affiliation(s)
- E Volokhina
- Department of Pediatric Nephrology; Amalia Children's Hospital, Radboud University Medical Center; Nijmegen The Netherlands
- Department of Laboratory Medicine; Radboud University Medical Center; Nijmegen The Netherlands
| | - K Wijnsma
- Department of Pediatric Nephrology; Amalia Children's Hospital, Radboud University Medical Center; Nijmegen The Netherlands
| | - R van der Molen
- Department of Laboratory Medicine; Radboud University Medical Center; Nijmegen The Netherlands
| | - N Roeleveld
- Department of Pediatric Nephrology; Amalia Children's Hospital, Radboud University Medical Center; Nijmegen The Netherlands
- Department of Health Evidence; Radboud University Medical Center; Nijmegen The Netherlands
| | - T van der Velden
- Department of Pediatric Nephrology; Amalia Children's Hospital, Radboud University Medical Center; Nijmegen The Netherlands
| | - J Goertz
- Department of Laboratory Medicine; Radboud University Medical Center; Nijmegen The Netherlands
| | - F Sweep
- Department of Laboratory Medicine; Radboud University Medical Center; Nijmegen The Netherlands
| | - RJ Brüggemann
- Department of Pharmacy; Radboud University Medical Center; Nijmegen The Netherlands
| | - J Wetzels
- Department of Nephrology; Radboud University Medical Center; Nijmegen The Netherlands
| | - N van de Kar
- Department of Pediatric Nephrology; Amalia Children's Hospital, Radboud University Medical Center; Nijmegen The Netherlands
| | - L van den Heuvel
- Department of Pediatric Nephrology; Amalia Children's Hospital, Radboud University Medical Center; Nijmegen The Netherlands
- Department of Laboratory Medicine; Radboud University Medical Center; Nijmegen The Netherlands
- Department of Pediatrics; University Hospitals Leuven; Leuven Belgium
| |
Collapse
|
|
22
|
Choo SZ, Brown F. Subclinical atypical haemolytic uremic syndrome relapse following discontinuation of eculizumab. Nephrology (Carlton) 2017; 22 Suppl 1:4-6. [DOI: 10.1111/nep.12931] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
| | - Fiona Brown
- Department of Nephrology; Monash Health; Australia
| |
Collapse
|
|
23
|
Fakhouri F, Fila M, Provôt F, Delmas Y, Barbet C, Châtelet V, Rafat C, Cailliez M, Hogan J, Servais A, Karras A, Makdassi R, Louillet F, Coindre JP, Rondeau E, Loirat C, Frémeaux-Bacchi V. Pathogenic Variants in Complement Genes and Risk of Atypical Hemolytic Uremic Syndrome Relapse after Eculizumab Discontinuation. Clin J Am Soc Nephrol 2017; 12:50-59. [PMID: 27799617 PMCID: PMC5220663 DOI: 10.2215/cjn.06440616] [Citation(s) in RCA: 134] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 09/28/2016] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND OBJECTIVES The complement inhibitor eculizumab has dramatically improved the outcome of atypical hemolytic uremic syndrome. However, the optimal duration of eculizumab treatment in atypical hemolytic uremic syndrome remains debated. We report on the French atypical hemolytic uremic syndrome working group's first 2-year experience with eculizumab discontinuation in patients with atypical hemolytic uremic syndrome. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS Using the French atypical hemolytic uremic syndrome registry database, we retrospectively identified all dialysis-free patients with atypical hemolytic uremic syndrome who discontinued eculizumab between 2010 and 2014 and reviewed their relevant clinical and biologic data. The decision to discontinue eculizumab was made by the clinician in charge of the patient. All patients were closely monitored by regular urine dipsticks and blood tests. Eculizumab was rapidly (24-48 hours) restarted in case of relapse. RESULTS Among 108 patients treated with eculizumab, 38 patients (nine children and 29 adults) discontinued eculizumab (median treatment duration of 17.5 months). Twenty-one patients (55%) carried novel or rare complement genes variants. Renal recovery under eculizumab was equally good in patients with and those without complement gene variants detected. After a median follow-up of 22 months, 12 patients (31%) experienced atypical hemolytic uremic syndrome relapse. Eight of 11 patients (72%) with complement factor H variants, four of eight patients (50%) with membrane cofactor protein variants, and zero of 16 patients with no rare variant detected relapsed. In relapsing patients, early reintroduction (≤48 hours) of eculizumab led to rapid (<7 days) hematologic remission and a return of serum creatinine to baseline level in a median time of 26 days. At last follow-up, renal function remained unchanged in nonrelapsing and relapsing patients compared with baseline values before eculizumab discontinuation. CONCLUSIONS Pathogenic variants in complement genes were associated with higher risk of atypical hemolytic uremic syndrome relapse after eculizumab discontinuation. Prospective studies are needed to identify biomarkers predictive of relapse and determine the best strategy of retreatment in relapsing patients.
Collapse
Affiliation(s)
- Fadi Fakhouri
- Due to the number of contributing authors, the affiliations are provided in the Supplemental Material
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
24
|
Macia M, de Alvaro Moreno F, Dutt T, Fehrman I, Hadaya K, Gasteyger C, Heyne N. Current evidence on the discontinuation of eculizumab in patients with atypical haemolytic uraemic syndrome. Clin Kidney J 2016. [PMID: 28621343 PMCID: PMC5466111 DOI: 10.1093/ckj/sfw115] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Background. Atypical haemolytic uraemic syndrome (aHUS) is a rare, life-threatening disorder for which eculizumab is the only approved treatment. Life-long treatment is indicated; however, eculizumab discontinuation has been reported. Methods. Unpublished authors' cases and published cases of eculizumab discontinuation are reviewed. We also report eculizumab discontinuation data from five clinical trials, plus long-term extensions and the global aHUS Registry. Results. Of six unpublished authors' cases, four patients had a subsequent thrombotic microangiopathy (TMA) manifestation within 12 months of discontinuation. Case reports of 52 patients discontinuing eculizumab were identified; 16 (31%) had a subsequent TMA manifestation. In eculizumab clinical trials, 61/130 patients discontinued treatment between 2008 and 2015. Median follow-up post-discontinuation was 24 weeks and during this time 12 patients experienced 15 severe TMA complications and 9 of the 12 patients restarted eculizumab. TMA complications occurred irrespective of identified genetic mutation, high risk polymorphism or auto-antibody. In the global aHUS Registry, 76/296 patients (26%) discontinued, 12 (16%) of whom restarted. Conclusions. The currently available evidence suggests TMA manifestations following discontinuation are unpredictable in both severity and timing. For evidence-based decision making, better risk stratification and valid monitoring strategies are required. Until these exist, the risk versus benefit of eculizumab discontinuation, either in specific clinical situations or at selected time points, should include consideration of the risk of further TMA manifestations.
Collapse
Affiliation(s)
- Manuel Macia
- Nephrology service, University Hospital NS de Candelaria, Santa Cruz de Tenerife, Spain
| | | | - Tina Dutt
- Roald Dahl Haemostasis and Thrombosis Centre, Royal Liverpool University Hospital, Liverpool, UK
| | - Ingela Fehrman
- Division of Transplant Surgery, Karolinska University Hospital, Stockholm, Sweden
| | - Karine Hadaya
- Divisions of Nephrology and Transplantation, Geneva University Hospitals, Geneva, Switzerland
| | | | - Nils Heyne
- Department of Endocrinology and Diabetology, Angiology, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
| |
Collapse
|
|
25
|
Goodship THJ, Cook HT, Fakhouri F, Fervenza FC, Frémeaux-Bacchi V, Kavanagh D, Nester CM, Noris M, Pickering MC, Rodríguez de Córdoba S, Roumenina LT, Sethi S, Smith RJH. Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference. Kidney Int 2016; 91:539-551. [PMID: 27989322 DOI: 10.1016/j.kint.2016.10.005] [Citation(s) in RCA: 461] [Impact Index Per Article: 51.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Revised: 10/10/2016] [Accepted: 10/20/2016] [Indexed: 02/06/2023]
Abstract
In both atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) complement plays a primary role in disease pathogenesis. Herein we report the outcome of a 2015 Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference where key issues in the management of these 2 diseases were considered by a global panel of experts. Areas addressed included renal pathology, clinical phenotype and assessment, genetic drivers of disease, acquired drivers of disease, and treatment strategies. In order to help guide clinicians who are caring for such patients, recommendations for best treatment strategies were discussed at length, providing the evidence base underpinning current treatment options. Knowledge gaps were identified and a prioritized research agenda was proposed to resolve outstanding controversial issues.
Collapse
Affiliation(s)
| | - H Terence Cook
- Centre for Complement and Inflammation Research, Department of Medicine, Imperial College Hammersmith Campus, London, UK
| | - Fadi Fakhouri
- INSERM, UMR-S 1064, and Department of Nephrology and Immunology, CHU de Nantes, Nantes, France
| | - Fernando C Fervenza
- Department of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | | | - David Kavanagh
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Carla M Nester
- Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA; Division of Nephrology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Marina Noris
- IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," Ranica, Bergamo, Italy
| | - Matthew C Pickering
- Centre for Complement and Inflammation Research, Department of Medicine, Imperial College Hammersmith Campus, London, UK
| | - Santiago Rodríguez de Córdoba
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain; Centro de Investigación Biomédica en Enfermedades Raras, Madrid, Spain
| | - Lubka T Roumenina
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S1138, Complément et Maladies, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France; Université Pierre et Marie Curie (UPMC-Paris-6), Paris, France
| | - Sanjeev Sethi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Richard J H Smith
- Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA; Division of Nephrology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
| | | |
Collapse
|
|
26
|
Go RS, Winters JL, Leung N, Murray DL, Willrich MA, Abraham RS, Amer H, Hogan WJ, Marshall AL, Sethi S, Tran CL, Chen D, Pruthi RK, Ashrani AA, Fervenza FC, Cramer CH, Rodriguez V, Wolanskyj AP, Thomé SD, Hook CC. Thrombotic Microangiopathy Care Pathway: A Consensus Statement for the Mayo Clinic Complement Alternative Pathway-Thrombotic Microangiopathy (CAP-TMA) Disease-Oriented Group. Mayo Clin Proc 2016; 91:1189-211. [PMID: 27497856 DOI: 10.1016/j.mayocp.2016.05.015] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Revised: 04/12/2016] [Accepted: 05/27/2016] [Indexed: 12/15/2022]
Abstract
Thrombotic microangiopathies (TMAs) comprise a heterogeneous set of conditions linked by a common histopathologic finding of endothelial damage resulting in microvascular thromboses and potentially serious complications. The typical clinical presentation is microangiopathic hemolytic anemia accompanied by thrombocytopenia with varying degrees of organ ischemia. The differential diagnoses are generally broad, while the workup is frequently complex and can be confusing. This statement represents the joint recommendations from a multidisciplinary team of Mayo Clinic physicians specializing in the management of TMA. It comprises a series of evidence- and consensus-based clinical pathways developed to allow a uniform approach to the spectrum of care including when to suspect TMA, what differential diagnoses to consider, which diagnostic tests to order, and how to provide initial empiric therapy, as well as some guidance on subsequent management.
Collapse
Affiliation(s)
- Ronald S Go
- Division of Hematology, Mayo Clinic, Rochester, MN.
| | - Jeffrey L Winters
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Nelson Leung
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
| | - David L Murray
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Maria A Willrich
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Roshini S Abraham
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Hatem Amer
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
| | | | | | - Sanjeev Sethi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Cheryl L Tran
- Division of Pediatric Nephrology, Mayo Clinic, Rochester, MN
| | - Dong Chen
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | | | | | | | - Carl H Cramer
- Division of Pediatric Nephrology, Mayo Clinic, Rochester, MN
| | | | | | | | | | | |
Collapse
|
|
27
|
Sahutoglu T, Basturk T, Sakaci T, Koc Y, Ahbap E, Sevinc M, Kara E, Akgol C, Caglayan FB, Unsal A, Daha MR. Can eculizumab be discontinued in aHUS?: Case report and review of the literature. Medicine (Baltimore) 2016; 95:e4330. [PMID: 27495036 PMCID: PMC4979790 DOI: 10.1097/md.0000000000004330] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND The management of atypical hemolytic uremic syndrome (aHUS) has evolved into better control of thrombotic microangiopathy (TMA) and recovery of renal functions since the recent introduction of the terminal complement cascade blocker, eculizumab, into clinical use. Better characterization of genotype-phenotype relations has become possible with genetic and clinical studies. However, these advances brought up some important issues, such as the possibility and timing of discontinuation of eculizumab and strategy of follow-up that need to be enlightened. CASE SUMMARY One of our aHUS cases with a novel complement factor H mutation, who developed unusual laboratory findings (thrombocytopenia and mild creatinine elevation without other features of TMA) following discontinuation of eculizumab was presented. Literature and case reports relevant to discontinuation of eculizumab in aHUS patients were reviewed. CONCLUSION Limited experience suggests that the risk of recurrence of TMA following discontinuation of eculizumab is relatively low for patients with MCP mutations, homozygous CFHR3/R1 deletions, anti-CFH antibodies, CFI mutations, and no identifiable mutations, whereas there is a major risk for patients with CFH mutations. Early detection of TMA recurrence and prompt retreatment with eculizumab seem to be efficient in controlling of TMA and restoration of kidney functions.
Collapse
Affiliation(s)
- Tuncay Sahutoglu
- Department of Nephrology, Sisli Hamidiye Etfal Educational and Research Hospital, Istanbul
- Correspondence: Tuncay Sahutoglu, Department of Nephrology, Sisli Hamidiye Etfal Educational and Research Hospital, Halaskargazi Cad. Etfal Sk., 34377 Sisli, Istanbul, Turkey (e-mail: )
| | - Taner Basturk
- Department of Nephrology, Sisli Hamidiye Etfal Educational and Research Hospital, Istanbul
| | - Tamer Sakaci
- Department of Nephrology, Sisli Hamidiye Etfal Educational and Research Hospital, Istanbul
| | - Yener Koc
- Department of Nephrology, Sisli Hamidiye Etfal Educational and Research Hospital, Istanbul
| | - Elbis Ahbap
- Department of Nephrology, Sisli Hamidiye Etfal Educational and Research Hospital, Istanbul
| | - Mustafa Sevinc
- Department of Nephrology, Sisli Hamidiye Etfal Educational and Research Hospital, Istanbul
| | - Ekrem Kara
- Department of Internal Medicine, Recep Tayyip Erdogan University, Rize, Turkey
| | - Cuneyt Akgol
- Department of Nephrology, Sisli Hamidiye Etfal Educational and Research Hospital, Istanbul
| | | | - Abdulkadir Unsal
- Department of Nephrology, Sisli Hamidiye Etfal Educational and Research Hospital, Istanbul
| | - Mohamed R. Daha
- Department of Nephrology, C3-P, Leiden University Medical Center, Leiden, The Netherlands
| |
Collapse
|
|
28
|
Abstract
The biology of atypical hemolytic uremic syndrome has been shown to involve inability to limit activation of the alternative complement pathway, with subsequent damage to systemic endothelial beds and the vasculature, resulting in the prototypic findings of a thrombotic microangiopathy. Central to this process is the formation of the terminal membrane attack complex C5b-9. Recently, application of a monoclonal antibody that specifically binds to C5, eculizumab, became available to treat patients with atypical hemolytic uremic syndrome, replacing plasma exchange or infusion as primary therapy. This review focuses on the evidence, based on published clinical trials, case series, and case reports, on the efficacy and safety of this approach.
Collapse
Affiliation(s)
- Lilian M Pereira Palma
- Pediatric Nephrology, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Craig B Langman
- The Feinberg School of Medicine, Northwestern University, and the Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
| |
Collapse
|
|
29
|
Habbig S, Bergmann C, Weber LT. Discontinuation of Eculizumab in a Patient With Atypical Hemolytic Uremic Syndrome Due to a Mutation in CFH. Am J Kidney Dis 2015; 67:532-3. [PMID: 26724167 DOI: 10.1053/j.ajkd.2015.11.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 11/08/2015] [Indexed: 11/11/2022]
Affiliation(s)
- Sandra Habbig
- University Children's Hospital Cologne, Cologne, Germany; University of Cologne, Cologne, Germany.
| | - Carsten Bergmann
- Bioscientia Center for Human Genetics, Ingelheim, Germany; University Freiburg Medical Center, Freiburg, Germany
| | - Lutz T Weber
- University Children's Hospital Cologne, Cologne, Germany
| |
Collapse
|
|
30
|
Ardissino G, Possenti I, Tel F. In Reply to ‘Discontinuation of Eculizumab Maintenance Treatment for Atypical Hemolytic Uremic Syndrome’. Am J Kidney Dis 2015; 65:342-3. [DOI: 10.1053/j.ajkd.2014.05.028] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Accepted: 05/30/2014] [Indexed: 11/11/2022]
|