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Tseng MH, Lin SH, Tsai JD, Wu MS, Tsai IJ, Chen YC, Chang MC, Chou WC, Chiou YH, Huang CC. Atypical hemolytic uremic syndrome: Consensus of diagnosis and treatment in Taiwan. J Formos Med Assoc 2023; 122:366-375. [PMID: 36323601 DOI: 10.1016/j.jfma.2022.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 09/03/2022] [Accepted: 10/14/2022] [Indexed: 11/06/2022] Open
Abstract
Atypical hemolytic uremic syndrome (aHUS), characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, is a rare but life-threatening systemic disorder caused by the dysregulation of the complement pathway. Current advances in molecular analysis and pathogenesis have facilitated the establishment of diagnosis and development of effective complement blockade. Based on this recent consensus, we provide suggestions regarding the diagnosis and management of aHUS in Taiwan. The diagnosis of aHUS is made by the presence of TMA with normal ADAMTS13 activity without known secondary causes. Although only 60% of patients with aHUS have mutations in genes involving the compliment and coagulation systems, molecular analysis is suggestive for helping establish diagnosis, clarifying the underlying pathophysiology, guiding the treatment decision-making, predicting the prognosis, and deciding renal transplantation. Complement blockade, anti-C5 monoclonal antibody, is the first-line therapy for patients with aHUS. Plasma therapy should be considered for removing autoantibody in patients with atypical HUS caused by anti-CFH or complement inhibitor is unavailable.
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Affiliation(s)
- Min-Hua Tseng
- Division of Nephrology, Department of Pediatrics, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
| | - Shih-Hua Lin
- Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Jeng-Daw Tsai
- Division of Nephrology, Department of Pediatrics, MacKay Children's Hospital, Taipei, Taiwan
| | - Mai-Szu Wu
- Division of Nephrology, Department of Internal Medicine, Taipei Medical University Shuang Ho Hospital, New Taipei City, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - I-Jung Tsai
- Division of Nephrology, Department of Pediatrics, National Taiwan University Children Hospital, Taipei, Taiwan
| | - Yeu-Chin Chen
- Division of Hematology/Oncology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Min-Chih Chang
- Division of Hematology/Oncology, Department of Internal Medicine, MacKay Children's Hospital, Taipei, Taiwan
| | - Wen-Chien Chou
- Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Yee-Hsuan Chiou
- Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
| | - Chiu-Ching Huang
- Division of Nephrology and the Kidney Institute, Department of Internal Medicine, China Medical University and Hospital, Taichung, Taiwan.
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Santarsiero D, Aiello S. The Complement System in Kidney Transplantation. Cells 2023; 12:cells12050791. [PMID: 36899927 PMCID: PMC10001167 DOI: 10.3390/cells12050791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 02/24/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Kidney transplantation is the therapy of choice for patients who suffer from end-stage renal diseases. Despite improvements in surgical techniques and immunosuppressive treatments, long-term graft survival remains a challenge. A large body of evidence documented that the complement cascade, a part of the innate immune system, plays a crucial role in the deleterious inflammatory reactions that occur during the transplantation process, such as brain or cardiac death of the donor and ischaemia/reperfusion injury. In addition, the complement system also modulates the responses of T cells and B cells to alloantigens, thus playing a crucial role in cellular as well as humoral responses to the allograft, which lead to damage to the transplanted kidney. Since several drugs that are capable of inhibiting complement activation at various stages of the complement cascade are emerging and being developed, we will discuss how these novel therapies could have potential applications in ameliorating outcomes in kidney transplantations by preventing the deleterious effects of ischaemia/reperfusion injury, modulating the adaptive immune response, and treating antibody-mediated rejection.
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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.
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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
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Vitkauskaitė M, Vinikovas A, Miglinas M, Rimševičius L, Čerkauskaitė A, Mačionienė E, Ašakienė E. Complement inhibitor eculizumab in thrombotic microangiopathy: Single-center case series. Clin Case Rep 2022; 10:e05573. [PMID: 35317070 PMCID: PMC8922540 DOI: 10.1002/ccr3.5573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 01/16/2022] [Accepted: 02/16/2022] [Indexed: 11/07/2022] Open
Abstract
Our case series showed that eculizumab is efficacious and safe in treating thrombotic microangiopathy, as well as it has positive effects on quality of life. Further extensive studies are required to develop unified treatment guidelines.
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Affiliation(s)
| | - Artūras Vinikovas
- Faculty of Medicine Vilnius University Vilnius Lithuania
- Clinic of Gastroenterology, Nephro-Urology and Surgery Faculty of Medicine Institute of Clinical Medicine Vilnius University Vilnius Lithuania
| | - Marius Miglinas
- Faculty of Medicine Vilnius University Vilnius Lithuania
- Clinic of Gastroenterology, Nephro-Urology and Surgery Faculty of Medicine Institute of Clinical Medicine Vilnius University Vilnius Lithuania
| | - Laurynas Rimševičius
- Faculty of Medicine Vilnius University Vilnius Lithuania
- Clinic of Gastroenterology, Nephro-Urology and Surgery Faculty of Medicine Institute of Clinical Medicine Vilnius University Vilnius Lithuania
| | - Agnė Čerkauskaitė
- Faculty of Medicine Vilnius University Vilnius Lithuania
- Clinic of Gastroenterology, Nephro-Urology and Surgery Faculty of Medicine Institute of Clinical Medicine Vilnius University Vilnius Lithuania
| | - Ernesta Mačionienė
- Faculty of Medicine Vilnius University Vilnius Lithuania
- Clinic of Gastroenterology, Nephro-Urology and Surgery Faculty of Medicine Institute of Clinical Medicine Vilnius University Vilnius Lithuania
| | - Eglė Ašakienė
- Faculty of Medicine Vilnius University Vilnius Lithuania
- Clinic of Gastroenterology, Nephro-Urology and Surgery Faculty of Medicine Institute of Clinical Medicine Vilnius University Vilnius Lithuania
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Qi R, Qin W. Role of Complement System in Kidney Transplantation: Stepping From Animal Models to Clinical Application. Front Immunol 2022; 13:811696. [PMID: 35281019 PMCID: PMC8913494 DOI: 10.3389/fimmu.2022.811696] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 01/31/2022] [Indexed: 12/23/2022] Open
Abstract
Kidney transplantation is a life-saving strategy for patients with end-stage renal diseases. Despite the advances in surgical techniques and immunosuppressive agents, the long-term graft survival remains a challenge. Growing evidence has shown that the complement system, part of the innate immune response, is involved in kidney transplantation. Novel insights highlighted the role of the locally produced and intracellular complement components in the development of inflammation and the alloreactive response in the kidney allograft. In the current review, we provide the updated understanding of the complement system in kidney transplantation. We will discuss the involvement of the different complement components in kidney ischemia-reperfusion injury, delayed graft function, allograft rejection, and chronic allograft injury. We will also introduce the existing and upcoming attempts to improve allograft outcomes in animal models and in the clinical setting by targeting the complement system.
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Affiliation(s)
| | - Weijun Qin
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
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Kang JH, Lee D, Park Y. Atypical Hemolytic Uremic Syndrome after Traumatic Rectal Injury: A Case Report. JOURNAL OF TRAUMA AND INJURY 2021. [DOI: 10.20408/jti.2020.0068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Atypical hemolytic uremic syndrome (aHUS) is a rare, progressive, life-threatening condition of thrombotic microangiopathy characterized by thrombocytopenia, microangiopathic hemolytic anemia, and renal impairment. The mechanisms underlying aHUS remain unclear. Herein, we present the first case in the literature of aHUS after a traumatic injury. A 55-year-old male visited the emergency department after a traumatic injury caused by a tree limb. Abdominal computed tomography revealed a rectal wall defect with significant air density in the perirectal space and preperitoneum, implying rectal perforation. Due to the absence of intraperitoneal intestinal perforation, we performed diverting sigmoid loop colostomy. An additional intermittent simple repair was performed due to perianal and anal injuries. One day postoperatively, his urine output abruptly decreased and serum creatinine level increased. His platelet level decreased, and a spiking fever occurred after 2 days. The patient was diagnosed with acute renal failure secondary to aHUS and was treated with fresh frozen plasma replacement. Continuous renal replacement therapy (CRRT) was also started for oliguria and uremic symptoms. The patient received CRRT for 3 days and intermittent hemodialysis thereafter. After hemodialysis and subsequent supportive treatment, his urine output and renal function improved. The hemolytic anemia and thrombocytopenia also gradually improved. Dialysis was terminated on day 22 of admission and the patient was discharged after recovery. This case suggests that that a traumatic event can trigger aHUS, which should be considered in patients who have thrombocytopenia and acute renal failure with microangiopathic hemolytic anemia. Early diagnosis and appropriate management are critical for favorable outcomes.
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Raina R, Vijayvargiya N, Khooblall A, Melachuri M, Deshpande S, Sharma D, Mathur K, Arora M, Sethi SK, Sandhu S. Pediatric Atypical Hemolytic Uremic Syndrome Advances. Cells 2021; 10:3580. [PMID: 34944087 PMCID: PMC8700093 DOI: 10.3390/cells10123580] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/12/2021] [Accepted: 12/15/2021] [Indexed: 12/30/2022] Open
Abstract
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.
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Affiliation(s)
- Rupesh Raina
- Akron Nephrology Associates/Cleveland Clinic Akron General Medical Center, Akron, OH 44307, USA; (N.V.); (A.K.); (S.D.); (K.M.); (M.A.)
- Department of Nephrology, Akron Children’s Hospital, Akron, OH 44308, USA
| | - Nina Vijayvargiya
- Akron Nephrology Associates/Cleveland Clinic Akron General Medical Center, Akron, OH 44307, USA; (N.V.); (A.K.); (S.D.); (K.M.); (M.A.)
| | - Amrit Khooblall
- Akron Nephrology Associates/Cleveland Clinic Akron General Medical Center, Akron, OH 44307, USA; (N.V.); (A.K.); (S.D.); (K.M.); (M.A.)
| | - Manasa Melachuri
- Department of Medicine, Northeast Ohio Medical University, Rootstown, OH 44272, USA; (M.M.); (D.S.)
| | - Shweta Deshpande
- Akron Nephrology Associates/Cleveland Clinic Akron General Medical Center, Akron, OH 44307, USA; (N.V.); (A.K.); (S.D.); (K.M.); (M.A.)
| | - Divya Sharma
- Department of Medicine, Northeast Ohio Medical University, Rootstown, OH 44272, USA; (M.M.); (D.S.)
| | - Kashin Mathur
- Akron Nephrology Associates/Cleveland Clinic Akron General Medical Center, Akron, OH 44307, USA; (N.V.); (A.K.); (S.D.); (K.M.); (M.A.)
| | - Manav Arora
- Akron Nephrology Associates/Cleveland Clinic Akron General Medical Center, Akron, OH 44307, USA; (N.V.); (A.K.); (S.D.); (K.M.); (M.A.)
| | - Sidharth Kumar Sethi
- Pediatric Nephrology & Pediatric Kidney Transplantation, Kidney and Urology Institute, Medanta, The Medicity Hospital, Gurgaon 122007, India;
| | - Sonia Sandhu
- Hematology and Oncology, Cleveland Clinic Akron General Medical Center, Akron, OH 44307, USA;
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Characteristics of and meningococcal disease prevention strategies for commercially insured persons receiving eculizumab in the United States. PLoS One 2020; 15:e0241989. [PMID: 33180804 PMCID: PMC7660549 DOI: 10.1371/journal.pone.0241989] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 10/25/2020] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Eculizumab is a licensed treatment for several rare, complement-mediated diseases. Eculizumab use is associated with an approximately 2,000-fold increased meningococcal disease risk. In the United States, meningococcal vaccines are recommended for eculizumab recipients but there are no recommendations on use of long-term antibiotic prophylaxis. We describe characteristics of and meningococcal vaccine and antibiotic receipt in U.S. eculizumab recipients to inform meningococcal disease prevention strategies. METHODS Persons in the IBM® MarketScan® Research Databases with ≥1 claim for eculizumab injection during 2007-2017 were included. Indication for eculizumab use, meningococcal vaccine receipt, and antibiotic receipt were assessed using International Classification of Diseases-9/10 diagnosis codes, vaccine administration procedure codes, and antibiotic codes from pharmacy claims, respectively. RESULTS Overall 696 persons met the inclusion criteria. Paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) were the most common indications for eculizumab use (41% and 37%, respectively); 20% had an undetermined indication. From June 2015 through December 2017, 28% (41/148) of continuously-enrolled patients received ≥1 serogroup B vaccine dose. For serogroup ACWY conjugate vaccine, 45% (91/201) of patients received ≥1 dose within five years of their most recent eculizumab dose, as recommended. Of eculizumab recipients with outpatient prescription data, 7% (41/579) received antibiotics for ≥50% of the period of increased risk for meningococcal disease. CONCLUSION Many eculizumab recipients had an undetermined indication for eculizumab use; few were up-to-date for recommended meningococcal vaccines or were prescribed antibiotics long-term. These findings can inform further investigation of how to best protect this population from meningococcal disease.
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Ochando J, Ordikhani F, Boros P, Jordan S. The innate immune response to allotransplants: mechanisms and therapeutic potentials. Cell Mol Immunol 2019; 16:350-356. [PMID: 30804476 DOI: 10.1038/s41423-019-0216-2] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Accepted: 02/12/2019] [Indexed: 02/08/2023] Open
Abstract
Surgical trauma and ischemia reperfusion injury (IRI) are unavoidable aspects of any solid organ transplant procedure. They trigger a multifactorial antigen-independent inflammatory process that profoundly affects both the early and long-term outcomes of the transplanted organ. The injury associated with donor organ procurement, storage, and engraftment triggers innate immune activation that inevitably results in cell death, which may occur in many different forms. Dying cells in donor grafts release damage-associated molecular patterns (DAMPs), which alert recipient innate cells, including macrophages and dendritic cells (DCs), through the activation of the complement cascade and toll-like receptors (TLRs). The long-term effect of inflammation on innate immune cells is associated with changes in cellular metabolism that skew the cells towards aerobic glycolysis, resulting in innate immune cell activation and inflammatory cytokine production. The different roles of proinflammatory cytokines in innate immune activation have been described, and these cytokines also stimulate optimal T-cell expansion during allograft rejection. Therefore, early innate immune events after organ transplantation determine the fate of the adaptive immune response. In this review, we summarize the contributions of innate immunity to allograft rejection and discuss recent studies and emerging concepts in the targeted delivery of therapeutics to modulate the innate immune system to enhance allograft survival.
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Affiliation(s)
- Jordi Ochando
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Immunología de Trasplantes, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain
| | - Farideh Ordikhani
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Peter Boros
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Stefan Jordan
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Wijnsma KL, Duineveld C, Wetzels JFM, van de Kar NCAJ. Eculizumab in atypical hemolytic uremic syndrome: strategies toward restrictive use. Pediatr Nephrol 2019; 34:2261-2277. [PMID: 30402748 PMCID: PMC6794245 DOI: 10.1007/s00467-018-4091-3] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Revised: 09/14/2018] [Accepted: 09/17/2018] [Indexed: 12/19/2022]
Abstract
With the introduction of the complement C5-inhibitor eculizumab, a new era was entered for patients with atypical hemolytic uremic syndrome (aHUS). Eculizumab therapy very effectively reversed thrombotic microangiopathy and reduced mortality and morbidity. Initial guidelines suggested lifelong treatment and recommended prophylactic use of eculizumab in aHUS patients receiving a kidney transplant. However, there is little evidence to support lifelong therapy or prophylactic treatment in kidney transplant recipients. Worldwide, there is an ongoing debate regarding the optimal dose and duration of treatment, particularly in view of the high costs and potential side effects of eculizumab. An increasing but still limited number of case reports and small cohort studies suggest that a restrictive treatment regimen is feasible. We review the current literature and focus on the safety and efficacy of restrictive use of eculizumab. Our current treatment protocol is based on restrictive use of eculizumab. Prospective monitoring will provide more definite proof of the feasibility of such restrictive treatment.
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Affiliation(s)
- Kioa L. Wijnsma
- Radboud Institute for Molecular Life Sciences, Amalia Children’s Hospital, Department of Pediatric Nephrology, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Caroline Duineveld
- Radboud Institute for Molecular Life Sciences, Amalia Children’s Hospital, Department of Pediatric Nephrology, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands ,Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jack F. M. Wetzels
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Nicole C. A. J. van de Kar
- Radboud Institute for Molecular Life Sciences, Amalia Children’s Hospital, Department of Pediatric Nephrology, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
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Cidon EU, Martinez PA, Hickish T. Gemcitabine-induced haemolytic uremic syndrome, although infrequent, can it be prevented: A case report and review of literature. World J Clin Cases 2018; 6:531-537. [PMID: 30397609 PMCID: PMC6212612 DOI: 10.12998/wjcc.v6.i12.531] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Revised: 09/08/2018] [Accepted: 10/09/2018] [Indexed: 02/05/2023] Open
Abstract
Gemcitabine is an antineoplastic used to treat several malignancies including pancreatic cancer. Its toxicity profile is well known with myelotoxicity, increased vascular permeability and peripheral oedema as most frequent adverse events. However, several cases of acute renal failure have been reported and haemolytic uremic syndrome (HUS) seems to be the underlying process. The cause of HUS remains unknown but its consequences can be lethal. Therefore, a high grade of suspicion is crucial to diagnose it and promptly treat it. This hopefully will reduce its morbidity. HUS is characterized by progressive renal failure associated with microangiopathic haemolytic anaemia and thrombocytopenia. The primary event is damage to endothelial cells and thrombotic microangiopathy (TMA) is the histopathological lesion. TMA affects mainly renal microvasculature. However, some cases evolve with central nervous or cardiovascular systems involvement. We present here a case of gemcitabine-induced HUS, with renal and cardiovascular system affected at the time of diagnosis which to our knowledge this is the first time of such case to be reported.
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Affiliation(s)
- Esther U Cidon
- Department of Medical Oncology, Royal Bournemouth and Christchurch Hospital NHS Foundation Trust, Bournemouth BH7 7DW, United Kingdom
| | - Pilar A Martinez
- Department of Oncology, Clinical University Hospital, Valladolid 47003, Spain
| | - Tamas Hickish
- Department of Medical Oncology, Royal Bournemouth and Christchurch Hospital NHS Foundation Trust and Bournemouth University, Bournemouth BH7 7DW, United Kingdom
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12
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Attar RZ, Ramel EI, Safdar OY, Desoky S. A case of patient with renal lupus with an initial presentation of hemolytic uremic syndrome triggered by streptococcal infection. Clin Case Rep 2018; 6:712-718. [PMID: 29636946 PMCID: PMC5889269 DOI: 10.1002/ccr3.1425] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Revised: 08/30/2017] [Accepted: 01/05/2018] [Indexed: 11/23/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a systemic disease that is presented in a myriad of ways. Renal involvement is common in SLE and usually presents clinically as glomerulonephritis. We describe patients with SLE presented initially with hemolytic uremic syndrome which is a distinctive initial presentation.
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Affiliation(s)
- Rahaf Z. Attar
- College of medicineKing Abdulaziz UniversityJeddahSaudi Arabia
| | - Enas I. Ramel
- College of medicineKing Abdulaziz UniversityJeddahSaudi Arabia
| | - Osama Y. Safdar
- Faculty of MedicinePediatric Nephrology Center of ExcellenceKing Abdulaziz UniversityJeddahSaudi Arabia
| | - Sherif Desoky
- Faculty of MedicinePediatric Nephrology Center of ExcellenceKing Abdulaziz UniversityJeddahSaudi Arabia
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Krishnappa V, Gupta M, Shah H, Das A, Tanphaichitr N, Novak R, Raina R. The use of eculizumab in gemcitabine induced thrombotic microangiopathy. BMC Nephrol 2018; 19:9. [PMID: 29329518 PMCID: PMC5767063 DOI: 10.1186/s12882-018-0812-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 01/01/2018] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Thrombotic microangiopathy (TMA) secondary to gemcitabine therapy (GiTMA) is a very rare pathology that carries a poor prognosis, with nearly half of the cases progressing to end stage renal disease. GiTMA is most commonly associated with adenocarcinomas, most notably pancreatic cancers. The mainstay of management is withdrawal of the offending drug and supportive care. Plasmapheresis has a limited role and hemodialysis may help in the management of fluid overload secondary to renal failure. Furthermore, a C5 inhibitor, eculizumab, has been successfully used in the treatment of GiTMA. CASE PRESENTATION A 64-year-old Caucasian female with history of pancreatic adenocarcinoma on gemcitabine chemotherapy presented with signs and symptoms of fluid overload and was found to have abnormal kidney function. Her BP was 195/110 mmHg, serum creatinine 4.48 mg/dl, hemoglobin 8.2 g/dl, platelets 53 × 103/cmm, lactate dehydrogenase 540 IU/L, and was found to have schistocytes on blood film. A diagnosis of TMA secondary to gemcitabine therapy was suspected. Hemodialysis for volume overload and daily plasmapheresis were initiated. After six days of plasmapheresis, renal function did not improve. Further work up revealed ADAMTS 13 activity >15%, low C3, and stool culture and Shiga-toxin PCR were negative. Renal biopsy was consistent with TMA. Gemcitabine was discontinued, but renal function failed to improve and eculizumab therapy was considered due to suspicion of aHUS. Serum creatinine >2.26 mg/dl and a platelet count of >/= 30 × 109/L is highly suggestive of aHUS, while TTP is more likely when creatinine is <2.26 mg/dl and platelet count of <30 × 109/L. She received intravenous eculizumab for eight months, which resulted in significant improvement of renal function. Other markers of hemolysis, namely LDH and bilirubin, also rapidly improved following eculizumab therapy. Plasmapheresis and hemodialysis were discontinued after two and eight weeks of initiation respectively. CONCLUSION Chemotherapy induced TMA is very rare and requires a high index of clinical suspicion for timely diagnosis. Discontinuation of the offending drug and supportive care is the main stay of treatment; however, eculizumab has been shown to be beneficial in GiTMA. Further research is required to validate this approach.
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Affiliation(s)
- Vinod Krishnappa
- Department of Internal Medicine and Nephrology, Cleveland Clinic Akron General, 1 Akron General Ave, Akron, OH 44307 USA
| | - Mohit Gupta
- Department of Internal Medicine and Nephrology, Cleveland Clinic Akron General, 1 Akron General Ave, Akron, OH 44307 USA
- Department of Nephrology, Weill Cornell Medicine/New York Presbyterian, New York, USA
| | - Haikoo Shah
- Northeast Ohio Medical University, Rootstown, OH USA
| | - Abhijit Das
- Northeast Ohio Medical University, Rootstown, OH USA
| | - Natthavat Tanphaichitr
- Department of Internal Medicine and Nephrology, Cleveland Clinic Akron General, 1 Akron General Ave, Akron, OH 44307 USA
| | - Robert Novak
- Department of Pathology, Akron Children’s Hospital, Akron, OH USA
| | - Rupesh Raina
- Department of Internal Medicine and Nephrology, Cleveland Clinic Akron General, 1 Akron General Ave, Akron, OH 44307 USA
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Midterm Outcomes of 12 Renal Transplant Recipients Treated With Eculizumab to Prevent Atypical Hemolytic Syndrome Recurrence. Transplantation 2017; 101:2924-2930. [DOI: 10.1097/tp.0000000000001909] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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15
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Brocklebank V, Kavanagh D. Complement C5-inhibiting therapy for the thrombotic microangiopathies: accumulating evidence, but not a panacea. Clin Kidney J 2017; 10:600-624. [PMID: 28980670 PMCID: PMC5622895 DOI: 10.1093/ckj/sfx081] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Accepted: 06/21/2017] [Indexed: 02/07/2023] Open
Abstract
Thrombotic microangiopathy (TMA), characterized by organ injury occurring consequent to severe endothelial damage, can manifest in a diverse range of diseases. In complement-mediated atypical haemolytic uraemic syndrome (aHUS) a primary defect in complement, such as a mutation or autoantibody leading to over activation of the alternative pathway, predisposes to the development of disease, usually following exposure to an environmental trigger. The elucidation of the pathogenesis of aHUS resulted in the successful introduction of the complement inhibitor eculizumab into clinical practice. In other TMAs, although complement activation may be seen, its role in the pathogenesis remains to be confirmed by an interventional trial. Although many case reports in TMAs other than complement-mediated aHUS hint at efficacy, publication bias, concurrent therapies and in some cases the self-limiting nature of disease make broader interpretation difficult. In this article, we will review the evidence for the role of complement inhibition in complement-mediated aHUS and other TMAs.
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Affiliation(s)
- Vicky Brocklebank
- The National Renal Complement Therapeutics Centre (NRCTC), Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - David Kavanagh
- The National Renal Complement Therapeutics Centre (NRCTC), Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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16
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Legendre CM, Campistol JM, Feldkamp T, Remuzzi G, Kincaid JF, Lommelé Å, Wang J, Weekers LE, Sheerin NS. Outcomes of patients with atypical haemolytic uraemic syndrome with native and transplanted kidneys treated with eculizumab: a pooled post hoc analysis. Transpl Int 2017; 30:1275-1283. [PMID: 28801959 DOI: 10.1111/tri.13022] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Revised: 03/20/2017] [Accepted: 07/31/2017] [Indexed: 12/31/2022]
Abstract
Atypical haemolytic uraemic syndrome (aHUS) often leads to end-stage renal disease (ESRD) and kidney transplantation; graft loss rates are high due to disease recurrence. A post hoc analysis of four prospective clinical trials in aHUS was performed to evaluate eculizumab, a terminal complement inhibitor, in patients with native or transplanted kidneys. The trials included 26-week treatment and extension periods. Dialysis, transplant and graft loss were evaluated. Study endpoints included complete thrombotic microangiopathy (TMA) response, TMA event-free status, haematologic and renal parameters and adverse events. Of 100 patients, 74 had native kidneys and 26 in the transplant subgroup had a collective history of 38 grafts. No patients lost grafts and only one with pre-existing ESRD received a transplant on treatment. Efficacy endpoints were achieved similarly in both subgroups. After 26 weeks, mean absolute estimated glomerular filtration rate increased from baseline to 61 and 37 ml/min/1.73 m2 in native (n = 71; P < 0.0001) and transplanted kidney (n = 25; P = 0.0092) subgroups. Two patients (one/subgroup) developed meningococcal infections; both recovered, one continued therapy. Eculizumab was well tolerated. Eculizumab improved haematologic and renal outcomes in both subgroups. In patients with histories of multiple graft losses, eculizumab protected kidney function.
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Affiliation(s)
- Christophe M Legendre
- Adult Kidney Transplant Unit, Université Paris Descartes and Hôpital Necker, Paris, France
| | - Josep M Campistol
- Renal Transplant Unit, Nephrology and Urology Department, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Thorsten Feldkamp
- Department of Nephrology and Hypertension, University Hospital Schleswig-Holstein, Christian Albrechts University Kiel, Kiel, Germany
| | - Giuseppe Remuzzi
- Unit of Nephrology, Division of Nephrology and Dialysis, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Azienda Ospedaliera Ospedale Papa Giovanni XXIII, Bergamo, Italy.,Department of Biomedical and Clinical Science, L. Sacco, University of Milan, Milan, Italy
| | - John F Kincaid
- Global Medical Affairs, Alexion Pharmaceuticals, Inc., New Haven, CT, USA
| | - Åsa Lommelé
- Medical & Scientific Communication, Alexion Pharma GmbH, Zürich, Switzerland
| | - Jimmy Wang
- Biostatistics, Alexion Pharmaceuticals, Inc., New Haven, CT, USA
| | - Laurent E Weekers
- Service of Nephrology, Dialysis and Transplantation, Centre Hospitalier Universitaire de Liège, Liège, Belgium
| | - Neil S Sheerin
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
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17
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Tatapudi VS, Montgomery RA. Pharmacologic Complement Inhibition in Clinical Transplantation. CURRENT TRANSPLANTATION REPORTS 2017; 4:91-100. [PMID: 29214126 PMCID: PMC5707230 DOI: 10.1007/s40472-017-0148-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Purpose of Review Over the past two decades, significant strides made in our understanding of the etiology of antibody-mediated rejection (AMR) in transplantation have put the complement system in the spotlight. Here, we review recent progress made in the field of pharmacologic complement inhibition in clinical transplantation and aim to understand the impact of this therapeutic approach on outcomes in transplant recipients. Recent Findings Encouraged by the success of agents targeting the complement cascade in disorders of unrestrained complement activation like paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), investigators are testing the safety and efficacy of pharmacologic complement blockade in mitigating allograft injury in conditions ranging from AMR to recurrent post-transplant aHUS, C3 glomerulopathies and antiphospholipid anti-body syndrome (APS). A recent prospective study demonstrated the efficacy of terminal complement inhibition with eculizumab in the prevention of acute AMR in human leukocyte antigen (HLA)-incompatible living donor renal transplant recipients. C1 esterase inhibitor (C1-INH) was well tolerated in two recent studies in the treatment of AMR and was associated with improved renal allograft function. Summary Pharmacologic complement inhibition is emerging as valuable therapeutic tool, especially in the management of highly sensitized renal transplant recipients. Novel and promising agents that target various elements in the complement cascade are in development. Graphical Abstractᅟ.
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Affiliation(s)
- Vasishta S Tatapudi
- Division of Nephrology, Department of Internal Medicine, NYU Langone Medical Center, New York, NY 10016 USA
| | - Robert A Montgomery
- NYU Langone Transplant Institute, 530 First Avenue, HCC 7A, New York, NY 10016 USA
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18
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Sun ZJ, Du X, Su LL, Zhang XD, Wang Y, Ren L, Wang W. Successful Renal Transplantation in a Patient with Atypical Hemolytic Uremic Syndrome Treated with Eculizumab in China. Chin Med J (Engl) 2017; 129:1379-81. [PMID: 27231180 PMCID: PMC4894053 DOI: 10.4103/0366-6999.182843] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Affiliation(s)
- Ze-Jia Sun
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Xin Du
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Lu-Lu Su
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Xiao-Dong Zhang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Yong Wang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Liang Ren
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Wei Wang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
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19
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Okumi M, Tanabe K. Prevention and treatment of atypical haemolytic uremic syndrome after kidney transplantation. Nephrology (Carlton) 2017; 21 Suppl 1:9-13. [PMID: 26988663 DOI: 10.1111/nep.12776] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Atypical haemolytic uraemic syndrome is a rare disorder characterized by an over-activated, dysregulated alternative complement pathway due to genetic mutation and environmental triggers. Atypical haemolytic uraemic syndrome is a serious, life-threatening disease characterized by thrombotic microangiopathy, which causes haemolytic anaemia, thrombocytopaenia, and acute renal failure. Since recurrences of atypical haemolytic uraemic syndrome frequently lead to end-stage kidney disease even in renal allografts, kidney transplantation for patients with end-stage kidney disease secondary to atypical haemolytic uraemic syndrome has long been contraindicated. However, over the past several years, advancements in the management of atypical haemolytic uraemic syndrome have allowed successful kidney transplantation in these patients. The key factor of this success is eculizumab, a humanized anti-C5 monoclonal antibody, which inhibits terminal membrane-attack complex formation and thrombotic microangiopathy progression. In the setting of kidney transplantation, there are different possible triggers of post-transplant atypical haemolytic uraemic syndrome recurrence, such as brain-death related injury, ischaemia-reperfusion injury, infections, the use of immunosuppressive drugs, and rejection. Principal strategies are to prevent endothelial damage that could potentially activate alternative complement pathway activation and subsequently lead to atypical haemolytic uraemic syndrome recurrence in kidney allograft. Published data shows that prophylactic eculizumab therapy is highly effective for the prevention of post-transplant atypical haemolytic uraemic syndrome recurrence, and prompt treatment with eculizumab as soon as recurrence is diagnosed is important to maintain renal allograft function. Further study to determine the optimal dosing and duration of prophylactic therapy and treatment of post-transplant atypical haemolytic uraemic syndrome recurrence is needed.
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Affiliation(s)
- Masayoshi Okumi
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Kazunari Tanabe
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
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20
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Harder MJ, Kuhn N, Schrezenmeier H, Höchsmann B, von Zabern I, Weinstock C, Simmet T, Ricklin D, Lambris JD, Skerra A, Anliker M, Schmidt CQ. Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation. Blood 2017; 129:970-980. [PMID: 28028023 PMCID: PMC5324716 DOI: 10.1182/blood-2016-08-732800] [Citation(s) in RCA: 113] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Accepted: 12/16/2016] [Indexed: 12/21/2022] Open
Abstract
Eculizumab inhibits the terminal, lytic pathway of complement by blocking the activation of the complement protein C5 and shows remarkable clinical benefits in certain complement-mediated diseases. However, several reports suggest that activation of C5 is not always completely suppressed in patients even under excess of eculizumab over C5, indicating that residual C5 activity may derogate the drug's therapeutic benefit under certain conditions. By using eculizumab and the tick-derived C5 inhibitor coversin, we determined conditions ex vivo in which C5 inhibition is incomplete. The degree of such residual lytic activity depended on the strength of the complement activator and the resulting surface density of the complement activation product C3b, which autoamplifies via the alternative pathway (AP) amplification loop. We show that at high C3b densities required for binding and activation of C5, both inhibitors reduce but do not abolish this interaction. The decrease of C5 binding to C3b clusters in the presence of C5 inhibitors correlated with the levels of residual hemolysis. However, by employing different C5 inhibitors simultaneously, residual hemolytic activity could be abolished. The importance of AP-produced C3b clusters for C5 activation in the presence of eculizumab was corroborated by the finding that residual hemolysis after forceful activation of the classical pathway could be reduced by blocking the AP. By providing insights into C5 activation and inhibition, our study delivers the rationale for the clinically observed phenomenon of residual terminal pathway activity under eculizumab treatment with important implications for anti-C5 therapy in general.
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Affiliation(s)
- Markus J Harder
- Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany
| | - Nadine Kuhn
- Lehrstuhl für Biologische Chemie, Technische Universität München, Freising, Germany
| | - Hubert Schrezenmeier
- Institute of Transfusion Medicine, University of Ulm, Ulm, Germany
- Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service and University Hospital of Ulm, Ulm, Germany; and
| | - Britta Höchsmann
- Institute of Transfusion Medicine, University of Ulm, Ulm, Germany
- Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service and University Hospital of Ulm, Ulm, Germany; and
| | - Inge von Zabern
- Institute of Transfusion Medicine, University of Ulm, Ulm, Germany
- Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service and University Hospital of Ulm, Ulm, Germany; and
| | - Christof Weinstock
- Institute of Transfusion Medicine, University of Ulm, Ulm, Germany
- Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service and University Hospital of Ulm, Ulm, Germany; and
| | - Thomas Simmet
- Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany
| | - Daniel Ricklin
- Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service and University Hospital of Ulm, Ulm, Germany; and
| | - John D Lambris
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
| | - Arne Skerra
- Lehrstuhl für Biologische Chemie, Technische Universität München, Freising, Germany
| | - Markus Anliker
- Institute of Transfusion Medicine, University of Ulm, Ulm, Germany
- Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service and University Hospital of Ulm, Ulm, Germany; and
| | - Christoph Q Schmidt
- Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany
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21
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Thurman JM, Le Quintrec M. Targeting the complement cascade: novel treatments coming down the pike. Kidney Int 2016; 90:746-52. [PMID: 27325183 DOI: 10.1016/j.kint.2016.04.018] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 03/09/2016] [Accepted: 04/07/2016] [Indexed: 12/19/2022]
Abstract
The complement cascade is a vital component of both the innate and adaptive immune systems. Complement activation also contributes to the pathogenesis of many diseases, however, and the kidney is particularly susceptible to complement-mediated injury. Drugs that block complement activation can rapidly reduce tissue inflammation and also attenuate the adaptive immune response to foreign and tissue antigens. Eculizumab is a monoclonal antibody that prevents the cleavage of C5. It has been approved for the treatment of atypical hemolytic uremic syndrome, and it has been used in selected patients with other kidney diseases. Many additional drugs are also in development for blocking the complement cascade, including new monoclonal antibodies, recombinant proteins, small molecules, and small interfering RNA agents. Validation of these new drugs as effective treatments for kidney diseases faces several challenges. Many complement-mediated kidney diseases are rare, so it is not feasible to test all of the new drugs in numerous different rare diseases. The onset and course of the diseases are heterogeneous; many of these diseases also carry a lifelong risk of recurrence, and it is not clear how long complement inhibition must be maintained. In spite of these challenges, new therapeutic options for targeting the complement system will likely become available in the near future and may prove useful for treating patients with kidney disease.
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Affiliation(s)
- Joshua M Thurman
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, USA.
| | - Moglie Le Quintrec
- Department of Nephrology and Renal Transplantation, Lapeyronnie Hospital and INSERM U1183, Institute of Regenerative Medicine and Biotherapies, Montpellier, France
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22
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Riedl M, Hofer J, Giner T, Rosales A, Häffner K, Simonetti GD, Walden U, Maier T, Heininger D, Jeller V, Weiss G, van den Heuvel L, Zimmerhackl LB, Würzner R, Jungraithmayr TC. Novel biomarker and easy to perform ELISA for monitoring complement inhibition in patients with atypical hemolytic uremic syndrome treated with eculizumab. J Immunol Methods 2016; 435:60-7. [PMID: 27238216 DOI: 10.1016/j.jim.2016.05.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 04/27/2016] [Accepted: 05/24/2016] [Indexed: 12/31/2022]
Affiliation(s)
- Magdalena Riedl
- Department of Pediatrics, Innsbruck Medical University, Anichstraße 35, 6020 Innsbruck, Austria
| | - Johannes Hofer
- Department of Pediatrics, Innsbruck Medical University, Anichstraße 35, 6020 Innsbruck, Austria
| | - Thomas Giner
- Department of Pediatrics, Innsbruck Medical University, Anichstraße 35, 6020 Innsbruck, Austria
| | - Alejandra Rosales
- Department of Pediatrics, Innsbruck Medical University, Anichstraße 35, 6020 Innsbruck, Austria
| | - Karsten Häffner
- Department of Pediatric Nephrology, University Hospital Freiburg, Mathildenstraße 1, 79106 Freiburg, Germany
| | - Giacomo D Simonetti
- Department of Pediatric Nephrology, Children's Hospital, University of Bern, Freiburgstraße 18, 3010 Bern, Switzerland
| | - Ulrike Walden
- Department of Pediatric Nephrology, Children's Hospital Augsburg, Stenglinstraße 2, 86156 Augsburg, Germany
| | - Tanja Maier
- Department of Nephrology, Philipps-University Marburg, Baldingerstraße, 35033 Marburg, Germany
| | - Dorothea Heininger
- Department of Internal Medicine IV-Nephrology and Hypertension, Innsbruck Medical University, Anichstraße 35, 6020 Innsbruck, Austria
| | - Verena Jeller
- Department of Pediatrics, Innsbruck Medical University, Anichstraße 35, 6020 Innsbruck, Austria
| | - Günter Weiss
- Department of Internal Medicine VI-Infectious Diseases, Immunology, Rheumatology, Pneumology, Innsbruck Medical University, 6020 Innsbruck, Austria
| | - Lambert van den Heuvel
- Laboratory of Pediatric Nephrology, Department of Development & Regeneration, KU Leuven, 3000 Leuven, Belgium; Department of Pediatric Nephrology, Radboud University Medical Center, Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, Netherlands
| | - Lothar B Zimmerhackl
- Department of Pediatrics, Innsbruck Medical University, Anichstraße 35, 6020 Innsbruck, Austria
| | - Reinhard Würzner
- Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Schöpfstraße 41, 6020 Innsbruck, Austria.
| | - Therese C Jungraithmayr
- Department of Pediatrics, Innsbruck Medical University, Anichstraße 35, 6020 Innsbruck, Austria
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23
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Igarashi T, Ito S, Sako M, Saitoh A, Hataya H, Mizuguchi M, Morishima T, Ohnishi K, Kawamura N, Kitayama H, Ashida A, Kaname S, Taneichi H, Tang J, Ohnishi M. Guidelines for the management and investigation of hemolytic uremic syndrome. Clin Exp Nephrol 2016; 18:525-57. [PMID: 25099085 DOI: 10.1007/s10157-014-0995-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Takashi Igarashi
- National Center for Child Health and Development (NCCHD), 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan,
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24
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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.
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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
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25
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Frazer-Abel A, Sepiashvili L, Mbughuni MM, Willrich MAV. Overview of Laboratory Testing and Clinical Presentations of Complement Deficiencies and Dysregulation. Adv Clin Chem 2016; 77:1-75. [PMID: 27717414 DOI: 10.1016/bs.acc.2016.06.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Historically, complement disorders have been attributed to immunodeficiency associated with severe or frequent infection. More recently, however, complement has been recognized for its role in inflammation, autoimmune disorders, and vision loss. This paradigm shift requires a fundamental change in how complement testing is performed and interpreted. Here, we provide an overview of the complement pathways and summarize recent literature related to hereditary and acquired angioedema, infectious diseases, autoimmunity, and age-related macular degeneration. The impact of complement dysregulation in atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, and C3 glomerulopathies is also described. The advent of therapeutics such as eculizumab and other complement inhibitors has driven the need to more fully understand complement to facilitate diagnosis and monitoring. In this report, we review analytical methods and discuss challenges for the clinical laboratory in measuring this complex biochemical system.
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Blasco Pelicano M, Rodríguez de Córdoba S, Campistol Plana JM. Síndrome hemolítico urémico atípico. Med Clin (Barc) 2015; 145:438-45. [DOI: 10.1016/j.medcli.2014.08.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Revised: 07/25/2014] [Accepted: 08/29/2014] [Indexed: 12/15/2022]
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27
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Campistol JM, Arias M, Ariceta G, Blasco M, Espinosa L, Espinosa M, Grinyó JM, Macía M, Mendizábal S, Praga M, Román E, Torra R, Valdés F, Vilalta R, Rodríguez de Córdoba S. An update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document. Nefrologia 2015; 35:421-47. [PMID: 26456110 DOI: 10.1016/j.nefro.2015.07.005] [Citation(s) in RCA: 124] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Revised: 06/30/2015] [Accepted: 07/03/2015] [Indexed: 02/07/2023] Open
Abstract
Haemolytic uraemic syndrome (HUS) is a clinical entity defined as the triad of nonimmune haemolytic anaemia, thrombocytopenia, and acute renal failure, in which the underlying lesions are mediated by systemic thrombotic microangiopathy (TMA). Different causes can induce the TMA process that characterizes HUS. In this document we consider atypical HUS (aHUS) a sub-type of HUS in which the TMA phenomena are the consequence of the endotelial damage in the microvasculature of the kidneys and other organs due to a disregulation of the activity of the complement system. In recent years, a variety of aHUs-related mutations have been identified in genes of the the complement system, which can explain approximately 60% of the aHUS cases, and a number of mutations and polymorphisms have been functionally characterized. These findings have stablished that aHUS is a consequence of the insufficient regulation of the activiation of the complement on cell surfaces, leading to endotelial damage mediated by C5 and the complement terminal pathway. Eculizumab is a monoclonal antibody that inhibits the activation of C5 and blocks the generation of the pro-inflammatory molecule C5a and the formation of the cell membrane attack complex. In prospective studies in patients with aHUS, the use of Eculizumab has shown a fast and sustained interruption of the TMA process and it has been associated with significative long-term improvements in renal function, the interruption of plasma therapy and important reductions in the need of dialysis. According to the existing literature and the accumulated clinical experience, the Spanish aHUS Group published a consensus document with recommendations for the treatment of aHUs (Nefrologia 2013;33[1]:27-45). In the current online version of this document, we update the aetiological classification of TMAs, the pathophysiology of aHUS, its differential diagnosis and its therapeutic management.
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Affiliation(s)
| | - Manuel Arias
- Servicio de Nefrología, Hospital Universitario Marqués de Valdecilla, Santander, España
| | - Gema Ariceta
- Servicio de Nefrología Pediátrica, Hospital Universitari Materno-Infantil Vall d'Hebrón, Universidad Autónoma de Barcelona, Barcelona, España
| | - Miguel Blasco
- Servicio de Nefrología, Hospital Clínic, Barcelona, España
| | - Laura Espinosa
- Servicio de Nefrología Pediátrica, Hospital La Paz, Madrid, España
| | - Mario Espinosa
- Servicio de Nefrología, Hospital Universitario Reina Sofía, Córdoba, España
| | - Josep M Grinyó
- Servicio de Nefrología, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, España
| | - Manuel Macía
- Servicio de Nefrología, Hospital Virgen de la Candelaria, Santa Cruz de Tenerife, España
| | | | - Manuel Praga
- Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, España
| | - Elena Román
- Servicio de Nefrología Pediátrica, Hospital La Fe, Valencia, España
| | - Roser Torra
- Enfermedades Renales Hereditarias, Fundació Puigvert, Barcelona, España
| | - Francisco Valdés
- Servicio de Nefrología, Complejo Hospitalario A Coruña, A Coruña, España
| | - Ramón Vilalta
- Servicio de Nefrología Pediátrica, Hospital Universitari Materno-Infantil Vall d'Hebrón, Universidad Autónoma de Barcelona, Barcelona, España
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28
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Sexton DJ, Reule S, Solid CA, Chen SC, Collins AJ, Foley RN. End-stage renal disease from hemolytic uremic syndrome in the United States, 1995-2010. Hemodial Int 2015; 19:521-30. [PMID: 25689876 PMCID: PMC4539282 DOI: 10.1111/hdi.12281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Management of hemolytic uremic syndrome (HUS) has evolved rapidly, and optimal treatment strategies are controversial. However, it is unknown whether the burden of end-stage renal disease (ESRD) from HUS has changed, and outcomes on dialysis in the United States are not well described. We retrospectively examined data for patients initiating maintenance renal replacement therapy (RRT) (n = 1,557,117), 1995-2010, to define standardized incidence ratios (SIRs) and outcomes of ESRD from HUS) (n = 2241). Overall ESRD rates from HUS in 2001-2002 were 0.5 cases/million per year and were higher for patients characterized by age 40-64 years (0.6), ≥65 years (0.7), female sex (0.6), and non-Hispanic African American race (0.7). Standardized incidence ratios remained unchanged (P ≥ 0.05) between 2001-2002 and 2009-2010 in the overall population. Compared with patients with ESRD from other causes, patients with HUS were more likely to be younger, female, white, and non-Hispanic. Over 5.4 years of follow-up, HUS patients differed from matched controls with ESRD from other causes by lower rates of death (8.3 per 100 person-years in cases vs. 10.4 in controls, P < 0.001), listing for renal transplant (7.6 vs. 8.6 per 100 person-years, P = 0.04), and undergoing transplant (6.9 vs. 9 per 100 person-years, P < 0.001). The incidence of ESRD from HUS appears not to have risen substantially in the last decade. However, given that HUS subtypes could not be determined in this study, these findings should be interpreted with caution.
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Affiliation(s)
- Donal J. Sexton
- Chronic Disease Research Group, Minneapolis Medical Research Foundation, Minneapolis, Minnesota
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota
| | - Scott Reule
- Chronic Disease Research Group, Minneapolis Medical Research Foundation, Minneapolis, Minnesota
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota
| | - Craig A. Solid
- Chronic Disease Research Group, Minneapolis Medical Research Foundation, Minneapolis, Minnesota
| | - Shu-Cheng Chen
- Chronic Disease Research Group, Minneapolis Medical Research Foundation, Minneapolis, Minnesota
| | - Allan J. Collins
- Chronic Disease Research Group, Minneapolis Medical Research Foundation, Minneapolis, Minnesota
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota
| | - Robert N. Foley
- Chronic Disease Research Group, Minneapolis Medical Research Foundation, Minneapolis, Minnesota
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota
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Mallett A, Hughes P, Szer J, Tuckfield A, Van Eps C, Cambell SB, Hawley C, Burke J, Kausman J, Hewitt I, Parnham A, Ford S, Isbel N. Atypical haemolytic uraemic syndrome treated with the complement inhibitor eculizumab: the experience of the Australian compassionate access cohort. Intern Med J 2015; 45:1054-65. [DOI: 10.1111/imj.12864] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 07/19/2015] [Indexed: 02/03/2023]
Affiliation(s)
- A. Mallett
- Department of Renal Medicine; Royal Brisbane and Women's Hospital; Brisbane Queensland Australia
- Centre for Kidney Disease Research; Centre for Chronic Disease; CKD.QLD; School of Medicine; University of Queensland; Brisbane Queensland Australia
| | - P. Hughes
- Department of Nephrology; Royal Melbourne Hospital; Melbourne Victoria Australia
| | - J. Szer
- Department of Clinical Haematology and BMT Service; Royal Melbourne Hospital; Melbourne Victoria Australia
| | - A. Tuckfield
- Department of Clinical Haematology and BMT Service; Royal Melbourne Hospital; Melbourne Victoria Australia
| | - C. Van Eps
- Centre for Kidney Disease Research; Centre for Chronic Disease; CKD.QLD; School of Medicine; University of Queensland; Brisbane Queensland Australia
- Department of Nephrology; Princess Alexandra Hospital; Brisbane Queensland Australia
| | - S. B. Cambell
- Centre for Kidney Disease Research; Centre for Chronic Disease; CKD.QLD; School of Medicine; University of Queensland; Brisbane Queensland Australia
- Department of Nephrology; Princess Alexandra Hospital; Brisbane Queensland Australia
| | - C. Hawley
- Centre for Kidney Disease Research; Centre for Chronic Disease; CKD.QLD; School of Medicine; University of Queensland; Brisbane Queensland Australia
- Department of Nephrology; Princess Alexandra Hospital; Brisbane Queensland Australia
| | - J. Burke
- Centre for Kidney Disease Research; Centre for Chronic Disease; CKD.QLD; School of Medicine; University of Queensland; Brisbane Queensland Australia
- Department of Nephrology; Princess Alexandra Hospital; Brisbane Queensland Australia
| | - J. Kausman
- Department of Nephrology; The Royal Children's Hospital Melbourne; Melbourne Victoria Australia
| | - I. Hewitt
- Department of Nephrology; Princess Margaret Hospital for Children; Perth Western Australia Australia
| | - A. Parnham
- Department of Nephrology; Gold Coast Hospital; Gold Coast Queensland Australia
| | - S. Ford
- Department of Nephrology; Monash Medical Centre; Melbourne Victoria Australia
| | - N. Isbel
- Centre for Kidney Disease Research; Centre for Chronic Disease; CKD.QLD; School of Medicine; University of Queensland; Brisbane Queensland Australia
- Department of Nephrology; Princess Alexandra Hospital; Brisbane Queensland Australia
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Davin JC, van de Kar NCAJ. Advances and challenges in the management of complement-mediated thrombotic microangiopathies. Ther Adv Hematol 2015; 6:171-85. [PMID: 26288712 PMCID: PMC4530367 DOI: 10.1177/2040620715577613] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Complement activation plays a major role in several renal pathophysiological conditions. The three pathways of complement lead to C3 activation, followed by the formation of the anaphylatoxin C5a and the terminal membrane attack complex (MAC) in blood and at complement activating surfaces, lead to a cascade of events responsible for inflammation and for the induction of cell lysis. In case of ongoing uncontrolled complement activation, endothelial cells activation takes place, leading to events in which at the end thrombotic microangiopathy can occur. Atypical haemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy characterized by excessive complement activation on the surface of the microcirculation. It is a severe, rare disease which leads to end-stage renal failure (ESRF) and/or to death in more than 50% of patients without treatment. In the first decade of the second millennium, huge progress in understanding the aetiology of this disease was made, which paved the way to better treatment. First, protocols of plasma therapy for treatment, prevention of relapses and for renal transplantation in those patients were set up. Secondly, in some severe cases, combined kidney and liver transplantation was reported. Finally, at the end of this decade, the era of complement inhibitors, as anti-C5 monoclonal antibody (anti-C5 mAb) began. The past five years have seen growing evidence of the favourable effect of anti-C5 mAb in aHUS which has made this drug the first-line treatment in this disease. The possible complication of meningococcal infection needs appropriate vaccination before its use. Unfortunately, the worldwide use of anti-C5 mAb is limited by its very high price. In the future, extension of indications for anti-C5 mAb use, the elaboration of generics and of mAbs directed towards other complement factors of the terminal pathway of the complement system might succeed in reducing the cost of this new valuable therapeutic approach and render it available worldwide for patients from all social classes.
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Affiliation(s)
- Jean-Claude Davin
- Paediatric Nephrology Department, Emma Children's Hospital-Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam Z-O, The Netherlands
| | - Nicole C A J van de Kar
- Department of Paediatric Nephrology, Radboud University Medical Centre, Amalia Children's Hospital, Nijmegen, The Netherlands
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31
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Fremeaux-Bacchi V. Treatment of atypical uraemic syndrome in the era of eculizumab. Clin Kidney J 2015; 5:4-6. [PMID: 26069738 PMCID: PMC4400466 DOI: 10.1093/ckj/sfr177] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Accepted: 12/15/2011] [Indexed: 11/28/2022] Open
Affiliation(s)
- Veronique Fremeaux-Bacchi
- Department of Immunology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
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Picard C, Burtey S, Bornet C, Curti C, Montana M, Vanelle P. Pathophysiology and treatment of typical and atypical hemolytic uremic syndrome. ACTA ACUST UNITED AC 2015; 63:136-43. [DOI: 10.1016/j.patbio.2015.03.001] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 03/03/2015] [Indexed: 12/21/2022]
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Abstract
Primary disease recurrence after renal transplantation is mainly diagnosed by examination of biopsy samples, but can also be associated with clinical symptoms. In some patients, recurrence can lead to graft loss (7-8% of all graft losses). Primary disease recurrence is generally associated with a high risk of graft loss in patients with focal segmental glomerulosclerosis, membranous proliferative glomerulonephritis, primary hyperoxaluria or atypical haemolytic uraemic syndrome. By contrast, disease recurrence is associated with a limited risk of graft loss in patients with IgA nephropathy, renal involvement associated with Henoch-Schönlein purpura, antineutrophil cytoplasmic antibody-associated glomerulonephritis or lupus nephritis. The presence of systemic diseases that affect the kidneys, such as sickle cell anaemia and diabetes mellitus, also increases the risk of delayed graft loss. This Review provides an overview of the epidemiology, pathophysiology and management of primary disease recurrence in paediatric renal graft recipients, and describes the overall effect on graft survival of each of the primary diseases listed above. With appropriate management, few paediatric patients should be excluded from renal transplantation programmes because of an increased risk of recurrence.
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34
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Assessing complement blockade in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab. Blood 2015; 125:775-83. [DOI: 10.1182/blood-2014-03-560540] [Citation(s) in RCA: 97] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Key Points
CH50 activity reflects C5 blockade in PNH patients treated with eculizumab and is directly related to circulating free eculizumab levels. Both CH50 and free eculizumab level markers look promising for the monitoring of complement blockade in patients with PNH receiving eculizumab.
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Abstract
BACKGROUND Atypical hemolytic uremic syndrome (aHUS) is a rare disease with a high recurrence rate after kidney transplantation. In most cases, aHUS are caused by genetic mutations of components of the complement alternative pathway. In this single-center series, we present our data of 12 consecutive patients with aHUS and the outcome after kidney transplantation. METHODS In this 10-year retrospective study, we identified 12 patients with aHUS who were managed in our center since 2003. We reviewed clinical data, including genetic testing, posttransplant course and response to therapy including the prophylactic use of eculizumab. RESULTS Overall, eight patients are women. Six of our patients have at least one genetic mutation causing aHUS, including 4 with complement factor H mutations. Nine patients had at least one previous kidney transplant that failed secondary to recurrent aHUS (75% of our patients). Three patients were treated with eculizumab and plasmapheresis for recurrent aHUS after kidney transplantation; two of them responded to the therapy. Four patients received prophylactic eculizumab; three of them received 6 months and one has been on life long therapy. No signs of recurrence have been observed in these 4 patients so far. CONCLUSION Genetic mutations of the complement alternative pathway were confirmed in half of our patients, most of those mutations are in CHF. We demonstrate that treatment or prophylaxis with eculizumab was effective in reversing or preventing aHUS whether or not genetic complement mutations were identified.
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36
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Alasfar S, Alachkar N. Atypical hemolytic uremic syndrome post-kidney transplantation: two case reports and review of the literature. Front Med (Lausanne) 2014; 1:52. [PMID: 25593925 PMCID: PMC4292050 DOI: 10.3389/fmed.2014.00052] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2014] [Accepted: 11/29/2014] [Indexed: 01/09/2023] Open
Abstract
Atypical hemolytic uremic syndrome (aHUS) is a rare disorder characterized by over-activation and dysregulation of the alternative complement pathway. Its estimated prevalence is 1–2 per million. The disease is characterized by thrombotic microangiopathy, which causes anemia, thrombocytopenia, and acute renal failure. aHUS has more severe course compared to typical (infection-induced) HUS and is frequently characterized by relapses that leads to end stage renal disease. For a long time, kidney transplantation for these patients was contraindicated because of high rate of recurrence and subsequent renal graft loss. The post-kidney transplantation recurrence rate largely depends on the pathogenetic mechanisms involved. However, over the past several years, advancements in the understanding and therapeutics of aHUS have allowed successful kidney transplantation in these patients. Eculizumab, which is a complement C5 antibody that inhibits complement factor 5a and subsequent formation of the membrane-attack complex, has been used in prevention and treatment of post-transplant aHUS recurrence. In this paper, we present two new cases of aHUS patients who underwent successful kidney transplantation in our center with the use of prophylactic and maintenance eculizumab therapy that have not been published before. The purpose of reporting these two cases is to emphasize the importance of using eculizumab as a prophylactic therapy to prevent aHUS recurrence post-transplant in high-risk patients. We will also review the current understanding of the genetics of aHUS, the pathogenesis of its recurrence after kidney transplantation, and strategies for prevention and treatment of post-transplant aHUS recurrence.
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Affiliation(s)
- Sami Alasfar
- Department of Medicine, Division of Nephrology, The Johns Hopkins University School of Medicine , Baltimore, MD , USA
| | - Nada Alachkar
- Department of Medicine, Division of Nephrology, The Johns Hopkins University School of Medicine , Baltimore, MD , USA
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37
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38
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Mella A, Messina M, Lavacca A, Biancone L. Complement cascade and kidney transplantation: The rediscovery of an ancient enemy. World J Transplant 2014; 4:168-175. [PMID: 25346889 PMCID: PMC4208079 DOI: 10.5500/wjt.v4.i3.168] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Revised: 06/28/2014] [Accepted: 09/10/2014] [Indexed: 02/05/2023] Open
Abstract
The identification of complement activity in serum and immunohistochemical samples represents a core element of nephropathology. On the basis of this observation, different experimental models and molecular studies have shown the role of this cascade in glomerular disease etiology, but the absence of inhibiting drugs have limited its importance. Since 2006, the availability of target-therapies re-defined this ancient pathway, and its blockage, as the new challenging frontier in renal disease treatment. In the graft, the complement cascade is able to initiate and propagate the damage in ischemia-reperfusion injury, C3 glomerulopathy, acute and chronic rejection, atypical hemolytic uremic syndrome and, probably, in many other conditions. The importance of complement-focused research is revealed by the evidence that eculizumab, the first complement-targeting drug, is now considered a valid option in atypical hemolytic uremic syndrome treatment but it is also under investigation in all the aforementioned conditions. In this review we evaluate the importance of complement cascade in renal transplantation diseases, focusing on available treatments, and we propose a speculative identification of areas where complement inhibition may be a promising strategy.
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39
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Yenerel MN. Atypical Hemolytic Uremic Syndrome: Differential Diagnosis from TTP/HUS and Management. Turk J Haematol 2014; 31:216-25. [PMID: 25319590 PMCID: PMC4287021 DOI: 10.4274/tjh.2013.0374] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Accepted: 07/09/2014] [Indexed: 01/17/2023] Open
Abstract
Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA). It has an unfavorable outcome with death rates as high as 25% during the acute phase and up to 50% of cases progressing to end-stage renal failure. Uncontrolled complement activation through the alternative pathway is thought to be the main underlying pathopysiology of aHUS and corresponds to all the deleterious findings of the disease. Thrombotic thrombocytopenic purpura (TTP) and Shiga toxin-associated HUS are the 2 other important TMA diseases. Although differentiating HUS from TTP is relatively easy in children with a preceding diarrheal illness or invasive S. pneumoniae, differentiating aHUS from TTP or other microangiopathic disorders can present a major diagnostic challenge in adults. ADAMTS13 analysis is currently the most informative diagnostic test for differentiating TTP, congenital TTP, and aHUS. Today empiric plasma therapy still is recommended by expert opinion to be used as early as possible in any patient with symptoms of aHUS. The overall treatment goal remains restoration of a physiological balance between activation and control of the alternative complement pathway. So it is a reasonable approach to block the terminal complement complex with eculizumab in order to prevent further organ injury and increase the likelihood organ recovery. Persistence of hemolysis or lack of improvement of renal function after 3-5 daily plasmaphereses have to be regarded as the major criteria for uncontrolled TMA even if platelet count has normalized and as an indication to switch the treatment to eculizumab. Eculizumab has changed the future perspectives of patients with aHUS and both the FDA and the EMA have approved it as life-long treatment. However, there are still some unresolved issues about the follow-up such as the optimal duration of eculizumab treatment and whether it can be stopped or how to stop the therapy.
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Affiliation(s)
- Mustafa N Yenerel
- İstanbul University İstanbul Faculty of Medicine, Department of Internal Medicine, Division of Hematology, İstanbul, Turkey. E-ma-il:
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40
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Ranch D, Crowther B, Arar M, Assanasen C. Prophylactic eculizumab for kidney transplantation in a child with atypical hemolytic uremic syndrome due to complement factor H mutation. Pediatr Transplant 2014; 18:E185-9. [PMID: 24931815 DOI: 10.1111/petr.12290] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/17/2014] [Indexed: 11/30/2022]
Abstract
We present a case of successful deceased-donor kidney transplantation in a three-yr-old child with aHUS due to complement factor H mutation, using only prophylactic eculizumab treatment prior to transplant. She developed disease exacerbation in the immediate post-operative period despite having therapeutic eculizumab concentrations and evidence for complete complement pathway blockade. The patient responded well to additional doses of eculizumab and has maintained excellent graft function and disease control in the first year post-transplantation. The optimal dosing scheme for eculizumab in the perioperative period remains to be determined. More sensitive biomarkers of early disease activity are needed to improve disease monitoring. Finally, the duration of eculizumab therapy in patients with aHUS remains to be determined.
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Affiliation(s)
- Daniel Ranch
- Department of Pediatrics, University of Texas Health Science Center, San Antonio, TX, USA
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41
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Cugno M, Gualtierotti R, Possenti I, Testa S, Tel F, Griffini S, Grovetti E, Tedeschi S, Salardi S, Cresseri D, Messa P, Ardissino G. Complement functional tests for monitoring eculizumab treatment in patients with atypical hemolytic uremic syndrome. J Thromb Haemost 2014; 12:1440-8. [PMID: 24853860 DOI: 10.1111/jth.12615] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Accepted: 05/14/2014] [Indexed: 11/29/2022]
Abstract
BACKGROUND Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy characterized by hemolysis, platelet consumption, and renal injury. Eculizumab, a mAb that blocks complement activity, has been successfully used in aHUS. OBJECTIVES To optimize eculizumab therapy in aHUS patients by monitoring complement functional tests and markers of disease activity. PATIENTS/METHODS We studied 18 patients with aHUS (10 males; eight females; age range, 2-40 years) treated with eculizumab to induce and/or maintain disease remission. Patients were followed up for a cumulative observation period of 160 months, during which blood samples were obtained at various time intervals to measure complement activity (Wieslab for the classical, alternative and mannose-binding lectin complement pathways) and the parameters of disease activity (haptoglobin and lactate dehydrogenase serum levels, and platelet count). The intravenous eculizumab doses of 12-33 mg kg(-1) were initially administered every week, with the interval between doses being gradually extended to 2 weeks, 3 weeks and 4 weeks on the basis of strict laboratory and clinical control. RESULTS Complement activity was normal before eculizumab treatment, regardless of the state of the disease (activity or remission). It was completely suppressed 1 week, 2 weeks and 3 weeks after the last eculizumab infusion (mean values ± standard deviation: 1% ± 1% to 3% ± 5% for both the classical and alternative pathways; P = 0.0001 vs. baseline), and partially suppressed after 4 weeks (22% ± 26% and 16% ± 27%; P = 0.0001 vs. baseline). The increase in the time interval between eculizumab infusions did not change disease activity markers. CONCLUSIONS Monitoring complement tests can allow a safe reduction in the frequency of eculizumab administration in aHUS while keeping the disease in remission.
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Affiliation(s)
- M Cugno
- Medicina Interna, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
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Abstract
The recombinant humanized monoclonal antibody eculizumab (Soliris(®)) is a complement inhibitor that is indicated for use in the treatment of atypical haemolytic uraemic syndrome (aHUS). This article reviews the clinical efficacy and tolerability of eculizumab in the treatment of patients with aHUS, as well as summarizing its pharmacological properties. Intravenous eculizumab inhibited complement-mediated thrombotic microangiopathy in patients aged ≥12 years with aHUS, according to the results of two noncomparative, multinational, 26-week, phase II trials. At 26 weeks, the platelet count was significantly increased in patients with progressing thrombotic microangiopathy despite plasma exchange/infusion, and thrombotic microangiopathic event-free status was achieved in 80 % of patients with a long disease duration and chronic kidney disease who received long-term plasma exchange/infusion. Renal function and health-related quality of life also improved with eculizumab therapy in both studies. Outcomes were maintained or further improved throughout 2 years of follow-up. Eculizumab was also effective in adult and paediatric patients with aHUS, according to the results of additional prospective or retrospective trials. Intravenous eculizumab was generally well tolerated in patients with aHUS. Eculizumab is associated with an increased susceptibility to meningococcal infection, so patients should be immunized with meningococcal vaccine. In conclusion, eculizumab is a valuable new agent for use in the treatment of aHUS.
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Affiliation(s)
- Gillian M Keating
- Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, 0754, Auckland, New Zealand,
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43
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Affiliation(s)
- Larry A Greenbaum
- Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, 2015 Uppergate Drive NE, Atlanta, GA 30322, USA.
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44
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Abstract
Atypical hemolytic-uremic syndrome (aHUS) is associated with genetic complement abnormalities/anti-complement factor H antibodies, which paved the way to treatment with eculizumab. We studied 44 aHUS patients and their relatives to (1) test new assays of complement activation, (2) verify whether such abnormality occurs also in unaffected mutation carriers, and (3) search for a tool for eculizumab titration. An abnormal circulating complement profile (low C3, high C5a, or SC5b-9) was found in 47% to 64% of patients, irrespective of disease phase. Acute aHUS serum, but not serum from remission, caused wider C3 and C5b-9 deposits than control serum on unstimulated human microvascular endothelial cells (HMEC-1). In adenosine 5'-diphosphate-activated HMEC-1, also sera from 84% and 100% of patients in remission, and from all unaffected mutation carriers, induced excessive C3 and C5b-9 deposits. At variance, in most patients with C3 glomerulopathies/immune complex-associated membranoproliferative glomerulonephritis, serum-induced endothelial C5b-9 deposits were normal. In 8 eculizumab-treated aHUS patients, C3/SC5b-9 circulating levels did not change posteculizumab, whereas serum-induced endothelial C5b-9 deposits normalized after treatment, paralleled or even preceded remission, and guided drug dosing and timing. These results point to efficient complement inhibition on endothelium for aHUS treatment. C5b-9 endothelial deposits might help monitor eculizumab effectiveness, avoid drug overexposure, and save money considering the extremely high cost of the drug.
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45
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Abstract
Hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. The atypical form of HUS is a disease characterized by complement overactivation. Inherited defects in complement genes and acquired autoantibodies against complement regulatory proteins have been described. Incomplete penetrance of mutations in all predisposing genes is reported, suggesting that a precipitating event or trigger is required to unmask the complement regulatory deficiency. The underlying genetic defect predicts the prognosis both in native kidneys and after renal transplantation. The successful trials of the complement inhibitor eculizumab in the treatment of atypical HUS will revolutionize disease management.
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Affiliation(s)
- David Kavanagh
- The Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
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46
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Managing and preventing atypical hemolytic uremic syndrome recurrence after kidney transplantation. Curr Opin Nephrol Hypertens 2014; 22:704-12. [PMID: 24076560 DOI: 10.1097/mnh.0b013e328365b3fe] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW Several genetic and acquired abnormalities leading to abnormal activation of the alternative pathway of complement have been identified in patients with atypical hemolytic uremic syndrome (aHUS). The purpose of this review is to shed light on how advances in the understanding of aHUS pathogenesis have impacted on prevention and cure of aHUS recurrence after kidney transplantation. RECENT FINDINGS Studies over the past decade have shown that the risk of posttransplant recurrence of aHUS depends on the underlying genetic abnormality. The risk is high in patients with mutations in genes encoding circulating complement proteins and regulators, whereas patients with mutations in membrane cofactor protein generally show good transplant outcome. Given the poor outcome associated with recurrence, isolated renal transplantation had been contraindicated in aHUS patients. Combined kidney-liver transplantation and prophylactic plasma exchange have been used to prevent posttransplant recurrences. More recent data have provided evidence about the efficacy of the anti-C5 monoclonal antibody eculizumab in the prevention and treatment of posttransplant aHUS recurrences. SUMMARY This review summarizes recent advances on preventing and managing aHUS recurrence after kidney transplantation and discusses the issues that still need clarification.
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47
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Kaplan BS, Ruebner RL, Spinale JM, Copelovitch L. Current treatment of atypical hemolytic uremic syndrome. Intractable Rare Dis Res 2014; 3:34-45. [PMID: 25343125 PMCID: PMC4204535 DOI: 10.5582/irdr.2014.01001] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Revised: 02/17/2014] [Accepted: 02/23/2014] [Indexed: 12/25/2022] Open
Abstract
Tremendous advances have been made in understanding the pathogenesis of atypical Hemolytic Uremic Syndrome (aHUS), an extremely rare disease. Insights into the molecular biology of aHUS resulted in rapid advances in treatment with eculizumab (Soliris(®), Alexion Pharmaceuticals Inc.). Historically, aHUS was associated with very high rates of mortality and morbidity. Prior therapies included plasma therapy and/or liver transplantation. Although often life saving, these were imperfect and had many complications. We review the conditions included under the rubric of aHUS: S. pneumoniae HUS (SpHUS), inborn errors of metabolism, and disorders of complement regulation, emphasizing their differences and similarities. We focus on the clinical features, diagnosis, and pathogenesis, and treatment of aHUS that results from mutations in genes encoding alternative complement regulators, SpHUS and HUS associated with inborn errors of metabolism. Mutations in complement genes, or antibodies to their protein products, result in unregulated activity of the alternate complement pathway, endothelial injury, and thrombotic microangiopathy (TMA). Eculizumab is a humanized monoclonal antibody that inhibits the production of the terminal complement components C5a and the membrane attack complex (C5b-9) by binding to complement protein C5a. This blocks the proinflammatory and cytolytic effects of terminal complement activation. Eculizumab use has been reported in many case reports, and retrospective and prospective clinical trials in aHUS. There have been few serious side effects and no reports of tachphylaxis or drug resistance. The results are very encouraging and eculizumab is now recognized as the treatment of choice for aHUS.
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Affiliation(s)
- Bernard S. Kaplan
- Division of Pediatric Nephrology, Department of Pediatrics, The Children's Hospital of Philadelphia, and The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Address correspondence to: Dr. Bernard S. Kaplan, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, USA. E-mail:
| | - Rebecca L. Ruebner
- Division of Pediatric Nephrology, Department of Pediatrics, The Children's Hospital of Philadelphia, and The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Joann M. Spinale
- Division of Pediatric Nephrology, Department of Pediatrics, The Children's Hospital of Philadelphia, and The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Lawrence Copelovitch
- Division of Pediatric Nephrology, Department of Pediatrics, The Children's Hospital of Philadelphia, and The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Cocaine-associated retiform purpura: a C5b-9-mediated microangiopathy syndrome associated with enhanced apoptosis and high levels of intercellular adhesion molecule-1 expression. Am J Dermatopathol 2014; 35:722-30. [PMID: 23392134 DOI: 10.1097/dad.0b013e31827eaf0b] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Cocaine-associated retiform purpura is a recently described entity characterized by striking hemorrhagic necrosis involving areas of skin associated with administration of cocaine. Levamisole, an adulterant in cocaine, has been suggested as the main culprit pathogenetically. Four cases of cocaine-associated retiform purpura were encountered in the dermatopathology practice of C. M. Magro. The light microscopic findings were correlated with immunohistochemical and immunofluorescence studies. All 4 cases showed a very striking thrombotic diathesis associated with intravascular macrophage accumulation. Necrotizing vasculitis was noted in 1 case. Striking intercellular adhesion molecule-1 (ICAM-1)/CD54 expression in vessel wall along with endothelial expression of caspase 3 and extensive vascular C5b-9 deposition was observed in all biopsies examined. Cocaine-induced retiform purpura is a C5b-9-mediated microvascular injury associated with enhanced apoptosis and prominent vascular expression of ICAM-1, all of which have been shown in prior in vitro and in vivo murine models to be a direct effect of cocaine metabolic products. Antineutrophilic cytoplasmic antibody and antiphospholipid antibodies are likely the direct sequelae of the proapoptotic microenvironment. The inflammatory vasculitic lesion could reflect the downstream end point reflective of enhanced ICAM-1 expression and the development of antineutrophilic cytoplasmic antibody. Levamisole likely works synergistically with cocaine in the propagation of this syndromic complex.
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Abstract
Immunosuppressive therapy in pediatrics continues to evolve. Over the past decade, newer immunosuppressive agents have been introduced into adult and pediatric transplant patients with the goal of improving patient and allograft survival. Unfortunately, large-scale randomized clinical trials are not commonly performed in children. The purpose of this review is to discuss the newer immunosuppressive agents available for induction therapy, maintenance immunosuppression, and the treatment of rejection.
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Affiliation(s)
- Christina Nguyen
- Division of Pediatric Nephrology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States
| | - Ron Shapiro
- Division of Transplant Surgery, UPMC Thomas E. Starzl Transplantation Institute, Pittsburgh, PA, United States
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Therapeutic plasma exchange for the treatment of pediatric renal diseases in 2013. Pediatr Nephrol 2014; 29:35-50. [PMID: 23812351 DOI: 10.1007/s00467-013-2479-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2012] [Revised: 03/01/2013] [Accepted: 03/26/2013] [Indexed: 02/06/2023]
Abstract
Therapeutic plasma exchange is an extracorporeal treatment modality that removes systemic circulating pathologic factors or replaces absent plasma components and plays a role in many nephrologic conditions. It presents a number of technical challenges in the pediatric population but has become an increasingly common practice in pediatric nephrology over the past several decades. While prospective evidence is often lacking, our increased understanding of the molecular pathogenesis underlying many pediatric renal diseases provides sound reasoning for the use of plasma exchange in treating these conditions. This review will present the currently accepted indications for plasma exchange in children, the technical aspects of the procedure and its potential complications.
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