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Obata S, Hullekes F, Riella LV, Cravedi P. Recurrent complement-mediated Hemolytic uremic syndrome after kidney transplantation. Transplant Rev (Orlando) 2024; 38:100857. [PMID: 38749097 DOI: 10.1016/j.trre.2024.100857] [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: 03/13/2024] [Revised: 04/25/2024] [Accepted: 04/26/2024] [Indexed: 06/16/2024]
Abstract
Hereditary forms of hemolytic uremic syndrome (HUS), formerly known as atypical HUS, typically involve mutations in genes encoding for components of the alternative pathway of complement, therefore they are often referred to as complement-mediated HUS (cHUS). This condition has a high risk of recurrence in the transplanted kidney, leading to accelerated graft loss. The availability of anti-complement component C5 antibody eculizumab has enabled successful transplantation with a notably reduced recurrence rate and improved prognosis. Open questions are related to the potential for complement inhibitor discontinuation, ideal timing of treatment withdrawal, and patient selection based on genetic abnormalities. Our review delves into the pathophysiology, classification, genetic predispositions, and management strategies for cHUS in the native and transplant kidneys.
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Affiliation(s)
- Shota Obata
- Precision Immunology Institute, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - Frank Hullekes
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America
| | - Leonardo V Riella
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America; Department of Medicine, Nephrology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America
| | - Paolo Cravedi
- Precision Immunology Institute, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
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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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Jehn U, Altuner U, Pavenstädt H, Reuter S. First Report on Successful Conversion of Long-Term Treatment of Recurrent Atypical Hemolytic Uremic Syndrome With Eculizumab to Ravulizumab in a Renal Transplant Patient. Transpl Int 2022; 35:10846. [PMID: 36262114 PMCID: PMC9573942 DOI: 10.3389/ti.2022.10846] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 09/22/2022] [Indexed: 11/13/2022]
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Leonova EI, Reshetnikov VV, Sopova JV. CRISPR/Cas-edited pigs for personalized medicine: more than preclinical test-system. RESEARCH RESULTS IN PHARMACOLOGY 2022. [DOI: 10.3897/rrpharmacology.8.83872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Novel CRISPR-Cas-based genome editing tools made it feasible to introduce a variety of precise genomic modifications in the pig genome, including introducing multiple edits simultaneously, inserting long DNA sequences into specifically targeted loci, and performing nucleotide transitions and transversions. Pigs serve as a vital agricultural resource and animal model in biomedical studies, given their advantages over the other models. Pigs share high similarities to humans regarding body/organ size, anatomy, physiology, and a metabolic profile. The pig genome can be modified to carry the same genetic mutations found in humans to replicate inherited diseases to provide preclinical trials of drugs. Moreover, CRISPR-based modification of pigs antigen profile makes it possible to offer porcine organs for xenotransplantation with minimal transplant rejection responses. This review summarizes recent advances in endonuclease-mediated genome editing tools and research progress of genome-edited pigs as personalized test-systems for preclinical trials and as donors of organs with human-fit antigen profile.
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Ravulizumab in Preemptive Living Donor Kidney Transplantation in Hereditary Atypical Hemolytic Uremic Syndrome. Transplant Direct 2022; 8:e1289. [PMID: 35187213 PMCID: PMC8806379 DOI: 10.1097/txd.0000000000001289] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/07/2021] [Accepted: 12/18/2021] [Indexed: 11/26/2022] Open
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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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González CC, López-Jiménez V, Vázquez-Sánchez T, Vázquez-Sánchez E, Cabello M, Hernández-Marrero D. Efficacy and Safety of Eculizumab in Kidney Transplant Patients With Primary Atypical Hemolytic-Uremic Syndrome. Transplant Proc 2021; 54:25-26. [PMID: 34906374 DOI: 10.1016/j.transproceed.2021.09.063] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 09/28/2021] [Indexed: 12/19/2022]
Abstract
The atypical hemolytic-uremic syndrome (aHUS) is characterized by the triad of non-immune hemolytic anemia, thrombocytopenia, and acute renal failure. The aHUS is related to complement dysregulation; since the approval of eculizumab for this entity (a monoclonal antibody that inhibits C5 activation and blocks the formation of the membrane attack complex) the prognosis has improved. The recurrence of aHUS after kidney transplantation is frequent and implies loss of the graft in a high percentage of cases. Eculizumab prophylaxis to prevent recurrence has allowed successful kidney transplantation in this group of patients. We present a series of kidney transplant patients with chronic kidney disease secondary to aHUS and the use of eculizumab for prevention of recurrence.
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Affiliation(s)
| | | | | | | | - Mercedes Cabello
- Nephrology Department, Regional University Hospital of Malaga, Malaga, Spain
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Noris M, Ruggenenti P, Remuzzi G. Kidney Transplantation in Patients With Atypical Hemolytic Uremic Syndrome: A Therapeutic Dilemma (or Not)? Am J Kidney Dis 2019; 70:754-757. [PMID: 29169515 DOI: 10.1053/j.ajkd.2017.08.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 08/11/2017] [Indexed: 11/11/2022]
Affiliation(s)
- Marina Noris
- IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases, Aldo e Cele Daccò Ranica, Bergamo, Italy.
| | - Piero Ruggenenti
- Azienda Socio-Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy
| | - Giuseppe Remuzzi
- IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases, Aldo e Cele Daccò Ranica, Bergamo, Italy; Azienda Socio-Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy; University of Milan, Milan, Italy
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9
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Abbas F, El Kossi M, Kim JJ, Shaheen IS, Sharma A, Halawa A. Complement-mediated renal diseases after kidney transplantation - current diagnostic and therapeutic options in de novo and recurrent diseases. World J Transplant 2018; 8:203-219. [PMID: 30370231 PMCID: PMC6201327 DOI: 10.5500/wjt.v8.i6.203] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 08/09/2018] [Accepted: 08/28/2018] [Indexed: 02/05/2023] Open
Abstract
For decades, kidney diseases related to inappropriate complement activity, such as atypical hemolytic uremic syndrome and C3 glomerulopathy (a subtype of membranoproliferative glomerulonephritis), have mostly been complicated by worsened prognoses and rapid progression to end-stage renal failure. Alternative complement pathway dysregulation, whether congenital or acquired, is well-recognized as the main driver of the disease process in these patients. The list of triggers include: surgery, infection, immunologic factors, pregnancy and medications. The advent of complement activation blockade, however, revolutionized the clinical course and outcome of these diseases, rendering transplantation a viable option for patients who were previously considered as non-transplantable cases. Several less-costly therapeutic lines and likely better efficacy and safety profiles are currently underway. In view of the challenging nature of diagnosing these diseases and the long-term cost implications, a multidisciplinary approach including the nephrologist, renal pathologist and the genetic laboratory is required to help improve overall care of these patients and draw the optimum therapeutic plan.
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Affiliation(s)
- Fedaey Abbas
- Nephrology Department, Jaber El Ahmed Military Hospital, Safat 13005, Kuwait
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
| | - Mohsen El Kossi
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Doncaster Royal Infirmary, Doncaster DN2 5LT, United Kingdom
| | - Jon Jin Kim
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Nottingham Children Hospital, Nottingham NG7 2UH, United Kingdom
| | - Ihab Sakr Shaheen
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Royal Hospital for Children, Glasgow G51 4TF, United Kingdom
| | - Ajay Sharma
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Royal Liverpool University Hospitals, Liverpool L7 8XP, United Kingdom
| | - Ahmed Halawa
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Sheffield Teaching Hospitals, Sheffield S57AU, United Kingdom
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Abbas F, El Kossi M, Kim JJ, Sharma A, Halawa A. Thrombotic microangiopathy after renal transplantation: Current insights in de novo and recurrent disease. World J Transplant 2018; 8:122-141. [PMID: 30211021 PMCID: PMC6134269 DOI: 10.5500/wjt.v8.i5.122] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2018] [Revised: 06/26/2018] [Accepted: 07/10/2018] [Indexed: 02/05/2023] Open
Abstract
Thrombotic microangiopathy (TMA) is one of the most devastating sequalae of kidney transplantation. A number of published articles have covered either de novo or recurrent TMA in an isolated manner. We have, hereby, in this article endeavored to address both types of TMA in a comparative mode. We appreciate that de novo TMA is more common and its prognosis is poorer than recurrent TMA; the latter has a genetic background, with mutations that impact disease behavior and, consequently, allograft and patient survival. Post-transplant TMA can occur as a recurrence of the disease involving the native kidney or as de novo disease with no evidence of previous involvement before transplant. While atypical hemolytic uremic syndrome is a rare disease that results from complement dysregulation with alternative pathway overactivity, de novo TMA is a heterogenous set of various etiologies and constitutes the vast majority of post-transplant TMA cases. Management of both diseases varies from simple maneuvers, e.g., plasmapheresis, drug withdrawal or dose modification, to lifelong complement blockade, which is rather costly. Careful donor selection and proper recipient preparation, including complete genetic screening, would be a pragmatic approach. Novel therapies, e.g., purified products of the deficient genes, though promising in theory, are not yet of proven value.
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Affiliation(s)
- Fedaey Abbas
- Nephrology Department, Jaber El Ahmed Military Hospital, Safat 13005, Kuwait
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
| | - Mohsen El Kossi
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Doncaster Renal Unit, Doncaster Royal Infirmary, Doncaster DN2 5LT, United Kingdom
| | - Jon Jin Kim
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Nottingham Children Hospital, Nottingham NG7 2UH, United Kingdom
| | - Ajay Sharma
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Transplant Surgery, Royal Liverpool University Hospitals, Liverpool UK L7 8XP, United Kingdom
| | - Ahmed Halawa
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Department of Transplantation Surgery, Sheffield Teaching Hospitals, Sheffield S57AU, United Kingdom
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Matsumoto T, Toyoda H, Amano K, Hirayama M, Ishikawa E, Fujimoto M, Ito M, Ohishi K, Katayama N, Yoshida Y, Matsumoto M, Kawamura N, Ikejiri M, Kawakami K, Miyata T, Wada H. Clinical Manifestation of Patients With Atypical Hemolytic Uremic Syndrome With the C3 p.I1157T Variation in the Kinki Region of Japan. Clin Appl Thromb Hemost 2018; 24:1301-1307. [PMID: 29695177 PMCID: PMC6714784 DOI: 10.1177/1076029618771750] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The gain-of-function variation p.I1157T in C3 was previously identified in 8 patients with atypical hemolytic uremic syndrome (aHUS) at Mie University Hospital. In the present study, we identified another 11 patients with aHUS with this variation, including 10 pediatric patients (onset age: 1-16 years). The variation seems to be geographically concentrated around Mie Prefecture in Japan. Fifteen of the 19 patients with aHUS experienced infection as probable triggering events. All 19 patients had renal dysfunction. Seven patients, including 2 from the previous study and 5 from the present study, were treated with eculizumab, with all showing a good response with hematological normalization. Among the 5 eculizumab-treated patients in the present study, 3 had an ambiguous diagnosis of aHUS due to low-grade hemolysis even with elevated levels of lactate dehydrogenase and bilirubin. In those cases, in-house targeted DNA sequencing identified the C3 p.I1157T variation carriers, which enabled the early initiation of treatment with eculizumab. The present study supports the early introduction of eculizumab in patients with aHUS, especially pediatric patients.
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Affiliation(s)
- Takeshi Matsumoto
- 1 Division of Blood Transfusion Medicine and Cell Therapy, Mie University Hospital, Tsu, Japan
| | - Hidemi Toyoda
- 2 Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan
| | - Keishirou Amano
- 2 Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan
| | - Masahiro Hirayama
- 2 Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan
| | - Eiji Ishikawa
- 3 Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Mika Fujimoto
- 3 Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Masaaki Ito
- 3 Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Kohshi Ohishi
- 1 Division of Blood Transfusion Medicine and Cell Therapy, Mie University Hospital, Tsu, Japan
| | - Naoyuki Katayama
- 4 Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Yoko Yoshida
- 5 Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Japan
| | - Masanori Matsumoto
- 5 Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Japan
| | | | - Makoto Ikejiri
- 7 Central Laboratory, Mie University Hospital, Tsu, Japan
| | - Keiki Kawakami
- 8 Department of Hematology, Suzuka General Hospital, Suzuka, Japan
| | - Toshiyuki Miyata
- 9 Departments of Molecular Pathogenesis and Cerebrovascular Medicine, National Central and Cardiovascular Center, Suita, Japan
| | - Hideo Wada
- 10 Department of Molecular and Laboratory Medicine, Mie University Graduate School of Medicine, Tsu, Mie, Japan
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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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de Andrade LGM, Contti MM, Nga HS, Bravin AM, Takase HM, Viero RM, da Silva TN, Chagas KDN, Palma LMP. Long-term outcomes of the Atypical Hemolytic Uremic Syndrome after kidney transplantation treated with eculizumab as first choice. PLoS One 2017; 12:e0188155. [PMID: 29136640 PMCID: PMC5685617 DOI: 10.1371/journal.pone.0188155] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 11/01/2017] [Indexed: 02/07/2023] Open
Abstract
Introduction The treatment of choice for Atypical Hemolytic Uremic Syndrome (aHUS) is the monoclonal antibody eculizumab. The objective of this study was to assess the efficacy and safety of eculizumab in a cohort of kidney transplant patients suffering from aHUS. Methods Description of the prospective cohort of all the patients primarily treated with eculizumab after transplantation and divided into the therapeutic (onset of aHUS after transplantation) and prophylactic use (patients with previous diagnosis of aHUS undergoing kidney transplantation). Results Seven cases were outlined: five of therapeutic use and two, prophylactic. From the five cases of therapeutic use, there was improvement of the thrombotic microangiopathy in the 48 hours following the start of the drug and no patient experienced relapse during an average follow-up of 21 months in the continuous use of eculizumab (minimum of 6 and maximum of 42 months). One patient died at 6 months, due to Aspergillus infection. From the two cases of prophylactic use, one patient experienced relapsed thrombotic microangiopathy after 4 months and another patient remained asymptomatic after 16 months of follow-up, both on chronic treatment. Discussion The therapeutic use of eculizumab showed to be effective, with improvement of the microangiopathy parameters and persisting up to the end of the follow-up, without relapses. The additional risk of immunosuppression, leading to opportunistic infections, was well tolerated. The prophylactic use showed to be effective and safe; however, the doses and intervals should be individualized in order to avoid relapsed microangiopathy, especially in patients with factor H mutation.
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Affiliation(s)
| | - Mariana Moraes Contti
- Department of Internal Medicine, University São Paulo State(UNESP), Botucatu, São Paulo State, Brazil
| | - Hong Si Nga
- Department of Internal Medicine, University São Paulo State(UNESP), Botucatu, São Paulo State, Brazil
| | - Ariane Moyses Bravin
- Department of Internal Medicine, University São Paulo State(UNESP), Botucatu, São Paulo State, Brazil
| | - Henrique Mochida Takase
- Department of Internal Medicine, University São Paulo State(UNESP), Botucatu, São Paulo State, Brazil
| | - Rosa Marlene Viero
- Department of Internal Medicine, University São Paulo State(UNESP), Botucatu, São Paulo State, Brazil
| | - Trycia Nunes da Silva
- Department of Internal Medicine, Hospital Estadual de Bauru, Bauru, São Paulo State, Brazil
| | - Kelem De Nardi Chagas
- Department of Internal Medicine, University of São Paulo (USP), São Paulo, São Paulo State, Brazil
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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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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: 30] [Impact Index Per Article: 3.8] [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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Cortina G, Ojinaga V, Giner T, Riedl M, Waldegger S, Rosales A, Trojer R, Hofer J. Therapeutic plasma exchange in children: One center's experience. J Clin Apher 2017; 32:494-500. [DOI: 10.1002/jca.21547] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Revised: 02/17/2017] [Accepted: 04/04/2017] [Indexed: 12/17/2022]
Affiliation(s)
- Gerard Cortina
- Department of Pediatrics; Medical University of Innsbruck; Innsbruck Austria
| | - Violeta Ojinaga
- Department of Pediatrics; Medical University of Innsbruck; Innsbruck Austria
| | - Thomas Giner
- Department of Pediatrics; Medical University of Innsbruck; Innsbruck Austria
| | - Magdalena Riedl
- Department of Pediatrics; Medical University of Innsbruck; Innsbruck Austria
| | - Siegfried Waldegger
- Department of Pediatrics; Medical University of Innsbruck; Innsbruck Austria
| | - Alejandra Rosales
- Department of Pediatrics; Medical University of Innsbruck; Innsbruck Austria
| | - Raphaela Trojer
- Department of Pediatrics; Medical University of Innsbruck; Innsbruck Austria
| | - Johannes Hofer
- Department of Pediatrics; Medical University of Innsbruck; Innsbruck Austria
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18
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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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19
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Abstract
Thrombotic thrombocytopenia purpura (TTP) and the hemolytic uremic syndrome (HUS) are rare thrombotic microangiopathies that can be rapidly fatal. Although the acquired versions of TTP and HUS are generally highest on this broad differential, multiple rarer entities can produce a clinical picture similar to TTP/HUS, including microangiopathic hemolysis, renal failure, and neurologic compromise. More recent analysis has discovered a host of genetic factors that can produce microangiopathic hemolytic syndromes. This article discusses the current understanding of thrombotic microangiopathy and outlines the pathophysiology and causative agents associated with each distinct syndrome as well as the most accepted treatments.
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Affiliation(s)
- Joseph J Shatzel
- Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA
| | - Jason A Taylor
- Division of Hematology and Medical Oncology, The Hemophilia Center, Portland VA Medical Center, Knight Cancer Institute, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, L586, Portland, OR 97239, USA.
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20
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Salvadori M, Bertoni E. Complement related kidney diseases: Recurrence after transplantation. World J Transplant 2016; 6:632-645. [PMID: 28058212 PMCID: PMC5175220 DOI: 10.5500/wjt.v6.i4.632] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 10/26/2016] [Accepted: 11/16/2016] [Indexed: 02/05/2023] Open
Abstract
The recurrence of renal disease after renal transplantation is becoming one of the main causes of graft loss after kidney transplantation. This principally concerns some of the original diseases as the atypical hemolytic uremic syndrome (HUS), the membranoproliferative glomerulonephritis (MPGN), in particular the MPGN now called C3 glomerulopathy. Both this groups of renal diseases are characterized by congenital (genetic) or acquired (auto-antibodies) modifications of the alternative pathway of complement. These abnormalities often remain after transplantation because they are constitutional and poorly influenced by the immunosuppression. This fact justifies the high recurrence rate of these diseases. Early diagnosis of recurrence is essential for an optimal therapeutically approach, whenever possible. Patients affected by end stage renal disease due to C3 glomerulopathies or to atypical HUS, may be transplanted with extreme caution. Living donor donation from relatives is not recommended because members of the same family may be affected by the same gene mutation. Different therapeutically approaches have been attempted either for recurrence prevention and treatment. The most promising approach is represented by complement inhibitors. Eculizumab, a monoclonal antibody against C5 convertase is the most promising drug, even if to date is not known how long the therapy should be continued and which are the best dosing. These facts face the high costs of the treatment. Eculizumab resistant patients have been described. They could benefit by a C3 convertase inhibitor, but this class of drugs is by now the object of randomized controlled trials.
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21
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Michelfelder S, Parsons J, Bohlender LL, Hoernstein SNW, Niederkrüger H, Busch A, Krieghoff N, Koch J, Fode B, Schaaf A, Frischmuth T, Pohl M, Zipfel PF, Reski R, Decker EL, Häffner K. Moss-Produced, Glycosylation-Optimized Human Factor H for Therapeutic Application in Complement Disorders. J Am Soc Nephrol 2016; 28:1462-1474. [PMID: 27932477 DOI: 10.1681/asn.2015070745] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 11/07/2016] [Indexed: 01/15/2023] Open
Abstract
Genetic defects in complement regulatory proteins can lead to severe renal diseases, including atypical hemolytic uremic syndrome and C3 glomerulopathies, and age-related macular degeneration. The majority of the mutations found in patients with these diseases affect the glycoprotein complement factor H, the main regulator of the alternative pathway of complement activation. Therapeutic options are limited, and novel treatments, specifically those targeting alternative pathway activation, are highly desirable. Substitution with biologically active factor H could potentially treat a variety of diseases that involve increased alternative pathway activation, but no therapeutic factor H is commercially available. We recently reported the expression of full-length recombinant factor H in moss (Physcomitrella patens). Here, we present the production of an improved moss-derived recombinant human factor H devoid of potentially immunogenic plant-specific sugar residues on protein N-glycans, yielding approximately 1 mg purified moss-derived human factor H per liter of initial P. patens culture after a multistep purification process. This glycosylation-optimized factor H showed full in vitro complement regulatory activity similar to that of plasma-derived factor H and efficiently blocked LPS-induced alternative pathway activation and hemolysis induced by sera from patients with atypical hemolytic uremic syndrome. Furthermore, injection of moss-derived factor H reduced C3 deposition and increased serum C3 levels in a murine model of C3 glomerulopathy. Thus, we consider moss-produced recombinant human factor H a promising pharmaceutical product for therapeutic intervention in patients suffering from complement dysregulation.
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Affiliation(s)
- Stefan Michelfelder
- Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Freiburg Medical Center, Freiburg, Germany
| | - Juliana Parsons
- Plant Biotechnology, Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Lennard L Bohlender
- Plant Biotechnology, Faculty of Biology, University of Freiburg, Freiburg, Germany
| | | | | | | | | | - Jonas Koch
- Greenovation Biotech GmbH, Freiburg, Germany
| | | | | | | | - Martin Pohl
- Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Freiburg Medical Center, Freiburg, Germany
| | - Peter F Zipfel
- Leibniz Institute for Natural Product Research and Infection Biology, Friedrich Schiller University, Jena, Germany
| | - Ralf Reski
- Plant Biotechnology, Faculty of Biology, University of Freiburg, Freiburg, Germany.,BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany; and.,FRIAS Freiburg Institute for Advanced Studies, University of Freiburg, Freiburg, Germany
| | - Eva L Decker
- Plant Biotechnology, Faculty of Biology, University of Freiburg, Freiburg, Germany;
| | - Karsten Häffner
- Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Freiburg Medical Center, Freiburg, Germany;
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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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Coppo R, Bonaudo R, Peruzzi RL, Amore A, Brunati A, Romagnoli R, Salizzoni M, Galbusera M, Gotti E, Daina E, Noris M, Remuzzi G. Liver transplantation for aHUS: still needed in the eculizumab era? Pediatr Nephrol 2016; 31:759-68. [PMID: 26604087 DOI: 10.1007/s00467-015-3278-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 10/28/2015] [Accepted: 10/28/2015] [Indexed: 12/25/2022]
Abstract
BACKGROUND The risk of disease recurrence after a kidney transplant is high in patients with atypical hemolytic uremic syndrome (aHUS) and mutations in the complement factor H (FH) gene (CFH). Since FH is mostly produced by the liver, a kidney transplant does not correct the genetic defect. The anti-C5 antibody eculizumab prevents post-transplant aHUS recurrence, but it does not cure the disease. Combined liver-kidney transplantation has been performed in few patients with CFH mutations based on the rationale that liver replacement provides a source of normal FH. METHODS We report the 9-year follow-up of a child with aHUS and a CFH mutation, including clinical data, extensive genetic characterization, and complement profile in the circulation and at endothelial level. The outcome of kidney and liver transplants performed separately 3 years apart are reported. RESULTS The patient showed incomplete response to plasma, with relapsing episodes, progression to end-stage renal disease, and endothelial-restricted complement dysregulation. Eculizumab prophylaxis post-kidney transplant did not achieve sustained remission, leaving the child at risk of disease recurrence. A liver graft given 3 years after the kidney transplant completely abrogated endothelial complement activation and allowed eculizumab withdrawal. CONCLUSIONS Liver transplant may definitely cure aHUS and represents an option for patients with suboptimal response to eculizumab.
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Affiliation(s)
- Rosanna Coppo
- Nephrology Dialysis and Transplantation, AOU Città della Salute e della Scienza di Torino, Turin and Fondazione Ricerca Molinette, Regina Margherita Hospital, Turin, Italy
| | - Roberto Bonaudo
- Nephrology Dialysis and Transplantation, AOU Città della Salute e della Scienza di Torino, Turin and Fondazione Ricerca Molinette, Regina Margherita Hospital, Turin, Italy
| | - R Licia Peruzzi
- Nephrology Dialysis and Transplantation, AOU Città della Salute e della Scienza di Torino, Turin and Fondazione Ricerca Molinette, Regina Margherita Hospital, Turin, Italy
| | - Alessandro Amore
- Nephrology Dialysis and Transplantation, AOU Città della Salute e della Scienza di Torino, Turin and Fondazione Ricerca Molinette, Regina Margherita Hospital, Turin, Italy
| | - Andrea Brunati
- Liver Transplantation Center, General Surgery Unit 2U, AOU Città della Salute e della Scienza di Torino, Molinette Hospital, University of Turin , Turin, Italy
| | - Renato Romagnoli
- Liver Transplantation Center, General Surgery Unit 2U, AOU Città della Salute e della Scienza di Torino, Molinette Hospital, University of Turin , Turin, Italy
| | - Mauro Salizzoni
- Liver Transplantation Center, General Surgery Unit 2U, AOU Città della Salute e della Scienza di Torino, Molinette Hospital, University of Turin , Turin, Italy
| | - Miriam Galbusera
- Clinical Research Center for Rare Diseases "Aldo e Cele Daccò", IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Villa Camozzi, 3-24020, Ranica (Bergamo), Italy.,Centro Anna Maria Astori, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Eliana Gotti
- Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
| | - Erica Daina
- Clinical Research Center for Rare Diseases "Aldo e Cele Daccò", IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Villa Camozzi, 3-24020, Ranica (Bergamo), Italy
| | - Marina Noris
- Clinical Research Center for Rare Diseases "Aldo e Cele Daccò", IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Villa Camozzi, 3-24020, Ranica (Bergamo), Italy.
| | - Giuseppe Remuzzi
- Clinical Research Center for Rare Diseases "Aldo e Cele Daccò", IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Villa Camozzi, 3-24020, Ranica (Bergamo), Italy.,Centro Anna Maria Astori, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Science and Technology Park Kilometro Rosso, Bergamo, Italy.,Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.,Department of Biomedical Sciences of Health, University of Milan, Milan, Italy
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24
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Teoh CW, Riedl M, Licht C. The alternative pathway of complement and the thrombotic microangiopathies. Transfus Apher Sci 2016; 54:220-31. [PMID: 27160864 DOI: 10.1016/j.transci.2016.04.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Thrombotic microangiopathies (TMA) are disorders defined by microangiopathic hemolytic anemia, non-immune thrombocytopenia and have multi-organ involvement including the kidneys, brain, gastrointestinal, respiratory tract and skin. Emerging evidence points to the central role of complement dysregulation in leading to microvascular endothelial injury which is crucial for the development of TMAs. This key insight has led to the development of complement-targeted therapy. Eculizumab is an anti-C5 monoclonal antibody, which has revolutionized the treatment of atypical hemolytic uremic syndrome. Several other anti-complement therapeutic agents are currently in development, offering a potential armamentarium of therapies available to treat complement-mediated TMAs. The development of sensitive, reliable and easy to perform assays to monitor complement activity and therapeutic efficacy will be key to devising an individualized treatment regime with the potential of safely weaning or discontinuing treatment in the appropriate clinical setting.
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Affiliation(s)
- Chia Wei Teoh
- Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada; Research Institute, Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Magdalena Riedl
- Research Institute, Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pediatrics, Innsbruck Medical University, Innsbruck, Austria
| | - Christoph Licht
- Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada; Research Institute, Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada.
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25
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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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26
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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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27
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Epidemiology of haemolytic uremic syndrome in children. Data from the North Italian HUS network. Eur J Pediatr 2016; 175:465-73. [PMID: 26498648 DOI: 10.1007/s00431-015-2642-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Revised: 09/24/2015] [Accepted: 09/28/2015] [Indexed: 12/31/2022]
Abstract
UNLABELLED Despite the severity of HUS and the fact that it represents a leading cause of acute kidney injury in children, the general epidemiology of HUS is all but well documented. The present study provides updated, population-based, purely epidemiological information on HUS in childhood from a large and densely populated area of northern Italy (9.6 million inhabitants, 1.6 million children). We systematically reviewed the files concerning patients with STEC-HUS and atypical HUS (aHUS) over a 10-year observation period (January 2003-December 2012). We included all incident cases with a documented first episode of HUS before the age of 18 years. We identified 101 cases of HUS during the 10 years. The overall mean annual incidence was 6.3 cases/million children aged <18 years (range 1.9-11.9), and 15.7/million of age-related population (MARP) among subjects aged <5 years; aHUS accounted for 11.9 % of the cases (mean incidence 0.75/MARP). The overall case fatality rate was 4.0 % (3.4 % STEC-HUS, 8.3 % aHUS). CONCLUSION Given the public health impact of HUS, this study provides recent, population-based epidemiological data useful for healthcare planning and particularly for estimating the financial burden that healthcare providers might have to face in treating HUS, whose incidence rate seems to increase in Northern Italy. WHAT IS KNOWN • HUS is a rare disease, but it represents the leading cause of acute kidney injury in children worldwide. • STEC-HUS (also called typical, D + HUS) is more common compared to atypical HUS, but recent, population-based epidemiological data (incidence) are scanty. What is New: • Comprehensive, population-based epidemiological data concerning both typical and atypical HUS based on a long observational period.
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28
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Magro CM, Momtahen S, Mulvey JJ, Yassin AH, Kaplan RB, Laurence JC. Role of the skin biopsy in the diagnosis of atypical hemolytic uremic syndrome. Am J Dermatopathol 2016; 37:349-56; quiz 357-9. [PMID: 25893747 DOI: 10.1097/dad.0000000000000234] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Atypical hemolytic uremic syndrome (aHUS) is a prototypic thrombotic microangiopathy attributable to complement dysregulation. In the absence of complement inhibition, progressive clinical deterioration occurs. The authors postulated that a biopsy of normal skin could corroborate the diagnosis of aHUS through the demonstration of vascular deposits of C5b-9. MATERIALS AND METHODS Biopsies of normal skin from 22 patients with and without aHUS were processed for routine light microscopy and immunofluorescent studies. An assessment was made for vascular C5b-9 deposition immunohistochemically and by immunofluorescence. The biopsies were obtained primarily from the forearm and/or deltoid. RESULTS Patients with classic features of aHUS showed insidious microvascular changes including loose luminal platelet thrombi, except in 2 patients in whom a striking thrombogenic vasculopathy was apparent in biopsied digital ulcers. Extensive microvascular deposits of the membrane attack complex/C5b-9 were identified, excluding 1 patient in whom eculizumab was initiated before biopsy. In 5 of the 7 patients where follow-up was available, the patients exhibited an excellent treatment response to eculizumab. Patients without diagnostic clinical features of aHUS failed to show significant vascular deposits of complement, except 2 patients with thrombotic thrombocytopenic purpura including 1 in whom a Factor H mutation was identified. CONCLUSIONS In a clinical setting where aHUS is an important diagnostic consideration, extensive microvascular deposition of C5b-9 supports the diagnosis of either aHUS or a subset of thrombotic thrombocytopenic purpura patients with concomitant complement dysregulation; significant vascular C5b-9 deposition predicts clinical responsiveness to eculizumab.
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Affiliation(s)
- Cynthia M Magro
- *Professor of Pathology and Laboratory Medicine, Dermatopathologist, Director of Dermatopathology, Department of Pathology and Laboratory Medicine and †Anatomic and Clinical Pathology Resident, Weill Cornell Medical College, Cornell University, New York, NY; ‡MD-PhD Candidate, Weill Cornell Graduate School of Medical Sciences, Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, New York, NY; §Research Assistant, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College of Cornell University, New York, NY; ¶Hematologist, Department of Hemostasis, Thrombosis Laboratory, The Western Pennsylvania Hospital Allegheny Health Network, Pittsburgh, PA; and #Professor of Medicine in the Division of Hematology-Oncology, Attending Physician, Department of Medicine Weill Cornell Medical College, NewYork-Presbyterian Hospital New York, NY
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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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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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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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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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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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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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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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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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Matsumoto T, Fan X, Ishikawa E, Ito M, Amano K, Toyoda H, Komada Y, Ohishi K, Katayama N, Yoshida Y, Matsumoto M, Fujimura Y, Ikejiri M, Wada H, Miyata T. Analysis of patients with atypical hemolytic uremic syndrome treated at the Mie University Hospital: concentration of C3 p.I1157T mutation. Int J Hematol 2014; 100:437-42. [PMID: 25135378 DOI: 10.1007/s12185-014-1655-2] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2014] [Revised: 08/07/2014] [Accepted: 08/07/2014] [Indexed: 12/30/2022]
Abstract
Atypical hemolytic uremic syndrome (aHUS) is caused by abnormalities of the complement system and has a significantly poor prognosis. The clinical phenotypes of 12 patients in nine families with aHUS with familial or recurrent onset and ADAMTS13 activity of ≥20 % treated at the Mie University Hospital were examined. In seven of the patients, the first episode of aHUS occurred during childhood and ten patients experienced a relapse. All patients had renal dysfunction and three had been treated with hemodialysis. Seven patients experienced probable triggering events including common cold, influenza, bacterial infection and/or vaccination for influenza. All patients had entered remission, and renal function was improved in 11 patients. DNA sequencing of six candidate genes, identified a C3 p.I1157T missense mutation in all eight patients in six families examined and this mutation was causative for aHUS. A causative mutation THBD p.D486Y was also identified in an aHUS patient. Four missense mutations, CFH p.V837I, p.Y1058H, p.V1060L and THBD p.R403K may predispose to aHUS manifestation; the remaining seven missense mutations were likely neutral. In conclusion, the clinical phenotypes of aHUS are various, and there are often trigger factors. The C3 p.I1157T mutation was identified as the causative mutation for aHUS in all patients examined, and may be geographically concentrated in or around the Mie prefecture in central Japan.
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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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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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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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Udagawa T, Motoyoshi Y, Matsumura Y, Takei A, Ariji S, Ito E, Chiga M, Nagasawa M, Morio T, Mizutani S. Effect of eculizumab and recombinant human soluble thrombomodulin combination therapy in a 7-year-old girl with atypical hemolytic uremic syndrome due to anti-factor H autoantibodies. CEN Case Rep 2014; 3:110-117. [PMID: 28509254 PMCID: PMC5411543 DOI: 10.1007/s13730-013-0097-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Accepted: 08/26/2013] [Indexed: 10/26/2022] Open
Abstract
Atypical hemolytic uremic syndrome (aHUS), which is defined as non-Shiga toxin-associated hemolytic uremic syndrome, is a type of thrombotic microangiopathy. This syndrome presents with hemolytic anemia, thrombocytopenia, and acute kidney injury. Excessive complement activation due to genetic disorders of the complement system or production of autoantibodies to factor H (FH) causes the disease. We report a successful treatment course using eculizumab and recombinant human soluble thrombomodulin (rTMD) for a 7-year-old girl with aHUS due to anti-FH autoantibodies. Although her chief complaints were abdominal pain and loose stools, we were finally able to diagnose her with aHUS because Shiga toxin-producing Escherichia coli was not detected in her feces and a hemolytic assay analyzing FH function was positive. We administrated rTMD to our patient because of signs of disseminated intravascular coagulation. Soon after the therapeutic intervention, the platelet count began to increase and abdominal pain was moderately improved. Plasma exchange limited the efficacy of her disease. Therefore, we administered eculizumab, monoclonal humanized antibody against C5, 3 weeks after admission. Platelet counts immediately increased and kidney function gradually recovered. Genetic disorders were not detected. However, anti-FH autoantibody was observed. There were no symptoms for recurrence of aHUS or kidney dysfunction for 15 months, as a result of the administration of eculizumab every other week. In conclusion, combination therapy of eculizumab and rTMD was effective for an aHUS patient. This therapy may be helpful for improving the prognosis and long-term kidney function of aHUS patients.
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Affiliation(s)
- Tomohiro Udagawa
- Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, 113-8519, Japan.
| | - Yaeko Motoyoshi
- Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Yu Matsumura
- Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Akira Takei
- Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Shohei Ariji
- Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Eisaku Ito
- Department of Clinical Pathology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Motoko Chiga
- Department of Nephrology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masayuki Nagasawa
- Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Tomohiro Morio
- Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Shuki Mizutani
- Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, 113-8519, Japan
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Use of eculizumab and plasma exchange in successful combined liver-kidney transplantation in a case of atypical HUS associated with complement factor H mutation. Pediatr Nephrol 2014; 29:477-80. [PMID: 24221349 DOI: 10.1007/s00467-013-2630-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Revised: 08/22/2013] [Accepted: 08/23/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND Atypical hemolytic uremic syndrome (aHUS) evolves into end-stage renal failure in nearly half of affected patients and is associated with defective regulation of the alternative complement pathway. Patients with a complement factor H (CFH) mutation have a 30-100% risk of graft loss due to aHUS recurrence or graft thrombosis. Since CFH is produced predominantly by the liver, combined liver-kidney transplant is a curative treatment option. One major unexpected risk includes liver failure secondary to uncontrolled complement activation. We report a successful combined liver-kidney transplantation with perioperative plasma exchange and use of the humanized anti-C5 monoclonal antibody eculizumab. CASE DIAGNOSIS/TREATMENT An 11-month-old female presented with oliguric renal failure after 3 weeks of flu-like symptoms in the absence of diarrhea. Following the identification of Escherichia coli 0157:H7 in her stool, she was discharged home on peritoneal dialysis with a diagnosis of Shiga toxin-associated HUS. Three months later, she developed severe anemia, thrombocytopenia, and neurological involvement. aHUS was diagnosed and confirmed, and genetic testing revealed a mutation in CFH SCR20. Once donor organs became available, she received preoperative plasma exchange followed by eculizumab infusion with intra-operative fresh frozen plasma prior to combined liver-kidney transplant. At 19 months post-transplant, she continues to have excellent allograft and liver function without signs of disease recurrence. CONCLUSION Perioperative use of eculizumab in conjunction with plasma exchange during simultaneous liver-kidney transplant can be used to inhibit terminal complement activity, thereby optimizing successful transplantation by reducing the risk of graft thrombosis.
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Mele C, Remuzzi G, Noris M. Hemolytic uremic syndrome. Semin Immunopathol 2014; 36:399-420. [PMID: 24526222 DOI: 10.1007/s00281-014-0416-x] [Citation(s) in RCA: 117] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Accepted: 01/19/2014] [Indexed: 12/25/2022]
Abstract
Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy defined by thrombocytopenia, nonimmune microangiopathic hemolytic anemia, and acute renal failure. The most frequent form is associated with infections by Shiga-like toxin-producing bacteria (STEC-HUS). Rarer cases are triggered by neuraminidase-producing Streptococcus pneumoniae (pneumococcal-HUS). The designation of aHUS is used to refer to those cases in which an infection by Shiga-like toxin-producing bacteria or S. pneumoniae can be excluded. Studies performed in the last two decades have documented that hyperactivation of the complement system is the pathogenetic effector mechanism leading to the endothelial damage and the microvascular thrombosis in aHUS. Recent data suggested the involvement of the complement system in the pathogenesis of STEC-HUS and pneumococcal-HUS as well. Clinical signs and symptoms may overlap among the different forms of HUS; however, pneumococcal-HUS and aHUS have a worse prognosis compared with STEC-HUS. Early diagnosis and identification of underlying pathogenetic mechanism allows instating specific support measures and therapies. In clinical trials in patients with aHUS, complement inhibition by eculizumab administration leads to a rapid and sustained normalization of hematological parameters with improvement in long-term renal function. This review summarizes current concepts about the epidemiological findings, the pathological and clinical aspects of STEC-HUS, pneumococcal-HUS, and aHUS, and their diagnosis and management.
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Affiliation(s)
- Caterina Mele
- IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Clinical Research Center for Rare Diseases "Aldo e Cele Daccò", Via Camozzi, 3, Ranica, Bergamo, 24020, Italy
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Long-term remission of atypical HUS with anti-factor H antibodies after cyclophosphamide pulses. Pediatr Nephrol 2014; 29:75-83. [PMID: 23868108 DOI: 10.1007/s00467-013-2558-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Revised: 04/23/2013] [Accepted: 05/22/2013] [Indexed: 01/31/2023]
Abstract
BACKGROUND Anti-complement factor H (CFH) autoantibody (Ab)-associated atypical hemolytic uremic syndrome (aHUS) has a poor prognosis, but no consensus exists on its treatment. METHODS We report the follow-up of four children with anti-CFH Ab (8,000 to >32,000 arbitrary units)-associated aHUS after plasma exchanges (PEs), prednisone, and cyclophosphamide pulse therapy with the evolution of anti-CFH Ab titers and kidney function. RESULTS Patient 1 received PEs + prednisone + cyclophosphamide pulses after two relapses following PEs and then PEs + rituximab. The other three patients were treated with PEs + prednisone + cyclophosphamide pulses as a first-line therapy. In our four patients, the induction protocol combining PEs + prednisone + cyclophosphamide pulses led to a rapid and sustained remission up to 6 years, 4 years and 4 months without any maintenance therapy. Kidney function was normal and anti-CFH Ab titer decreased, but remained detectable during remission without any clinical or biological signs of relapse. CONCLUSIONS We demonstrate the long-term efficiency and safety of cyclophosphamide pulses combined with PEs and prednisone in anti-CFH Ab-associated aHUS leading to a prolonged decrease in anti-CFH Ab titers and prevention of relapses without the need for maintenance therapy.
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Liebau MC. An emerging molecular understanding and novel targeted treatment approaches in pediatric kidney diseases. Front Pediatr 2014; 2:68. [PMID: 25050320 PMCID: PMC4076740 DOI: 10.3389/fped.2014.00068] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Accepted: 06/17/2014] [Indexed: 12/31/2022] Open
Abstract
The evaluation and treatment of the heterogeneous group of kidney diseases poses a challenging field in pediatrics. Many of the pediatric disorders resulting in severe renal affection are exceedingly rare and therapeutic approaches have remained symptomatic for most of these disease entities. The insights obtained from cellular and molecular studies of rare disorders by recent genetic studies have now substantially changed our mechanistic understanding of various important pediatric renal diseases and positive examples of targeted treatment approaches are emerging. Three fields of recent breathtaking developments in pediatric nephrology are the pathophysiology of nephrotic syndrome and proteinuria, the molecular mechanisms underlying atypical hemolytic uremic syndrome, and the genetics and cellular biology of inherited cystic kidney diseases. In all three areas, the combined power of molecular basic science together with deeply characterizing clinical approaches has led to the establishment of novel pathophysiological principles and to the first clinical trials of targeted treatment approaches.
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Affiliation(s)
- Max Christoph Liebau
- Department of Pediatrics and Center for Molecular Medicine, University Hospital of Cologne , Cologne , Germany ; Nephrology Research Laboratory, Department II of Internal Medicine, University Hospital of Cologne , Cologne , Germany
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48
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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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Hardinger KL, Brennan DC. Novel immunosuppressive agents in kidney transplantation. World J Transplant 2013; 3:68-77. [PMID: 24392311 PMCID: PMC3879526 DOI: 10.5500/wjt.v3.i4.68] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 08/26/2013] [Accepted: 10/16/2013] [Indexed: 02/05/2023] Open
Abstract
Excellent outcomes have been achieved in the field of renal transplantation. A significant reduction in acute rejection has been attained at many renal transplant centers using contemporary immunosuppressive, consisting of an induction agent, a calcineurin inhibitor, an antiproliferative agent plus or minus a corticosteroid. Despite improvements with these regimens, chronic allograft injury and adverse events still persist. The perfect immunosuppressive regimen would limit or eliminate calcineurin inhibitors and/or corticosteroid toxicity while providing enhanced allograft outcomes. Potential improvements to the calcineurin inhibitor class include a prolonged release tacrolimus formulation and voclosporin, a cyclosporine analog. Belatacept has shown promise as an agent to replace calcineurin inhibitors. A novel, fully-human anti-CD40 monoclonal antibody, ASKP1240, is currently enrolling patients in phase 2 trials with calcineurin minimization and avoidance regimens. Another future goal of transplant immunosuppression is effective and safe treatment of allograft rejection. Novel treatments for antibody mediated rejection include bortezomib and eculizumab. Several investigational agents are no longer being pursed in transplantation including the induction agents, efalizumab and alefacept, and maintenance agents, sotrastaurin and tofacitinib. The purpose of this review is to consolidate the published evidence of the effectiveness and safety of investigational immunosuppressive agents in renal transplant recipients.
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50
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Reindl-Schwaighofer R, Oberbauer R. Blood disorders after kidney transplantation. Transplant Rev (Orlando) 2013; 28:63-75. [PMID: 24211181 DOI: 10.1016/j.trre.2013.10.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2013] [Revised: 09/21/2013] [Accepted: 10/01/2013] [Indexed: 02/07/2023]
Abstract
Post transplant anemia (PTA) is a common issue in kidney transplant recipients. Most importantly it is associated with an impaired allograft function. Other important factors associated with PTA are immunosuppressive drugs (MPA, AZA and SRL), iron deficiency, infections (Parvo B19), older donor age, rejection episodes, an increased inflammatory state, and erythropoietin hyporesponsiveness. As there are no adequately powered RCTs in the kidney transplant population on anemia treatment with ESA, we have to rely on what we know from the large RCTs in the CKD population. The recently published KDIGO guidelines do not recommend treatment with ESA if Hb is >10 g/dl. Repletion of iron stores is emphasized. Post transplant leukopenia (PTL) and thrombocytopenia (PTT) are frequent complications especially in the first six months after kidney transplantation. Myelosuppression caused by immunosuppressive agents (MPA, AZA, SRL, rATG), antimicrobial drugs (VGCV), and CMV infection is the predominant cause. There are no widely accepted guidelines on treatment strategies, but most often dose reduction or discontinuation of causative medication is done. Most clinicians tend to decrease MPA dose, but this is eventually associated with an increase in acute rejection episodes. VGCV dose reduction (preemptive treatment instead of CMV prophylaxis) may be a successful strategy. In severe cases G-CSF treatment is an important management option and seems to be safe.
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Affiliation(s)
| | - Rainer Oberbauer
- Department of Nephrology, KH Elisabethinen, Linz, Austria; Department of Nephrology, Medical University of Vienna, Vienna, Austria.
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